Archive for the ‘Regenerative Biology and Medicine’ Category

Bzzz! Are fruitflies like us?

Posted in Cell Biology, Signaling & Cell Circuits, Curation, Genome Biology, Metabolomics, Molecular Genetics & Pharmaceutical, Nutrigenomics, Proteomics, Regenerative Biology and Medicine, RNA Biology, Cancer and Therapeutics, Signaling, Translational Research, Translational Science, tagged cell regulation, fruit fly, RNA, Transcriptomics on July 7, 2014| Leave a Comment »

Larry H. Bernstein, MD, FCAP, Curator

http://pharmaceuticalintelligence.com/7/7/2014/Bzzz! Are fruitflies like us?

We are following closely the developments in genomics that have had a progression since the Double-Helix dogma served the Nobel Prize to Watson and Crick, and that achievement led to the completion of a provisional Human Genome at the birth of the 21st century.  Since then there has been exploration of cellular regulation, signaling pathways, and protein-protein as well as protein membrane interactions in eukaryotes.  But we can go further back prior to the double-helix and remind ourselves of the huge contributions that led up to the double helix.  This was a time of great research that set the tone for what is now called molecular biology.  We associate the work with the genetic studies of Thomas Hunt Morgan on the fruit fly.  There may yet be a new chapter that is stradling the gap between DNA, RNA and transcription turning toward a deeper understanding of gene expression and organ specificities.  Is it a new beginning?  There is certainly going to be a deeper understanding of the several roles of RNA as well as proteins.

 

The Gateway Opens

THOMAS HUNT MORGAN AT COLUMBIA UNIVERSITY
Genes, Chromosomes, and the Origins of Modern Biology
Eric R. Kandel, MD
2000 recipent of Nobel Prize in Medicine

University Professor & Kavli Professor of Brain Science,
Co-director, Mind Brain Behavior Initiative
Director, The Kavli Institute for Brain Science
Senior Investigator, Howard Hughes Medical Institute
Columnia University

When future historians turn to examine the major intellectual accomplishments of the twentieth century, they will undoubtedly give a special place to the extraordinary achievements in biology, achievements that have revolutionized our understanding of life’s processes and of disease. Important intimations of what was to happen in biology were already apparent in the second half of the nineteenth century. Darwin had delineated the evolution of animal species, Mendel had discovered some basic rules about inheritance, and Weissman, Roux, Driesch, de Vries, and other embryologists were beginning to decipher how an organism develops from a single cell. What was lacking at the end of the nineteenth century, however, was an overarching sense of how these bold advances were related to one another.

The insight that unified these three fields- heredity, evolution, and development- and set biology on the course toward its current success came only at the beginning of the twentieth century. It derived from the discovery that the gene, localized to specific positions on the chromosome, was at once the unit of Mendelian heredity, the driving force for Darwinian evolution, and the control switch for development. This remarkable discovery can be traced directly to one person and to one institution: Thomas Hunt Morgan and Columbia University. Much as Darwin’s insights into the evolution of animal species first gave coherence to nineteenth-century biology as a descriptive science, Morgan’s findings about genes and their location on chromosomes helped transform biology into an experimental science.

“ aware that abstract thinking, remote from, and even antagonistic to the study of nature, leads easily into dogma, taboos and fettering of free thinking because it does not carry its own corrective, the recourse to factual evidence. The scientist, therefore, with all respect for the many facets of the human mind, is more impressed by the revolutions in thinking brought about by great factual discoveries, which by their very nature lead to generalizations which change at once the outlook of many, if not all, lines of thought.”

. . . . the rise and development of genetics to mature age is another instance of an all-comprising and all-affecting generalization based upon an overwhelming body of integrated facts, . . . [and] will rank in the history of science with such other great events ..”

–Richard B. Goldschmidt, The Impact of Genetics Upon Science (1950)

Even more important, Morgan’s discoveries made it possible to address a series of questions regarding the function and structure of genes. What is their chemical nature? How do genes duplicate themselves? What goes wrong when genes mutate? How do genes provide the basis for understanding genetic disease? How do genes determine the properties of cells, the development of organisms, and the course of evolution?

Thomas Hunt Morgan

 

Morgan

 

Eric Kandel

 

New Study of Fruit Fly Genome Reveals Complexity of RNA and Provides a Model for Studying Mechanisms for Hereditary Diseases in Humans

July 7, 2014

This investigation of the fruit fly’s transcriptome—the complete collection of the genome’s RNA—unearthed thousands of new genes, transcripts, and proteins

Scientists have teased another level of information out of the genome. This time, the new insights were developed from studies of the fruit fly’s transcriptome. This knowledge will give pathologists another channel of information that may be useful in developing assays to support more precise diagnosis and therapeutic decisions.

The findings were published in a recent issue of Nature. The study focused on the transcriptome—a complete collection of the genome’s RNA—of the common fruit fly−Drosophila melangogaster.

Why Studies of the Fruit Fly Are Useful

The fruit fly has been used as a genetics model to study human genetics for more than a 100 years. Not only are they easy to care for and work with, but they share 75% of the same genes as humans. Today, the fruit fly genome has emerged as a critical tool tor understanding human biology and disease, by providing an understanding of genes and life processes that are conserved over extensive evolutionary changes.

The research consortium included 41 researchers from 11 universities and institutes that are members of the National Human Genome Research Institute’s Model Organism Encyclopedia of DNA Elements, called modENCODE for short. This project used state-of-the-art gene sequencing to study all of the expressed RNAs produced by a genome in greater detail than ever before accomplished.

RNA Sequenced in Diverse Tissues at Different Stages of Development

RNA was sequenced at different stages of development, in diverse tissues, in cells growing in culture, and in flies stressed by environmental contaminants, stated a IU press release issued by Indiana University Bloomington (IUB).

The modENCODE study revealed that the fruit fly genome is far more complex than previously suspected. These new findings suggest that this also may be true for the genomes of higher animals. Specifically, the researchers found that:

• a small set of genes in the nervous system is responsible for much of the complexity;
• long regulatory and antisense RNA (asRNA), a single-stranded RNA complementary to a messenger RNA transcribed within a cell, are prominent during gonadal development;
• splicing factors, proteins involved in controlling maturation of RNAs, are themselves spliced in complex ways; and,
• the fruit fly transcriptome undergoes major changes in response toenvironmental stressors.

How Study of Fruit Fly RNA Benefits Human Genome Research

“The modENCODE work is intended to provide a new baseline for research using Drosophila,” declared Peter Cherbas, Ph.D., an IUB Professor Emeritus of Biology and one of 10 IUB researchers who served as co-authors of the study. “The goal is to provide researchers working on particular processes with much of the detailed background information they would otherwise need to collect for themselves.

Click here for photo
Peter Cherbas, Ph.D. (pictured), Professor Emeritus of Biology at Indiana University Bloomington, says that the modENCORE study of the fruit fly’s complete RNA answered a lot of questions about the genome of organisms, but raised even more questions that science will want to answer. (Photo copyright Indiana University Bloomington.)

“As usual in science, we’ve answered a number of questions and raised even more,” observed Cherbas. “For example, we identified 1,468 new genes, of which 536 were found to reside in previously uncharacterized gene-free zones.”

“We think these results could influence gene regulation research in all animals,” added Thom Kaufman, Ph.D., IUB Distinguished Professor of Biology who also co-authored the study. “This exhaustive study also identified a number of phenomena previously reported only in mammals, and that alone is really telling about the versatility of Drosophila melanogaster as a model organism. The new work provides a number of new potential uses for this powerful model system,” he stressed.

Click here for photo
Thom Kaufman, Ph.D. (pictured), Indiana University Bloomington Distinguished Professor of Biology, says that the modENCORE study provides a powerful model for studying gene regulation in all organisms. (Photo copyright Indiana University Bloomington.)

Impact of Environmental Stressors on Gene Expression

Both Kaufman and Cherbas cited perturbation experiments that identified genes and transcripts. The new genes were identified after subjecting adult fruit flies to heat and cold shock, then exposing them to heavy metals, caffeine and the herbicide paraquat. Fruit fly larvae were treated with heavy metals, caffeine, ethanol, or the insecticide rotenone.

These environmental stressors generated small changes in the expression level of thousands of genes. One treatment experiment resulted in four newly modeled genes being expressed altogether differently, noted the researchers. Perturbation experiments, in fact, revealed a total of 5,249 transcript models for 811 genes.

In fact, the findings from these perturbation experiments mirror similar findings made following the 2010 British Petroleum Deepwater Horizon oil spill in the Gulf of Mexico. Researchers studying the impact on marsh fishes found that, similar to the fruit flies, these fish responded to chronic hydrocarbon exposure with a number of expressions beyond the heat shock pathway. These expressions included the down regulation of genes encoding eggshell and yolk proteins.

The response overlap between species indicates that the modENCODE consortium may have identified a conserved metazoan [animal] stress response that enhances metabolism and suppresses genes involved in reproduction.

What This Means for Pathologists and Laboratory Professionals

This study is significant for pathologists and medical laboratory professionals because it peels away another layer of information encoded in DNA and RNA. The findings of this study also show how genomic knowledge is moving to the next level in the quest to understand the origins of disease.
—by Patricia Kirk

 

Study of complete RNA collection of fruit fly uncovers unprecedented complexity

IU plays key role in consortium; 1,468 new genes discovered March 17, 2014  

BLOOMINGTON, Ind. — Scientists from Indiana University are part of a consortium that has described the transcriptome of the fruit fly Drosophila melanogaster in unprecedented detail, identifying thousands of new genes, transcripts and proteins.

In the new work, published Sunday in the journal Nature, scientists studied the transcriptome — the complete collection of RNAs produced by a genome — at different stages of development, in diverse tissues, in cells growing in culture, and in flies stressed by environmental contaminants. To do so, they used contemporary sequencing technology to sequence all of the expressed RNAs in greater detail than ever before possible.

The paper shows that the Drosophila genome is far more complex than previously suspected and suggests that the same will be true of the genomes of other higher organisms. The paper also reports a number of novel, particular results: that a small set of genes used in the nervous system are responsible for a disproportionate level of complexity; that long regulatory and so-called “antisense” RNAs are especially prominent during gonadal development; that “splicing factors” (proteins that control the maturation of RNAs by splicing) are themselves spliced in complex ways; and that the Drosophila transcriptome undergoes large and interesting changes in response to environmental stresses.

The importance of Drosophila melanogaster as a model system cannot be overstated. Using it, the mechanisms of heredity were worked out about 100 years ago. Today, as biologists have developed increasing appreciation of how well genes and critical life processes are conserved over long evolutionary distances, flies have emerged as critical tools for understanding human biology and disease. Drosophila research is an area that has long had associations with IU, beginning with Nobel Laureate Herman J. Muller.

IU has 10 co-authors on the paper from the IU Bloomington College of Arts and Sciences’ Department of Biology and the university’s Center for Genomics and Bioinformatics. They are included among the 41 co-authors from 11 universities and institutes that are members of the National Human Genome Research Institute’s Model Organism Encyclopedia of DNA Elements project, or modENCODE. Among the IU co-authors are Professor Emeritus of Biology Peter Cherbas, who helped manage the expansive project, and Distinguished Professor of Biology Thom Kaufman, who helped oversee design of the project and the production of biological samples.

“The modENCODE work is intended to provide a new baseline for research using Drosophila,” Cherbas said. “The goal is to provide researchers working on particular processes with much of the detailed background information they would otherwise need to collect for themselves.

“As usual in science, we’ve answered a number of questions and raised even more. For example, we identified 1,468 new genes, of which 536 were found to reside in previously uncharacterized gene-free zones.”

“We think these results could influence gene regulation research in all animals,” Kaufman said. “This exhaustive study also identified a number of phenomena previously reported only in mammals, and that alone is really telling about the versatility of Drosophila melanogaster as a model organism. The new work provides a number of new potential uses for this powerful model system.”

An example they pointed to was the perturbation experiments that identified new genes and transcripts. New genes were identified in experiments where adults were challenged with heat shock, cold shock, exposure to heavy metals, the drug caffeine and the herbicide paraquat, while larvae were treated with heavy metals, caffeine, ethanol or the insecticide rotenone.

Those environmental stresses resulted in small changes in expression level at thousands of genes; and in one treatment, four newly modeled genes were expressed altogether differently. In total, 5,249 transcript models for 811 genes were revealed only under perturbed conditions.

As did the flies in this new research, scientists who studied the Deepwater Horizon incident in the Gulf of Mexico found that marsh fishes responding to chronic hydrocarbon exposure had a number of expressional responses beyond the heat shock pathway, including the down regulation of genes encoding eggshell and yolk proteins as did the flies. To see this response overlap across phyla means the consortium may have identified a conserved metazoan stress response involving enhanced metabolism and the suppression of genes involved in reproduction.

Indiana University co-authors with Cherbas and Kaufman were co-first author Robert Eisman, Justen Andrews, Lucy Cherbas, Brian D. Eads, David Miller, Keithanne Mockaitis, Johnny Roberts and Dayu Zhang. All were associated with the Department of Biology and/or the Center for Genomics and Bioinformatics.

“Diversity and dynamics of the Drosophila transcriptome,” published March 16 in the journal Nature, also included 31 other co-authors whose affiliations were with the University of California, Berkeley; Lawrence Berkeley National Laboratory; University of Connecticut Health Center; Cold Spring Harbor Laboratory; Sloan-Kettering Institute; National Institute of Diabetes and Digestive and Kidney Diseases; RIKEN Yokohama Institute (Japan); Harvard Medical School; and Howard Hughes Medical Institute.

Antisense RNA

From Wikipedia, the free encyclopedia

Antisense RNA (asRNA) is a single-stranded RNA that is complementary to a messenger RNA (mRNA) strand transcribed within a cell. Some authors have used the term micRNA (mRNA-interfering complementary RNA) to refer to these RNAs but it is not widely used.^[1]

Antisense RNA may be introduced into a cell to inhibit translation of a complementary mRNA by base pairing to it and physically obstructing the translation machinery.^[2] [3] This effect is therefore stoichiometric. An example of naturally occurring mRNA antisense mechanism is the hok/sok system of the E. coli R1 plasmid. Antisense RNA has long been thought of as a promising technique for disease therapy; the only such case to have reached the market is the drug fomivirsen. One commentator has characterized antisense RNA as one of “dozens of technologies that are gorgeous in concept, but exasperating in [commercialization]”.^[4] Generally, antisense RNA still lack effective design, biological activity, and efficient route of administration.^[5]

Historically, the effects of antisense RNA have often been confused with the effects of RNA interference (RNAi), a related process in which double-stranded RNA fragments called small interfering RNAs trigger catalytically mediated gene silencing, most typically by targeting the RNA-induced silencing complex (RISC) to bind to and degrade the mRNA. Attempts to genetically engineer transgenic plants to express antisense RNA instead activate the RNAi pathway, although the processes result in differing magnitudes of the same downstream effect; gene silencing. Well-known examples include the Flavr Savr tomato and two cultivars of ringspot-resistant papaya.^[6][7]

Transcription of longer cis-antisense transcripts is a common phenomenon in the mammalian transcriptome.^[8] Although the function of some cases have been described, such as the Zeb2/Sip1 antisense RNA, no general function has been elucidated. In the case of Zeb2/Sip1,^[9] the antisense noncoding RNA is opposite the 5′ splice site of an intron in the 5’UTR of the Zeb2 mRNA. Expression of the antisense ncRNA prevents splicing of an intron that contains a ribosome entry site necessary for efficient expression of the Zeb2 protein. Transcription of long antisense ncRNAs is often concordant with the associated protein-coding gene,^[10] but more detailed studies have revealed that the relative expression patterns of the mRNA and antisense ncRNA are complex.^[11][12]

 

 

Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase

 

Structure of the N-terminal domain of the yeast Hsp90 chaperone

 

 

Pincer movement of Hsp90 coupled to the ATPase cycle. NTD = N-terminal domain, MD = middle domain, CTD = C-terminal domain.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Cancer Labs at School of Medicine @ Technion: Janet and David Polak Cancer and Vascular Biology Research Center

Posted in Academic Publishing, Autologous Cell Therapy, Bio Instrumentation in Experimental Life Sciences Research, BioBanking, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiac muscle regeneration, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Circulating Progenitor Cells, Computational Biology/Systems and Bioinformatics, Cytoskeleton, Diagnostic Immunology, Drug Delivery Platform Technology, Drug Toxicity, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Immunodiagnostics, Innovation in Immunology Diagnostics, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, Interviews with Scientific Leaders, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical R&D Investment, Pharmacogenomics, Pharmacologic toxicities, Population Health Management, Genetics & Pharmaceutical, Proteomics, Regenerative Biology and Medicine, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Scientist: Career considerations, Signaling, Stem Cells for Regenerative Medicine, Technology Transfer: Biotech and Pharmaceutical, Translational Science, Ubiquitinylation on May 28, 2014| Leave a Comment »

Cancer Labs at School of Medicine @ Technion

Reporter: Aviva Lev-Ari, PhD, RN

Article ID #139: Cancer Labs at School of Medicine @ Technion: Janet and David Polak Cancer and Vascular Biology Research Center. Published on 5/28/2014

WordCloud Image Produced by Adam Tubman

Janet and David Polak Cancer and Vascular Biology Research Center. The Rappaport Faculty of Medicine Research Institute and Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel

The center was established in 2003 to promote an in-depth interdisciplinary basic and clinical research on the control of cellular and molecular processes that are involved in cancer initiation and progression. We strongly believe that the understanding of basic biological processes that underlie normal development and their deregulation in cancer, is crucial for our ability to identify molecular targets for early detection, intervention, and cure of the disease. We are interested in a broad view of cancer – from the single malignantly transformed cell and its microenvironment, through the entire tumor in the animal. We focus on targeted ubiquitin-mediated degradation of key regulatory proteins that are involved in malignant transformation [Prof. Aaron Ciechanover (Nobel Prize in Chemistry 2004)], angiogenesis and cancer progression (Prof. Gera Neufeld), metastasis and tumor microenvironment (Prof. Israel Vlodavsky), as well as genetic and genomic dissection of embryonic and cancer transcriptional networks (Dr. Amir Orian). Towards these objectives, we combine molecular, biochemical, cell biological with Drosophila genetic and genomics experimental approaches, as well as employing advanced models of angiogenesis and metastasis.

We believe that scientific excellence and collegiality go together. Therefore, the center has an open and friendly atmosphere, creating a highly stimulating environment. The center is located in the 11th Floor of the Rappaport Faculty of Medicine building. It currently trains 45 graduate students, post-doctoral fellows, clinicians and researchers that are at the heart of our research. Formal and informal collaborations between individuals and laboratories are on-going and encouraged. We are running a series of joint seminars to which we invite researchers from Israel and abroad. The Center has advanced state-of-the-art microscopic and image analysis equipment, as well as other shared pieces of infrastructural equipment . The center is an integral part of the Faculty of Medicine and the Rappaport Research Institute which are home for excellent research groups, and enjoys their advanced Interdepartmental Equipment Unit. It is also adjacent to the Rambam Medical Center – the major hospital in the north of Israel – which provides us with access to rich clinical material and collaboration with clinicians. Many of them spend active research periods in our laboratories and bring the bench closer to the patient bed and vice versa. The Center is in an active phase of growth, and offers excellent research opportunities, space and facilities for students, post-doctoral fellows, and physicians.

Research Groups The Ubiquitin System and Cellular Protein Turnover and Interactions Immunity and Host Defense Cardiovascular Biology The Central Nervous System in Health and Disease Developmental Biology and Cancer Research Genetics

SOURCE 

http://www.rappaport.org.il/Rappaport/Templates/ShowPage.asp?DBID=1&TMID=842&FID=76

The cancer and vascular biology research center was established in 2003 to promote an in-depth interdisciplinary basic and clinical research on the control of cellular and molecular processes that are involved in cancer development and progression. Our goal is to advance knowledge in fundamental biological questions that are highly relevant for cancer.

	The cancer and vascular biology research center was established in 2003 to promote an in-depth interdisciplinary basic and clinical research on the control of cellular and molecular processes that are involved in cancer development and progression. Our goal is to advance knowledge in fundamental biological questions that are highly relevant for cancer.

SOURCE

http://www.technioncancer.co.il/index.php

Home  >>  Research Groups

Aaron Ciechanover Protein Turnover Intracellular protein degradation and mechanisms of cancer Israel Vlodavsky Cancer Biology Impact of heparanase and the tumor microenvironment on cancer progression: Basic aspects and clinical implications Gera Neufeld Tumor Progression & Angiogenesis Blood vessels and tumor progression: The neuropilin connection Amir Orian Genetic Networks Genetic networks in development and cancer

Home About the Cancer Centers Research Groups Administration / Contact Join – Us Seminars and Events Links Beyond Science Friends and supporters Ms. Sigal Alfasi – Izrael, Center’s coordinator e-mail: gsigal@tx.technion.ac.il Tel: +972-4-829-5424 Fax: +972-4-852-3947

SOURCE

http://www.technioncancer.co.il/ResearchGroups.php

Yuval Shaked, PhD

Publications by Yuval Shaked, PhD

Assistant Professor of Molecular Pharmacology

PhD, 2004 – Hebrew University, Israel

Understanding host – tumor interactions during cancer therapy

Personalized medicine holds promise of better cures with fewer side effects for many diseases. Individualized cancer therapy is sometimes utilized after multiple attempts of standard therapies and is based on several considerations, such as tumor type, acquired resistance to a specific therapy, previous treatment protocols, and other tumor-related factors. We have recently demonstrated that many cancer therapies can induce pro-tumorigenic or metastatic effects that derive not only from the tumor cells themselves, but also from host cells within the tumor microenvironment. The focus of research in my laboratory is to identify, characterize, and seek ways to block such pro-tumorigenic host effects observed after anti-cancer therapy, and thus potentially improve the outcome of current cancer therapies. Our findings may foster a paradigm shift in cancer therapy by minimizing the gap between preclinical findings and the clinical setting, laying the foundation for development of entirely new strategies for improving cancer therapy.

SOURCE

http://www.rappaport.org.il/Rappaport/Templates/ShowPage.asp?DBID=1&TMID=610&FID=77&PID=0&IID=1268

 

Other Related articled published on this Open Access Online Scientific Journal included the following:

D&D NT’s Solution: Galectin Proteins for Therapy and Diagnosis of Autoimmune Inflammatory and Cancer Diseases, Dr. Itshak Golan, CEO

http://pharmaceuticalintelligence.com/2014/05/28/dd-nts-solution-galectin-proteins-for-therapy-and-diagnosis-of-autoimmune-inflammatory-and-cancer-diseases-dr-itshak-golan-ceo/

MaimoniDex RA:  Monoclonal Antibodies for Therapy and Diagnosis of Cancer and Autoimmune Inflammatory Diseases – Dr. Itshak Golan, CEO

http://pharmaceuticalintelligence.com/2014/05/28/maimonidex-ra-monoclonal-antibodies-for-therapy-and-diagnosis-of-cancer-and-autoimmune-inflammatory-diseases-dr-itshak-golan-ceo/

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Epilogue: Volume 4 – Translational, Post-Translational and Regenerative Medicine in Cardiology

Posted in Acute Myocardial Infarction, Bone marrow derived cells, Cardiac & Vascular Repair Tools Subsegment, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, Curation, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Experimental validation, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Hematopoiesis, Mechanical Assist Devices: LVAD, RVAD, BiVAD, Artificial Heart, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, PCI, Regenerative Biology and Medicine, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stents & Tools, tagged ACS, AMI, Atrial fibrillation, cell regulatory processes, miRNA, myocardial remodelling, myocardial repair, NT-proBNP risk ratio, Omega 3 index, stem cells, ventricullar tachyarrhythmia on May 12, 2014| Leave a Comment »

Epilogue: Volume 4 – Translational, Post-Translational and Regenerative Medicine in Cardiology

• Larry H Bernstein, MD, FCAP, Author and Curator, Volume Four, Co-Editor
• Justin Pearlman, MD, PhD, FACC, Content Consultant for Series A: Cardiovascular Diseases
• Aviva Lev-Ari, PhD, RN, Co-Editor of Volume Four and Editor-in-Chief, BioMed e-Series

 

This completes Chapter 4 in two parts on the most dynamic developments in the regulatory pathways guiding cardiovascular dynamics and function in health and disease.  I have covered key features of these in two summaries, so I shall try to look further into important expected future directions and their anticipated implications.

1. Mechanisms of Disease

Signal Transduction: Akt Phosphorylates HK-II at Thr-473 and Increases Mitochondrial HK-II Association to Protect Cardiomyocytes

David J. Roberts, Valerie P. Tan-Sah, Jeffery M. Smith and Shigeki Miyamoto
J. Biol. Chem. 2013, 288:23798-23806.  http://dx.doi.org/ 10.1074/jbc.M113.482026

Backgound: Hexokinase II binds to mitochondria and promotes cell survival.
Results: Akt phosphorylates HK-II but not the threonine 473 mutant. The phosphomimetic T473D mutant decreases its dissociation from mitochondria induced by G-6P and increases cell viability against stress.
Conclusion: Akt phosphorylates HK-II at Thr-473, resulting in increased mitochondrial HK-II and cell protection.
Significance: The Akt-HK-II signaling nexus is important in cell survival.

HK-II Phosphorylation

 

 

 

 

 

 

It has been demonstrated that an increased level of HK-II at mitochondria is protective and is increased by protective interventions but decreased under stress.

It   has not  been fully determined   which  molecular  signals  regulate  the    level    of  HK-II at mitochondria.

Thr-473 in HK-II  is phosphorylated by Akt and this phosphorylation  leads to  increases  in  mitochondrial  HK-II binding  through inhibition  of  G-6P-dependent  dissociation, conferring resistance to oxidative stress  (Fig.     7).

Overexpression of  WTHK-II increases mitochondrial HK-II and confers protection against  hydrogen peroxide,  which  is enhanced significantly  in   HK-II   T473D-expressing  cells, whereas  NHK-II, lacking the ability to bind to mitochondria, does not confer protection.   Conversely,  mitochondrial  HK-II from mitochondria (Fig.6, A and B) inhibits  the  IGF-1-mediated increase in mitochondrial HK-II and cellular protection.   Similar   dose-dependent  curves were obtained in mitochondrial   HK-II     against stress    (15–25).

Gene Expression and Genetic Variation in Human Atria

Honghuang Lin PhD, Elena V. Dolmatova MD, Michael P. Morley, PhD, Kathryn L. Lunetta PhD, David D. McManus MD, ScM, et al.
Heart Rhythm  2013   http://dx.doi.org/10.1016/j.hrthm.2013.10.051

Background— The human left and right atria have different susceptibilities to develop atrialfibrillation (AF). However, the molecular events related to structural and functional changes that
enhance AF susceptibility are still poorly understood.
Objective— To characterize gene expression and genetic variation in human atria.
Results— We found that 109 genes were differentially expressed between left and right atrial tissues. A total of 187 and 259 significant cis-associations between transcript levels and genetic
variants were identified in left and right atrial tissues, respectively. We also found that a SNP at a known AF locus, rs3740293, was associated with the expression of MYOZ1 in both left and right
atrial tissues.
Conclusion— We found a distinct transcriptional profile between the right and left atrium, and extensive cis-associations between atrial transcripts and common genetic variants. Our results
implicate MYOZ1 as the causative gene at the chromosome 10q22 locus for AF.

Long-Term Caspase Inhibition Ameliorates Apoptosis, Reduces Myocardial Troponin-I Cleavage, Protects Left Ventricular Function, and Attenuates Remodeling in Rats With Myocardial Infarction

Y. Chandrashekhar,  Soma Sen, Ruth Anway,  Allan Shuros,  Inder Anand,

J Am Col  Cardiol  2004; 43(2)   http://dx.doi.org/10.1016/j.jacc.2003.09.026

This study was designed to evaluate whether in vivo caspase inhibition can prevent myocardial contractile protein degradation, improve myocardial function, and attenuate ventricular remodeling.
Apoptosis is thought to play an important role in the development and progression of heart failure (HF) after a myocardial infarction (MI). However, it is not known whether inhibiting apoptosis can attenuate left ventricular (LV) remodeling and minimize systolic dysfunction.

A 28-day infusion of caspase inhibitor was administeredimmediately after an anterior MI. In addition, five sham-operated rats given the caspase inhibitor were compared with 17 untreated sham-operated animals to study effects in non-MI rats. Left ventricular function, remodeling parameters, and hemodynamics were studied four weeks later. Myocardial caspase 3 activation and troponin-I contractile protein cleavage were studied in the non-infarct, remote LV myocardium using Western blots. Apoptosis was assessed using immunohistochemistry for activated caspase-positive cells as well as the TUNEL method. Collagen volume was estimated using morphometry.

Caspase inhibition reduced myocardial caspase 3 activation. This was accompanied by less cleavage of troponin-I, an important component of the cardiac contractile apparatus, and fewer apoptotic cardiomyocytes. Furthermore, caspase inhibition reduced LV-weight-to- body-weight ratio, decreased myocardial interstitial collagen deposition, attenuated LV remodeling, and better preserved LV systolic function after MI.

Caspase inhibition, started soon after MI and continued for four weeks, preserves myocardial contractile proteins, reduces systolic dysfunction, and attenuates ventricular remodeling.

These findings may have important therapeutic implications in post-MI HF. J Am Col Cardiol 2004;43:295–301)

Precardiac deletion of Numb and Numblike reveals renewal of cardiac progenitors

Lincoln T Shenje,  Peter P Rainer , Gun-sik Cho , Dong-ik Lee , Weimin Zhong , Richard P Harvey , David A Kass , Chulan Kwon *,  et al.
eLife 2014.    http://dx.doi.org/10.7554/eLife.02164.001

Cardiac progenitor cells (CPCs) must control their number and fate to sustain the rapid heart growth during development, yet the intrinsic factors and environment governing these processes remain unclear. Here, we show that deletion of the ancient cell-fate regulator Numb (Nb) and its homologue Numblike (Nbl) depletes CPCs in second pharyngeal arches (PA2s) and is associated with an atrophic heart. With histological, fow cytometric and functional analyses, we fnd that CPCs remain undifferentiated and expansive in the PA2, but differentiate into cardiac cells as they exit the arch. Tracing of Nb- and Nbl-defcient CPCs by lineage-specifc mosaicism reveals that the CPCs normally populate in the PA2, but lose their expansion potential in the PA2. These fndings demonstrate that Nb and Nbl are intrinsic factors crucial for the renewal of CPCs in the PA2 and
that the PA2 serves as a microenvironment for their expansion.

2. Diagnostics and Risk Assessment

Classical and Novel Biomarkers for Cardiovascular Risk Prediction in the United States

Aaron R. Folsom
J Epidemiol 2013;23(3):158-162   http://dx.doi.org/10.2188/jea.JE20120157

Cardiovascular risk prediction models based on classical risk factors identified in epidemiologic cohort studies are useful in primary prevention of cardiovascular disease in individuals. This article briefly reviews aspects of
cardiovascular risk prediction in the United States and efforts to evaluate novel risk factors. Even though many novel risk markers have been found to be associated with cardiovascular disease, few appear to improve risk prediction
beyond the powerful, classical risk factors. A recent US consensus panel concluded that clinical measurement of certain novel markers for risk prediction was reasonable, namely,

1. hemoglobin A1c (in all adults),
2. microalbuminuria (in patients with hypertension or diabetes), and
3. C-reactive protein,
4. lipoprotein-associated phospholipase,
5. coronary calcium,
6. carotid intima-media thickness, and
7. ankle/brachial index (in patients deemed to be at intermediate cardiovascular risk, based on traditional risk factors).

Diagnostic accuracy of NT-proBNP ratio (BNP-R) for early diagnosis of tachycardia-mediated cardiomyopathy: a pilot study

Amir M. Nia, Natig Gassanov, Kristina M. Dahlem, Evren Caglayan, Martin Hellmich, et al.
Clin Res Cardiol (2011) 100:887–896    http://dx.doi.org/10.1007/s00392-011-0319-y

Tachycardia-mediated cardiomyopathy (TMC) occurs as a consequence of prolonged high heart rate due to ventricular and supraventricular tachycardia. In animal models, rapid pacing induces severe biventricular remodeling with dilation and dysfunction [7]. On a cellular basis, cardiomyocytes exert fundamental morphological and functional roles.

When heart failure and tachycardia occur simultaneously, a useful diagnostic tool for early discrimination of patients with benign tachycardia-mediated  cardiomyopathy (TMC) versus major structural heart disease  (MSHD) is not available. Such a tool is required to prevent unnecessary and wearing diagnostics in patients with reversible TMC. Moreover, it could lead to early additional diagnostics and therapeutic approaches in patients with  MSHD.

A total of 387 consecutive patients with supraventricular arrhythmia underwent assessment.  Of these patients, 40 fulfilled the inclusion criteria
with a resting heart rate C100 bpm and an impaired left ventricular ejection fraction \40%. In all patients, successful electrical cardioversion was performed. At baseline, day 1 and weekly for 4 weeks, levels of NT-proBNP and echocardiographic parameters were evaluated.

NT-proBNP ratio (BNP-R) was calculated as a quotient of baseline NT-proBNP/follow-up NT-proBNP. After 4 weeks, cardiac catheterization was performed to identify patients with a final diagnosis of TMC versus MSHD.

Initial NT-proBNP concentrations were elevated and consecutively decreased after cardioversion in all patients studied. The area under the ROC curve for BNP-R to detect TMC was 0.90 (95% CI 0.79–1.00; p \ 0.001) after 1 week  and 0.995 (95% CI 0.99–1.00; p \ 0.0001) after 4 weeks. One week after cardioversion already, a BNP-R cutoff C2.3 was useful for TMC diagnosis indicated by an accuracy of 90%, sensitivity of 84% and specificity of 95%.

BNP-R was found to be highly accurate for the early diagnosis of TMC.

Omega-3 Index and Cardiovascular Health

Clemens von Schacky
Nutrients 2014; 6: 799-814;  http://dx. doi.org/10.3390/nu602099

Fish, marine oils, and their concentrates all serve as sources of the two marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as do some products from algae.
To demonstrate an effect of EPA + DHA on heart health, a number of randomized, controlled intervention studies with clinical endpoints like overall mortality or a combination of adverse cardiac events were conducted in populations with elevated cardiovascular risk. One early intervention study with oily fish, rich in EPA + DHA, and some early studies with fish oil or fish oil concentrate or even purified EPA at doses ranging between 0.9 and 1.8 g/day indeed demonstrated effects in terms of fewer sudden cardiac deaths, fatal or non-fatal myocardial infarctions, or a combination of adverse cardiac events.

Recent meta-analyses found no significant benefits on total mortality, cardiovascular mortality, and other adverse cardiac or cardiovascular events [13–18]. This is in contrast to findings in epidemiologic studies, where intake of EPA + DHA had been found to correlate generally with an up to 50% lower incidence of adverse cardiac events [18,19], and in even sharper contrast to epidemiologic studies based on levels of EPA + DHA, demonstrating e.g., a 10-fold lower incidence of sudden cardiac death associated with high levels of the
fatty acids, as compared to low levels.

This seemingly contradictory evidence has led the American Heart Association to recommend “omega-3 fatty acids from fish or fish oil capsules (1 g/day) for cardiovascular disease risk reduction” for secondary prevention, whereas the European Society for Cardiology recommends “Fish at least twice a week, one of which to be oily fish”, but no supplements for cardiovascular prevention.

A similar picture emerges for atrial fibrillation: In epidemiologic studies, consumption of EPA + DHA or higher levels of EPA + DHA were associated with lower risk for developing atrial fibrillation, while intervention studies found no effect. Pertinent guidelines do not mention EPA + DHA. A similar picture also emerges for severe ventricular rhythm disturbances.

Why is it that trial results are at odds with results from epidemiology? What needs to be done to better translate the epidemiologic findings into trial results? The current review will try to shed some light on this  issue, with a special consideration of the Omega-3 Index.

Recent large trials with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the cardiovascular field did not demonstrate a beneficial effect in terms of reductions of clinical endpoints like

• total mortality,
• sudden cardiac arrest or
• other major adverse cardiac events.

Pertinent guidelines do not uniformly recommend EPA + DHA for cardiac patients. In contrast,

• in epidemiologic findings, higher blood levels of EPA + DHA were consistently associated with a lower risk for the endpoints mentioned.

The following points argue for the use of erythrocytes: erythrocyte fatty acid
composition has a low biological variability, erythrocyte fat consists almost exclusively of phospholipids, erythrocyte fatty acid composition reflects tissue fatty acid composition, pre-analytical stability, and other points.  In 2004, EPA + DHA in erythrocyte fatty acids were defined as the Omega-3 Index and suggested as a risk factor for sudden cardiac death [39]. Integral to the definition was a specific and standardized analytical procedure, conforming the quality management routinely implemented in the field of clinical chemistry.

The laboratories adhering to the HS-Omega-3 Index methodology perform regular proficiency testing, as mandated in routine Clinical Chemistry labs. So far, the HS-Omega-3 Index is the only analytical procedure used in several laboratories. A standardized analytical procedure is a prerequisite to generate the data base necessary to transport a laboratory parameter from research into clinical routine. Moreover, standardization of the analytical procedure is the first important criterion for establishing a new biomarker for cardiovascular risk set forth by the American Heart Association and the US Preventive Services Task Force.

Because of low biological and analytical variability, a standardized analytical procedure, a large database and for other reasons,

• blood levels of EPA + DHA are frequently assessed in erythrocytes, using the HS-Omega-3 Index methodology.

Table 1. Mean HS-Omega-3 Index values in various populations, Mean (±standard deviation (SD)). Please note that in every population studied, a lower value was found to be associated with a worse condition than a higher value. References are given, if not, unpublished, n = number of individuals measured.

All levels of fatty acids are determined by the balance of substance entering the body and those leaving the body. Neither a recent meal, even if rich in EPA + DHA, nor severe cardiac events altered the HS-Omega-3 Index. However, while long-term intake of EPA + DHA, e.g., as assessed with food questionnaires, was the main predictor of the HS-Omega-3 Index, long-term intake explained only 12%–25% of its variability. A hereditary component of 24% exists. A number of other factors correlated positively (+) or negatively (−), like age (+), body mass index (−), socioeconomic status (+), smoking (−), but no other conventional cardiac risk factors. More factors determining the level of the HS-Omega-3 Index, especially regarding efflux remain to be  defined. Therefore, it is impossible to predict the HS-Omega-3 Index in an individual, as it is impossible to predict the increase in the HS-Omega-3 Index in an individual in response to a given dose of EPA + DHA. In Table 2, current evidence is presented on the relation of the HS-Omega-3 Index to CV events.

The HS-Omega-3 Index has made it possible to reclassify individuals from intermediate cardiovascular risk into the respective high risk and low risk strata, the third criterion for establishing a new biomarker for CV  risk.

A low Omega-3 Index fulfills the current criteria for a novel cardiovascular risk factor.

Increasing the HS-Omega-3 Index by increased intake of EPA + DHA in randomized controlled trials improved a number of surrogate parameters for cardiovascular risk:

1. heart rate was reduced,
2. heart rate variability was increased,
3. blood pressure was reduced,
4. platelet reactivity was reduced,
5. triglycerides were reduced,
6. large buoyant low-density lipoprotein (LDL)-particles were increased and
7. small dense LDL-particles were reduced,
8. large buoyant high-density lipoproteins (HDL)2 were increased,
9. very low-density lipoprotein (VLDL1) + 2 was reduced,
10. pro-inflammatory cytokines (e.g., tumor necrosis factor alpha, interleukin-1β, interleukins-6,8,10 and monocyte chemoattractant protein-1) were reduced,
11. anti-inflammatory oxylipins were increased.

Importantly, in a two-year randomized double-blind angiographic intervention trial, increased erythrocyte EPA + DHA

• reduced progression and increased regression of coronary lesions, an intermediate parameter.

Taken together, increasing the HS-Omega-3 Index improved surrogate and intermediate parameters for cardiovascular events. A large intervention trial with clinical endpoints based on the HS-Omega-3 Index remains to be conducted. Therefore, the fourth criterion, proof of therapeutic consequence of determining the HS-Omega- Index, is only partially fulfilled.

 

Neutral results of intervention trials can be explained by issues of bioavailability and trial design that surfaced after the trials were initiated.

In the future, incorporating the Omega-3 Index into trial designs by

1. recruiting participants with a low Omega-3 Index and
2. treating them within a pre-specified target range (e.g., 8%–11%),
3. will make more efficient trials possible and
   • provide clearer answers to the questions asked than previously possible.

 

3. Stem Cells and Regenerative Biology

Adult Stem Cells Reverse Muscle Atrophy In Elderly Mice   http://www.science20.com/profile/news_staff

Bioengineers at the University of California, Berkeley in a new study published in Nature say they have identified two key regulatory pathways that control how well adult stem cells repair and replace damaged tissue. They then tweaked how those stem cells reacted to those biochemical signals to revive the ability of muscle tissue in old mice to repair itself nearly as well as the muscle in the mice’s much younger counterparts. Irina Conboy, an assistant professor of bioengineering and an investigator at the Berkeley Stem Cell Center and at the California Institute for Quantitative Biosciences (QB3), led the research team conducting this study. Because the findings relate to adult stem cells that reside in existing tissue, this approach to rejuvenating degenerating muscle eliminates the ethical and medical complications associated with transplanting tissues grown from embryonic stem cells. The researchers focused on

• the interplay of two competing molecular pathways that control the stem cells,

which sit next to the mature, differentiated cells that make up our working body parts. When the mature cells are damaged or wear out, the stem cells are called into action to begin the process of rebuilding.

old muscle tissue is left with

 

 

 

 

 

 

 

 

 

 

 

 

“We don’t realize it, but as we grow our bodies are constantly being remodeled,” said Conboy. “We are constantly falling apart, but we don’t notice it much when we’re young because we’re always being restored. As we age, our stem cells are prevented, through chemical signals, from doing their jobs.” The good news, the researchers said, is that

• the stem cells in old tissue are still ready and able to perform their regenerative function
• if they receive the appropriate chemical signals.

Studies have shown that when old tissue is placed in an environment of young blood, the stem cells behave as if they are young again. “Conversely, we have found in a study published last year that even young stem cells rapidly age when placed among blood and tissue from old mice,” said Carlson, who will stay on at UC Berkeley to expand his work on stem cell engineering.

• Adult stem cells have a receptor called Notch that, when activated,
• tells them that it is time to grow and divide
• stem cells also have a receptor for the protein TGF-beta
• that sets off a chain reaction activatingthemoleculepSmad3 and
  • ultimately producing cyclin-dependent kinase (CDK) inhibitors, which regulate the cell’s ability to divide.
• activated Notch competeswithactivatedpSmad3 for
  • binding to the regulatory regions of the same CDK inhibitors in the stem cell

“We found that Notch is capable of physically kicking off pSmad3 from the promoters for the CDK inhibitors within the stem cell’s nucleus, which tells us that a precise manipulation of the balance of these pathways would allow the ability to control stem cell responses.” Notch and TGF-beta are well known in molecular biology, but Conboy’s lab is the first to connect them to the process of aging, and the first to show that they act in opposition to each other within the nucleus of the adult stem cell. Aging and the inevitable march towards death are, in part, due to the progressive decline of Notch and the increased levels of TGF-beta , producing a one-two punch to the stem cell’s capacity to effectively rebuild the body, the researchers said.

The researchers disabled the “aging pathway” that tells stem cells to stop dividing by using an established method of RNA interference that reduced levels of pSmad3. The researchers then examined the muscle of the different groups of mice one to five days after injury to compare how well the tissue repaired itself. As expected,

•  muscle tissue in the young mice easily replaced damaged cells with new, healthy cells. In contrast,
• the areas of damaged muscle in the control group of old mice were characterized by fibroblasts and scar tissue. However,
• muscles in the old mice whose stem cell “aging pathway”had been dampened showed levels of cellular regeneration that were
  • comparable to their much younger peers, and that were 3 to 4 times greater than those of the group of “untreated” old mice.

Adult Stem Cells To Repair Damaged Heart Muscle

http://www.science20.com/profile/news_staff

In the first trial of its kind in the world, 60 patients who have recently suffered a major heart attack will be injected with selected stem cells from their own bone marrow during routine coronary bypass surgery. The Bristol trial will test

• whether the stem cells will repair heart muscle cells damaged by the heart attack,
• by preventing late scar formation and hence impaired heart contraction.

“ Cardiac stem cell therapy aims to repair the damaged heart as it has the potential to replace the damaged tissue.” We have elected to use a very promising stem cell type selected from the patient’s own bone marrow. This approach ensures no risk of rejection or infection. It also gets around the ethical issues that would result from use of stem cells from embryonic or foetal tissue.

In this trial (known as TransACT), all patients will have bone marrow harvested before their heart operation. Then either stem cells from their own bone marrow or a placebo will be injected into the patients’ damaged hearts during routine coronary bypass surgery. The feasibility and safety of this technique has already been demonstrated. As a result of the chosen double blind placebo-controlled design, neither the patients nor the surgeon knows whether the patient is going to be injected with stem cells or placebo. This ensures that results are not biased in any way, and is the most powerful way to prove whether or not the new treatment is effective.

Research of Stem Cells Repair Damaged Heart

By Kelvinlew Minhan | March 26th 2008

Under highly specific growth conditions in laboratory culture dishes, stem cells

• can be coaxed into developing as new cardiomyocytes and vascular endothelial cells (Kirschstein and Skirboll, 2001).

Discoveries that have triggered the interest in the application of adult stem cells to heart muscle repair in animal models have been made by researchers in the past few years (Kirschstein and Skirboll, 2001). One  study demonstrated that cardiac tissue can be regenerated in the mouse heart attack model through the introduction of adult stem cells from mouse bone marrow (Kirschstein and Skirboll, 2001). These cells were transplanted into the marrow of irradiated mice approximately 10 weeks before the recipient mice were subjected to heart attack thru tying off different major heart blood vessel, the left anterior descending (LAD) coronary artery. The survival rate was 26 percent at two to four weeks after the induced cardiac injury (Kirschstein and Skirboll, 2001). Another study of the region surrounding the damaged tissue in surviving mice showed the presence of donor-derived cardiomyocytes and endothelial cells (Kirschstein and Skirboll, 2001).

• the mouse hematopoietic stem cells transplanted into the bone marrow had migrated to the border part of the damaged area, and differentiated into several types of tissue for cardiac repair.

Regenerating heart tissue through stem cell therapy

http://www.mayo.edu/research/discoverys-edge/regenerating-heart-tissue-stem-cell-therapy

Summary

A groundbreaking study on repairing damaged heart tissue through stem cell therapy has given patients hope that they may again live active lives. An international team of Mayo Clinic researchers and collaborators has done it by discovering a way to regenerate heart tissue.

“It’s a paradigm shift,” says Andre Terzic, M.D., Ph.D., director of Mayo Clinic’s Center for Regenerative Medicine and senior investigator of the stem cell trial. “We are moving from traditional medicine, which addresses the symptoms of disease to cure disease.” Treating patients with cardiac disease has typically involved managing heart damage with medication.  In collaboration with European researchers, Mayo Clinic researchers have discovered a novel way to repair a damaged heart. In Mayo Clinic’s breakthrough process,

• stem cells are harvested from a patient’s bone marrow.
•  undergo a laboratory treatment that guides them into becoming cardiac cells,
• which are then injected into the patient’s heart in an effort to grow healthy heart tissue.

The study is the first successful demonstration in people of the feasibility and safety of transforming adult stem cells into cardiac cells. Beyond heart failure, the Mayo Clinic research also is a milestone in the emerging field of regenerative medicine, which seeks to fully heal damaged tissue and organs.

Creating a heart repair kit

This image shows the process used in the clinical trials to repair damaged hearts. Cardioprogenitor cells is another term for cardiopoietic cells, those that were transformed into cardiac cells.

Transformation: The cardiopoietic cells on the left react to the cardiac environment, cluster together with like cells and form tissue.

 Mayo Clinic researchers pursued this research, inspired by an intriguing discovery. In the early 2000s, they analyzed stem cells from 11 patients undergoing heart bypass surgery. The stem cells from two of the patients had an unusually high expression of certain transcription factors — the proteins that control the flow of genetic information between cells. Clinically, the two patients appeared no different from the others, yet their stem cells seemed to show unique capacity for heart repair.

That observation drove them to  determine how to convert  nonreparative stem cells to become reparative. Doing so required determining precisely how the human heart naturally develops, at a subcellular level. That painstaking work was led by Atta Behfar, M.D., Ph.D., a cardiovascular researcher at Mayo Clinic in Rochester, Minn. With other members of the Terzic research team, Dr. Behfar identified hundreds of proteins involved in the process of heart development (cardiogenesis). The researchers then set out to identify which of these proteins are essential in driving a stem cell to become a cardiac cell. Using computer models,

• they simulated the effects of eliminating proteins one by one from the process of heart development.
• That method yielded about 25 proteins.
  • The team then pared that number down to 8 proteins that their data indicated were essential.

The research team was then able to develop the lab procedure that guides stem cells to become heart cells.

The treated stem cells were dubbed cardiopoietic, or heart creative. A proof of principle study about guided cardiopoiesis, whose results were published in the Journal of the American College of Cardiology in 2010, demonstrated that animal models with heart disease that had been injected with caridiopoietic cells had improved heart function compared with animals injected with untreated stem cells. Hailed as “landmark work,” by the journal’s editorial writer, the study showed it was indeed possible to teach stem cells to become cardiac cells. Stem cells from each patient in the cardiopoiesis group were successfully guided to become cardiac cells. The treated cells were injected into the heart wall of each of those patients without apparent complications.
“Ihis newprocessofcardiopoiesiswas achieved in 100 percent of cases, with a very good safety profile,” Dr.Terzic says. “We are enabling the heart toregainitsinitial structure and function,” Dr.Terzic says, “and we will not stop here.” The clinicaltrialfindingsareexpectedto be published in the Journal of the American College of Cardiology in 2013.  Meanwhile, research to improve the injection process and effectiveness is underway.

Stem Cells from Humans Repair Heart Damage in Monkeys

• Kevin Mayer

GEN News Highlights  May1, 2014

implanted graft of cardiac cells derived from human stem cells (green)

Regeneration of the heart by 4 different classes of proteins

Stem cells have shown promise in small-animal models, that is, in mice and rats. Still, it was unclear whether human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) could be produced in adequate numbers, and cryopreserved with sufficient viability, to even approach human application In a step up from small-animal models, scientists at the University of Washington used a monkey model of myocardial infarction to test how well hESC-CMs could replace damaged tissue with new heart cells and restore failing hearts to normal function. The scientists injected 1 billion heart muscle cells derived from hESC-CMs into the infarcted muscle of pigtail macaques (Macaca nemestrina). This was 10 times more of these types of cells than researchers have ever been able to generate before.

The researchers found that over subsequent weeks, the stem-cell derived heart muscle cells infiltrated into the damaged heart tissue, then matured, assembled into muscle fibers, and began to beat in synchrony with the macaque heart cells. After three months, the cells appeared to have fully integrated into the macaque heart muscle. The research team published its results April 30 in Nature, in an article entitled “Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts.” In this article, the authors indicated that their work demonstrated that

• hESCs can be grown,
• differentiated into cardiomyocytes, and
• cryopreserved at a scale sufficient to treat a large-animal model of myocardial infarction.

“With further refinements in manufacturing, the scale up to trials in humanpatientsseemsfeasible,” the researchers wrote. “Large-animal models are important forerunners to human trials, because they impart real-world rigor to issues such as cell production, delivery, and end-point analyses, while permitting mechanistic studies not possible in patients.”

Molecule Implicated In Leukemia Also Important In Muscle Repair

http://www.science20.com/profile/news_staff

The study shows that immature muscle cells require the molecule, called miR-29, to become mature, and that

• the molecule is nearly missing in cells from rhabdomyosarcoma, a cancer caused by the proliferation of immature muscle cells.

Cells from human rhabdomyosarcoma tumors showed levels of the molecule that were

• 10 percent or less of those in normal muscle cells.
• Artificially raising the level of the molecule in the cancer cells
  • cut their growth by half and caused them
  • to begin maturing, slowing down tumor growth.

MiR-29 is a type of microRNA, a family of molecules that helps regulate the proteins cells produce. Researchers say this study is unusual because
it also sheds light on the how a microRNA itself is regulated.

• The gene for miR-29 is silenced by the action of a protein, called NF kappa B.
•  this protein is present at highlevelsinrhabdomyosarcoma cells, and
  • this keeps miR-29 shut off,
  • preventing muscle progenitor cells from maturing.

When they raised the level of the microRNA molecule in the cells,

• or lowered the level of the NF kappa B protein,
  • the cells’ growth rate dropped two fold, and

they began taking on the appearance of mature muscle cells.

4. Drug Discovery

GPCR Insights Brighten Drug Discovery Outlook

Ken Doyle, Ph.D.

GEN Apr 15, 2014 (Vol. 34, No. 8)

Recent years have seen major advances in understanding the structure-function relationships of G protein-coupled receptors (GPCRs). This large superfamily of transmembrane receptors comprises over 800 members in humans.

GPCRs regulate a wide variety of physiological processes including

• sensation (vision, taste, and smell),
• growth,
• hormone responses, and
• regulation of the immune and
• autonomic nervous systems.

Their involvement in multiple disease pathways makes GPCRs attractive targets for drug discovery efforts.

These multifaceted proteins will be the subject of “GPCR Structure, Function and Drug Discovery,” a Global Technology Community conference scheduled to take place May 22–23 in Boston. The conference is expected to cover a broad range of topics including biased signaling, membrane protein structures, GPCR signaling dynamics, computational approaches to disease.

According to Bryan Roth, M.D., Ph.D., Michael Hooker Distinguished Professor at the University of North Carolina, Chapel Hill,

• drugs that can selectively target various downstream GPCR pathways hold the most promise.

Dr. Roth’s laboratory studies approximately 360 different GPCRs with therapeutic potential using massively parallel screening methods. His research focuses on “functional selectivity,” which he describes as

• “the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor.”

Dr. Roth notes that structural data have demonstrated that GPCRs exist in multiple conformations: “The structures of the 5-hydroxytryptamine 2B receptor and the recent high-resolution delta-opioid receptor structure have provided evidence for conformational rearrangements that contribute to functional selectivity.” Drugs that take advantage of this selectivity by preferentially stabilizing certain conformations may have unique therapeutic utility.

“Generally, we look at G protein versus arrestin-based signaling, although it’s also possible to examine how drugs activate one G protein-mediated signaling pathway versus another.

 

fluorescently tagged Arrestin and GPRC of interest

 

 

 

 

 

 

 

• β-Arrestins constitute a major class of intracellular scaffolding proteins that regulate GPCR signaling by preventing or enhancing the binding of GPCRs to intracellular signaling molecules. Laura Bohn, Ph.D., associate professor at Scripps Florida,  studies the roles that β-arrestins play in GPCR-mediated signaling.
• a particular β-arrestin can play multiple, tissue-specific roles—shutting down the signaling of a receptor in one tissue while activating signaling in another.
• different ligands can direct GPCR signaling to different effectors, which could result in different physiological effects,” comments Dr. Bohn. “Our challenge is in determining what signaling pathways to harness to promote certain effects, while avoiding others.”

Arrestin binding to active GPCR kinase (GRK)-phosphorylated GPCRs blocks G protein coupling

 

 

 

 

 

 

 

 

 

 

 

Using Designer Proteins

The multifunctional signaling abilities of β-arrestins has prompted large-scale study of their properties. Vsevolod Gurevich, Ph.D., professor of pharmacology at Vanderbilt University, studies

1. the structure,
2. function, and
3. biology of arrestin proteins.

β-arrestins have three main functions.

1. First, they prevent the coupling of GPCRs to G proteins, thereby blocking further G protein-mediated signaling (a process known as desensitization).
2. Second, the binding of a GCPR releases the β-arrestin’s carboxy-terminal “tail” and promotes internalization of the receptor.
3. Third, receptor-bound β-arrestins bind other signaling proteins, resulting in a second wave of arrestin-mediated signaling.

Dr. Gurevich’s laboratory studies β-arrestin biology through the use of three types of specially designed mutants—

1. enhanced phosphorylation-dependent,
2. receptor-specific, and
3. signaling-biased mutants.

an enhanced mutant of visual β-arrestin-1 partially compensates for defects of rhodopsin phosphorylation in vivo,

“Several congenital disorders are caused by mutant GPCRs that cannot be normally phosphorylated because they have lost GPCR kinase (GRK) sites. Enhanced super-active arrestins have the potential to compensate for these defects, bringing the signaling closer to normal.”

• Dr. Gurevich explains the strategy involved in creating designer β-arrestins: “We identify residues critical for individual β-arrestin functions by mutagenesis, using limited structural information as a guide.
• We also work on getting more structural information. In collaboration with different crystallographers, we solved the crystal structures of all four vertebrate β-arrestin subtypes in the basal state, as well as the structure of the arrestin-1-rhodopsin complex.”
• Dr. Gurevich believes that designer β-arrestins “are the next step in research and therapy, moving way beyond what small molecules can achieve.
• The difference in capabilities between redesigned signaling proteins, including β-arrestins, and conventional small molecule drugs is about the same as that between airplanes and horse-driven carriages.”
• Dr. Gurevich observes that redesigned signaling proteins face considerable obstacles in terms of gene delivery, but that the efforts are worth it. “Using designer signaling proteins, we can tell the cell what to do in a language it cannot disobey,” asserts Dr. Gurevich.

Synthesis and Antihypertensive Screening of Novel Substituted 1,2- Pyrazoline Sulfonamide Derivatives

Avinash M. Bhagwat , Anilchandra R. Bha , Mahesh S. Palled , Anand P. Khadke , Anuradha M. Patil, et al.

Am. J. PharmTech Res. 2014; 4(2).    http://www.ajptr.com/ 

Angiotensin II receptor antagonists, also known as angiotensin receptor blockers , AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system. Their main use is in hypertension, diabetic nephropathy and congestiveheart failure. These substances are AT1-receptor antagonists which

• block the activationof angiotensin II AT1 receptors.

Blockade of AT1 receptors directly causes

1 vasodilation,

2 reduces secretion of vasopressin,

3 reduces production and secretion of aldosterone, amongst other actions –

4 the combined effect of which is reduction of blood pressure.

Irbesartan is a safe and effectiveangiotensin II receptor antagonist with an affinity for the AT1 receptor that is more than 8,500times greater than its affinity for AT2 receptor. This agent has a higher bioavailability (60-80%) than other drugs in its class . In both Losartan and Irbesartan structures imidazole moiety is being present. A structure analog of losartan and Irbesartan are designed by incorporating the heterocycles like pyrazoline group. We felt it would be interesting to explore the possibilities of 1,2-pyrazoline derivatives for Angiotensin II receptor antagonistic activity.

The Irbesartan structure was a modified Losartan structure, which had all the identity of a Losartan molecule but with groups that would fit the hydrophobic cavity with a tetramethylene group and an alkyl side chain that would fit in the pocket in the AT1 receptor. The hydroxyl methyl group of Losartan being replaced with carbonyl group of Irbesartan. With a view to introduce a hydrogen bonding interaction with AT1 receptor, these structures were further modified with a view of retaining both hydrogen bonding characteristics and as well as lipophilic groups. Losartan and Irbesartan structure contains a diphenyl molecule & imidazole ring.

In Losartan and Irbesartan diphenyl molecule is attached to the nitrogen of the imidazole ring. It is interesting to to see the activity of compounds containing two phenyl rings attached at two different positions namely3,5 position of 1, 2-pyrazoline ring. The sulphonamide derivatives known for its diuretics activity which reduces renal hypertension. We use to synthesize sulphonamide and pyrazoline in one molecule to check its possible Angiotensin II receptor antagonist property. For this reason chalcones were synthesized reacted with hydrazine hydrate to yield the corresponding 1,2-pyrazoline derivatives which further condensed with sulphanilamide and formaldehyde by mannich condensation reaction.

Acute Toxicity Study (LD50)

This study was carried out in order to establish the therapeutic and toxic doses of the newly synthesized 1,2 pyrazoline derivatives. To establish LD50 of these compounds the method described by Miller & Tainter was employed.

We report new 1,2 pyrazolines which defined combination of substituents confers appropriate polarity and charge distribution for good activity. The spectral data of compounds confirms the structures.

We also report various derivatives of 1,2 pyrazolines from Chalcones to achieve the promising and selective inhibition. The synthesized 1,2 pyrazoline derivatives have resemblance to some of Angiotensin II blocking agents like Irbesartan and Losartan. Hence it was thought of carrying out Angiotensin II blocking screening by 1K-1C Goldblatt noninvasive blood pressure measurement method. As a result, the screened compounds have shown significant Angiotensin II blocking activity. Irbesartan was used as the standard drug for Angiotensin II blocking activity.
Compounds synthesized have shown the significant Angiotensin II blocking activity when compared with the control but however are not comparable to the standard Irbesartan. The results were calculated by taking mean SE and finding the ‘P’ values. Hence from the SAR studies the chloro substituted compounds PH-2 and PH-7 exhibit better Angiotensin II blocking activityamongst the synthesized compounds. The structures of all the synthesized compounds were established on the basis of M.P., TLC, IR, NMR (PMR) . The compounds synthesized were found to be non-toxic and could be synthesized in good yields. The active compounds could be taken as lead for structural and molecular modification was thought of in future.

The present work, which was undertaken is a bonafide and novel work on the synthesis of 1,2 pyrazoline derivatives. We have made an attempt in reviewing the literature on 1,2 pyrazoline derivatives for their medicinal uses with the help of chemical abstract, journals and internet surfing. For the synthesis of 1,2 pyrazoline derivatives scheme were established. Around eight derivatives were synthesized. The synthesized compounds were tested for their purity, preliminary tests, physical constants and TLC. The structure of the final compound were confirmed by IR, H-NMR spectra and GCMS. The compounds synthesized were found to be non-toxic and could be synthesized in good yields.

5. Synthetic Biology

Artists and biologists team up to ush boundaries of synthetic biology

Kenrick Vezina | May 1, 2014 | Genetic Literacy Project

Synthetic biologists are often accused of “playing God,” of tampering with his Creation. Well, if you’re going to Create then you might as well do so with the help of some creative individuals? That’s just what the biologists in the pages of the new book Synthetic Aesthetics, from MIT Press, aims to do. Its arrival is well-timed, with the

first synthetic yeast chromosome having been created last month amid a flurry of scientific milestones in biotechnology.

Alun Anderson has reviewed the new book for New Scientist. Unlike the typically defensive posture found in biotech broadly, he writes, the spirit captured by this book is “freewheeling” and collaborative, with 20 authors ranging from the arts and sciences putting their minds together to generate original ideas. Anderson notes that parts of the book “may irritate conventional scientists – some of the ideas were dreamed up while ‘performing a dance based on the myth of the Golem’, for example. But it certainly explains the key ideas of the field and leads you to many lateral conversations about what it may become.” The book is itself an offshoot of a larger project, which you can check out at its official page. It describes itself as an “experimental, international research project between synthetic biology, art, design and social science” It has roots at the University of Edinburgh, Scotland, and Stanford University, California. And the main project team is comprised of bioengineers Drew Endy (Stanford) and Alistair Elfick (Edinburgh), social scientists Jane Calvert (Edinburgh) and Pablo Schyfter (Edinburgh), and designer/artist Alexandra Daisy Ginsberg.

In the book Synthetic Aesthetics, Ginsberg provides a thought-provoking counterpoint to the engineering definition of “design”.  Anderson explains in his review: An engineer might think of designing a bridge to a particular specification; a synthetic biologist of designing a microorganism with a new commercial application, pumping out green gasoline for example; but a real designer, a fashion designer, for example, is doing something else. As artist Daisy Ginsberg puts it, design “is about possibility”, the unimagined things that life could be.

Synthetic biology, she writes, has been addressing “humanity’s needs” – limitless fuel, for example – rather than “our needs as individual, diverse and complex humans”.  This is refreshing: worries about the separation between the top-down design of the future and those who must live with the results are quite rare in science. These words ring true, given the intensely “problem oriented” approach to most synthetic biology research. This approach extends to the coverage of this research in the media, where even a research achievement with sweeping potential like the synthetic yeast chromosome ends up broken down into pragmatic chunks. (Yeast could mass-produce medicines! Help process fuels!) Alistair Elfick, one of the leads on the Synthetics Aesthetics project, has written a fascinating opinion piece at The Conversation to accompany the release of his book. In it, he puts forth the idea it’s time for synthetic biologists to stop thinking “like scientists,” lest they hamstring themselves.

Kenrick Vezina is Gene-ius Editor for the Genetic Literacy Project and a freelance science writer, educator, and naturalist based in the Greater Boston area. Sources:

•  ”Synthetic biology gets reborn as an aesthetic dream,” Alun Anderson | New Scientist
• “If synthetic biologists think like scientists, they may miss their eureka moment,” Alistair Elfick | The Conversation
• Synthetic Aesthetics project

• “Breakthrough biology: First synthetic chromosome for yeast created, capping month of biotech innovations,” Kenrick Vezina | Genetic Literacy Project

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Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Posted in Academic Publishing, Acute Myocardial Infarction, Advanced Drug Manufacturing Technology, Alzheimer's Disease, Atherogenic Processes & Pathology, Autologous Cell Therapy, Automated Cell Processing, Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Bone Disease and Musculoskeletal Disease, Bone marrow derived cells, Ca2+ triggered activation, Ca2+ triggered activation, Cachexia, Calcium Signaling, Calmodulin, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Computational Biology/Systems and Bioinformatics, Curation, Cytoskeleton, Diabetes Mellitus, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Drug Toxicity, Electrophysiology, Endothelial cells, Epigenetics and Cardiovascular Risks, Etiology, Evolutionary cognition, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Expression, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, Interviews with Scientific Leaders, Medical and Population Genetics, Medical Device Therapies for Altzheimer’s Disease, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Metabolomics, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Na-K transport, Na-K-ATPase, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Oxidative phosphorylation, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Phosphorylation, PKC, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Regenerative Biology and Medicine, S-nitrosylation, Signaling, Skeletal muscle regeneration, Statistical Methods for Research Evaluation, Stem Cells for Regenerative Medicine, Stents & Tools, Synaptic vesicle, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Translational Effectiveness, Translational Science, Ubiquitinylation, Water Transporters, tagged bioengineering, Cardiovascular Disorders, computational biology, Coronary artery disease, DNA Sequencing, functional proteomics, gene expression, gene silencing, genetic engineering, Heart Failure, Human Genome Project, Hypertension, MicroRNA, mtRNA, myocardial infarction, nitric oxide, Nitric oxide synthase, Personalized medicine, protein modifications, Proteomics, reverse engineering, RNA, signaling pathways, Stem cell, synbiology on April 28, 2014| Leave a Comment »

Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Article ID #135: Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1. Published on 4/28/2014

WordCloud Image Produced by Adam Tubman

 

Part 1 of Volume 4 in the e-series A: Cardiovascular Diseases and Translational Medicine, provides a foundation for grasping a rapidly developing surging scientific endeavor that is transcending laboratory hypothesis testing and providing guidelines to:

• Target genomes and multiple nucleotide sequences involved in either coding or in regulation that might have an impact on complex diseases, not necessarily genetic in nature.
• Target signaling pathways that are demonstrably maladjusted, activated or suppressed in many common and complex diseases, or in their progression.
• Enable a reduction in failure due to toxicities in the later stages of clinical drug trials as a result of this science-based understanding.
• Enable a reduction in complications from the improvement of machanical devices that have already had an impact on the practice of interventional procedures in cardiology, cardiac surgery, and radiological imaging, as well as improving laboratory diagnostics at the molecular level.
• Enable the discovery of new drugs in the continuing emergence of drug resistance.
• Enable the construction of critical pathways and better guidelines for patient management based on population outcomes data, that will be critically dependent on computational methods and large data-bases.

What has been presented can be essentially viewed in the following Table:

 

Summary Table for TM – Part 1

 

 

 

There are some developments that deserve additional development:

1. The importance of mitochondrial function in the activity state of the mitochondria in cellular work (combustion) is understood, and impairments of function are identified in diseases of muscle, cardiac contraction, nerve conduction, ion transport, water balance, and the cytoskeleton – beyond the disordered metabolism in cancer.  A more detailed explanation of the energetics that was elucidated based on the electron transport chain might also be in order.

2. The processes that are enabling a more full application of technology to a host of problems in the environment we live in and in disease modification is growing rapidly, and will change the face of medicine and its allied health sciences.

 

Electron Transport and Bioenergetics

Deferred for metabolomics topic

Synthetic Biology

Introduction to Synthetic Biology and Metabolic Engineering

Kristala L. J. Prather: Part-1    <iBiology > iBioSeminars > Biophysics & Chemical Biology >

http://www.ibiology.org Lecturers generously donate their time to prepare these lectures. The project is funded by NSF and NIGMS, and is supported by the ASCB and HHMI.
Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”.

http://synthetic_biology/Introduction_to_Synthetic_Biology_and_Metabolic_Engineering/Kristala_ L.J._Prather/E2/iBiology.htm#/sthash.71kZ0ofr.dpuf

Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.  Learn more about how Kris became a scientist at

http://science360.gov/obj/video/753bb4fa-aafb-4315-848e-51066ed9799a/finding-way-kristala-l-jones-prather-phd 

Prather 1: Synthetic Biology and Metabolic Engineering  2/6/14IntroductionLecture Overview In the first part of her lecture, Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”. The key material in building these machines is synthetic DNA. Synthetic DNA can be added in different combinations to biological hosts, such as bacteria, turning them into chemical factories that can produce small molecules of choice. In Part 2, Prather describes how her lab used design principles to engineer E. coli that produce glucaric acid from glucose. Glucaric acid is not naturally produced in bacteria, so Prather and her colleagues “bioprospected” enzymes from other organisms and expressed them in E. coli to build the needed enzymatic pathway. Prather walks us through the many steps of optimizing the timing, localization and levels of enzyme expression to produce the greatest yield. Speaker Bio: Kristala Jones Prather received her S.B. degree from the Massachusetts Institute of Technology and her PhD at the University of California, Berkeley both in chemical engineering. Upon graduation, Prather joined the Merck Research Labs for 4 years before returning to academia. Prather is now an Associate Professor of Chemical Engineering at MIT and an investigator with the multi-university Synthetic Biology Engineering Reseach Center (SynBERC). Her lab designs and constructs novel synthetic pathways in microorganisms converting them into tiny factories for the production of small molecules. Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.

VIEW VIDEOS

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=0

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=12

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=74

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=129

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=168

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk

 

David Bartel: micro-RNAs

 

I. Introduction to microRNAs

https://www.youtube.com/watch?feature=player_embedded&v=dupzE66J8u4#t=0

– See more at: http://www.ibiology.org/ibioseminars/genetics-gene-regulation/david-bartel-part-1.html#sthash.nGGr1tIt.dpuf

II. Regulatory Effects of Mammalian microRNAs

https://www.youtube.com/watch?feature=player_embedded&v=TcZK_A_wcWQ#t=0

https://www.youtube.com/watch?feature=player_embedded&v=TcZK_A_wcWQ

Calcium Cycling in Synthetic and Contractile Phasic or Tonic Vascular Smooth Muscle Cells

in INTECH
Current Basic and Pathological Approaches to
the Function of Muscle Cells and Tissues – From Molecules to HumansLarissa Lipskaia, Isabelle Limon, Regis Bobe and Roger Hajjar
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/48240

1. Introduction
Calcium ions (Ca ) are present in low concentrations in the cytosol (~100 nM) and in high concentrations (in mM range) in both the extracellular medium and intracellular stores (mainly sarco/endo/plasmic reticulum, SR). This differential allows the calcium ion messenger that carries information
as diverse as contraction, metabolism, apoptosis, proliferation and/or hypertrophic growth. The mechanisms responsible for generating a Ca signal greatly differ from one cell type to another.

In the different types of vascular smooth muscle cells (VSMC), enormous variations do exist with regard to the mechanisms responsible for generating Ca signal. In each VSMC phenotype (synthetic/proliferating and contractile [1], tonic or phasic), the Ca signaling system is adapted to its particular function and is due to the specific patterns of expression and regulation of Ca.
For instance, in contractile VSMCs, the initiation of contractile events is driven by mem- brane depolarization; and the principal entry-point for extracellular Ca is the voltage-operated L-type calcium channel (LTCC). In contrast, in synthetic/proliferating VSMCs, the principal way-in for extracellular Ca is the store-operated calcium (SOC) channel.
Whatever the cell type, the calcium signal consists of  limited elevations of cytosolic free calcium ions in time and space. The calcium pump, sarco/endoplasmic reticulum Ca ATPase (SERCA), has a critical role in determining the frequency of SR Ca release by upload into the sarcoplasmic
sensitivity of  SR calcium channels, Ryanodin Receptor, RyR and Inositol tri-Phosphate Receptor, IP3R.
Synthetic VSMCs have a fibroblast appearance, proliferate readily, and synthesize increased levels of various extracellular matrix components, particularly fibronectin, collagen types I and III, and tropoelastin [1].
Contractile VSMCs have a muscle-like or spindle-shaped appearance and well-developed contractile apparatus resulting from the expression and intracellular accumulation of thick and thin muscle filaments [1].

Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

 

Figure 1. Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs.

Left panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Contractile re-sponse is initiated by extracellular Ca influx due to activation of Receptor Operated Ca (through phosphoinositol-coupled receptor) or to activation of L-Type Calcium channels (through an increase in luminal pressure). Small increase of cytosolic due IP3 binding to IP3R (puff) or RyR activation by LTCC or ROC-dependent Ca influx leads to large SR Ca IP3R or RyR clusters (“Ca -induced Ca SR calcium pumps (both SERCA2a and SERCA2b are expressed in quiescent VSMCs), maintaining high concentration of cytosolic Ca and setting the sensitivity of RyR or IP3R for the next spike.
Contraction of VSMCs occurs during oscillatory Ca transient.
Middle panel: schematic representa tion of atherosclerotic vessel wall. Contractile VSMC are located in the media layer, synthetic VSMC are located in sub-endothelial intima.
Right panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Agonist binding to phosphoinositol-coupled receptor leads to the activation of IP3R resulting in large increase in cytosolic Ca calcium pumps (only SERCA2b, having low turnover and low affinity to Ca depletion leads to translocation of SR Ca sensor STIM1 towards PM, resulting in extracellular Ca influx though opening of Store Operated Channel (CRAC). Resulted steady state Ca transient is critical for activation of proliferation-related transcription factors ‘NFAT).
Abbreviations: PLC – phospholipase C; PM – plasma membrane; PP2B – Ca /calmodulin-activated protein phosphatase 2B (calcineurin); ROC- receptor activated channel; IP3 – inositol-1,4,5-trisphosphate, IP3R – inositol-1,4,5- trisphosphate receptor; RyR – ryanodine receptor; NFAT – nuclear factor of activated T-lymphocytes; VSMC – vascular smooth muscle cells; SERCA – sarco(endo)plasmic reticulum Ca sarcoplasmic reticulum.

 

Time for New DNA Synthesis and Sequencing Cost Curves

By Rob Carlson

I’ll start with the productivity plot, as this one isn’t new. For a discussion of the substantial performance increase in sequencing compared to Moore’s Law, as well as the difficulty of finding this data, please see this post. If nothing else, keep two features of the plot in mind: 1) the consistency of the pace of Moore’s Law and 2) the inconsistency and pace of sequencing productivity. Illumina appears to be the primary driver, and beneficiary, of improvements in productivity at the moment, especially if you are looking at share prices. It looks like the recently announced NextSeq and Hiseq instruments will provide substantially higher productivities (hand waving, I would say the next datum will come in another order of magnitude higher), but I think I need a bit more data before officially putting another point on the plot.

 

cost-of-oligo-and-gene-synthesis

Illumina’s instruments are now responsible for such a high percentage of sequencing output that the company is effectively setting prices for the entire industry. Illumina is being pushed by competition to increase performance, but this does not necessarily translate into lower prices. It doesn’t behoove Illumina to drop prices at this point, and we won’t see any substantial decrease until a serious competitor shows up and starts threatening Illumina’s market share. The absence of real competition is the primary reason sequencing prices have flattened out over the last couple of data points.

Note that the oligo prices above are for column-based synthesis, and that oligos synthesized on arrays are much less expensive. However, array synthesis comes with the usual caveat that the quality is generally lower, unless you are getting your DNA from Agilent, which probably means you are getting your dsDNA from Gen9.

Note also that the distinction between the price of oligos and the price of double-stranded sDNA is becoming less useful. Whether you are ordering from Life/Thermo or from your local academic facility, the cost of producing oligos is now, in most cases, independent of their length. That’s because the cost of capital (including rent, insurance, labor, etc) is now more significant than the cost of goods. Consequently, the price reflects the cost of capital rather than the cost of goods. Moreover, the cost of the columns, reagents, and shipping tubes is certainly more than the cost of the atoms in the sDNA you are ostensibly paying for. Once you get into longer oligos (substantially larger than 50-mers) this relationship breaks down and the sDNA is more expensive. But, at this point in time, most people aren’t going to use longer oligos to assemble genes unless they have a tricky job that doesn’t work using short oligos.

Looking forward, I suspect oligos aren’t going to get much cheaper unless someone sorts out how to either 1) replace the requisite human labor and thereby reduce the cost of capital, or 2) finally replace the phosphoramidite chemistry that the industry relies upon.

IDT’s gBlocks come at prices that are constant across quite substantial ranges in length. Moreover, part of the decrease in price for these products is embedded in the fact that you are buying smaller chunks of DNA that you then must assemble and integrate into your organism of choice.

Someone who has purchased and assembled an absolutely enormous amount of sDNA over the last decade, suggested that if prices fell by another order of magnitude, he could switch completely to outsourced assembly. This is a potentially interesting “tipping point”. However, what this person really needs is sDNA integrated in a particular way into a particular genome operating in a particular host. The integration and testing of the new genome in the host organism is where most of the cost is. Given the wide variety of emerging applications, and the growing array of hosts/chassis, it isn’t clear that any given technology or firm will be able to provide arbitrary synthetic sequences incorporated into arbitrary hosts.

 TrackBack URL: http://www.synthesis.cc/cgi-bin/mt/mt-t.cgi/397

 

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

28 Nov 2013 | PR Web

Dr. Jon Rowley and Dr. Uplaksh Kumar, Co-Founders of RoosterBio, Inc., a newly formed biotech startup located in Frederick, are paving the way for even more innovation in the rapidly growing fields of Synthetic Biology and Regenerative Medicine. Synthetic Biology combines engineering principles with basic science to build biological products, including regenerative medicines and cellular therapies. Regenerative medicine is a broad definition for innovative medical therapies that will enable the body to repair, replace, restore and regenerate damaged or diseased cells, tissues and organs. Regenerative therapies that are in clinical trials today may enable repair of damaged heart muscle following heart attack, replacement of skin for burn victims, restoration of movement after spinal cord injury, regeneration of pancreatic tissue for insulin production in diabetics and provide new treatments for Parkinson’s and Alzheimer’s diseases, to name just a few applications.

While the potential of the field is promising, the pace of development has been slow. One main reason for this is that the living cells required for these therapies are cost-prohibitive and not supplied at volumes that support many research and product development efforts. RoosterBio will manufacture large quantities of standardized primary cells at high quality and low cost, which will quicken the pace of scientific discovery and translation to the clinic. “Our goal is to accelerate the development of products that incorporate living cells by providing abundant, affordable and high quality materials to researchers that are developing and commercializing these regenerative technologies” says Dr. Rowley

 

Life at the Speed of Light

http://kcpw.org/?powerpress_pinw=92027-podcast

NHMU Lecture featuring – J. Craig Venter, Ph.D.
Founder, Chairman, and CEO – J. Craig Venter Institute; Co-Founder and CEO, Synthetic Genomics Inc.

J. Craig Venter, Ph.D., is Founder, Chairman, and CEO of the J. Craig Venter Institute (JVCI), a not-for-profit, research organization dedicated to human, microbial, plant, synthetic and environmental research. He is also Co-Founder and CEO of Synthetic Genomics Inc. (SGI), a privately-held company dedicated to commercializing genomic-driven solutions to address global needs.

In 1998, Dr. Venter founded Celera Genomics to sequence the human genome using new tools and techniques he and his team developed.  This research culminated with the February 2001 publication of the human genome in the journal, Science. Dr. Venter and his team at JVCI continue to blaze new trails in genomics.  They have sequenced and a created a bacterial cell constructed with synthetic DNA,  putting humankind at the threshold of a new phase of biological research.  Whereas, we could  previously read the genetic code (sequencing genomes), we can now write the genetic code for designing new species.

The science of synthetic genomics will have a profound impact on society, including new methods for chemical and energy production, human health and medical advances, clean water, and new food and nutritional products. One of the most prolific scientists of the 21st century for his numerous pioneering advances in genomics,  he  guides us through this emerging field, detailing its origins, current challenges, and the potential positive advances.

His work on synthetic biology truly embodies the theme of “pushing the boundaries of life.”  Essentially, Venter is seeking to “write the software of life” to create microbes designed by humans rather than only through evolution. The potential benefits and risks of this new technology are enormous. It also requires us to examine, both scientifically and philosophically, the question of “What is life?”

J Craig Venter wants to digitize DNA and transmit the signal to teleport organisms

http://pharmaceuticalintelligence.com/2013/11/01/j-craig-venter-wants-to-digitize-dna-and-transmit-the-signal-to-teleport-organisms/

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

http://pharmaceuticalintelligence.com/2013/02/11/2013-genomics-the-era-beyond-the-sequencing-human-genome-francis-collins-craig-venter-eric-lander-et-al/

Human Longevity Inc (HLI) – $70M in Financing of Venter’s New Integrative Omics and Clinical Bioinformatics

http://pharmaceuticalintelligence.com/2014/03/05/human-longevity-inc-hli-70m-in-financing-of-venters-new-integrative-omics-and-clinical-bioinformatics/

 

 

Where Will the Century of Biology Lead Us?

By Randall Mayes

A technology trend analyst offers an overview of synthetic biology, its potential applications, obstacles to its development, and prospects for public approval.

• In addition to boosting the economy, synthetic biology projects currently in development could have profound implications for the future of manufacturing, sustainability, and medicine.
• Before society can fully reap the benefits of synthetic biology, however, the field requires development and faces a series of hurdles in the process. Do researchers have the scientific know-how and technical capabilities to develop the field?

Biology + Engineering = Synthetic Biology

Bioengineers aim to build synthetic biological systems using compatible standardized parts that behave predictably. Bioengineers synthesize DNA parts—oligonucleotides composed of 50–100 base pairs—which make specialized components that ultimately make a biological system. As biology becomes a true engineering discipline, bioengineers will create genomes using mass-produced modular units similar to the microelectronics and computer industries.

Currently, bioengineering projects cost millions of dollars and take years to develop products. For synthetic biology to become a Schumpeterian revolution, smaller companies will need to be able to afford to use bioengineering concepts for industrial applications. This will require standardized and automated processes.

A major challenge to developing synthetic biology is the complexity of biological systems. When bioengineers assemble synthetic parts, they must prevent cross talk between signals in other biological pathways. Until researchers better understand these undesired interactions that nature has already worked out, applications such as gene therapy will have unwanted side effects. Scientists do not fully understand the effects of environmental and developmental interaction on gene expression. Currently, bioengineers must repeatedly use trial and error to create predictable systems.

Similar to physics, synthetic biology requires the ability to model systems and quantify relationships between variables in biological systems at the molecular level.

The second major challenge to ensuring the success of synthetic biology is the development of enabling technologies. With genomes having billions of nucleotides, this requires fast, powerful, and cost-efficient computers. Moore’s law, named for Intel co-founder Gordon Moore, posits that computing power progresses at a predictable rate and that the number of components in integrated circuits doubles each year until its limits are reached. Since Moore’s prediction, computer power has increased at an exponential rate while pricing has declined.

DNA sequencers and synthesizers are necessary to identify genes and make synthetic DNA sequences. Bioengineer Robert Carlson calculated that the capabilities of DNA sequencers and synthesizers have followed a pattern similar to computing. This pattern, referred to as the Carlson Curve, projects that scientists are approaching the ability to sequence a human genome for $1,000, perhaps in 2020. Carlson calculated that the costs of reading and writing new genes and genomes are falling by a factor of two every 18–24 months. (see recent Carlson comment on requirement to read and write for a variety of limiting  conditions).

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

http://pharmaceuticalintelligence.com/2013/11/28/startup-to-strengthen-synthetic-biology-and-regenerative-medicine-industries-with-cutting-edge-cell-products/

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

http://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

Synthesizing Synthetic Biology: PLOS Collections

http://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

Capturing ten-color ultrasharp images of synthetic DNA structures resembling numerals 0 to 9

http://pharmaceuticalintelligence.com/2014/02/05/capturing-ten-color-ultrasharp-images-of-synthetic-dna-structures-resembling-numerals-0-to-9/

Silencing Cancers with Synthetic siRNAs

http://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/

Genomics Now—and Beyond the Bubble

Futurists have touted the twenty-first century as the century of biology based primarily on the promise of genomics. Medical researchers aim to use variations within genes as biomarkers for diseases, personalized treatments, and drug responses. Currently, we are experiencing a genomics bubble, but with advances in understanding biological complexity and the development of enabling technologies, synthetic biology is reviving optimism in many fields, particularly medicine.

BY MICHAEL BROOKS    17 APR, 2014     http://www.newstatesman.com/

Michael Brooks holds a PhD in quantum physics. He writes a weekly science column for the New Statesman, and his most recent book is The Secret Anarchy of Science.

The basic idea is that we take an organism – a bacterium, say – and re-engineer its genome so that it does something different. You might, for instance, make it ingest carbon dioxide from the atmosphere, process it and excrete crude oil.

That project is still under construction, but others, such as using synthesised DNA for data storage, have already been achieved. As evolution has proved, DNA is an extraordinarily stable medium that can preserve information for millions of years. In 2012, the Harvard geneticist George Church proved its potential by taking a book he had written, encoding it in a synthesised strand of DNA, and then making DNA sequencing machines read it back to him.

When we first started achieving such things it was costly and time-consuming and demanded extraordinary resources, such as those available to the millionaire biologist Craig Venter. Venter’s team spent most of the past two decades and tens of millions of dollars creating the first artificial organism, nicknamed “Synthia”. Using computer programs and robots that process the necessary chemicals, the team rebuilt the genome of the bacterium Mycoplasma mycoides from scratch. They also inserted a few watermarks and puzzles into the DNA sequence, partly as an identifying measure for safety’s sake, but mostly as a publicity stunt.

What they didn’t do was redesign the genome to do anything interesting. When the synthetic genome was inserted into an eviscerated bacterial cell, the new organism behaved exactly the same as its natural counterpart. Nevertheless, that Synthia, as Venter put it at the press conference to announce the research in 2010, was “the first self-replicating species we’ve had on the planet whose parent is a computer” made it a standout achievement.

Today, however, we have entered another era in synthetic biology and Venter faces stiff competition. The Steve Jobs to Venter’s Bill Gates is Jef Boeke, who researches yeast genetics at New York University.

Boeke wanted to redesign the yeast genome so that he could strip out various parts to see what they did. Because it took a private company a year to complete just a small part of the task, at a cost of $50,000, he realised he should go open-source. By teaching an undergraduate course on how to build a genome and teaming up with institutions all over the world, he has assembled a skilled workforce that, tinkering together, has made a synthetic chromosome for baker’s yeast.

 

Stepping into DIYbio and Synthetic Biology at ScienceHack

Posted April 22, 2014 by Heather McGaw and Kyrie Vala-Webb

We got a crash course on genetics and protein pathways, and then set out to design and build our own pathways using both the “Genomikon: Violacein Factory” kit and Synbiota platform. With Synbiota’s software, we dragged and dropped the enzymes to create the sequence that we were then going to build out. After a process of sketching ideas, mocking up pathways, and writing hypotheses, we were ready to start building!

The night stretched long, and at midnight we were forced to vacate the school. Not quite finished, we loaded our delicate bacteria, incubator, and boxes of gloves onto the bus and headed back to complete our bacterial transformation in one of our hotel rooms. Jammed in between the beds and the mini-fridge, we heat-shocked our bacteria in the hotel ice bucket. It was a surreal moment.

While waiting for our bacteria, we held an “unconference” where we explored bioethics, security and risk related to synthetic biology, 3D printing on Mars, patterns in juggling (with live demonstration!), and even did a Google Hangout with Rob Carlson. Every few hours, we would excitedly check in on our bacteria, looking for bacterial colonies and the purple hue characteristic of violacein.

Most impressive was the wildly successful and seamless integration of a diverse set of people: in a matter of hours, we were transformed from individual experts and practitioners in assorted fields into cohesive and passionate teams of DIY biologists and science hackers. The ability of everyone to connect and learn was a powerful experience, and over the course of just one weekend we were able to challenge each other and grow.

Returning to work on Monday, we were hungry for more. We wanted to find a way to bring the excitement and energy from the weekend into the studio and into the projects we’re working on. It struck us that there are strong parallels between design and DIYbio, and we knew there was an opportunity to bring some of the scientific approaches and curiosity into our studio.

 

 

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