julilili42/papers huggingface dataset:
Risk factors for human Leptospira seropositivity in South Germany
2016-10-18

We analyzed risk factors for <i>Leptospira</i> seropositivity in humans, using data from a population-based cross-sectional zoonosis survey in South Germany (2008/9). Out of 1007 participants 42 (4.2 %) were sero-positive (19/446 men; 23/561 women), indicating that <i>Leptospira</i> exposure and sero-conversion is much more frequent than commonly assumed. Relative risks (RR) for seropositivity with exact 95 % confidence intervals (CI; adjusted for specificity and sensitivity of the ELISA test) were calculated for various exposure factors. Contact with pet rats (RR = 13.9 CI [4.8; 25.3]), guinea pigs (3.0[1.1; 7.4]), cattle (3.7[1.3; 9.6]), poultry (3.6[1.3; 8.6]) or livestock (2.3[1.1; 4.9]) as well as occupation as forestry worker (9.2[2.6; 21.4]) were identified as important exposure factors. None of the participants has ever been diagnosed with leptospirosis, yet 45 had experienced symptoms which may have been caused by <i>Leptospira</i> infection (12 with scleral icterus, 25 dark urine, 8 liver inflammation, 7 kidney failure). Three times as many participants with prior symptoms were seropositive as participants without symptoms (RR = 3.4[1.3; 8.3]), suggesting that sero-positive patients with severe symptoms may frequently not be diagnosed as leptospirosis cases. Physicians should consider leptospirosis as a differential diagnosis. Currently, the vast majority of symptomatic leptospirosis patients may neither be diagnosed nor reported.
Prevention of Early Mortality by Presumptive Tuberculosis Therapy Study: An Open Label, Randomized Controlled Trial
2016-10-18

Abstract Early mortality after initiation of antiretroviral therapy (ART) occurs in 9–39% of patients in sub-Saharan Africa. A significant proportion of deaths are attributable to tuberculosis (TB). Low baseline CD4 T-cell count and low body mass index (BMI) are strongly associated with early mortality. We hypothesized that initiation of ART concurrent with presumptive anti-TB chemotherapy in high-risk patients would reduce mortality within the first 6 months by treating unrecognized TB. From October 2011 to December 2012, ART-naive, smear-negative participants with a CD4 T-cell count &lt; 50 cells/μL and BMI &lt; 18 kg/m 2 were randomly assigned to undergo either empiric four-drug anti-TB treatment followed 2 weeks later by efavirenz-based ART ( N = 23) (ART + TB) or ART only ( N = 20). This open-label, 1:1 randomized, controlled trial took place in Uganda, Mozambique, and Gabon and was stopped prematurely by the sponsor for slow recruitment. Overall, the 43 participants had a median CD4 of 22 (interquartile range [IQR]: 9–35) cells/μL and a median BMI of 17.5 (IQR: 16.6–18.0) kg/m 2 . The mortality was 14% (95% confidence interval [CI]: 5.3–27.9); two (10.0%) participants (ART-only group), and four (17.4%; ART + TB group). The associated hazard ratio (HR) for all-cause mortality was 1.6 (95% CI: 0.30–8.90). Despite limited enrollment, the study did not suggest that empiric TB treatment in severely immunosuppressed patients with low BMI decreased mortality and, had an HR in the opposite direction than expected. Notably, two participants in the ART + TB group died with autopsy-confirmed drug-induced hepatotoxicity. Improved TB diagnostics sensitive in immunosuppressed patients presenting late to care are urgently needed for more targeted interventions.
Evading agreement: A new perspective on low nominative agreement in Icelandic
2016-10-18

Hartmann J, Heycock C. Evading agreement: A new perspective on low nominative agreement in Icelandic. In: Hammerly C, Prickett B, eds. &lt;em&gt;NELS 46 : proceedings of the forty-sixth annual meeting of the North East Linguistic Society. Vol. 2&lt;/em&gt;. \\tProceedings of the North East Linguistic Society (NELS). Vol 46. Amherst, MA: University of Massachusetts; 2016: 67-80.
Bmi1 Loss in the Organ of Corti Results in p16ink4a Upregulation and Reduced Cell Proliferation of Otic Progenitors In Vitro
2016-10-18

The mature mammalian organ of Corti does not regenerate spontaneously after injury, mainly due to the absence of cell proliferation and the depletion of otic progenitors with age. The polycomb gene B lymphoma Mo-MLV insertion region 1 homolog (Bmi1) promotes proliferation and cell cycle progression in several stem cell populations. The cell cycle inhibitor p16ink4a has been previously identified as a downstream target of Bmi1. In this study, we show that Bmi1 is expressed in the developing inner ear. In the organ of Corti, Bmi1 expression is temporally regulated during embryonic and postnatal development. In contrast, p16ink4a expression is not detectable during the same period. Bmi1-deficient mice were used to investigate the role of Bmi1 in cochlear development and otosphere generation. In the absence of Bmi1, the postnatal organ of Corti displayed normal morphology at least until the end of the first postnatal week, suggesting that Bmi1 is not required for the embryonic or early postnatal development of the organ of Corti. However, Bmi1 loss resulted in the reduced sphere-forming capacity of the organ of Corti, accompanied by the decreased cell proliferation of otic progenitors in otosphere cultures. This reduced proliferative capacity was associated with the upregulation of p16ink4a in vitro. Viral vector-mediated overexpression of p16ink4a in wildtype otosphere cultures significantly reduced the number of generated otospheres in vitro. The findings strongly suggest a role for Bmi1 as a promoter of cell proliferation in otic progenitor cells, potentially through the repression of p16ink4a.
Extrapulmonary Aspergillus infection in patients with CARD9 deficiency
2016-10-19

Invasive pulmonary aspergillosis is a life-threatening mycosis that only affects patients with immunosuppression, chemotherapy-induced neutropenia, transplantation, or congenital immunodeficiency. We studied the clinical, genetic, histological, and immunological features of 2 unrelated patients without known immunodeficiency who developed extrapulmonary invasive aspergillosis at the ages of 8 and 18. One patient died at age 12 with progressive intra-abdominal aspergillosis. The other patient had presented with intra-abdominal candidiasis at age 9, and developed central nervous system aspergillosis at age 18 and intra-abdominal aspergillosis at age 25. Neither patient developed <i>Aspergillus</i> infection of the lungs. One patient had homozygous M1I <i>CARD9</i> (caspase recruitment domain family member 9) mutation, while the other had homozygous Q295X <i>CARD9</i> mutation; both patients lacked CARD9 protein expression. The patients had normal monocyte and Th17 cell numbers in peripheral blood, but their mononuclear cells exhibited impaired production of proinflammatory cytokines upon fungus-specific stimulation. Neutrophil phagocytosis, killing, and oxidative burst against <i>Aspergillus fumigatus</i> were intact, but neither patient accumulated neutrophils in infected tissue despite normal neutrophil numbers in peripheral blood. The neutrophil tissue accumulation defect was not caused by defective neutrophil-intrinsic chemotaxis, indicating that production of neutrophil chemoattractants in extrapulmonary tissue is impaired in CARD9 deficiency. Taken together, our results show that CARD9 deficiency is the first known inherited or acquired condition that predisposes to extrapulmonary <i>Aspergillus</i> infection with sparing of the lungs, associated with impaired neutrophil recruitment to the site of infection.
Reducing Capacities and Distribution of Redox-Active Functional Groups in Low Molecular Weight Fractions of Humic Acids
2016-10-19

Humic substances (HS) are redox-active organic compounds with a broad spectrum of molecular sizes and reducing capacities, that is, number of electrons donated or accepted. However, it is unknown which role the distribution of redox-active functional groups in different molecule sizes plays for HS redox reactions in varying pore sizes microenvironments. We used dialysis experiments to separate bulk humic acids (HA) into low molecular weight fractions (LMWF) and retentate, for example, the remaining HA in the dialysis bag. LMWF accounted for only 2% of the total organic carbon content of the HA. However, their reducing capacities per gram of carbon were up to 33 times greater than either those of the bulk HA or the retentate. For a structural/mechanistic understanding of the high reducing capacity of the LMWF, we used fluorescence spectroscopy. We found that the LWMF showed significant fluorescence intensities for quinone-like functional groups, as indicated by the quinoid π-π* transition, that are probably responsible for the high reducing capacities. Therefore, the small-sized HS fraction can play a major role for redox transformation of metals or pollutants trapped in soil micropores (<2.5 nm diameter).
Early Evidence for the Extensive Heat Treatment of Silcrete in the Howiesons Poort at Klipdrift Shelter (Layer PBD, 65 ka), South Africa
2016-10-19

Heating stone to enhance its flaking qualities is among the multiple innovative adaptations introduced by early modern human groups in southern Africa, in particular during the Middle Stone Age Still Bay and Howiesons Poort traditions. Comparatively little is known about the role and impact of this technology on early modern human behaviors and cultural expressions, due, in part, to the lack of comprehensive studies of archaeological assemblages documenting the heat treatment of stone. We address this issue through an analysis of the procedure used for heating and a technological analysis of a lithic assemblage recovered from one Howiesons Poort assemblage at Klipdrift Shelter (southern Cape, South Africa). The resulting data show extensive silcrete heat treatment, which adds a new dimension to our understanding of fire-related behaviors during the Howiesons Poort, highlighting the important role played by a heat treatment stage in the production of silcrete blades. These results are made possible by our new analytical procedure that relies on the analysis of all silcrete artifacts. It provides direct evidence of a controlled use of fire which took place during an early stage of core exploitation, thereby impacting on all subsequent stages of the lithic chaîne opératoire, which, to date, has no known equivalent in the Middle Stone Age or Middle Paleolithic record outside of southern Africa.
Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in <b><i>GRN</i></b>-Negative Frontotemporal Dementia
2016-10-19

&lt;b&gt;&lt;i&gt;Background and Objective:&lt;/i&gt;&lt;/b&gt; Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene &lt;i&gt;(GRN)&lt;/i&gt;. However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to &lt;i&gt;GRN &lt;/i&gt;mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in &lt;i&gt;GRN&lt;/i&gt;-negative FTD. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for &lt;i&gt;GRN&lt;/i&gt; mutations, yielding a target cohort of 34 patients without pathogenic mutations in &lt;i&gt;GRN&lt;/i&gt; (&lt;i&gt;GRN&lt;/i&gt;-negative cohort) and 3 &lt;i&gt;GRN&lt;/i&gt; mutation carriers (2 LoF variants and 1 novel missense variant). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Not only the &lt;i&gt;GRN&lt;/i&gt; mutation carriers but also the &lt;i&gt;GRN&lt;/i&gt;-negative patients showed decreased CSF levels of progranulin (serum levels in&lt;i&gt; GRN&lt;/i&gt;-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel &lt;i&gt;GRN&lt;/i&gt; missense variant (c.1117C&gt;T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with &lt;i&gt;GRN&lt;/i&gt; LoF mutations, suggesting a pathogenic effect of this missense variant. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by &lt;i&gt;GRN&lt;/i&gt; LoF mutations, but also contributes to the more common &lt;i&gt;GRN-&lt;/i&gt;negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations.
Parsing with first-class derivatives
2016-10-19

Brzozowski derivatives, well known in the context of regular expressions, have recently been rediscovered to give a simplified explanation to parsers of context-free languages. We add derivatives as a novel first-class feature to a standard parser combinator language. First-class derivatives enable an inversion of the control flow, allowing to implement modular parsers for languages that previously required separate pre-processing steps or cross-cutting modifications of the parsers. We show that our framework offers new opportunities for reuse and supports a modular definition of interesting use cases of layout-sensitive parsing.
Genome-wide association study in essential tremor identifies three new loci
2016-10-20

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
Linagliptin as add‐on to empagliflozin and metformin in patients with type 2 diabetes: Two 24‐week randomized, double‐blind, double‐dummy, parallel‐group trials
2016-10-20

Aim To evaluate the efficacy and safety of linagliptin vs placebo as add‐on to empagliflozin and metformin in patients with type 2 diabetes. Materials and methods Patients with inadequate glycaemic control despite stable‐dose metformin received open‐label empagliflozin 10 mg (study 1) or 25 mg (study 2) as add‐on therapy for 16 weeks. Subsequently, those with HbA1c ≥7.0 and ≤10.5% (&gt;53 and ≤91 mmol/mol) (N = 482) were randomized to 24 weeks’ double‐blind, double‐dummy treatment with linagliptin 5 mg or placebo in study 1, or to linagliptin 5 mg or placebo in study 2; all patients continued treatment with metformin and empagliflozin 10 mg (study 1) or metformin and empagliflozin 25 mg (study 2). The primary endpoint was change from baseline (defined as the last value before first intake of randomized, double‐blind treatment) in HbA1c at week 24. Results At week 24, HbA1c (mean baseline 7.82‐8.04 [62‐64 mmol/mol]) was significantly reduced with linagliptin vs placebo; adjusted mean ( SE ) differences in change from baseline in HbA1c with linagliptin vs placebo were −.32% (.10) (−3.59 [1.08] mmol/mol) ( P = .001) for patients on empagliflozin 10 mg and metformin, and −0.47% (0.10) (−5.15 [1.04] mmol/mol) ( P &lt; 0.001) for patients on empagliflozin 25 mg and metformin. Adverse events were reported in more patients receiving placebo than in those receiving linagliptin: 55.5% vs 48.4% in study 1 and 58.9% vs 52.7% in study 2. Conclusions Linagliptin as add‐on to empagliflozin and metformin for 24 weeks improved glycaemic control vs placebo, and was well tolerated.
Effect of phosphate availability on cyanophycin accumulation in Synechocystis sp. PCC 6803 and the production strain BW86
2016-10-20

The cyanobacterial wild-type strain Synechocystis sp. PCC 6803 and its engineered strain BW86 were cultivated under defined conditions in photobioreactors to investigate the effect of phosphate availability on cyanophycin accumulation. Cyanophycin, multi-l-arginyl-poly-l-aspartate, can be deployed as amino acid source or can be chemically converted into polyaspartic acid, a biodegradable polymer. In previous studies it was demonstrated that a single point mutation in the PII signaling protein from the Synechocystis wild type is sufficient to unlock the arginine pathway causing an over accumulation of the biopolymer cyanophycin in BW86. One process strategy to evoke cyanophycin synthesis in Synechocystis is nutrient starvation. Therefore, different phosphate concentrations from 17.5 to 175 μM were tested. Progressive phosphate starvation resulted in an increased cyanophycin accumulation. The highest obtained cyanophycin amounts in g cyanophycin per g cell dry mass were 18% and 40% for Synechocystis sp. PCC 6803 wild type and BW86 respectively, demonstrating that phosphate starvation is an effective route for biotechnological cyanophycin production. By evaluating cyanophycin and phosphor quotas per cell dry mass, it was possible to determine the specific required amount of phosphor to accumulate cyanophycin and to initialize stationary growth phase. Phosphor quotas in the range of 4 to 1 mg phosphor per g cell dry mass triggered cyanophycin biosynthesis while Synechocystis entered the stationary phase at phosphor quotas of 1 mg phosphor per g cell dry mass or less. Additionally, light kinetics was determined. Photon flux densities exceeding 46 μmol photons m−2 s− 1 result in a maximum growth rate of 1.32 d− 1.
Revised variational approach to QCD in Coulomb gauge
2016-10-20

The variational approach to QCD in Coulomb gauge is revisited. By assuming the non-Abelian Coulomb potential to be given by the sum of its infrared and ultraviolet parts, i.e.~by a linearly rising potential and an ordinary Coulomb potential, and by using a Slater determinant ansatz for the quark wave functional, which contains the coupling of the quarks and the gluons with two different Dirac structures, we obtain variational equations for the kernels of the fermionic vacuum wave functional, which are free of ultraviolet divergences. Thereby, a Gaussian type wave functional is assumed for the gluonic part of the vacuum. By using the results of the pure Yang--Mills sector for the gluon propagator as input, we solve the equations for the fermionic kernels numerically and calculate the quark condensate and the effective quark mass in leading order. Assuming a value of for the Coulomb string tension (where is the usual Wilsonian string tension) the phenomenological value of the quark condensate is reproduced with a value of for the strong coupling constant of the quark-gluon vertex.
Induced pluripotent stem cells (iPSCs) derived from a symptomatic carrier of a S305I mutation in the microtubule-associated protein tau (MAPT)-gene causing frontotemporal dementia
2016-10-20

Frontotemporal dementia with parkinsonism linked to chromosome 17q21.2 (FTDP-17) is an autosomal-dominant neurodegenerative disorder. Mutations in the gene coding the microtubule-associated protein tau (MAPT) can cause FTDP-17 but the underlying mechanisms of the disease are still unknown. Induced pluripotent stem cells (iPSCs) hold great promise to model FTDP-17 as such cells can be differentiated in vitro to the required neuronal cell type. Here, we report the generation of iPSCs from a 44-year-old symptomatic woman carrying a S305I mutation in the MAPT-gene.
Evidence for superior neurobiological and behavioral inhibitory control abilities in non-offending as compared to offending pedophiles
2016-10-21

Neurobehavioral models of pedophilia and child sexual offending suggest a pattern of temporal and in particular prefrontal disturbances leading to inappropriate behavioral control and subsequently an increased propensity to sexually offend against children. However, clear empirical evidence for such mechanisms is still missing. Using a go/nogo paradigm in combination with functional magnetic resonance imaging (fMRI) we compared behavioral performance and neural response patterns among three groups of men matched for age and IQ: pedophiles with (N = 40) and without (N = 37) a history of hands-on sexual offences against children as well as healthy non-offending controls (N = 40). As compared to offending pedophiles, non-offending pedophiles exhibited superior inhibitory control as reflected by significantly lower rate of commission errors. Group-by-condition interaction analysis also revealed inhibition-related activation in the left posterior cingulate and the left superior frontal cortex that distinguished between offending and non-offending pedophiles, while no significant differences were found between pedophiles and healthy controls. Both areas showing distinct activation pattern among pedophiles play a critical role in linking neural networks that relate to effective cognitive functioning. Data therefore suggest that heightened inhibition-related recruitment of these areas as well as decreased amount of commission errors is related to better inhibitory control in pedophiles who successfully avoid committing hands-on sexual offences against children. Hum Brain Mapp 38:1092-1104, 2017. © 2016 Wiley Periodicals, Inc.
Silencing of ASC in Cutaneous Squamous Cell Carcinoma
2016-10-21

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an important adaptor protein for inflammasome activation, mediating the secretion of protumorigenic innate cytokines. However, ASC is also known to trigger apoptosis in tumor cells, acting as a tumor-suppressor gene, which is lost in several human cancers. The aim of this study was to evaluate the clinical significance of ASC in human cutaneous squamous cell carcinoma (SCC). Initially, ASC expression was immunohistochemically evaluated in non-metastic and metastatic SCC. While ASC expression does not correlate with metastatic potential, it correlates with the degree of dedifferentiation. Using methylation specific PCR we were able to demonstrate ASC silencing by promotor specific methylation and impaired inflammasome function in methylated cell lines, linking epigenetic modifications to innate immune activation in keratinocytes. Interestingly, upon ASC restoration by treatment with demethylating agents, we were able to restore AIM2 and NLRP3 activation. In summary, loss of ASC driven tumor development is counterbalanced in the identical cell by the inhibition of pro-tumorigenic inflammation in the tumor cell itself.