gebhart/patrepeval huggingface dataset:
Metabolic Functions of Myostatin and GDF11 (2010)

Myostatin is a member of the transforming growth factor β superfamily of secreted growth factors that negatively regulates skeletal muscle size. Mice null for the myostatin gene have a dramatically increased mass of individual muscles, reduced adiposity, increased insulin sensitivity, and resistance to obesity. Myostatin inhibition in adult mice also increases muscle mass which raises the possibility that anti-myostatin therapy could be a useful approach for treating diseases such as obesity or diabetes in addition to muscle wasting diseases. In this review I will describe the present state of our understanding of the role of myostatin and the closely related growth factor growth/differentiation factor 11 on metabolism.
HDAC6 and Microtubules Are Required for Autophagic Degradation of Aggregated Huntingtin (2005)

CNS neurons are endowed with the ability to recover from cytotoxic insults associated with the accumulation of proteinaceous polyglutamine aggregates via a process that appears to involve capture and degradation of aggregates by autophagy. The ubiquitin-proteasome system protects cells against proteotoxicity by degrading soluble monomeric misfolded aggregation-prone proteins but is ineffective against, and impaired by, non-native protein oligomers. Here we show that autophagy is induced in response to impaired ubiquitin proteasome system activity. We show that ATG proteins, molecular determinants of autophagic vacuole formation, and lysosomes are recruited to pericentriolar cytoplasmic inclusion bodies by a process requiring an intact microtubule cytoskeleton and the cytoplasmic deacetylase HDAC6. These data suggest that HDAC6-dependent retrograde transport on microtubules is used by cells to increase the efficiency and selectivity of autophagic degradation.
Caspases: cellular demolition experts (2001)

Apoptosis is co-ordinated by a family of cysteine proteases, the caspases, that dismantle the cell by targeting a panoply of proteins for limited proteolysis. The mammalian caspase family contains 14 members, a subset of which participates in apoptosis, with the remainder likely to be involved in the processing of pro-inflammatory cytokines. Apical caspase activation events are typically initiated by adaptor molecules that promote caspase aggregation and facilitate caspase autoactivation. In contrast, distal caspase activation events are controlled by caspases activated earlier in the cascade. Many cellular stresses provoke apoptosis by damaging mitochondria which results in the release of factors [such as cytochrome c and SMAC (second mitochondrial-derived activator of caspase)/Diablo] that trigger caspase activation and cell death. Here, we discuss the hierarchical nature of the caspase cascade that is triggered upon the release of mitochondrial cytochrome c into the cytoplasm, and the role of specific caspases within this cascade in targeting proteins for degradation. Finally, feedback amplification loops and important control points within the caspase cascade will be discussed.
Biogenesis of hepatitis C virus envelope glycoproteins (2001)

Microbiology Society journals contain high-quality research papers and topical review articles. We are a not-for-profit publisher and we support and invest in the microbiology community, to the benefit of everyone. This supports our principal goal to develop, expand and strengthen the networks available to our members so that they can generate new knowledge about microbes and ensure that it is shared with other communities.
Electrophysiological Responses of Human Bone Cells to Mechanical Stimulation: Evidence for Specific Integrin Function in Mechanotransduction (1997)

Bone cells respond to mechanical stimuli, but the transduction mechanisms responsible are not fully understood. Integrins, a family of heterodimeric transmembrane glycoproteins, which link components of the extracellular matrix with the actin cytoskeleton, have been implicated as mechanoreceptors. We have assessed the roles of integrins in the transduction of cyclical mechanical stimuli to human bone cells (HBCs), which results in changes in membrane potential. HBC showed membrane depolarization following 0.104 Hz mechanical stimulation and membrane hyperpolarization following stimulation at 0.33 Hz. The membrane depolarization response involved tetrodotoxin-sensitive sodium channels and could be inhibited by antibodies against alpha V, beta 1, and beta 5 integrins. In contrast, the hyperpolarization response was inhibited by gadolinium and antibodies to the integrin-associated protein (CD47), alpha 5 and beta 1 integrin. Both responses could be abrogated by ARg-Gly-Asp (RGD)-containing peptides, inhibition of tyrosine kinase activity, and disruption of the cytoskeleton. These results demonstrate differential electrophysiological responses of HBC to different frequencies of mechanical strain. Furthermore, they suggest that integrins act as HBC mechanoreceptors with distinct signaling pathways being activated by different frequencies of mechanical stimuli.
Salvage antiretroviral therapy in HIV infection (2002)

Highly-active antiretroviral (ARV) therapy (HAART) has lead to a sharp decline in AIDS-related morbidity and mortality. Treatment failure is a common, significant problem and as many as 50% of patients have detectable plasma HIV RNA despite being on combination ARV therapy. Clinicians must be knowledgeable about the reasons for treatment failure and the best options available for management. Treatment failure can occur because of non-compliance, drug discontinuation, lack of drug potency, inadequate drug plasma concentration and drug resistance. Strategies used when selecting salvage therapy include the use of resistance testing to choose a regimen, the exploitation of pharmacokinetic interactions by boosting protease inhibitor (PI) trough levels and counselling the patient on compliance. When selecting the agents to use in salvage therapy, the new regimen should ideally include as many new agents to which no or minimal resistance is anticipated and at least one new class of drugs if possible. Data on salvage therapy mostly comes from anecdotal reports and retrospective cohort studies. With a paucity of clinical trial data, clinicians are often forced to prescribe unproven regimens based on what is anticipated about cross-resistance and drug interactions. It is important that new agents and new targets continue to be developed as an increasing number of patients in practice have exhausted all treatment options.
Pathology of preinvasive and excellent-prognosis breast cancer (2000)

Our review of recent developments in breast cancer emphasizes clinical utility of tissue samples from patients. We highlight indicators of increased cancer risk and lesions without metastatic capacity at time of detection (but of sufficient risk of attaining metastatic capacity that treatment is mandated, ie, ductal carcinoma in situ). This review also includes invasive lesions with little capacity for metastatic behavior and indicators of low malignant potential. Histologic criteria for their recognition, as well as biologic and clinical characterization, are discussed. Several papers reviewing the usefulness of histologic grading, emphasizing mitotic counts and definitions of microinvasion, are included.
Gestational Diabetes Mellitus: Heterogeneity of Maternal Age, Weight, Insulin Secretion, HLA Antigens, and Islet Cell Antibodies and the Impact of Maternal Metabolism on Pancreatic B-Cell and Somatic Development in the Offspring (1985)

We have examined gravida with gestational diabetes mellitus (GDM), as defined by the National Diabetes Data Group (Diabetes 1979; 28:1039), for phenotypic and genotypic heterogeneity. Fasting plasma glucose (FPG) at diagnosis was used for further stratification of GDM according to putative metabolic severity into class A1 (FPG less than 105 mg/dl [N = 129]), class A2 (FPG 105-129 mg/dl [N = 47]), and class B1 (FPG greater than or equal to 130 mg/dl [N = 23]). All GDM classes tended to be older and heavier than consecutive gravida with documented normal glucose tolerance (controls, N = 148). Subdivision into "lean" and "obese" indicated that plasma immunoreactive insulin (IRI) was greater after overnight fast in the obese of all groups except B1. However, absolute increases in IRI above fasting levels in response to glucose during OGTT were significantly enhanced by obesity only in class A2 gravida. Adjustment for the effects of age and weight by covariate analysis indicated that the IRI response to glycemic stimulation is usually attenuated in all forms of GDM. Mean values for increases in IRI above fasting values during the first 15 min and IRI increments relative to the increases in plasma glucose throughout the 180-min OGTT were below control values in all GDM groups and progressively so, i.e., A1 less than A2 less than B1. The absolute insulinopenia was not invariable; a small number of gravida from all GDM groups displayed well-preserved IRI responses to oral glucose. Genotypic evaluation of the GDM population disclosed an increased occurrence of "markers" known to be associated with type I diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)
Rethink the virtual machine template (2011)

Server virtualization technology facilitates the creation of an elastic computing infrastructure on demand. There are cloud applications like server-based computing and virtual desktop that concern startup latency and require impromptu requests for VM creation in a real-time manner. Conventional template-based VM creation is a time consuming process and lacks flexibility for the deployment of stateful VMs. In this paper, we present an abstraction of VM substrate to represent generic VM instances in miniature. Unlike templates that are stored as an image file in disk, VM substrates are docked in memory in a designated VM pool. They can be activated into stateful VMs without machine booting and application initialization. The abstraction leverages an arrange of techniques, including VM miniaturization, generalization, clone and migration, storage copy-on-write, and on-the-fly resource configuration, for rapid deployment of VMs and VM clusters on demand. We implement a prototype on a Xen platform and show that a server with typical configuration of TB disk and GB memory can accommodate more substrates in memory than templates in disk and stateful VMs can be created from the same or different substrates and deployed on to the same or different physical hosts in a cluster without causing any configuration conflicts. Experimental results show that general purpose VMs or a VM cluster for parallel computing can be deployed in a few seconds. We demonstrate the usage of VM substrates in a mobile gaming application.
Discovery of AZD2716: A Novel Secreted Phospholipase A2 (sPLA2) Inhibitor for the Treatment of Coronary Artery Disease (2016)

Expedited structure-based optimization of the initial fragment hit <b>1</b> led to the design of (<i>R</i>)-<b>7</b> (AZD2716) a novel, potent secreted phospholipase A<sub>2</sub> (sPLA<sub>2</sub>) inhibitor with excellent preclinical pharmacokinetic properties across species, clear <i>in vivo</i> efficacy, and minimized safety risk. Based on accumulated profiling data, (<i>R</i>)-<b>7</b> was selected as a clinical candidate for the treatment of coronary artery disease.
A Protein Kinase Associated with Apoptosis and Tumor Suppression (2001)

Death-associated protein kinase (DAPK) has been implicated in apoptosis and tumor suppression, depending on cellular conditions, and associated with mechanisms of disease. However, DAPK has not been characterized as an enzyme due to the lack of protein or peptide substrates. Therefore, we determined the structure of DAPK catalytic domain, used a homology model of docked peptide substrate, and synthesized positional scanning substrate libraries in order to discover peptide substrates with K(m) values in the desired 10 microm range and to obtain knowledge about the preferences of DAPK for phosphorylation site sequences. Mutagenesis of DAPK catalytic domain at amino acids conserved among protein kinases or unique to DAPK provided a link between structure and activity. An enzyme assay for DAPK was developed and used to measure activity in adult brain and monitor protein purification based on the physical and chemical properties of the open reading frame of the DAPK cDNA. The results allow insight into substrate preferences and regulation of DAPK, provide a foundation for proteomic investigations and inhibitor discovery, and demonstrate the utility of the experimental approach, which can be extended potentially to kinase open reading frames identified by genome sequencing projects or functional genetics screens and lacking a known substrate.
A micro strain gauge with mechanical amplifier (1997)

A passive micro strain gauge with a mechanical amplifier has been designed, analyzed, and tested. The mechanical amplifier provides a high gain such that residual strain in thin films can be directly measured under an optical microscope. This strain gauge can be in situ fabricated with active micro sensors or actuators for monitoring residual strain effects, and both tensile and compressive residual strains can be measured via the strain gauge. It is shown that a very fine resolution of 0.001% strain readouts can be achieved for a micro strain gauge with a 500 /spl mu/m-long indicator beam. Beam theories have been used to analyze the strain gauge with a mechanical amplifier, and the results were verified by a finite-element analysis. Experimental measurements of both polysilicon and silicon-riched silicon-nitride thin films fabricated by surface micromachining processes are presented.
Immunogenetic and immunologic studies of differentiated thyroid cancer (1989)

The authors have studied in detail human leukocyte antigen (HLA) association in 87 Hungarian patients with thyroid epithelial carcinoma. The authors also examined in a small group of patients, five parameters of cell-mediated immunity and related them to HLA as well as to lymphocytic infiltration of the tumor/normal tissue interface. HLA-DR1 was significantly associated with thyroid carcinoma; the strongest association was in patients with follicular histologic features and DR1 homozygotes were not at greater risk for thyroid cancer. The HLA-DR3 was nonsignificantly increased in patients with papillary or mixed histologic features. The HLA-DR1, 3 heterozygotes were highly associated with follicular carcinoma, carried no risk for papillary carcinoma, and an intermediate risk for tumors with mixed histologic features. Because of the small proportion of DR1, 3 heterozygotes in the follicular and mixed histologic group, its predictive value at the population level was low. Better predictive potential was shown for the phenotype DR1 and/or DR3. Neither metastatic disease nor age at diagnosis (less than 45 years) could be related to HLA phenotypes. Patients in all histologic variants showed some measure of cell-mediated immunity compared to controls. Patients with papillary carcinoma showed an overall better response than those with tumors with follicular or mixed histology. The HLA-DR could not be related to cell-mediated immune response. Patients with papillary carcinoma with a good cell-mediated immune response occurred with much lower infiltration of the tumor boundary with lymphocyte whereas the follicular carcinoma less cell-mediated immunity was associated with dense lymphocytic infiltration, suggesting the biological relevance of lymphocytic infiltration may be different for the two histologic variants.
Artemisone—A Highly Active Antimalarial Drug of the Artemisinin Class (2006)

Artemisinin—the next generation: Efficacies of artemisone against the malaria parasite are substantially greater than those of the current artemisinin “gold standard”, artesunate. Also, in contrast to most current artemisinins it displays low lipophilicity and negligible neuro- and cytotoxicity in in vitro and in vivo assays. Thus, the drug offers promise for use in artemisinin-based combination therapy. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2006/z503071_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Evolution, biogenesis, expression, and target predictions of a substantially expanded set of Drosophila microRNAs (2007)

MicroRNA (miRNA) genes give rise to small regulatory RNAs in a wide variety of organisms. We used computational methods to predict miRNAs conserved among Drosophila species and large-scale sequencing of small RNAs from Drosophila melanogaster to experimentally confirm and complement these predictions. In addition to validating 20 of our top 45 predictions for novel miRNA loci, the large-scale sequencing identified many miRNAs that had not been predicted. In total, 59 novel genes were identified, increasing our tally of confirmed fly miRNAs to 148. The large-scale sequencing also refined the identities of previously known miRNAs and provided insights into their biogenesis and expression. Many miRNAs were expressed in particular developmental contexts, with a large cohort of miRNAs expressed primarily in imaginal discs. Conserved miRNAs typically were expressed more broadly and robustly than were nonconserved miRNAs, and those conserved miRNAs with more restricted expression tended to have fewer predicted targets than those expressed more broadly. Predicted targets for the expanded set of microRNAs substantially increased and revised the miRNA-target relationships that appear conserved among the fly species. Insights were also provided into miRNA gene evolution, including evidence for emergent regulatory function deriving from the opposite arm of the miRNA hairpin, exemplified by mir-10, and even the opposite strand of the DNA, exemplified by mir-iab-4.
Interleukin-12 is chemotactic for natural killer cells and stimulates their interaction with vascular endothelium (1994)

We investigated the chemotactic activity of interleukin (IL)-12 on human natural killer (NK) cells and other leukocyte subsets. It was found that IL-12 induced directional migration of highly enriched preparations of NK cells (> 80% CD16+ and CD56+) and CD3-activated T cells (both of CD4 and CD8 subset), but not resting T cells and monocytes. On the contrary, purified polymorphonuclear cells (PMN) showed significant and reproducible chemotactic response to IL-12. The effects of IL-12 on leukocyte migration were observed in a narrow concentration range with a peak at approximately 7.5 ng/mL, and were abrogated by monoclonal antibody (MoAb) anti-IL-12 or after cytokine boiling. We also investigated the interaction of NK cells with vascular endothelium in vitro. Overnight treatment of NK cells with IL-12 augmented their binding to cultured endothelial cells (EC) obtained from umbilical veins. IL-12-increased binding was better observed when resting rather than IL-1-activated EC were used as substratum of adhesion. IL-12-augmented binding of NK cells to resting or IL-1-activated EC involved the LFA-1/ICAM-1 and VLA-4/VCAM-1 pathways. Thus, by inducing migration and interaction with EC, IL-12 regulates crucial determinants of NK-cell recruitment in tissues.
Experimental Malaria Infection Triggers Early Expansion of Natural Killer Cells (2008)

In order to gain a better understanding of gene expression during early malaria infection, we conducted microarray analysis of early blood responses in mice infected with erythrocytic-stage Plasmodium chabaudi. Immediately following infection, we observed coordinated and sequential waves of immune responses, with interferon-associated gene transcripts dominating by 16 h postinfection, followed by strong increases in natural killer (NK) cell-associated and major histocompatibility complex class I-related transcripts by 32 h postinfection. We showed by flow cytometry that the observed elevation in NK cell-associated transcripts was the result of a dramatic increase in the proportion of NK cells in the blood during infection. Subsequent microarray analysis of NK cells isolated from the peripheral blood of infected mice revealed a cell proliferation expression signature consistent with the observation that NK cells replicate in response to infection. Early proliferation of NK cells was directly observed in studies with adoptively transferred cells in infected mice. These data indicate that the early response to P. chabaudi infection of the blood is marked by a primary wave of interferon with a subsequent response by NK cells.
Covalent Attachment of Cell-Adhesive, (Arg-Gly-Asp)-Containing Peptides to Titanium Surfaces (1998)

A three-step reaction procedure was applied to introduce RGD-containing peptides on the titanium surface. Water−vapor−plasma-pretreated titanium surfaces were first silanized with (3-aminopropyl)triethoxysilane, resulting in a multilayer film of poly(3-aminopropyl)siloxane. In a second reaction step, the free primary amino groups were linked to one of the three hetero-cross-linkers: N-succinimidyl-6-maleimidylhexanoate, N-succinimidyl-3-maleimidylpropionate, and N-succinimidyl trans-4-(maleimidylmethyl)cyclohexane-1-carboxylate. Onto the resulting terminal-maleimide surface, two model, cell-adhesive peptides, H-Gly-Arg-Gly-Asp-Ser-Pro-Cys-OH and H-Arg-Gly-Asp-Cys-OH were immobilized through covalent addition of the cysteine thiol (−SH) group. X-ray photoelectron spectroscopy, infrared reflection absorption spectroscopy, and radiolabeling techniques were applied to characterize the surfaces. From independent quantitative analysis, an approximate coverage of 0.2∼0.4 peptides/nm2 was calculated.
Poultry coccidiosis: recent advancements in control measures and vaccine development (2006)

Coccidiosis is recognized as the major parasitic disease of poultry and is caused by the apicomplexan protozoan Eimeria. Coccidiosis seriously impairs the growth and feed utilization of infected animals resulting in loss of productivity. Conventional disease control strategies rely heavily on chemoprophylaxis and, to a certain extent, live vaccines. Combined, these factors inflict tremendous economic losses to the world poultry industry in excess of USD 3 billion annually. Increasing regulations and bans on the use of anticoccidial drugs coupled with the associated costs in developing new drugs and live vaccines increases the need for the development of novel approaches and alternative control strategies for coccidiosis. This paper aims to review the current progress in understanding the host immune response to Eimeria and discuss current and potential strategies being developed for coccidiosis control in poultry.
Investigation of red blood cell antigens with highly fluorescent and stable semiconductor quantum dots (2005)

We report a new methodology for red blood cell antigen expression determination by a simple labeling procedure employing luminescent semiconductor quantum dots. Highly luminescent and stable core shell cadmium sulfide/cadmium hydroxide colloidal particles are obtained, with a predominant size of 9 nm. The core-shell quantum dots are functionalized with glutaraldehyde and conjugated to a monoclonal anti-A antibody to target antigen-A in red blood cell membranes. Erythrocyte samples of blood groups A+, A2+, and O+ are used for this purpose. Confocal microscopy images show that after 30 min of conjugation time, type A+ and A2+ erythrocytes present bright emission, whereas the O+ group cells show no emission. Fluorescence intensity maps show different antigen expressions for the distinct erythrocyte types. The results obtained strongly suggest that this simple labeling procedure may be employed as an efficient tool to investigate quantitatively the distribution and expression of antigens in red blood cell membranes.