bluuebunny/crossref_metadata_2025_split huggingface dataset:
A systematic screen of breast cancer patients’ exomes for retrotransposon insertions reveals disease associated genes
Authors: De Brakeleer Sylvia , De Grève Jacques , Teugels Erik 
Published: June 2020

ABSTRACTBackgroundRetrotransposons are genetic elements that jump within the genome via an RNA intermediate. Although they had a strong impact on human genome evolution, only a very tiny fraction of them can be reactivated nowadays, most often with neutral or detrimental consequences. The pathological outcomes associated with such genetic alterations are poorly investigated in the clinic, merely due to their difficult detection.ResultsWe developed a strategy to detect rare retrotransposon mediated insertions in Whole Exome Sequencing data from 65 familial breast cancer patients. When restricting our search to high confidence retrotransposition events occurring in less than 10% of the samples, we identified only ten different Alu elements, two L1 elements, one SVA and two processed pseudogenes. Only two of these insertions occurred within protein coding sequences and interestingly, several of the targeted genes have been previously linked to cancer, in three cases even to increased breast cancer risk (GHR, DMBT1andNEK10). When investigating the molecular consequences of four Alu insertions at the mRNA level, we found that the element present in the 3’UTR ofGHRrepressed expression of the corresponding allele. oMreover, the analysis of a near exonic Alu insertion inPTPN14(a mediator ofP53tumor suppressor activity) revealed that this gene was imprinted and that the presence of an intronic Alu element can lead to loss of imprinting.ConclusionsOur data underline the relevance of incorporating the search for uncommon retrotransposition events in Next Generation Sequencing pipelines when analyzing patients with a suspected genetic disease.
Improving emotional-action control by targeting long-range phase-amplitude neuronal coupling
Authors: Bramson Bob , den Ouden Hanneke , Toni Ivan , Roelofs Karin 
Published: June 2020

AbstractControl over emotional action tendencies is essential for every-day interactions. This cognitive function can fail during socially challenging situations, and is chronically attenuated in social psychopathologies such as social anxiety and aggression. Previous studies have shown that control over social-emotional action tendencies depends on phase-amplitude coupling between prefrontal theta-band (6 Hz) rhythmic activity and broadband gamma-band activity in sensorimotor areas. Here, we delivered dual-site phase-coupled brain stimulation to facilitate theta-gamma phase-amplitude coupling between frontal regions known to implement that form of control, while participants were challenged to control their automatic action tendencies in a social-emotional approach/avoidance-task. Participants had increased control over their emotional action tendencies, depending on the relative phase and dose of the intervention. Concurrently measured fMRI effects of task and stimulation, and estimated changes in effective connectivity, indicated that the intervention improved control by increasing the efficacy of anterior prefrontal inhibition over sensorimotor cortex. This enhancement of emotional action control provides causal evidence for a phase-amplitude coupling mechanism guiding action selection during emotional-action control. More generally, the finding illustrates the potential of physiologically-grounded interventions aimed at reducing neural noise in cerebral circuits where communication relies on phase-amplitude coupling.
Targeting methionine synthase in a fungal pathogen causes a metabolic imbalance that impacts cell energetics, growth and virulence
Authors: Scott Jennifer , Sueiro-Olivares Monica , Thornton Benjamin P. , Owens Rebecca A. , Muhamadali Howbeer , Fortune-Grant Rachael , Thomson Darren , Thomas Riba , Hollywood Katherine , Doyle Sean , Goodacre Royston , Tabernero Lydia , Bignell Elaine , Amich Jorge 
Published: June 2020

ABSTRACTThere is an urgent need to develop novel antifungals to tackle the threat fungal pathogens pose to human health. In this work, we have performed a comprehensive characterisation and validation of the promising target methionine synthase (MetH). We uncover that inAspergillus fumigatusthe absence of this enzymatic activity triggers a metabolic imbalance that causes a reduction in intracellular ATP, which prevents fungal growth even in the presence of methionine. Interestingly, growth can be recovered in the presence of certain metabolites, which evidences thatmetHis a conditionally essential gene. As this implies that for a correct validation MetH should be targeted in established infections, we have validated the use of the tetOFF genetic model for fungal research and optimised its performance to mimic treatment of established infections. We show that repression ofmetHin growing hyphae halts growthin vitro, which translates into a beneficial effect when targeting established infections using this modelin vivo. Finally, a structural-based virtual screening of methionine synthases reveals key differences between the human and fungal structures and unravels features in the fungal enzyme that can guide the design of novel specific inhibitors. Therefore, methionine synthase is a valuable target for the development of new antifungals.IMPORTANCEFungal pathogens are responsible for millions of life-threatening infections on an annual basis worldwide. The current repertoire of antifungal drugs is very limited and, worryingly, resistance has emerged and already become a serious threat to our capacity to treat fungal diseases. The first step to develop new drugs often is to identify molecular targets which inhibition during infection can prevent pathogen growth. However, the current models are not suitable to validate targets in established infections. Here we have characterised the promising antifungal target methionine synthase in great detail, using the prominent fungal pathogenAspergillus fumigatusas a model. We have uncovered the underlying reason for its essentiality and confirmed its druggability. Furthermore, we have optimised the use of a genetic system to show a beneficial effect of targeting methionine synthase in established infections. Therefore, we believe that antifungal drugs to target methionine synthase should be pursued and additionally, we propose that antifungal targets should be validated in a model of established infection.
High Resolution Biomolecular Condensate Phase Diagrams with a Combinatorial Microdroplet Platform
Authors: Arter William E. , Qi Runzhang , Erkamp Nadia A. , Krainer Georg , Didi Kieran , Welsh Timothy J. , Acker Julia , Nixon-Abell Jonathan , Qamar Seema , Guillén-Boixet Jordina , Franzmann Titus M. , Kuster David , Hyman Anthony A. , Borodavka Alexander , St George-Hyslop Peter , Alberti Simon , Knowles Tuomas P.J. 
Published: June 2020

AbstractThe assembly of intracellular proteins into biomolecular condensates is a fundamental process underlying the organisation of intracellular space and the regulation of many cellular processes. Mapping and characterising phase behaviour of biomolecules is essential to understand the mechanisms of condensate assembly, and to develop therapeutic strategies targeting biomolecular condensate systems. A central concept for characterising phase-separating systems is the phase diagram. Phase diagrams are typically built from numerous individual measurements sampling different parts of the parameter space. However, even when performed in microwell plate format, this process is slow, low throughput and requires significant sample consumption. To address this challenge, we present here a combinatorial droplet microfluidic platform, termed PhaseScan, for rapid and high-resolution acquisition of multidimensional biomolecular phase diagrams. Using this platform, we characterise the phase behaviour of a wide range of systems under a variety of conditions and demonstrate that this approach allows the quantitative characterisation of the effect of small molecules on biomolecular phase transitions.
Production the industrial levels of bioethanol from glycerol by engineered yeast “Bioethanol-4thgeneration”
Authors: Khattab Sadat Mohamed Rezk , Watanabe Takashi 
Published: June 2020

Besides the pledges for expanding uses of biofuels to sustain the humanosphere, abruptly massive needs emerged for sanitizers with turns COVID-19 to a pandemic. Therefore, ethanol is topping the social-demanding, although the three generations of production, from molasses/starch, lignocelluloses, and algae. Owing to the limited-availability of fermentable sugars from these resources, we addressed glycerol as a fourth bio-based carbon resource from biodiesel, soap, and fatty acid industries, which considers as a non-applicable source for bioethanol production. Here, we show the full strategy to generate efficient glycerol fermenting yeast by innovative rewriting the oxidation of cytosolic nicotinamide-adenine-dinucleotide (NADH) by O2-dependent dynamic shuttle while abolishing glycerol biosynthesis route. Besides, imposing a vigorous glycerol-oxidative pathway, the engineered strain demonstrated a breakthrough in conversion efficiency (up to 98%). Its capacity extending to produce up to 90g /l ethanol and > 2 g 1-1h-1, which promoting the industrial view. Visionary metabolic engineering here provides horizons for further tremendous economic and health benefits with assuring for its enhancing for the other scenarios of biorefineries.SummaryEfficiently fermenting glycerol in yeast was developed by comprehensive engineering the glycerol pathways and rewriting NADH pathways.
Fibroblasts as an Alternative to Mesenchymal Stem Cells with Successful Treatment and Immune Modulation in EAE Model of Multiple Sclerosis
Authors: Ichim Thomas E , O’Heeron Pete , Perez Jesus , Liu Peter , Min Wei-Ping , Kesari Santosh 
Published: June 2020

AbstractThe immune modulatory potential of mesenchymal stem cells (MSCs) is well known and is the basis for multiple clinical trials in treatment of autoimmune conditions. Unfortunately, MSCs are relatively rare, difficult to expand in culture, and methods of obtaining MSCs are complicated and expensive. In contrast, fibroblasts are found in copious amounts in various tissues, are a robust cellular population, and can be cultured without need for costs associated with culture media. Previous studies by our group and others have demonstrated fibroblasts possess regenerative activities. In the current study we demonstrated: a) fibroblasts inhibit mixed lymphocyte reaction; b) suppress T cell activation; c) inhibit DC maturation; and d) stimulate T regulatory (Treg) cell formation. Importantly, administration of fibroblasts in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis resulted in disease inhibition, which was abrogated upon depletion of Treg cells. This data, combined with existing clinical safety data on fibroblast administration, supports the clinical translation of fibroblast-based therapies for multiple sclerosis.
An economic dilemma between weapon systems may explain an arachno-atypical venom in wasp spiders (Argiope bruennichi)
Authors: Lüddecke Tim , von Reumont Björn M. , Förster Frank , Billion André , Timm Thomas , Lochnit Günter , Vilcinskas Andreas , Lemke Sarah 
Published: June 2020

AbstractSpiders use venom to subdue their prey, but little is known about the diversity of venoms in different spider families. Given the limited data available for orb-weaver spiders (Araneidae) we selected the wasp spiderArgiope bruennichifor detailed analysis. Our strategy combined a transcriptomics pipeline based on multiple assemblies with a dual proteomics workflow involving parallel mass spectrometry techniques and electrophoretic profiling. We found that the remarkably simple venom ofA. bruennichihas an atypical composition compared to other spider venoms, prominently featuring members of the CAP superfamily and other, mostly high-molecular-weight proteins. We also detected a subset of potentially novel toxins similar to neuropeptides. We discuss the potential function of these proteins in the context of the unique hunting behavior of wasp spiders, which rely mostly on silk to trap their prey. We propose that the simplicity of the venom evolved to solve an economic dilemma between two competing yet metabolically expensive weapon systems. This study emphasizes the importance of cutting-edge methods to encompass smaller lineages of venomous species that have yet to be characterized in detail, allowing us to understand the biology of their venom systems and to mine this prolific resource for translational research.
The impact of transposable elements on tomato diversity
Authors: Domínguez Marisol , Dugas Elise , Benchouaia Médine , Leduque Basile , Jimenez-Gomez José , Colot Vincent , Quadrana Leandro 
Published: June 2020

ABSTRACTTomatoes come in a multitude of shapes and flavors despite a narrow genetic pool. Here, we leveraged whole-genome resequencing data available for 602 cultivated and wild accessions to determine the contribution of transposable elements (TEs) to tomato diversity. We identified 6,906 TE insertions polymorphisms (TIPs), which result from the mobilization of 337 distinct TE families. Most TIPs are low frequency variants and disproportionately located within or adjacent to genes involved in environmental response. In addition, we show that genic TE insertions tend to have strong transcriptional effects and can notably lead to the generation of multiple transcript isoforms. We also uncovered through genome-wide association studies (GWAS) ~180 TIPs associated with extreme variations in major agronomic traits or secondary metabolites. Importantly, these TIPs tend to affect loci that are distinct from those tagged by SNPs. Collectively, our findings suggest a unique and important role for TE mobilization in tomato diversification, with important implications for future breeding.
Sensitivity of radio-photoluminescence glass dosimeters to accumulated doses
Authors: Kim Dong Wook , Sung Jiwon , Son Jaeman , Shin Han-Back , Kim Min-Joo , Noh Yu-Yun , Kim Hojae , Han Min Cheol , Kim Jihun , Han Su Chul , Chang Kyung Hwan , Kim Hojin , Park Kwangwoo , Yoon Myonggeun , Kim Jinsung , Shin Dongoh 
Published: June 2020

AbstractBackgroundThis study investigated the effect of accumulated doses on radio-photoluminescence glass dosimeters (RPLGDs) from measurements involving mega-voltage photons.MethodsForty-five commercially available RPLGDs were irradiated to estimate their dose responses. Photon beams of 6, 10, and 15 MV were irradiated onto the RPLGDs inside a phantom, which were divided into five groups with different doses and energies. Groups 1 and 2 were irradiated at 1, 5, 10, 50, and 100 Gy in a sequential manner; Group 3 was irradiated 10 times with a dose of 10 Gy; and Groups 4 and 5 followed the same method as that of Group 3, but with doses of 50 Gy and 100 Gy, respectively.ResultsFor the annealed Group 1, RPLGD exhibited a linearity response with variance within 5%. For the non-annealed Group 2, readings demonstrated hyperlinearity at 6 MV and 10 MV, and linearity at 15 MV. Following the 100 Gy irradiation, the readings for Group 2 were 118.7 ± 1.9%, 112.2 ± 2.7%, and 101.5 ± 2.3% at 6, 10, and 15 MV, respectively. For Groups 3, 4, and 5, the responsiveness of the RPLGDs gradually decreased as the number of repeated irradiations increased. The percentage readings for the 10th beam irradiation with respect to the readings for the primary beam irradiation were 84.6 ± 1.9%, 87.5 ± 2.4%, and 93.0 ± 3.0% at 6 MV, 10 MV, and 15 MV, respectively.ConclusionsThe non-annealed RPLGD response to dose was hyperlinear for the 6 MV and 10 MV photon beams but not for the 15 MV photon beam. Additionally, the annealed RPLGD exhibited a fading phenomenon when the measurement was repeated several times and demonstrated a relatively large fading effect at low energies than at high energies.
The role of gene dosage in budding yeast centrosome scaling and spontaneous diploidization
Authors: Chen Jingjing , Xiong Zhiyong , Miller Danny E. , Yu Zulin , McCroskey Scott , Bradford William D. , Cavanaugh Ann M. , Jaspersen Sue L. 
Published: June 2020

AbstractPloidy is the number of whole sets of chromosomes in a species. Ploidy is typically a stable cellular feature that is critical for survival. Polyploidization is a route recognized to increase gene dosage, improve fitness under stressful conditions and promote evolutionary diversity. However, the mechanism of regulation and maintenance of ploidy is not well characterized. Here, we examine the spontaneous diploidization associated with mutations in components of theSaccharomyces cerevisiaecentrosome, known as the spindle pole body (SPB). Although SPB mutants are associated with defects in spindle formation, we show that two copies of the mutant in a haploid yeast favors diploidization in some cases, leading us to speculate that the increased gene dosage in diploids ‘rescues’ SPB duplication defects, allowing cells to successfully propagate with a stable diploid karyotype. This copy number-based rescue is linked to SPB scaling: certain SPB subcomplexes do not scale or only minimally scale with ploidy. We hypothesize that acquisition of lesions in structures with incompatible allometries such as the centrosome may drive changes such as whole genome duplication, which have shaped the evolutionary landscape of many eukaryotes.Author SummaryPloidy is the number of whole sets of chromosomes in a species. Most eukaryotes alternate between a diploid (two copy) and haploid (one copy) state during their life and sexual cycle. However, as part of normal human development, specific tissues increase their DNA content. This gain of entire sets of chromosomes is known as polyploidization, and it is observed in invertebrates, plants and fungi, as well. Polyploidy is thought to improve fitness under stressful conditions and promote evolutionary diversity, but how ploidy is determined is poorly understood. Here, we use budding yeast to investigate mechanisms underlying the ploidy of wild-type cells and specific mutants that affect the centrosome, a conserved structure involved in chromosome segregation during cell division. Our work suggests that different scaling relationships (allometry) between the genome and cellular structures underlies alterations in ploidy. Furthermore, mutations in cellular structures with incompatible allometric relationships with the genome may drive genomic changes such duplications, which are underly the evolution of many species including both yeasts and humans.
Spatial distribution and factors associated with low birth weight in Ethiopia using data from Ethiopian demographic and health survey 2016: spatial and multilevel analysis
Authors: Liyew Alemneh Mekuriaw , Sisay Malede Mequanent , Muche Achenef Asmamaw 
Published: June 2020

AbstractBackgroundLow birth weight (LBW) was a leading cause of neonatal mortality. It showed an increasing trend in Sub-Saharan Africa for the last one and half decade. Moreover, it was a public health problem in Ethiopia. Even though different studies were conducted to identify its predictors, contextual factors were insufficiently addressed in Ethiopia. There was also limited evidence on the spatial distribution of low birth weight. Therefore, this study aimed to explore spatial distribution and factors associated with low birth weight in Ethiopia.MethodSecondary data analysis was conducted using the 2016 EDHS data. A total of 1502 (weighted sample) mothers whose neonates were weighed at birth five years preceding the survey were included. GIS 10.1, SaTscan, stata, and Excel were used for data cleaning and analysis. A multi-level mixed-effects logistic regression model was fitted to identify factors associated with low birth weight. Finally, hotspot areas from GIS results, log-likelihood ratio (LLR) and relative risk with p-value of spatial scan statistics, AOR with 95% CI and random effects for mixed-effects logistic regression model were reported.ResultsLow birth weight was spatially clustered in Ethiopia. Primary(LLR=11.57; P=0.002) clusters were detected in the Amhara region. Whereas secondary (LLR=11.4; P=0.003;LLR=10.14,P=0.0075)clusters were identified at Southwest Oromia, north Oromia, south Afar, and Southeast Amhara regions. Being severely anemic (AOR=1.47;95%CI1.04,2.01), having no education (AOR=1.82;95%CI1.12,2.96), Prematurity (AOR=5.91;95%CI3.21,10.10) female neonate (AOR=1.38;95%CI1.04,1.84)were significantly associated with LBWConclusionLBW was spatially clustered in Ethiopia with high-risk areas in Amhara,Oromia, and Afar regions and it was affected by socio demographic factors. Therefore, focusing the policy intervention in those geogrsphically low birth weight risk areas and improving maternal education and nutrtion could be vital to reduce the low birth weight disparity in Ethiopia.
Fine tuning of calcium constitutive entry by optogenetically-controlled membrane polarization: impact on cell migration
Authors: Chapotte-Baldacci C-A. , Lizot G. , Jajkiewicz C. , Lévêque M. , Penna A. , Magaud C. , Thoreau V. , Bois P. , Sebille S. , Chatelier A. 
Published: June 2020

AbstractAnomalies in constitutive calcium entry (CCE) have been commonly attributed to cell dysfunction in pathological conditions such as cancer. Calcium influxes of this type rely on channels, such as TRP, to be constitutively opened and strongly depend on membrane potential and calcium driving force. We developed an optogenetic approach based on expression of the halorhodopsin chloride pump to study CCE in non-excitable cells. Using C2C12 cells, we found that halorhodopsin can be used to achieve a finely-tuned control of membrane polarization. Escalating the membrane polarization by incremental changes in light led to a concomitant increase in CCE through TRPV2 channels. Moreover, light-induced calcium entry through TRPV2 channels promoted cell migration. Our study shows for the first time that by modulating CCE and related physiological responses such as cell motility, halorhodopsin serves as a potentially powerful tool that could open new avenues for the study of CCE and associated cellular behaviors.
SOX21 modulates SOX2-initiated differentiation of epithelial cells in the extrapulmonary airways
Authors: Eenjes Evelien , Buscop-van Kempen Marjon , Boerema-de Munck Anne , de Kreij-de Bruin Lisette , Schnater J. Marco , Tibboel Dick , Collins Jennifer J.P. , Rottier Robbert J. 
Published: June 2020

ABSTRACTSOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe SOX21 patterning of the proximal airway epithelium which coincides with high levels of SOX2. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. We show that loss of SOX21 results in increased differentiation of progenitor cells during murine lung development. SOX21 inhibits SOX2-induced differentiation by antagonizing SOX2 binding on different promotors. SOX21 remains expressed in adult tracheal epithelium and submucosal glands, where SOX21 modulates SOX2-induced differentiation in a similar fashion. Using fetal lung organoids and adult bronchial epithelial cells, we show that SOX2+SOX21+ regionalization is conserved in human. Thus SOX21 modulates SOX2-initiated differentiation in extrapulmonary epithelial cells during development and regeneration after injury.