julilili42/papers huggingface dataset:
Probing the structure–activity relationship of endogenous histone deacetylase complexes with immobilized peptide‐inhibitors
2016-04-12

Abstract Histone deacetylases (HDACs) are key regulators of numerous cellular proteins by removing acetylation marks from modified lysine residues. Peptide‐based HDAC probes containing α‐aminosuberic acid ω‐hydroxamate have been established as useful tools for investigating substrate selectivity and composition of endogenous HDAC complexes in cellular lysates. Here we report a structure–activity study of potential HDAC‐probes containing derivatives of the hydroxamate moieties. While most of these probes did not recruit significant amounts of endogenous HDACs from cellular lysates, peptides containing N ε‐acetyl‐ N ε‐hydroxy‐L‐lysine served as HDAC probe. The recruitment efficiency varied between HDACs and was generally lower than that of α‐aminosuberic acid ω‐hydroxamate probes, but showed a similar global interaction profile. These findings indicate that N ε‐acetyl‐ N ε‐hydroxy‐L‐lysine might be a useful tool for investigations on HDAC complexes and the development of HDAC inhibitors. Copyright © 2016 European Peptide Society and John Wiley &amp; Sons, Ltd.
Human CD8+T Cells Target Multiple Epitopes in Respiratory Syncytial Virus Polymerase
2016-04-12

Respiratory syncytial virus (RSV) infection is a serious health problem in young children, immunocompromised patients, and the elderly. The development of novel prevention strategies, such as a vaccine to RSV, is a high priority. One strategy is to design a peptide-based vaccine that activates appropriate CD8(+) T-cell responses. However, this approach is limited by the low number of RSV peptide epitopes defined to date that activate CD8(+) T cells. We aimed to identify peptide epitopes that are presented by common human leukocyte antigen types (HLA-A*01, -A*02, and -B*07). We identify one novel HLA-A*02-restricted and two novel HLA-A*01-restricted peptide epitopes from RSV polymerase. Peptide-HLA multimer staining of specific T cells from healthy donor peripheral blood mononuclear cell, the memory phenotype of such peptide-specific T cells ex vivo, and functional IFNγ responses in short-term stimulation assays suggest that these peptides are recognized during RSV infection. Such peptides are candidates for inclusion into a peptide-based RSV vaccine designed to stimulate defined CD8(+) T-cell responses.
Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network
2016-04-13

Distraction and rumination are distinct response styles that determine how an individual deals with negative thoughts and feelings. Rumination is accompanied by an elevated self-focus, which is associated with increased resting state functional connectivity and decreased reactivity within the default mode network. Interestingly, the NMDA receptor antagonist ketamine reduces functional connectivity in this network, while its effects on blood oxygenation level-dependent (BOLD) responses during stimulus perception are not known. Ketamine might lead to a more variable processing of the external world with an attenuated self-focus by reducing the resting state connectivity. Here, we used an emotional picture-viewing task in combination with functional magnetic resonance imaging to test the hypothesis that a single ketamine administration to healthy subjects increases BOLD reactivity to negative stimuli. We found a region specific increase in BOLD reactivity in the pregenual anterior cingulate cortex and not in a posterior control region after ketamine compared with placebo administration. Moreover, a linear regression revealed that the increase in BOLD reactivity was more pronounced for subjects with a low ability to apply distraction during negative experiences. Our results implicate that ketamine attenuates a potentially pathological increased self-focus during negative experiences.
High Frequency of Pathogenic Rearrangements in SPG11 and Extensive Contribution of Mutational Hotspots and Founder Alleles
2016-04-13

Biallelic loss-of-function mutations in SPG11 cause a wide spectrum of recessively inherited, neurodegenerative disorders including hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease. By comprehensive screening of three large cohorts of HSP index patients, we identified 83 alleles with "small" mutations and 13 alleles that carry large genomic rearrangements. Including relevant data from previous studies, we estimate that copy number variants (CNVs) account for ∼19% of pathogenic SPG11 alleles. The breakpoints for all novel and some previously reported CNVs were determined by long-range PCR and sequencing. This revealed several Alu-associated recombination hotspots. We also found evidence for additional mutational mechanisms, including for a two-step event in which an Alu retrotransposition preceded the actual rearrangement. Apparently independent samples with identical breakpoints were analyzed by microsatellite PCRs. The resulting haplotypes suggested the existence of two rearrangement founder alleles. Our findings widen the spectra of mutations and mutational mechanisms in SPG11, underscore the pivotal role played by Alus, and are of high diagnostic relevance for a wide spectrum of clinical phenotypes including the most frequent form of recessive HSP.
A search for very high-energy flares from the microquasars GRS 1915+105, Circinus X-1, and V4641 Sgr using contemporaneous H.E.S.S. and RXTE observations
2016-04-13

Context. Microquasars are potential γ -ray emitters. Indications of transient episodes of γ -ray emission were recently reported in at least two systems: Cyg X-1 and Cyg X-3. The identification of additional γ -ray-emitting microquasars is required to better understand how γ -ray emission can be produced in these systems. Aim. Theoretical models have predicted very high-energy (VHE) γ -ray emission from microquasars during periods of transient outburst. Observations reported herein were undertaken with the objective of observing a broadband flaring event in the γ -ray and X-ray bands. Methods. Contemporaneous observations of three microquasars, GRS 1915+105, Circinus X-1, and V4641 Sgr, were obtained using the High Energy Spectroscopic System (H.E.S.S.) telescope array and the Rossi X-ray Timing Explorer (RXTE) satellite. X-ray analyses for each microquasar were performed and VHE γ -ray upper limits from contemporaneous H.E.S.S. observations were derived. Results. No significant γ -ray signal has been detected in any of the three systems. The integral γ -ray photon flux at the observational epochs is constrained to be I (&gt;560 GeV) &lt; 7.3 × 10 −13 cm −2 s −1 , I (&gt;560 GeV ) &lt; 1.2 × 10 −12 cm −2 s −1 , and I (&gt;240 GeV) &lt; 4.5 × 10 −12 cm −2 s −1 for GRS 1915+105, Circinus X-1, and V4641 Sgr, respectively. Conclusions. The γ -ray upper limits obtained using H.E.S.S. are examined in the context of previous Cherenkov telescope observations of microquasars. The effect of intrinsic absorption is modelled for each target and found to have negligible impact on the flux of escaping γ -rays. When combined with the X-ray behaviour observed using RXTE, the derived results indicate that if detectable VHE γ -ray emission from microquasars is commonplace, then it is likely to be highly transient.
Actions of Tryptophan Prenyltransferases Toward Fumiquinazolines and their Potential Application for the Generation of Prenylated Derivatives by Combining Chemical and Chemoenzymatic Syntheses
2016-04-13

Abstract D i m ethyl a llyl t ryptophan s ynthases (DMATSs) catalyze regiospecific transfer reactions of a prenyl moiety from dimethylallyl diphosphate to various positions of the indole ring of tryptophan. For example, FgaPT2, 5‐DMATS, and 7‐DMATS from Aspergillus fungi catalyze tryptophan prenylation at C‐4, C‐5, and C‐7, while 5‐DMATS Sc and 6‐DMATS Sa from Streptomyces strains are tryptophan C‐5 and C‐6 prenyltransferases, respectively. In this study, our objective is to demonstrate the possibility of producing prenylated analogues of ardeemin fumiquinazoline (FQ) ( 1a ), a precursor of the m ulti d rug r esistance (MDR) export pump inhibitor ardeemin, by using DMATSs. All ardeemin FQ stereoisomers were chemically synthesized and used as substrates for enzyme assays with DMATSs. Biochemical investigations revealed different features of these enzymes toward ardeemin FQ analogues, regarding activity and prenylation position. Isolation and structural elucidation showed that 7‐DMATS catalyzed mainly regiospecific prenylation at C‐7, which is also observed for its natural substrate L ‐tryptophan. Up to four prenylated derivatives were identified in the reaction mixtures of other enzymes. In total, 18 new prenylated ardeemin FQ analogues were obtained in this study. Molecular modelling of ardeemin FQ analogues with the crystal structure of FgaPT2 led to the identification of two potential amino acid residues for guidance of the prenylation position. The two generated mutants FgaPT2_M328L and FgaPT2_Y398F showed significant prenylation shifts with 1a . magnified image
Medical teachers’ perception of professional roles in the framework of the German National Competence-Based Learning Objectives for Undergraduate Medical Education (NKLM)—A multicenter study
2016-04-13

Medical teachers considered NKLM roles relevant for medical practice, although their role perception differed considerably. The value and risk matrix visualizes the specific role profile and offers strategic implications for NKLM communication and handling, thus supporting change management.
Detecting distortions of peripherally-presented letter stimuli under crowded conditions
2016-04-13

Abstract When visual features in the periphery are close together they become difficult to recognise: something is present but it is unclear what. This is called “crowding”. Here we investigated sensitivity to features in highly familiar shapes (letters) by applying spatial distortions. In Experiment 1, observers detected which of four peripherally-presented (8 deg of retinal eccentricity) target letters was distorted (spatial 4AFC). The letters were presented either isolated or surrounded by four undistorted flanking letters, and distorted with one of two types of distortion at a range of distortion frequencies and amplitudes. The bandpass noise distortion (“BPN”) technique causes spatial distortions in cartesian space, whereas radial frequency distortion (“RF”) causes shifts in polar coordinates. Detecting distortions in target letters was more difficult in the presence of flanking letters, consistent with the effect of crowding. The BPN distortion type showed evidence of tuning, with sensitivity to distortions peaking at approximately 6.5 c/deg for un-flanked letters. The presence of flanking letters causes this peak to rise to approximately 8.5 c/deg. In contrast to the tuning observed for BPN distortions, RF distortion sensitivity increased as the radial frequency of distortion increased. In a series of follow-up experiments we found that sensitivity to distortions is reduced when flanking letters were also distorted, that this held when observers were required to report which target letter was undistorted, and that this held when flanker distortions were always detectable. The perception of geometric distortions in letter stimuli is impaired by visual crowding.
Psychological Distress, Anxiety, and Depression of Cancer‐Affected BRCA1/2 Mutation Carriers: a Systematic Review
2016-04-14

Abstract Understanding the intermediate‐ and long‐term psychological consequences of genetic testing for cancer patients has led to encouraging research, but a clear consensus of the psychosocial impact and clinical routine for cancer‐affected BRCA1 and BRCA2 mutation carriers is still missing. We performed a systematic review of intermediate‐ and long‐term studies investigating the psychological impact like psychological distress, anxiety, and depression in cancer‐affected BRCA mutation carriers compared to unaffected mutation carriers. This review included the screening of 1243 studies. Eight intermediate‐ and long‐term studies focusing on distress, anxiety, and depression symptoms among cancer‐affected mutation carriers at least six months after the disclosure of genetic testing results were included. Studies reported a great variety of designs, methods, and patient outcomes. We found evidence indicating that cancer‐affected mutation carriers experienced a negative effect in relation to psychological well‐being in terms of an increase in symptoms of distress, anxiety, and depression in the first months after test disclosure. In the intermediate‐ and long‐term, no significant clinical relevant symptoms occurred. However, none of the included studies used specific measurements, which can clearly identify psychological burdens of cancer‐affected mutation carriers. We concluded that current well‐implemented distress screening instruments are not sufficient for precisely identifying the psychological burden of genetic testing. Therefore, future studies should implement coping strategies, specific personality structures, the impact of genetic testing, supportive care needs and disease management behaviour to clearly screen for the possible intermediate‐ and long‐term psychological impact of a positive test disclosure.
Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak
2016-04-14

ABSTRACT The pro-apoptotic multidomain Bcl-2 proteins Bax and Bak (also known as BAK1) are considered the gatekeepers of the intrinsic pathway of apoptosis by triggering the mitochondrial release of cytochrome c. The role of the third Bax- and Bak-homologous multidomain protein Bok, however, is still unresolved. As cells doubly deficient for Bax and Bak are largely resistant to various apoptotic stimuli, it has been proposed that Bok is either dispensable for apoptosis or that its role is dependent on Bax and Bak. Here, we demonstrate, in several cell systems, that Bok efficiently induces cytochrome c release and apoptosis even in the complete absence of both Bak and Bax. Moreover, modulation of endogenous Bok levels affects the apoptosis response. By RNA interference and targeted deletion of the Bok gene, we demonstrate that Bok can significantly influence the apoptotic response to chemotherapeutic drugs in ovarian carcinoma cells. Hence, our results not only establish Bok as a Bak- and Bax-independent apoptosis inducer, but also suggest a potential impact of Bok expression in ovarian cancer therapy.
Dual-Energy Computed Tomography of the Knee, Ankle, and Foot: Noninvasive Diagnosis of Gout and Quantification of Monosodium Urate in Tendons and Ligaments
2016-04-14

Gout is a true crystal deposition arthropathy caused by the precipitation of monosodium urate into joints and periarticular soft tissues. It is the most common inflammatory arthropathy in men and women of older age with a male-to-female ratio of 3 to 8:1. The disease may progress from asymptomatic hyperuricemia through symptomatic acute gout attacks with asymptomatic periods into chronic symptomatic tophaceous gout. Although invasive arthrocentesis and demonstration of monosodium urate crystals on polarized light microscopy is definitive for the diagnosis of gout, dual-energy computed tomography (CT) allows for noninvasive visualization and reproducible volume quantification of monosodium urate crystals. Based on the high diagnostic performance, dual-energy CT has been included in the 2015 American College of Rheumatology/European League Against Rheumatism Collaborative Initiative Classification Criteria for Gout. Increasing evidence indicates the usefulness of dual-energy CT to guide the management of patients with suspected gout and monitor the effectiveness of urate-lowering medical therapy.
Peer Grading in a Course on Algorithms and Data Structures
2016-04-14

Peer grading is the process of students reviewing each others' work, such as homework submissions, and has lately become a popular mechanism used in massive open online courses (MOOCs). Intrigued by this idea, we used it in a course on algorithms and data structures at the University of Hamburg. Throughout the whole semester, students repeatedly handed in submissions to exercises, which were then evaluated both by teaching assistants and by a peer grading mechanism, yielding a large dataset of teacher and peer grades. We applied different statistical and machine learning methods to aggregate the peer grades in order to come up with accurate final grades for the submissions (supervised and unsupervised, methods based on numeric scores and ordinal rankings). Surprisingly, none of them improves over the baseline of using the mean peer grade as the final grade. We discuss a number of possible explanations for these results and present a thorough analysis of the generated dataset.
Differentiation of human CD14+ monocytes: an experimental investigation of the optimal culture medium and evidence of a lack of differentiation along the endothelial line
2016-04-15

The aim of this study was to determine the optimal culturing media for human CD14+ monocytes and to evaluate whether these cells are capable of differentiating into vascular endothelial cells. Human monocytes isolated from peripheral blood were cultured for 1, 3, 7, 10 or 14 days in different media containing either 10% fetal bovine serum (FBS), 10% autologous donor serum (Auto), 10% FBS with interleukin-3 and macrophage colony stimulating factor (FBS-WF) or 10% Auto and the same growth factors (AU-WF). The cells were differentiated using endothelial cell conditioning medium (EC). Viability was measured using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and the cells were characterized by histology, immunohistochemistry and western blot analysis. Monocytes treated with Auto, FBS-WF or AU-WF medium generated a significant higher yield of vital cells after 7 days in culture compared with FBS-only medium (mean difference (MD)=0.318, P=0.01; MD=1.83, P=0.04; or MD=0.271, P=0.01 and MD=0.318, P=0.102). All tested media led to the differentiation of monocytes into macrophages, identified by CD68, especially in the FBS-WF medium (MD=+18.3%; P=0.04). Differentiation into ECs caused a significant decrease in cell viability in all media. Endothelial cell markers, including CD31, CD144, VEGF, VEGF-R2 and CD34, could not be detected. Autologous serum significantly increases the yield of monocyte-derived cells with a higher effectiveness than commonly used FBS-only serum. There is no further benefit in culturing monocytes longer than 7 days. The cultivation of monocytes in the tested media leads preferentially to differentiation into macrophages. Differentiation into endothelial cells did not take place.
Serum Levels of Progranulin Do Not Reflect Cerebrospinal Fluid Levels in Neurodegenerative Disease
2016-04-15

Altered progranulin levels play a major role in neurodegenerative diseases, like Alzheimer’s dementia (AD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), even in the absence of GRN mutations. Increasing progranulin levels could hereby provide a novel treatment strategy. However, knowledge on progranulin regulation in neurodegenerative diseases remains limited. We here demonstrate that cerebrospinal fluid progranulin levels do not correlate with its serum levels in AD, FTD and ALS, indicating a differential regulation of its central and peripheral levels in neurodegeneration. Blood progranulin levels thus do not reliably predict central nervous progranulin levels and their response to future progranulin-increasing therapeutics. Keywords: Alzheimer’s dementia, amyotrophic lateral sclerosis, biomarker, case-control study, cerebrospinal fluid, frontotemporal dementia, GRN, progranulin, serum.
Ten Simple Rules for Taking Advantage of git and GitHub
2016-04-15

Abstract A ‘Ten Simple Rules’ guide to git and GitHub. We describe and provide examples on how to use these software to track projects, as users, teams and organizations. We document collaborative development using branching and forking, interaction between collaborators using issues and continuous integration and automation using, for example, Travis CI and codevoc. We also describe dissemination and social aspects of GitHub such as GitHub pages, following and watching repositories, and give advice on how to make code citable.
Differential neural mechanisms for early and late prediction error detection
2016-04-15

Abstract Emerging evidence indicates that prediction, instantiated at different perceptual levels, facilitate visual processing and enable prompt and appropriate reactions. Until now, the mechanisms underlying the effect of predictive coding at different stages of visual processing have still remained unclear. Here, we aimed to investigate early and late processing of spatial prediction violation by performing combined recordings of saccadic eye movements and fast event-related fMRI during a continuous visual detection task. Psychophysical reverse correlation analysis revealed that the degree of mismatch between current perceptual input and prior expectations is mainly processed at late rather than early stage, which is instead responsible for fast but general prediction error detection. Furthermore, our results suggest that conscious late detection of deviant stimuli is elicited by the assessment of prediction error’s extent more than by prediction error per se . Functional MRI and functional connectivity data analyses indicated that higher-level brain systems interactions modulate conscious detection of prediction error through top-down processes for the analysis of its representational content, and possibly regulate subsequent adaptation of predictive models. Overall, our experimental paradigm allowed to dissect explicit from implicit behavioral and neural responses to deviant stimuli in terms of their reliance on predictive models.
Slowly progressive LGI1 encephalitis with isolated late‐onset cognitive dysfunction: a treatable mimic of Alzheimer's disease
2016-04-15

Table S1. Neuropsychological functioning at baseline (prior to treatment) and 4 months after treatment. Table S2. CSF analysis. Figure S1. FDG PET imaging. Appendix S1. Method for LGI1 staining. 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.
MOMP in the absence of BH3-only proteins
2016-04-15

The minimum requirement for mitochondrial apoptosis has been controversial ever since the discovery of BCL-2 as a cell death regulator. In this issue of Genes &amp; Development , O'Neill and colleagues (pp. 973–988) end a long-standing debate by creating a cellular system free of BCL-2 family proteins, thereby identifying the outer mitochondrial membrane rather than BH3-only proteins as the only requirement for BAX/BAK activation and mitochondrial outer membrane permeabilization (MOMP).
Draft Genome Sequence of Pseudomonas putida BW11M1, a Banana Rhizosphere Isolate with a Diversified Antimicrobial Armamentarium
2016-04-15

ABSTRACT In this study, we report the draft genome of Pseudomonas putida BW11M1, a banana rhizosphere isolate producing various antimicrobial compounds, including a lectin-like bacteriocin, an R-type tailocin, the cyclic lipopeptide xantholysin, and the fatty acid–derived pseudopyronine.