julilili42/papers huggingface dataset:
Clubfoot treatment with Ponseti method – Parental distress during plaster casting
2020-06-12

Abstract Background Clubfoot is one of the most prevalent musculoskeletal congenital defects. Gold standard treatment of idiopathic clubfoot is the conservative Ponseti method, including the reduction of deformity with weekly serial plaster casting and percutaneous Achilles tenotomy. It is well known that parents of children with severe and chronic illnesses are mentally stressed, but in recent studies regarding clubfoot treatment, parents were only asked about their satisfaction with the treatment. Largely unknown is parental distress before and during plaster casting in clubfoot.Therefore, we want to determinate first, how pronounced the parents' worries are before treatment and if they decrease during the therapy. Second, we hypothesized that parents faced with an extreme deformity (high Pirani-Score), reveal more distress, than parents whose children have a less pronounced deformity (low Pirani-Score). Therefore, we wanted to investigate weather the Pirani score correlates with the parents' mental resilience in relation to the therapy of the child as a global distress parameter. Methods: To answer this question, we developed a questionnaire with the following emphases: Physical capacity, mental resilience, motion score, parents score and child score with point scores 1 (not affected) to 6 (high affected). Subsequently, we interviewed 20 parents whose children were treated with clubfeet and determined the Pirani score of the infants at the beginning (T 0 ) and at the end (T E ) of the treatment with plaster casting. Results High values were obtained in child score (Mean (M) = 3.11), motion score (M = 2.63) and mental resilience (M = 2.25). During treatment, mental resilience improved (p = 0.015) significantly. The Spearman correlation coefficient between Pirani-Score (T 0 ) and mental resilience (T 0 ) is 0.21, so the initial hypothesis had to be rejected. Conclusion The issues of the children are in the focus of parental worries concerning clubfoot treatment, especially the assumed future motion and the assumed ability to play with other children. Particular emphasis should be placed on educating parents about the excellent long-term results in the function of the treated feet especially as this topic shows the greatest parental distress.
An Integrative Genetic, Epigenetic and Proteomic Characterization of Pancreatic Neuroendocrine Neoplasms (PanNENs) defines Distinct Molecular Features of α- and β-cell like Subgroups
2020-06-12

Abstract Pancreatic Neuroendocrine Neoplasms (PanNENs) comprise a rare and heterogeneous group of tumors derived from neuroendocrine cells of the pancreas. Despite recent genetic and epigenetic characterization, biomarkers for improved patient stratification and personalized therapy are sparse and targeted therapies, including the mTOR inhibitor Everolimus, have shown limited success. To better define PanNENs tumors we performed multi-omic analyses on 59 tumors with varying grades (NET G1, NET G2, NET G3 and NEC), combining mutational profiling with epigenetic analysis and targeted proteomics. An unsupervised approach using DNA methylation profiles uncovered two major subgroups in PanNENs resembling α-like and β-like cells. DNA copy number analysis further divided the α-like subgroup into two distinct groups, indicating differential mechanisms of tumorigenesis from α-cells. β-like tumors however showed two distinct groups at the epigenetic level and suggest NET G3/NEC samples are of β-cell origin. DNA mutation profiling clearly separated α and β-cell derived PanNENs, whereby only α-like tumors had mutations within MEN1/DAXX/ATRX tumor suppressor genes. Targeted proteomic analysis further indicated overexpression of distinct components of the mTOR pathway. Our data provide further insights into the potential mechanisms behind PanNEN heterogeneity and form a basis for future diagnostic and therapy relevant patient stratification.
Reovirus σ1 conformational flexibility modulates the efficiency of host cell attachment
2020-06-12

ABSTRACT Reovirus attachment protein σ1 is a trimeric molecule containing tail, body, and head domains. During infection, σ1 engages sialylated glycans and junctional adhesion molecule-A (JAM-A), triggering uptake into the endocytic compartment, where virions are proteolytically converted to infectious subvirion particles (ISVPs). Further disassembly allows σ1 release and escape of transcriptionally active reovirus cores into the cytosol. Electron microscopy has revealed a distinct conformational change in σ1 from a compact form on virions to an extended form on ISVPs. To determine the importance of σ1 conformational mobility, we used reverse genetics to introduce cysteine mutations that can crosslink σ1 by establishing disulfide bonds between structurally adjacent sites in the tail, body, and head domains. We detected phenotypic differences among the engineered viruses. A mutant with a cysteine pair in the head domain replicates with enhanced kinetics, forms large plaques, and displays increased avidity for JAM-A relative to the parental virus, mimicking properties of ISVPs. However, unlike ISVPs, particles containing cysteine mutations that crosslink the head domain uncoat and transcribe viral positive-sense RNA with kinetics similar to the parental virus and are sensitive to ammonium chloride. Together, these data suggest that σ1 conformational flexibility modulates the efficiency of reovirus host cell attachment. IMPORTANCE Nonenveloped virus entry is an incompletely understood process. For reovirus, the functional significance of conformational rearrangements in the attachment protein, σ1, that occur during entry and particle uncoating are unknown. We engineered and characterized reoviruses containing cysteine mutations that crosslink σ1 monomers in non-reducing conditions. We found that the introduction of a cysteine pair in the receptor-binding domain of σ1 yielded a virus that replicates with faster kinetics than the parental virus and forms larger plaques. Using functional assays, we found that crosslinking the σ1 receptor-binding domain modulates reovirus attachment but not uncoating or transcription. These data suggest that σ1 conformational rearrangements mediate the efficiency of reovirus host cell attachment.
Whole genome characterization of autochthonous Bos taurus brachyceros and introduced Bos indicus indicus cattle breeds in Cameroon regarding their adaptive phenotypic traits and pathogen resistance
2020-06-12

Abstract Background : West African indigenous taurine cattle display unique adaptive traits shaped by husbandry management, regional climate and exposure to endemic pathogens. They are less productive with respect to milk and meat production which has been associated with amongst others, small size, traditional beliefs and husbandry practices. This resulted in the severe dwindling of their population size rendering them vulnerable to extinction. The Namchi taurine cattle breed is referred to as [Namchi (Doayo)] and shows resistance traits against trypanosome infection and exposure to tick infestation. Nonetheless, the historically later introduced Zebu cattle are the main cattle breeds in Africa today, even though they suffer more from locally prevailing pathogens. By using a reference-based whole genome sequencing approach, we sequenced with high depth for the first time the genomes of five cattle breeds from Cameroon in order to provide a valuable genetic resource for future African cattle breeding: the Namchi , an endangered trypano-tolerant taurine breed, the Kapsiki, an indigenous trypano-susceptible taurine breed, and three Zebu ( Bos indicus indicus ) breeds: Ngaoundere Gudali, White Fulani and Red Fulani. Results: Approximately 167 Gigabases of raw sequencing data were generated for each breed and mapped to the cattle reference genomes ARS-UCD1.2 and UMD3.1.The coverage was 103 to 140-fold when aligning the reads to ARS-UCD1.2 with an average mapping rate of ~99%, and 22 to 30-fold when aligning the reads to UMD3.1 with an average mapping rate of ~64%. The single nucleotide polymorphisms (SNPs) obtained from analysis using the genome ARS-UCD1.2 were compared with reference genomes of European Bos taurus Holstein, the Asian Bos indicus Brahman, and the African trypanotolerant N’Dama breeds.A total of ~100 million (M) SNPs were identified and 7.7 M of those were breed-specific. An approximately 11.1 M constituted of small insertions and deletions. By using only breed-specific non-synonymous variants we identified genes as genetic traits and associated Gene Ontology (GO) terms that could explain certain cattle-breed specific phenotypes such as increased tolerance against trypanosome parasites in the Namchi breed and heat tolerance in the Kapsiki breed. Phylogenetic analysis grouped, except for Namchi, the Bos taurus breeds Kapsiki, N’Dama and Holstein together while the B. indicus breeds White and Red Fulani, Gudali and Brahman clustered separately. The deviating result for Namchi indicates a hybrid status of the selected animal with a recent introgression of Zebu genes into its genome. Conclusions: The findings provide the first comprehensive set of genome-wide variant data of the most important Cameroonian cattle breeds. The genomic data shall constitute a foundation for breed amelioration whilst exploiting the heritable traits and support conservation efforts for the endangered local cattle breeds.
Onset features and time to diagnosis in Friedreich´s Ataxia
2020-06-12

Abstract Background: In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich ́s Ataxia (FRDA), a genetic disorder usually caused by homozygous GAA-repeat expansions. Methods: 611 genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov-Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit. Results: In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (n=57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR=2-9) years and it improved significantly after the introduction of genetic testing (2(IQR=1-5) years, p &lt;0.001). Still, after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI[5.5,7.9] vs 4.5, [4.2,5] years in those with neurological presentation, p =0.001) as well as in b) patients with late-onset (3(IQR=1-7) vs 2(IQR=1-5) years compared to typical onset &lt;25 years of age, p =0.03). Age at onset significantly correlated with the length of the shorter GAA repeat (GAA1) in case of neurological onset (r=-0,6; p &lt;0,0001), but not in patients with non-neurological presentation (r=-0,1; p =0,4). Across 54 siblings’ pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r=-0,14, p =0,3). Conclusions: In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history.
The biodiversity - N cycle relationship: a 15N tracer experiment with soil from plant mixtures of varying diversity to model N pool sizes and transformation rates
2020-06-13

Abstract We conducted a 15 N tracer experiment in laboratory microcosms with field-fresh soil samples from a biodiversity experiment to evaluate the relationship between grassland biodiversity and N cycling. To embrace the complexity of the N cycle, we determined N exchange between five soil N pools (labile and recalcitrant organic N, dissolved NH 4 + and NO 3 − in soil solution, and exchangeable NH 4 + ) and eight N transformations (gross N mineralization from labile and recalcitrant organic N, NH 4 + immobilization into labile and recalcitrant organic N, autotrophic nitrification, heterotrophic nitrification, NO 3 − immobilization, adsorption of NH 4 + ) expected in aerobic soils with the help of the N-cycle model Ntrace . We used grassland soil of the Jena Experiment, which includes plant mixtures with 1 to 60 species and 1 to 4 functional groups (legumes, grasses, tall herbs, small herbs). The 19 soil samples of one block of the Jena Experiment were labeled with either 15 NH 4 + or 15 NO 3 - or both. In the presence of legumes, gross N mineralization and autotrophic nitrification increased significantly because of higher soil N concentrations in legume-containing plots and high microbial activity. Similarly, the presence of grasses significantly increased the soil NH 4 + pool, gross N mineralization, and NH 4 + immobilization, likely because of enhanced microbial biomass and activity by providing large amounts of rhizodeposits through their dense root systems. In our experiment, previously reported plant species richness effects on the N cycle, observed in a larger-scale field experiment within the Jena Experiment, were not seen. However, specific plant functional groups had a significant positive impact on the N cycling in the incubated soil samples.
Development and evaluation of Classical and Pickering emulsions containing crude or fractionated extracts of Libidibia ferrea pods
2020-06-13

<b>Objective:</b> The development of medicinal plants for clinical use represents an important direction in biomedical research, despite the technological difficulties.<b>Significance:</b> The aim of this study was to compare pharmaceutical characteristics and <i>in vitro</i> release of Classical and Pickering emulsions containing crude or fractionated extracts of <i>Libidibia ferrea</i>.<b>Methods:</b> After evaluating the extract's solubility in formulation, a dispersion of hydroxypropyl methylcellulose (HPMC) was prepared in water. For Pickering emulsions, the aqueous phase was HPMC and the oil phase was Miglyol<sup>®</sup> 812; for Classical emulsions, water with Tween<sup>®</sup> 20 and Miglyol<sup>®</sup> 812 with Span<sup>®</sup> 80 were used for aqueous and oil phases, respectively. Crude or fractionated extracts were added to the aqueous phase (5% w/v). Both phases were heated (40 °C); then, the oil phase was poured into the aqueous phase and homogenized using an Ultra-Turrax. Emulsions were characterized for 90 days by pH, polyphenol content, phytomarker content, macroscopic characteristics, droplet size, and zeta potential.<b>Results:</b> These formulations displayed satisfactory stability for 90 days when stored at 25 °C. Regarding the investigation of rheological properties, Pickering emulsions displayed higher viscosity with lesser deformation than Classical emulsions. Moreover, the emulsions displayed similar <i>in vitro</i> release behavior.<b>Conclusion:</b> Based on the results of present study, the Pickering emulsions were obtainable and displayed higher stability than Classical emulsions. Additionally, maintenance of system integrity points to promising systems for delivery of active pharmaceutical ingredients in the internal phase, despite the complex chemical mixture added to the external phase.
Impaired cardiac function is associated with mortality in patients with acute COVID-19 infection
2020-06-14

Abstract Background COVID-19 infection may cause severe respiratory distress and is associated with increased morbidity and mortality. Impaired cardiac function and/or pre-existing cardiovascular disease may be associated with poor prognosis. In the present study, we report a comprehensive cardiovascular characterization in the first consecutive collective of patients that was admitted and treated at the University Hospital of Tübingen, Germany. Methods 123 consecutive patients with COVID-19 were included. Routine blood sampling, transthoracic echocardiography and electrocardiography were performed at hospital admission. Results We found that impaired left-ventricular and right-ventricular function as well as tricuspid regurgitation &gt; grade 1 were significantly associated with higher mortality. Furthermore, elevated levels of myocardial distress markers (troponin-I and NT pro-BNP) were associated with poor prognosis in this patient collective. Conclusion Impaired cardiac function is associated with poor prognosis in COVID-19 positive patients. Consequently, treatment of these patients should include careful guideline-conform cardiovascular evaluation and treatment. Thus, formation of a competent Cardio-COVID-19 team may represent a major clinical measure to optimize therapy of cardiovascular patients during this pandemic.
Image guidance in radiation therapy for better cure of cancer
2020-06-14

The key goal and main challenge of radiation therapy is the elimination of tumors without any concurring damages of the surrounding healthy tissues and organs. Radiation doses required to achieve sufficient cancer‐cell kill exceed in most clinical situations the dose that can be tolerated by the healthy tissues, especially when large parts of the affected organ are irradiated. High‐precision radiation oncology aims at optimizing tumor coverage, while sparing normal tissues. Medical imaging during the preparation phase, as well as in the treatment room for localization of the tumor and directing the beam, referred to as image‐guided radiotherapy (IGRT), is the cornerstone of precision radiation oncology. Sophisticated high‐resolution real‐time IGRT using X‐rays, computer tomography, magnetic resonance imaging, or ultrasound, enables delivery of high radiation doses to tumors without significant damage of healthy organs. IGRT is the most convincing success story of radiation oncology over the last decades, and it remains a major driving force of innovation, contributing to the development of personalized oncology, for example, through the use of real‐time imaging biomarkers for individualized dose delivery.
Activation of transcription factor circuity in 2i-induced ground state pluripotency is independent of repressive global epigenetic landscapes
2020-06-15

Abstract Mouse embryonic stem cells (mESCs) cultured with MEK/ERK and GSK3β (2i) inhibitors transition to ground state pluripotency. Gene expression changes, redistribution of histone H3K27me3 profiles and global DNA hypomethylation are hallmarks of 2i exposure, but it is unclear whether epigenetic alterations are required to achieve and maintain ground state or occur as an outcome of 2i signal induced changes. Here we show that ESCs with three epitypes, WT, constitutively methylated, or hypomethylated, all undergo comparable morphological, protein expression and transcriptome changes independently of global alterations of DNA methylation levels or changes in H3K27me3 profiles. Dazl and Fkbp6 expression are induced by 2i in all three epitypes, despite exhibiting hypermethylated promoters in constitutively methylated ESCs. We identify a number of activated gene promoters that undergo 2i dependent loss of H3K27me3 in all three epitypes, however genetic and pharmaceutical inhibition experiments show that H3K27me3 is not required for their silencing in non-2i conditions. By separating and defining their contributions, our data suggest that repressive epigenetic systems play minor roles in mESC self-renewal and naïve ground state establishment by core sets of dominant pluripotency associated transcription factor networks, which operate independently from these epigenetic processes.
Discovery of a novel small protein factor involved in the coordinated degradation of phycobilisomes in cyanobacteria
2020-06-15

Abstract Phycobilisomes are the major pigment-protein antenna complexes that perform photosynthetic light harvesting in cyanobacteria, rhodophyte and glaucophyte algae. Up to 50% of the cellular nitrogen can be stored in their giant structures. Accordingly, upon nitrogen depletion, phycobilisomes are rapidly degraded. This degradation is tightly coordinated, follows a genetic program and involves small proteins serving as proteolysis adaptors. Here, we describe the role of NblD, a novel factor in this process in cyanobacteria. NblD is a cysteine-rich, 66-amino acid small protein that becomes rapidly induced upon nitrogen starvation. Deletion of the nblD gene in the cyanobacterium Synechocystis prevents the degradation of phycobilisomes, leading to a nonbleaching ( nbl ) phenotype. Competition experiments provided direct evidence for the physiological importance of NblD. Complementation by a plasmid-localized gene copy fully restored the phenotype of the wild type. Overexpression of NblD under nitrogen-replete conditions showed no effect, in contrast to the unrelated proteolysis adaptors NblA1 and NblA2, which can trigger phycobilisome degradation ectopically. Transcriptome analysis revealed that nitrogen starvation correctly induces nblA1/2 transcription in the Δ nblD strain implying that NblD does not act as a transcriptional (co-)regulator. However, fractionation and coimmunoprecipitation experiments indicated the presence of NblD in the phycobilisome fraction and identified the β-phycocyanin subunit as its target. These data add NblD as a new factor to the genetically programmed response to nitrogen starvation and demonstrate that it plays a crucial role in the coordinated dismantling of phycobilisomes when nitrogen becomes limiting. Significance Statement During genome analysis, genes encoding small proteins are frequently neglected. Accordingly, small proteins have remained underinvestigated in all domains of life. Based on a previous systematic search for such genes, we present the functional analysis of the small protein NblD in a photosynthetic cyanobacterium. We show that NblD plays a crucial role during the coordinated dismantling of phycobilisome light-harvesting complexes. This disassembly is triggered when the cells run low in nitrogen, a condition that frequently occurs in nature. Similar to the NblA proteins that label phycobiliproteins for proteolysis, NblD binds to phycocyanin polypeptides but has a different function. The results show that, even in a well-investigated process, crucial new players can be discovered if small proteins are taken into consideration.
Autorité oblige: The Rise and Fall of Hans Kelsen’s Legal Concept of International Institutions
2020-06-15

Abstract Hans Kelsen and his Vienna School in International Law developed a highly original legal concept of international institutions. It originated in the Interbellum and aimed at bolstering the new institutional structures created in the League era by promoting egalitarian legal structures and strong judicial controls of both member states and the organs of the institution. Against the background of this new approach to international organization, Kelsen, after World War II, developed a first and particularly harsh critique of the UN Charter.