tbuckley/cabot-search huggingface dataset:
Proteomics in neurons and animals: substrates and therapeutic potential of alpha-and beta-secretase
Authors: Stefan Lichtenthaler
Journal: Molecular Neurodegeneration (2013)

The aspartyl protease BACE1 is involved in myelination – through neuregulin-1 cleavage and is a major drug target for Alzheimer’s disease, where it acts as the beta-secretase cleaving the amyloid precursor protein. However, little is known about other substrates in vivo. Recently, we and others identified over 20 new BACE1 substrates in neurons. To elucidate which of them are particularly relevant in vivo, a comprehensive proteomic analysis of BACE1deficient mouse brains and CSF was carried out. A few membrane proteins, including the cell adhesion proteins CHL1 and contactin-2 as well as the APP protein family, were identified as BACE1 substrates in vivo and point to a central function of BACE1 in neurite outgrowth and synapse formation. Validation of substrates and detailed characterization of their cleavage was done in primary neurons, CSF and mouse brains. Additionally, the new substrates can be used as biomarkers for the efficacy and potential side-effects of BACE1 inhibitors in clinical trials of Alzheimer’s disease. Mechanistic analysis of substrate cleavage suggests that BACE1 controls the cell surface levels of its substrates and thus their function. Levels of most other proteins were not significantly changed in BACE1-/brains, suggesting that therapeutic BACE1 inhibition is unlikely to lead to major proteome changes. The talk will also present new substrates and functions for ADAM10 in the brain. Published: 13 September 2013
Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells.
Authors: T Nagel, N Resnick, W J Atkinson, C F Dewey, M A Gimbrone
Journal: Journal of Clinical Investigation (1994)

Hemodynamic forces induce various functional changes in vascular endothelium, many of which reflect alterations in gene expression. We have recently identified a cis-acting transcriptional regulatory element, the shear stress response element (SSRE), present in the promoters of several genes, that may represent a common pathway by which biomechanical forces influence gene expression. In this study, we have examined the effect of shear stress on endothelial expression of three adhesion molecules: intercellular adhesion molecule-1 (ICAM-1), which contains the SSRE in its promoter, and E-selectin (ELAM-1) and vascular cell adhesion molecule-1 (VCAM-1), both of which lack the SSRE. Cultured human umbilical vein endothelial cells, subjected to a physiologically relevant range of laminar shear stresses (2.5-46 dyn/cm2) in a cone and plate apparatus for up to 48 h, showed time-dependent but force-independent increases in surface immunoreactive ICAM-1. Upregulated ICAM-1 expression was correlated with increased adhesion of the JY lymphocytic cell line. Northern blot analysis revealed increased ICAM-1 transcript as early as 2 h after the onset of shear stress. In contrast, E-selectin and vascular cell adhesion molecule-1 transcript and cell-surface protein were not upregulated at any time point examined. This selective regulation of adhesion molecule expression in vascular endothelium suggests that biomechanical forces, in addition to humoral stimuli, may contribute to differential endothelial gene expression and thus represent pathophysiologically relevant stimuli in inflammation and atherosclerosis.
ACE Inhibitors to Prevent End-Stage Renal Disease
Authors: Piero Ruggenenti, Annalisa Perna, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2001)

ABSTRACT. In this post hoc, secondary analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, an angiotensin-converting enzyme (ACE) inhibition risk/benefit profile was assessed in 322 patients with nondiabetic, proteinuric chronic nephropathies and different degrees of renal insufficiency. The rate of GFR decline (ΔGFR) and the incidence of end-stage renal disease (ESRD) during ramipril or non-ACE inhibitor treatment were compared within three tertiles of basal GFR. ΔGFR was comparable in the three tertiles, whereas the incidence of ESRD was higher in the lowest tertile than in the middle and highest tertiles. Ramipril decreased ΔGFR by 22%, 22%, and 35% and the incidence of ESRD by 33% (P < 0.05), 37%, and 100% (P < 0.01) in the lowest, middle, and highest tertiles, respectively. ΔGFR reduction was predicted by basal systolic (P < 0.0001), diastolic (P = 0.02), and mean (P < 0.001) BP and proteinuria (P < 0.0001) but not by basal GFR (P = 0.12). ESRD risk reduction was predicted by basal proteinuria (P < 0.01) and GFR (P < 0.0001) and was strongly dependent on treatment duration (P < 0.0001). Adverse events were comparable among the three tertiles and within each tertile in the two treatment groups. Thus, disease progression and response to ACE inhibition do not depend on severity of renal insufficiency. The risk of ESRD and the absolute number of events saved by ACE inhibition is highest in patients with the lowest GFR. However, renoprotection is maximized when ACE inhibition is started earlier and when long-lasting treatment may result in GFR stabilization and definitive prevention of ESRD.
Differential Requirements for Vav Proteins in DAP10- and ITAM-mediated NK Cell Cytotoxicity
Authors: Marina Cella, Keiko Fujikawa, Ilaria Tassi, Sunjin Kim, Kevin Latinis, Shinzo Nishi, Wayne Yokoyama, Marco Colonna, Wojciech Swat
Journal: The Journal of Experimental Medicine (2004)

Natural killer (NK) cells express multiple activating receptors that initiate signaling cascades through DAP10- or immunoreceptor tyrosine-based activation motif–containing adapters, including DAP12 and FcRγ. Among downstream signaling mediators, the guanine nucleotide exchange factor Vav1 carries out a key role in activation. However, whether Vav1 regulates only some or all NK cell–activating pathways is matter of debate. It is also possible that two other Vav family molecules, Vav2 and Vav3, are involved in NK cell activation. Here, we examine the relative contribution of each of these exchange factors to NK cell–mediated cytotoxicity using mice lacking one, two, or all three Vav proteins. We found that Vav1 deficiency is sufficient to disrupt DAP10-mediated cytotoxicity, whereas lack of Vav2 and Vav3 profoundly impairs FcRγ- and DAP12-mediated cytotoxicity. Our results provide evidence that these three Vav proteins function specifically in distinct pathways that trigger NK cell cytotoxicity.
THE SOLUBLE MALARIAL ANTIGEN IN THE SERUM OF MONKEYS INFECTED WITH PLASMODIUM KNOWLESI
Authors: Monroe D. Eaton
Journal: The Journal of Experimental Medicine (1939)

A soluble malarial antigen which fixes complement with immune serum is found in the serum of monkeys infected with Plasmodium knowlesi. The amount of antigen in the serum is related to the parasite count during the acute phase of the infection. The antigen is not excreted in the urine. Intravenous injection into normal monkeys of serum containing the antigen stimulates the production of specific complement-fixing antibodies which react with antigens extracted from parasitized cells, as well as with the antigen present in serum obtained during the acute phase of infection. Monkeys immunized with serum antigen apparently possess very little or no immunity to infection. The soluble malarial antigen is labile to acids and alkalies, is not destroyed by a temperature of 56 degrees C., and is precipitated, for the most part, in the albumin fraction of the serum by ammonium sulfate.
Proliferative Changes in the Epithelium of the Human Lithiasic Gallbladder2
Authors: P. Putz, G. Willems
Journal: JNCI Journal of the National Cancer Institute (1978)

Surgical specimens from 9 normal human gallbladders and from 9 lithiasic gallbladders were incubated in vitro with [3H]thymidine. Autoradiography was used to observe the cells in DNA synthesis in the mucosal epithelium. The percentages of labeled cells (labeling index) and of mitotic figures (mitotic index) were estimated. In the normal gallbladder, the labeling index was low and mitotic figures were exceptional; the labeled cells in the epithelium were observed against the basal membrane. In the lithiasic gallbladder, the labeling index was 23 times higher (P>0.01) and a definite number of mitotic figures was seen; the uptake of [3H]thymidine was not restricted to basal epithelial cells and occurred at any level of the mucosa. Our data showed that the proliferative activity was increased in the mucosa of the human lithiasic gallbladder. To the extent that the labeled cells against the basal membrane in the normal gallbladder represent the epithelial progenitors, our results also indicated modifications in the spatial distribution of labeled cells in the lithiasic gallbladder mucosa. Such concomitant quantitative and qualitative changes in cell kinetics could have a parallel in known precancerous conditions in the digestive tract.
Randomized, Controlled Trial Investigating Short-Term Health-Related Quality of Life With Doxorubicin and Paclitaxel Versus Doxorubicin and Cyclophosphamide As First-Line Chemotherapy in Patients With Metastatic Breast Cancer: European Organization for Research and Treatment of Cancer Breast Cancer Group, Investigational Drug Branch for Breast Cancer and the New Drug Development Group Study
Authors: Andrew Bottomley, Laura Biganzoli, Tanja Cufer, Robert E. Coleman, Corneel Coens, Fabio Efficace, Hilary Allan Calvert, Teresa Gamucci, Chris Twelves, Pierre Fargeot, Martine Piccart
Journal: Journal of Clinical Oncology (2004)

To compare health-related quality of life (HRQOL) in patients with metastatic breast cancer receiving the combination of doxorubicin and paclitaxel (AT) or doxorubicin and cyclophosphamide (AC) as first-line chemotherapy treatment.Eligible patients (n = 275) with anthracycline-naive measurable metastatic breast cancer were randomly assigned to AT (doxorubicin 60 mg/m(2) as an intravenous bolus plus paclitaxel 175 mg/m(2) as a 3-hour infusion) or AC (doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2)) every 3 weeks for a maximum of six cycles. Dose escalation of paclitaxel (200 mg/m(2)) and cyclophosphamide (750 mg/m(2)) was planned at cycle 2 to reach equivalent myelosuppression in the two groups. HRQOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and the EORTC Breast Module at baseline and the start of cycles 2, 4, and 6, and 3 months after the last cycle.Seventy-nine percent of the patients (n = 219) completed a baseline measure. However, there were no statistically significant differences in HRQOL between the two treatment groups. In both groups, selected aspects of HRQOL were impaired over time, with increased fatigue, although some clinically significant improvements in emotional functioning were seen, as well as a reduction in pain over time. Overall, global quality of life was maintained in both treatment groups.This information is important when advising women patients of the expected HRQOL consequences of treatment regimens and should help clinicians and their patients make informed treatment decisions.
Kappa-alpha plot derived structural alphabet and BLOSUM-like substitution matrix for rapid search of protein structure database
Authors: Chi-Hua Tung, Jhang-Wei Huang, Jinn-Moon Yang
Journal: Genome biology (2007)

Abstract We present a novel protein structure database search tool, 3D-BLAST, that is useful for analyzing novel structures and can return a ranked list of alignments. This tool has the features of BLAST (for example, robust statistical basis, and effective and reliable search capabilities) and employs a kappa-alpha (κ, α) plot derived structural alphabet and a new substitution matrix. 3D-BLAST searches more than 12,000 protein structures in 1.2 s and yields good results in zones with low sequence similarity.
Cerebral vasoconstriction during head-upright tilt-induced vasovagal syncope. A paradoxic and unexpected response.
Authors: B P Grubb, G Gerard, K Roush, P Temesy-Armos, P Montford, L Elliott, H Hahn, P Brewster
Journal: Circulation (1991)

To determine the effect of vasovagally mediated syncope on the cerebral circulation, transcranial Doppler sonography was used to assess changes in cerebral blood flow velocity during head-upright tilt-induced syncope.Thirty patients (17 men and 13 women; mean age, 43 +/- 22 years) with recurrent unexplained syncope were evaluated by use of an upright tilt-table test for 30 minutes, with or without an infusion of intravenous isoproterenol (1-4 micrograms/min), in an attempt to provoke bradycardia, hypotension, or both. Transcranial Doppler sonography was used to assess middle cerebral artery systolic velocity (Vs), diastolic velocity (Vd), ratio of systolic to diastolic velocities, pulsatility index (PI = Vs-Vd/Vmean), and resistance index (RI = Vs-Vd/Vs) before, during, and after tilt. Syncope occurred in six patients (20%) during the baseline tilt and 14 (46%) during isoproterenol infusion (total positives, 66%). In the tilt-positive patients, concomitant with the development of hypotension and bradycardia, transcranial Doppler sonography showed a 75 +/- 17% decrease in diastolic velocity, unchanged systolic velocity, a 46 +/- 17% decrease in mean velocity, a 295 +/- 227% increase in pulsatility index, and a 73 +/- 34% increase in resistance index.These findings reflect increased cerebrovascular resistance secondary to arteriolar vasoconstriction distal to the insonation point of the middle cerebral artery. This is paradoxic because the expected response of the cerebral circulation to hypotension is vasodilation. We conclude that abnormal baroreceptor responses triggered during vasovagal syncope result in a derangement of cerebral autoregulation with paradoxic vasoconstriction in the face of increasing hypotension.
Mechanism of action of the C4 nephritic factor. Deregulation of the classical pathway of C3 convertase.
Authors: I Gigli, J Sorvillo, L Mecarelli-Halbwachs, J Leibowitch
Journal: The Journal of Experimental Medicine (1981)

Three mechanisms that regulate the formation and function of the classical pathway C3 convertase (C4b2a) have been elucidated: (a) an intrinsic decay of the enzyme that is temperature dependent; (b) an extrinsic decay mediated by the effect of the serum protein C4b binding protein (C4-bp); and (c) inactivation of C4b by the proteolytic action of C4b/C3b inactivator (C4b/C3bINA), which cleaves that alpha' chain of C4b to yield C4d (alpha 2) and C4c (alpha 3, alpha 4, beta, and gamma chains). A fourth mechanism described here is based on the observation that the IgG fraction of the serum of certain patients with glomerulonephritis contains a protein termed C4 nephritic factor (NFc), which prevents the intrinsic decay of C4b2a. This protein, which prolongs the half-life of surface-bound C4b2a from 7.5 min to greater than 5 h, increases the use of C3 and C5. It also inhibits the decay produced by C4-bp by preventing the dissociation of C2a from the C4b2a complex. Additionally, the C2b/C3bINA alone, or in the presence of C4-bp, fails to cleave the alpha' chain of C4b in the surface-bound stabilized C4b2a complex. This protective property of NFc requires the presence of C2a, because C4b was not protected unless it was bound to C2a. Thus in the presence of NFc, the three natural controls of the function of the classical pathway convertase, intrinsic decay, extrinsic decay, and proteolytic cleavage, are bypassed.
Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1
Authors: Frank Rosenbauer, Bronwyn M Owens, Li Yu, Joseph R Tumang, Ulrich Steidl, Jeffery L Kutok, Linda K Clayton, Katharina Wagner, Marina Scheller, Hiromi Iwasaki, Chunhui Liu, Björn Hackanson, Koichi Akashi, Achim Leutz, Thomas L Rothstein, Christoph Plass, Daniel G Tenen
Journal: Nature Genetics (2005)
Combined pulmonary fibrosis and emphysema in patients exposed to agrochemical compounds
Authors: Z. Daniil, A. Koutsokera, K. Gourgoulianis
Journal: European Respiratory Journal (2006)

To the Editors: 

In the very interesting article concerning the clinical syndrome resulting from combined pulmonary fibrosis and emphysema (CPFE) published in the European Respiratory Journal , Cottin et al . 1 speculated that both emphysema and fibrosis might be related to a common environmental trigger and/or genetic factor, with tobacco exposure playing a central role.

Here, we report our clinical experience of the same syndrome in order to emphasise the possible role of environmental …
Dietary Fibers and Glycemic Load, Obesity, and Plasma Adiponectin Levels in Women With Type 2 Diabetes
Authors: Lu Qi, James B. Meigs, Simin Liu, JoAnn E. Manson, Christos Mantzoros, Frank B. Hu
Journal: Diabetes Care (2006)

OBJECTIVE—The purpose of this study was to examine the associations of dietary fibers and glycemic load with plasma adiponectin in diabetic women and investigate the modification effect of obesity. RESEARCH DESIGN AND METHODS—We conducted a cross-sectional analysis in 902 women with type 2 diabetes from the Nurses’ Health Study. Dietary information was obtained using semiquantitative food frequency questionnaires. RESULTS—After adjustment for age, smoking, alcohol consumption, physical activity, aspirin use, HbA1c, history of hypertension and hypercholesterolemia, and postmenopausal hormone use, intakes of cereal fiber and fruit fiber (P for trend = 0.002 and 0.036, respectively) were significantly associated with an increasing trend of plasma adiponectin concentrations. Further adjustment for BMI did not appreciably change the associations for cereal fiber but attenuated the associations for fruit fiber. Adiponectin concentrations were 24% higher in the highest compared with the lowest quintile of cereal fiber. Dietary glycemic load and glycemic index were significantly associated with lower plasma adiponectin levels, after adjustment for BMI and other covariates (P for trend = 0.01 and 0.03, respectively). The percent differences in adiponectin concentration between the highest and the lowest quintiles of dietary glycemic load and glycemic index were 17 and 18%, respectively. The associations between dietary factors and plasma adiponectin were consistent across lean (BMI &amp;lt;25 kg/m2), overweight (25 ≤ BMI &amp;lt;30 kg/m2), and obese subjects (BMI ≥30 kg/m2). CONCLUSIONS—Our data indicate that dietary cereal fiber and glycemic load/index are associated with the circulating adiponectin concentration. Such associations were not modified by obesity status.
Mitochondrial cytochrome redox states and respiration in acute pulmonary oxygen sensing
Authors: N. Sommer, O. Pak, S. Schorner, T. Derfuss, A. Krug, E. Gnaiger, H. A. Ghofrani, R. T. Schermuly, C. Huckstorf, W. Seeger, F. Grimminger, N. Weissmann
Journal: European Respiratory Journal (2010)

Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism to optimise lung gas exchange. We aimed to decipher the proposed oxygen sensing mechanism of mitochondria in HPV. Cytochrome redox state was assessed by remission spectrophotometry in intact lungs and isolated pulmonary artery smooth muscle cells (PASMC). Mitochondrial respiration was quantified by high-resolution respirometry. Alterations were compared with HPV and hypoxia-induced functional and molecular readouts on the cellular level. Aortic and renal arterial smooth muscle cells (ASMC and RASMC, respectively) served as controls. The hypoxia-induced decrease of mitochondrial respiration paralleled HPV in isolated lungs. In PASMC, reduction of respiration and mitochondrial cytochrome c and aa3 (complex IV), but not of cytochrome b (complex III) matched an increase in matrix superoxide levels as well as mitochondrial membrane hyperpolarisation with subsequent cytosolic calcium increase. In contrast to PASMC, RASMC displayed a lower decrease in respiration and no rise in superoxide, membrane potential or intracellular calcium. Pharmacological inhibition of mitochondria revealed analogous kinetics of cytochrome redox state and strength of HPV. Our data suggest inhibition of complex IV as an essential step in mitochondrial oxygen sensing of HPV. Concomitantly, increased superoxide release from complex III and mitochondrial membrane hyperpolarisation may initiate the cytosolic calcium increase underlying HPV.
Translational Success Stories: Angiotensin Receptor 1 Antagonists in Heart Failure
Authors: Louis J. Dell'Italia
Journal: Circulation Research (2011)

The title of the proposed series of reviews is Translational Success Stories. The definition of "translation" according to Webster is, "an act, process, or instance of translating as a rendering of one language into another." In the context of this inaugural review, it is the translation of Tigerstedt's and Bergman's(1) discovery in 1898 of the vasoconstrictive effects of an extract of rabbit kidney to the treatment of heart failure. As recounted by Marks and Maxwell,(2) their discovery was heavily influenced by the original experiments of the French physiologist Brown-Séquard, who was the author of the doctrine that "many organs dispense substances into the blood which are not ordinary waste products, but have specific functions." They were also influenced by Bright's(3) original observation that linked kidney disease with hypertension with the observation that patients dying with contracted kidneys often exhibited a hard, full pulse and cardiac hypertrophy. However, from Tigerstedt's initial discovery, there was a long and arduous transformation of ideas and paradigms that eventually translated to clinical applications. Although the role of the renin-angiotensin system in the pathophysiology of hypertension and heart failure was suspected through the years, beneficial effects from its blockade were not realized until the early 1970s. Thus, this story starts with a short historical perspective that provides the reader some insight and appreciation into the long delay in translation.
The premature breech.
Authors: M S Hopper
Journal: BMJ (1979)

a week after my own report.In other words, I'm afraid, Now!, quite legitimately, "scooped" the Lancet on its own territory on this occasion.Although it verges on pedantry to expect a lay publication like Now! to be as scrupulous as a relatively academic joumal such as the BMJ in quoting recondite sources, I entirely agree that sources should be quoted.We will always give credit where it is due, and I hope the BMJ will try harder in future to do the same.