Miracle-dz/UniFAR-FTUs huggingface dataset:
LGBT* After Loss: A Mixed-Method Analysis on the Effect of Partner Bereavement on Interpersonal Relationships and Subsequent Partnerships

Grief and bereavement are universal human experiences that do not discriminate based on sex, gender, or sexual orientation. Existing literature provides valuable insight into the bereavement experiences of persons who identify as heterosexuals, but much less can be found on persons who identify as lesbian, gay, bisexual, or transgender/queer* (LGBT*). Given that the historical experiences of loss and personal characteristics such as interpersonal, familial, and social patterns of coping with grief are likely to influence the bereavement process, this study focused on the impact of partner bereavement on the interpersonal relationships and subsequent partnerships of the LGBT* bereaved. To this end, the purpose of this study was to use a mixed-methods approach to better understand how LGBT* persons described their experiences with partner bereavement and to identify what effect these experiences had on interpersonal relationships and subsequent partnerships.
Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension.

RATIONALE Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. OBJECTIVES To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs). METHODS A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Single-nucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort. MEASUREMENTS AND MAIN RESULTS Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months. CONCLUSIONS ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.
Functional Brain Network Topology Discriminates between Patients with Minimally Conscious State and Unresponsive Wakefulness Syndrome

Consciousness arises from the functional interaction of multiple brain structures and their ability to integrate different complex patterns of internal communication. Although several studies demonstrated that the fronto-parietal and functional default mode networks play a key role in conscious processes, it is still not clear which topological network measures (that quantifies different features of whole-brain functional network organization) are altered in patients with disorders of consciousness. Herein, we investigate the functional connectivity of unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS) patients from a topological network perspective, by using resting-state EEG recording. Network-based statistical analysis reveals a subnetwork of decreased functional connectivity in UWS compared to in the MCS patients, mainly involving the interhemispheric fronto-parietal connectivity patterns. Network topological analysis reveals increased values of local-community-paradigm correlation, as well as higher clustering coefficient and local efficiency in UWS patients compared to in MCS patients. At the nodal level, the UWS patients showed altered functional topology in several limbic and temporo-parieto-occipital regions. Taken together, our results highlight (i) the involvement of the interhemispheric fronto-parietal functional connectivity in the pathophysiology of consciousness disorders and (ii) an aberrant connectome organization both at the network topology level and at the nodal level in UWS patients compared to in the MCS patients.
SHORT COMMUNICATION The inhibitory subunit of cardiac troponin (cTnI) is modified by arginine methylation in the human heart

: Background The inhibitory subunit of cardiac troponin (cTnI) is a gold standard cardiac biomarker and also an essential protein in cardiomyocyte excitation-contraction coupling. The interactions of cTnI with other proteins are fine-tuned by post-translational modification of cTnI. Mutations in cTnI can lead to hypertrophic cardiomyopathy. Here we report, for the first time, that cTnI is modified by arginine methylation in human myocardium. Using Western blot, we observed reduced levels of cTnI arginine methylation in human hypertrophic cardiomyopathy compared to dilated cardiomyopathy biopsies. Similarly, using a rat model of cardiac hypertrophy we observed reduced levels of cTnI arginine methylation compared to sham controls. Using mass spectrometry, we identified cTnI methylation sites at R74/R79 and R146/R148 in human cardiac samples. R146 and R148 lie at the boundary between the critical cTnI inhibitory and switch peptides; PRMT1 methylated an extended inhibitory peptide at R146 and R148 in vitro . Mutations at R145 that have been associated with hypertrophic cardiomyopathy hampered R146/R148 methylation by PRMT1 in vitro . H9c2 cardiac-like cells transfected with plasmids encoding for a methylation-deficient R146A/R148A cTnI protein developed cell hypertrophy, with a 32% increase in cell size after 72 h, compared to control cells. Our results provide evidence for a novel and significant cTnI post-translational modification. Our work opens the door to translational investigations of cTnI arginine methylation as a biomarker of disease, which can include e.g. cardiomyopathies, myocardial infarction and heart failure, and offers a novel way to investigate the effect of cTnI mutations in the inhibitory/switch peptides. desorption ionisation - time of flight (MALDI-TOF), protein arginine methyltransferases (PRMTs), S -adenosyl- L -methionine (SAM).
Impact of KIR/HLA Incompatibilities on NK Cell Reconstitution and Clinical Outcome after T Cell–Replete Haploidentical Hematopoietic Stem Cell Transplantation with Posttransplant Cyclophosphamide

Little is known regarding the effect of KIR/HLA incompatibilities (inc.) in the setting of T-replete haploidentical allogeneic hematopoietic stem cell transplantation using posttransplant cyclophosphamide (PTCy). In this retrospective study, the impact of KIR/HLA inc. on clinical outcomes and NK cell reconstitution was studied in a cohort of 51 consecutive patients receiving a T cell–replete haploidentical allogeneic hematopoietic stem cell transplantation after a reduced-intensity conditioning using peripheral blood stem cells as the source of the graft and PTCy as graft-versus-host disease (GvHD) prophylaxis. The NK cell repertoire reconstitution was examined by multiparameter flow cytometry in 34 of these 51 patients from day 0 to day 100 posttransplant. Genetic KIR2DL/HLA inc. were found to be significantly associated with more GvHD (81.2 versus 45.7%, p = 0.01) and less relapse (6.2 versus 42.8%, p = 0.008) in this context. GvHD is associated with increased levels of differentiated and activated NK cells. A significant loss of KIR2DL2/3+ NK cells was observed at day 30 in patients with inhibitory KIR/HLA inc., suggesting that responsive KIR NK cells are particularly targeted by the immunosuppressive PTCy treatment. Further investigations are needed from a larger cohort with an identical clinical approach to consolidate these results and to identify the NK cell subsets that may be beneficial for the graft-versus-leukemia effect observed. Because many haploidentical donors can be identified in a family, the prediction of KIR NK cell alloreactivity could be of crucial importance for donor selection and patient outcome.
Gene mutations do not operate in a vacuum: the increasing importance of epigenetics in juvenile myelomonocytic leukemia

ABSTRACT Juvenile myelomonocytic leukemia (JMML) stands out among malignant neoplasms of childhood in several ways. First, JMML is a model condition to elucidate the relevance of deregulated Ras signal transduction in human cancer. Second, the identification of Ras pathway mutations in JMML has informed the field of germline cancer predisposition and advanced the understanding of molecular mechanisms underlying the progression from predisposition to neoplasia. Third and not least, genomic DNA methylation was discovered to play a salient role in the classification and prognostication of the disease. This article discusses the evolution of epigenetic research on JMML over the past years and reviews the relevance of aberrant DNA methylation in the diagnosis, concept, and clinical decision-making of JMML.
An In Vitro Brain Endothelial Model for Studies of Cryptococcal Transmigration into the Central Nervous System

Cryptococcus neoformans is an environmental yeast found worldwide that causes lethal brain infections, particularly in immunocompromised hosts. In 2016, there were 280,000 cases of cryptococcal meningitis in the HIV+ population, two‐thirds of them fatal; other immunocompromised patients are also affected. The burden of cryptococcal disease and the limits of current chemotherapy create a pressing need for improved treatment. One hindrance to the development of new therapies is lack of understanding of how this pathogen breaches the barriers protecting the brain. Here we describe a tool for investigating this process. This simple in vitro blood‐brain‐barrier (BBB) model, based on a human brain endothelial cell line grown on a permeable membrane, may be used to assay the BBB transmigration of C. neoformans or other neurotropic pathogens. © 2019 by John Wiley & Sons, Inc.
Discovery of novel carbohydrate-active enzymes through the rational exploration of the protein sequences space

Significance In the context of genome and metagenome sequencing, the assignment of function to sequences is a serious issue. In the case of enzymes of strong substrate specificity, such as those involved in the breakdown of polysaccharides (e.g., glycoside hydrolases and polysaccharide lyases), assignments become unreliable when sequence similarity to experimentally studied enzymes is low. To better explore the sequence-to-function relationships of these enzymes, we successfully applied a strategy based on a rational bioinformatic selection of enzyme targets, synthetic gene synthesis, and screening of recombinant proteins on a wide diversity of carbohydrate substrates. Seventy-nine of our 564 targets exhibited enzymatic activity, including three activities that have not been described previously, and 13 novel enzyme families could be defined. Over the last two decades, the number of gene/protein sequences gleaned from sequencing projects of individual genomes and environmental DNA has grown exponentially. Only a tiny fraction of these predicted proteins has been experimentally characterized, and the function of most proteins remains hypothetical or only predicted based on sequence similarity. Despite the development of postgenomic methods, such as transcriptomics, proteomics, and metabolomics, the assignment of function to protein sequences remains one of the main challenges in modern biology. As in all classes of proteins, the growing number of predicted carbohydrate-active enzymes (CAZymes) has not been accompanied by a systematic and accurate attribution of function. Taking advantage of the CAZy database, which groups CAZymes into families and subfamilies based on amino acid similarities, we recombinantly produced 564 proteins selected from subfamilies without any biochemically characterized representatives, from distant relatives of characterized enzymes and from nonclassified proteins that show little similarity with known CAZymes. Screening these proteins for activity on a wide collection of carbohydrate substrates led to the discovery of 13 CAZyme families (two of which were also discovered by others during the course of our work), revealed three previously unknown substrate specificities, and assigned a function to 25 subfamilies.
Identification and Characterization of a Dendritic Cell Precursor in Parenchymal Lung Tissue

&NA; The pulmonary parenchymal and mucosal microenvironments are constantly exposed to the external environment and thus require continuous surveillance to maintain steady‐state immunological homeostasis. This is achieved by a mobile network of pulmonary dendritic cells (DC) and macrophages (mø) that constantly sample and process microenvironmental antigens into signals that can initiate or dampen inflammation, either locally or after onward migration to draining lymph nodes. The constant steady‐state turnover of pulmonary DC and mø requires replenishment from bone marrow precursors; however, the nature of the pulmonary precursor cell (PC) remains unclear, although recent studies suggest that subsets of pulmonary DC may derive from circulating monocytic precursors. In the current study, we describe a population of cells in steady‐state mouse lung tissue that has the surface phenotypic and ultrastructural characteristics of a common DC progenitor. Irradiation and reconstitution studies confirmed the bone marrow origins of this PC and showed that it had rapid depletion and reconstitution kinetics that were similar to those of DC, with a 50% repopulation by donor‐derived cells by Days 7‐9 after reconstitution. This was significantly faster than the rates observed for mø, which showed 50% repopulation by donor‐derived cells beyond Days 16‐21 after reconstitution. Purified PC gained antigen‐presenting function and a cell surface phenotype similar to that of pulmonary DC after maturation in vitro, with light and electron microscopy confirming a myeloid DC morphology. To the best of our knowledge, this is the first study to describe a PC for DC in lung tissue; the findings have implications for the restoration of pulmonary immunological homeostasis after bone marrow transplant.
ALIAS (Albumin in Acute Ischemic Stroke) Trials: Analysis of the Combined Data From Parts 1 and 2

Background and Purpose— The ALIAS (Albumin in Acute Ischemic Stroke) part 1 and 2 trials evaluated whether 25% human serum albumin improves clinical outcomes after acute ischemic stroke above and beyond standard of care using similar protocols. The part 1 trial ended prematurely because of safety concerns, and the part 2 trial terminated early because of futility of finding a statistically significant effect of albumin over saline (control) administration. We combine the subject-level data of the part 1 and 2 trials to reevaluate the efficacy and safety outcomes with the larger sample size. Methods— The combined data analyses closely follow those conducted in the part 2 trial. The primary outcome is the composite of the modified Rankin Scale and the National Institutes of Health Stroke Scale defined as a composite of modified Rankin Scale score 0 to 1 and National Institutes of Health Stroke Scale score 0 to 1 at 90 days from randomization. The unadjusted analyses use a simple Chi-square test, and those adjusting for baseline covariates use a generalized linear model with log link (to obtain relative risks). Results— The participant characteristics at baseline were generally similar between the treatment groups and between the trials; however, thrombolysis use was greater in part 2 (84% versus 75%), and the upper age limit imposed in part 2 resulted in a younger sample (mean age in part 1 was 69 versus 64 in part 2). In the combined sample, the proportions of good outcome in the 2 treatment groups were identical (41%). Similar results were observed in all secondary efficacy outcomes. Pulmonary edema was a consistent safety concern, with a 6-fold increase in the albumin arm (13%) compared with saline (2%; relative risk =7.76, 95% confidence interval 3.87–15.57). Conclusions— Treatment with intravenous albumin 25% at 2 g/kg was not associated with improved outcome at 90 days and was associated with increased rates of intracerebral hemorrhage and pulmonary edema. Clinical Trial Registration— URL: https://www.clinicaltrials. gov. Unique identifier: NCT00235495.
Accounting for spectroscopic effects in laser‐based open‐path eddy covariance flux measurements

A significant portion of the production and consumption of trace gases (e.g. CO2, CH4, N2O, NH3, etc.) by world ecosystems occurs in areas without sufficient infrastructure or easily available grid power to run traditional closed‐path flux stations. Open‐path analyzer design allows such measurements with power consumption 10–150 times below present closed‐path technologies, helping to considerably expand the global coverage and improve the estimates of gas emissions and budgets, informing the remote sensing and modeling communities and policy decisions, all the way to IPCC reports. Broad‐band nondispersive infrared devices have been used for open‐path CO2 and H2O measurements since the late 1970s, but since recently, a growing number of new narrow‐band laser‐based instruments are being rapidly developed. The new design comes with its own challenges, specifically: (a) mirror contamination, and (b) uncontrolled air temperature, pressure and humidity, affecting both the gas density and the laser spectroscopy of the measurements. While the contamination can be addressed via automated cleaning, and density effects can be addressed via the Webb‐Pearman‐Leuning approach, the spectroscopic effects of the in situ temperature, pressure and humidity fluctuations on laser‐measured densities remain a standing methodological question. Here we propose a concept accounting for such effects in the same manner as Webb et al. proposed to account for respective density effects. Derivations are provided for a general case of flux of any gas, examined using a specific example of CH4 fluxes from a commercially available analyzer, and then tested using “zero‐flux” experiment. The proposed approach helps reduce errors in open‐path, enclosed, and temperature‐ or pressure‐uncontrolled closed‐path laser‐based flux measurements due to the spectroscopic effects from few percents to multiple folds, leading to methodological advancement and geographical expansion of the use of such systems providing reliable and consistent results for process‐level studies, remote sensing and Earth modeling applications, and GHG policy decision‐making.
A systematic literature review to examine the potential for social media to impact HPV vaccine uptake and awareness, knowledge, and attitudes about HPV and HPV vaccination

ABSTRACT This article summarizes the findings from a systematic literature review to examine how social media may impact HPV vaccine uptake and HPV and HPV vaccine related awareness, knowledge, and attitudes. Study inclusion criteria was original data collection of at least one data point about social media and HPV and/or HPV vaccination, such that the study provided insight into how social media content may influence HPV and HPV vaccine related knowledge, attitudes, and/or behaviors. A total of 44 relevant articles were identified using the following databases: PubMed, PsycINFO, Communication Source, Sociological Abstracts, Business Source Elite, and the Educational Resources Information Center (ERIC). Most studies analyzed the valence, type, and frequency of social media content about HPV vaccination, and some found associations between potential exposure to negative, anti-vacc`11qine content and lower vaccination rates. Some studies that included primary human subject data collection found that engagement with HPV related social media content was associated with improved awareness and knowledge but not with increased vaccine uptake. The literature overall is lacking in systematic and rigorous research examining the effects of social media on HPV related knowledge, attitudes, and behaviors and needs further examination as social media increasingly becomes a source of health information.
NEAT1 mediates paclitaxel-resistance of non-small cell of lung cancer through activation of Akt/mTOR signalling pathway

Abstract Development of paclitaxel-resistance is a main problem during non-small cell lung cancer (NSCLC) chemotherapy. Nuclear paraspeckle assembly transcript 1 (NEAT1) is an oncogenic long non-coding RNA (lncRNA) which has been proved to be aberrantly upregulated in many human malignancies. In this study, we investigated the mechanism by which NEAT1 contributed to paclitaxel-resistance in NSCLC. NEAT1 was upregulated significantly in paclitaxel-resistant NSCLC cell line, compared with other NSCLC cell lines and normal bronchial epithelial (BE) cell line. Knockdown of NEAT1 could reverse the paclitaxel-resistance through induction of apoptosis by increasing cleaved PARP and cleaved caspase-3 expression. Moreover, NEAT1 was associated with Akt/mTOR signalling pathway activation by increasing expression of p-Akt, p-mTOR, Bcl-2 and decreasing expression of Bax. In conclusion, these results demonstrated that NEAT1 underlay paclitaxel-resistance in NSCLC.
Bayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees

Conservation of DNA sequence over evolutionary time is a strong indicator of function, and gain or loss of sequence conservation can be used to infer changes in function across a phylogeny. Changes in evolutionary rates on particular lineages in a phylogeny can indicate shared functional shifts, and thus can be used to detect genomic correlates of phenotypic convergence. However, existing methods do not allow easy detection of patterns of rate variation, which causes challenges for detecting convergent rate shifts or other complex evolutionary scenarios. Here we introduce PhyloAcc, a new Bayesian method to model substitution rate changes in conserved elements across a phylogeny. The method assumes several categories of substitution rate for each branch on the phylogenetic tree, estimates substitution rates per category, and detects changes of substitution rate as the posterior probability of a category switch. Simulations show that PhyloAcc can detect genomic regions with rate shifts in multiple target species better than previous methods and has a higher accuracy of reconstructing complex patterns of substitution rate changes than prevalent Bayesian relaxed clock models. We demonstrate the utility of PhyloAcc in two classic examples of convergent phenotypes: loss of flight in birds and the transition to marine life in mammals. In each case, our approach reveals numerous examples of conserved non-exonic elements with accelerations specific to the phenotypically convergent lineages. Our method is widely applicable to any set of conserved elements where multiple rate changes are expected on a phylogeny.