julilili42/papers huggingface dataset:
Case Report: Apremilast for Therapy-Resistant Pemphigus Vulgaris
2020-10-27

Background: In pemphigus, elucidating the disease-causing immune mechanism and developing new therapeutic strategies are needed. In this context, the second messenger 3',5'-cyclic adenosine monophosphate (cAMP) is gaining attention. cAMP is important in hematological and auto-inflammatory disorders. A class of enzymes called phosphodiesterases (PDEs) control intracellular cAMP levels. In pemphigus, cAMP levels increase following IgG binding to Dsg3. This appears to be a mechanism to preserve epithelial integrity. Objectives: To determine whether apremilast, an inhibitor of the PDE4 normally used in psoriasis, may be of benefit in the blistering skin disorder pemphigus. Methods: Here we report of a 62 years old patient with chronic debilitating and recalcitrant pemphigus not responding to several previous treatments, who received treatment with apremilast over a period of 32 weeks. Desmoglein autoantibody levels were assessed by Enzyme-linked Immunosorbent Assay (ELISA), whereas disease severity and quality of life were assessed by the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). In an attempt to explain the effects of apremilast in pemphigus, peripheral blood mononuclear cells (PBMCs) were analyzed for the duration of treatment by flow cytometry for the distribution of specialized T cell subsets. The frequencies of circulating T helper (Th) 1, Th2, Th17, Th17.1 and T follicular helper (Tfh) 1, Tfh2, Tfh17, and Tfh17.1 were analyzed by CCR6, CXCR3, and CXCR5 expression of CD4(+) T cells. Further, based on the different expressions of CXCR5, CD127, and CD25, we analyzed the T regulatory (Treg) and T follicular regulatory (Tfreg) compartment. Results: In response to apremilast treatment, Dsg-specific autoantibody titers decreased, blistering ceased and lesions healed, showing a long-lasting effect. While the frequencies of most of the Th and Tfh cell subsets remained unchanged, we observed a continuous increase in Treg and Tfreg cell levels. Conclusion: Our findings are encouraging and warrant extension of the beneficial effect of PDE4 inhibition on a larger cohort of pemphigus patients.
Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease
2020-10-27

Abstract Background Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α‐synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci. Methods Genome‐wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross‐trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild‐type mice. Genetic variability of candidate genes was further investigated using independent whole‐exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls. Results We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild‐type mice and had elevated burden of protein‐coding variants in independent MSA and inflammatory bowel disease cohorts. Conclusion Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Secretion of and Self-Resistance to the Novel Fibupeptide Antimicrobial Lugdunin by Distinct ABC Transporters in Staphylococcus lugdunensis
2020-10-27

Lugdunin is the first reported nonribosomally synthesized antibiotic from human microbiomes. Its production by the commensal Staphylococcus lugdunensis eliminates the pathogen Staphylococcus aureus from human nasal microbiomes. The cycloheptapeptide lugdunin is the founding member of the new class of fibupeptide antibiotics, which have a novel mode of action and represent promising new antimicrobial agents. How S. lugdunensis releases and achieves producer self-resistance to lugdunin has remained unknown.
Prevalence of cranial trauma in Eurasian Upper Paleolithic humans
2020-10-27

Abstract Objectives This study characterizes patterns of cranial trauma prevalence in a large sample of Upper Paleolithic (UP) fossil specimens (40,000–10,000 BP). Materials and Methods Our sample comprised 234 individual crania (specimens), representing 1,285 cranial bones (skeletal elements), from 101 Eurasian UP sites. We used generalized linear mixed models (GLMMs) to assess trauma prevalence in relation to age‐at‐death, sex, anatomical distribution, and between pre‐ and post‐Last Glacial Maximum (LGM) samples, while accounting for skeletal preservation. Results Models predicted a mean cranial trauma prevalence of 0.07 (95% CI 0.003–0.19) at the level of skeletal elements, and of 0.26 (95% CI 0.08–0.48) at the level of specimens, each when 76–100% complete. Trauma prevalence increased with skeletal preservation. Across specimen and skeletal element datasets, trauma prevalence tended to be higher for males, and was consistently higher in the old age group. We found no time‐specific trauma prevalence patterns for the two sexes or age cohorts when comparing samples from before and after the LGM. Samples showed higher trauma prevalence in the vault than in the face, with vault remains being affected predominantly in males. Discussion Cranial trauma prevalence in UP humans falls within the variation described for Mesolithic and Neolithic samples. According to our current dataset, UP males and females were exposed to slightly different injury risks and trauma distributions, potentially due to different activities or behaviors, yet both sexes exhibit more trauma among the old. Environmental stressors associated with climatic changes of the LGM are not reflected in cranial trauma prevalence. To analyze trauma in incomplete skeletal remains we propose GLMMs as an informative alternative to crude frequency calculations.
Possible New Strategies for the Treatment of Congenital Hyperinsulinism
2020-10-27

NN414 seems to provide a good alternative to the currently used K<sub>ATP</sub> channel opener diazoxide. Targeting K<sub>Ca</sub>3.1 channels by channel openers or L-type Ca<sup>2+</sup> channels by DXM or simvastatin might be valuable approaches for treatment of CHI caused by mutations of K<sub>ATP</sub> channels not sensitive to K<sub>ATP</sub> channel openers.
Treatment and resistance mechanisms in castration-resistant prostate cancer: new implications for clinical decision making?
2020-10-27

<b>Introduction</b>: The armamentarium of treatment options in metastatic and non-metastatic CRPC is rapidly evolving. However, the question of how individual treatment decisions should be balanced by available predictive clinical parameters, pharmacogenetic and drug interaction profiles, or compound-associated molecular biomarkers is a major challenge for clinical practice.<b>Areas covered</b>: We discuss treatment and resistance mechanisms in PC with regard to their association to drug efficacy and tolerability. Current efforts of combination treatment and putative predictive biomarkers of available and upcoming compounds are highlighted with regard to their implication on clinical decision-making.<b>Expert opinion</b>: Several treatment approaches are delineated, where identification of resistance mechanisms in CRPC may guide treatment selection. To date, most of these candidate biomarkers will however be found only in a small subset of patients. While current approaches of combination treatment in CRPC are proving synergistic effects on cancer biology, higher complexity with regard to biomarker analysis and interaction profiles of the respective compounds may be expected. Among other aspects of personalized treatment, consideration of drug-drug interaction and pharmacogenetics is an underrepresented issue. However, the non-metastatic castration resistant prostate cancer situation may be an example for treatment selection based on drug interaction profiles in the future.
The Development of Web Based Information System at Universitas Klabat Career Center
2020-10-27

A web-based information system is used to collect, process, store existing data, and provide information for decision-making. The use of web-based information systems can help support various business processes and integrate all the processes. Universitas Klabat, with the Career Center that carries out alumni tracer study, still does not have an integrated system in its implementation. An information system that can integrate every tracer study implementation can encourage productivity and improve higher education quality in the accreditation process. This study aims to create a web-based tracer study information system at Universitas Klabat's Career Center. In developing the system, a PHP based programming language framework, namely Laravel, was employed to develop the system. The resulting web-based information system can integrate every process of the tracer study. The information system has four types of users, namely administrators, operators, alumni, and employers. The information system can also generate reports needed by Universitas Klabat and report purposes to the Ministry of Research and Technology.
Acute relaxation during pregnancy leads to a reduction in maternal electrodermal activity, changes in cardiovascular activity and subjective stress levels depending on the week of gestation.
2020-10-27

Background: Prenatal maternal stress can have adverse effects on birth outcomes and fetal development. Relaxation techniques have been examined as one potential countermeasure. This study investigates different relaxation techniques and their effect on mood and physiological stress levels in pregnant women.Methods: 36 pregnant women (30 to 40 weeks of gestation) were randomly assigned to one of three groups: music, guided imagery or resting. Dependent measures included self-report questionnaires, subjective ratings of stress levels as well as physiological measures, i.e. cardiovascular and electrodermal activity.Results: All three forms of relaxation led to reduced maternal stress: decreased heart rate and decreased skin conductance levels. Based on heart rate, skin conductance level and stress ratings there were no significant differences between relaxation interventions. Subjective post-intervention stress ratings indicated that more relaxation occured after intervention in earlier gestation than in late gestation.Conclusion: Independent of relaxation technique, a 20-minute period of acute relaxation can reduce maternal stress. Notably, women earlier in pregnancy reported to be more relaxed after the intervention than women later in gestation. Hence, gestational age can influence perceived stress levels and should be considered when evaluating relaxation or stress management interventions during pregnancy.
The inflammation in cutaneous lichen planus is dominated by IFN‐ϒ and IL‐21—A basis for therapeutic JAK1 inhibition
2020-10-28

Abstract Cutaneous lichen planus (CLP) and psoriasis (PSO) are both common chronic inflammatory skin diseases for which development of new treatments requires the identification of key targets. While PSO is a typical Th17/IL‐17‐disorder, there is some evidence that Th1/IFN‐ɣ dominate the inflammatory process in CLP. Nonetheless, the immunopathogenesis of CLP is not fully explained and key immunological factors still have to be recognized. In this study, we compared the immune signature of CLP lesions with the well‐characterized inflammation present in PSO skin. First, we analysed the histological and immunohistological characteristics of CLP and PSO. Second, we assessed the cytokine expression ( IL1A, IL1B, IL4, IL6, IL8, IL10, IL17A, IL19, IL21, IL22, IL23A, IL13, IFNG, TNF, IL12A, IL12B and IL36G) of lesional skin of CLP with PSO by qPCR. Histology revealed a similar epidermal thickness in CLP and PSO. Immunohistochemically, both diseases presented with an inflammatory infiltrate mainly composed by CD3 + CD4 + T cells rather than CD3 + CD8 + . Importantly, mRNA analysis showed a distinct cytokine signature: while levels of IL12B , IL1A , IL6 and IL23 were similar between the two groups, the characteristic PSO‐associated cytokines IL8 , IL17A , IL22 , IL19 and IL36G were expressed at very low levels in CLP. In contrast, CLP lesional skin was dominated by the expression of IFNG , IL21 , IL4 , IL12A and TNF . Immunohistochemistry confirmed the dominance of IL‐21, IFN‐ɣ and also pSTAT1 in the dermal infiltrate of CLP, while IL‐17A was more present in PSO. Collectively, this study improves our understanding of the immunological factors dominating CLP. The dominating cytokines and signalling proteins identified suggest that anti‐cytokine therapeutics like JAK inhibitors may be beneficial in CLP.
Tumor and microenvironment response but no cytotoxic T-cell activation in classic Hodgkin lymphoma treated with anti-PD1
2020-10-28

Abstract Classic Hodgkin lymphoma (cHL) is the cancer type most susceptible to antibodies targeting programmed cell death protein 1 (PD1) and is characterized by scarce Hodgkin and Reed-Sternberg cells (HRSCs), perpetuating a unique tumor microenvironment (TME). Although anti-PD1 effects appear to be largely mediated by cytotoxic CD8+ T cells in solid tumors, HRSCs frequently lack major histocompatibility complex expression, and the mechanism of anti-PD1 efficacy in cHL is unclear. Rapid clinical responses and high interim complete response rates to anti-PD1 based first-line treatment were recently reported for patients with early-stage unfavorable cHL treated in the German Hodgkin Study Group phase 2 NIVAHL trial. To investigate the mechanisms underlying this very early response to anti-PD1 treatment, we analyzed paired biopsies and blood samples obtained from NIVAHL patients before and during the first days of nivolumab first-line cHL therapy. Mirroring the rapid clinical response, HRSCs had disappeared from the tissue within days after the first nivolumab application. The TME already shows a reduction in type 1 regulatory T cells and PD-L1+ tumor-associated macrophages at this early time point of treatment. Interestingly, a cytotoxic immune response and a clonal T-cell expansion were not observed in the tumors or peripheral blood. These early changes in the TME were distinct from alterations found in a separate set of cHL biopsies at relapse during anti-PD1 therapy. We identify a unique very early histologic response pattern to anti-PD1 therapy in cHL that is suggestive of withdrawal of prosurvival factors, rather than induction of an adaptive antitumor immune response, as the main mechanism of action.
Direct measurement of the contribution of street lighting to satellite observations of nighttime light emissions from urban areas
2020-10-28

Nighttime light emissions are increasing in most countries worldwide, but which types of lighting are responsible for the increase remains unknown. Also unknown is what fraction of outdoor light emissions and associated energy use are due to public light sources (i.e. streetlights) or various types of private light sources (e.g. advertising). Here we show that it is possible to measure the contribution of street lighting to nighttime satellite imagery using ‘smart city’ lighting infrastructure. The city of Tucson, USA, intentionally altered its streetlight output over 10 days, and we examined the change in emissions observed by satellite. We find that streetlights operated by the city are responsible for only 13% of the total radiance (in the 500–900 nm band) observed from Tucson from space after midnight (95% confidence interval 10–16%). If Tucson did not dim their streetlights after midnight, the contribution would be 18% (95% confidence interval 15–23%). When streetlights operated by other actors are included, the best estimates rise to 16% and 21%, respectively. Existing energy and lighting policy related to the sustainability of outdoor light use has mainly focused on street lighting. These results suggest an urgent need for consideration of other types of light sources in outdoor lighting policy.
Fully Automated and Standardized Segmentation of Adipose Tissue Compartments via Deep Learning in 3D Whole-Body MRI of Epidemiologic Cohort Studies
2020-10-28

Automated adipose tissue segmentation is feasible in 3D whole-body MRI datasets and is generalizable to different epidemiologic cohort studies with the proposed DCNet.<i>Supplemental material is available for this article.</i>© RSNA, 2020.
Arsenic behavior in groundwater in Hanoi (Vietnam) influenced by a complex biogeochemical network of iron, methane, and sulfur cycling
2020-10-28

The fate of arsenic (As) in groundwater is determined by multiple interrelated microbial and abiotic processes that contribute to As (im)mobilization. Most studies to date have investigated individual processes related to As (im)mobilization rather than the complex networks present in situ. In this study, we used RNA-based microbial community analysis in combination with groundwater hydrogeochemical measurements to elucidate the behavior of As along a 2 km transect near Hanoi, Vietnam. The transect stretches from the riverbank across a strongly reducing and As-contaminated Holocene aquifer, followed by a redox transition zone (RTZ) and a Pleistocene aquifer, at which As concentrations are low. Our analyses revealed fermentation and methanogenesis as important processes providing electron donors, fueling the microbially mediated reductive dissolution of As-bearing Fe(III) minerals and ultimately promoting As mobilization. As a consequence of high CH<sub>4</sub> concentrations, methanotrophs thrive across the Holocene aquifer and the redox transition zone. Finally, our results underline the role of SO<sub>4</sub><sup>2-</sup>-reducing and putative Fe(II)-/As(III)-oxidizing bacteria as a sink for As, particularly at the RTZ. Overall, our results suggest that a complex network of microbial and biogeochemical processes has to be considered to better understand the biogeochemical behavior of As in groundwater.
The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood
2020-10-28

Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G&gt;T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.
Immunomodulatory role of reactive oxygen species and nitrogen species during T cell-driven neutrophil-enriched acute and chronic cutaneous delayed-type hypersensitivity reactions
2020-10-28

<b>Rationale:</b> Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important regulators of inflammation. The exact impact of ROS/RNS on cutaneous delayed-type hypersensitivity reaction (DTHR) is controversial. The aim of our study was to identify the dominant sources of ROS/RNS during acute and chronic trinitrochlorobenzene (TNCB)-induced cutaneous DTHR in mice with differently impaired ROS/RNS production. <b>Methods:</b> TNCB-sensitized wild-type, NADPH oxidase 2 (NOX2)- deficient (gp91<sup>phox-/-</sup>), myeloperoxidase-deficient (MPO<sup>-/-</sup>), and inducible nitric oxide synthase-deficient (iNOS<sup>-/-</sup>) mice were challenged with TNCB on the right ear once to elicit acute DTHR and repetitively up to five times to induce chronic DTHR. We measured ear swelling responses and noninvasively assessed ROS/RNS production <i>in vivo</i> by employing the chemiluminescence optical imaging (OI) probe L-012. Additionally, we conducted extensive <i>ex vivo</i> analyses of inflamed ears focusing on ROS/RNS production and the biochemical and morphological consequences. <b>Results:</b> The <i>in vivo</i> L-012 OI of acute and chronic DTHR revealed completely abrogated ROS/RNS production in the ears of gp91<sup>phox-/-</sup> mice, up to 90 % decreased ROS/RNS production in the ears of MPO<sup>-/-</sup> mice and unaffected ROS/RNS production in the ears of iNOS<sup>-/-</sup> mice. The DHR flow cytometry analysis of leukocytes derived from the ears with acute DTHR confirmed our <i>in vivo</i> L-012 OI results. Nevertheless, we observed no significant differences in the ear swelling responses among all the experimental groups. The histopathological analysis of the ears of gp91<sup>phox-/-</sup> mice with acute DTHRs revealed slightly enhanced inflammation. In contrast, we observed a moderately reduced inflammatory immune response in the ears of gp91<sup>phox-/-</sup> mice with chronic DTHR, while the inflamed ears of MPO<sup>-/-</sup> mice exhibited the strongest inflammation. Analyses of lipid peroxidation, 8-hydroxy-2'deoxyguanosine levels, redox related metabolites and genomic expression of antioxidant proteins revealed similar oxidative stress in all experimental groups. Furthermore, inflamed ears of wild-type and gp91<sup>phox-/-</sup> mice displayed neutrophil extracellular trap (NET) formation exclusively in acute but not chronic DTHR. <b>Conclusions:</b> MPO and NOX2 are the dominant sources of ROS/RNS in acute and chronic DTHR. Nevertheless, depletion of one primary source of ROS/RNS exhibited only marginal but conflicting impact on acute and chronic cutaneous DTHR. Thus, ROS/RNS are not a single entity, and each species has different properties at certain stages of the disease, resulting in different outcomes.