tbuckley/cabot-search huggingface dataset:
Characterization of homeodomain-leucine zipper genes in the fern Ceratopteris richardii and the evolution of the homeodomain-leucine zipper gene family in vascular plants
Authors: K. Aso, M. Kato, J. A. Banks, M. Hasebe
Journal: Molecular Biology and Evolution (1999)

The homeodomain-leucine zipper (HD-Zip) genes encode transcription factors that are characterized by the presence of both a homeodomain and a leucine zipper motif. They belong to the homeobox gene superfamily and have been reported only from flowering plants. This article is the first report on the ferm HD-Zip genes (named Crhb1-Crhb11) isolated from the homosporous ferm Ceratopteris richardii. Phylogenetic analyses of the II Crhb genes with previously reported angiosperm HD-Zip genes show that the Crhb genes belong to three of the four different angiosperm HD-Zip subfamilies (HD-Zip I, II, and IV), indicating that these subfamilies of HD-Zip genes originated before the diversification of the ferm and seed plant lineages. The Crhb4-Crhb8 and Crhb11 genes belong to the HD-Zip I subfamily but differ from angiosperm HD-Zip I genes by the presence of a seven-amino-acid indel in the leucine zipper motif. By the northern analyses, Crhb1 and Crhb3 were expressed only in gametophyte tissue. Expression of Crhb2 and Crhb11 genes could not be detected in any tissue examined, while all other Crhb genes were expressed in most sporophytic and gametophytic tissues. Although the functions of the Crhb genes in Ceratopteris are unknown, their patterns of expression suggest that they regulate developmental or physiological processes common to both the gametophyte and the sporophyte generations of the fern. Differences in the expression of Crhb1 between male gametophytes and male-hermaphrodite mixed populations of gametophytes suggests that the Crhb1 gene is involved in gametophytic sex determination.
Early occupational therapy programme increases hand grip strength at 3 months: results from a randomised, blind, controlled study in early rheumatoid arthritis
Authors: R Mathieux, H Marotte, L Battistini, A Sarrazin, M Berthier, P Miossec
Journal: Annals of the Rheumatic Diseases (2008)

Aim: The goal of occupational therapy (OT) is to facilitate adjustments to lifestyle and to prevent function loss. This study evaluated the effects of an early OT programme in early rheumatoid arthritis (RA). Methods: We conducted a randomised, blind, controlled trial enrolling 60 patients with early RA, divided into 2 groups. At baseline, group 1 received the full information programme and group 2 received no information. In an extension phase, patients in group 2 received the full information programme at 3 months and were assessed at 6 months. The main outcomes were grip strength of hands (as objective assessment) and Health Assessment Questionnaire (HAQ) score (as subjective assessment). Results: At 3 months, grip strength of the dominant and non-dominant hands increased more in group 1 than in group 2 (p = 0.021 and 0.047 respectively). HAQ score decreased more in group 1 than in group 2 (p&lt;0.001). In the extension phase, changes in grip strength and HAQ score in group 2 were similar to those seen in group 1 between baseline and 3 months. Conclusions: This study comparing two schedules of OT programme showed that an early extended information programme improved hand function in patients with early RA.
Genes and pathways underlying regional and cell type changes in Alzheimer's disease
Authors: Jeremy A Miller, Randall L Woltjer, Jeff M Goodenbour, Steve Horvath, Daniel H Geschwind
Journal: Genome Medicine (2013)

Transcriptional studies suggest Alzheimer's disease (AD) involves dysfunction of many cellular pathways, including synaptic transmission, cytoskeletal dynamics, energetics, and apoptosis. Despite known progression of AD pathologies, it is unclear how such striking regional vulnerability occurs, or which genes play causative roles in disease progression.To address these issues, we performed a large-scale transcriptional analysis in the CA1 and relatively less vulnerable CA3 brain regions of individuals with advanced AD and nondemented controls. In our study, we assessed differential gene expression across region and disease status, compared our results to previous studies of similar design, and performed an unbiased co-expression analysis using weighted gene co-expression network analysis (WGCNA). Several disease genes were identified and validated using qRT-PCR.We find disease signatures consistent with several previous microarray studies, then extend these results to show a relationship between disease status and brain region. Specifically, genes showing decreased expression with AD progression tend to show enrichment in CA3 (and vice versa), suggesting transcription levels may reflect a region's vulnerability to disease. Additionally, we find several candidate vulnerability (ABCA1, MT1H, PDK4, RHOBTB3) and protection (FAM13A1, LINGO2, UNC13C) genes based on expression patterns. Finally, we use a systems-biology approach based on WGCNA to uncover disease-relevant expression patterns for major cell types, including pathways consistent with a key role for early microglial activation in AD.These results paint a picture of AD as a multifaceted disease involving slight transcriptional changes in many genes between regions, coupled with a systemic immune response, gliosis, and neurodegeneration. Despite this complexity, we find that a consistent picture of gene expression in AD is emerging.
Review of<i>Sleep Deprivation, Stimulant Medications, and Cognition</i>
Authors: Matt T. Bianchi
Journal: JAMA Neurology (2013)

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In Vivo Instruction of Suppressor Commitment in Naive T Cells
Authors: Irina Apostolou, Harald von Boehmer
Journal: The Journal of Experimental Medicine (2004)

The induction of antigen-specific tolerance in the mature immune system of the intact organism has met with limited success. Therefore, nonspecific immunosuppression has been the treatment of choice to prevent unwanted immunity. Here, it is shown that prolonged subcutaneous infusion of low doses of peptide by means of osmotic pumps transforms mature T cells into CD4+25+ suppressor cells that can persist for long periods of time in the absence of antigen and confer specific immunologic tolerance upon challenge with antigen. The described procedure resembles approaches of tolerance induction used decades ago, induces tolerance in the absence of immunity, and holds the promise to become an effective means of inducing antigen-specific tolerance prospectively, whereas its power to suppress already ongoing immune responses remains to be determined.
The University of Michigan Dioxin Exposure Study: Methods for an Environmental Exposure Study of Polychlorinated Dioxins, Furans, and Biphenyls
Authors: David H. Garabrant, Alfred Franzblau, James Lepkowski, Brenda W. Gillespie, Peter Adriaens, Avery Demond, Barbara Ward, Kathy LaDronka, Elizabeth Hedgeman, Kristine Knutson, Lynn Zwica, Kristen Olson, Timothy Towey, Qixuan Chen, Biling Hong
Journal: Environmental Health Perspectives (2008)

BackgroundThe University of Michigan Dioxin Exposure Study (UMDES) was undertaken in response to concerns that the discharge of dioxin-like compounds from the Dow Chemical Company facilities in Midland, Michigan, resulted in contamination of soils in the Tittabawassee River floodplain and areas of the city of Midland, leading to an increase in residents' body burdens of polychlorinated dibenzodioxins and polychlorinated dibenzofurans.ObjectivesThe UMDES is a hypothesis-driven study designed to answer important questions about human exposure to dioxins in the environment of Midland, where the Dow Chemical Company has operated for > 100 years, and in neighboring Saginaw, Michigan. In addition, the UMDES includes a referent population from an area of Michigan in which there are no unusual sources of dioxin exposure and from which inferences regarding the general Michigan population can be derived. A central goal of the study is to determine which factors explain variation in serum dioxin levels and to quantify how much variation each factor explains.ConclusionsIn this article we describe the study design and methods for a large population-based study of dioxin contamination and its relationship to blood dioxin levels. The study collected questionnaire, blood, dust, and soil samples on 731 people. This study provides a foundation for understanding the exposure pathways by which dioxins in soils, sediments, fish and game, and homegrown produce lead to increased body burdens of these compounds.
Angiotensin-Converting Enzyme Inhibitors
Authors: Hongmei Peng, Oscar A. Carretero, Nikola Vuljaj, Tang-Dong Liao, Apurva Motivala, Edward L. Peterson, Nour-Eddine Rhaleb
Journal: Circulation (2005)

Background— Angiotensin-converting enzyme (ACE) inhibitors are valuable agents for the treatment of hypertension, heart failure, and other cardiovascular and renal diseases. The cardioprotective effects of ACE inhibitors are mediated by blockade of both conversion of angiotensin (Ang) I to Ang II and kinin hydrolysis. Here, we report a novel mechanism that may explain the cardiac antifibrotic effect of ACE inhibition, involving blockade of the hydrolysis of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Methods and Results— To study the role of Ac-SDKP in the therapeutic effects of the ACE inhibitor captopril, we used a model of Ang II–induced hypertension in rats treated with the ACE inhibitor either alone or combined with a blocking monoclonal antibody (mAb) to Ac-SDKP. These hypertensive rats had left ventricular hypertrophy (LVH) as well as increases in cardiac fibrosis, cell proliferation, transforming growth factor-β (TGF-β) expression, and phosphorylation of Smad2 (P-Smad2), a signaling mediator of the effects of TGF-β. The ACE inhibitor did not decrease either blood pressure or LVH; however, it significantly decreased LV collagen from 13.3±0.9 to 9.6±0.6 μg/mg dry wt ( P &lt;0.006), and this effect was blocked by the mAb (12.1±0.6; P &lt;0.034, ACE inhibitor versus ACE inhibitor+mAb). In addition, analysis of interstitial collagen volume fraction and perivascular collagen (picrosirius red staining) showed a very similar tendency. Likewise, the ACE inhibitor significantly decreased LV monocyte/macrophage infiltration, cell proliferation, and TGF-β expression, and these effects were blocked by the mAb. Ang II increased Smad2 phosphorylation 3.2±0.9-fold; the ACE inhibitor lowered this to 0.6±0.1-fold ( P &lt;0.001), and the mAb blocked this decrease to 2.1±0.3 ( P &lt;0.001, ACE inhibitor versus ACE inhibitor+mAb). Similar findings were seen when the ACE inhibitor was replaced by Ac-SDKP. Conclusions— We concluded that in Ang II–induced hypertension, the cardiac antifibrotic effect of ACE inhibitors is a result of the inhibition of Ac-SDKP hydrolysis, resulting in a decrease in cardiac cell proliferation (probably fibroblasts), inflammatory cell infiltration, TGF-β expression, Smad2 activation, and collagen deposition.
Alcohol has no effect on hepatitis C virus replication: a meta-analysis
Authors: B S Anand
Journal: Gut (2005)

Patients with chronic hepatitis C virus (HCV) infection who consume large quantities of alcohol have more severe liver disease compared with HCV patients without a history of alcohol consumption. The mechanism by which alcohol worsens HCV related liver disease is not properly understood. One possibility is that alcohol stimulates HCV replication, and the present meta-analysis was performed to examine this issue.The effect of alcohol on viral titres was assessed in three ways: comparison of the heaviest drinkers with non-drinkers; effect of graded doses of alcohol; and effect of abstinence in the same individual.A total of 14 studies were identified. Comparison of patients with the highest alcohol use with the abstinent group showed a significant association with viral load in three studies, five studies had a positive direction, while the remaining four studies found a negative relationship. Analysis of the combined results showed no association between alcohol consumption and virus levels (p = 0.29). Assessment of graded doses of alcohol also showed no significant difference between non-drinkers and moderate drinkers (p = 0.50), between non-drinkers and heavy drinkers (p = 0.35), or between moderate drinkers and heavy drinkers (p = 0.32). Five studies examined the influence of abstinence on viral titres but none provided sufficient data for statistical analysis.The present study has failed to show an association between alcohol use and HCV viral titres. These observations raise the possibility that the hepatic damage caused by alcohol and HCV may be purely additive, involving different mechanisms and pathways.
Detection of Citrobacter koseri carrying beta-lactamase KPC-2 in a hospitalised patient, Greece, July 2011
Authors: A Mavroidi, I Neonakis, A Liakopoulos, A Papaioannou, M Ntala, F Tryposkiadis, V Miriagou, E Petinaki
Journal: Eurosurveillance (2011)

This report describes the detection of Citrobacter koseri carrying K. pneumoniae carbapenemase (KPC-2) isolated in July 2011 from a Greek patient, who was also colonised by a Klebsiella pneumoniae strain co-producing KPC-2 and Verona integron-encoded metallo-beta-lactamase (VIM)-1.
Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2
Authors: Karo Tanaka, Ascia Eskin, Fabrice Chareyre, Walter J. Jessen, Jan Manent, Michiko Niwa-Kawakita, Ruihong Chen, Cory H. White, Jeremie Vitte, Zahara M. Jaffer, Stanley F. Nelson, Allan E. Rubenstein, Marco Giovannini
Journal: Clinical Cancer Research (2013)

Abstract Purpose: The growth and survival of neurofibromatosis type 2 (NF2)–deficient cells are enhanced by the activation of multiple signaling pathways including ErbBs/IGF-1R/Met, PI3K/Akt, and Ras/Raf/Mek/Erk1/2. The chaperone protein HSP90 is essential for the stabilization of these signaling molecules. The aim of the study was to characterize the effect of HSP90 inhibition in various NF2-deficient models. Experimental Design: We tested efficacy of the small-molecule NXD30001, which has been shown to be a potent HSP90 inhibitor. The antiproliferative activity of NXD30001 was tested in NF2-deficient cell lines and in human primary schwannoma and meningioma cultures in vitro. The antitumor efficacy of HSP90 inhibition in vivo was verified in two allograft models and in one NF2 transgenic model. The underlying molecular alteration was further characterized by a global transcriptome approach. Results: NXD30001 induced degradation of client proteins in and suppressed proliferation of NF2-deficient cells. Differential expression analysis identified subsets of genes implicated in cell proliferation, cell survival, vascularization, and Schwann cell differentiation whose expression was altered by NXD30001 treatment. The results showed that NXD30001 in NF2-deficient schwannoma suppressed multiple pathways necessary for tumorigenesis. Conclusions: HSP90 inhibition showing significant antitumor activity against NF2-related tumor cells in vitro and in vivo represents a promising option for novel NF2 therapies. Clin Cancer Res; 19(14); 3856–70. ©2013 AACR.
Exposure of Human Vascular Endothelial Cells to Sustained Hydrostatic Pressure Stimulates Proliferation
Authors: Eric A. Schwartz, Rena Bizios, Marvin S. Medow, Mary E. Gerritsen
Journal: Circulation Research (1999)

The present study investigated the effects of sustained hydrostatic pressure (SHP; up to 4 cm H2O) on human umbilical vein endothelial cell (HUVEC) proliferation, focal adhesion plaque (FAP) organization, and integrin expression. Exposure of HUVECs to SHP stimulated cell proliferation and a selective increase in the expression of integrin subunit alphaV. The increase in alphaV was observed as early as 4 hours after exposure to pressure and preceded detectable increases in the bromodeoxyuridine labeling index. Laser confocal microscopy studies demonstrated colocalization of the alphaV integrin to FAPs. The individual FAPs in pressure-treated cells demonstrated a reduced area and increased aspect ratio and were localized to both peripheral and more central regions of the cells, in contrast to the predilection for the cell periphery in cells maintained under control pressure conditions. The pressure-induced changes in alphaV distribution had functional consequences on the cells: adhesivity of the cells to vitronectin was increased, and alphaV antagonists blocked the pressure-induced proliferative response. Thus, the present study suggests a role for alphaV integrins in the mechanotransduction of pressure by endothelial cells.
Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial
Authors: Alasdair J Coles, Cary L Twyman, Douglas L Arnold, Jeffrey A Cohen, Christian Confavreux, Edward J Fox, Hans-Peter Hartung, Eva Havrdova, Krzysztof W Selmaj, Howard L Weiner, Tamara Miller, Elizabeth Fisher, Rupert Sandbrink, Stephen L Lake, David H Margolin, Pedro Oyuela, Michael A Panzara, D Alastair S Compston
Journal: The Lancet (2012)
Deficits in Gain of Smooth Pursuit Eye Movements in Schizophrenia and Affective Disorder Patients and Their Unaffected Relatives
Authors: Norbert Kathmann, Andrea Hochrein, Ruth Uwer, Brigitta Bondy
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Disturbance of smooth pursuit eye movements has been discussed as marking a putative endophenotype closely associated with the genetic basis of schizophrenia. Previous studies are not conclusive in regard to the specificity of this marker. Therefore, oculomotor pursuit was evaluated in unaffected family members of index probands diagnosed as having either schizophrenia or affective disorders. METHOD: A series of eye tracking tasks were performed by 54 patients with schizophrenia or schizoaffective disorder, 46 patients with an affective disorder, 43 unaffected first-degree relatives of the schizophrenia patients, 36 unaffected first-degree relatives of the affective disorder patients, and 84 healthy comparison subjects. The gain, which relates the velocity of the eye movement to the velocity of the target, was determined to index the intactness of the oculomotor pursuit system. RESULTS: Mean pursuit gain was significantly lower in the schizophrenia and affective disorder patients than in the healthy comparison subjects. Moreover, the relatives of both the schizophrenia and affective disorder patients showed significant gain deficits of about one-half the size of those observed in the patients. CONCLUSIONS: Gain deficits are present in psychotic patients and in their unaffected biological relatives. This finding supports a genetic origin of eye tracking disturbances in major psychotic disorders. There is no evidence for diagnostic or familial specificity. The weak sensitivity of the marker suggests that it refers to a nonnecessary genetic factor in schizophrenic and affective disorders.
ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome
Authors: Dario Cattaneo, Piero Ruggenenti, Sara Baldelli, Nicola Motterlini, Eliana Gotti, Silvio Sandrini, Maurizio Salvadori, Giuseppe Segoloni, Paolo Rigotti, Donato Donati, Norberto Perico, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2009)

Cyclosporine A (CsA) is a substrate of P-glycoprotein, an efflux transporter encoded by the ABCB1 gene. Compared with carriers of the wild-type gene, carriers of T allelic variants in exons 21 or 26 have reduced P-glycoprotein activity and, secondarily, increased intracellular concentration of CsA; therefore, carriers of T variants might be at increased risk for CsA-related adverse events. We evaluated the associations between ABCB1 genotypes (in exons 12, 21, and 26) and CsA-related outcomes in 147 renal transplant recipients who were receiving CsA-based immunosuppression and were included in the Mycophenolate Steroids Sparing study. During a median of 65.5 mo follow-up, carriers of T allelic variants in exons 21 or 26 had a three-fold risk for delayed graft function (DGF), a trend to slower recovery of renal function and lower GFR at study end, and significantly higher incidences of new-onset diabetes and cytomegalovirus reactivation compared with carriers of the wild-type genotype. T variants in both exons 21 and 26 were independently associated with 3.8- and 3.5-fold higher risk for DGF, respectively (P = 0.022 and P = 0.034). The incidence of acute rejection and the mean CsA dose and blood levels were comparable in genotype groups. In conclusion, renal transplant recipients with T allelic variants in ABCB1 exons 21 or 26 are at increased risk for CsA-related adverse events. Genetic evaluation may help to identify patients at risk and to modulate CsA therapy to optimize graft and patient outcomes.
The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host
Authors: Alida Coppi, Ramya Natarajan, Gabriele Pradel, Brandy L. Bennett, Eric R. James, Mario A. Roggero, Giampietro Corradin, Cathrine Persson, Rita Tewari, Photini Sinnis
Journal: The Journal of Experimental Medicine (2011)

Plasmodium sporozoites make a remarkable journey from the mosquito midgut to the mammalian liver. The sporozoite’s major surface protein, circumsporozoite protein (CSP), is a multifunctional protein required for sporozoite development and likely mediates several steps of this journey. In this study, we show that CSP has two conformational states, an adhesive conformation in which the C-terminal cell-adhesive domain is exposed and a nonadhesive conformation in which the N terminus masks this domain. We demonstrate that the cell-adhesive domain functions in sporozoite development and hepatocyte invasion. Between these two events, the sporozoite must travel from the mosquito midgut to the mammalian liver, and N-terminal masking of the cell-adhesive domain maintains the sporozoite in a migratory state. In the mammalian host, proteolytic cleavage of CSP regulates the switch to an adhesive conformation, and the highly conserved region I plays a critical role in this process. If the CSP domain architecture is altered such that the cell-adhesive domain is constitutively exposed, the majority of sporozoites do not reach their target organs, and in the mammalian host, they initiate a blood stage infection directly from the inoculation site. These data provide structure–function information relevant to malaria vaccine development.