julilili42/papers huggingface dataset:
Glucose-Raising Polymorphisms in the Human Clock Gene Cryptochrome 2 (CRY2) Affect Hepatic Lipid Content
2016-01-04

Circadian rhythms govern vital functions. Their disruption provokes metabolic imbalance favouring obesity and type-2 diabetes. The aim of the study was to assess the role of clock genes in human prediabetes. To this end, genotype-phenotype associations of 121 common single nucleotide polymorphisms (SNPs) tagging ARNTL, ARNTL2, CLOCK, CRY1, CRY2, PER1, PER2, PER3, and TIMELESS were assessed in a study population of 1,715 non-diabetic individuals metabolically phenotyped by 5-point oral glucose tolerance tests. In subgroups, hyperinsulinaemic-euglycaemic clamps, intravenous glucose tolerance tests, and magnetic resonance imaging/spectroscopy were performed. None of the tested SNPs was associated with body fat content, insulin sensitivity, or insulin secretion. Four CRY2 SNPs were associated with fasting glycaemia, as reported earlier. Importantly, carriers of these SNPs' minor alleles revealed elevated fasting glycaemia and, concomitantly, reduced liver fat content. In human liver tissue samples, CRY2 mRNA expression was directly associated with hepatic triglyceride content. Our data may point to CRY2 as a novel switch in hepatic fuel metabolism promoting triglyceride storage and, concomitantly, limiting glucose production. The anti-steatotic effects of the glucose-raising CRY2 alleles may explain why these alleles do not increase type-2 diabetes risk.
Exploratory decision-making as a function of lifelong experience, not cognitive decline.
2016-01-04

Older adults perform worse than younger adults in some complex decision-making scenarios, which is commonly attributed to age-related declines in striatal and frontostriatal processing. Recently, this popular account has been challenged by work that considered how older adults' performance may differ as a function of greater knowledge and experience, and by work showing that, in some cases, older adults outperform younger adults in complex decision-making tasks. In light of this controversy, we examined the performance of older and younger adults in an exploratory choice task that is amenable to model-based analyses and ostensibly not reliant on prior knowledge. Exploration is a critical aspect of decision-making poorly understood across the life span. Across 2 experiments, we addressed (a) how older and younger adults differ in exploratory choice and (b) to what extent observed differences reflect processing capacity declines. Model-based analyses suggested that the strategies used by the 2 groups were qualitatively different, resulting in relatively worse performance for older adults in 1 decision-making environment but equal performance in another. Little evidence was found that differences in processing capacity drove performance differences. Rather the results suggested that older adults' performance might result from applying a strategy that may have been shaped by their wealth of real-word decision-making experience. While this strategy is likely to be effective in the real world, it is ill suited to some decision environments. These results underscore the importance of taking into account effects of experience in aging studies, even for tasks that do not obviously tap past experiences.
Two galactose-α-1,3-galactose carrying peptidases from pork kidney mediate anaphylactogenic responses in delayed meat allergy
2016-01-05

Two cell-membrane proteins carrying α-Gal epitopes were identified in pork kidney. For the first time, isolated meat proteins were shown to induce basophil activation in patients with delayed anaphylaxis to red meat providing further confirmation for the clinical relevance of these α-Gal-carrying proteins.
PSM Peptides of Staphylococcus aureus Activate the p38–CREB Pathway in Dendritic Cells, Thereby Modulating Cytokine Production and T Cell Priming
2016-01-05

Abstract The challenging human pathogen Staphylococcus aureus has highly efficient immune evasion strategies for causing a wide range of diseases, from skin and soft tissue to life-threatening infections. Phenol-soluble modulin (PSM) peptides are major pathogenicity factors of community-associated methicillin-resistant S. aureus strains. In previous work, we demonstrated that PSMs in combination with TLR2 ligand from S. aureus induce tolerogenic dendritic cells (DCs) characterized by the production of high amounts of IL-10, but no proinflammatory cytokines. This in turn promotes the activation of regulatory T cells while impairing Th1 response; however, the signaling pathways modulated by PSMs remain elusive. In this study, we analyzed the effects of PSMs on signaling pathway modulation downstream of TLR2. TLR2 stimulation in combination with PSMα3 led to increased and prolonged phosphorylation of NF-κB, ERK, p38, and CREB in mouse bone marrow–derived DCs compared with single TLR2 activation. Furthermore, inhibition of p38 and downstream MSK1 prevented IL-10 production, which in turn reduced the capacity of DCs to activate regulatory T cells. Interestingly, the modulation of the signaling pathways by PSMs was independent of the known receptor for PSMs, as shown by experiments with DCs lacking the formyl peptide receptor 2. Instead, PSMs penetrate the cell membrane most likely by transient pore formation. Moreover, colocalization of PSMs and p38 was observed near the plasma membrane in the cytosol, indicating a direct interaction. Thus, PSMs from S. aureus directly modulate the signaling pathway p38–CREB in DCs, thereby impairing cytokine production and in consequence T cell priming to increase the tolerance toward the pathogen.
Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia
2016-01-05

Most inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here, we explore the role of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an additional genetic deletion of HCN1 on the function and survival of photoreceptors in a mouse model of CNGB1-linked retinitis pigmentosa (RP). We found that the absence of HCN1 in Cngb1 knockout (KO) mice exacerbated photoreceptor degeneration. The deleterious effect was reduced by expression of HCN1 using a viral vector. Moreover, pharmacological inhibition of HCN1 also enhanced rod degeneration in Cngb1 KO mice. Patch-clamp recordings revealed that the membrane potentials of Cngb1 KO and Cngb1/Hcn1 double-KO rods were both significantly depolarized. We also found evidence for altered calcium homeostasis and increased activation of the protease calpain in Cngb1/Hcn1 double-KO mice. Finally, the deletion of HCN1 also exacerbated degeneration of cone photoreceptors in a mouse model of CNGA3-linked achromatopsia. Our results identify HCN1 as a major modifier of photoreceptor degeneration and suggest that pharmacological inhibition of HCN channels may enhance disease progression in RP and achromatopsia patients.
Prediction of missing sequences and branch lengths in phylogenomic data
2016-01-05

Abstract Motivation: The presence of missing data in large-scale phylogenomic datasets has negative effects on the phylogenetic inference process. One effect that is caused by alignments with missing per-gene or per-partition sequences is that the inferred phylogenies may exhibit extremely long branch lengths. We investigate if statistically predicting missing sequences for organisms by using information from genes/partitions that have data for these organisms alleviates the problem and improves phylogenetic accuracy. Results: We present several algorithms for correcting excessively long branch lengths induced by missing data. We also present methods for predicting/imputing missing sequence data. We evaluate our algorithms by systematically removing sequence data from three empirical and 100 simulated alignments. We then compare the Maximum Likelihood trees inferred from the gappy alignments and on the alignments with predicted sequence data to the trees inferred from the original, complete datasets. The datasets with predicted sequences showed one to two orders of magnitude more accurate branch lengths compared to the branch lengths of the trees inferred from the alignments with missing data. However, prediction did not affect the RF distances between the trees. Availability and implementation: https://github.com/ddarriba/ForeSeqs Contact: diego.darriba@h-its.org Supplementary information: Supplementary data are available at Bioinformatics online.
Pre-Analytical Parameters Affecting Vascular Endothelial Growth Factor Measurement in Plasma: Identifying Confounders
2016-01-05

VEGF-A measurement results can be affected significantly by the identified pre-analytical parameters. We recommend the use of CTAD anticoagulant, a standardized type of centrifuge and one central laboratory using the same analyzing method for all samples.
Pooled Analysis of the Prognostic Relevance of Circulating Tumor Cells in Primary Breast Cancer
2016-01-06

Abstract Purpose: Although unequivocal evidence has shown the prognostic relevance of circulating tumor cells (CTC) in the peripheral blood of patients with metastatic breast cancer, less evidence is available for the prognostic relevance of CTCs at the time of primary diagnosis. Experimental Design: We conducted a pooled analysis of individual data from 3,173 patients with nonmetastatic (stage I–III) breast cancer from five breast cancer institutions. The prevalence and numbers of CTCs were assessed at the time of primary diagnosis with the FDA-cleared CellSearch System (Janssen Diagnostics, LLC). Patient outcomes were analyzed using meta-analytic procedures, univariate log-rank tests, and multivariate Cox proportional hazard regression analyses. The median follow-up duration was 62.8 months. Results: One or more CTCs were detected in 20.2% of the patients. CTC-positive patients had larger tumors, increased lymph node involvement, and a higher histologic tumor grade than did CTC-negative patients (all P &amp;lt; 0.002). Multivariate Cox regressions, which included tumor size, nodal status, histologic tumor grade, and hormone receptor and HER2 status, confirmed that the presence of CTCs was an independent prognostic factor for disease-free survival [HR, 1.82; 95% confidence interval (CI), 1.47–2.26], distant disease-free survival (HR, 1.89; 95% CI, 1.49–2.40), breast cancer–specific survival (HR, 2.04; 95% CI, 1.52–2.75), and overall survival (HR, 1.97; 95% CI, 1.51–2.59). Conclusions: In patients with primary breast cancer, the presence of CTCs was an independent predictor of poor disease-free, overall, breast cancer–specific, and distant disease-free survival. Clin Cancer Res; 22(10); 2583–93. ©2016 AACR.
Isoxazolines: A Novel Chemotype Highly Effective on Ectoparasites
2016-01-06

Abstract Efficient control of arthropod ectoparasite infestations has a long‐standing history in the agriculture and veterinary sectors, aiming to decrease the parasite burden of affected crops and animals. Ligand‐gated chloride channels (LGCCs) modulated by γ‐aminobutyric acid (GABA) and glutamate have been identified as suitable molecular targets, and several classes of potent parasiticides have been devised. Due to the increase in cross‐resistance and decreased development of new chemical entities, an urgent need for new parasiticides or prevention schemes has emerged. In the last decade, an innovative isoxazoline chemotype appears to offer promise for inhibiting LGCCs with a new mode of action and distinct binding site from that of historical agents. Considerable efforts have focused on optimizing the antiparasitic activity of isoxazolines and may provide the potential for future human use.
In situ development of high‐elevation, low‐relief landscapes via duplex deformation in the Eastern Himalayan hinterland, Bhutan
2016-01-06

Abstract Prior studies have proposed tectonic and climatic mechanisms to explain surface uplift throughout the Bhutan Himalaya. While the resulting enigmatic, low‐relief landscapes, elevated above deeply incised canyons, are a popular setting to test ideas of interacting tectonic and climatic forces, when and why these landscapes formed is still debated. We test the idea that these landscapes were created by a spatially variable and recent increase in rock uplift rate associated with the formation of structural duplexes at depth. We utilize a new suite of erosion rates derived from detrital cosmogenic nuclide techniques, geomorphic observations, and a landscape evolution model to demonstrate the viability of this hypothesis. Low‐relief landscapes in Bhutan are eroding at a rate of ~70 m/Ma, while basins from surrounding steep landscapes yield erosion rates of ~950 m/Ma, demonstrating that this portion of the range is in a transient period of increasing relief. Applying insights from our erosion rates, we explore the influence of an active duplex on overlying topography using a landscape evolution model by imposing a high rock uplift rate in the middle of a mountain range. Our simulations show that low‐relief landscapes with thick alluvial fills form upstream of convex knickpoints as rivers adjust to higher uplift rates downstream, a pattern consistent with geologic, geomorphic, and thermochronometric data from Bhutan. With our new erosion rates, reconstructed paleo‐river profiles, and landscape evolution simulations, we show that the low‐relief landscapes were formed in situ as they were uplifted ~800 m in the past ~0.8–1 Ma.
Shear-Resistant Binding to von Willebrand Factor AllowsStaphylococcus lugdunensisto Adhere to the Cardiac Valves and Initiate Endocarditis
2016-01-06

S. lugdunensis binds directly to VWF, which proved to be vital for withstanding shear forces and for its adhesion to the vessel wall and cardiac valves. This mechanism explains why S. lugdunensis causes more-aggressive infections, including endocarditis, compared with other coagulase-negative staphylococci.
Approach and Withdrawal Tendencies during Written Word Processing: Effects of Task, Emotional Valence, and Emotional Arousal
2016-01-06

The affective dimensions of emotional valence and emotional arousal affect processing of verbal and pictorial stimuli. Traditional emotional theories assume a linear relationship between these dimensions, with valence determining the direction of a behavior (approach vs. withdrawal) and arousal its intensity or strength. In contrast, according to the valence-arousal conflict theory, both dimensions are interactively related: positive valence and low arousal (PL) are associated with an implicit tendency to approach a stimulus, whereas negative valence and high arousal (NH) are associated with withdrawal. Hence, positive, high-arousal (PH) and negative, low-arousal (NL) stimuli elicit conflicting action tendencies. By extending previous research that used several tasks and methods, the present study investigated whether and how emotional valence and arousal affect subjective approach vs. withdrawal tendencies toward emotional words during two novel tasks. In Study 1, participants had to decide whether they would approach or withdraw from concepts expressed by written words. In Studies 2 and 3 participants had to respond to each word by pressing one of two keys labeled with an arrow pointing upward or downward. Across experiments, positive and negative words, high or low in arousal, were presented. In Study 1 (explicit task), in line with the valence-arousal conflict theory, PH and NL words were responded to more slowly than PL and NH words. In addition, participants decided to approach positive words more often than negative words. In Studies 2 and 3, participants responded faster to positive than negative words, irrespective of their level of arousal. Furthermore, positive words were significantly more often associated with “up” responses than negative words, thus supporting the existence of implicit associations between stimulus valence and response coding (positive is up and negative is down). Hence, in contexts in which participants' spontaneous responses are based on implicit associations between stimulus valence and response, there is no influence of arousal. In line with the valence-arousal conflict theory, arousal seems to affect participants' approach-withdrawal tendencies only when such tendencies are made explicit by the task, and a minimal degree of processing depth is required.
Increases in Soil Aggregation Following Phosphorus Additions in a Tropical Premontane Forest are Not Driven by Root and Arbuscular Mycorrhizal Fungal Abundances
2016-01-06

Tropical ecosystems have an important role in global change scenarios, in part\\nbecause they serve as a large terrestrial carbon pool. Carbon protection is\\nmediated by soil aggregation processes, whereby biotic and abiotic factors\\ninfluence the formation and stability of aggregates. Nutrient additions may\\naffect soil structure indirectly by simultaneous shifts in biotic factors,\\nmainly roots, and fungal hyphae, but also via impacts on abiotic soil\\nproperties. Here, we tested the hypothesis that soil aggregation will be\\naffected by nutrient additions primarily via changes in arbuscular mycorrhizal\\nfungal (AMF) hyphae and root length in a pristine tropical forest system.\\nTherefore, the percentage of water-stable macroaggregates (&gt; 250 μm) (WSA) and\\nthe soil mean weight diameter (MWD) was analyzed, as well as nutrient\\ncontents, pH, root length, and AMF abundance. Phosphorus additions\\nsignificantly increased the amount of WSA, which was consistent across two\\ndifferent sampling times. Despite a positive effect of phosphorus additions on\\nextra-radical AMF biomass, no relationship between WSA and extra-radical AMF\\nnor roots was revealed by regression analyses, contrary to the proposed\\nhypothesis. These findings emphasize the importance of analyzing soil\\nstructure in understudied tropical systems, since it might be affected by\\nincreasing nutrient deposition expected in the future.
BORDER EFFECTS AMONG CATALAN DIALECTS
2016-01-06

Abstract In this study, we investigate which factors influence the linguistic dis-tance of Catalan dialectal pronunciations from standard Catalan. We use pronun-ciations from three regions where the northwestern variety of the Catalan language is spoken (Catalonia, Aragon and Andorra). In contrast to Aragon, Catalan has an official status in both Catalonia and Andorra, which likely influences standardiza-tion. Because we are interested in the potentially large range of differences that standardization might promote, we examine 357 words in Catalan varieties and in particular their pronunciation distances with respect to the standard. In order to be sensitive to differences among the words, we fit a generalized additive mixed-effects regression model to this data. This allows us to examine simultaneously the general (i.e. aggregate) patterns in pronunciation distance and to detect those words that diverge substantially from the general pattern. The results reveal higher pronunciation distances from standard Catalan in Aragon than in the other regions. Furthermore, speakers in Catalonia and Andorra, but not in Aragon, show a clear standardization pattern, with younger speakers having dialectal pronunciations
The 5300-year-old Helicobacter pylori genome of the Iceman
2016-01-07

Stomach ache for a European mummy Five thousand years ago in the European Alps, a man was shot by an arrow, then clubbed to death. His body was subsequently mummified by ice until glacier retreat exhumed him in 1991. Subsequently, this ancient corpse has provided a trove of intriguing information about copper-age Europeans. Now, Maixner et al. have identified the human pathogen Helicobacter pylori within the mummy's stomach contents. The strain the “Iceman” hosted appears to most closely resemble pathogenic Asian strains found today in Central and Southern Asia. Science , this issue p. 162
Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome
2016-01-07

Key Points A phenotype with albinism, early-onset seizures, neurodevelopmental delay, infection susceptibility, and neutropenia is caused by AP3D1 mutations. AP3δ deficiency destabilizes the AP3 complex and defines a novel type of Hermansky-Pudlak syndrome with severe neurologic involvement.
Feasibility of Active Machine Learning for Multiclass Compound Classification
2016-01-07

A common task in the hit-to-lead process is classifying sets of compounds into multiple, usually structural classes, which build the groundwork for subsequent SAR studies. Machine learning techniques can be used to automate this process by learning classification models from training compounds of each class. Gathering class information for compounds can be cost-intensive as the required data needs to be provided by human experts or experiments. This paper studies whether active machine learning can be used to reduce the required number of training compounds. Active learning is a machine learning method which processes class label data in an iterative fashion. It has gained much attention in a broad range of application areas. In this paper, an active learning method for multiclass compound classification is proposed. This method selects informative training compounds so as to optimally support the learning progress. The combination with human feedback leads to a semiautomated interactive multiclass classification procedure. This method was investigated empirically on 15 compound classification tasks containing 86-2870 compounds in 3-38 classes. The empirical results show that active learning can solve these classification tasks using 10-80% of the data which would be necessary for standard learning techniques.
The single‐chain anti‐TNF‐α antibody DLX105 induces clinical and biomarker responses upon local administration in patients with chronic plaque‐type psoriasis
2016-01-07

Abstract It is not clear whether TNF ‐ α antagonists used in the treatment of psoriasis need to act systemically, or whether local inhibition of skin‐produced TNF ‐ α would be sufficient to silence skin inflammation. To answer this question, we conducted two multicentre, double‐blinded, randomized, placebo‐controlled clinical trials with the novel single‐chain anti‐ TNF ‐ α ‐ PENTRA ® ‐antibody DLX 105. Upon intra‐dermal injection, DLX 105 induced a mean local PASI decrease of 33% over baseline after 2 weeks of treatment, while the placebo response was only 12% ( P = 0.001). The clinical response was accompanied by changes in biomarkers such as reductions in K16, Ki67 and epidermal thickness as well as decreased mRNA levels of IL ‐17, TNF ‐ α , IL ‐23p19, IL ‐12p40 and IFN ‐ γ . Next, we applied the drug topically twice daily in a 0.5% hydrogel formulation. While the local PASI did not change, topical DLX 105 mediated significant reductions of mRNA levels of key proinflammatory cytokines when compared to placebo, and this effect was further enhanced after weekly tape stripping of plaques to increase drug penetration. These results suggest that longer treatment periods and/or increased local drug concentrations might result in better therapeutic efficacy of topically applied DLX 105. In sum, we can show for the first time that local inhibition of TNF ‐ α is sufficient to mediate a biological response in psoriasis that translates into clinical efficacy.