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The structure of our visual and auditory system

Posted in Biochemical pathways, Cell Biology, Chemical Biology and its relations to Metabolic Disease, Curation, Disease Biology, Experimental validation, Explanatory, Gene Regulation and Evolution, Genome Biology, Innovations in Neurophysiology & Neuropsychology, Molecular Genetics & Pharmaceutical, Neurohumoral Transmission, Neurological Diseases, tagged vision research on September 6, 2015| Leave a Comment »

The structure of our visual and auditory system

Larry H. Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Intelligence

Series E. 2; 5.8

Revised 9/30/2015

Torsten N. Wiesel (1921— )
President Emeritus
Vincent and Brooke Astor Professor Emeritus – Rockefeller Univerity
1981 Nobel Prize in Physiology or Medicine

Torsten N. Wiesel

The structure of our visual system, beginning at the eyes and ending at the primary visual cortex at the back of the brain, is a little like a maze, intricately constructed to send visual signals through myriad portals and passageways to reach just the right neurons at the end of the path. In the 1950s, H. Keffer Hartline, a member of The Rockefeller Institute for Medical Research, charted the first avenues of that maze when he revealed how the visual stimulus received by the retina is divided, altered and sharpened by the optic nerve network in order to send a more useful picture to the brain. Former Rockefeller president Torsten N. Wiesel, along with his colleague David H. Hubel, continued Dr. Hartline’s exploration at their Harvard Medical School laboratory by delving further back, into the brain, and described for the first time how the system develops innately, how experience shapes it further and how it analyzes visual signals. For this work, Drs. Wiesel and Hubel shared the 1981 Nobel Prize in Physiology or Medicine.

The complex array of stimuli in our visual field passes first through several distinct layers of cells known collectively as the retina. Next they are analyzed by the optic nerve and make their way to the lateral geniculate nucleus (LGN), the first visual processing center in the brain, located in the thalamus of each brain hemisphere. From the LGN, the signals are sent to the primary visual cortex, also known as the striate cortex. Working with cats and rhesus macaque monkeys, Drs. Wiesel and Hubel recorded the electrical impulses of cortical cells in response to various patterns flashed before the eyes. They coined the terms “simple” and “complex” for cells that respond to only one type of stimulus and those that respond to multiple and opposite stimuli.

To understand the differentiation, the scientists conducted a series of experiments to observe the brain’s response when one eye is kept closed for different periods of time. They discovered that animals with one eye closed for the first three months of life become blind in that eye. Examinations revealed no change in the eye itself or in the retina; the LGN cells devoted to that eye had shrunken but still responded to stimulation of the deprived eye as efficiently as those for the normal eye. The difference, they concluded, must therefore be in the striate cortex.

Awards: Nobel Prize in Physiology or Medicine, Louisa Gross Horwitz Prize, National Medal of Science for Biological Sciences

Swedish-born American neurobiologist Torsten N. Wiesel was raised at Beckomberga Hospital, the mental institute where his father was chief psychiatrist. He described himself as a lazy student until his late teens, before embarking on a career of research into the physiology of vision. Wiesel was awarded the Nobel Prize for Medicine in 1981, along with his long-time collaborator David H. Hubel, for mapping the visual or striate cortex, the posterior section of the cerebral cortex. Roger W. Sperry shared that year’s Nobel honors, for work conducted at CalTech. Wiesel also demonstrated the importance of early diagnosis of childhood visual problems.

When a reporter informed him he had won the Nobel Prize, Wiesel’s first response was, “Oh, no, I was afraid of that”, explaining that he feared the hubbub might prove a distraction from his work. In the 1990s he was President of Rockefeller University, and since 2000, he has been Secretary-General of the Human Frontier Science Program, a group which supports collaboration across different scientific fields. He also served more than a decade as Chair of the Human Rights Committee for the National Academy of Sciences.

In 2001, he was named to a high-level post at the National Institutes of Health, but his nomination was scuttled by then-Secretary of Health and Human Services Tommy Thompson, with the official explanation that he had “signed too many full-page letters in the New York Times critical of President Bush.” Wiesel responded, “I have not signed a statement against Bush, but nonetheless for some reason I am on the administration’s blacklist. Perhaps [it is because of] my human rights activities and being contrary in general.”

Structure and evolution of hearing

9.2015 The Scientist

Inner Ear Cartography

Scientists map the position of cells within the organ of Corti. by Ruth Williams

Age-related hearing loss caused by damage to the sensory hair cells within the cochlea is extremely common, but studying the inner ear is tough. “It’s in the densest bone in the body, so you don’t have access,” says John Brigande of Oregon Health and Science University in Portland. Even if you can extract cells, he says, “there are so darn few of them.” Despite these technical difficulties, researchers have gleaned gene-expression information about different cell types within the organ of Corti—home to the sensory cells within the cochlea. But “it’s not only important to know what a cell expresses,” says Robert Durruthy-Durruthy, a postdoc in the Stanford University lab of Stefan Heller. “It’s also important to know where it can be found within a tissue.” To this end, Durruthy-Durruthy, Heller, and postdoc Jörg Waldhaus have derived a 2-D map of organ of Corti cells from neonatal mice. First, the team sorted all cell types across the medial-to-lateral axis (or width) of the organ based on marker gene expression. The approximately 900 sorted cells, representing nine cell types, were then each quantitatively analyzed for the expression of 192 selected genes. Computational analysis of these expression data then enabled reconstruction of the cells’ positions along the organ’s apical-to-basal (length) and medial-to-lateral axes. In principle, the technique, which harnesses gene-expression information to determine cells’ spatial organization, could be applied to generate 2-D maps of any complex tissue, says Durruthy-Durruthy. Within the mammalian cochlea, apical cells retain regenerative capacity for a few weeks after birth, but basal cells do not. “Spatial mapping allows us to get at the differences [between these cells],” says Brigande, and that could ultimately highlight possible ways to reinstate regeneration in the adult ear. (Cell Reports, 11:1385-99, 2015) To build a map of cells within the organ of Corti—where sound is translated to neural activity— scientists divide the cochlea in two. Each half of the organ of Corti is then broken up into its constituent cells, which comprise nine cell types (represented by the nine colors) spanning the organ’s medial-to-lateral axis.

FROM CELLS TO GENE-EXPRESSION: Each cell is analyzed for the expression of 192 selected genes. Based on the pattern of expression, a cell is given a position within the organ of Corti along both the basal-apical and the medial-lateral axes. Each column represents one of the nine cell types.

Human Hearing: A Primer

Semicircular canals of the vestibular system OSSICLES Ear canal Tympanic membrane (eardrum) When sound enters the ear canal, it vibrates the tympanic membrane, or eardrum. These vibrations are passed through the inner ear via three small bones called ossicles: the malleus, the incus, and the stapes. Finally, vibrations of the stapes stimulate the movement of a fluid called perilymph within the bony labyrinth of the inner ear.

Cochlea – How the human ear translates sound waves into nervous impulses.

Perilymph fills the both the vestibular and tympanic ducts of the cochlea. Between these two channels lies the cochlear duct, which is home to the organ of Corti. There, the soundinduced movement of perilymph in the cochlea is translated to an electrical signal that is sent to the brain for processing.

The organ of Corti sits on the basilar membrane, which separates the cochlear duct from the tympanic duct. As the basilar membrane vibrates in response to fluid movement, it pushes the organ along the tectorial membrane, which shifts laterally over the hair cells. This shift bends projections at the tips of the cells, called stereocilia, resulting in the generation of electrical signals.

The bending of the stereocilia results in the depolarization of the inner hair cell and initiates a nerve impulse through the spinal ganglion neuron at the base of the cell. A series of outer hair cells serves to mechanically amplify the vibrations that trigger the inner hair cells to fire. High-frequency sounds stimulate hair cells at the base of the cochlea, while low-frequency sounds stimulate hair cells at the apex.

Aural History -The form and function of the ears of modern land vertebrates cannot be understood without knowing how they evolved.

by Geoffrey A. Manley

Unlike eyes, which are generally instantly recognizable, ears differ greatly in their appearance throughout the animal kingdom. Some hearing structures may not be visible at all. For example, camouflaged in the barn owl’s facial ruff—a rim of short, brown feathers surrounding the bird’s white face—are clusters of stiff feathers that act as external ears on either side of its head. These feather structures funnel sound collected by two concave facial disks to the ear canal openings, increasing the bird’s hearing sensitivity by 20 decibels—approximately the difference between normal conversation and shouting.

Similar increases in sensitivity result from the large and often mobile external structures, or pinnae, of many mammals, such as cats and bats. Internally, the differences among hearing organs are even more dramatic.

Although fish can hear, only amphibians and true land vertebrates—including the aquatic species that descended from them, such as whales and pinnipeds—have dedicated hearing organs. In land vertebrates belonging to the group Amniota, including lizards, birds, and mammals, sound usually enters through an external canal and impinges on an eardrum that is connected through middle-ear bones to the inner ear. There, hundreds or thousands of sensory hair cells are spread along an elongated membrane that acts as a spectral analyzer, with the result that each local group of hair cells responds best to a certain range of pitches, or sound frequencies. The hair cells then feed this information into afferent nerve fibers that carry the information to the brain. (See “Hearing Primer” on page 34.)

Together, these hair cells and nerve fibers encode a wide range of sounds that enter the ear on that side of the head. Two ears complete the picture, allowing animals’ brains to localize the source of the sounds they hear by comparing the two inputs. Although it seems obvious that the ability to process nearby sounds would be enormously useful, modern amniote ears in fact arose quite late in evolutionary history, and to a large extent independently in different lineages. As a result, external, middle, and inner ears of various amniotes are characteristically different.1

Moreover, the early evolution of these dedicated auditoryorgans in land vertebrates led to the loss of the heavy otolithic membrane that overlies the hair-cell bundles of vestibular organs and is responsible for their slow responses. What remains is the watery macromolecular gel known as the tectorial membrane, which assures that local groups of hair cells move synchronously, resulting in greater sensitivity.

Good high-frequency hearing did not exist from the start, however. For a period of at least 50 million years after amniotes arose, the three main lineages were most likely quite hard of hearing. They had not yet evolved any mechanism for absorbing sound energy from air; they lacked the middle ear and eardrum that are vital for the function of modern hearing organs. As such, ancestral amniotes most likely perceived only sounds of relatively low frequency and high amplitude that reached the inner ear via the limbs or, if the skull were rested on the ground, through the tissues of the head. It is unclear what kind of stimuli could have existed that would have led to the retention of such hearing organs for such a long time.

The magnificent middle ear

During the Triassic period, some 250 to 200 million years ago, a truly remarkable thing happened. Independently, but within just 20 million to 30 million years of one another, all three amniote lineages evolved a tympanic middle ear from parts of the skull and the jaws.2 The tympanic middle ear is the assemblage of tiny bones that connects at one end to an eardrum and at the other end to the oval window, an aperture in the bone of the inner ear. Despite the temporal coincidence in the evolution of these structures in the three amniote lineages and the functional similarities of the adaptations, the groups were by this time so far separated that the middle ears evolved from different structures into two different configurations. The single middle-ear bone, the columella, of archosaurs and lepidosaurs derived from the hyomandibular, a bone that earlier had formed a large strut connecting the braincase to the outer skull.

Research on hearing organs have revealed the remarkable history of this unexpected diversity of ears. Divergence from a common origin Amniote vertebrates comprise three lineages of extant groups that diverged roughly 300 million years ago: the lepidosaurs, which include lizards and snakes; the archosaurs, which include crocodilians and birds; and mammals, which include egg-laying, pouched, and placental mammals. By comparing the skulls of the extinct common ancestors of these three lineages, as well as the ears of the most basal modern amniotes, researchers have concluded that ancestral amniotes had a small (perhaps less than 1 millimeter in length) but dedicated hearing organ: a sensory epithelium called a basilar papilla, with perhaps a few hundred sensory hair cells supported by a thin basilar membrane that is freely suspended in fluid. These rudimentary structures evolved from the hair cells of vestibular organs, which help organisms maintain their balance by responding to physical input, such as head rotation or gravity. Initially, the hearing organ only responded to low-frequency sounds. On their apical surface, all hair cells have tight tufts or bundles of large, hairlike villi known as stereovilli (or, more commonly stereocilia, even though they are not true cilia), which give hair cells their name. Between these stereovilli are proteinaceous links, most of which are closely coupled to sensory transduction channels that respond to a tilting of the stereovilli bundles caused by sound waves.

MODERN INNER EARS

Arose starting about 200 million years ago In all three lineages, hair cells are arranged along the auditory papilla from low- to high-frequency sensitivity, called a tonotopic organization. In both archosaurs and mammals, one type of hair cell serves to amplify the sound signal received by the other type. In lepidosaurs, the auditory papilla ranges from a few hundred micrometers to 2 millimeters in length and contains two types of hair cells: one with taller bundles and fewer stereovilli that responds to sounds below 1 kHz and another with shorter, thicker bundles that responds to higher-frequency pitches.

The archosaur papilla, which reaches lengths of up to 10 millimeters in some owls, contains many thousands of hair cells of types: tall hair cells, which serve to detect sound, and short hair cells, which amplify the signal. In most mammals, the auditory papilla, called the organ of Corti, evolved to be so long that it began to coil on top of itself. The papilla ranges from 1.5 to 4 coils and 7 millimeters (mouse) to 75 millimeters (blue whale) in length. Mammals have two types of hair cells: covering the oval window, which detect sound, and outer hair cells, which inner hair cells amplify it.

Tectorial membrane

Tall hair cell

Short hair cell

Basilar membrane

Inner

hair cell

Outer

hair cell

In modern representatives, the columella is long and thin, with several, usually cartilaginous extensions known as the extracolumella. One of these, the “inferior process,” connects the inner surface of the eardrum and the columella, which then connects to the footplate that covers the oval window of the inner ear. This two-part system forms a lever that, together with the pressure increase incurred by transmitting from the much larger eardrum to the footplate, greatly magnifies sound entering the inner ear.

In the mammals of the Triassic, the equivalent events were more complex, but the functional result was remarkably similar. Mammal ancestors reduced the number of bones in the lower jaw from seven to one and, in the process, formed a new jaw joint. Initially, the old and new jaw structures existed in parallel, but over time the old joint moved towards the rear of the head. This event, which at any other time would likely have led to the complete loss of the old joint bones, occurred simultaneously with the origin of the mammalian tympanic middle ear. Older paleontological and newer developmental evidence from Shigeru Kuratani’s lab at RIKEN in Japan indicate that the mammalian eardrum evolved at a lower position on the skull relative to that of the other amniotes, a position outside the old jaw joint.3 In time, the bones of this old joint, together with the hyomandibula, became the three bony ossicles (malleus, incus, and stapes) of the new middle ear. Like the middle ear of archosaurs and lepidosaurs, these ossicles form a lever system that, along with the large area difference between eardrum and footplate, greatly magnifies sound input. Thus, remarkably, these complex events led independently to all modern amniotes possessing a middle ear that, at frequencies below 10 kHz, works equally effectively despite the diverse structures and origins. There is also evidence that the three-ossicle mammalian middle ear itself evolved at least twice—in egg-laying mammals such as the platypus, and in therians, which include marsupials and placentals—with similar outcomes.

More…

Aural History

The form and function of the ears of modern land vertebrates cannot be understood without knowing how they evolved.

http://www.the-scientist.com//?articles.view/articleNo/43806/title/Aural-History/

By Geoffrey A. Manley | September 1, 2015

PHOTO CREDITS SEE END OF ARTICLE
http://www.the-scientist.com/Sept2015/feature1.jpg

For a period of at least 50 million years after amniotes arose, the three main lineages were most likely quite hard of hearing.

Divergence from a common origin

Amniote vertebrates comprise three lineages of extant groups that diverged roughly 300 million years ago: the lepidosaurs, which include lizards and snakes; the archosaurs, which include crocodilians and birds; and mammals, which include egg-laying, pouched, and placental mammals. By comparing the skulls of the extinct common ancestors of these three lineages, as well as the ears of the most basal modern amniotes, researchers have concluded that ancestral amniotes had a small (perhaps less than 1 millimeter in length) but dedicated hearing organ: a sensory epithelium called a basilar papilla, with perhaps a few hundred sensory hair cells supported by a thin basilar membrane that is freely suspended in fluid. These rudimentary structures evolved from the hair cells of vestibular organs, which help organisms maintain their balance by responding to physical input, such as head rotation or gravity. Initially, the hearing organ only responded to low-frequency sounds. On their apical surface, all hair cells have tight tufts or bundles of large, hairlike villi known as stereovilli (or, more commonly stereocilia, even though they are not true cilia), which give hair cells their name. Between these stereovilli are proteinaceous links, most of which are closely coupled to sensory transduction channels that respond to a tilting of the stereovilli bundles caused by sound waves.

The amniote hearing organ evolved as a separate group of hair cells that lay between two existing vestibular epithelia. Low-frequency vestibular hair cells became specialized to transduce higher frequencies, requiring much faster response rates. This change is attributable in part to modifications in the ion channels of the cell membrane, such that each cell is “electrically tuned” to a particular frequency, a phenomenon still observed in some modern amniote ears. Moreover, the early evolution of these dedicated auditory organs in land vertebrates led to the loss of the heavy otolithic membrane that overlies the hair-cell bundles of vestibular organs and is responsible for their slow responses. What remains is the watery macromolecular gel known as the tectorial membrane, which assures that local groups of hair cells move synchronously, resulting in greater sensitivity.

The magnificent middle ear

http://www.the-scientist.com/Sept2015/Manleyonline.jpg

CONVERGING ON THE EAR: Starting around 250 million years ago, the three amniote lineages—lepidosaurs (lizards and snakes), archosaurs (crocodilians and birds), and mammals—separately evolved a tympanic middle ear, followed by evolution of the inner ear, both of which served to increase hearing sensitivity. Despite the independent origin of hearing structures in the three lineages, the outcomes were functionally quite similar, serving as a remarkable example of convergent evolution.
See full infographic: JPG

ILLUSTRATIONS: PHEBE LI FOR THE SCIENTIST. ICONS: ISTOCK.COMDuring the Triassic period, some 250 to 200 million years ago, a truly remarkable thing happened. Independently, but within just 20 million to 30 million years of one another, all three amniote lineages evolved a tympanic middle ear from parts of the skull and the jaws.²

The tympanic middle ear is the assemblage of tiny bones that connects at one end to an eardrum and at the other end to the oval window, an aperture in the bone of the inner ear. Despite the temporal coincidence in the evolution of these structures in the three amniote lineages and the functional similarities of the adaptations, the groups were by this time so far separated that the middle ears evolved from different structures into two different configurations. The single middle-ear bone, the columella, of archosaurs and lepidosaurs derived from the hyomandibular, a bone that earlier had formed a large strut connecting the braincase to the outer skull. In modern representatives, the columella is long and thin, with several, usually cartilaginous extensions known as the extracolumella. One of these, the “inferior process,” connects the inner surface of the eardrum and the columella, which then connects to the footplate that covers the oval window of the inner ear. This two-part system forms a lever that, together with the pressure increase incurred by transmitting from the much larger eardrum to the footplate, greatly magnifies sound entering the inner ear.

In the mammals of the Triassic, the equivalent events were more complex, but the functional result was remarkably similar. Mammal ancestors reduced the number of bones in the lower jaw from seven to one and, in the process, formed a new jaw joint. Initially, the old and new jaw structures existed in parallel, but over time the old joint moved towards the rear of the head. This event, which at any other time would likely have led to the complete loss of the old joint bones, occurred simultaneously with the origin of the mammalian tympanic middle ear. Older paleontological and newer developmental evidence from Shigeru Kuratani’s lab at RIKEN in Japan indicate that the mammalian eardrum evolved at a lower position on the skull relative to that of the other amniotes, a position outside the old jaw joint.³ In time, the bones of this old joint, together with the hyomandibula, became the three bony ossicles (malleus, incus, and stapes) of the new middle ear. Like the middle ear of archosaurs and lepidosaurs, these ossicles form a lever system that, along with the large area difference between eardrum and footplate, greatly magnifies sound input.

Thus, remarkably, these complex events led independently to all modern amniotes possessing a middle ear that, at frequencies below 10 kHz, works equally effectively despite the diverse structures and origins. There is also evidence that the three-ossicle mammalian middle ear itself evolved at least twice—in egg-laying mammals such as the platypus, and in therians, which include marsupials and placentals—with similar outcomes.

Inner-ear evolution

http://www.the-scientist.com/Sept2015/piano_med.jpg

PITCH PERFECT: The hearing organs of amniotes are organized tonotopically, with hair cells sensitive to high frequencies at the basal end of the papilla, grading into low-frequency hair cells at the apical end.BASED ON MED-EL WWW.MEDEL.COMThe evolution of tympanic middle ears kick-started the evolution of modern inner ears, where sound waves are converted into the electrical signals that are sent to the brain. The inner ear is least developed in the lepidosaurs, most of which retained a relatively small auditory papilla, in some just a few hundred micrometers long. Many lepidosaurs, predominantly diurnal species, also lost their eardrum. Snakes reduced their middle ear, limiting their hearing to frequencies less than 1 kHz, about two octaves above middle C. (For comparison, humans can hear sounds up to about 15 or 16 kHz.) Clearly, hearing was not under strong selective pressure in this group. There are a few exceptions, however. In geckos, for example, which are largely nocturnal, the papillar structure shows unique specializations, accompanied by high sensitivity and strong frequency selectivity. Indeed, the frequency selectivity of gecko auditory nerve fibers exceeds that of many mammals.

One part of the inner ear that did improve in lizards (but not in snakes) is the hair cells, with the papillae developing different areas occupied by two structural types of these sound-responsive cells. One of these hair cell groups responds to sounds below 1 kHz and perhaps corresponds to the ancestral version. The higher-frequency hair cells have a more specialized structure, particularly with regard to the size and height of the stereovilli, with bundle heights and stereovillus numbers varying consistently along the papilla’s length. Taller bundles with fewer stereovilli, which are much less stiff and therefore respond best to low frequencies, are found at one end of the membrane, while shorter, thicker bundles with more stereovilli that respond best to higher frequencies are found at the other end—a frequency distribution known as a tonotopic organization. Still, with the exception of one group of geckos, lizard hearing is limited to below 5 to 8 kHz.

In contrast to the relatively rudimentary lepidosaur inner ear, the auditory papilla of archosaurs (birds, crocodiles, and their relatives) evolved much greater length. Owls, highly proficient nocturnal hunters, boast the longest archosaur papilla, measuring more than 10 millimeters and containing many thousands of hair cells. As in lizards, archosaur hair cells show strong tonotopic organization, with a gradual change in the diameter and height of the stereovillar bundles contributing to the gradually changing frequency sensitivity along the papilla. In addition, the hair cells are divided along and across the basilar membrane, with tall hair cells (THCs) resting on the inner side and the apical end, most distant from the middle ear, grading into short hair cells (SHCs) on the outer side and at the basal end. Interestingly, many SHCs completely lack afferent innervation, which is the only known case of sensory cells lacking a connection to the brain. Instead of transmitting sensory information to the brain, these hair cells likely amplify the signal received by the inner ear. Despite the more complex anatomy, however, bird hearing is also generally limited to between 5 and 8 kHz, with the exception of some owls, which can hear up to 12 kHz.

The mammalian papilla, called the organ of Corti, also evolved to be larger—generally, but not always, longer than those of birds—but the extension in length varies in different lineages.⁴ Mammalian papillae also have a unique cellular arrangement. The papillae of modern egg-laying monotremes, which likely resemble those of the earliest mammals, include two groups of hair cells separated by numerous supporting pillar cells that form the tunnel of Corti. In any given cross section, there are approximately five inner hair cells (IHCs) on the inner side of the pillar cells, closer to the auditory nerve, and eight outer hair cells (OHCs) on the outer side. In therian mammals (marsupials and placentals), the numbers of each cell group have been much reduced, with only two pillar cells forming the tunnel in any given cross-section, and generally just a single IHC and three or four OHCs, though the functional consequences of this reduction remain unclear. About 90 percent of afferent fibers innervate IHCs, while only 10 percent or fewer innervate OHCs, despite the fact that OHCs account for some 80 percent of all hair cells. As with bird SHCs that lack afferent innervation, there are indications that the main function of OHCs is to amplify the physical sound signal at very low sound-pressure levels.

Therian mammals also evolved another key hearing adaptation: the cochlea. Shortly before marsupial and placental lineages diverged, the elongating hearing organ, which had always been curved, reached full circle. The only way to further increase its length was to form more than one full coil, a state that was reached roughly 120 million years ago. The result is hearing organs with 1.5 to 4 coils and lengths from 7 millimeters (mouse) to 75 millimeters (blue whale). Hearing ranges also diverged, partly depending on the size of the animal (larger mammals tend to have lower upper-frequency limits), but with a number of remarkable specializations, as expected in a lineage that radiated greatly during several evolutionary episodes.

As a result of these adaptations, most mammals have an upper frequency-response limit that well exceeds those of lepidosaurs and archosaurs. Human hearing extends to frequencies of about 15 kHz; a guinea pig can hear sounds up to about 45 kHz; and in the extreme cases of many bats and toothed whales, hearing extends into ultrasonic frequencies, sometimes as high as 180 kHz, allowing these animals to echolocate in air and water. This impressive increase in frequency limits is due to an extremely stiff middle ear, as well as a stiff cochlea. During early therian evolution, the bone of the canal surrounding the soft tissues invaded the supporting ridges of the basilar membrane, creating stiff laminae. Such bony ridges were retained in species perceiving ultrasonic frequencies, but tended to be reduced and replaced by softer connective-tissue supports in those with lower-frequency limits, such as humans.

Amplification within the ear

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HAIRS OF THE EAR: Rows of inner-ear hair cells have villous bundles (blue) on their apical surface that convert sound waves to nervous signals sent to the brain.© STEVE GSCHMEISSNER/SCIENCE SOURCEIn addition to the specialized structures of the middle and inner ears of amniotes that served to greatly increase hearing sensitivity, the hair cells themselves can produce active movements that further amplify sound stimuli. The evolutionarily oldest such active mechanism was discovered in the late 1980s by Jim Hudspeth’s group, then at the University of California, San Francisco, School of Medicine, working with frogs,⁵ and Andrew Crawford and Robert Fettiplace, then at the University of Cambridge, working with turtles.⁶ The amplification mechanism, called the active bundle mechanism, probably evolved in the ancestors of vertebrates and helped overcome the viscous forces of the surrounding fluids, which resist movement. When sound stimuli move the hair-cell bundle and thus open transduction channels to admit potassium ions, some calcium ions also enter the cell. These calcium ions bind to and influence the open transduction channels, increasing the speed with which these channels close. Such closing forces are exerted in phase with the incoming sound waves, increasing the distance that the hair cells move in response, and thereby increasing their sensitivity. It is likely that this mechanism operates in all vertebrate hair cells.⁵ In lizards, my group provided evidence that this bundle mechanism really does operate in the living animal.⁷

In 1986, a second mechanism of hair cell–driven sound amplification was discovered in mammalian OHCs by Bill Brownell’s group, then at the University of Florida School of Medicine. Brownell and his colleagues showed that mammalian OHCs, but not IHCs, changed their length very rapidly in phase with the signal if exposed to an alternating electrical field.⁸ Such fields occur when hair cells respond to sound. Subsequent experiments showed that the change in cell length is due to changes in the molecular configuration of a protein, later named prestin, which occurs in high density along the lateral cell membrane of OHCs. In mammals, the force produced by the OHCs is so strong that the entire organ of Corti, which includes all cell types that surround the hair cells and the basilar membrane itself, is driven in an up-and-down motion. This movement can amplify sounds by at least 40dB, allowing very quiet noises to be detected. There is evidence for the independent evolution of specific molecular configurations of prestins that allow for the amplification of very high ultrasonic frequencies in bats and whales.⁹

Bird ears also appear to produce active forces that amplify sound. The SHCs have bundles comprising up to 300 stereovilli (about three times as many as the bundles of mammalian OHCs),¹⁰ and the movement of these bundles probably drives the movement of THCs indirectly via the tectorial membrane. Also, very recent data from the lab of Fettiplace, now at the University of Wisconsin–Madison, suggests that in birds, prestin (albeit in a different molecular form) may work in the plane across the hearing organ (i.e., not up and down as in mammals), perhaps reinforcing the influence of the bundle active mechanism on the THCs via the tectorial membrane.¹¹

Three hundred million years of evolution have resulted in a fascinating variety of ear configurations that, despite their structural diversity, show remarkably similar physiological responses.

In addition to amplifying hair-cell activity, these active mechanisms manifest as spontaneous movements of the hearing organ, oscillating even in the absence of sound stimuli. Such spontaneous movements actually produce sound that is emitted through the middle ear to the outside world and can be measured in the ear canal. These spontaneous otoacoustic emissions (SOAEs) enable remote sensing of what is going on within the inner ear and have permitted increasingly important research on inner-ear mechanisms and new clinical diagnostic methods to monitor the health of the ear’s sensory epithelium. We recently showed that spectral patterns of SOAEs in lizards, birds, and mammals are remarkably similar, despite up to 70-fold differences in the size of the hearing organs, suggesting that there are profound commonalities among the inner ears of amniotes that we still do not really understand.¹²

Remarkable convergence

Three hundred million years of evolution have resulted in a fascinating variety of ear configurations that, despite their structural diversity, show remarkably similar physiological responses. There are hardly any differences in sensitivity between the hearing of endothermal birds and mammals, and the frequency selectivity of responses is essentially the same in most lizards, birds, and mammals. The combined research efforts of paleontologists, anatomists, physiologists, and developmental biologists over several decades have clarified the major evolutionary steps in all lineages that modified the malleable middle and inner ears into their present-day kaleidoscopic variety of form, yet a surprising consensus in their function.

Geoffrey A. Manley is a retired professor from the Institute of Zoology at the Technical University in Munich, Germany. He is currently a guest scientist in the laboratory of his wife, Christine Köppl, at Oldenburg University in Germany.

References

G.A. Manley, C. Köppl, “Phylogenetic development of the cochlea and its innervation,” Curr Opin Neurobiol, 8:468-74, 1998.
J.A. Clack, “Patterns and processes in the early evolution of the tetrapod ear,” J Neurobiol, 53:251-64, 2002.
T. Kitazawa et al., “Developmental genetic bases behind the independent origin of the tympanic membrane in mammals and diapsids,” Nat Commun, 6:6853, 2015.
G.A. Manley, “Evolutionary paths to mammalian cochleae,” JARO, 13:733-43, 2012.
A.J. Hudspeth, “How the ear’s works work: Mechanoelectrical transduction and amplification by hair cells,” C R Biol, 328:155-62, 2005.
A.C. Crawford, R. Fettiplace, “The mechanical properties of ciliary bundles of turtle cochlear hair cells,” J Physiol, 364:359-79, 1985.
G.A. Manley et al., “In vivo evidence for a cochlear amplifier in the hair-cell bundle of lizards,” PNAS, 98:2826-31, 2001.
B. Kachar et al., “Electrokinetic shape changes of cochlear outer hair cells,” Nature, 322:365-68, 1986.
Y. Liu et al., “Convergent sequence evolution between echolocating bats and dolphins,” Curr Biol, 20:R53-R54, 2010.
C. Köppl et al., “Big and powerful: A model of the contribution of bundle motility to mechanical amplification in hair cells of the bird basilar papilla,” in Concepts and Challenges in the Biophysics of Hearing, ed. N.P. Cooper, D.T. Kemp (Singapore: World Scientific, 2009), 444-50.
M. Beurg et al., “A prestin motor in chicken auditory hair cells: Active force generation in a nonmammalian species,” Neuron, 79:69-81, 2013.
C. Bergevin et al., “Salient features of otoacoustic emissions are common across tetrapod groups and suggest shared properties of generation mechanisms,” PNAS, 112:3362-67, 2015.

Sea Lion: © iStock/LFStewart; Squirrel: © Erik Mandre/Shutterstock; Frog: ©Frank B. Yuwono/Shutterstock; Owl: ©XNature.Photography/Shutterstock; Lizard: ©Andrew Wijesuriya/Shutterstock; Bat: © iStock/GlobalP; Ostrich: © Jamen Percy/Shutterstock; Dog: ©Annette Shaff/Shutterstock; Lynx: © Dmitri Gomon/Shutterstock

Correction (September 15, 2015): Citation #8 of this story has been updated to accurately reflect the research referenced in the text. The Scientist regrets the error.

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The Neurogenetics of Language – Patricia Kuhl

Posted in Autism Spectrum Disorders, Behavior, Behavioral Genetics, Biological Networks, Child and Adolescent Psychiatry, Clinical & Translational, Cognition, Curation, Discovery process, Explanatory, Genetics & Innovations in Treatment, Innovations in Neurophysiology & Neuropsychology, Interviews with Scientific Leaders, Population Health Management, tagged babies learn, cognitive science, linguistics, Neuroscience on September 6, 2015| Leave a Comment »

The Neurogenetics of Language – Patricia Kuhl

Larry H. Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Innovation

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WordCloud Image Produced by Adam Tubman

Series E. 2; 5.7

2015 George A. Miller Award

In neuroimaging studies using structural (diffusion weighted magnetic resonance imaging or DW-MRI) and functional (magnetoencephalography or MEG) imaging, my laboratory has produced data on the neural connectivity that underlies language processing, as well as electrophysiological measures of language functioning during various levels of language processing (e.g., phonemic, lexical, or sentential). Taken early in development, electrophysiological measures or “biomarkers” have been shown to predict future language performance in neurotypical children as well as children with autism spectrum disorders (ASD). Work in my laboratory is now combining these neuroimaging approaches with genetic sequencing, allowing us to understand the genetic contributions to language learning.

Patricia Kuhl: The linguistic genius of babies | TED Talk | TED.com

http://www.youtube.com/watch%3Fv%3DG2XBIkHW954

http://www.youtube.com/watch%3Fv%3DM-ymanHajN8

Patricia Kuhl shares astonishing findings about how babies learn one language over another — by listening to the humans around them

Kuhl Constructs: How Babies Form Foundations for Language

MAY 3, 2013

by Sarah Andrews Roehrich, M.S., CCC-SLP

Years ago, I was captivated by an adorable baby on the front cover of a book, The Scientist in the Crib: What Early Learning Tells Us About the Mind, written by a trio of research scientists including Alison Gopknik, PhD, Andrew Meltzoff, PhD, and Patricia Kuhl, PhD.

At the time, I was simply interested in how babies learn about their worlds, how they conduct experiments, and how this learning could impact early brain development. I did not realize the extent to which interactions with family, caretakers, society, and culture could shape the direction of a young child’s future.

Now, as a speech-language pathologist in Early Intervention in Massachusetts, more cognizant of the myriad of factors that shape a child’s cognitive, social-emotional, language, and literacy development, I have been absolutely delighted to discover more of the work of Dr. Kuhl, a distinguished speech-and-language pathologist at The University of Washington. So, last spring, when I read that Dr. Kuhl was going to present “Babies’ Language Skills” as one part of a 2-part seminar series sponsored by the Mind, Brain, and Behavior Annual Distinguished Lecture Series at Harvard University¹, I was thrilled to have the opportunity to attend. Below are some highlights from that experience and the questions it has since sparked for me:

	Lip ‘Reading’ Babies According to a study by Dr. Patricia Kuhl and Dr. Andrew Meltzoff, “Bimodal Perception of Speech in Infancy” (Science, 1982), cited in the 2005 Seattle Times article, “Infant Science: How do Babies Learn to Talk?” by Paula Bock, Drs. Patricia Kuhl and Andrew Meltzoff showed that babies as young as 18 weeks of age could listen to “Ah ah ah” or “Ee ee ee” vowel sounds and gaze at the correct, corresponding lip shape on a video monitor.
This image from Kuhl’s 2011 TED talk shows how a baby is trained to turn his head in response to a change in such vowel sounds, and is immediately rewarded by watching a black box light up while a panda bear inside pounds a drum. Images provided courtesy of Dr. Patricia Kuhl’s Lab at the University of Washington.

Who is Dr. Patricia Kuhl and how has her work re-shaped our knowledge about how babies learn language?

Dr. Kuhl, who is co-director of the Institute for Learning and Brain Sciences at The University of Washington, has been internationally recognized for her research on early language and brain development, and for her studies on how young children learn. In her most recent research experiments, she’s been using magnetoencephalography (MEG)–a relatively new neuroscience technology that measures magnetic fields generated by the activity of brain cells–to investigate how, where, and with what frequency babies from around the world process speech sounds in the brain when they are listening to adults speak in their native and non-native languages.

A 6-month-old baby sits in a magnetoencephalography machine, which maps brain activity, while listening to various languages in earphones and playing with a toy. Image originally printed in “Brain Mechanisms in Early Language Acquisition” (Neuron review, Cell Press, 2010) and provided courtesy of Dr. Patricia Kuhl’s Lab at the University of Washington.

Not only does Kuhl’s research point us in the direction of how babies learn to process phonemes, the sound units upon which many languages are built, but it is part of a larger body of studies looking at infants across languages and cultures that has revolutionized our understanding of language development over the last half of the 20th century—leading to, as Kuhl puts it, “a new view of language acquisition, that accounts for both the initial state of linguistic knowledge in infants, and infants’ extraordinary ability to learn simply by listening to their native language.”²

What is neuroplasticity and how does it underlie child development?

Babies are born with 100 billion neurons, about the same as the number of stars in the Milky Way.³ In The Whole Brain Child,Daniel Siegel, MD and Tina Payne Bryson, PhD explain that when we undergo an experience, these brain cells respond through changes in patterns of electrical activity—in other words, they “fire” electrical signals called “action potentials.”⁴

In a child’s first years of life, the brain exhibits extraordinary neuroplasticity, refining its circuits in response to environmental experiences. Synapses—the sites of communication between neurons—are built, strengthened, weakened and pruned away as needed. Two short videos from the Center on the Developing Child at Harvard, “Experiences Build Brain Architecture” and “Serve and Return Interaction Shapes Brain Circuitry”, nicely depict how some of this early brain development happens.⁵

Since brain circuits organize and reorganize themselves in response to an infant’s interactions with his or her environment, exposing babies to a variety of positive experiences (such as talking, cuddling, reading, singing, and playing in different environments) not only helps tune babies in to the language of their culture, but it also builds a foundation for developing the attention, cognition, memory, social-emotional, language and literacy, and sensory and motor skills that will help them reach their potential later on.

When and how do babies become “language-bound” listeners?

In her 2011 TED talk, “The Linguistic Genius of Babies,” Dr. Kuhl discusses how babies under 8 months of age from different cultures can detect sounds in any language from around the world, but adults cannot do this.⁶ So when exactly do babies go from being “citizens of the world”, as Kuhl puts it, to becoming “language-bound” listeners, specifically focused on the language of their culture?”

Between 8-10 months of age, when babies are trying to master the sounds used in their native language, they enter a critical period for sound development.¹ Kuhl explains that in one set of experiments, she compared a group of babies in America learning to differentiate the sounds “/Ra/” and “/La/,” with a group of babies in Japan. Between 6-8 months, the babies in both cultures recognized these sounds with the same frequency. However, by 10-12 months, after multiple training sessions, the babies in Seattle, Washington, were much better at detecting the “/Ra/-/La/” shift than were the Japanese babies.

Kuhl explains these results by suggesting that babies “take statistics” on how frequently they hear sounds in their native and non-native languages. Because “/Ra/” and “/La/” occur more frequently in the English language, the American babies recognized these sounds far more frequently in their native language than the Japanese babies. Kuhl believes that the results in this study indicate a shift in brain development, during which babies from each culture are preparing for their own languages and becoming “language-bound” listeners.

In what ways are nurturing interactions with caregivers more valuable to babies’ early language development than interfacing with technology?

If parents, caretakers, and other children can help mold babies’ language development simply by talking to them, it is tempting to ask whether young babies can learn language by listening to the radio, watching television, or playing on their parents’ mobile devices. I mean, what could be more engaging than the brightly-colored screens of the latest and greatest smart phones, iPads, iPods, and computers? They’re perfect for entertaining babies. In fact, some babies and toddlers can operate their parents’ devices before even having learned how to talk.

However, based on her research, Kuhl states that young babies cannot learn language from television and it is necessary for babies to have lots of face-to-face interaction to learn how to talk.¹In one interesting study, Kuhl’s team exposed 9 month old American babies to Mandarin in various forms–in person interactions with native Mandarin speakers vs. audiovisual or audio recordings of these speakers–and then looked at the impact of this exposure on the babies’ ability to make Mandarin phonetic contrasts (not found in English) at 10-12 months of age. Strikingly, twelve laboratory visits featuring in person interactions with the native Mandarin speakers were sufficient to teach the American babies how to distinguish the Mandarin sounds as well as Taiwanese babies of the same age. However, the same number of lab visits featuring the audiovisual or audio recordings made no impact. American babies exposed to Mandarin through these technologies performed the same as a control group of American babies exposed to native English speakers during their lab visits.

This diagram depicts the results of a Kuhl study on American infants exposed to Mandarin in various forms–in person interactions with native speakers versus television or audio recordings of these speakers. As the top blue triangle shows, the American infants exposed in person to native Mandarin speakers performed just as well on a Mandarin phoneme distinction task as age-matched Taiwanese counterparts. However, those American infants exposed to television or audio recordings of the Mandarin speakers performed the same as a control group of American babies exposed to native English speakers during their lab visits. Diagram displayed in Kuhl’s TED TAlk ⁶, provided courtesy of Dr. Patricia Kuhl’s Lab at the University of Washington.

Kuhl believes that this is primarily because a baby’s interactions with others engages the social brain, a critical element for helping children learn to communicate in their native and non-native languages.⁶ In other words, learning language is not simply a technical skill that can be learned by listening to a recording or watching a show on a screen. Instead, it is a special gift that is handed down from one generation to the next.

Language is learned through talking, singing, storytelling, reading, and many other nurturing experiences shared between caretaker and child. Babies are naturally curious; they watch every movement and listen to every sound they hear around them. When parents talk, babies look up and watch their mouth movements with intense wonder. Parents respond in turn, speaking in “motherese,” a special variant of language designed to bathe babies in the sound patterns and speech sounds of their native language. Motherese helps babies hear the “edges” of sound, the very thing that is difficult for babies who exhibit symptoms of dyslexia and auditory processing issues later on.

Over time, by listening to and engaging with the speakers around them, babies build sound maps which set the stage for them to be able to say words and learn to read later on. In fact, based on years of research, Kuhl has discovered that babies’ abilities to discriminate phonemes at 7 months-old is a predictor of future reading skills for that child at age 5.⁷

I believe that educating families about brain development, nurturing interactions, and the benefits and limits of technology is absolutely critical to helping families focus on what is most important in developing their children’s communication skills. I also believe that Kuhl’s work is invaluable in this regard. Not only has it focused my attention on how babies form foundations for language, but it has illuminated my understanding of how caretaker-child interactions help set the stage for babies to become language-bound learners.

Sources

(1) Kuhl, P. (April 3, 2012.) Talk on “Babies’ Language Skills.” Mind, Brain, and Behavior Annual Distinguished Lecture Series, Harvard University.

(2) Kuhl, P. (2000). “A New View of Language Acquisition.” This paper was presented at the National Academy of Sciences colloquium “Auditory Neuroscience: Development, Transduction, and Integration,” held May 19–21, 2000, at the Arnold and Mabel Beckman Center in Irvine, CA. Published by the National Academy of Sciences.

(3) Bock, P. (2005.) “The Baby Brain. Infant Science: How do Babies Learn to Talk?” Pacific Northwest: The Seattle Times Magazine.

(4) Siegel, D., Bryson, T. (2011.) The Whole-Brain Child: 12 Revolutionary Strategies to Nurture Your Child’s Developing Mind. New York, NY: Delacorte Press, a division of Random House, Inc.

(5) Center on the Developing Child at Harvard University. “Experiences Build Brain Architecture” and “Serve and Return Interaction Shapes Brain Circuitry” videos, two parts in the three-part series, “Three Core Concepts in Early Development.

http://developingchild.harvard.edu/resources/multimedia/videos

(6) Kuhl, P. (February 18, 2011.) “The Linguistic Genius of Babies,” video talk on TED.com, a TEDxRainier event.

www.ted.com/talks/patricia_kuhl_the_linguistic_genius_of_babies.html

(7) Lerer, J. (2012.) “Professor Discusses Babies’ Language Skills.” The Harvard Crimson.

Andrew Meltzoff & Patricia Kuhl: Joint attention to mind

Sarah DeWeerdt 11 Feb 2013

Power couple: In addition to a dizzying array of peer-reviewed publications, Andrew Meltzoff and Patricia Kuhl have written a popular book on brain development, given TED talks and lobbied political leaders.

Andrew Meltzoff shares many things with his wife — research dollars, authorship, a keen interest in the young brain — but he does not keep his wife’s schedule.

“It’s one of the agreements we have,” he says, laying out the rule with a twinkle in his eye that conveys both the delights and the complications of working with one’s spouse.

Meltzoff, professor of psychology at the University of Washington in Seattle, and his wife, speech and hearing sciences professor Patricia Kuhl, are co-directors of the university’s Institute for Learning and Brain Sciences, which focuses on the development of the brain and mind during the first five years of life.

Between them, they have shown that learning is a fundamentally social process, and that babies begin this social learning when they are just weeks or even days old.

You could say the couple is attached at the cerebral cortex, but not at the hip: They take equal roles in running the institute, but they each have their own daily rhythms and distinct, if overlapping, scientific interests.

Kuhl studies how infants “crack the language code,” as she puts it — how they figure out sounds and meanings and eventually learn to produce speech. Meltzoff’s work focuses on social building blocks such as imitation and joint attention, or a shared focus on an object or activity. Meltzoff says these basic behaviors help children develop theory of mind, a sophisticated awareness and understanding of others’ thoughts and feelings.

All of these abilities are impaired in children with autism. Most of the couple’s studies have focused on typically developing infants, because, they say, it’s essential to understand typical development in order to appreciate the irregularities in autism.

Both also study autism, which can in turn help explain typical development.

In addition to a dizzying array of peer-reviewed publications, the duo have written a popular book on developmental psychiatry, The Scientist in the Crib, and promote their ideas through TED talks and by lobbying political leaders.

Geraldine Dawson, chief science officer of the autism science and advocacy organization Autism Speaks and a longtime collaborator, calls Meltzoff and Kuhl “the dynamic duo.” “They’re sort of bigger-than-life type people, who fill the room when they walk into it,” she says.

Making a match:

Meltzoff and Kuhl’s story began with a scientific twist on a standard rom-com meet cute.

It was the early 1980s, and Kuhl, who had recently joined the faculty at the University of Washington, wanted to understand how infants hear and see vowels. But she was having trouble designing an effective experiment.

“I kept running into Andy’s office,” which was near hers, to talk it through, Kuhl recalls.

Meltzoff had done some research on how babies integrate what they see with what they touch, a process called cross-modal matching¹. Soon he and Kuhl realized that they could adapt his experimental design to her question, and decided to collaborate.

They showed babies two video screens, each featuring a person mouthing a different vowel sound – “ahhh” or “eeee.” A speaker placed between the two screens played one of those two vowel sounds.

They found that babies as young as 18 to 20 weeks look longer at the face that matches the sound they hear, integrating faces with voices².

But that wasn’t the only significant result from those experiments.

“Speaking only for myself, I will say I became very interested in the very attractive, smart blonde that I was collaborating with,” Meltzoff says. “Criticizing each other’s scientific writing at the same time the relationship was building was… interesting.”

And effective: Their paper appeared in Science in 1982, and the couple married three years later.

Listening to Meltzoff tell that story, it’s easy to understand why some colleagues say he is funny but they can’t quite explain why. His humor is subtle and wry. More obvious is his passion, not just for science, but for working out the theory underlying empirical results. Even his wife describes his personality as “cerebral.”

“He just has this laser vision for homing in on what is the heart of the issue,” says Rechele Brooks, research assistant professor of psychiatry and behavioral sciences at the University of Washington, who collaborates with Meltzoff on studies of gaze.

For example, in one of his earliest papers, Meltzoff wanted to investigate how babies learn to imitate. He found that infants just 12 to 21 days old can imitate both facial expressions and hand gestures, much earlier than previously thought³.

“It really turned the scientific community on its head,” Brooks says.

Early insights:

Face to face: Meltzoff and Kuhl are developing a method to simultaneously record the brain activity of two people as they interact.

Meltzoff continued to study infants, tracing back the components of theory of mind to their earliest developmental source. That sparked the interest of Dawson, who had gotten to know Meltzoff as a student at the University of Washington in the 1970s, and became the first director of the university’s autism center in 1996.

Meltzoff and Dawson together applied his techniques to study young, often nonverbal, children with autism. In one study, they found that children with autism have more trouble imitating others than do either typically developing children or those with Down syndrome⁴.

In another study, they found that children with autism are less interested in social sounds such as clapping or hearing their name called than are their typically developing peers⁵. They also found that how children with autism imitate and play with toys when they are 3 or 4 years old predicts their communication skills two years later⁶.

Most previous studies of autism had focused on older children, Dawson says, and this work helped paint a picture of the disorder earlier in childhood.

Kuhl began her career with studies showing that monkeys⁷ and even chinchillas⁸ can distinguish the difference between speech sounds, or phonemes, such as “ba” and “pa,” just as human infants can.

“The bottom line was that animals were sharing this aspect of perception,” Kuhl says.

So why are people so much better than animals at learning language? Kuhl has been trying to answer that question ever since, first through behavioral studies and then by measuring brain activity using imaging techniques.

Kuhl is soft-spoken, but a listener wants to lean in to catch every word. Scientists who have worked with her describe her as poised and perfectly put together, a master of gentle yet effective diplomacy.

“She has her sort of magnetic power to pull people together,” says Yang Zhang, associate professor of speech-language-hearing sciences at the University of Minnesota in Rochester, who was a graduate student and postdoctoral researcher in Kuhl’s lab beginning in the late 1990s.

Listen and learn:

At one point, Kuhl turned her considerable powers of persuasion on a famously smooth negotiator, then-President Bill Clinton.

Kuhl had shown that newborns hear virtually all speech sounds, but by 6 months of age they lose the ability to distinguish sounds that aren’t part of their native language⁹.

At the White House Conference on Early Childhood Development and Learning in 1997, she described how infants learn by listening, long before they can speak.

Clinton, ever the policy wonk, asked her how much babies need to hear in order to learn. Kuhl said she didn’t know — but if Clinton gave her the funds, she would find out. “Even the president could see that research on the effects of language input on the young brain had impact on society,” she says.

Kuhl used the funds Clinton gave her to design a study in which 9-month-old babies in the U.S. received 12 short Mandarin Chinese ‘lessons.’ The babies quickly learned to distinguish speech sounds in the second language, her team found — but only if the speaker was live, not in a video¹⁰.

Those results contributed to Kuhl’s ‘social gating’ hypothesis, which holds that social interaction is necessary for picking up on the sounds and patterns of language. “We’re saying that social interaction is a kind of gate to an interest in learning, the kind that humans are completely masters of,” she says.

Her results also suggest that the language problems in children with autism may be the result of their social deficits.

“Children with autism will have a very difficult time acquiring language if language requires the social gate to be open,” she says.

Over the years, Kuhl and Meltzoff have had largely independent research programs, but her recent focus on the social roots of language dovetails with his long-time focus on social interaction.

These days, they are trying to develop ‘face-to-face neuroscience,’ which involves simultaneously recording brain activity from two people as they interact with each other.

This approach would allow researchers to observe, for example, what happens in an infant’s brain when she hears her mother’s voice, and what happens in the mother’s brain as she sees her infant respond to her. “It’s going to be very special to do,” Meltzoff says enthusiastically, even though the effort is more directly related to Kuhl’s work than to his own.

It’s clear that this fervor for each other’s work goes both ways.

“That’s one of the great things about being married to a scientist,” Meltzoff says. “When you come home and think, ‘God, I really nailed this methodologically,’ your wife, instead of yawning, leans forward and says, ‘You did? Tell me about the method, that’s so exciting.’”

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Meltzoff A.N. and R.W. Borton Nature 282, 403-404 (1979) PubMed

2: Kuhl P.K. and A.N. Meltzoff Science 218, 1138-1141 (1982) PubMed

3: Meltzoff A.N. and M.K. Moore Science 198, 75-78 (1977) PubMed

4: Dawson G. et al. Child Dev. 69, 1276-1285 (1998) PubMed

5: Dawson G. et al. J. Autism Dev. Disord. 28, 479-485 (1998) PubMed

6: Toth K. et al. J. Autism Dev. Disord. 36, 993-1005 (2006) PubMed

7: Kuhl P.K. and D.M. Padden Percept. Psychophys. 32, 542-550 (1982) PubMed

8: Kuhl P.K. and J.D. Miller Science 190, 69-72 (1975) PubMed

9: Kuhl P.K. et al. Science 255, 606-608 (1992) PubMed

10: Kuhl P.K. et al. Proc. Natl. Acad. Sci. U.S.A. 100, 9096-9101 (2003) PubMed

Using genetic data in cognitive neuroscience: from growing pains to genuine insights

Adam E. Green, Marcus R. Munafò, Colin G. DeYoung, John A. Fossella, Jin Fan & Jeremy R. Gray
Nature Reviews Neuroscience 2008 Sep; 9, 710-720
http://dx.doi.org:/10.1038/nrn2461

Research that combines genetic and cognitive neuroscience data aims to elucidate the mechanisms that underlie human behaviour and experience by way of ‘intermediate phenotypes’: variations in brain function. Using neuroimaging and other methods, this approach is poised to make the transition from health-focused investigations to inquiries into cognitive, affective and social functions, including ones that do not readily lend themselves to animal models. The growing pains of this emerging field are evident, yet there are also reasons for a measured optimism.

NSF – Cognitive Neuroscience Award

The cross-disciplinary integration and exploitation of new techniques in cognitive neuroscience has generated a rapid growth in significant scientific advances. Research topics have included sensory processes (including olfaction, thirst, multi-sensory integration), higher perceptual processes (for faces, music, etc.), higher cognitive functions (e.g., decision-making, reasoning, mathematics, mental imagery, awareness), language (e.g., syntax, multi-lingualism, discourse), sleep, affect, social processes, learning, memory, attention, motor, and executive functions. Cognitive neuroscientists further clarify their findings by examining developmental and transformational aspects of such phenomena across the span of life, from infancy to late adulthood, and through time.

New frontiers in cognitive neuroscience research have emerged from investigations that integrate data from a variety of techniques. One very useful technique has been neuroimaging, including positron emission tomography (PET), functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), optical imaging (near infrared spectroscopy or NIRS), anatomical MRI, and diffusion tensor imaging (DTI). A second class of techniques includes physiological recording such as subdural and deep brain electrode recording, electroencephalography (EEG), event-related electrical potentials (ERPs), and galvanic skin responses (GSRs). In addition, stimulation methods have been employed, including transcranial magnetic stimulation (TMS), subdural and deep brain electrode stimulation, and drug stimulation. A fourth approach involves cognitive and behavioral methods, such as lesion-deficit neuropsychology and experimental psychology. Other techniques have included genetic analysis, molecular modeling, and computational modeling. The foregoing variety of methods is used with individuals in healthy, neurological, psychiatric, and cognitively-impaired conditions. The data from such varied sources can be further clarified by comparison with invasive neurophysiological recordings in non-human primates and other mammals.

Findings from cognitive neuroscience can elucidate functional brain organization, such as the operations performed by a particular brain area and the system of distributed, discrete neural areas supporting a specific cognitive, perceptual, motor, or affective operation or representation. Moreover, these findings can reveal the effect on brain organization of individual differences (including genetic variation), plasticity, and recovery of function following damage to the nervous system.

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Heroes in Basic Medical Research – Robert J. Lefkowitz

Posted in Cardiovascular Pharmacogenomics, Cell Biology, Chemical Biology and its relations to Metabolic Disease, Clinical & Translational, Curation, Disease Biology, Frontiers in Cardiology and Cardiovascular Disorders, Gene Regulation, Genomic Endocrinology, Genomics Pharmacy, Historical relevance, Innovations in Neurophysiology & Neuropsychology, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Drug Discovery, Technology Advance Assessment of, tagged G-Protein Coupled Receptors (GPCRs), Nobel Prize in Chemistry, Robert Lefkowitz on September 6, 2015| Leave a Comment »

Heroes in Basic Medical Research – Robert J. Lefkowitz

Author & Curator: Larry H Bernstein, MD, FCAP

Robert J. Lefkowitz, MD

Robert J. Lefkowitz MD, a Howard Hughes Medical Institute investigator who has spent his entire 39-year research career at the Duke University Medical Center, is sharing the 2012 Nobel Prize in Chemistry with Brian K. Kobilka of Stanford University School of Medicine, who was a post-doctoral fellow in Lefkowitz’s lab in the 1980s.

They are being recognized for their work on a class of cell surface receptors that have become the target of prescription drugs, including antihistamines, ulcer drugs and beta blockers to relieve hypertension, angina and coronary disease.

The receptors catch chemical signals from the outside and transmit their messages into the cell, providing the cell with information about changes occurring within the body. These particular receptors are called seven-transmembrane G protein-coupled receptors, or just “G-coupled receptors” for short. Serpentine in appearance, G-coupled receptors weave through the surface of the cell seven times.

The human genome contains code to make at least 1,000 different forms of these trans-membrane receptors, all of which are quite similar. The receptors also bear a strong resemblance to receptors that detect light in the eyes, smells in the nose and taste on the tongue. (See playlist of Lefkowitz science videos here.)

“Bob’s seminal discoveries related to G-protein coupled receptors ultimately became the basis for a great many medications that are in use today across many disease areas,” said Victor J. Dzau, MD, Chancellor for Health Affairs and CEO, Duke University Health System. “He is an outstanding example of a physician-scientist whose impact can be seen in the lives of the countless patients who have benefited from his scientific discoveries. We are very proud of his magnificent achievements and grateful for his many contributions to Duke Medicine.”

After attending public elementary and junior high schools I entered The Bronx High School of Science (10th grade) in the autumn of 1956, graduating at age 16 in 1959. “Bronx Science” is one of several public high schools in New York City which admits students on the basis of a competitive examination. The student body, representing approximately the top 5% based on the exam, are gifted and interested in science and math. The accomplishments of graduates of this high school are quite remarkable. For example, I am the 8th Nobel Laureate to have graduated from this school, the 7 previous ones having received their prizes in Physics. For me, attending this school was a formative experience. Whereas in elementary and junior high school I was not greatly challenged, here I was among a group of remarkably bright, interesting and stimulating classmates. The curriculum featured many advanced classes at the college level. I was particularly drawn to chemistry and, as a result of taking these college level classes, I was able to receive full credit for two years of chemistry when I entered Columbia College in 1959. Thus I began as a college freshman with organic chemistry, a course generally taken by juniors.

The level of scholarship maintained by the student body was such that even with an average of about 94% my final class rank was about 100th out of 800. A classmate and friend at the time and at present, the famous geneticist David Botstein, had an almost identical average, a fact we tease each other about to this day.

Along with dozens of classmates, I moved on to Columbia University where I enrolled as a pre-medical student majoring in chemistry. The two year core curriculum in “Contemporary Civilization” was required of all students. With an emphasis on reading classic texts in history, philosophy, sociology and the political sciences and discussing these in small seminars, it was for me an opening to a whole new world. In addition, I took courses with and was exposed to, such intellectual giants as the literary critic Lionel Trilling, the cultural historian Jacques Barzun and the sociologist Daniel Bell, among others. I have very fond memories from this period of spending many hours in the public reading room at the 42nd Street New York Public Library, researching papers for those classes.

I also studied advanced Organic Chemistry with Cheves Walling and Physical Chemistry in a department which was strongly influenced by the then recently retired prominent physical organic chemist, Louis Hammett. However, the chemistry professor who had the most profound influence on me was actually a young Assistant Professor of Chemistry, Ronald Breslow. As a college senior I took an advanced seminar in biochemistry which he taught single handedly. This introduction to the chemistry of processes in living organisms really excited me in part, I suspect, because of his very lively teaching style. None of this, however, in any way diverted me from my goal of studying to become a practicing physician.

I greatly enjoyed my four years in medical school. I had dreamed about becoming a physician since grade school and now I was finally doing it. As a freshman immersed in the basic medical sciences I was able to deepen my interest in, and fascination with, biochemistry. Our biochemistry professors included a remarkable array of scholars (not that any of us appreciated that at the time). We heard lectures on metabolism from David Rittenberg, Chair of the Department; from David Shemin on porphyrins; from Irwin Chargaff on nucleic acids; and from David Nachmansohn on cholinergic neurotransmission.

One young professor left a lasting impression on me. Paul Marks was then a young academic hematologist who taught the Introduction to Clinical Medicine course in which we studied clinical problems for the first time, examined case histories, and looked at blood specimens. Not only was he a good clinician but he assigned readings from the basic science literature that were relevant in a very meaningful way to the cases we studied. This showed me how scientific information could be brought to bear on clinical problems. Among my classmates and friends in medical school was Harold Varmus, who was the co-recipient of the 1989 Nobel Prize for the discovery of oncogenes.

On July 1, 1968 I moved my family (now including the recently born Cheryl) to Rockville, Maryland to begin my research career at the NIH in nearby Bethesda, Maryland. I had been assigned, through a matching program, to work with Drs. Jesse Roth and Ira Pastan in the Clinical Endocrinology Branch of the National Institute of Arthritis and Metabolic Diseases (NIAMD), now known as NIDDK, the National Institute of Diabetes and Digestive and Kidney Diseases. I was a Clinical Associate, meaning that in addition to doing full time research ten months out of the year, for two months I also supervised a clinical endocrinology in-patient service. Because of this, I gained a remarkable exposure to unusual endocrine diseases which were under study at the time. An example of this was acromegaly.

It was the heyday of interest in second messenger signaling after the discovery of cAMP by Earl Sutherland. He would receive the Nobel Prize in Medicine and Physiology for this in 1971. One hormone after another was being shown to stimulate the enzyme adenylate cyclase thus increasing intracellular levels of cAMP. The idea that these different hormones might work through distinct receptors was talked about but was controversial. Moreover, at the time there were no direct methods for studying the receptors. I was assigned the challenging task of developing a radioligand binding method to study the putative receptors for adrenocorticotropic hormone (ACTH) in plasma membranes derived from an ACTH responsive adrenocortical carcinoma passaged in nude mice.

Recently, two Nobel Laureates, Mike Brown and Joe Goldstein, published a brief essay discussing the remarkable number of Nobel Laureates (9 so far) who have in common the fact that they came to the NIH as physicians during the brief space between 1964–1972 for postdoctoral research training. (1)

They dissect the unique convergence of circumstances which may have been responsible for this extraordinary result, including the quality of basic science mentors on the full time NIH staff, the competitiveness of “the best and the brightest” to obtain these positions during the Vietnam War years, and the now bygone emphasis on teaching of basic sciences in medical schools in the 1960s.

Lineages among Nobel Laureates are often commented upon. In my case, Jesse Roth had trained with Solomon Berson and Rosalyn Yalow whose development of radioimmunoassay led to the Nobel Prize in Medicine and Physiology to Yalow (1977) after Berson’s untimely death in 1972. Moreover, training in Ira Pastan’s laboratory contemporaneously with me was my medical school and house staff classmate and future Nobel Laureate, Harold Varmus. Ira had himself trained in the lab of another NIH career scientist, Earl Stadtman, who also trained a future Nobel Laureate, Mike Brown.

Dr. Edgar Haber, the Chief of Cardiology and a prominent immunochemist, allowed me to begin working in his lab. I was fascinated by receptors and what I saw as their potential to form the basis for a whole new field of research just waiting to be explored. I spent a great deal of time analyzing which receptor I should attempt to study. As an aspiring academic cardiologist I wanted to work on something related to the cardiovascular system. I also wanted a receptor known to be coupled to adenylate cyclase. I initially focused on two models, the cardiac glucagon and β-adrenergic receptors. However, my attention quickly became focused on the latter, for very practical reasons. Unlike the case for peptide hormones such as glucagon or ACTH, literally dozens, if not hundreds of analogs of adrenaline and noradrenaline, as well as their antagonists were available which could be chemically modified to develop the types of new tools which would need to be developed to study the receptors. These would include radioligands, photoaffinity probes, affinity chromatography matrices and the like. Moreover, the first β-adrenergic receptor blocker (“β-blocker”) had recently been approved for clinical use in the United States, adding further to the attractiveness of this target to me.

So in the early months of 1971 I began the quest to prove the existence of β-adrenergic receptors, to study their properties, to learn about their chemical nature, how they were regulated and how they functioned. This work has consumed me for the past forty years. Over the next several years in Boston, working mostly with membrane fractions derived from canine myocardium, I sought to develop radioligand binding approaches to tag the β-adrenergic receptors. I focused initially on the use of [3H]labeled catecholamines such as norepinephrine, which are agonists for the receptor. Specific saturable binding could be demonstrated, and I thought initially that we had developed a valid approach to label the receptors. However, it became increasingly clear over the next few years that the sites being labeled lacked many of the properties that would be expected for true physiological receptor binding sites. Coming to this realization was difficult.

During this time I also published some of the very first studies demonstrating GTP regulation of β-adrenergic receptor stimulated adenylate cyclase following after the work of Martin Rodbell on GTP regulation of glucagon sensitive adenylate cyclase. I was now a cardiology fellow. As at the NIH, nights on call were often spent in the lab doing experiments while hoping that my on call beeper would remain quiet. During these years, I had many stimulating and profitable discussions with Geoffrey Sharpe, a faculty member in the Nephrology Division with an interest in cell signaling and adenylate cyclase.

In work with postdoc Marc Caron in the spring of 1974, we succeeded in developing [3H]dihydroalprenolol. Contemporaneously, Gerald Aurbach at the NIH, and Alex Levitzki at the Hebrew University in Jerusalem also developed similar approaches using different radioligands. This was a watershed event because it finally opened the door to direct study of the receptors. Together with M.D./Ph.D. student Rusty Williams we developed comparable assays for the α-adrenergic receptors shortly thereafter.

Brian Kent Kobilka is an American physiologist and a corecipient of the 2012 Nobel Prize in Chemistry with Robert Lefkowitz for discoveries that reveal the inner workings of an important family G protein-coupled receptors.

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Proteins that control neurotransmitter release

Posted in Academic Publishing, Biological Networks, Cell Biology, Cerebrovascular and Neurodegenerative Diseases, Clinical & Translational, Clinical Genomics, Disease Biology, Gene Regulation, Genetics & Pharmaceutical, Genome Biology, Innovations in Neurophysiology & Neuropsychology, Intellectual Property, International Global Work in Pharmaceutical, Investment in Technological Breakthrough, Molecular Genetics & Pharmaceutical, Neurological Diseases, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmacogenomics, Population Health Management, Proteins, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Schizophrenia, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, tagged Genentech, Neuroscience, Richard H. Scheller, Roche Holding, Stanford University School of Medicine on September 6, 2015| Leave a Comment »

Proteins that control neurotransmitter release

Author & Curator: Larry H. Bernstein, MD, FCAP

Richard H. Scheller, PhD

The sec6/8 Complex Is Located at Neurite Outgrowth and Axonal Synapse-Assembly Domains

Christopher D. Hazuka, Davide L. Foletti, Shu-Chan Hsu, Yun Kee, F. Woodward Hopf, and Richard H. Scheller
Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305-5428

The Journal of Neuroscience, February 15, 1999, 19(4):1324–1334 http://www.jneurosci.org/content/19/4/1324.full.pdf

The molecules that specify domains on the neuronal plasma membrane for the delivery and accumulation of vesicles during neurite outgrowth and synapse formation are unknown. We investigated the role of the sec6/8 complex, a set of proteins that specifies vesicle targeting sites in yeast and epithelial cells, in neuronal membrane trafficking. This complex was found in layers of developing rat brain undergoing synaptogenesis. In cultured hippocampal neurons, the sec6/8 complex was present in regions of ongoing membrane addition: the tips of growing neurites, filopodia, and growth cones. In young axons, the sec6/8 complex was also confined to periodic domains of the plasma membrane. The distribution of synaptotagmin, synapsin1, sec6, and FM1–43 labeling in cultured neurons suggested that the plasma membrane localization of the sec6/8 complex preceded the arrival of synaptic markers and was downregulated in mature synapses. We propose that the sec6/8 complex specifies sites for targeting vesicles at domains of neurite outgrowth and potential active zones during synaptogenesis. Key words: synaptogenesis; neurotransmission; secretion; exocytosis; synaptic vesicle; vesicle targeting

Targeting of vesicles to synaptic sites during development may use similar mechanisms as those involved in vesicle fusion underlying membrane outgrowth. Before contact with a postsynaptic target, axons possess mobile vesicle clusters bearing synaptotagmin, which fuse with the plasma membrane after stimulation (Matteoli et al., 1992; Kraszewski et al., 1995; Dai and Peng, 1996). Thus, growing axons must contain the molecular machinery required for constitutive exocytosis, endocytosis, and activitydependent vesicle release. However, it is unclear how vesicles become clustered at synapses. Although vesicle fusion in axons might occur anywhere along the plasma membrane, there must be membrane targets that signal the clustering of vesicles for synapse formation. Furthermore, it is unclear how sites of vesicle exocytosis are modified as the neuron forms stable contacts with postsynaptic partners.

Identification of a Novel Rab11/25 Binding Domain Present in Eferin and Rip Proteins

Rytis Prekeris*, Jason M. Davies*, and Richard H. Scheller#
JBC Papers in Press. Published on July 31, 2001 as Manuscript M106133200
http://www.jbc.org/content/early/2001/07/31/jbc.M106133200.full.pdf

Rab11, a low molecular weight GTP binding protein, has been shown to play a key role in a variety of cellular processes, including endosomal recycling, phagocytosis, and transport of secretory proteins from the TGN. In this study we describe a novel Rab11 effector, EF hands containing Rab11 interacting protein (eferin). In addition, we identify a 20 amino acid domain that is present at the C-terminus of eferin and other Rab11/25 interacting proteins, such as Rip11 and nRip11. Using biochemical techniques we demonstrate that this domain is necessary and sufficient for Rab11 binding in vitro and that it is required for localization of Rab11 effector proteins in vivo. The data suggest that various Rab effectors compete with each other for the binding to Rab11/25 possibly accounting for the diversity of Rab11 functions.

Members of the Rab/Ypt GTPase family have emerged as important regulators of vesicular trafficking (1). Rab proteins have been proposed to mediate a variety of functions, including vesicle translocation and docking at a specific fusion sites. Like all small GTPases, Rabs cycle between active (GTP bound) and inactive (GDP bound) conformations (2). In the GTP bound state, Rab proteins can bind a variety of downstream effector proteins, while GTP hydrolysis leads to a conformational change in the “switch” region that renders the Rab GTPase unrecognizable to its effector proteins (3,4). A key question in understanding the interactions between Rabs and their effectors concerns the mechanisms by which Rab GTPases specifically bind a diverse spectrum of effectors and how this is regulated by the common structural motif used as a GTP switch. Biochemical and genetic studies have identified several hypervariable regions that might be involved in determining Rab specificity, including N- and C-termini, as well as α3/β5 by guest on September 6, 2015 http://www.jbc.org/ Downloaded from loop (5,6). Indeed, the recently reported structure of Rab3a bound to a putative effector, rabphillin-3a, revealed that Rab3a/rabphillin-3a complex interacts through two main regions (7). The first consists of conformationally sensitive “switch” regions of Rab3a bound to the a1 helix and the C-terminal part of rabphillin-3a. The second involves the SGAWFF domain of rabphillin-3a which fits into a pocket formed by the three hypervariable complementary determining regions (CDRs) of Rab3a, corresponding to the N- and C-termini and α3/β5 loop. Thus, it appears that the hypervariable RabCDR are involved in determining the specificity of effector binding, while the conserved “switch” regions impart GTP dependency and binding. It remains to be determined, however, whether this paradigm also applies to other Rab/effector complexes. Rab11a, -11b, and -25 are closely related members of Rab GTPase family that have been implicated in regulating a variety of different post-Golgi trafficking pathways, such as protein recycling (8), phagocytosis (9), insulin-stimulated Glut4 insertion in the plasma membrane (10), and membrane trafficking from early endosomes to the transGolgi network (11). During the last few years several Rab11/25 interacting proteins have been identified, including Rab11BP/Rabphilin-11, Rip11, nRip11, and myosin Vb (12- 15). However, the mechanisms of their function, as well as molecular aspects of their interactions with Rab11, remain to be fully understood. In the present study, we report the identification of EF-hands containing Rab11/25 interacting protein (eferin). Furthermore, we characterized a Rab binding domain (RBD11) which is present at the Cterminus of eferin as well as other Rab11/25 binding proteins, such as Rip11 and nRip11. Using biochemical techniques we demonstrated that RBD11 is the region which encodes the specificity for Rab11/25, but is distinct from the region interacting with Rab “switch” domain, since its interactions with the Rab11/25 are not GTP-dependent.

The functional significance of the differences in Rip and eferin interactions with Rab11/25 remains to be determined. One possibility is that additional cellular factors can regulate the affinity of Rab11/25 binding to its effectors. Indeed, the recombinant full length Rip11 binds poorly to Rab11a in pull down and yeast-two hybrid assays as compared to full length endogenous Rip11 from cellular TX-100 extracts (data not shown). Furthermore, it has been previously shown that Rip11 can also interact with γSNAP and cytoskeleton (13,24). Thus, the interactions of Rips and eferin with different factors could be used as a means of differentially regulating Rab11/25 binding. Alternatively, the Rab11/25 binding motif in eferin and Rip11 might be conformationlly hidden and require activation before binding to Rab11/25. We have previously demonstrated that phosphorylation of Rip11 plays an important role in its trafficking (13). Thus, differential phosphorylation on Rab11/25 binding motifs could also play a role in regulating the binding of Rip11 and eferin to Rab GTPases. Despite to recent progress in understanding the roles of Rabs and their effectors in regulating membrane trafficking, we are only beginning to unravel the structural determinants of their function. Identification and characterization of the Rab11/25 binding regions in Rip and Eferin proteins will be of a crucial importance in understanding the molecular mechanisms involved in differential regulation of the variety of Rab11-dependent trafficking pathways.

Rapid identification of reactive cysteine residues for site-specific labeling of antibody-Fabs.

J. Immunol. Methods

J Immunol Methods 2008 Mar 14;332(1-2):41-52. Epub 2008 Jan 14.

Jagath R Junutula, Sunil Bhakta, Helga Raab, Karen E Ervin, Charles Eigenbrot, Richard Vandlen, Richard H Scheller,Henry B Lowman

Genentech Inc., 1DNA Way, South San Francisco, California, 94080, United States. jagath@gene.com

Cysteines with reactive thiol groups are attractive tools for site-specific labeling of proteins. Engineering a reactive cysteine residue into proteins with multiple disulfide bonds is often a challenging task as it may interfere with structural and functional properties of the protein. Here we developed a phage display-based biochemical assay, PHESELECTOR (Phage ELISA for Selection of Reactive Thiols) to rapidly screen reactive thiol groups on antibody fragments without interfering with their antigen binding, using trastuzumab-Fab (hu4D5Fab) as a model system

Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index.

Nat. Biotechnol.

Nat Biotechnol 2008 Aug 20;26(8):925-32. Epub 2008 Jul 20.

Genentech Inc, South San Francisco, California 94080, USA.

Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display-based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding.

Isolation and characterization of a Drosophila neuropeptide gene.

Neuron

Neuron 2008 Nov;60(3):400-1

Richard H Scheller, John R Nambu

Engineered thio-trastuzumab-DM1 conjugate with an improved therapeutic index to target human epidermal growth factor receptor 2-positive breast cancer.

Clin. Cancer Res.

Clin Cancer Res 2010 Oct 30;16(19):4769-78. Epub 2010 Aug 30.

Genentech, Inc., South San Francisco, California 94080, USA. jagath@gene.com

Antibody drug conjugates (ADCs) combine the ideal properties of both antibodies and cytotoxic drugs by targeting potent drugs to the antigen-expressing tumor cells, thereby enhancing their antitumor activity. Successful ADC development for a given target antigen depends on optimization of antibody selection, linker stability, cytotoxic drug potency, and mode of linker-drug conjugation to the antibody. Here, we systematically examined the in vitro potency as well as in vivo preclinical efficacy and safety profiles of a heterogeneous preparation of conventional trastuzumab-mcc-DM1 (TMAb-mcc-DM1) ADC with that of a homogeneous engineered thio-trastuzumab-mpeo-DM1 (thioTMAb-mpeo-DM1) conjugate.

Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent trafficking of Rabin8 to the centrosome.

Proc. Natl. Acad. Sci. U.S.A.

Proc Natl Acad Sci U S A 2011 Feb 27;108(7):2759-64. Epub 2011 Jan 27.

Christopher J Westlake, Lisa M Baye, Maxence V Nachury, Kevin J Wright, Karen E Ervin, Lilian Phu, Cecile Chalouni,John S Beck, Donald S Kirkpatrick, Diane C Slusarski, Val C Sheffield, Richard H Scheller, Peter K Jackson

Genentech, South San Francisco, CA 94080, USA.

Sensory and signaling pathways are exquisitely organized in primary cilia. Bardet-Biedl syndrome (BBS) patients have compromised cilia and signaling. BBS proteins form the BBSome, which binds Rabin8, a guanine nucleotide exchange factor (GEF) activating the Rab8 GTPase, required for ciliary assembly.

Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates.

Nat. Biotechnol.

Nat Biotechnol 2012 Feb 22;30(2):184-9. Epub 2012 Jan 22.

Genentech Inc., 1 DNA Way, S. San Francisco, California, USA.

The reactive thiol in cysteine is used for coupling maleimide linkers in the generation of antibody conjugates. To assess the impact of the conjugation site, we engineered cysteines into a therapeutic HER2/neu antibody at three sites differing in solvent accessibility and local charge. The highly solvent-accessible site rapidly lost conjugated thiol-reactive linkers in plasma owing to maleimide exchange with reactive thiols in albumin, free cysteine or glutathione.

Rac and Rab GTPases dual effector Nischarin regulates vesicle maturation to facilitate survival of intracellular bacteria.

EMBO J.

EMBO J 2013 Mar 5;32(5):713-27. Epub 2013 Feb 5.

Coenraad Kuijl, Manohar Pilli, Suresh K Alahari, Hans Janssen, Poh-Sim Khoo, Karen E Ervin, Monica Calero,Sobhanaditya Jonnalagadda, Richard H Scheller, Jacques Neefjes, Jagath R Junutula

Genentech Inc., South San Francisco, CA 94080, USA. kuijlc@gene.com

The intracellular pathogenic bacterium Salmonella enterica serovar typhimurium (Salmonella) relies on acidification of the Salmonella-containing vacuole (SCV) for survival inside host cells. The transport and fusion of membrane-bound compartments in a cell is regulated by small GTPases, including Rac and members of the Rab GTPase family, and their effector proteins. However, the role of these components in survival of intracellular pathogens is not completely understood.

In search of the molecular mechanism of intracellular membrane fusion and neurotransmitter release.

Nat. Med.

Nat Med 2013 Oct;19(10):1232-5

Richard H Scheller

Genentech Research and Early Development, 1 DNA Way, San Francisco, California, USA.

An improved and robust DNA immunization method to develop antibodies against extracellular loops of multi-transmembrane proteins.

MAbs

MAbs 2014 Jan-Feb;6(1):95-107

Meredith Hazen, Sunil Bhakta, Rajesh Vij, Steven Randle, Dara Kallop, Vicki Chiang, Isidro Hötzel, Bijay S Jaiswal, Karen E Ervin, Bing Li, Robby M Weimer, Paul Polakis, Richard H Scheller, Jagath R Junutula, Jo-Anne S Hongo

Multi-transmembrane proteins are especially difficult targets for antibody generation largely due to the challenge of producing a protein that maintains its native conformation in the absence of a stabilizing membrane. Here, we describe an immunization strategy that successfully resulted in the identification of monoclonal antibodies that bind specifically to extracellular epitopes of a 12 transmembrane protein, multi-drug resistant protein 4 (MRP4). These monoclonal antibodies were developed following hydrodynamic tail vein immunization with a cytomegalovirus (CMV) promoter-based plasmid expressing MRP4 cDNA and were characterized by flow cytometry.

Site-specific trastuzumab maytansinoid antibody-drug conjugates with improved therapeutic activity through linker and antibody engineering.

J. Med. Chem.

J Med Chem 2014 Oct 18;57(19):7890-9. Epub 2014 Sep 18.

Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.

Antibody-drug conjugates (ADCs) have a significant impact toward the treatment of cancer, as evidenced by the clinical activity of the recently approved ADCs, brentuximab vedotin for Hodgkin lymphoma and ado-trastuzumab emtansine (trastuzumab-MCC-DM1) for metastatic HER2+ breast cancer. DM1 is an analog of the natural product maytansine, a microtubule inhibitor that by itself has limited clinical activity and high systemic toxicity. However, by conjugation of DM1 to trastuzumab, the safety was improved and clinical activity was demonstrated.

Richard H Scheller, PhD

Published on 16 Sep 2014

The Keck School of Medicine of USC is the first medical school in the nation to host the Lasker Lectures, featuring recipients of the prestigious 2013 Albert Lasker Basic Medical Research Award. In this installment, Richard H. Scheller, PhD, executive vice president of Genentech research and early development, discusses breakthoughs in drug development that are turning the tide in the war against cancer.

https://www.youtube.com/watch?v=Fx54EVJMcxM

Kavli Prize 2015

Xenon Pharmaceuticals Appoints Dr. Richard H. Scheller to Its Board of Directors http://fb.me/78z2HoJKa

Biopharmaceutical company Xenon Pharmaceuticals (NasdaqGM:XENE) reported on Monday the addition of Richard H. Scheller, PhD to its board of directors.

Most recently, Dr Scheller has served as chief science officer and head of Therapeutics at 23andMe.

Previously Dr Scheller was the executive vice president at Genentech Research and Early Development & a member of the Roche Corporate Executive Committee; chief scientific officer, executive vice president of Research and senior vice president of Research at Genentech; as well as a professor of Molecular and Cellular Physiology and of Biological Sciences at Stanford University Medical Center and an investigator of the Howard Hughes Medical Institute.

Dr Scheller is currently an adjunct professor in the Department of Biochemistry and Biophysics, School of Medicine at the University of California, San Francisco.

He has been a Director at Xenon Pharmaceuticals Inc. since March 16, 2015 and Medrio, Inc. since November 2012. He serves as a Member of the Medical and Scientific Review Board of Evotec (US), Inc. (Renovis Inc.). In 2014, he was named a trustee of Caltech. He served as a Member of Scientific Advisory Board of Intra-Cellular Therapies, Inc. and Rinat Neuroscience Corporation.

He served on numerous advisory boards including the National Advisory Mental Health Council of the National Institutes of Health. Dr. Scheller served as chairman of the Genentech Foundation’s board of directors. He is a globally recognized leader in biomedical research.

He has published over 200 papers in scientific journals, and worked in cell biology. He has received several additional awards for his work elucidating the molecular mechanisms governing neurotransmitter release, including the 2013 Albert Lasker Basic Medical Research Award, the 2014 California Institute of Technology’s Caltech Distinguished Alumni Award, the 2010 Kavli Prize in Neuroscience, and the 1997 U.S. National Academy of Sciences Award in Molecular Biology. He is a Fellow of the American Academy of Arts and Sciences. Dr. Scheller holds a Doctorate in Chemistry from the California Institute of Technology in 1980, where he was also a Postdoctoral Fellow, Division of Biology. He was also a Postdoctoral Fellow at Columbia University, College of Physicians & Surgeons. He has Bachelor’s Degree in Biochemistry in 1975 at the University of Wisconsin, Madison.

Education: 1971-1975 University of Wisconsin-Madison B.S. – Biochemistry with Honors 1975-1980 California Institute of Technology Ph.D. – Chemistry – Advisor: Eric H. Davidson 1980-1981 California Institute of Technology Postdoctoral Fellow-Division of Biology Advisor: Eric H. Davidson 1981-1982 Columbia University-College of Physicians & Surgeons Postdoctoral Fellow-Molecular Neurobiology Advisors: Richard Axel and Eric R. Kandel Industry Positions: 2001-2003 Senior Vice President – Research Genentech, Inc. 2003-2009 Executive Vice President – Research Genentech, Inc. 2008-2009 Chief Scientific Officer and Executive Vice President – Research Genentech, Inc. 2009- Executive Vice President – Genentech Research and Early Development (gRED) and Member of the Enlarged Roche Corporate Executive Committee Academic Appointments: 1982-1987 Assistant Professor, Department of Biological Sciences, Stanford University 1987-1990 Associate Professor, Department of Biological Sciences, Stanford University 1990-1993 Associate Professor, Department of Molecular and Cellular Physiology, Stanford University Associate Professor (by courtesy), Department of Biological Sciences, Stanford University

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Subcellular Localizations of C9orf72 in Amyotrophic Lateral Sclerosis

Posted in Innovations in Neurophysiology & Neuropsychology on July 22, 2015| Leave a Comment »

Subcellular Localizations of C9orf72 in Amyotrophic Lateral Sclerosis

Reporter: Aviva Lev-Ari, PhD, RN

Ann Neurol. 2015 Jul 14. doi: 10.1002/ana.24469. [Epub ahead of print]

Isoform Specific Antibodies Reveal Distinct Subcellular Localizations of C9orf72 in Amyotrophic Lateral Sclerosis.

Xiao S¹, MacNair L^1,², McGoldrick P¹, McKeever PM^1,², McLean JR¹, Zhang M¹, Keith J^2,³, Zinman L^2,³, Rogaeva E¹, Robertson J¹.

Author information

Abstract

OBJECTIVE:

A noncoding hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). It has been reported that the repeat expansion causes a downregulation of C9orf72 transcripts, suggesting that haploinsufficiency may contribute to disease pathogenesis. Two protein isoforms are generated from three alternatively spliced transcripts of C9orf72; a long form (C9-L) and a short form (C9-S) and their function(s) are largely unknown due to lack of specific antibodies.

METHODS:

To investigate C9orf72 protein properties, we developed novel antibodies that recognize either C9-L or C9-S. Multiple techniques including western blot, immunohistochemistry and co-immunoprecipitation were used to determine the expression levels and subcellular localizations of C9-L and C9-S.

RESULTS:

Investigation of expression of C9-L and C9-S demonstrated distinct biochemical profiles, region-specific changes and distinct subcellular localizations in ALS tissues. In particular, C9-L antibody exhibited a diffuse cytoplasmic staining in neurons, and labeled large speckles in cerebellar Purkinje cells. In contrast, C9-S antibody gave very specific labeling of the nuclear membrane in healthy neurons, with apparent re-localization to the plasma membrane of diseased motor neurons in ALS. Co-immunoprecipitation experiments revealed an interaction of the C9-isoforms with both Importin β1 and Ran-GTPase, components of the nuclear pore complex.

INTERPRETATION:

Using these antibodies, we have shown that C9orf72 may be involved in nucleocytoplasmic shuttling and this may have relevance to pathophysiology of ALS/FTLD. Our antibodies have provided improved detection of C9orf72 protein isoforms, which will help elucidate its physiological function and role in ALS/FTLD. This article is protected by copyright. All rights reserved.

SOURCE

http://www.ncbi.nlm.nih.gov/pubmed/26174152

Journal Reference:

Shangxi Xiao, Laura MacNair, Philip McGoldrick, Paul M McKeever, Jesse R McLean, Ming Zhang, Julia Keith, Lorne Zinman, Ekaterina Rogaeva, Janice Robertson. Isoform Specific Antibodies Reveal Distinct Subcellular Localizations of C9orf72 in Amyotrophic Lateral Sclerosis.Annals of Neurology, 2015; DOI: 10.1002/ana.24469

University of Toronto research team has discovered new details about a key gene involved in ALS, perhaps humanity’s most puzzling, intractable disease.

In this fatal disorder with no effective treatment options, scientists (including members of U of T) achieved a major breakthrough in 2011 when they discovered mutations in the gene C9orf72, as the most frequent genetic cause of ALS and frontotemporal dementia. But little was known about how this gene and its related protein worked in the cell.

To solve this problem, Professor Janice Robertson and her team at the Tanz Centre for Research in Neurodegenerative Diseases developed novel antibodies that not only specifically detected C9orf72 in human tissues, but could also distinguish between both the long and short isoforms.

“Using these antibodies we have made the remarkable discovery that C9orf72 is localized to the nuclear membrane in healthy neurons, but is mislocalized to the plasma (outer membrane) in diseased neurons,” says Robertson, whose research was published July 14 online in the journal Annals of Neurology.

Robertson and her team also showed that C9orf72 directly interacts with components of the nuclear shuttling complex, which is responsible for the movement of proteins across the nuclear membrane. One such protein is TDP-43, which normally resides in the nucleus but is wrongly localized to the cytoplasm in diseased neurons in ALS. TDP-43 accumulation and aggregation in the cytoplasm diagnoses most ALS cases — but the link with C9orf72 was absent.

Now through the use of the C9orf72 antibodies the Robertson lab has found that loss of C9orf72 from the nuclear membrane correlates with TDP-43 pathology. These results suggest that defects in C9orf72 affect the proper functioning of the nuclear shuttling complex, resulting in TDP-43 build up in the cytoplasm.

“We’ve discovered a link between the genetic cause of ALS and its pathology that appears to be important for all cases, not just familial ones,” says Robertson, a Canada Research Chair in ALS. “The possible involvement of C9orf72 in the shuttling between nucleus and cytoplasm opens intriguing new avenues of research into the causes of ALS — and hopefully, one day an effective treatment or cure.”

SOURCE

http://www.sciencedaily.com/releases/2015/07/150715122405.htm

Journal Reference:

Shangxi Xiao, Laura MacNair, Philip McGoldrick, Paul M McKeever, Jesse R McLean, Ming Zhang, Julia Keith, Lorne Zinman, Ekaterina Rogaeva, Janice Robertson. Isoform Specific Antibodies Reveal Distinct Subcellular Localizations of C9orf72 in Amyotrophic Lateral Sclerosis.Annals of Neurology, 2015; DOI: 10.1002/ana.24469

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Scientists have managed to build a fully functional neuron by using organic bioelectronics

Posted in Innovations in Neurophysiology & Neuropsychology, Neuroscience, Organic BioElectronics on June 29, 2015| Leave a Comment »

Scientists have managed to build a fully functional neuron by using organic bioelectronics

Reporter: Aviva Lev-Ari, PhD, RN

Scientists at Karolinska Institutet have managed to build a fully functional neuron by using organic bioelectronics. This artificial neuron contain no ‘living’ parts, but is capable of mimicking the function of a human nerve cell and communicate in the same way as our own neurons do.

Neurons are isolated from each other and communicate with the help of chemical signals, commonly called neurotransmitters or signal substances. Inside a neuron, these chemical signals are converted to an electrical action potential, which travels along the axon of the neuron until it reaches the end. Here at the synapse, the electrical signal is converted to the release of chemical signals, which via diffusion can relay the signal to the next nerve cell.

To date, the primary technique for neuronal stimulation in human cells is based on electrical stimulation. However, scientists at the Swedish Medical Nanoscience Centre (SMNC) at Karolinska Institutet’s Department of Neuroscience in collaboration with collegues at Linköping University, have now created an organic bioelectronic device that is capable of receiving chemical signals, which it can then relay to human cells.

“Our artificial neuron is made of conductive polymers and it functions like a human neuron”, says lead investigator Agneta Richter-Dahlfors, professor of cellular microbiology. “The sensing component of the artificial neuron senses a change in chemical signals in one dish, and translates this into an electrical signal. This electrical signal is next translated into the release of the neurotransmitter acetylcholine in a second dish, whose effect on living human cells can be monitored.“

Sourced through Scoop.it from: ki.se

See on Scoop.it – Cardiovascular and vascular imaging

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Injectable brain implant spies on individual neurons

Posted in Innovations in Neurophysiology & Neuropsychology on June 9, 2015| Leave a Comment »

Injectable brain implant spies on individual neurons

Reporter: Aviva Lev-Ari, PhD, RN

Electronic mesh has potential to unravel workings of mammalian brain.

A simple injection is now all it takes to wire up a brain. A diverse team of physicists, neuroscientists and chemists has implanted mouse brains with a rolled-up, silky mesh studded with tiny electronic devices, and shown that it unfurls to spy on and stimulate individual neurons.

The implant has the potential to unravel the workings of the mammalian brain in unprecedented detail. “I think it’s great, a very creative new approach to the problem of recording from large number of neurons in the brain,” says Rafael Yuste, director of the Neurotechnology Center at Columbia University in New York, who was not involved in the work.

If eventually shown to be safe, the soft mesh might even be used in humans to treat conditions such as Parkinson’s disease, says Charles Lieber, a chemist at Harvard University on Cambridge, Massachusetts, who led the team. The work was published inNature Nanotechnology on 8 June1.

Neuroscientists still do not understand how the activities of individual brain cells translate to higher cognitive powers such as perception and emotion. The problem has spurred a hunt for technologies that will allow scientists to study thousands, or ideally millions, of neurons at once, but the use of brain implants is currently limited by several disadvantages. So far, even the best technologies have been composed of relatively rigid electronics that act like sandpaper on delicate neurons. They also struggle to track the same neuron over a long period, because individual cells move when an animal breathes or its heart beats.

The Harvard team solved these problems by using a mesh of conductive polymer threads with either nanoscale electrodes or transistors attached at their intersections. Each strand is as soft as silk and as flexible as brain tissue itself. Free space makes up 95% of the mesh, allowing cells to arrange themselves around it.

Sourced through Scoop.it from: www.nature.com

See on Scoop.it – Cardiovascular and vascular imaging

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Stress and Anxiety

Posted in Cell Biology, Signaling & Cell Circuits, Child and Adolescent Psychiatry, Cognition, Curation, Disease Biology, Epigenetics and Cardiovascular Risks, Gastroenterology, HTN, Indigent Nutrition, Innovations in Neurophysiology & Neuropsychology, Lipids, Liver & Digestive Diseases Research, Neurological Diseases, Nitric Oxide in Health and Disease, Nutrition and Phytochemistry, Nutrition Disorders, Origins of Cardiovascular Disease, Population Health Management, Population Health Management, Nutrition and Phytochemistry, Prescription Drugs Costs, Uninsured and Underinsured, tagged adults, anxiety, behavioral treatments, geriatrics, pediatrics, psychosomatic illness, Stress on March 4, 2015| Leave a Comment »

Stress and Anxiety

Writer and Curator: Larry H Bernstein, MD, FCAP

Introduction

This article follows immediately after two on diet and obesity and diet and exercise. The hypothalamus has been discussed in some detail, although There is more that needs to be said about glutamate receptors, which is a topic in itself. However, this material fits in place quite well. There is a considerable amount of obesity, and exercise is limited by time and commitment. The shrinking middle class and the working poor, and the unemployed poor as well, have a struggle to make ends meet, and with the divorce rates that we are seeing, it is stressful for a single mother to carry on a complete life as mother and caregiver, and it is not unusual to see one or both couples in a household, regardless of sex, to hold two jobs. Students enter colleges for higher education and leave with significant debts. Graduates with advanced degrees may have to compete with a crowd of qualified applicants for an academic position, or even for a job in technology. In addition, there is an increase in stress related disorders in the pre-school, elementary and middle school population. We no longer have to read the front pages to learn that a violent act has been carried out somewhere, in some neighborhood in our great nation that has experienced a great civil war, two world wars, the Mc Carthy hearings, the Cold War, and Vietnam, and the Iraq War, all of which was accompanied by migrations, immigration, and outsourcing of jobs. The following is another look at how we are adjusting.

Effectiveness of a meditation-based stress management program as an adjunct to pharmacotherapy in patients with anxiety disorder

Sang Hyuk Lee, Seung Chan Ahn, Yu Jin Lee, Tae Kyu Choi, et al.
J Psychosomatic Research 62 (2007) 189–195
http://dx.doi.org:/10.1016/j.jpsychores.2006.09.009

Objective: The objective of this study was to examine the effectiveness of a meditation-based stress management program in patients with anxiety disorder.
Methods: Patients with anxiety disorder were randomly assigned to an 8-week clinical trial of either a meditation-based stress management program or an anxiety disorder education program. The Hamilton Anxiety Rating Scale (HAM-A), the Hamilton Depression Rating Scale (HAM-D), the State–Trait Anxiety Inventory (STAI), the Beck Depression Inventory, and the Symptom Checklist- 90 — Revised (SCL-90-R) were used to measure outcome at 0, 2, 4, and 8 weeks of the program. Results: Compared to the education group, the meditation-based stress management group showed significant improvement in scores on all anxiety scales (HAM-A, P=.001; STAI state, P=.001; STAI trait, P=.001; anxiety subscale of SCL-90-R,P=.001) and in the SCL-90-R hostility subscale (P=.01). Findings on depression measures were inconsistent, with no significant improvement shown by subjects in the meditation-based stress management group compared to those in the education group. The meditation-based stress management group did not show significant improvement in somatization, obsessive–compulsive symptoms, and interpersonal sensitivity scores, or in the SCL-90-R phobic anxiety subscale compared to the education group. Conclusions: A meditation-based stress management program can be effective in relieving anxiety symptoms in patients with anxiety disorder. However, well-designed, randomized, and controlled trials are needed to scientifically prove the worth of this intervention prior to treatment.

Evidence and Potential Mechanisms for Mindfulness Practices and Energy Psychology for Obesity and Binge-Eating Disorder

Renee Sojcher, Susan Gould Fogerite, and Adam Perlman
Explore 2012; 8(5):271-276
http://dx.doi.org/10.1016/j.explore.2012.06.003

Obesity is a growing epidemic. Chronic stress produces endocrine and immune factors that are contributors to obesity’s etiology. These biochemical alsocan affect appetite and eating behaviors that can lead to binge-eating disorder. The inadequacies of standard care and the problem of patient noncompliance have inspired a search for alternative treatments. Proposals in the literature have called for combination therapies involving behavioral or new biological therapies. This manuscript suggests that mindbody interventions would be ideal for such combinations. Two mind body modalities, energy psychology and mindfulness meditation, are reviewed for their potential in treating weight loss, stress, and behavior modiﬁcation related to binge-eating disorder.

Whereas mindfulness meditation and practices show more compelling evidence, energy psychology, in the infancy stages of elucidation, exhibits initially promising outcomes but requires further evidence-based trials. “Diets Don’t Work” has been a mantra repeated over and over in the media. In fact, in a 2006 study in which investigators compared several popular diets comprising either high carbohydrates, high protein, or high fat, they found a rapid regression of compliance after six months, to the extent that it did not matter which diet had initially been more effective. In another study, authors examined a combination of diet and exercise compared with diet alone and observed that 50% of their subjects in both groups regained the weight that they lost after one year, despite their having lost more weight with the combination therapy. Despite the failure of diet alone in most studies, strategies incorporating both diet and exercise can be effective: a Cochrane review on exercise for overweight or obesity concluded that exercise had a positive effect on body weight and cardiovascular risk factors and that this effect was enhanced by a combination of exercise with dietary interventions.

The authors of a more recent study found that the beneﬁts of exercise in inducing weight loss may come through psychological pathways rather than through actual energy expenditure. These factors include self-regulation and self-efﬁcacy, which may mediate the relationship between exercise and weight change. Psychological interventions, particularly behavioral therapy and CBT, have been shown to be effective, especially when combined with diet and exercise. However, these interventions are costly and require extensive clinical contact for long durations to achieve efﬁcacy. The authors of a recent randomized controlled trial (RCT) with a three-year follow-up period looked at a new form of CBT that addresses patients’ overeating and low level of activity, as well as factors that impede weight maintenance, and found that this form of therapy did not result in improved weight maintenance. These authors concluded that CBT is not sufﬁciently effective in helping patients maintain their weight loss in the long term. Although 20% of people will not change their eating behaviors under stress, most do; approximately 40% will increase and 40% will decrease their eating.

The emotional eaters, who tend to increase food intake, are more likely to crave high-fat/sweet and rewarding comfort foods. The basis for this behavior is becoming understood to entail brain pathways that involve learning and memory of reward and pleasure. Habit formation and decreased cognitive control are also involved. These habits form the basis of BED. Binge eating occurs when a person eats larger amounts of food than normal in a short amount of time. It therefore involves a loss of control and is often precipitated by a range of negative emotions, such as anxiety, depression, anger, and loneliness. Overweight subjects may or may not be characterized as binge eaters.

The stress response, also known as the “ﬁght or ﬂight response,” involves the interaction of the autonomic nervous system, which includes the sympathetic and the parasympathetic nervous systems, the hypothalamic pituitary adrenal axis and endocrine secretion. Together, these systems comprise neuro-endocrine pathways that collaborate to maintain the body’s regulation of homeostasis. This mechanism is very effective when stress is acute, but in the case of chronic stress, the effect can be injurious to one’s physiological state. Over time, chronic exposure to stress hormones contributes to“ allostatic load.” The stress hormones released by the body, mostly cortisol, can alter the body’s fuel metabolism, especially by adipose tissue, leading to an increase in upper-body obesity. Furthermore, hormones such as leptin, ghrelin, and neuropeptide Y can affect appetite and cause changes in fat mass storage. This results in the linking of stress and obesity.

Given the limited success of conventional approaches and the new information about the psychological and physiological mechanisms underlying obesity, we propose that a speciﬁc sub-group of mind-body therapies, including energy psychology and mindfulness-based approaches, could add an important new dimension to the integrative treatment of eating disorders. Energy psychology refers to a family of therapies that are used for treating physical disorders and psychological symptoms, which includes Thought Field Therapy, Emotional Freedom Techniques (EFT), Eye Movement Desensitization and Reprocessing, and Tapas Acupressure Technique (TAT). These therapies incorporate concepts originating from non-Western healing and spiritual systems, including acupuncture, acupressure, yoga, meditation, and qigong, and they combine physical activity with mental activation on the basis of the premise that the body is composed of electrical signals or energy ﬁelds. Energy psychology has been quite controversial among psychotherapists and has been the subject of much heated debate in the literature. Nonetheless, the clinical application of these practices is growing and is beginning to be investigated for efﬁcacy. Mindfulness-Based Eating Awareness Training (ie,MB-EAT) involves the cultivation of mindfulness, mindful eating, emotional balance, and self-acceptance.

A pilot trial of a six-week group curriculum for providing mindfulness training to obese individuals, called Mindful Eating and Living (ie,MEAL), showed signiﬁcant increases in measures of mindfulness and cognitive restraint around eating and signiﬁcant decreases in weight, eating disinhibition, bingeeating, depression, perceived stress, physical symptoms, negative affect ,and C-reactive protein. In a recent systematic review of eight studies, authors examined a variety of mindfulness techniques in treating eating disorders, including anorexia, bulimia, and BED. Because trial quality varied and sample sizes were small, the researchers concluded that mindfulness may be effective in treating eating disorders but that further research was needed. The authors noted, however, that all of the articles that met the study’s criterion reported positive outcomes for the mindfulness intervention. Two additional studies recently addressed the treatment of obesity with a combination of mindfulness strategies and ACT. Lillis et al. conducted a RCT on 87 subjects who had all completed at least a six-month weight loss program. Using a wait list control against treatment of the experimental group through a one-day workshop, the authors found that, compared with the control group, the experimental group showed greater improvements in obesity-related stigma, quality of life, psychological distress, and reduction of body mass in a three-month follow-up. Alberts et al. conducted an RCT on 19 participants in a 10-week dietary group treatment that examined the effect of mindfulness plus ACT on food cravings. Experimental subjects underwent an additional seven-week, manual-based mindfulness/acceptance training. The control group received information on healthy food choices. The experimental group showed signiﬁcantly lower food cravings, a lower preoccupation with food in four subscales, less loss of control, and better positive outcome expectancy, as compared with the control group. There was no signiﬁcant effect observed for emotional craving. The authors of both of these studies conclude that mindfulness strategies combined with acceptance are effective in reducing the behaviors that lead many obese patients to overeat. With regards to stress, mindfulness can reduce psychological factors that have been shown to contribute to obesity.

In a recent well conducted systematic review, Mars and Abbey examined 22 studies with conditions ranging from participants with Axis I disorders, various diagnosed medical disorders, and healthy subjects. Axis I disorders include a range of psychopathologies such as childhood developmental and adjustment abnormalities, adult anxiety, and mood, sleep, and sexual disorders. Subjects with BED are known to have greater comorbidity forAxis I disorders. The authors report that ﬁve studies examining Axis I disorders showed statistically signiﬁcant results for an eight-week, two hours per week MBCT program in reducing psychological stress, recurring bouts of depression, and pain. They conclude that, despite some methodological difﬁculties in the trials, mindfulness therapy may have a positive impact on reducing stress and depression. Despite increasing public awareness of obesity’s detrimental effects on health, the conventional approaches to managing this condition have not been effective. The recommended standard care for overweight and obesity, namely diet and exercise, are for the most part ineffective in the long term. Behavioral therapy and CBT may have some effect but are costly and difﬁcult to implement. Issues with bariatric surgery and pharmacological therapies attributable to cost and the potential for harm, as well as lack of long-term efﬁcacy, have limited their utility.

The effectiveness of a stress coping program based on mindfulness meditation on the stress, anxiety, and depression experienced by nursing students in Korea

Yune Sik Kang, So Young Choi, Eunjung Ryu
Nurse Education Today 29 (2009) 538–543
http://dx.doi.org:/10.1016/j.nedt.2008.12.003

This study examined the effectiveness of a stress coping program based on mindfulness meditation on the stress, anxiety, and depression experienced by nursing students in Korea. A nonequivalent, control group, pre-posttest design was used. A convenience sample of 41 nursing students were randomly assigned to experimental (n=21) and control groups (n=20). Stress was measured with the PWI-SF(5-point) developed by Chang. Anxiety was measured with Spieberger’s state anxiety y inventory. Depression was measured with the Beck depression inventory. The experimental group attended 90-min sessions for eight weeks. No intervention was administered to the control group. Nine participants were excluded from the analysis because they did not complete the study due to personal circumstances, resulting in16 participants in each group for the ﬁnal analysis. Results for the two groups showed

(1) a signiﬁcant difference in stress scores (F=6.145,p=0.020),

(2) a signiﬁcant difference in anxiety scores (F=6.985,p=0.013), and

(3) no signiﬁcant difference in depression scores (t=1.986,p=0.056).

A stress coping program based on mindfulness meditation was an effective intervention for nursing students to decrease their stress and anxiety, and could be used to manage stress in student nurses. In the future, long-term studies should be pursued to standardize and detail the program, with particular emphasis on studies to conﬁrm the effects of the program in patients with diseases, such as cancer.

Meditation and Anxiety Reduction: A Literature Review

M. M. Delmonte Clin
Psychol Rev 1985; 5: 91-102
Meditation is increasingly being practiced as a therapeutic technique. The effects of practice on psychometrically assessed anxiety levels has been extensively researched. Prospective meditators tend to report above average anxiety. In general, high anxiety levels predict a subsequent low frequency of practice. However, the evidence suggests that those who practice regularly tend to show significant decreases in anxiety. Meditation does not appear to be more effective than comparative interventions in reducing anxiety. There is evidence to suggest that hypnotizability and expectancy may both play a role in reported anxiety decrease. Certain individuals with a capacity to engage in autonomous self-absorbed relaxation, may benefit most from meditation.

Meta-analysis on the effectiveness of mindfulness-based stress reduction therapy on mental health of adults with a chronic disease: What should the reader not make of it?

Ernst Bohlmeijer, Rilana Prenger, ErikTaal
Letters to the Editor/J Psychosom Res 69 (2010) 613–615
http://dx.doi.org:/10.1016/j.jpsychores.2010.09.005

In a letter to the editor, Nyklíček et al. discuss the study of Bohlmeijer et al. [1]on the meta-analysis on the effectiveness of mindfulness-based stress reduction (MBSR) therapy on mental health of adults with a chronic disease. They claim that the effects of MBSR are underestimated in this meta-analysis due to the inclusion of a study using an active education support group as control group and to the omission of some subscales for which larger effect sizes have been found. We do not agree that the study using an active education support group as a control group should not have been included in the meta-analysis. It is a common procedure to include studies with various types of control groups, e.g., waiting-list, placebo, minimal interventions, or evidence-based treatment. Normally, subgroup analyses can be conducted, contrasting studies that use differen ttypes of control groups. As seven studies used a waiting-list control condition and only one study used an education support group, this subgroup comparison was not useful. However, when we conducted a meta-analysis of the seven RCTs using a waiting-list control group an overall effect size of 0.30 instead of 0.26 was found. In addition, it is often found in meta-analyses that the largest effect sizes are reported in studies that use waiting-list control groups, e.g. ,Refs.[2,3]. The fact that almost all studies included in our meta-analysis in fact used waiting-list control groups makes it unlikely that the effects of MBSR were underestimated. As to the second claim by Nyklíček e tal.that some outcomes were selectively omitted from the meta-analysis, we can state that the subscales of the POMS were included in the meta-analysis.The program that was used in our study, Comprehensive Meta-Analysis, combined the scales that measure the same outcome, e.g., anxiety in one study. So the larger effects sizes for the subscales of the POMS were included in the meta-analysis. Lastly, Nyklíčeketal. State that ‘decentering’ is not an exclusive process of MBCT but is a central feature of MBSR as well. MBCT was specifically developed for people with recurrent depression and on the basis of a thorough analysis of the role of specific cognitions in people with recurrent depression. In ouropinion, this may explain the large effect sizes that have been found in randomized controlled trials, e.g., [4]. In general, other studies have shown that integrating MBSR in behavioral therapy is a very promising strategy for enhancing the efficacy of treatments of psychological distress[5,6]. However, more studies with different target groups are needed to answer the question as to which mindfulness-based intervention is most effective for which target group in which setting. Overall, in response to the letter to the editor by Nyklíček et al. we cannot corroborate their claim that the effects of MBSR were underestimated and have to stand with our conclusion that, on the basis of current RCTs, MBSR has small leffects on depression and anxiety in people with chronic medical diseases.

[1] BohlmeijerET, PrengerR, TaalE, CuijpersP.
The effects of mindfulness-based stress reduction therapy on the mental health of adults with a chronic medical disease: A meta-analysis.
JPsychosom Res 2010; 68:539–44.

[2]Powers MB, Zum Vörde Sive Vörding MB, Emmelkamp PMG.
Acceptance and commitment therapy: A meta-analytic review.
Psychoth Psychosom 2009; 78:73–80.

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Diet and Exercise

Posted in Curation, Health Economics and Outcomes Research, HealthCare IT, Innovations, Innovations in Neurophysiology & Neuropsychology, Lipids, Nutrition, Nutrition and Phytochemistry, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Population Health Management, Population Health Management, Nutrition and Phytochemistry, Social Development, Statistical Methods for Research Evaluation, Stress Disorders, Systemic Inflammatory Response Related Disorders, Translational Effectiveness, Translational Research, Translational Science, tagged adolescent habits, Aging, cardiovascular and lung disease, childhood development, diet, exercise, geriatrics, lipid disorders, Obesity, running, social contacts, swimming, theories of living habits, walkable neighborhoods, walking on March 4, 2015| Leave a Comment »

Diet and Exercise

Writer and Curator: Larry H. Bernstein, MD, FCAP

Introduction

In the last several decades there has been a transformation in the diet of Americans, and much debate about obesity, type 2 diabetes mellitus, hyperlipidemia, and the transformation of medical practice to a greater emphasis on preventive medicine. This occurs at a time that the Western countries are experiencing a large portion of the obesity epidemic, which actually diverts attention from a larger share of malnutrition in parts of Africa, Asia, and to a greater extent in India. This does not mean that obesity or malnutrition is exclusively in any parts of the world. But there is a factor at play that involves social factors, poverty, education, cognition, anxiety, and eating behaviors, food preferences and food balance, and activities of daily living. The epidemic of obesity also involves the development of serious long term health problems, such as, type 2 diabetes mellitus, sarcopenia, fracture risk, pulmonary disease, sleep apnea in particular, and cardiovascular and stroke risk. Nevertheless, this generation of Western society is also experiencing a longer life span than its predecessors. In this article I shall explore the published work on diet and exercise.

‘‘Go4Life’’ exercise counseling, accelerometer feedback, and activity levels in older people

Warren G. Thompson, CL Kuhle, GA Koepp, SK McCrady-Spitzer, JA Levine
Archives of Gerontology and Geriatrics 58 (2014) 314–319
http://dx.doi.org/10.1016/j.archger.2014.01.004

Older people are more sedentary than other age groups. We sought to determine if providing an accelerometer with feedback about activity and counseling older subjects using Go4Life educational material would increase activity levels. Participants were recruited from independent living areas within assisted living facilities and the general public in the Rochester, MN area. 49 persons aged 65–95(79.5 + 7.0 years) who were ambulatory but sedentary and overweight participated in this randomized controlled crossover trial for one year. After a baseline period of 2 weeks, group 1 received an accelerometer and counseling using Go4Life educational material (www.Go4Life.nia.nih.gov) for 24 weeks and accelerometer alone for the next 24 weeks. Group 2 had no intervention for the ﬁrst 24 weeks and then received an accelerometer and Go4Life based counseling for 24 weeks. There were no signiﬁcant baseline differences between the two groups. The intervention was not associated with a signiﬁcant change inactivity, body weight, % body fat, or blood parameters (p > 0.05). Older (80–93) subjects were less active than younger (65–79) subjects (p = 0.003). Over the course of the 48 week study, an increase in activity level was associated with a decline in % body fat (p = 0.008). Increasing activity levels beneﬁts older patients. However, providing an accelerometer and a Go4Life based exercise counseling program did not result in a 15% improvement in activity levels in this elderly population. Alternate approaches to exercise counseling may be needed in elderly people of this age range.

It is generally recommended that older adults be moderately or vigorously active for 150 min each week. A systematic review demonstrated that only 20–60% of older people are achieving this goal. These studies determined adherence to physical activity recommendations by questionnaire. Using NHANES data, it has been demonstrated that older people meet activity recommendations 62% of the time using a self-report questionnaire compared to 9.6% of the time when measured by accelerometry. Thus, objective measures suggest that older people are falling even more short of the goal than previously thought. Most studies have measured moderate and vigorous activity. However, light activity or NEAT (non-exercise activity thermogenesis) also has an important effect on health. For example, increased energy expenditure was associated with lower mortality in community-dwelling older adults. More than half of the extra energy expenditure in the high energy expenditure group came from non-exercise (light) activity. In addition to reduced total mortality, increased light and moderate activity has been associated with better cognitive function, reduced fracture rate (Gregg et al., 1998), less cardiovascular disease, and weight loss in older people. A meta-analysis of middle-aged and older adults has demonstrated greater all-cause mortality with increased sitting time. Thus, any strategy which can increase activity (whether light or more vigorous) has the potential to save lives and improve quality of life for older adults. A variety of devices have been used to measure physical activity.

A tri-axial accelerometer measures movement in three dimensions. Studies comparing tri-axial accelerometers with uniaxial accelerometers and pedometers demonstrate that only certain tri-axial accelerometers provide a reliable assessment of energy expenditure. This is usually due to failure to detect light activity. Since light activity accounts for a substantial portion of older people’s energy expenditure, measuring activity with a questionnaire or measuring steps with a pedometer do not provide an accurate reﬂection of activity in older people.

A recent review concluded that there is only weak evidence that physical activity can be improved. Since increasing both light and moderate activity beneﬁt older people, studies demonstrating that physical activity can be improved are urgently needed. Since accelerometry is the best way to accurately assess light activity, we performed a study to determine if an activity counseling program and using an accelerometer which gives feedback on physical activity, can result in an increase in light and moderate activity in older people. We also sought to determine whether counseling and accelerometer feedback would result in weight loss, change in % body fat, glucose, hemoglobin A1c, insulin, and fasting lipid proﬁle.

The main results of the study are both the experimental and control group lost weight (about 1 kg) at 6months (p = 0.04 and 0.02, respectively). The experimental group was less active at 6 months but not signiﬁcantly while the control group was signiﬁcantly less active at 6 months (p = 0.006) than at baseline. The experimental group had a modest decline in cholesterol (p = 0.03) and an improvement in Get Up & go time (p = 0.03) while the control group had a slight improvement in HgbA1c (p = 0.01). However, the main ﬁnding of the study was that there were no differences between the two groups on any of these variables. Thus, providing this group of older participants with an accelerometer and Go4Life based counseling resulted in no increase in physical activity, weight loss or change in glucose, lipids, blood pressure, or body fat. There were no differences within either group or between groups from 6 to 12 months on any of the variables (data not shown). While age was correlated with baseline activity, it did not affect activity change indicating that younger participants did not respond to the program better than older participants. Performance on the Get Up and Go test and season of the year did not inﬂuence the change in activity. There were no differences in physical activity levels at 3 or 9 months.

There was a signiﬁcant correlation (r = -0.38, p = 0.006) between change in activity and change in body fat over the course of the study. Those subjects (whether in the experimental or control group) who increased their activity over the course of the year were likely to have a decline in % body fat over the year while those whose activity declined were likely to have increased %body fat. There was no correlation between change in activity and any of the other parameters including weight and waist circumference (data not shown).

Older adults are the fastest growing segment of the population in the US, but few meet the minimum recommended 30 min of moderate activity on 5 days or more per week (Centers for Disease Control and Prevention, 2002). Our study found that within the geriatric population, activity declines as people age. We saw a 2.4% decline per year cross-sectionally. This ﬁnding agrees with a recent cohort study (Bachman et al., 2014). In that study, the annual decline accelerated with increasing age. Thus, there is a need to increase activity particularly in the oldest age groups. The United States Preventive Services Task Force concluded that the evidence that counseling improves physical activity is weak (Moyer and US Preventive Services Task Force, 2012). The American Heart Association reached similar conclusions (Artinian et al., 2010). Thus, new ways of counseling older patients to counter the natural decline in activity with age are urgently needed.

Applying health behavior theory to multiple behavior change: Considerations and approaches

Seth M. Noar, Melissa Chabot, Rick S. Zimmerman
Preventive Medicine 46 (2008) 275–280
http://dx.doi.org:/10.1016/j.ypmed.2007.08.001

Background.There has been a dearth of theorizing in the area of multiple behavior change. The purpose of the current article was to examine how health behavior theory might be applied to the growing research terrain of multiple behavior change. Methods. Three approaches to applying health behavior theory to multiple behavior change are advanced, including searching the literature for potential examples of such applications. Results. These three approaches to multiple behavior change include

(1) a behavior change principles approach;

(2) a global health/behavioral category approach, and

(3) a multiple behavioral approach.

Each approach is discussed and explicated and examples from this emerging literature are provided. Conclusions. Further study in this area has the potential to broaden our understanding of multiple behaviors and multiple behavior change. Implications for additional theory-testing and application of theory to interventions are discussed.

Many of the leading causes of death in the United States are behavior-related and thus preventable. While a number of health behaviors are a concern individually, increasingly the impact of multiple behavioral risks is being appreciated. As newer initiatives funded by the National Institutes of Health and Robert Wood Johnson Foundation begin to stimulate research in this important area, a critical question emerges: How can we understand multiple health behavior change from a theoretical standpoint? While multiple behavior change interventions are beginning to be developed and evaluated, to date there have been few efforts to garner a theory-based understanding of the process of multiple health behavior change. Given that so little theoretical work currently exists in this area, our main purpose is to advance the conversation on how health behavior theory can help us to achieve a greater understanding of multiple behavior change. The approaches discussed have implications for both theory-testing as well as intervention design.

A critical question that must be asked, is whether there is a common set of principles of health behavior change that transcend individual health behaviors. This is an area where much data already exists, as health behavior theories have been tested across numerous health behaviors.The integration of findings from studies across diverse behavioral areas, is not what it could be. Godin and Kok (1996) reviewed studies of the TPB applied to numerous health-related behaviors. Across seven categories of health behaviors, they found TPB components to offer similar prediction of intention but inconsistent prediction of behavior.They concluded that the nature of differing health behaviors may require additional constructs to be added to the TPB, such as actual (versus perceived) behavioral control. Prochaska et al. (1994) examined decisional balance across stages of change for 12 health-related behaviors. Similar patterns were found across nearly all of these health behaviors, with the “pros” of changing generally increasing across the stages, the “cons” decreasing, and a pro/con crossover occurring in the contemplation or preparation stages of change. Prochaska et al. (1994) concluded that clear commonalties exist across these differing health behaviors which were examined in differing samples. Finally, Rosen (2000) examined change processes from the TTM across six behavioral categories, examining whether the trajectory of change processes is similar or different across stages of change in those health areas. He found that for smoking cessation, cognitive change processes were used more in earlier stages of change than behavioral processes, while for physical activity and dietary change, both categories of change processes increased together.

A second approach is the following: Rather than applying theoretical concepts to specific behaviors, such concepts might be applied at the general or global level. A general orientation toward health may not lead directly to specific health behaviors, but it may increase the chances of particular health-related attitudes, which may in turn lead to specific health behaviors. In fact, although Ajzen and Timko (1986) found general health attitudes to be poor predictors of behavior, such attitudes were significantly related to specific health attitudes and perceived behavioral control over specific behaviors. It is likely that when we consider multiple behaviors that we may discover an entire network of health attitudes and beliefs that are interrelated. In fact, studies of single behaviors essentially take those behaviors out of the multi-attitude and multi-behavioral context in which they are embedded. For instance, although attitudes toward walking may be a better predictor of walking behavior than attitudes toward physical activity, walking behavior is part of a larger “physical activity” behavioral category. While predicting that particular behavior may be best served by the specific measure, the larger category is both relevant and of interest. Thus, it may be that there are higher order constructs to be understood here.

A third approach is a multiple behavioral approach, or one which focuses on the linkages among health behaviors. It shares some similarities to the approach just described. Here the focus is more strictly on how particular interventions were superior to comparison groups for 21 of 41 (51%) studies (3 physical activity, 7 diet, 11 weight loss/physical activity and diet). Twenty-four studies had indeterminate results, and in four studies the comparison conditions outperformed eHealth interventions. Conclusions: Published studies of eHealth interventions for physical activity and dietary behavior change are in their infancy. Results indicated mixed ﬁndings related to the effectiveness of eHealth interventions. Interventions that feature interactive technologies need to be reﬁned and more rigorously evaluated to fully determine their potential as tools to facilitate health behavior change.

A prospective evaluation of the Transtheoretical Model of Change applied to exercise in young people

Patrick Callaghan, Elizabeth Khalil, Ioannis Morres
Intl J Nursing Studies 47 (2010) 3–12
http://dx.doi.org:/10.1016/j.ijnurstu.2009.06.013

Objectives:To investigate the utility of the Transtheoretical Model of Change in predicting exercise in young people. Design: A prospective study: assessments were done at baseline and follow-up 6 months later. Method: Using stratiﬁed random sampling 1055 Chinese high school pupils living in Hong Kong, 533 of who were followed up at 6 months, completed measures of stage of change (SCQ), self-efﬁcacy (SEQ), perceptions of the pros and cons of exercising (DBQ) and processes of change (PCQ). Data were analyzed using one-way ANOVA, repeated measures ANOVA and independent sample t tests.
Results:The utility of the TTM to predict exercise in this population is not strong; increases in self-efﬁcacy and decisional balance discriminated between those remaining active at baseline and follow-up, but not in changing from an inactive (e.g.,Precontemplation or Contemplation) to an active state (e.g.,Maintenance) as one would anticipate given the staging algorithm of the TTM.
Conclusion:The TTM is a modest predictor of future stage of change for exercise in young Chinese people. Where there is evidence that TTM variables may shape movement over time, self-efﬁcacy, pros and behavioral processes of change appear to be the strongest predictors

A retrospective study on changes in residents’ physical activities, social interactions, and neighborhood cohesion after moving to a walkable community

Xuemei Zhu,Chia-Yuan Yu, Chanam Lee, Zhipeng Lu, George Mann
Preventive Medicine 69 (2014) S93–S97
http://dx.doi.org/10.1016/j.ypmed.2014.08.013

Objective. This study is to examine changes in residents’ physical activities, social interactions, andneighbor-hood cohesion after they moved to a walkable community in Austin, Texas.
Methods. Retrospective surveys (N=449) were administered in 2013–2014 to collect pre-and post-move data about the outcome variables and relevant personal, social, and physical environmental factors. Walkability of each resident’s pre-move community was measured using the Walk Score. T tests were used to examine the pre–post move differences in the outcomes in the whole sample and across subgroups with different physical activity levels, neighborhood conditions, and neighborhood preferences before the move. Results. After the move, total physical activity increased signiﬁcantly in the whole sample and all subgroups except those who were previously sufﬁciently active; lived in communities with high walkability, social interactions, or neighborhood cohesion; or had moderate preference for walkable neighborhoods. Walking in the community increased in the whole sample and all subgroups except those who were previously sufﬁciently active, moved from high-walkability communities, or had little to no preference for walkable neighborhoods. Social interactions and neighborhood cohesion increased signiﬁcantly after the move in the whole sample and all subgroups.
Conclusion.This study explored potential health beneﬁts of a walkable community in promoting physically and socially active lifestyles, especially for populations at higher risk of obesity. The initial result is promising, suggesting the need for more work to further examine the relationships between health and community design using pre–post assessments.

Application of the transtheoretical model to identify psychological constructs inﬂuencing exercise behavior: A questionnaire survey

Young-Ho Kim
Intl J Nursing Studies 44 (2007) 936–944
http://dx.doi.org:/10.1016/j.ijnurstu.2006.03.008

Background: Current research on exercise behavior has largely been attempted to identify the relationship between psychological attributes and the initiation or adherence of exercise behavior based on psychological theories. A limited data are available on the psychological predictors of exercise behavior in public health. Objectives: The present study examined the theorized association of TTM of behavior change constructs by stage of change for exercise behavior. Methods: A total of 228 college students selected from 2 universities in Seoul were surveyed. Four Korean-version questionnaires were used to identify the stage of exercise behavior and psychological attributes of adolescents. Data were analyzed by frequency analysis, MANOVA, correlation analysis, and discriminant function analysis.
Results: Multivariate F-test indicated that behavioral and cognitive processes of change, exercise efﬁcacy, and pros differentiated participants across the stages of exercise behavior. Furthermore, exercise behavior was signiﬁcantly correlated with the TTM constructs, and that overall classiﬁcation accuracy across the stages of change was 61.0%. Conclusions:The present study supports the internal and external validity of the Transtheoretical Model for explaining exercise behavior. As this study highlights, dissemination must increase awareness but also inﬂuences perceptions regarding theoretically based and practically important exercise strategies for public health professionals.

Does more education lead to better health habits? Evidence from the school reforms in Australia?

Jinhu Li, Nattavudh Powdthavee
Social Science & Medicine 127 (2015) 83-91
http://dx.doi.org/10.1016/j.socscimed.2014.07.021

The current study provides new empirical evidence on the causal effect of education on health-related behaviors by exploiting historical changes in the compulsory schooling laws in Australia. Since World War II, Australian states increased the minimum school leaving age from 14 to 15 in different years. Using differences in the laws regarding minimum school leaving age across different cohorts and across different states as a source of exogenous variation in education, we show that more education improves people’s diets and their tendency to engage in more regular exercise and drinking moderately, but not necessarily their tendency to avoid smoking and to engage in more preventive health checks. The improvements in health behaviors are also reﬂected in the estimated positive effect of education on some health outcomes. Our results are robust to alternative measures of education and different estimation methods.

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The Reconstruction of Life Processes requires both Genomics and Metabolomics to explain Phenotypes and Phylogenetics

Posted in Amino acids, Ca2+ triggered activation, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Curation, Cytoskeleton, De novo synthesis, Developmental biology, Dialectic, Discovery process, Disease Biology, Embryology, Epigenetics and Cardiovascular Risks, Evolutionary cognition, Explanatory, Gene Regulation and Evolution, Genome Biology, Historical relevance, Innovations in Neurophysiology & Neuropsychology, Metabolism, Metabolomics, Mutant Gene Expression, Na-K-ATPase, Nitric Oxide in Health and Disease, Nutrition, Pentose monophosphate shunt, Proteins, Proteomics, RNA Biology, Signaling, Signaling & Cell Circuits, tagged adaptiaton, Evolution, habitats, metabolites, oligomers, oligonucleotides, phenotypes, predators, protein conformation, protein interactions, protein synthesis, respiration, temperature, trrain, water salinity on February 25, 2015| Leave a Comment »

The Reconstruction of Life Processes requires both Genomics and Metabolomics to explain Phenotypes and Phylogenetics

Writer and Curator: Larry H. Bernstein, MD, FCAP

phylogenetics

http://upload.wikimedia.org/wikipedia/commons/thumb/1/12/CollapsedtreeLabels-simplified.svg/200px-CollapsedtreeLabels-simplified.svg.png

This discussion that completes and is an epicrisis (summary and critical evaluation) of the series of discussions that preceded it.

Innervation of Heart and Heart Rate
Action of hormones on the circulation
Allogeneic Transfusion Reactions
Graft-versus Host reaction
Unique problems of perinatal period
High altitude sickness
Deep water adaptation
Heart-Lung-and Kidney
Acute Lung Injury

The concept inherent in this series is that the genetic code is an imprint that is translated into a message. It is much the same as a blueprint, or a darkroom photographic image that has to be converted to a print. It is biologically an innovation of evolutionary nature because it establishes a simple and reproducible standard for the transcription of the message through the transcription of the message using strings of nucleotides (oligonucleotides) that systematically transfer the message through ribonucleotides that communicate in the cytoplasm with the cytoskeleton based endoplasmic reticulum (ER), composing a primary amino acid sequence. This process is a quite simple and convenient method of biological activity. However, the simplicity ends at this step. The metabolic components of the cell are organelles consisting of lipoprotein membranes and a cytosol which have particularly aligned active proteins, as in the inner membrane of the mitochondrion, or as in the liposome or phagosome, or the structure of the ER, each of which is critical for energy transduction and respiration, in particular, for the mitochondria, cellular remodeling or cell death, with respect to the phagosome, and construction of proteins with respect to the ER, and anaerobic glycolysis and the hexose monophosphate shunt in the cytoplasmic domain. All of this refers to structure and function, not to leave out the membrane assigned transport of inorganic, and organic ions (electrolytes and metabolites).

I have identified a specific role of the ER, the organelles, and cellular transactions within and between cells that is orchestrated. But what I have outlined is a somewhat limited and rigid model that does not reach into the dynamics of cellular transactions. The DNA has expression that may be old, no longer used messages, and this is perhaps only part of a significant portion of “dark matter”. There is also nuclear DNA that is enmeshed with protein, mRNA that is a copy of DNA, and mDNA is copied to ribosomal RNA (rRNA). There is also rDNA. The classic model is DNA to RNA to protein. However, there is also noncoding RNA, which plays an important role in regulation of transcription.

This has been discussed in other articles. But the important point is that proteins have secondary structure through disulfide bonds, which is determined by position of sulfur amino acids, and by van der Waal forces, attraction and repulsion. They have tertiary structure, which is critical for 3-D structure. When like subunits associate, or dissimilar oligomers, then you have heterodimers and oligomers. These constructs that have emerged over time interact with metabolites within the cell, and also have an important interaction with the extracellular environment.

When you take this into consideration then a more complete picture emerges. The primitive cell or the multicellular organism lives in an environment that has the following characteristics – air composition, water and salinity, natural habitat, temperature, exposure to radiation, availability of nutrients, and exposure to chemical toxins or to predators. In addition, there is a time dimension that proceeds from embryonic stage to birth in mammals, a rapid growth phase, a tapering, and a decline. The time span is determined by body size, fluidity of adaptation, and environmental factors. This is covered in great detail in this work. The last two pieces are in the writing stage that completes the series. Much content has already be presented in previous articles.

The function of the heart, kidneys and metabolism of stressful conditions have already been extensively covered in http://pharmaceuticalintelligence.com in the following and more:

The Amazing Structure and Adaptive Functioning of the Kidneys: Nitric Oxide – Part I

http://pharmaceuticalintelligence.com/2012/11/26/the-amazing-structure-and-adaptive-functioning-of-the-kidneys/

Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II

http://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-and-inos-have-key-roles-in-kidney-diseases/

The pathological role of IL-18Rα in renal ischemia/reperfusion injury – Nature.com

http://pharmaceuticalintelligence.com/2014/10/24/the-pathological-role-of-il-18r%CE%B1-in-renal-ischemiareperfusion-injury-nature-com/

Summary, Metabolic Pathways

http://pharmaceuticalintelligence.com/2014/10/23/summary-metabolic-pathways/

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Archive for the ‘Innovations in Neurophysiology & Neuropsychology’ Category

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