Miracle-dz/UniFAR-FTUs huggingface dataset:
Immunotherapy of Murine Retrovirus-Induced Acquired Immunodeficiency by CD4 T Regulatory Cell Depletion and PD-1 Blockade

ABSTRACT LP-BM5 retrovirus induces a complex disease featuring an acquired immunodeficiency syndrome termed murine AIDS (MAIDS) in susceptible strains of mice, such as C57BL/6 (B6). CD4 T helper effector cells are required for MAIDS induction and progression of viral pathogenesis. CD8 T cells are not needed for viral pathogenesis, but rather, are essential for protection from disease in resistant strains, such as BALB/c. We have discovered an immunodominant cytolytic T lymphocyte (CTL) epitope encoded in a previously unrecognized LP-BM5 retroviral alternative (+1 nucleotide [nt]) gag translational open reading frame. CTLs specific for this cryptic gag epitope are the basis of protection from LP-BM5-induced immunodeficiency in BALB/c mice, and the inability of B6 mice to mount an anti-gag CTL response appears critical to the initiation and progression of LP-BM5-induced MAIDS. However, uninfected B6 mice primed by LP-BM5-induced tumors can generate CTL responses to an LP-BM5 retrovirus infection-associated epitope(s) that is especially prevalent on such MAIDS tumor cells, indicating the potential to mount a protective CD8 T-cell response. Here, we utilized this LP-BM5 retrovirus-induced disease system to test whether modulation of normal immune down-regulatory mechanisms can alter retroviral pathogenesis. Thus, following in vivo depletion of CD4 T regulatory (Treg) cells and/or selective interruption of PD-1 negative signaling in the CD8 T-cell compartment, retroviral pathogenesis was significantly decreased, with the combined treatment of CD4 Treg cell depletion and PD-1 blockade working in a synergistic fashion to substantially reduce the induction of MAIDS.
HDAC6 and Microtubules Are Required for Autophagic Degradation of Aggregated Huntingtin*

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.
Rescue from anti-MHC class II antibody-mediated marrow graft failure by c-kit ligand.

Dogs given 920 cGy of total body irradiation (TBI) followed by autologous marrow infusion uniformly achieve sustained hematopoietic reconstitution. We have previously shown that administration of the anti-MHC class II monoclonal antibody (MoAb) H81.98. 21 (IgG2a) at 0.6 mg/kg/d immediately after transplantation results in delayed graft failure. A second noncrossblocking anti-MHC class II MoAb, B1F6, of the same isotype, at the same dose, did not interfere with sustained engraftment, suggesting that the observed effect was epitope dependent. Although higher concentrations of B1F6 were required, in the present study both MoAbs interfered with the propagation of long-term marrow cultures. When MoAb B1F6 was given in vivo at 1.2 mg/kg/d, ie, twice the dose used previously, dogs so treated also developed delayed marrow graft failure. Marrow failure with either MoAb involved myeloid, erythroid, and megakaryocytic lineages. Administration of recombinant canine c-kit ligand/stem cell factor (SCF) for 7 or 21 days posttransplant resulted in reversal of graft failure. Although the short course did induce a broad transient early peak of granulocytes, the longer course of SCF was accompanied by earlier sustained recovery than the short course. In conclusion, therefore, marrow graft failure induced by anti-MHC class II MoAb does not appear to be epitope dependent, involves all hematopoietic lineages, and is overcome by the administration of c-kit ligand.
Binding of matrix attachment regions to lamin polymers involves single-stranded regions and the minor groove

Chromatin in eukaryotic nuclei is thought to be partitioned into functional loop domains that are generated by the binding of defined DNA sequences, named MARs (matrix attachment regions), to the nuclear matrix. We have previously identified B-type lamins as MAR-binding matrix components (M. E. E. Ludérus, A. de Graaf, E. Mattia, J. L. den Blaauwen, M. A. Grande, L. de Jong, and R. van Driel, Cell 70:949-959, 1992). Here we show that A-type lamins and the structurally related proteins desmin and NuMA also specifically bind MARs in vitro. We studied the interaction between MARs and lamin polymers in molecular detail and found that the interaction is saturable, of high affinity, and evolutionarily conserved. Competition studies revealed the existence of two different types of interaction related to different structural features of MARs: one involving the minor groove of double-stranded MAR DNA and one involving single-stranded regions. We obtained similar results for the interaction of MARs with intact nuclear matrices from rat liver. A model in which the interaction of nuclear matrix proteins with single-stranded MAR regions serves to stabilize the transcriptionally active state of chromatin is discussed.
A comparison of rates of residual insomnia symptoms following pharmacotherapy or cognitive-behavioral therapy for major depressive disorder.

OBJECTIVE A number of pharmacologic studies have documented that insomnia is among the most commonly reported residual symptoms after remission from depression. Residual symptoms after remission are particularly relevant because these symptoms confer greater risk for subsequent depression. This study was the first to date to examine residual insomnia after cognitive-behavioral therapy (CBT) for depression and to compare CBT with pharmacotherapy for depression on residual insomnia rates. METHOD This naturalistic study examined rates of posttreatment insomnia complaints in patients (N = 94) who had been diagnosed with major depressive disorder (MDD), according to DSM-IV criteria, and who remitted from MDD after completing at least 20 weeks of either CBT or pharmacotherapy at an outpatient clinic specializing in mood disorders. Participants were randomly assigned to the treatment conditions, but only the data from those who completed treatment and remitted were analyzed. Primary outcome measure was the 17-item Hamilton Rating Scale for Depression. Data were collected from October 1, 1999, to September 23, 2003. Groups were compared using a chi(2) for nominal data. RESULTS The rate of posttreatment insomnia was 22% for sleep-onset insomnia, 26% for sleep-maintenance insomnia, and 17% for early morning awakenings, and the rates did not statistically differ across the 2 treatment groups. CONCLUSION Although CBT and pharmacotherapy effectively addressed depression in these patients and addressed insomnia symptoms for many, there were a number of patients with residual insomnia. Whereas there appears to be no difference between CBT and pharmacotherapy with regard to rates of residual insomnia, the rates of such insomnia remaining after these treatments suggest that adjunctive sleep treatment to specifically address insomnia may be necessary for some MDD patients.
H5N1 Virus-Like Particle Vaccine Elicits Cross-Reactive Neutralizing Antibodies That Preferentially Bind to the Oligomeric Form of Influenza Virus Hemagglutinin in Humans

ABSTRACT Transmission of pathogenic avian influenza viruses (AIV) from wild birds to domestic poultry and humans is continuing in multiple countries around the world. In preparation for a potential AIV pandemic, multiple vaccine candidates are under development. In the case of H5N1 AIV, a clear shift in transmission from clade 1 to clade 2 viruses occurred in recent years. The virus-like particle (VLP) represents an economical approach to pandemic vaccine development. In the current study, we evaluated the humoral immune response in humans vaccinated with H5N1 A/Indonesia/05/2005 (clade 2.1) VLP vaccine manufactured in Sf9 insect cells. The VLPs were comprised of the influenza virus hemagglutinin (HA), neuraminidase (NA), and matrix 1 (M1) proteins. In an FDA-approved phase I/II human clinical study, two doses of H5N1 VLPs at 15, 45, or 90 μg HA/dose resulted in seroconversion and production of functional antibodies. Moreover, cross-reactivity against other clade 2 subtypes was demonstrated using virus neutralization assays. H5N1 whole-genome fragment phage display libraries (GFPDL) were used to elucidate the antibody epitope repertoire in postvaccination human sera. Diverse epitopes in HA1/HA2 and NA were recognized by postvaccination sera from the two high-dose groups, including large segments spanning the HA1 receptor binding domain. Importantly, the vaccine elicited sera that preferentially bound to an oligomeric form of recombinant HA1 compared with monomeric HA1. The oligomeric/monomeric HA1 binding ratios of the sera correlated with the virus neutralizing titers. Additionally, the two high-dose VLP vaccine groups generated NA-inhibiting antibodies that were associated with binding to a C-terminal epitope close to the sialic acid binding site. These findings represent the first report describing the quality of the antibody responses in humans following AIV VLP immunization and support further development of such vaccines against emerging influenza virus strains.
Community views on health sector reform and their participation in health priority setting: case of Lushoto and Muheza districts, Tanzania.

BACKGROUND Community participation (CP) is a key concept under 'primary health care' programmes and 'Health Sector Reform' (HSR) in many countries. However, international literature with current empirical evidence on CP in health priority setting and HSR in Tanzania is scanty. OBJECTIVES To explore and describe community views on HSR and their participation in setting health priorities. METHODS A multistage sampling of wards and villages was done, involving group discussions with members of households, Village Development Committees (VDCs) and Ward Development Committees (WDCs). RESULTS Respondents at village and ward levels in both districts related HSR with a cost sharing system at public health facilities. Views on the advantages or disadvantages of HSR were mixed, most of the residents pointing out that user charges burden the poor, there is a shortage of drugs at peripheral health facilities, the performance of government health service staff and village health workers does not satisfy community needs, health insurance is promoted more than people actually benefit, VDC and WDC poorly function as compared to local community-participatory priority-setting structures. CONCLUSION HSR may not meet the desired health needs unless more efforts are made to enhance the performance of the existing HSR structures and community knowledge and enhance trust and participation in the health sector programmes at all levels.
Hyperspectral Recovery from RGB Images using Gaussian Processes

We propose to recover spectral details from RGB images of known spectral quantization by modeling natural spectra under Gaussian Processes and combining them with the RGB images. Our technique exploits Process Kernels to model the relative smoothness of reflectance spectra, and encourages non-negativity in the resulting signals for better estimation of the reflectance values. The Gaussian Processes are inferred in sets using clusters of spatio-spectrally correlated hyperspectral training patches. Each set is transformed to match the spectral quantization of the test RGB image. We extract overlapping patches from the RGB image and match them to the hyperspectral training patches by spectrally transforming the latter. The RGB patches are encoded over the transformed Gaussian Processes related to those hyperspectral patches and the resulting image is constructed by combining the codes with the original processes. Our approach infers the desired Gaussian Processes under a fully Bayesian model inspired by Beta-Bernoulli Process, for which we also present the inference procedure. A thorough evaluation using three hyperspectral datasets demonstrates the effective extraction of spectral details from RGB images by the proposed technique.
Delays and diversity in the practice of local research ethics committees.

OBJECTIVES: To compare the practices of local research ethics committees and the time they take to obtain ethical approval for a multi-centre study. DESIGN: A retrospective analysis of outcome of applications for a multi-centre study to local research ethics committees. SETTING: Thirty-six local research ethics committees covering 38 district health authorities in England. MAIN MEASURES: Response of chairmen and women, the time required to obtain approval, and questions asked in application forms. RESULTS: We received replies from all 36 chairmen contacted: four (11%) granted their approval, and 32 (89%) required our proposal to be considered by their local research ethics committee. Three committees asked us to attend their meetings. The application was approved by all 36 local research ethics committees but the time to obtain ethical approval varied between six to 208 days. One third of the committees did not approve the project within three months, and three took longer than six months. There was considerable variation in the issues raised by local research ethics committees and none conformed exactly to the Royal College of Physicians' guidelines. CONCLUSION: Obtaining ethical approval for a multi-centre study is time-consuming. There is much diversity in the practice of local research ethics committees. Our data support the recommendation for a central or regional review body of multi-centre studies which will be acceptable to all local research ethics committees.
Characterization of the activation of glutaminase induced by N‐methyl‐D‐aspartate and potassium in cerebellar granule cells

Chronic stimulation of cerebellar granule cells with N‐methyl‐D‐aspartate (NMDA) or KCl induces a specific activation of the enzymes directly involved in glutamate neurotransmitter synthesis. Phosphate‐activated glutaminase (PAG) activity is enhanced in cultured granule neurons incubated with 150 μM NMDA or 25 mM KCl. Other enzymes are not affected by this treatment like lactate dehydrogenase (LDH) and glutamate dehydrogenase (GLDH), which is also a mitochondrial enzyme but not directly involved in neurotransmitter synthesis. This effect is dependent on protein synthesis and is induced after 12 hr of NMDA or KCl stimulation. Kinetics of PAG activity showed that Km values were unaffected, in contrast to Vmax values that were increased approximately 70% and 215% over control by NMDA and KCl treatment, respectively. For GLDH, we found two isoforms that were affected differentially by the experimental conditions. Western blot analysis clearly evidenced an increase of approximately 120–180% in the amount of PAG in NMDA‐ and KCl‐treated cells, whereas GLDH was not significantly modified. These results demonstrate that the NMDA‐ and KCl‐induced activation of PAG are not due to the modification of the preexisting enzyme, but to an increase in the synthesis of this enzyme. This suggests that NMDA receptor stimulation during critical periods of the cerebellar granule cell development leads to the activation of gene expression involved in the process of cell differentiation. © 1996 Wiley‐Liss, Inc.
Preparation of Low‐Input and Ligation‐Free ChIP‐seq Libraries Using Template‐Switching Technology

Chromatin immunoprecipitation (ChIP) followed by high‐throughput sequencing (ChIP‐seq) has become the gold standard for mapping of transcription factors and histone modifications throughout the genome. However, for ChIP experiments involving few cells or targeting low‐abundance transcription factors, the small amount of DNA recovered makes ligation of adapters very challenging. In this unit, we describe a ChIP‐seq workflow that can be applied to small cell numbers, including a robust single‐tube and ligation‐free method for preparation of sequencing libraries from sub‐nanogram amounts of ChIP DNA. An example ChIP protocol is first presented, resulting in selective enrichment of DNA‐binding proteins and cross‐linked DNA fragments immobilized on beads via an antibody bridge. This is followed by a protocol for fast and easy cross‐linking reversal and DNA recovery. Finally, we describe a fast, ligation‐free library preparation protocol, featuring DNA SMART technology, resulting in samples ready for Illumina sequencing. © 2016 by John Wiley & Sons, Inc.
Species Specificity of Protein Kinase R Antagonism by Cytomegalovirus TRS1 Genes

ABSTRACT The host antiviral protein kinase R (PKR) has rapidly evolved during primate evolution, likely in response to challenges posed by many different viral antagonists, such as the TRS1 gene of cytomegaloviruses (CMVs). In turn, viral antagonists have adapted to changes in PKR. As a result of this “arms race,” modern TRS1 alleles in CMVs may function differently in cells derived from alternative species. We have previously shown that human CMV TRS1 (HuTRS1) blocks the PKR pathway and rescues replication of a vaccinia virus mutant lacking its major PKR antagonist in human cells. We now demonstrate that HuTRS1 does not have these activities in Old World monkey cells. Conversely, the rhesus cytomegalovirus homologue of HuTRS1 (RhTRS1) fulfills these functions in African green monkey cells, but not rhesus or human cells. Both TRS1 proteins bind to double-stranded RNA and, in the cell types in which they can rescue VVΔE3L replication, they also bind to PKR and prevent phosphorylation of the α-subunit of eukaryotic initiation factor 2. However, while HuTRS1 binds to inactive human PKR and prevents its autophosphorylation, RhTRS1 binds to phosphorylated African green monkey PKR. These studies reveal that evolutionary adaptations in this critical host defense protein have altered its binding interface in a way that has resulted in a qualitatively altered mechanism of PKR antagonism by viral TRS1 alleles from different CMVs. These results suggest that PKR antagonism is likely one of the factors that contributes to species specificity of cytomegalovirus replication.
Evidence‐based prescription of antibiotics in urology: a 5‐year review of microbiology

To analyse the results of positive urine cultures over a 5‐year period in a large hospital and urology department (amongst both inpatients and outpatients), assess the prevalence of different organisms and the resistance profiles of a range of antibiotics, and thus provide information on which organisms are likely to cause urosepsis.
Basal Ubiquitin-independent Internalization of Interferon α Receptor Is Prevented by Tyk2-mediated Masking of a Linear Endocytic Motif*

Linear endocytic motifs of signaling receptors as well as their ubiquitination determine the rate of ligand-induced endocytosis that mediates down-regulation of these receptors and restricts the magnitude and duration of their respective signal transduction pathways. We previously hypothesized that, in the absence of its cognate ligand, type I interferon (IFN), the IFNα receptor chain 1 (IFNAR1) receptor chain is protected from basal endocytosis by a hypothetical masking complex that prevents the Tyr-based endocytic motif within IFNAR1 from interacting with components of the adaptin protein complex 2 (AP2). Here we identify a member of the Janus kinase (Jak) family, Tyk2, as a component of such a masking complex. In the absence of ligand or of receptor chain ubiquitination, binding of Janus kinase Tyk2 within the proximity of the Tyr-based linear motif of IFNAR1 is required to prevent IFNAR1 internalization and to maintain its cell surface expression. Furthermore, interaction experiments revealed that Tyk2 physically shields this Tyr-based motif from the recognition by the AP50 subunit of AP2. These data delineate a long-sought ligand- and ubiquitin-independent mechanism by which Tyk2 contributes to both the regulation of total IFNAR1 levels as well as the regulation of the cell surface density of this receptor chain.
Nearest Neighbor Classifiers over Incomplete Information: From Certain Answers to Certain Predictions

Machine learning (ML) applications have been thriving recently, largely attributed to the increasing availability of data. However, inconsistency and incomplete information are ubiquitous in real-world datasets, and their impact on ML applications remains elusive. In this paper, we present a formal study of this impact by extending the notion of Certain Answers for Codd tables , which has been explored by the database research community for decades, into the field of machine learning. Specifically, we focus on classification problems and propose the notion of "Certain Predictions" (CP) --- a test data example can be certainly predicted (CP'ed) if all possible classifiers trained on top of all possible worlds induced by the incompleteness of data would yield the same prediction. We study two fundamental CP queries: (Q1) checking query that determines whether a data example can be CP'ed; and (Q2) counting query that computes the number of classifiers that support a particular prediction (i.e., label). Given that general solutions to CP queries are, not surprisingly, hard without assumption over the type of classifier, we further present a case study in the context of nearest neighbor (NN) classifiers, where efficient solutions to CP queries can be developed --- we show that it is possible to answer both queries in linear or polynomial time over exponentially many possible worlds. We demonstrate one example use case of CP in the important application of "data cleaning for machine learning (DC for ML). " We show that our proposed CPClean approach built based on CP can often significantly outperform existing techniques, particularly on datasets with systematic missing values. For example, on 5 datasets with systematic missingness, CPClean (with early termination) closes 100% gap on average by cleaning 36% of dirty data on average, while the best automatic cleaning approach BoostClean can only close 14% gap on average.
Identification of pathogenic Neisseria species with the RapID NH system

The RapID NH system (Innovative Diagnostics Systems, Inc., Decatur, Ga.) is a 4-h test used in the identification of Neisseria and Haemophilus species. The system was evaluated for accuracy and reliability and compared with conventional (cystine proteose peptone agar; Prepared Media Laboratory, Tualatin, Ore.) carbohydrate degradation tests with Neisseria gonorrhoeae and N. meningitidis, as well as a variety of Neisseria, Branhamella, and Moraxella species. The RapID NH system correctly identified all N. gonorrhoeae, N. meningitidis, and N. lactamica isolates, but the level of accuracy varied considerably for the remaining organisms. One strain of N. subflava was misidentified as a pathogenic Neisseria strain. The RapID NH tests were concluded in 4 h, whereas the cystine proteose peptone agar tests required up to 48 h for results to be useful. The RapID NH system is an accurate, reliable, and useful method for the identification of pathogenic Neisseria species. It has been proven that it shortens identification time and specimen turnaround time by at least 24 h.