Potential drug candidates for "bird flu"
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Looking to prepare for a possible outbreak of drug-resistant avian flu, NIGMS-funded researchers have identified more than two dozen new candidate drugs. (Source: NIGMS - Results)
Source: NIGMS - Results - July 4, 2008 Category: Biomedical Science Source Type: news
P53 brings a new twist to the smad signaling network.
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p53 brings a new twist to the Smad signaling network.
Sci Signal. 2008;1(26):pe33
Authors: Atfi A, Baron R
Transforming growth factor beta (TGF-beta) signaling regulates a plethora of cellular responses, including specification of developmental fate during embryogenesis, cell proliferation, differentiation, and apoptosis. Components of this pathway are often mutated in cancers and other human disorders. TGF-beta signaling involves activation of transcriptional regulators of the Smad family. The tumor suppressor p53 is an essential partner of Smads, affecting TGF-beta signaling at various points in the pathway. ...
Source: Science Signaling - July 4, 2008 Category: Biomedical Science Authors: Atfi A, Baron R Tags: Sci Signal Source Type: journals
Uncoupling the role of sonic hedgehog in limb development: growth and specification.
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Sonic hedgehog (Shh) signaling is essential for the anterior-posterior (A-P) patterning of the embryonic limb bud. An additional role for Shh has now been identified in the mouse and chick, in which Shh promotes the proliferation of limb mesenchymal cells, which increases the number of digits that form. Surprisingly, these data are not consistent with any of the previous models in the mouse that described roles for Shh and the zone of polarizing activity in the patterning of the A-P axis. Therefore, new light is shed on the mechanisms of Shh action, which both challenges our understanding of limb development and gives ...
Source: Science Signaling - July 4, 2008 Category: Biomedical Science Authors: Francis-West P, Hill R Tags: Sci Signal Source Type: journals
Differential expression pattern of protein arvcf in nephron segments of human and mouse kidney
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Abstract The protein ARVCF is a member of the p120 subfamily of armadillo proteins whose members have been described to occur in junction-bound and non-junction-bound forms. Studies on ARVCF were
constrained because the endogenous protein was difficult to detect with the available reagents. We have generated novel monoclonal
and polyclonal antibodies usable for biochemical and localization studies. By systematic immunohistochemical analysis of various
tissues protein ARVCF is prominently detected in mouse, bovine and human kidney. Using antibodies against specific markers
of nephron segments protein ARVCF is...
Source: Histochemistry and Cell Biology - July 4, 2008 Category: Biomedical Science Tags: Histochemistry and Cell Biology Source Type: journals
Increased number of microglia in the brain of severe combined immunodeficient (scid) mice
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Abstract To assess the in vivo influence of the systemic immune system upon microglia, six defined brain regions of adult SCID mice
(n = 10) lacking functional T- and B-lymphocytes have been analyzed by NDPase histochemistry, morphometry and immunohistochemistry.
Despite absence of neuropathology and lack of microglial activation, microglial numerical density was significantly increased
in SCID mice. Elevation was most marked in the cerebellar granular layer (by 32.6%; 95% confidence interval: 9.9–58.7%), followed
by the fimbria hippocampi and the molecular layer of hippocampal CA1/CA3 region. Th...
Source: Histochemistry and Cell Biology - July 4, 2008 Category: Biomedical Science Tags: Histochemistry and Cell Biology Source Type: journals
Cognitive computation
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Cognitive Computation is an international, peer-reviewed, interdisciplinary journal that publishes cutting-edge articles describing original basic and applied work involving biologically-inspired computational accounts of all aspects of natural and artificial cognitive systems. It provides a new platform for the dissemination of research, current practices and future trends in the emerging ... (Source: Springer Biomedical Sciences titles)
Source: Springer Biomedical Sciences titles - July 3, 2008 Category: Biomedical Science Tags: Neurosciences Source Type: organizations
Understanding anesthesia fact sheet
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(Source: NIGMS - What's New)
Source: NIGMS - What's New - July 3, 2008 Category: Biomedical Science Source Type: organizations
Cell-type-specific expression of murine multifunctional galectin-3 and its association with follicular atresia/luteolysis in contrast to pro-apoptotic galectins-1 and -7
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This study demonstrates cell-type specificity and cycle-associated regulation for galectin-3 with increased presence in atretic
preantral follicles and in late stages of luteolysis.
Content Type Journal ArticleCategory Original PaperDOI 10.1007/s00418-008-0465-0Authors
Michaela Lohr, Ludwig Maximilians University Institute of Physiological Chemistry, Faculty of Veterinary Medicine Munich GermanyHerbert Kaltner, Ludwig Maximilians University Institute of Physiological Chemistry, Faculty of Veterinary Medicine Munich GermanyMartin Lensch, Ludwig Maximilians University Institute of Physiological Chemistry, Faculty of Ve...
Source: Histochemistry and Cell Biology - July 3, 2008 Category: Biomedical Science Tags: Histochemistry and Cell Biology Source Type: journals
Reactive oxygen species in phagocytic leukocytes
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Abstract Phagocytic leukocytes consume oxygen and generate reactive oxygen species in response to appropriate stimuli. The phagocyte
NADPH oxidase, a multiprotein complex, existing in the dissociated state in resting cells becomes assembled into the functional
oxidase complex upon stimulation and then generates superoxide anions. Biochemical aspects of the NADPH oxidase are briefly
discussed in this review; however, the major focus relates to the contributions of various modes of microscopy to our understanding
of the NADPH oxidase and the cell biology of phagocytic leukocytes.
Content Type Journal Articl...
Source: Histochemistry and Cell Biology - July 3, 2008 Category: Biomedical Science Tags: Histochemistry and Cell Biology Source Type: journals
Nih support for conferences and scientific meetings (parent r13/u13)
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(Source: NIGMS - What's New)
Source: NIGMS - What's New - July 2, 2008 Category: Biomedical Science Source Type: organizations
New checkpoint in cell division
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NIGMS-funded researchers have discovered a previously unknown checkpoint that helps cells divide only when they're ready. (Source: NIGMS - Results)
Source: NIGMS - Results - July 2, 2008 Category: Biomedical Science Source Type: news
Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the cns of siv-infected macaques
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HIV infiltrates the CNS soon after an individual has become infected with the virus, and can cause dementia and encephalitis in late-stage disease. Here, a global metabolomics approach was used to find and identify metabolites differentially regulated in the cerebrospinal fluid (CSF) of rhesus macaques with SIV-induced CNS disease, as we hypothesized that this might provide biomarkers of virus-induced CNS damage. The screening platform used a non-targeted, mass-based metabolomics approach beginning with capillary reverse phase chromatography and electrospray ionization with accurate mass determination, followed by novel, n...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: William R. Wikoff, Gurudutt Pendyala, Gary Siuzdak, Howard S. Fox Source Type: journals
Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model
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Disablement of cell death programs in cancer cells contributes to drug resistance and in some cases has been associated with altered translational control. As eukaryotic translation initiation factor 4E (eIF4E) cooperates with c-Myc during lymphomagenesis, induces drug resistance, and is a genetic modifier of the rapamycin response, we have investigated the effect of dysregulation of the ribosome recruitment phase of translation initiation on tumor progression and chemosensitivity. eIF4E is a subunit of eIF4F, a complex that stimulates ribosome recruitment during translation initiation by delivering the DEAD-box RNA helica...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Marie-Eve Bordeleau, Francis Robert, Baudouin Gerard, Lisa Lindqvist, Samuel M.H. Chen, Hans-Guido Wendel, Brigitte Brem, Harald Greger, Scott W. Lowe, John A. Porco, Jerry Pelletier Source Type: journals
Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice
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In this study, we have taken advantage of the highly restricted coexpression of adipocyte/macrophage fatty acid–binding proteins (FABPs) aP2 (FABP4) and mal1 (FABP5) to examine the contribution of these lipid chaperones in macrophages and adipocytes to local and systemic inflammation and metabolic homeostasis in mice. Deletion of FABPs in adipocytes resulted in reduced expression of inflammatory cytokines in macrophages, whereas the same deletion in macrophages led to enhanced insulin signaling and glucose uptake in adipocytes. Using radiation chimerism through bone marrow transplantation, we generated mice with FA...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Masato Furuhashi, Raquel Fucho, Cem Z. Görgün, Gürol Tuncman, Haiming Cao, Gökhan S. Hotamisligil Source Type: journals
Tgf-{beta}-dependent suppressive function of tregs requires wild-type levels of cd18 in a mouse model of psoriasis
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This study may provide a step forward in our understanding of the unique role of CD18 expression levels in avoiding autoimmunity. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Honglin Wang, Thorsten Peters, Anca Sindrilaru, Daniel Kess, Tsvetelina Oreshkova, Xue-Zhong Yu, Anne Maria Seier, Heike Schreiber, Meinhard Wlaschek, Robert Blakytny, Jan Röhrbein, Guido Schulz, Johannes M. Weiss, Karin Scharffetter-Kochanek Source Type: journals
Variations in the g6pc2/abcb11 genomic region are associated with fasting glucose levels
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Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 × 10–7). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Wei-Min Chen, Michael R. Erdos, Anne U. Jackson, Richa Saxena, Serena Sanna, Kristi D. Silver, Nicholas J. Timpson, Torben Hansen, Marco Orrù, Maria Grazia Piras, Lori L. Bonnycastle, Cristen J. Willer, Valeriya Lyssenko, Haiqing Shen, Johanna Kuu Source Type: journals
Acquired resistance to egfr tyrosine kinase inhibitors in cancer cells is mediated by loss of igf-binding proteins
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Although some cancers are initially sensitive to EGFR tyrosine kinase inhibitors (TKIs), resistance invariably develops. We investigated mechanisms of acquired resistance to the EGFR TKI gefitinib by generating gefitinib-resistant (GR) A431 squamous cancer cells. In GR cells, gefitinib reduced phosphorylation of EGFR, ErbB-3, and Erk but not Akt. These cells also showed hyperphosphorylation of the IGFI receptor (IGFIR) and constitutive association of IRS-1 with PI3K. Inhibition of IGFIR signaling disrupted the association of IRS-1 with PI3K and restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inh...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Marta Guix, Anthony C. Faber, Shizhen Emily Wang, Maria Graciela Olivares, Youngchul Song, Sherman Qu, Cammie Rinehart, Brenda Seidel, Douglas Yee, Carlos L. Arteaga, Jeffrey A. Engelman Source Type: journals
Genetic variants of mirna sequences and non-small cell lung cancer survival
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Recent evidence indicates that small noncoding RNA molecules known as microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Mutation, misexpression, and altered mature miRNA processing are implicated in carcinogenesis and tumor progression. Because SNPs in pre-miRNAs could alter miRNA processing, expression, and/or binding to target mRNA, we conducted a systematic survey of common pre-miRNA SNPs and their surrounding regions and evaluated in detail the association of 4 of these SNPs with the survival of individuals with non–small cell lung cancer (NSCLC). When we assumed that disease susceptibility wa...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Zhibin Hu, Jiaping Chen, Tian Tian, Xiaoyi Zhou, Haiyong Gu, Lin Xu, Yi Zeng, Ruifen Miao, Guangfu Jin, Hongxia Ma, Yijiang Chen, Hongbing Shen Source Type: journals
Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice
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Infantile hemangioma is a benign endothelial tumor composed of disorganized blood vessels. It exhibits a unique life cycle of rapid postnatal growth followed by slow regression to a fibrofatty residuum. Here, we have reported the isolation of multipotential stem cells from hemangioma tissue that give rise to hemangioma-like lesions in immunodeficient mice. Cells were isolated based on expression of the stem cell marker CD133 and expanded from single cells as clonal populations. The CD133-selected cells generated human blood vessels 7 days after implantation in immunodeficient mice. Cell retrieval experiments showed the cel...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Zia A. Khan, Elisa Boscolo, Arnaud Picard, Sarah Psutka, Juan M. Melero-Martin, Tatianna C. Bartch, John B. Mulliken, Joyce Bischoff Source Type: journals
Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli
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Increased hunger and food intake during attempts to maintain weight loss are a critical problem in clinical management of obesity. To determine whether reduced body weight maintenance is accompanied by leptin-sensitive changes in neural activity in brain regions affecting regulatory and hedonic aspects of energy homeostasis, we examined brain region–specific neural activity elicited by food-related visual cues using functional MRI in 6 inpatient obese subjects. Subjects were assessed at their usual weight and, following stabilization at a 10% reduced body weight, while receiving either twice daily subcutaneous inje...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Michael Rosenbaum, Melissa Sy, Katherine Pavlovich, Rudolph L. Leibel, Joy Hirsch Source Type: journals
Cigarette smoke-induced neurogenic inflammation is mediated by {alpha},{beta}-unsaturated aldehydes and the trpa1 receptor in rodents
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Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 α,β-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce neurogenic inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca2+ in cultured gu...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Eunice Andrè, Barbara Campi, Serena Materazzi, Marcello Trevisani, Silvia Amadesi, Daniela Massi, Christophe Creminon, Natalya Vaksman, Romina Nassini, Maurizio Civelli, Pier Giovanni Baraldi, Daniel P. Poole, Nigel W. Bunnett, Pierangelo Geppetti Source Type: journals
Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent dc functions and regulates experimental graft-versus-host disease in mice
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Histone deacetylase (HDAC) inhibitors are antitumor agents that also have antiinflammatory properties. However, the mechanisms of their immunomodulatory functions are not known. We investigated the mechanisms of action of 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and ITF 2357, on mouse DC responses. Pretreatment of DCs with HDAC inhibitors significantly reduced TLR-induced secretion of proinflammatory cytokines, suppressed the expression of CD40 and CD80, and reduced the in vitro and in vivo allostimulatory responses induced by the DCs. In addition, injection of DCs treated ex vivo with HDAC inhibitors redu...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Pavan Reddy, Yaping Sun, Tomomi Toubai, Raimon Duran-Struuck, Shawn G. Clouthier, Elizabeth Weisiger, Yoshinobu Maeda, Isao Tawara, Oleg Krijanovski, Erin Gatza, Chen Liu, Chelsea Malter, Paolo Mascagni, Charles A. Dinarello, James L.M. Ferrara Source Type: journals
Fever-induced qtc prolongation and ventricular arrhythmias in individuals with type 2 congenital long qt syndrome
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Type 2 congenital long QT syndrome (LQT-2) is linked to mutations in the human ether a-go-go–related gene (HERG) and is characterized by rate-corrected QT interval (QTc) prolongation, ventricular arrhythmias, syncope, and sudden death. Recognized triggers of these cardiac events include emotional and acoustic stimuli. Here we investigated the repeated occurrence of fever-induced polymorphic ventricular tachycardia and ventricular fibrillation in 2 LQT-2 patients with A558P missense mutation in HERG. ECG analysis showed increased QTc with fever in both patients. WT, A558P, and WT+A558P HERG were expressed heterologo...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Ahmad S. Amin, Lucas J. Herfst, Brian P. Delisle, Christine A. Klemens, Martin B. Rook, Connie R. Bezzina, Heather A.S. Underkofler, Katherine M. Holzem, Jan M. Ruijter, Hanno L. Tan, Craig T. January, Arthur A.M. Wilde Source Type: journals
Vamp8 is the v-snare that mediates basolateral exocytosis in a mouse model of alcoholic pancreatitis
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In rodents and humans, alcohol exposure has been shown to predispose the pancreas to cholinergic or viral induction of pancreatitis. We previously developed a rodent model in which exposure to an ethanol (EtOH) diet, followed by carbachol (Cch) stimulation, redirects exocytosis from the apical to the basolateral plasma membrane of acinar cells, resulting in ectopic zymogen enzyme activation and pancreatitis. This redirection of exocytosis involves a soluble NSF attachment receptor (SNARE) complex consisting of syntaxin-4 and synapse-associated protein of 23 kDa (SNAP-23). Here, we investigated the role of the zymogen granu...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Laura I. Cosen-Binker, Marcelo G. Binker, Cheng-Chun Wang, Wanjin Hong, Herbert Y. Gaisano Source Type: journals
Succinate receptor gpr91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney
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Diabetes mellitus is the most common and rapidly growing cause of end-stage renal disease in developed countries. A classic hallmark of early diabetes mellitus includes activation of the renin-angiotensin system (RAS), which may lead to hypertension and renal tissue injury, but the mechanism of RAS activation is elusive. Here we identified a paracrine signaling pathway in the kidney in which high levels of glucose directly triggered the release of the prohypertensive hormone renin. The signaling cascade involved the local accumulation of succinate and activation of the kidney-specific G protein–coupled metabolic re...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Ildikó Toma, Jung Julie Kang, Arnold Sipos, Sarah Vargas, Eric Bansal, Fiona Hanner, Elliott Meer, János Peti-Peterdi Source Type: journals
Dna damage induced by chronic inflammation contributes to colon carcinogenesis in mice
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Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epitheli...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Lisiane B. Meira, James M. Bugni, Stephanie L. Green, Chung-Wei Lee, Bo Pang, Diana Borenshtein, Barry H. Rickman, Arlin B. Rogers, Catherine A. Moroski-Erkul, Jose L. McFaline, David B. Schauer, Peter C. Dedon, James G. Fox, Leona D. Samson Source Type: journals
Phosphorylation of gsk-3{beta} by cgmp-dependent protein kinase ii promotes hypertrophic differentiation of murine chondrocytes
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cGMP-dependent protein kinase II (cGKII; encoded by PRKG2) is a serine/threonine kinase that is critical for skeletal growth in mammals; in mice, cGKII deficiency results in dwarfism. Using radiographic analysis, we determined that this growth defect was a consequence of an elongated growth plate and impaired chondrocyte hypertrophy. To investigate the mechanism of cGKII-mediated chondrocyte hypertrophy, we performed a kinase substrate array and identified glycogen synthase kinase–3β (GSK-3β; encoded by Gsk3b) as a principal phosphorylation target of cGKII. In cultured mouse chondrocytes, phosphoryl...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Yosuke Kawasaki, Fumitaka Kugimiya, Hirotaka Chikuda, Satoru Kamekura, Toshiyuki Ikeda, Naohiro Kawamura, Taku Saito, Yusuke Shinoda, Akiro Higashikawa, Fumiko Yano, Toru Ogasawara, Naoshi Ogata, Kazuto Hoshi, Franz Hofmann, James R. Woodgett, Kozo Nakamu Source Type: journals
Mutations in the nervous system-specific hsn2 exon of wnk1 cause hereditary sensory neuropathy type ii
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We report here that HSN2 is a nervous system–specific exon of the with-no-lysine(K)–1 (WNK1) gene. WNK1 mutations have previously been reported to cause pseudohypoaldosteronism type II but have not been studied in the nervous system. Given the high degree of conservation of WNK1 between mice and humans, we characterized the structure and expression patterns of this isoform in mice. Immunodetections indicated that this Wnk1/Hsn2 isoform was expressed in sensory components of the peripheral nervous system and CNS associated with relaying sensory and nociceptive signals, including satellite cells, Schwann cell...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Masoud Shekarabi, Nathalie Girard, Jean-Baptiste Rivière, Patrick Dion, Martin Houle, André Toulouse, Ronald G. Lafrenière, Freya Vercauteren, Pascale Hince, Janet Laganiere, Daniel Rochefort, Laurence Faivre, Mark Samuels, Guy A. Source Type: journals
Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke
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In this study, human OECs/olfactory nerve fibroblasts (hOECs/ONFs) specifically secreted trophic factors including stromal cell–derived factor–1α (SDF-1α). Rats with intracerebral hOEC/ONF implantation showed more improvement on behavioral measures of neurological deficit following stroke than control rats. [18F]fluoro-2-deoxyglucose PET (FDG-PET) showed increased glucose metabolic activity in the hOEC/ONF-treated group compared with controls. In mice, transplanted hOECs/ONFs and endogenous homing stem cells including intrinsic neural progenitor cells and bone marrow stem cells colocalized w...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Woei-Cherng Shyu, Demeral David Liu, Shinn-Zong Lin, Wen-Wen Li, Ching-Yuan Su, Ying-Chen Chang, Hsiao-Jung Wang, Hsing-Won Wang, Chang-Hai Tsai, Hung Li Source Type: journals
Hypocretin/orexin and nociceptin/orphanin fq coordinately regulate analgesia in a mouse model of stress-induced analgesia
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Stress-induced analgesia (SIA) is a key component of the defensive behavioral “fight-or-flight” response. Although the neural substrates of SIA are incompletely understood, previous studies have implicated the hypocretin/orexin (Hcrt) and nociceptin/orphanin FQ (N/OFQ) peptidergic systems in the regulation of SIA. Using immunohistochemistry in brain tissue from wild-type mice, we identified N/OFQ-containing fibers forming synaptic contacts with Hcrt neurons at both the light and electron microscopic levels. Patch clamp recordings in GFP-tagged mouse Hcrt neurons revealed that N/OFQ hyperpolarized, decreased...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Xinmin Xie, Jonathan P. Wisor, Junko Hara, Tara L. Crowder, Robin LeWinter, Taline V. Khroyan, Akihiro Yamanaka, Sabrina Diano, Tamas L. Horvath, Takeshi Sakurai, Lawrence Toll, Thomas S. Kilduff Source Type: journals
Hip1r is expressed in gastric parietal cells and is required for tubulovesicle formation and cell survival in mice
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In this study, we demonstrate that Hip1r is abundantly expressed in the gastric parietal cell, predominantly localizing with F-actin to canalicular membranes. Hip1r may provide a critical function in vivo, as demonstrated by extensive changes to parietal cells and the gastric epithelium in Hip1r-deficient mice. Electron microscopy revealed abnormal apical canalicular membranes and loss of tubulovesicles in mutant parietal cells, suggesting that Hip1r is necessary for the normal trafficking of these secretory membranes. Accordingly, acid secretory dynamics were altered in mutant parietal cells, with enhanced activation and ...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Renu N. Jain, Asma A. Al-Menhali, Theresa M. Keeley, Jianhua Ren, Mohammed El-Zaatari, Xunsheng Chen, Juanita L. Merchant, Theodora S. Ross, Catherine S. Chew, Linda C. Samuelson Source Type: journals
Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed
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The current model of measles virus (MV) pathogenesis implies that apical infection of airway epithelial cells precedes systemic spread. An alternative model suggests that primarily infected lymphatic cells carry MV to the basolateral surface of epithelial cells, supporting MV shedding into the airway lumen and contagion. This model predicts that a mutant MV, unable to enter cells through the unidentified epithelial cell receptor (EpR), would remain virulent but not be shed. To test this model, we identified residues of the MV attachment protein sustaining EpR-mediated cell fusion. These nonpolar or uncharged polar residues...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Vincent H.J. Leonard, Patrick L. Sinn, Gregory Hodge, Tanner Miest, Patricia Devaux, Numan Oezguen, Werner Braun, Paul B. McCray, Michael B. McChesney, Roberto Cattaneo Source Type: journals
Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin
discuss this article
Neutrophil granulocytes form the body’s first line of antibacterial defense, but they also contribute to tissue injury and noninfectious, chronic inflammation. Proteinase 3 (PR3) and neutrophil elastase (NE) are 2 abundant neutrophil serine proteases implicated in antimicrobial defense with overlapping and potentially redundant substrate specificity. Here, we unraveled a cooperative role for PR3 and NE in neutrophil activation and noninfectious inflammation in vivo, which we believe to be novel. Mice lacking both PR3 and NE demonstrated strongly diminished immune complex–mediated (IC-mediated) neutrophil in...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Kai Kessenbrock, Leopold Fröhlich, Michael Sixt, Tim Lämmermann, Heiko Pfister, Andrew Bateman, Azzaq Belaaouaj, Johannes Ring, Markus Ollert, Reinhard Fässler, Dieter E. Jenne Source Type: journals
Chronic lymphocytic leukemia t cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug
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Cancer is associated with immune deficiency, but the biologic basis of this is poorly defined. Here we demonstrate that impaired actin polymerization results in CD4+ and CD8+ T cells from patients with chronic lymphocytic leukemia (CLL) exhibiting defective immunological synapse formation with APCs. Although this synapse dysfunction was in part a result of the CLL cells having poor APC function, defective actin polymerization was also identified in T cells from patients with CLL. We further demonstrate that, following contact with CLL cells, defects in immune synapse formation were induced in healthy allogeneic T cells. Th...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Alan G. Ramsay, Amy J. Johnson, Abigail M. Lee, Güllü Gorgün, Rifca Le Dieu, William Blum, John C. Byrd, John G. Gribben Source Type: journals
The transcription factor ifn regulatory factor-4 controls experimental colitis in mice via t cell-derived il-6
discuss this article
The proinflammatory cytokine IL-6 seems to have an important role in the intestinal inflammation that characterizes inflammatory bowel diseases (IBDs) such as Crohn disease and ulcerative colitis. However, little is known about the molecular mechanisms regulating IL-6 production in IBD. Here, we assessed the role of the transcriptional regulator IFN regulatory factor–4 (IRF4) in this process. Patients with either Crohn disease or ulcerative colitis exhibited increased IRF4 expression in lamina propria CD3+ T cells as compared with control patients. Consistent with IRF4 having a regulatory function in T cells, in a ...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Jonas Mudter, Lioubov Amoussina, Mirjam Schenk, Jingling Yu, Anne Brüstle, Benno Weigmann, Raja Atreya, Stefan Wirtz, Christoph Becker, Arthur Hoffman, Imke Atreya, Stefan Biesterfeld, Peter R. Galle, Hans A. Lehr, Stefan Rose-John, Christoph Muel Source Type: journals
Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice
discuss this article
Hedgehog (HH) signaling has emerged as a critical pathway involved in the pathogenesis of a variety of tumors. As a result, HH antagonists are currently being evaluated as potential anticancer therapeutics. Conversely, activation of HH signaling in the adult heart may be beneficial, as HH agonists have been shown to increase coronary vessel density and improve coronary function after myocardial infarction. To investigate a potential homeostatic role for HH signaling in the adult heart, we ablated endogenous HH signaling in murine myocardial and perivascular smooth muscle cells. HH signaling was required for proangiogenic g...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Kory J. Lavine, Attila Kovacs, David M. Ornitz Source Type: journals
Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent vegf expression in mice
discuss this article
To meet tissue requirements for oxygen, capillaries must be properly distributed without excess or shortage. In this process, tissue oxygen concentration is well known to determine capillary density via the hypoxia-induced cascade, in which HIFs and VEGF play key roles. However, some additional mechanisms modulating this cascade are suggested to be involved in precise capillary network formation. Here, we showed that leukemia inhibitory factor (LIF) was predominantly expressed in developing endothelium, while its receptor was expressed in surrounding cells such as retinal astrocytes. The retinas of Lif–/– m...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Yoshiaki Kubota, Masanori Hirashima, Kazuo Kishi, Colin L. Stewart, Toshio Suda Source Type: journals
Mechanisms of resistance to erbb-targeted cancer therapeutics
discuss this article
The ErbB receptors, such as EGFR, have been intensely pursued as targets for cancer therapeutics. However, a large percentage of patients who are initially responsive to ErbB-targeted therapies experience tumor recurrence and become refractory to therapy. In this issue of the JCI, Guix et al. demonstrate that downregulation of IGF-binding protein 3 (IGFBP-3) and -4, the negative regulators of IGF-I receptor signaling, contributes to the resistance of human squamous cell carcinomas to the EGFR inhibitor gefitinib (see the related article beginning on page 2609). Understanding the mechanisms involved in the resistance of som...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Qiang Wang, Mark I. Greene Source Type: journals
Measles virus breaks through epithelial cell barriers to achieve transmission
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Measles is a highly contagious disease that causes immunosuppression in patients. Measles virus infection has been thought to begin in the respiratory epithelium and then spread to lymphoid tissue. In this issue of the JCI, Leonard et al. provide data to suggest an alternative model of measles virus pathogenesis (see the related article beginning on page 2448). In human primary epithelial cells and rhesus monkeys in vivo, the authors show that initial infection of respiratory epithelium is not necessary for the virus to enter the host but that viral entry into epithelial cells via interaction of the virus with a receptor l...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Makoto Takeda Source Type: journals
How irritating: the role of trpa1 in sensing cigarette smoke and aerogenic oxidants in the airways
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Airway irritants cause a variety of lung pathologies. Two separate studies, the first recently reported in the JCI by Bessac et al. and the second reported by Andrè et al. in the current issue of the JCI (see the related article beginning on page 2574), have identified irritants that activate transient receptor potential cation channel, subfamily A, member 1 (TRPA1) receptors in airway sensory neurons, resulting in neurogenic inflammation and respiratory hypersensitivity. The identification of TRPA1 activation by toxicants from cigarette smoke and polluted air, such as crotonaldehyde, acrolein, and oxidizing agents...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Sidney A. Simon, Wolfgang Liedtke Source Type: journals
Revisiting leptin’s role in obesity and weight loss
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Maintenance of weight loss is often unsuccessful because of metabolic adaptations that conserve energy. Studies in rodents suggest that a reduction in leptin level during weight loss signals to the brain to increase feeding and decrease energy expenditure. In this issue of the JCI, Rosenbaum et al. examined this concept in obese patients who lost weight and were maintained at 10% below their initial weight (see the related article beginning on page 2583). Brain activity responses to visual food stimuli were visualized using functional MRI. Leptin levels fell during weight loss and increased brain activity in areas involved...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Rexford S. Ahima Source Type: journals
Molecular pathogenesis of pulmonary arterial hypertension
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Recent investigations have suggested that it might be possible to reverse the pathology of pulmonary arterial hypertension (PAH), a disorder that can be rapidly progressive and fatal despite current treatments including i.v. prostacyclin. This review will address the cellular and molecular processes implicated in clinical, genetic, and experimental studies as underlying the pulmonary vascular abnormalities associated with PAH. Emerging treatments are aimed at inducing apoptosis of abnormal vascular cells that obstruct blood flow and at promoting regeneration of “lost” distal vasculature. (Source: Journal of...
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Marlene Rabinovitch Source Type: journals
William and lawrence bragg, father and son
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(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Jan Drenth Source Type: journals
Your inner fish
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(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Jennifer A. Clack Source Type: journals
Gina: making it safe to know what’s in your genes
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(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Karen Honey Source Type: journals
Publish or perish, but at what cost?
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The academic scientific enterprise rewards those with the longest CVs and the most publications. Under pressure to generate voluminous output, scientists often fall prey to double publishing, self plagiarism, and submitting the “minimal publishable unit.” Are these ethical gray areas, or true transgressions? (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Authors: Ushma S. Neill Source Type: journals
In this issue
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(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - July 2, 2008 Category: Biomedical Science Source Type: journals
New role for mitochondria could lead to targeted therapies
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NIGMS-funded researchers have found that human cells can shift tRNAs into their mitochondria. (Source: NIGMS - Results)
Source: NIGMS - Results - July 1, 2008 Category: Biomedical Science Source Type: news
Supercomputer helps track oxygen in myoglobin
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A half century after the structure of myoglobin was solved, NIGMS-funded researchers discovered exactly how oxygen moves in the protein. (Source: NIGMS - Results)
Source: NIGMS - Results - July 1, 2008 Category: Biomedical Science Source Type: news
Probe can reveal protein interactions
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A new type of probe can be used to see thousands of interactions between proteins in a living cell, report NIGMS-funded researchers. (Source: NIGMS - Results)
Source: NIGMS - Results - July 1, 2008 Category: Biomedical Science Source Type: news
