MedWorm: Biomedical Science

PKM2 Tyrosine Phosphorylation and Glutamine Metabolism Signal a Different View of the Warburg Effect.

Science Signaling — Fri, 20 Nov 2009 01:16:03 +0100

Authors: Dang CV New evidence suggests that the receptor tyrosine kinase FGFR1 (fibroblast growth factor receptor 1) directly phosphorylates pyruvate kinase M2 (PKM2), resulting in reduced conversion of phosphoenolpyruvate to pyruvate, which is further catabolized to lactate by lactate dehydrogenase A. Mutation of the critical tyrosine Tyr(105) to Phe rendered PKM2 more active but was associated with decreased cellular lactate production, increased oxygen consumption, and decreased hypoxic cell proliferation relative to wild-type PKM2. The apparent paradoxical effect of growth signaling through tyrosine phosphorylation, which decreases rather than increases PKM2 activity, stimulates a revised perspective of the Warburg effect. This effect, which describes the propensity for cancer cell...

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Acetylation Goes Global: The Emergence of Acetylation Biology.

Science Signaling — Fri, 20 Nov 2009 01:16:03 +0100

Authors: Norris KL, Lee JY, Yao TP For the first 30 years since its discovery, reversible protein acetylation has been studied and understood almost exclusively in the context of histone modification and gene transcription. With the discovery of non-histone acetylated proteins and acetylation-modifying enzymes in cellular compartments outside the nucleus, the regulatory potential of reversible acetylation has slowly been recognized in the last decade. However, the scope of protein acetylation involvement in complex biological processes remains uncertain. The recent development of new technology has enabled, for the first time, the identification and quantification of the acetylome, acetylation events at the whole-proteome level. These efforts have uncovered a stunning complexity of the...

Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth.

Science Signaling — Fri, 20 Nov 2009 01:16:03 +0100

Authors: Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, Dong S, Lonial S, Wang X, Chen GZ, Xie J, Gu TL, Polakiewicz RD, Roesel JL, Boggon TJ, Khuri FR, Gilliland DG, Cantley LC, Kaufman J, Chen J The Warburg effect describes a pro-oncogenic metabolism switch such that cancer cells take up more glucose than normal tissue and favor incomplete oxidation of glucose even in the presence of oxygen. To better understand how tyrosine kinase signaling, which is commonly increased in tumors, regulates the Warburg effect, we performed phosphoproteomic studies. We found that oncogenic forms of fibroblast growth factor receptor type 1 inhibit the pyruvate kinase M2 (PKM2) isoform by direct phosphorylation of PKM2 tyrosine residue 105 (Y(105)). This inhibits the formation of acti...

Trypanosoma cruzi Targets Akt in Host Cells as an Intracellular Antiapoptotic Strategy.

Science Signaling — Fri, 20 Nov 2009 01:16:03 +0100

Authors: Chuenkova MV, Pereiraperrin M The parasite Trypanosoma cruzi, which causes Chagas' disease, differentiates in the cytosol of its host cell and then replicates and spreads infection, processes that require the long-term survival of the infected cells. Here, we show that in the cytosol, parasite-derived neurotrophic factor (PDNF), a trans-sialidase that is located on the surface of T. cruzi, is both a substrate and an activator of the serine-threonine kinase Akt, an antiapoptotic molecule. PDNF increases the expression of the gene that encodes Akt while suppressing the transcription of genes that encode proapoptotic factors. Consequently, PDNF elicits a sustained functional response that protects host cells from apoptosis induced by oxidative stress and the proinflammatory cytok...

ALBAclone (Alba Bioscience Limited)

What's New at CBER — Thu, 19 Nov 2009 19:39:00 +0100

(Source: What's New at CBER)

Herbal Medicine May Counter Pain Killer's Liver Toxicity

NIGMS - Results — Thu, 19 Nov 2009 19:15:04 +0100

A well-known Eastern herbal supplement may help avoid the most common cause of liver transplantation, according to an NIGMS-supported study. (Source: NIGMS - Results)

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NIGMS ‘Challenge’ Areas Get Millions in Recovery Act Funds

NIGMS - What's New — Thu, 19 Nov 2009 15:00:41 +0100

NIGMS has invested $16.4 million of Recovery Act funds to jump-start a range of two-year research projects that address critical gaps in the basic biomedical and behavioral sciences. (Source: NIGMS - What's New)

Scientists identify DNA that regulates antibody production

The Rockefeller University Newswire — Thu, 19 Nov 2009 14:30:00 +0100

When foreign invaders trip the immune systems alarm, antibodies need to be specially sculpted to attack them head on. New research now shows that gene segments called enhancers control the reshuffling of antibody genes that makes such a precise and coordinated attack possible. (Source: The Rockefeller University Newswire)

New research helps explain why bird flu has not caused a pandemic

Imperial College News — Thu, 19 Nov 2009 00:00:00 +0100

Research suggests human to human transmission of H5 influenza viruses is unlikely - News Release (Source: Imperial College News)

Synchronous culture of Plasmodium falciparum at high parasitemia levels

Nature Protocols — Thu, 19 Nov 2009 00:00:00 +0100

Authors: Azar Radfar, Darío Méndez, Carlos Moneriz, María Linares, Patricia Marín-García, Antonio Puyet, Amalia Diez & José M Bautista This protocol describes a method for preparing cultures of Plasmodium falciparum synchronized at any intraerythrocytic stage. Using this method, around 60% parasitized cells may be obtained. On the basis of Trager and Jensen's original continuous culture method, our approach relies on the use of (Source: Nature Protocols)

Global identification of protein kinase substrates by protein microarray analysis

Nature Protocols — Thu, 19 Nov 2009 00:00:00 +0100

Authors: Janine Mok, Hogune Im & Michael Snyder Herein, we describe a protocol for the global identification of in vitro substrates targeted by protein kinases using protein microarray technology. Large numbers of fusion proteins tagged at their carboxy-termini are purified in 96-well format and spotted in duplicate onto amino-silane-coated slides in a (Source: Nature Protocols)

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Determination of gene expression patterns using in situ hybridization to Drosophila testes

Nature Protocols — Thu, 19 Nov 2009 00:00:00 +0100

We describe a whole-mount RNA in situ hybridization (ISH) method optimized for detection of the cellular and subcellular distributions of specific mRNA within Drosophila testes and male genital tract. Digoxygenin (dig)-labeled antisense RNA probes are in vitro transcribed from a template synthesized (Source: Nature Protocols)

Protocols to detect senescence-associated beta-galactosidase (SA-βgal) activity, a biomarker of senescent cells in culture and in vivo

Nature Protocols — Thu, 19 Nov 2009 00:00:00 +0100

Protocols to detect senescence-associated beta-galactosidase (SA-βgal) activity, a biomarker of senescent cells in culture and in vivo Nature Protocols 4, 1798 (2009). doi:10.1038/nprot.2009.191 Authors: Florence Debacq-Chainiaux, Jorge D Erusalimsky, Judith Campisi & Olivier Toussaint Normal cells can permanently lose the ability to proliferate when challenged by potentially oncogenic stress, a process termed cellular senescence. Senescence-associated beta-galactosidase (SA-βgal) activity, detectable at pH 6.0, permits the identification of senescent cells in culture and mammalian tissues. Here we describe first a cytochemical (Source: Nature Protocols)

Hydrodynamic modulation of embryonic stem cell differentiation by rotary orbital suspension culture

Biotechnology and Bioengineering — Thu, 19 Nov 2009 00:00:00 +0100

Embryonic stem cells (ESCs) can differentiate into all somatic cell types, but the development of effective strategies to direct ESC fate is dependent upon defining environmental parameters capable of influencing cell phenotype. ESCs are commonly differentiated via cell aggregates referred to as embryoid bodies (EBs), but current culture methods, such as hanging drop and static suspension, yield relatively few or heterogeneous populations of EBs. Alternatively, rotary orbital suspension culture enhances EB formation efficiency, cell yield, and homogeneity without adversely affecting differentiation. Thus, the objective of this study was to systematically examine the effects of hydrodynamic conditions created by rotary orbital shaking on EB formation, structure, and differentiation. Mouse E...

How Viruses Destroy Bacteria

NIGMS - Results — Wed, 18 Nov 2009 18:59:22 +0100

A team of NIGMS-supported researchers is exploring how viruses, armed with transformer-like weapons, attack bacteria. The findings may aid in the treatment of bacterial infections. (Source: NIGMS - Results)

Prolonged Administration Enhances the Renoprotective Effect of Pentoxifylline via Anti-Inflammatory Activity in Streptozotocin-Induced Diabetic Nephropathy

Inflammation — Wed, 18 Nov 2009 05:18:52 +0100

This study investigates whether prolonged administration of PTX (40 mg/kg, per oral) is effective in streptozotocin-induced diabetic nephropathy. The amount of urinary protein was higher in the diabetic rats than in the control rats. The amount remained unchanged after 4 weeks and decreased after 8 weeks of PTX treatment. Accumulation of monocyte chemoattractant peptide-1 (MCP-1) and mouse monoclonal anti-monocyte/macrophage antibody (ED-1) positive cells was higher in untreated diabetic rats than in the control rats. PTX administration ameliorated the urinary MCP-1 excretion and interstitial infiltration of ED-1 positive cells at 4 weeks. Further, in diabetic rats, administration of PTX for 4 weeks inhibited the renal inflammatory reaction, and when administ...

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Expression and immunolocalization of ERG1 potassium channels in the rat kidney

Histochemistry and Cell Biology — Wed, 18 Nov 2009 00:08:19 +0100

Abstract Potassium (K+) channels participate in K+ secretion, K+ recycling, and cell volume regulation and help to maintain the resting potential in mammalian kidneys. Previously, we identified a set of voltage-gated K+ channels (Kv1) in the inner medullary collecting duct of the rat kidney. In the present work, we identified the voltage-gated K+ channel ether-à-go-go-related gene (ERG) in the rat kidney. mRNAs of ERG1a and its N-terminal splice-variant ERG1b were detected. Immunoblots of the cortex and medulla revealed two molecular mass proteins of 135 and 80 kDa, consistent in size with the nonglycosylated ERG1a and ERG1b isoforms, respectively. However, bands of 155 and 95 kDa, corresponding to mature glycosylated ERG1a and ERG1b, respectively, were also obser...

Computational simulation of spontaneous bone straightening in growing children.

Biomechanics and Modeling in Mechanobiology — Wed, 18 Nov 2009 00:00:00 +0100

Authors: Carpenter RD, Carter DR Periosteal surface pressures have been shown to inhibit bone formation and induce bone resorption, while tensile strains perpendicular to the periosteal surface have been shown to inhibit bone resorption and induce new bone deposition. A new computational model was developed to incorporate these experimental findings into simulations of spontaneous bone straightening in children with congenital posteromedial bowing of the tibia. Three-dimensional finite element models of the periosteum were used to determine the relationships between the defect angle and the distribution of bone surface pressures and strains due to growth-generated tensile strains in the periosteum. These relationships were incorporated into an iterative simulation to model development ...

Eight religions come together at Imperial to mark National InterFaith Week

Imperial College News — Wed, 18 Nov 2009 00:00:00 +0100

Representatives from different religions share insights and dialogue at Imperial- News (Source: Imperial College News)

Students plan record-breaking zero emission ‘supercar’ journey along world’s longest road

Imperial College News — Wed, 18 Nov 2009 00:00:00 +0100

Imperial’s Racing Green Endurance team showcases its electric supercar at the College - News (Source: Imperial College News)

Cytoskeleton Directs Chromosome Dance in Meiosis

NIGMS - Results — Tue, 17 Nov 2009 22:17:44 +0100

New findings by NIGMS-supported scientists show that the cell's cytoskeleton, which moves things around in the cell, plays a critical role in helping chromosomes find mates and pair up during meiosis. (Source: NIGMS - Results)

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Shaham and Chalasani named winners of 2009 Blavatnik Awards

The Rockefeller University Newswire — Tue, 17 Nov 2009 17:00:00 +0100

Associate Professor Shai Shaham and Postdoctoral Fellow Sreekanth H. Chalasani, who were named finalists in the third annual competition in September, were honored last night with six other winners at the New York Academy of Sciences Science and the City Gala. (Source: The Rockefeller University Newswire)

Stimulus Funds Go to Stem Cell Research in Nebraska

NIGMS - Results — Tue, 17 Nov 2009 00:07:42 +0100

A Nebraska researcher was recently selected to receive federal stimulus funds to extend his work on induced pluripotent stem cells. (Source: NIGMS - Results)

Antioxidant Has Implications for Treating Cystic Fibrosis

NIGMS - Results — Tue, 17 Nov 2009 00:01:28 +0100

An antioxidant found in vegetables may help treat inflammation-based disorders like cystic fibrosis, according to a new NIGMS-supported study. (Source: NIGMS - Results)

Imperial Sustainable Energy Futures MSc scoops Innovation award

Imperial College News — Tue, 17 Nov 2009 00:00:00 +0100

Imperial course recognised with Institute of Chemical Engineers' Award for Innovation and Excellence (Source: Imperial College News)

HIV vaccine failure probably caused by virus used, says new research

Imperial College News — Tue, 17 Nov 2009 00:00:00 +0100

Immunity to adenovirus means some people had a higher risk of HIV infection in STEP Trial - News Release (Source: Imperial College News)

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Scientists discover cells that control inflammation in chronic disease

Imperial College News — Tue, 17 Nov 2009 00:00:00 +0100

New kind of immune cell can go out of control in diseases like psoriasis and asthma - News Release (Source: Imperial College News)

A mechanistic model of infection: why duration and intensity of contacts should be included in models of disease spread

Theoretical Biology and Medical Modelling — Tue, 17 Nov 2009 00:00:00 +0100

Conclusions: The importance of highly connected individuals, so-called super-spreaders, for disease spread seems to be overestimated when a constant per-contact transmission probability is assumed. This holds particularly for diseases with low basic reproduction numbers. Simulations of disease spread should weight contacts by duration and intensity. (Source: Theoretical Biology and Medical Modelling)

Scientists Guide Immune Cells with Light and Microparticles

NIGMS - Results — Mon, 16 Nov 2009 23:58:16 +0100

A team of scientists partly supported by NIGMS has developed a new approach to studying how immune cells chase down bacteria in our bodies. (Source: NIGMS - Results)

Why Some Drug Combinations Backfire

NIGMS - Results — Mon, 16 Nov 2009 23:53:48 +0100

Just as some drugs work better together, some drug pairings are counter-productive, according to a new NIGMS-supported study. (Source: NIGMS - Results)

Imaging study shows HIV particles assembling around its genome

The Rockefeller University Newswire — Mon, 16 Nov 2009 19:30:00 +0100

The genesis of one the planets most lethal viruses, HIV, has been caught on tape. New imaging experiments show individual HIV genomes strands of RNA docking on the inner membrane of an infected cell wall as they are ensconced by HIV structural proteins. (Source: The Rockefeller University Newswire)

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Predicting Side Effects and Repurposing Drugs

NIGMS - What's New — Mon, 16 Nov 2009 17:17:18 +0100

A team of NIGMS-supported pharmaceutical chemists has devised a method for predicting a drug's close contacts inside the body, providing a new way to identify unwanted interactions and novel therapeutic targets. (Source: NIGMS - What's New)

Predicting Side Effects and Repurposing Drugs

NIGMS Computing Life — Mon, 16 Nov 2009 16:00:00 +0100

As a drug binds to a protein to lower cholesterol or inhibit the growth of breast cancer cells, it also brushes up against thousands of other molecules. These on- and off-target interactions determine a drug's beneficial effect as well as its side effects. Now, a team of pharmaceutical chemists has devised a method for predicting a drug's close contacts inside the body, providing a new way to identify unwanted interactions and novel therapeutic targets. (Source: NIGMS Computing Life)

Assessment of risk factors for osteoporosis and fractures in children with meningomyelocele.

Advances in Medical Sciences — Mon, 16 Nov 2009 00:00:00 +0100

Conclusions: Low-energetic fractures in MMC children may result from metabolic disturbances that are a consequence of excessive renal calcium loss or excessive fatty tissue content. PMID: 19919941 [PubMed - as supplied by publisher] (Source: Advances in Medical Sciences)

Sleep-wake schedules in preschool children who snore.

Advances in Medical Sciences — Mon, 16 Nov 2009 00:00:00 +0100

Conclusion: In preschool age children, when the daytime nap begins to disappear, snoring may have an effect on daytime schedule through an increased need for daytime sleep. PMID: 19919942 [PubMed - as supplied by publisher] (Source: Advances in Medical Sciences)

Rector of Imperial College London

Imperial College News — Mon, 16 Nov 2009 00:00:00 +0100

Sir Roy Anderson to return focus to international research and advisory career; Sir Keith O'Nions is Acting Rector from 1 January 2010 - News release (Source: Imperial College News)

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Imperial inspires school pupils with creative science

Imperial College News — Mon, 16 Nov 2009 00:00:00 +0100

School pupils find out about the creativity of science as Imperial joins its neighbours for Creative Quarter 2009 - News (Source: Imperial College News)

Sex Hormones and Immunity to Infection

Springer Biomedical Sciences titles — Sat, 14 Nov 2009 09:02:18 +0100

Why sex mattersAmong human and nonhuman animals, the prevalence and intensity of infection typically is higher in males than females and may reflect differences in exposure as well as susceptibility to pathogens. Elevated immunity among females is a double-edged sword in which it is beneficial against infectious diseases but is detrimental in terms of increased development of autoimmune ... (Source: Springer Biomedical Sciences titles)

A microscale protein NMR sample screening pipeline.

Journal of Bimolecular NMR — Sat, 14 Nov 2009 00:00:00 +0100

Authors: Rossi P, Swapna GV, Huang YJ, Aramini JM, Anklin C, Conover K, Hamilton K, Xiao R, Acton TB, Ertekin A, Everett JK, Montelione GT As part of efforts to develop improved methods for NMR protein sample preparation and structure determination, the Northeast Structural Genomics Consortium (NESG) has implemented an NMR screening pipeline for protein target selection, construct optimization, and buffer optimization, incorporating efficient microscale NMR screening of proteins using a micro-cryoprobe. The process is feasible because the newest generation probe requires only small amounts of protein, typically 30-200 mug in 8-35 mul volume. Extensive automation has been made possible by the combination of database tools, mechanization of key process steps, and the use of a micro-cryop...

Platelet PGD Test System (2009)

What's New at CBER — Fri, 13 Nov 2009 19:16:00 +0100

Substantially Equivalent 510(k) submission; cleared 11/10/2009 (Source: What's New at CBER)

Schisantherin A Exhibits Anti-inflammatory Properties by Down-Regulating NF-κB and MAPK Signaling Pathways in Lipopolysaccharide-Treated RAW 264.7 Cells

Inflammation — Fri, 13 Nov 2009 18:28:07 +0100

Abstract Schisantherin A, a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera, has been used as an antitussive, tonic, and sedative agent under the name of Wuweizi in Chinese traditional medicine. In the present study, we carry out a screening program to identify the anti-inflammatory potentials of schisantherin A. We found that schisantherin A reduced lipopolysaccharide (LPS (1 mg/L))-induced levels of TNF-α, IL-6, NO, and PGE2 (p < 0.01 or p < 0.05), and also reduced levels of iNOS and COX-2 in RAW 264.7 macrophages in a concentration-dependent manner. We further investigated signal transduction mechanisms to determine how schisantherin A affects. RAW264.7 cells were pretreated with 0.5, 2.5, or 25 mg/L of schisanther...

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Erratum to: Ultrastructural characterization of giant endosomes induced by GTPase-deficient Rab5

Histochemistry and Cell Biology — Fri, 13 Nov 2009 18:22:11 +0100

Content Type Journal ArticleCategory ErratumDOI 10.1007/s00418-009-0660-7Authors Catherine Sem Wegner, The Norwegian Radium Hospital, Oslo University Hospital Department of Biochemistry, Institute for Cancer Research Montebello 0310 Oslo NorwayLene Malerød, The Norwegian Radium Hospital, Oslo University Hospital Department of Biochemistry, Institute for Cancer Research Montebello 0310 Oslo NorwayNina Marie Pedersen, The Norwegian Radium Hospital, Oslo University Hospital Department of Biochemistry, Institute for Cancer Research Montebello 0310 Oslo NorwayCinzia Progida, University of Oslo Department of Molecular Biosciences 1041, Blindernveien 31 0316 Oslo NorwayOddmund Bakke, University of Oslo Department of Molecular Biosciences 1041, Blindernveien 31 0316 Oslo NorwayHarald Stenmark...

Notes to Contributors

Metabolism - Clinical and Experimental — Fri, 13 Nov 2009 16:01:54 +0100

(Source: Metabolism - Clinical and Experimental)

Editorial Board

Metabolism - Clinical and Experimental — Fri, 13 Nov 2009 16:01:54 +0100

(Source: Metabolism - Clinical and Experimental)

Metabolism - Clinical and Experimental — Fri, 13 Nov 2009 16:01:54 +0100

(Source: Metabolism - Clinical and Experimental)

Masthead

Metabolism - Clinical and Experimental — Fri, 13 Nov 2009 16:01:48 +0100

(Source: Metabolism - Clinical and Experimental)

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Draft Guidance for Industry: Recommendations for the Assessment of Blood Donor Suitability, Blood Product Safety, and Preservation of the Blood Supply in Response to Pandemic (H1N1) 2009 Virus

What's New at CBER — Fri, 13 Nov 2009 11:20:00 +0100

11/13/2009 (Source: What's New at CBER)

Seams in HIV Coat Could Lead to New Drugs

NIGMS - Results — Fri, 13 Nov 2009 00:51:41 +0100

NIGMS-supported structural biologists have identified functionally important ‘seams’ within the coat that surrounds the HIV genome. (Source: NIGMS - Results)

Lipids Trigger Death of Brain Cells in Rare Disorder

NIGMS - Results — Fri, 13 Nov 2009 00:51:07 +0100

NIGMS-supported scientists reveal new details linking lipid build-up with catastrophic calcium imbalance in brain cells of patients with rare, inherited disorder. (Source: NIGMS - Results)

Reactive oxygen and nitrogen species induce protein and DNA modifications driving arthrofibrosis following total knee arthroplasty

Fibrogenesis and Tissue Repair — Fri, 13 Nov 2009 00:00:00 +0100

Conclusions: Based on our current findings, we suggest that ROS/RNS initiate and sustain the arthrofibrotic response driving aggressive fibroblast proliferation and subsequent HO. (Source: Fibrogenesis and Tissue Repair)

Enhancement of ethanol and biogas production from high-crystalline cellulose by different modes of NMO pretreatment

Biotechnology and Bioengineering — Fri, 13 Nov 2009 00:00:00 +0100

Pretreatment of high-crystalline cellulose with N-methyl-morpholine-N-oxide (NMO or NMMO) to improve bioethanol and biogas production was investigated. The pretreatments were performed at 90 and 120°C for 0.5-15 h in three different modes, including dissolution (85% NMO), ballooning (79% NMO), and swelling (73% NMO). The pretreated materials were then enzymatically hydrolyzed and fermented to ethanol or anaerobically digested to biogas (methane). The pretreatment at 85% NMO, 120°C and 2.5 h resulted in 100% yield in the subsequent enzymatic hydrolysis and around 150% improvement in the yield of ethanol compared to the untreated and water-treated material. However, the best results of biogas production were obtained when the cellulose was treated with swelling and ballooning mode, which g...

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Two proteins act as molecular tailors in DNA repair

The Rockefeller University Newswire — Thu, 12 Nov 2009 20:15:00 +0100

On average, our cells encounter a very lethal form of DNA damage 10 times a day. Lucky for us, we have the capacity to repair each and every one of them. New research now reveals exactly how two well-known proteins are involved in the process, a finding that not only helps shed light on cancer but also on how our cells maintain the integrity of our genome. (Source: The Rockefeller University Newswire)

Two submucosal nerve plexus in human intestines

Histochemistry and Cell Biology — Thu, 12 Nov 2009 18:38:52 +0100

We examined the architecture of human submucosal nerve networks of gut segments derived from 12 individuals (each six from small and large intestines). Twelve undivided submucosal wholemounts were prepared and immunohistochemically stained for peripherin (nerve elements) and for α-smooth muscle actin (remnants of attached muscle bundles). We found two ganglionic nerve networks. The plexus submucosus externus was generally monolayered and located under the outermost surface of the submucosal wholemounts. Its nerve fibre strands frequently joined each other in acute or obtuse angles, the meshes of the network were relatively wide and frequently polyangular shaped. The plexus submucosus internus was generally multi-(mostly two- or three-)layered and occupied at least the inner half of ...

Focus Issue: Coping with Cellular Stress.

Science Signaling — Thu, 12 Nov 2009 15:38:03 +0100

Authors: Wong W Organisms constantly face potential damage from internal and external sources, thus necessitating signaling cascades that couple specific cellular stresses to the appropriate responses. This Focus Issue of Science Signaling highlights the signaling pathways that are activated by and that mediate responses to diverse types of stresses. PMID: 19903934 [PubMed - as supplied by publisher] (Source: Science Signaling)

Science Signaling Podcast: 10 November 2009.

Science Signaling — Thu, 12 Nov 2009 15:38:03 +0100

Authors: Snyder SH, Vanhook AM This is a conversation with Solomon Snyder about a Research Article published in the 10 November 2009 issue of Science Signaling. PMID: 19903935 [PubMed - as supplied by publisher] (Source: Science Signaling)

Aiming Straight for the Heart: Prolyl Hydroxylases Set the BAR.

Science Signaling — Thu, 12 Nov 2009 15:38:03 +0100

Authors: Garcia JA The cellular response to a reduced oxygen state (or hypoxia) includes de novo alterations in gene expression patterns, many of which are controlled by hypoxia-inducible factor (HIF) transcription factors. HIF signaling is predominantly regulated by the dioxygenase family of prolyl hydroxylases (PHDs), also known as EGL nine homologs (EGLNs). The PHD family in higher eukaryotes, like the HIF alpha family, is composed of multiple members that have some shared biochemical properties yet have unique biological roles. Although HIF members are the major substrates identified to date for the PHD members, a reasonable expectation is that other proteins whose activities are altered by hypoxia may also serve as PHD substrates. Indeed, the beta(2)-adrenergic receptor, a major a...

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A New Mechanism of Phosphoregulation in Signal Transduction Pathways.

Science Signaling — Thu, 12 Nov 2009 15:38:03 +0100

Authors: Jung K, Jung H Histidine protein kinases and serine, threonine, or tyrosine protein kinases play essential roles in signal transduction in prokaryotes and eukaryotes. A third type of protein kinase, an arginine protein kinase, has been identified. McsB of Bacillus subtilis phosphorylates the heat shock transcriptional regulator CtsR and can be regarded as the founding member of arginine protein kinases. PMID: 19903937 [PubMed - as supplied by publisher] (Source: Science Signaling)

A Gluconeogenic Tryst in the Nucleus, with ER Stress as the Third Wheel.

Science Signaling — Thu, 12 Nov 2009 15:38:03 +0100

Authors: Rutkowski DT The transcriptional output of a cell reflects the sum of cooperative and competing interactions among hundreds of transcriptional regulators that are themselves regulated according to cellular conditions. In this way, disparate signaling cascades intersect at the level of gene expression; perturbation in one area of the cell will necessarily and fundamentally affect other areas as the cell strives to integrate information from multiple pathways. The consequences of such transcriptional cross-talk are highlighted by a newly discovered connection, through a common co-regulator, between stress in the endoplasmic reticulum and control of gluconeogenesis. These findings hint at the possible functions of stress pathways as regulators of basal cellular homeostasis. P...

FBXO31: A New Player in the Ever-Expanding DNA Damage Response Orchestra.

Science Signaling — Thu, 12 Nov 2009 15:38:03 +0100

Authors: Shiloh Y The DNA damage response (DDR)-a central axis in the maintenance of genomic stability-has emerged as a complex signaling network that affects many aspects of cellular metabolism. A major arm of the DDR activates special checkpoints that temporarily arrest cell cycle progression while damage is being assessed and processed. Many DDR arms are driven by several parallel pathways acting in concert. Such is the case with the damage-induced G(1)/S checkpoint. A new pathway driving this checkpoint draws attention to the complexity of the DDR, which allows tight but fine-tuned control of the cellular response to threats to genomic integrity. PMID: 19903939 [PubMed - as supplied by publisher] (Source: Science Signaling)

Nutrition-Minded Cell Cycle.

Science Signaling — Thu, 12 Nov 2009 15:38:03 +0100

Authors: Shiozaki K For decades, the fission yeast Schizosaccharomyces pombe has been used as an excellent model with which to explore how cellular growth is coordinated with the division cycle, a yet-unanswered question in biology. New studies in this organism show that TOR (target of rapamycin) kinase and stress-responsive MAPK (mitogen-activated protein kinase) form a signaling pathway that readjusts the timing of mitotic onset in response to poor nutrient conditions. Nutritional environment appears to be translated into graded activity of the protein kinases that influence the activation of Cdc2, a cyclin-dependent kinase driving cell-cycle progression. PMID: 19903940 [PubMed - as supplied by publisher] (Source: Science Signaling)

H2S Signals Through Protein S-Sulfhydration.

Science Signaling — Thu, 12 Nov 2009 15:38:03 +0100

Authors: Mustafa AK, Gadalla MM, Sen N, Kim S, Mu W, Gazi SK, Barrow RK, Yang G, Wang R, Snyder SH Hydrogen sulfide (H(2)S), a messenger molecule generated by cystathionine gamma-lyase, acts as a physiologic vasorelaxant. Mechanisms whereby H(2)S signals have been elusive. We now show that H(2)S physiologically modifies cysteines in a large number of proteins by S-sulfhydration. About 10 to 25% of many liver proteins, including actin, tubulin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), are sulfhydrated under physiological conditions. Sulfhydration augments GAPDH activity and enhances actin polymerization. Sulfhydration thus appears to be a physiologic posttranslational modification for proteins. PMID: 19903941 [PubMed - as supplied by publisher] (Source: Science Signalin...

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Pharmaceutical Suspensions

Springer Biomedical Sciences titles — Thu, 12 Nov 2009 13:26:17 +0100

From Formulation Development to Manufacturing Suspension dosage form is a preferred and widely accepted dosage forms for insoluble or poorly soluble drugs for various therapeutic applications. The suspension dosage form has long been used for insoluble and poorly soluble drugs for making oral, topical and parenteral products. Pharmaceutical Suspensions, From Formulation Development to Manufacturing provides the reader ... (Source: Springer Biomedical Sciences titles)

Trafficking Inside Cells

Springer Biomedical Sciences titles — Thu, 12 Nov 2009 13:14:35 +0100

Pathways, Mechanisms and Regulation series: Molecular Biology Intelligence Unit The human body is made up of trillions of tiny cells that cannot be seen by the naked eye. The functioning units inside these cells are macromolecules that need to travel in the three-dimensional cell-space to distances ten thousand times their size. This movement is highly ordered, requires energy and takes place on molecular tracks that serve as a sophisticated transport ... (Source: Springer Biomedical Sciences titles)

Optical Imaging of Cancer

Springer Biomedical Sciences titles — Thu, 12 Nov 2009 12:47:55 +0100

Clinical Applications Optical detection represents the next great horizon for cancer imaging. As molecularly targeted therapeutic agents are delivered to the clinic in increasing numbers, there is a parallel opportunity to advance optical imaging techniques. Because of its limited toxicity and potential for real-time information, optical imaging represents an underdeveloped modality in clinical ... (Source: Springer Biomedical Sciences titles)

Biological Boundaries and Biological Age.

Acta Biotheoretica — Thu, 12 Nov 2009 00:00:00 +0100

Authors: Demongeot J The chronologic age classically used in demography is often unable to give useful information about which exact stage in development or aging processes has reached an organism. Hence, we propose here to explain in some applications for what reason the chronologic age fails in explaining totally the observed state of an organism, which leads to propose a new notion, the biological age. This biological age is essentially determined by the number of divisions before the Hayflick's limit the tissue or mitochondrion in a critical organ (in the sense where its loss causes the death of the whole organism) has already used for its development and adult phases. We give a precise definition of the biological age of an organ based on the Hayflick's limit of its cells and we i...

Simultaneous analysis of reactive oxygen species and reduced glutathione content in living cells by polychromatic flow cytometry

Nature Protocols — Thu, 12 Nov 2009 00:00:00 +0100

Authors: Andrea Cossarizza, Roberta Ferraresi, Leonarda Troiano, Erika Roat, Lara Gibellini, Linda Bertoncelli, Milena Nasi & Marcello Pinti Reactive oxygen species (ROS) are continuously produced in the cell as a consequence of aerobic metabolism, and are controlled by several antioxidant mechanisms. An accurate measurement of ROS is essential to evaluate the redox status of the cell, or the effects of molecules with the (Source: Nature Protocols)

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Efficient expression of tyrosine-sulfated proteins in E. coli using an expanded genetic code

Nature Protocols — Thu, 12 Nov 2009 00:00:00 +0100

We describe a protocol for the heterologous expression of selectively tyrosine-sulfated proteins in Escherichia coli through the use of an expanded genetic (Source: Nature Protocols)

High-throughput haplotype determination over long distances by haplotype fusion PCR and ligation haplotyping

Nature Protocols — Thu, 12 Nov 2009 00:00:00 +0100

Authors: Daniel J Turner & Matthew E Hurles When combined with haplotype fusion PCR (HF-PCR), ligation haplotyping is a robust, high-throughput method for empirical determination of haplotypes, which can be applied to assaying both sequence and structural variation over long distances. Unlike alternative approaches to haplotype determination, such as allele-specific PCR and long (Source: Nature Protocols)

High-yield cell-free protein production from P-gel

Nature Protocols — Thu, 12 Nov 2009 00:00:00 +0100

Authors: Nokyoung Park, Jason S Kahn, Edward J Rice, Mark R Hartman, Hisakage Funabashi, Jianfeng Xu, Soong Ho Um & Dan Luo Cell-free systems represent a promising approach to quickly and easily produce preparative amounts of proteins. However, it is still challenging to obtain high volumetric yields (>mg ml−1) of proteins from the present cell-free systems. This protocol presents a cell-free protein synthesis method using (Source: Nature Protocols)

Research gives new insights into 4 billion year-old meteorites

Imperial College News — Thu, 12 Nov 2009 00:00:00 +0100

Scientists reveal how tiny grains inside Carbonaceous Chondrites preserved their ‘primitive chemistry’ - News (Source: Imperial College News)

Imperial to lead £2.7 million study as part of UK's response to swine flu

Imperial College News — Thu, 12 Nov 2009 00:00:00 +0100

Research aims to find out why some people have severe symptoms - News (Source: Imperial College News)

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A century of supporting sport celebrated at Imperial’s Harlington Sports Ground

Imperial College News — Thu, 12 Nov 2009 00:00:00 +0100

Rector surprises three long serving staff -News (Source: Imperial College News)

£4.9 million to develop metamaterials for 'invisibility cloaks' and 'perfect lenses'

Imperial College News — Thu, 12 Nov 2009 00:00:00 +0100

Imperial receives major new funding grant from The Leverhulme Trust - News Release (Source: Imperial College News)

High fat diet increases inflammation in the mouse colon

The Rockefeller University Newswire — Wed, 11 Nov 2009 22:15:00 +0100

In mice fed a diet high in fat and low in fiber, vitamin D and calcium the so-called Western diet expression of a series of genes collectively associated with immune and inflammatory responses was altered. The findings show that a Western diet induces oxidative stress and alters immune responses in the colon of mice long before tumors occur. (Source: The Rockefeller University Newswire)

New Four-Step Approach to Genome Annotation

NIGMS - Results — Wed, 11 Nov 2009 21:34:22 +0100

A team of NIGMS-supported bioengineers has taken some of the guesswork out of genome annotation with a new four-step method. (Source: NIGMS - Results)

Characterization of ERK Activation in Human Mast Cells Stimulated by Contact with T Cells

Inflammation — Wed, 11 Nov 2009 19:28:40 +0100

Abstract Close physical proximity between mast cells and T cells has been demonstrated in several human conditions. We have identified and characterized a novel mast cell activation pathway initiated by contact with T cells, and showed that this pathway is associated with cytokine release. It has been shown recently that Ras is activated in this pathway. Thus, in the present study we further explore the downstream events associated with Ras activation and cytokine release in human mast cells stimulated by contact with T cells. ERK activation in human mast cells stimulated by either contact with T cells or by crosslinking the FC epsilon receptor was studied. Photobleaching experiments were used to study ERK localization. Enzyme linked immunosorbent assay was used to study t...

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Simultaneous RP-HPLC-DAD quantification of bromocriptine, haloperidol and its diazepane structural analog in rat plasma with droperidol as internal standard for application to drug-interaction pharmacokinetics.

Biomedical Chromatography : BMC — Wed, 11 Nov 2009 00:00:00 +0100

Authors: Billups J, Jones C, Jackson TL, Ablordeppey SY, Spencer SD A simple and rapid RP-HPLC-DAD method was developed and validated for simultaneous determination of the dopamine antagonists haloperidol, its diazepane analog, and the dopamine agonist bromocriptine in rat plasma, to perform pharmacokinetic drug-interaction studies. Samples were prepared for analysis by acetonitrile (22.0 mug/mL) plasma protein precipitation with droperidol as an internal standard, followed by a double-step liquid-liquid extraction with hexane : chloroform (70:30) prior to C-18 separation. Isocratic elution was achieved using a 0.1% (v/v) trifluoroacetic acid in deionized water, methanol and acetonitrile (45/27.5/27.5, v/v/v). Triple-wavelength diode-array detection at the lambda(max) of 245 nm for hal...

A simple, selective and rapid validated method for estimation of anastrazole in human plasma by liquid chromatography-tandem mass spectrometry and its application to bioequivalence study.

Biomedical Chromatography : BMC — Wed, 11 Nov 2009 00:00:00 +0100

Authors: Jangid AG, Pudage AM, Joshi SS, Pabrekar PN, Tale RH, Vaidya VV A rapid, simple and specific method for estimation of anastrazole in human plasma was validated using letrozole as internal standard. The analyte and internal standard were extracted from plasma using simple solid-phase extraction. The compound were separated on a reverse-phase column with an isocratic mobile phase consisting of 0.1% formic acid in water and acetonitrile (12 : 88, v/v) and detected by tandem mass spectrometry in positive ion mode. The ion transitions recorded in multiple reaction monitoring mode were m/z 294.1 --> 225.1 for anastrazole and m/z 286.1 --> 217.1 for internal standard. Linearity in plasma was observed over the concentration range 0.3-30 ng/mL for anastrazole. The mean recovery f...

Quantitative sphingosine measurement as a surrogate for total ceramide concentration-preclinical and potential translational applications.

Biomedical Chromatography : BMC — Wed, 11 Nov 2009 00:00:00 +0100

Authors: Kindt E, Wetterau J, Mueller SB, Castle C, Boustany-Kari CM Biomarkers are an increasingly important constituent of the drug development process, offering the potential of increased efficiency through reduced compound attrition and earlier proof of mechanism and/or efficacy. Assays developed for compound screening that can be directly translated for clinical trials are especially valuable, but their successful adoption requires a careful balance between assay performance and implementation costs. One such 'fit-for-purpose' biomarker assay, the indirect measurement of pharmacological modulation of sphingolipid biosynthesis and disposition, is presented here. Among spingolipids, numerous ceramide species are readily detectable in different lipoprotein fractions of mammalian plas...

Liquid chromatography-mass spectrometry methods for urinary biomarker detection in metabonomic studies with application to nutritional studies.

Biomedical Chromatography : BMC — Wed, 11 Nov 2009 00:00:00 +0100

Authors: Legido-Quigley C, Stella C, Perez-Jimenez F, Lopez-Miranda J, Ordovas J, Powell J, van-der-Ouderaa F, Ware L, Lindon JC, Nicholson JK, Holmes E The effects of sample preparation and chromatographic method differences on the classification and recovery of metabolic biomarkers from UPLC-MS measurements on urine samples of humans exposed to different dietary interventions have been investigated. Eight volunteers consumed three high-fat meals (rich in saturated, monounsaturated and polyunsaturated fatty acids, respectively) in randomized order with a washout period in between. For each participant, urine samples were obtained prior to and at three timed intervals after each meal. Samples were processed either by dilution (1 : 4) or by liquid-liquid extraction and then run under tw...

Side chain: backbone projections in aromatic and ASX residues from NMR cross-correlated relaxation.

Journal of Bimolecular NMR — Wed, 11 Nov 2009 00:00:00 +0100

Authors: Vögeli B, Riek R The measurements of cross-correlated relaxation rates between H(N)-N and C(beta)-C(gamma) intraresidual and sequential dipolar interactions is demonstrated in ASN, ASP and aromatic residues. The experiment can be used for deuterated samples and no additional knowledge such as Karplus parametrizations is required for the analysis. The data constitutes a new type of information since no other method relates the C(beta)-C(gamma) bond to H(N)-N. Using this method the dominant populations of rotamer states of chi1 can be readily cross checked provided that phi or psi are known. In addition, dynamics on all timescales can be probed. As opposed to standard dynamics analysis of isolated bonds, the presented observables depend on relative dynamics with an interest...

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Drug shrinks lung cancer tumours in mice

Imperial College News — Wed, 11 Nov 2009 00:00:00 +0100

Researchers plan to take treatment to clinical trials - News Release (Source: Imperial College News)

Influenza A (H1N1) 2009 Monovalent Vaccine (ID Biomedical Corporation of Quebec)

What's New at CBER — Tue, 10 Nov 2009 22:30:00 +0100

(Source: What's New at CBER)

Rockefeller joins first national research study recruitment registry

The Rockefeller University Newswire — Tue, 10 Nov 2009 22:00:00 +0100

Rockefeller University has joined more than 50 U.S. research institutions in making information about its clinical research trials available on ResearchMatch, the countrys first registry for recruiting research participants. The secure Web site offers a free and safe way for volunteers to connect with thousands of researchers who are conducting research on a wide range of diseases. (Source: The Rockefeller University Newswire)

Celecoxib loaded liposomes: effect of cholesterol on encapsulation and in vitro release characteristics.

Bioscience Reports — Tue, 10 Nov 2009 00:00:00 +0100

We describe here the encapsulation of CLX in multilamellar vesicles (MLVs) composed of DSPC and variable amounts of cholesterol. The effect of cholesterol content on liposome size, percent drug loading and in vitro drug release profiles were investigated. Differential scanning calorimetry and Fourier transform infrared (FTIR) spectroscopy were used to determine molecular interactions between CLX, cholesterol and DSPC. The phase transition temperature (Tm) of vesicles was reduced in a synergistic manner in the presence of both CLX and cholesterol. Encapsulation efficiency, loading and release of CLX decreased with increasing cholesterol content. FTIR data indicated that this decrease was due to a competition between CLX and cholesterol for the cooperativity region of the phospholipids. In t...

Development of a method to measure methadone enantiomers and its metabolites without enantiomer standard compounds for the plasma of methadone maintenance patients.

Biomedical Chromatography : BMC — Tue, 10 Nov 2009 00:00:00 +0100

Authors: Wang SC, Ho IK, Wu SL, Liu SC, Kuo HW, Lin KM, Liu YL A liquid chromatography-photodiode array (LC-PDA) method using a chiral analytical column was developed to determine the plasma levels of enantiomers of methadone and its chiral metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), without the standard compounds of R-form or S-form enantiomers. This method was established by the characteristics of recombinant cytochrome P-450 (CYP) isozymes, where CYP2C19 prefers to metabolize R-methadone and CYP2B6 prefers to metabolize S-methadone. We incubated the racemic methadone standard with either enzyme for 24 h. We identified the retention times of R- and S-methadone to be around 10.72 and 14.46 min, respectively. Furthermore, we determined the retention times of R...

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High-performance liquid chromatography with solid-phase extraction for the quantitative determination of nilotinib in human plasma.

Biomedical Chromatography : BMC — Tue, 10 Nov 2009 00:00:00 +0100

Authors: Miura M, Takahashi N, Sawada KI A simple, rapid and sensitive high-performance liquid chromatography (HPLC)-based method with ultraviolet detection was developed for the quantitation of nilotinib, a tyrosine kinase inhibitor, in human plasma. Nilotinib and the internal standard dasatinib were separated using a mobile phase of 0.5% KH(2)PO(4) (pH2.5)-acetonitrile-methanol (55:25:20, v/v/v) on a Capcell Pak MG II column (250 x 4.6 mm) at a flow rate of 0.5 mL/min and optical measurement at 250 nm. Analysis required only 100 muL of plasma and involved a rapid and simple solid-phase extraction with an Oasis HLB cartridge, which gave recoveries from 72 to 78% for nilotinib and from 74 to 76% for dasatinib. The lower limit of quantification for nilotinib was 10 ng/mL. The linear ran...

Enantioresolution of DL-penicillamine.

Biomedical Chromatography : BMC — Tue, 10 Nov 2009 00:00:00 +0100

Authors: Bhushan R, Kumar R Penicillamine (PenA) is a nonproteinogenic amino acid containing a thiol group. The three functional groups in penicillamine undergo characteristic chemical reactions and differ in their ability to participate in various chemical and biochemical reactions. d-penicillamine is more active pharmacologically, while the l-isomer occurs 'naturally'. This review deals with the enantioresolution of PenA both by direct and indirect methods using liquid chromatography. HPLC separation of its diastereomers prepared with different chiral derivatizing reagents (on reversed-phase columns) and separation of the derivatives prepared with achiral reagents (on chiral columns or via ligand exchange mode) has been discussed. Separation of enantiomers tagged with achiral reagent...

Hypoxia and non alcoholic fatty liver disease

Clinical Science — Tue, 10 Nov 2009 00:00:00 +0100

Non alcoholic fatty liver disease (NAFLD) represents a spectrum of fatty liver diseases associated with increased risk of type 2 diabetes and cardiovascular disease. The spectrum of fatty liver diseases, comprises simple steatosis, steatosis with inflammation (i.e. non alcoholic steatohepatitis or NASH), fatty liver disease with inflammation and fibrosis (severe NASH) and cirrhosis. The molecular mechanisms contributing to NASH are the subject of considerable investigation, as a better understanding of the pathogenesis of NASH will lead to novel therapies for a condition that hitherto remains difficult to treat. In this edition of the Journal Piquet et al have investigated the effects of hypoxia in the PTEN deficient mouse, a mouse model that develops NAFLD. Piquet et al show that a short ...

Tissue reaction to three different types of tissue glues in an experimental aorta dissection model: a quantitative approach

Histochemistry and Cell Biology — Mon, 09 Nov 2009 19:13:40 +0100

Abstract Tissue glues are used during surgical treatment of acute aorta dissection although some glues release toxic products and thus alter the histological structure of the vessel wall. The aim of our study was to use a porcine experimental model of infrarenal aorta dissection to compare histological changes of the vessel wall 1, 6 and 12 months after application of BioGlue, Gelatin-resorcin-formaldehyde (GRF) glue and Tissucol. For quantification, stereological methods were used. All types of glue caused stenosis, GRF most and Tissucol least severely. With increasing postoperative survival time, stenosis was again reduced. Elastine length density decreased with increasing survival time in Control as well as in all Experimental groups. The immunohistochemical phenoty...

Scientists Visualize Bacteria Talking to One Another

NIGMS - Results — Mon, 09 Nov 2009 16:55:49 +0100

NIGMS-supported researchers have developed tools that enable them to visualize how different populations of cells communicate. (Source: NIGMS - Results)

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“GO” Grant to Advance Drug Development from Plants

NIGMS - Results — Mon, 09 Nov 2009 15:44:45 +0100

An NIGMS Grand Opportunities stimulus grant will support research on how several plants make medicinal compounds. (Source: NIGMS - Results)

Iconic bridge wins award with a little help from Imperial students

Imperial College News — Mon, 09 Nov 2009 00:00:00 +0100

Constructionarium initiative helps major engineering company win prestigious award - News (Source: Imperial College News)

Deputy Rector of Imperial College London

Imperial College News — Mon, 09 Nov 2009 00:00:00 +0100

Professor Stephen Richardson, Principal of the Faculty of Engineering, takes on new role - News release (Source: Imperial College News)

Effects of auricular electrical stimulation on vagal activity in healthy men: Evidence from a three-armed randomized trial

Clinical Science — Mon, 09 Nov 2009 00:00:00 +0100

The activity of the vagus nerve is negatively associated with risk factors such as stress and smoking, morbidity, and mortality. In contrast it is also a target of therapeutic intervention. Vagus nerve stimulation is used in depression and epilepsy. Due to its high invasivity and exclusive application to therapy-resistant patients, there is interest in less invasive methods affecting the vagus nerve. Several studies examining acupuncture report beneficial effects on vagal activity. However, findings are inconsistent and applied methods are heterogeneous resulting in difficulties in interpretation. The purpose of the present study was evaluation of the effects of acupuncture on vagal activity in a three-armed randomized trial while controlling several disturbing factors. Fourteen healthy me...

Stem Cell Biology in Health and Disease

Springer Biomedical Sciences titles — Sat, 07 Nov 2009 23:38:14 +0100

presents an up-to-date overview about the dual role of stem cells in health and disease. The Editors have drawn together an international team of experts providing chapters which, in this fully-illustrated volume, discuss: - the controversial debate on the great expectations concerning stem cell based regeneration therapies raised by the pluripotency of ... (Source: Springer Biomedical Sciences titles)

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The Hippo tumor suppressor pathway: a brainstorming workshop.

Science Signaling — Sat, 07 Nov 2009 02:10:03 +0100

Authors: Blandino G, Shaul Y, Strano S, Sudol M, Yaffe M Researchers from around the world met for two days in April this year in Rome, Italy, to discuss progress in the rapidly developing field of Hippo signaling, which is relevant to cancer and the control of organ size. Most of the participants presented data related to previously uncharacterized proteins that physically and functionally interact with known components of the Hippo pathway and regulate its biological output. PMID: 19887678 [PubMed - in process] (Source: Science Signaling)

In with the TRP channels: intracellular functions for TRPM1 and TRPM2.

Science Signaling — Sat, 07 Nov 2009 02:10:03 +0100

Authors: Patel S, Docampo R Transient receptor potential (TRP) channels are a large family of cation channels, many of which are predominantly localized to the plasma membrane, where they transduce the effects of diverse and often sensory stimuli. Two members of the TRP melastatin subfamily, TRPM1 and TRPM2, are localized in intracellular compartments and are involved in melanin synthesis and oxidative stress-induced cell death, respectively. These findings provide new insight into the location and function of TRP channels. PMID: 19887679 [PubMed - in process] (Source: Science Signaling)

The Rfx4 transcription factor modulates Shh signaling by regional control of ciliogenesis.

Science Signaling — Sat, 07 Nov 2009 02:10:03 +0100

Authors: Ashique AM, Choe Y, Karlen M, May SR, Phamluong K, Solloway MJ, Ericson J, Peterson AS Regulatory factor X (Rfx) homologs regulate the transcription of genes necessary for ciliogenesis in invertebrates and vertebrates. Primary cilia are necessary for Hedgehog signaling and regulation of the activity of the transcriptional regulators known as Gli proteins, which are targets of Hedgehog signaling. Here, we describe an Rfx4(L298P) mouse mutant with distinct dorsoventral patterning defects in the ventral spinal cord and telencephalon due to aberrant Sonic hedgehog (Shh) signaling and Gli3 activity. We find that Ift172, which encodes an intraflagellar transport protein necessary for ciliogenesis, is a direct transcriptional target of Rfx4, and the decrease in its expression in the ...

Activation of a bacterial virulence protein by the GTPase RhoA.

Science Signaling — Sat, 07 Nov 2009 02:10:03 +0100

Authors: Christen M, Coye LH, Hontz JS, LaRock DL, Pfuetzner RA, Megha , Miller SI The Rho family of guanosine triphosphatases (GTPases) are essential eukaryotic signaling molecules that regulate cellular physiology. Virulence factors from various pathogens alter the signaling of GTPases by acting as GTPase activating factors, guanine nucleotide exchange factors, or direct covalent modifiers; however, bacterial virulence factors that sense rather than alter the signaling states of Rho GTPases have not been previously described. Here, we report that the translocated Salmonellae virulence factor SseJ binds to the guanosine triphosphate-bound form of RhoA. This interaction stimulates the lipase activity of SseJ, which results in the esterification of cholesterol in the host cell membrane....

Comprehensive determination of (3)J (HNHalpha) for unfolded proteins using (13)C'-resolved spin-echo difference spectroscopy.

Journal of Bimolecular NMR — Sat, 07 Nov 2009 00:00:00 +0100

Authors: Otten R, Wood K, Mulder FA An experiment is presented to determine (3)J(HNHalpha) coupling constants, with significant advantages for applications to unfolded proteins. The determination of coupling constants for the peptide chain using 1D (1)H, or 2D and 3D (1)H-(15)N correlation spectroscopy is often hampered by extensive resonance overlap when dealing with flexible, disordered proteins. In the experiment detailed here, the overlap problem is largely circumvented by recording (1)H-(13)C' correlation spectra, which demonstrate superior resolution for unfolded proteins. J-coupling constants are extracted from the peak intensities in a pair of 2D spin-echo difference experiments, affording rapid acquisition of the coupling data. In an application to the cytoplasmic domain of hu...

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How Plants Defend Themselves From Bacteria

NIGMS - Results — Fri, 06 Nov 2009 21:19:47 +0100

An NIGMS-funded plant pathologist has shown how a receptor molecule in plants pairs with a specific molecule on invading bacteria, triggering an immune reaction. (Source: NIGMS - Results)

Federal Funds Support Malaria Research

NIGMS - Results — Fri, 06 Nov 2009 21:13:19 +0100

NIGMS has issued a supplement grant to a researcher who is studying how the malaria parasite evolved resistance to the medication chloroquine. (Source: NIGMS - Results)

Guidance for Industry: Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Donors of Whole Blood and Blood Components Intended for Transfusion

What's New at CBER — Fri, 06 Nov 2009 18:05:00 +0100

(Source: What's New at CBER)

Approval History, Letters, Reviews and Related Documents - Berinert

What's New at CBER — Fri, 06 Nov 2009 13:30:00 +0100

(Source: What's New at CBER)

Tumor Biology

Springer Biomedical Sciences titles — Fri, 06 Nov 2009 00:35:13 +0100

Tumor Markers, Tumor Targeting and Translational Cancer Research (Source: Springer Biomedical Sciences titles)

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Application of Change-Point Problem to the Detection of Plant Patches.

Acta Biotheoretica — Fri, 06 Nov 2009 00:00:00 +0100

Authors: López I, Gámez M, Garay J, Standovár T, Varga Z In ecology, if the considered area or space is large, the spatial distribution of individuals of a given plant species is never homogeneous; plants form different patches. The homogeneity change in space or in time (in particular, the related change-point problem) is an important research subject in mathematical statistics. In the paper, for a given data system along a straight line, two areas are considered, where the data of each area come from different discrete distributions, with unknown parameters. In the paper a method is presented for the estimation of the distribution change-point between both areas and an estimate is given for the distributions separated by the obtained change-point. The solution of this ...

‘Self-manufacturing pill’ wins students international prizes

Imperial College News — Fri, 06 Nov 2009 00:00:00 +0100

Imperial College London students win a clutch of prizes at the 2009 International Genetically Engineered Machines (iGEM) (Source: Imperial College News)

CHO gene expression profiling in biopharmaceutical process analysis and design

Biotechnology and Bioengineering — Fri, 06 Nov 2009 00:00:00 +0100

Increase in both productivity and product yields in biopharmaceutical process development with recombinant protein producing mammalian cells can be mainly attributed to the advancements in cell line development, media, and process optimization. Only recently, genome-scale technologies enable a system-level analysis to elucidate the complex biomolecular basis of protein production in mammalian cells promising an increased process understanding and the deduction of knowledge-based approaches for further process optimization. Here, the use of gene expression profiling for the analysis of a low titer (LT) and high titer (HT) fed batch process using the same IgG producing CHO cell line was investigated. We found that gene expression (i) significantly differed in HT versus LT process conditions ...

Distribution, development and proliferation of interstitial cells of Cajal in murine colon: an immunohistochemical study from neonatal to adult life

Histochemistry and Cell Biology — Thu, 05 Nov 2009 18:57:31 +0100

Abstract This paper aimed at investigating the alterations in interstitial cells of Cajal (ICC) in the proximal, middle and distal colon of mice from 0-day to 56-day post-partum (P0–P56) by immunohistochemistry. The Kit+ ICC, which situated around myenteric nerve plexus (ICC–MY) were prominent at birth, meanwhile those cells within the smooth muscle layers (ICC–IM) and in the connective tissue beneath serosa (ICC–SS) began to appear. ICC–SM, which located at the submucosal border of circular muscle layer emerged at P6 in the proximal colon and subsequently in the distal colon at P8, and ICC in the oral side of colon revealed an earlier development in morphology and a higher density than that in the anal side. The density of ICC altered obviously during postnatal p...

Just Found

NIGMS Findings — Thu, 05 Nov 2009 14:00:00 +0100

Read about the body's inner clock, why we sleep, arsenic eating algae and more. Read more. (Source: NIGMS Findings)

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Special Delivery

NIGMS Findings — Thu, 05 Nov 2009 14:00:00 +0100

Lola Eniola-Adefeso takes aim at a top killer—heart disease—with microscopic plastic beads. These beads will deliver medicine in a controlled way to blood vessels. Read more. (Source: NIGMS Findings)

Green Light

NIGMS Findings — Thu, 05 Nov 2009 14:00:00 +0100

Using a molecule that makes creatures glow green, Marc Zimmer shows his students that chemistry can be cool. He also enlists his family pets—mice and fish that can turn a rainbow of colors. Read more. (Source: NIGMS Findings)

Measuring bone blood supply in mice using fluorescent microspheres

Nature Protocols — Thu, 05 Nov 2009 00:00:00 +0100

Nature Protocols 4, 1779 (2009). doi:10.1038/nprot.2009.190 Author: Maria A Serrat Fluorescent microspheres are commonly used to assess bone blood supply in large animals, but the technique is not widely used in smaller mammals, as traditional methods such as reference blood sampling, ventilation and catheterization are not easily applied. This protocol describes a viable alternative for (Source: Nature Protocols)

Evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb ischemia

Nature Protocols — Thu, 05 Nov 2009 00:00:00 +0100

Authors: Anne Limbourg, Thomas Korff, L Christian Napp, Wolfgang Schaper, Helmut Drexler & Florian P Limbourg Blood vessel growth in adult organisms involves the following two fundamental processes: angiogenesis, the proliferation and extension of capillary networks; and arteriogenesis, the growth of functional arteries. We provide a protocol for the evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb (Source: Nature Protocols)

Array painting: a protocol for the rapid analysis of aberrant chromosomes using DNA microarrays

Nature Protocols — Thu, 05 Nov 2009 00:00:00 +0100

Authors: Susan M Gribble, Bee Ling Ng, Elena Prigmore, Tomas Fitzgerald & Nigel P Carter Array painting is a technique that uses microarray technology to rapidly map chromosome translocation breakpoints. Previous methods to map translocation breakpoints have used fluorescence in situ hybridization (FISH) and have consequently been labor-intensive, time-consuming and restricted to the low breakpoint resolution imposed by the (Source: Nature Protocols)

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Assessment of pyrogenic contaminations with validated human whole-blood assay

Nature Protocols — Thu, 05 Nov 2009 00:00:00 +0100

We present an internationally validated protocol for the evaluation of pyrogenic contaminations using human whole blood. In the in vitro pyrogen test (IPT) the sample is incubated with fresh or cryopreserved human whole blood, and the proinflammatory cytokine interleukin-1β (IL-1β) is detected by enzyme-linked (Source: Nature Protocols)

TROSY-selected ZZ-exchange experiment for characterizing slow chemical exchange in large proteins.

Journal of Bimolecular NMR — Thu, 05 Nov 2009 00:00:00 +0100

Authors: Li Y, Palmer AG A TROSY-selected ZZ-exchange experiment is described for measuring slow chemical exchange rates by monitoring the TROSY component of (15)N longitudinal magnetization. Application of the proposed pulse sequence to the cadherin 8 N-terminal extracelluar domain demonstrates that enhanced sensitivity is obtained, compared to a previously described TROSY-detected ZZ-exchange sequence (Sahu et al. J Am Chem Soc 129: 13232-13237, 2007), by preserving the TROSY effect during the mixing period as well as the frequency encoding periods. PMID: 19890725 [PubMed - as supplied by publisher] (Source: Journal of Bimolecular NMR)

Anterior mitral leaflet curvature in the beating ovine heart: a case study using videofluoroscopic markers and subdivision surfaces.

Biomechanics and Modeling in Mechanobiology — Thu, 05 Nov 2009 00:00:00 +0100

Authors: Göktepe S, Bothe W, Kvitting JP, Swanson JC, Ingels NB, Miller DC, Kuhl E The implantation of annuloplasty rings is a common surgical treatment targeted to re-establish mitral valve competence in patients with mitral regurgitation. It is hypothesized that annuloplasty ring implantation influences leaflet curvature, which in turn may considerably impair repair durability. This research is driven by the vision to design repair devices that optimize leaflet curvature to reduce valvular stress. In pursuit of this goal, the objective of this manuscript is to quantify leaflet curvature in ovine models with and without annuloplasty ring using in vivo animal data from videofluoroscopic marker analysis. We represent the surface of the anterior mitral leaflet based on 23 radiopaque...

Important Registration and Listing Reminder for Manufacturers of Biological Drug Products Subject to 21 C.F.R. Part 207

What's New at CBER — Wed, 04 Nov 2009 19:46:00 +0100

(Source: What's New at CBER)

Clearer View on Eye Lens Proteins

NIGMS - Results — Wed, 04 Nov 2009 18:59:04 +0100

An NIGMS-funded study reveals how proteins critical for the transparency of the eye lens are properly sorted and located. (Source: NIGMS - Results)

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Gene Networks Involved in Alcohol Dependency

NIGMS - Results — Wed, 04 Nov 2009 18:55:57 +0100

NIGMS-funded researchers have used drunken fruit flies to identify networks of genes--also present in humans--that play a role in drinking behavior. (Source: NIGMS - Results)

Evolution of Human Complexity

NIGMS - Results — Wed, 04 Nov 2009 18:42:31 +0100

An NIGMS-funded analysis of thousands of genes and proteins shows that humans are complex, in part, because of the way we evolved to cope with redundancies among duplicate genes. (Source: NIGMS - Results)

Finding May Expedite Cholesterol Drug Production

NIGMS - Results — Wed, 04 Nov 2009 18:40:01 +0100

Researchers funded by NIGMS have successfully reconstituted the enzyme responsible for producing the blockbuster cholesterol-lowering drug lovastatin. (Source: NIGMS - Results)

Scientists reveal a new mechanism that increases atherosclerosis in mice

The Rockefeller University Newswire — Wed, 04 Nov 2009 15:15:00 +0100

For all the good it does, a liver protein that senses and gets rid of drugs and pollutants from our body has a downside. For the first time, it has been shown that when it is chronically activated, the protein, called PXR, rejiggers how cholesterol is processed in the liver and increases the risk of developing atherosclerosis. The work has direct clinical consequences to patients under long-term treatment of PXR-activating drugs, including several antibiotic and anti-cancer medications and your daily latte. (Source: The Rockefeller University Newswire)

Clopidogrel application: beyond coronary artery disease

Clinical Science — Wed, 04 Nov 2009 00:00:00 +0100

Dual antiplatelet therapy with aspirin and clopidogrel, a P2Y12 antagonist, is a cornerstone for treatment of patients with stroke, peripheral arterial disease, and acute coronary artery disease followed with or without percutaneous coronary intervention. Giachini and colleagues found that clopidogrel could normalize the increased phenylephrine-induced vascular contraction and impaired acetylcholine-induced vasodilatation in mesenteric arteries from angiotensin II-infused Sprague-Dawley rats. This might develop a new area for clopidogrel application. However, whether clopidogrel can improve the arterial function in patients with hypertension or diabetes, or whether clopidogrel outweighs the beneficial effect aspirin in those patients, remains an open field for future inquiry. (Source: Clin...

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The Energy Futures Lab celebrates becoming an Imperial institute and the opening of new premises

Imperial College News — Wed, 04 Nov 2009 00:00:00 +0100

New hub for energy research opens at the Imperial College London – News (Source: Imperial College News)

The Anti-Inflammatory Effects of a Methanolic Extract from Radix Isatidis in Murine Macrophages and Mice

Inflammation — Tue, 03 Nov 2009 21:34:03 +0100

Abstract Radix Isatidis is the dried root of the plant Isatidis indigotica Fort (family Cruciferae) and traditionally used as an anti-viral, anti-bacterial, anti-endotoxic, and immune regulatory agent in the folk medicine of Korea and China. The aim of the present study was to determine the anti-inflammatory effects of methanolic extracts of Radix Isatidis (RIME) in lipopolysaccharide (LPS)-stimulated murine macrophages and in a TPA-induced ear edema animal model. Anti-inflammatory effects of RIME were examined in LPS-stimulated RAW 264.7 macrophages. In order to investigate the effects of RIME in vivo, activation of myeloperoxidase, and histological assessment were examined in the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced mouse ear edema model. RIME significantl...

Immune system uses a leash to restrict HIVs spread

The Rockefeller University Newswire — Tue, 03 Nov 2009 21:00:00 +0100

New research shows how an antiviral protein, tetherin, lashes newborn viral particles to infected cells, slowing the spread of infection. Understanding how this immune system defense works against HIV, Ebola and other deadly viruses could lead to better antiviral therapies. (Source: The Rockefeller University Newswire)

Wider Vaccination Could Slow Flu Evolution

NIGMS - Results — Tue, 03 Nov 2009 20:12:44 +0100

An NIGMS-funded study suggests that vaccinating more people would slow the evolution of seasonal flu viruses, making vaccines more effective. (Source: NIGMS - Results)

ProQuad

What's New at CBER — Tue, 03 Nov 2009 16:51:00 +0100

The Approval Letter and Approved Final Draft Labeling for Merck's Efficacy Supplement for Measles, Mumps, Rubella, and Varicella Vaccine, Live, (ProQuad®), to include concomitant administration with hepatitis A vaccine (VAQTA®) and/or pneumococcal conjugate vaccine (Prevnar®), use of ProQuad® in children 15 months to 12 years of age if a second dose of measles, mumps, rubella, and varicella is needed, additional safety data after a first or second dose of ProQuad®, and to comply with the Physician’s Labeling Rule format, have been issued. (Source: What's New at CBER)

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Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

(Source: Journal of Clinical Investigation)

Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

Arteriovenous malformations (AVMs) are vascular anomalies where arteries and veins are directly connected through a complex, tangled web of abnormal arteries and veins instead of a normal capillary network. AVMs in the brain, lung, and visceral organs, including the liver and gastrointestinal tract, result in considerable morbidity and mortality. AVMs are the underlying cause of three major clinical symptoms of a genetic vascular dysplasia termed hereditary hemorrhagic telangiectasia (HHT), which is characterized by recurrent nosebleeds, mucocutaneous telangiectases, and visceral AVMs and caused by mutations in one of several genes, including activin receptor–like kinase 1 (ALK1). It remains unknown why and how selective blood vessels form AVMs, and there have been technical limita...

Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

We describe here the development of what we believe to be a novel in vitro model of HIV-1 latency that we used to search for compounds that can reverse latency. Human primary CD4+ T cells were transduced with the prosurvival molecule Bcl-2, and the resulting cells were shown to recapitulate the quiescent state of resting CD4+ T cells in vivo. Using this model system, we screened small-molecule libraries and identified a compound that reactivated latent HIV-1 without inducing global T cell activation, 5-hydroxynaphthalene-1,4-dione (5HN). Unlike previously described latency-reversing agents, 5HN activated latent HIV-1 through ROS and NF-κB without affecting nuclear factor of activated T cells (NFAT) and PKC, demonstrating that TCR pathways can be dissected and utilized to purge late...

The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

Patients with classic fibrodysplasia ossificans progressiva, a disorder characterized by extensive extraskeletal endochondral bone formation, share a recurrent mutation (R206H) within the glycine/serine-rich domain of ACVR1/ALK2, a bone morphogenetic protein type I receptor. Through a series of in vitro assays using several mammalian cell lines and chick limb bud micromass cultures, we determined that mutant R206H ACVR1 activated BMP signaling in the absence of BMP ligand and mediated BMP-independent chondrogenesis that was enhanced by BMP. We further investigated the interaction of mutant R206H ACVR1 with FKBP1A, a glycine/serine domain–binding protein that prevents leaky BMP type I receptor activation in the absence of ligand. The mutant protein exhibited reduced binding to FKBP1...

Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

In this study, when mice housed in a rodent, specific pathogen–free barrier room were challenged with MHC I mAb, there was significant protection from TRALI compared with nonbarrier mice. Priming mice with LPS restored lung injury with mAb challenge. Using TLR4-deficient bone marrow chimeras, the priming phenotype was restricted to animals with WT hematopoietic cells, and depletion of either neutrophils or platelets was protective. Both neutrophils and platelets were sequestered in the lungs of mice with TRALI, and retention of platelets was neutrophil dependent. Interestingly, treatment with aspirin prevented lung injury and mortality, but blocking the P selectin or CD11b/CD18 pathways did not. These data suggest a 2-step mechanism of TRALI: priming of hematopoietic cells, followe...

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Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

Atrial fibrillation is the most common clinical cardiac arrhythmia. It is often initiated by ectopic beats arising from the pulmonary veins and atrium, but the source and mechanism of these beats remains unclear. The melanin synthesis enzyme dopachrome tautomerase (DCT) is involved in intracellular calcium and reactive species regulation in melanocytes. Given that dysregulation of intracellular calcium and reactive species has been described in patients with atrial fibrillation, we investigated the role of DCT in this process. Here, we characterize a unique DCT-expressing cell population within murine and human hearts that populated the pulmonary veins, atria, and atrioventricular canal. Expression profiling demonstrated that this population expressed adrenergic and muscarinic receptors an...

Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

Rhabdomyosarcoma (RMS) is a childhood cancer originating from skeletal muscle, and patient survival is poor in the presence of metastatic disease. Few determinants that regulate metastasis development have been identified. The receptor tyrosine kinase FGFR4 is highly expressed in RMS tissue, suggesting a role in tumorigenesis, although its functional importance has not been defined. Here, we report the identification of mutations in FGFR4 in human RMS tumors that lead to its activation and present evidence that it functions as an oncogene in RMS. Higher FGFR4 expression in RMS tumors was associated with advanced-stage cancer and poor survival, while FGFR4 knockdown in a human RMS cell line reduced tumor growth and experimental lung metastases when the cells were transplanted into mice. Mor...

The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

A key adaptation to environmental hypoxia is an increase in erythropoiesis, driven by the hormone erythropoietin (EPO) through what is traditionally thought to be primarily a renal response. However, both neurons and astrocytes (the largest subpopulation of glial cells in the CNS) also express EPO following ischemic injury, and this response is known to ameliorate damage to the brain. To investigate the role of glial cells as a component of the systemic response to hypoxia, we created astrocyte-specific deletions of the murine genes encoding the hypoxia-inducible transcription factors HIF-1α and HIF-2α and their negative regulator von Hippel–Lindau (VHL) as well as astrocyte-specific deletion of the HIF target gene Vegf. We found that loss of the hypoxic response in...

Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

Tumor growth and progression rely upon angiogenesis, which is regulated by pro- and antiangiogenic factors, including members of the semaphorin family. By analyzing 3 different mouse models of multistep carcinogenesis, we show here that during angiogenesis, semaphorin 3A (Sema3A) is expressed in ECs, where it serves as an endogenous inhibitor of angiogenesis that is present in premalignant lesions and lost during tumor progression. Pharmacologic inhibition of endogenous Sema3A during the angiogenic switch, the point when pretumoral lesions initiate an angiogenic phase that persists throughout tumor growth, enhanced angiogenesis and accelerated tumor progression. By contrast, when, during the later stages of carcinogenesis following endogenous Sema3A downmodulation, Sema3A was ectopically r...

Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

The pathogenic mechanisms underlying acute pancreatitis are not clear. Two key pathologic acinar cell responses of this disease are vacuole accumulation and trypsinogen activation. We show here that both result from defective autophagy, by comparing the autophagic responses in rodent models of acute pancreatitis to physiologic autophagy triggered by fasting. Pancreatitis-induced vacuoles in acinar cells were greater in number and much larger than those induced with fasting. Degradation of long-lived proteins, a measure of autophagic efficiency, was markedly inhibited in in vitro pancreatitis, while it was stimulated by acinar cell starvation. Further, processing of the lysosomal proteases cathepsin L (CatL) and CatB into their fully active, mature forms was reduced in pancreatitis, as were...

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Autophagy regulates adipose mass and differentiation in mice

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

The relative balance between the quantity of white and brown adipose tissue can profoundly affect lipid storage and whole-body energy homeostasis. However, the mechanisms regulating the formation, expansion, and interconversion of these 2 distinct types of fat remain unknown. Recently, the lysosomal degradative pathway of macroautophagy has been identified as a regulator of cellular differentiation, suggesting that autophagy may modulate this process in adipocytes. The function of autophagy in adipose differentiation was therefore examined in the current study by genetic inhibition of the critical macroautophagy gene autophagy-related 7 (Atg7). Knockdown of Atg7 in 3T3-L1 preadipocytes inhibited lipid accumulation and decreased protein levels of adipocyte differentiation factors. Knockdown...

Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

In this study, we show that the abnormal cytokine production is related to impaired TLR4 signaling. Despite their abnormal response to LPS, Hfe KO macrophages produced amounts of TNF-α similar to those in WT cells after TLR2 stimulation. Consistent with this finding, LPS-induced activation of Mal/MyD88-dependent events was normal in the mutant macrophages. However, LPS-induced IFN-β expression, a TRAM/TRIF-dependent response activated by TLR4, was reduced by Hfe deficiency. This reduction could be replicated in WT macrophages with the use of iron chelators. In contrast, TLR3-activated expression of IFN-β, a TRIF-dependent response, was normal in Hfe KO macrophages and was unaffected by iron chelation. Our data suggest that low intracellular iron selectively impairs ...

Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

Spontaneous antitumor T cell responses in cancer patients are strongly controlled by Tregs, and increased numbers of tumor-infiltrating Tregs correlate with reduced survival. However, the tumor antigens recognized by Tregs in cancer patients and the impact of these cells on tumor-specific T cell responses have not been systematically characterized. Here we used a broad panel of long synthetic peptides of defined tumor antigens and normal tissue antigens to exploit a newly developed method to identify and compare ex vivo the antigen specificities of Tregs with those of effector/memory T cells in peripheral blood of colorectal cancer patients and healthy subjects. Tregs in tumor patients were highly specific for a distinct set of only a few tumor antigens, suggesting that Tregs exert T cell ...

Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm in mice

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

Aortic arch artery patterning defects account for approximately 20% of congenital cardiovascular malformations and are observed frequently in velocardiofacial syndrome (VCFS). In the current study, we screened for chromosome rearrangements in patients suspected of VCFS, but who lacked a 22q11 deletion or TBX1 mutation. One individual displayed hemizygous CHD7, which encodes a chromodomain protein. CHD7 haploinsufficiency is the major cause of coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, and ear anomalies/deafness (CHARGE) syndrome, but this patient lacked the major diagnostic features of coloboma and choanal atresia. Because a subset of CHARGE cases also display 22q11 deletions, we explored the embryological relationship between CHARGE and V...

Inactivation of Notch signaling in the renal collecting duct causes nephrogenic diabetes insipidus in mice

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

The heterogeneous cellular composition of the mammalian renal collecting duct enables regulation of fluid, electrolytes, and acid-base homeostasis, but the molecular mechanism of its development has yet to be elucidated. The Notch signaling pathway is involved in cell fate determination and has been implicated in proximal-distal patterning in the mammalian kidney. To investigate the role of Notch signaling in renal collecting duct development, we generated mice in which Mind bomb-1 (Mib1), an E3 ubiquitin ligase required for the initiation of Notch signaling, was specifically inactivated in the ureteric bud of the developing kidney. Mice lacking Mib1 in the renal collecting duct displayed increased urinary production, decreased urinary osmolality, progressive hydronephrosis, sodium wasting...

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Tregs control the development of symptomatic West Nile virus infection in humans and mice

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

West Nile virus (WNV) causes asymptomatic infection in most humans, but for undefined reasons, approximately 20% of immunocompetent individuals develop West Nile fever, a potentially debilitating febrile illness, and approximately 1% develop neuroinvasive disease syndromes. Notably, since its emergence in 1999, WNV has become the leading cause of epidemic viral encephalitis in North America. We hypothesized that CD4+ Tregs might be differentially regulated in subjects with symptomatic compared with those with asymptomatic WNV infection. Here, we show that in 32 blood donors with acute WNV infection, Tregs expanded significantly in the 3 months after index (RNA+) donations in all subjects. Symptomatic donors exhibited lower Treg frequencies from 2 weeks through 1 year after index donation y...

Tyrosine and serine phosphorylation of {alpha}-synuclein have opposing effects on neurotoxicity and soluble oligomer formation

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

Mutations in the neuronal protein α-synuclein cause familial Parkinson disease. Phosphorylation of α-synuclein at serine 129 is prominent in Parkinson disease and influences α-synuclein neurotoxicity. Here we report that α-synuclein is also phosphorylated at tyrosine 125 in transgenic Drosophila expressing wild-type human α-synuclein and that this tyrosine phosphorylation protects from α-synuclein neurotoxicity in a Drosophila model of Parkinson disease. Western blot analysis of fly brain homogenates showed that levels of soluble oligomeric species of α-synuclein were increased by phosphorylation at serine 129 and decreased by tyrosine 125 phosphorylation. Tyrosine 125 phosphorylation diminished during the normal aging process in both...

Suppression of KATP channel activity protects murine pancreatic {beta} cells against oxidative stress

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

The enhanced oxidative stress associated with type 2 diabetes mellitus contributes to disease pathogenesis. We previously identified plasma membrane–associated ATP-sensitive K+ (KATP) channels of pancreatic β cells as targets for oxidants. Here, we examined the effects of genetic and pharmacologic ablation of KATP channels on loss of mouse β cell function and viability following oxidative stress. Using mice lacking the sulfonylurea receptor type 1 (Sur1) subunit of KATP channels, we found that, compared with insulin secretion by WT islets, insulin secretion by Sur1–/– islets was less susceptible to oxidative stress induced by the oxidant H2O2. This was likely, at least in part, a result of the reduced ability of H2O2 to hyperpolarize plasma membrane ...

Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in mice

Journal of Clinical Investigation — Tue, 03 Nov 2009 15:54:21 +0100

In this study, we found by RT-PCR analysis that mouse hepatocytes expressed the membrane proteoglycans syndecan-1, -2, and -4 and glypican-1 and -4. Analysis of available proteoglycan-deficient mice showed that only syndecan-1 mutants (Sdc1–/– mice) accumulated plasma triglycerides. Sdc1–/– mice also exhibited prolonged circulation of injected human VLDL and intestinally derived chylomicrons. We found that mice lacking both syndecan-1 and hepatocyte heparan sulfate did not display accentuated triglyceride accumulation compared with single mutants, suggesting that syndecan-1 is the primary HSPG mediating hepatic triglyceride clearance. Immunoelectron microscopy showed that syndecan-1 was expressed specifically on the microvilli of hepatocyte basal membranes, ...

MedWorm: Biomedical Science

PKM2 Tyrosine Phosphorylation and Glutamine Metabolism Signal a Different View of the Warburg Effect.

Acetylation Goes Global: The Emergence of Acetylation Biology.

Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth.

Trypanosoma cruzi Targets Akt in Host Cells as an Intracellular Antiapoptotic Strategy.

ALBAclone (Alba Bioscience Limited)

Herbal Medicine May Counter Pain Killer's Liver Toxicity

NIGMS ‘Challenge’ Areas Get Millions in Recovery Act Funds

Scientists identify DNA that regulates antibody production

New research helps explain why bird flu has not caused a pandemic

Synchronous culture of Plasmodium falciparum at high parasitemia levels

Global identification of protein kinase substrates by protein microarray analysis

Determination of gene expression patterns using in situ hybridization to Drosophila testes

Protocols to detect senescence-associated beta-galactosidase (SA-βgal) activity, a biomarker of senescent cells in culture and in vivo

Hydrodynamic modulation of embryonic stem cell differentiation by rotary orbital suspension culture

How Viruses Destroy Bacteria

Prolonged Administration Enhances the Renoprotective Effect of Pentoxifylline via Anti-Inflammatory Activity in Streptozotocin-Induced Diabetic Nephropathy

Expression and immunolocalization of ERG1 potassium channels in the rat kidney

Computational simulation of spontaneous bone straightening in growing children.

Eight religions come together at Imperial to mark National InterFaith Week

Students plan record-breaking zero emission ‘supercar’ journey along world’s longest road

Cytoskeleton Directs Chromosome Dance in Meiosis

Shaham and Chalasani named winners of 2009 Blavatnik Awards

Stimulus Funds Go to Stem Cell Research in Nebraska

Antioxidant Has Implications for Treating Cystic Fibrosis

Imperial Sustainable Energy Futures MSc scoops Innovation award

HIV vaccine failure probably caused by virus used, says new research

Scientists discover cells that control inflammation in chronic disease

A mechanistic model of infection: why duration and intensity of contacts should be included in models of disease spread

Scientists Guide Immune Cells with Light and Microparticles

Why Some Drug Combinations Backfire

Imaging study shows HIV particles assembling around its genome

Predicting Side Effects and Repurposing Drugs

Predicting Side Effects and Repurposing Drugs

Assessment of risk factors for osteoporosis and fractures in children with meningomyelocele.

Sleep-wake schedules in preschool children who snore.

Rector of Imperial College London

Imperial inspires school pupils with creative science

Sex Hormones and Immunity to Infection

A microscale protein NMR sample screening pipeline.

Platelet PGD Test System (2009)

Schisantherin A Exhibits Anti-inflammatory Properties by Down-Regulating NF-κB and MAPK Signaling Pathways in Lipopolysaccharide-Treated RAW 264.7 Cells

Erratum to: Ultrastructural characterization of giant endosomes induced by GTPase-deficient Rab5

Notes to Contributors

Editorial Board

Contents

Masthead

Draft Guidance for Industry: Recommendations for the Assessment of Blood Donor Suitability, Blood Product Safety, and Preservation of the Blood Supply in Response to Pandemic (H1N1) 2009 Virus

Seams in HIV Coat Could Lead to New Drugs

Lipids Trigger Death of Brain Cells in Rare Disorder

Reactive oxygen and nitrogen species induce protein and DNA modifications driving arthrofibrosis following total knee arthroplasty

Enhancement of ethanol and biogas production from high-crystalline cellulose by different modes of NMO pretreatment

Two proteins act as molecular tailors in DNA repair

Two submucosal nerve plexus in human intestines

Focus Issue: Coping with Cellular Stress.

Science Signaling Podcast: 10 November 2009.

Aiming Straight for the Heart: Prolyl Hydroxylases Set the BAR.

A New Mechanism of Phosphoregulation in Signal Transduction Pathways.

A Gluconeogenic Tryst in the Nucleus, with ER Stress as the Third Wheel.

FBXO31: A New Player in the Ever-Expanding DNA Damage Response Orchestra.

Nutrition-Minded Cell Cycle.

H2S Signals Through Protein S-Sulfhydration.

Pharmaceutical Suspensions

Trafficking Inside Cells

Optical Imaging of Cancer

Biological Boundaries and Biological Age.

Simultaneous analysis of reactive oxygen species and reduced glutathione content in living cells by polychromatic flow cytometry

Efficient expression of tyrosine-sulfated proteins in E. coli using an expanded genetic code

High-throughput haplotype determination over long distances by haplotype fusion PCR and ligation haplotyping

High-yield cell-free protein production from P-gel

Research gives new insights into 4 billion year-old meteorites

Imperial to lead £2.7 million study as part of UK's response to swine flu

A century of supporting sport celebrated at Imperial’s Harlington Sports Ground

£4.9 million to develop metamaterials for 'invisibility cloaks' and 'perfect lenses'

High fat diet increases inflammation in the mouse colon

New Four-Step Approach to Genome Annotation

Characterization of ERK Activation in Human Mast Cells Stimulated by Contact with T Cells

Simultaneous RP-HPLC-DAD quantification of bromocriptine, haloperidol and its diazepane structural analog in rat plasma with droperidol as internal standard for application to drug-interaction pharmacokinetics.

A simple, selective and rapid validated method for estimation of anastrazole in human plasma by liquid chromatography-tandem mass spectrometry and its application to bioequivalence study.

Quantitative sphingosine measurement as a surrogate for total ceramide concentration-preclinical and potential translational applications.

Immune system uses a leash to restrict HIVs spread