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Larry H Bernstein, MD, FCAP, Repost
Leaders in Pharmaceutical  Intelligence
http://pharmaceuticalintelligence.com/2013/04/29/francois-jacob…-lwoff/

Dr. Francois Jacob dies at 92; Nobel-winning biologist
A biologist who shared a Nobel Prize in 1965, Dr. Francois Jacob helped unlock the mysteries of RNA.
April 24, 2013, 7:21 p.m.
When James Watson and Francis Crick deciphered the structure of DNA in 1953, their discovery answered a crucial question in biology: How is genetic information passed down from parent to child?
Their work also created conundrums, however. They and others showed that every cell of an organism contains all of its genetic material. How, then, does an individual cell know which genes to use and when? And how does information from DNA get to the cell’s protein-making machinery?
The seminal insight into those questions came from three biologists at the Pasteur Institute in Paris — Dr. Francois Jacob, Jacques Monod and Andre Lwoff. They identified messenger RNA which, as the name implies, carries the blueprint for a protein from cellular DNA to the ribosome, where proteins are built. They also identified the complex system of regulatory genes that turn protein-making genes on and off.
Their achievement ushered in the modern age of molecular biology. It also won them the 1965 Nobel Prize in Medicine or Physiology, only five years after Watson and Crick received theirs.
Jacob died Friday in Paris at 92. His death was announced by the French government, but no details were released.
The inspiration for Jacob’s achievements came in the early 1950s, while he was working in Lwoff’s laboratory studying bacteriophages, viruses that infect only bacteria. They studied a bacteriophage, or phage, that infected the common bacterium Escherichia coli. They observed that the phage could infect bacterial cells and lie dormant in its genes until something triggered explosive replication that caused the cell to split open.
In related experiments with male and female bacteria, they found that male DNA that was infected with a dormant phage could be transferred to a female cell, but not vice versa. They concluded that something in the cells was suppressing the activity of the phage genes.
Nobel-winner Dr. Francois Jacob dies
That led Jacob and Monod to study E. coli that normally live on the sugar glucose. But if the bacteria are deprived of glucose and placed in a medium containing the more complicated sugar lactose, they suddenly begin producing three enzymes that: 1) take lactose into the cell; 2) break it down into its constituents glucose and galactose; and 3) break galactose down into glucose.
Through an elegant series of experiments, the researchers showed that the genes that serve as the blueprints for those three enzymes are each accompanied by another gene called the operator. In this system, glucose acts as a repressor, binding to the operator and physically preventing the blueprint gene from being copied into messenger RNA.
In other words, when the gene is not needed, it is shut off.
But when lactose is present, it binds more strongly to the operator than does glucose, pushing out the latter and allowing the structural gene to be copied. The researchers called this system of two genes an “operon” and the specific system for lactose the lactose or lac operon. They submitted their findings to the Journal of Molecular Biology on Christmas Eve in 1960 and it was published the next year.
In a review in the journal Science, molecular biologist Gunther S. Stent called it “one of the monuments in the literature of molecular biology.” Introducing the three biologists at the Nobel awards ceremony, Sven Gard of the Royal Karolinska Institute proclaimed that the French workers “opened up a field of research which in the truest sense of the word can be described as molecular biology.”
Francois Jacob was born June 17, 1920, in Nancy, France, the son of a merchant. He began studying medicine at the University of Paris with the intention of becoming a surgeon, but the war intervened after his first two years. At the age of 20, he caught one of the last vessels to England, where he joined the Free French forces.
With his two years of medical training, he served as a doctor with the Free French armored forces throughout North Africa. After the Allies’ 1944 Normandy invasion, as his armored brigade was nearing Paris, Jacob was severely wounded in a German attack when he used his own body to protect his lieutenant. He spent seven months in a hospital, missing the Free French forces’ grand reentry into the city. Damage to his hand ended his hopes of becoming a surgeon.
For his service, he received the Companion of the Liberation, the country’s highest World War II decoration for valor. He was also awarded the Legion d’Honneur and the Croix de Guerre.
After he received his medical degree in 1947, he joined a company that was attempting to make a French version of penicillin and helped in the development of a related antibiotic called tyrothrycin. In 1950, at the age of 30, he decided he was interested in cellular genetics and obtained a fellowship at the Pasteur Institute, receiving his doctor of science degree in 1954.
He later studied mechanisms of cell division and the early development of the mouse embryo.
In addition to his many research papers, he authored four books, including the 1988 autobiography “The Statue Within.”
He married the pianist Lysiane “Lise” Bloch in 1947, and they had four children. After her death, he married Genevieve Barrier in 1999. Information about survivors was unavailable.
news.obits@latimes.com

http://pgabiram.scientificlegacies.org/doc/7_nobelist_abs_1991.pdf

Stained glass window in the dining hall of Gon...

Stained glass window in the dining hall of Gonville and Caius College, in Cambridge (UK), commemorating Francis Crick, who co-discovered the molecular structure of DNA, received a Nobel Prize and was an honorary fellow of the college. The window represents a double helix; the text on the windows reads: F.H.C. CRICK, HONORARY FELLOW 1976. (Photo credit: Wikipedia)

Diagram of a eukaryotic gene

Diagram of a eukaryotic gene (Photo credit: Wikipedia)

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struktura infliximabu

struktura infliximabu (Photo credit: Wikipedia)

Larry H Bernstein, MD, FCAP, Reporter

GI Disease, inflammation, elastase-inhibitor, membrane junctions and fatty acids

Sci Transl Med 2012; 4(158): 158ra144

Sci. Transl. Med. DOI: 10.1126/scitranslmed.3004212

RESEARCH ARTICLE
INFLAMMATORY BOWEL DISEASES
Food-Grade Bacteria Expressing Elafin Protect Against Inflammation and Restore Colon Homeostasis
Jean-Paul Motta1,2,3,*, Luis G. Bermúdez-Humarán4,*, Céline Deraison1,2,3, Laurence Martin1,2,3, Corinne Rolland1,2,3, Perrine Rousset1,2,3, Jérôme Boue1,2,3, Gilles Dietrich1,2,3, Kevin Chapman5, Pascale Kharrat4, Jean-Pierre Vinel3,6, Laurent Alric3,6, Emmanuel Mas1,2,3,7, Jean-Michel Sallenave8,9,10, Philippe Langella4,* and Nathalie Vergnolle1,2,3,5,†

1INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse F-31300, France.
2CNRS, U5282, Toulouse F-31300, France.
3CPTP, Université de Toulouse, Université Paul Sabatier (UPS), Toulouse F-31300, France.
4Institut National de la Recherche Agronomique (INRA), UMR 1319 Micalis, Commensal and Probiotics-Host Interactions Laboratory, Domaine de Vilvert, 78352 Jouy-en-Josas Cedex, France.
5Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
6Pôle Digestif, CHU Purpan, Toulouse F-31059, France.
7Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital, Toulouse F-31059, France.
8Institut Pasteur, Unité de Défense Innée et Inflammation, Paris F-75015, France.
9INSERM U874, Paris F-75724, France.
10Universite Paris Diderot, Sorbonne Paris Cite, Cellule Pasteur F-75013, France.

ABSTRACT

Elafin, a natural protease inhibitor expressed in healthy intestinal mucosa, has pleiotropic anti-inflammatory properties in vitro and in animal models. We found that mucosal expression of Elafin is diminished in patients with inflammatory bowel disease (IBD). This defect is associated with increased elastolytic activity (elastase-like proteolysis) in colon tissue. We engineered two food-grade strains of lactic acid bacteria (LAB) to express and deliver Elafin to the site of inflammation in the colon to assess the potential therapeutic benefits of the Elafin-expressing LAB. In mouse models of acute and chronic colitis, oral administration of Elafin-expressing LAB decreased elastolytic activity and inflammation and restored intestinal homeostasis. Furthermore, when cultures of human intestinal epithelial cells were treated with LAB secreting Elafin, the inflamed epithelium was protected from increased intestinal permeability and from the release of cytokines and chemokines, both of which are characteristic of intestinal dysfunction associated with IBD. Together, these results suggest that oral delivery of LAB secreting Elafin may be useful for treating IBD in humans.

Copyright © 2012, American Association for the Advancement of Science
Citation: J.-P. Motta, L. G. Bermúdez-Humarán, C. Deraison, L. Martin, C. Rolland, P. Rousset, J. Boue, G. Dietrich, K. Chapman, P. Kharrat, J.-P. Vinel, L. Alric, E. Mas, J.-M. Sallenave, P. Langella, N. Vergnolle, Food-Grade Bacteria Expressing Elafin Protect Against Inflammation and Restore Colon Homeostasis. Sci. Transl. Med. 4, 158ra144 (2012).

Cytokines involved in IBD

Cytokines involved in IBD (Photo credit: Wikipedia)

Metabolism

Front. Physio., 10 October 2012 | doi: 10.3389/fphys.2012.00401
Outlook: membrane junctions enable the metabolic trapping of fatty acids by intracellular acyl-CoA synthetases
Joachim Füllekrug*, Robert Ehehalt and Margarete Poppelreuther
Molecular Cell Biology Laboratory, Internal Medicine IV, University of Heidelberg, Heidelberg, Germany
The mechanism of fatty acid uptake is of high interest for basic research and clinical interventions. Recently, we showed that mammalian long chain fatty acyl-CoA synthetases (ACS) are not only essential enzymes for lipid metabolism but are also involved in cellular fatty acid uptake. Overexpression, RNAi depletion or hormonal stimulation of ACS enzymes lead to corresponding changes of fatty acid uptake. Remarkably, ACS are not localized to the plasma membrane where fatty acids are entering the cell, but are found instead at the endoplasmic reticulum (ER) or other intracellular organelles like mitochondria and lipid droplets. This is in contrast to current models suggesting that ACS enzymes function in complex with transporters at the cell surface. Drawing on recent insights into non-vesicular lipid transport, we suggest a revised model for the cellular fatty acid uptake of mammalian cells which incorporates trafficking of fatty acids across membrane junctions. Intracellular ACS enzymes are then metabolically trapping fatty acids as acyl-CoA derivatives. These local decreases in fatty acid concentration will unbalance the equilibrium of fatty acids across the plasma membrane, and thus provide a driving force for fatty acid uptake.

English: Acyl-CoA from the cytosol to the mito...

English: Acyl-CoA from the cytosol to the mitochondrial matrix. Français : Transport de l’Acyl-CoA du Cytosol jusqu’à la matrice mitochondriale. (Photo credit: Wikipedia)

English: The mechanism for Long Chain Fatty Ac...

English: The mechanism for Long Chain Fatty Acyl-CoA Synthetase (Photo credit: Wikipedia)

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