bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nucleosome composition regulates the histone H3 tail conformational ensemble and accessibility
Authors: Morrison Emma A. , Baweja Lokesh , Poirier Michael G. , Wereszczynski Jeff , Musselman Catherine A. 
Published: June 2020

AbstractSub-nucleosomal complexes including hexasomes and tetrasomes have been identified as intermediates in nucleosome assembly and disassembly. Their formation is promoted by certain histone chaperones and ATP-dependent remodelers, as well as through transcription by RNA polymerase II. In addition, hexasomes appear to be maintained in transcribed genes and could be an important regulatory factor. While nucleosome composition affects the structure and accessibility of the nucleosomal DNA, its influence on the histone tails is largely unknown. Previously, we found that the H3 tail accessibly is occluded in the context of the nucleosome due to interactions with DNA (Morrison et al, 2018). Here, we investigate the conformational dynamics of the H3 tail in the hexasome and tetrasome. Using a combination of NMR spectroscopy, MD simulations, and trypsin proteolysis, we find that the conformational ensemble of the H3 tail is regulated by nucleosome composition. Similar to what we previously found for the nucleosome, the H3 tails bind robustly to DNA within the hexasome and tetrasome, but upon loss of the H2A/H2B dimer, we determined that the adjacent H3 tail has an altered conformational ensemble, increase in dynamics, and increase in accessibility. Similar to observations of DNA dynamics, this is seen to be asymmetric in the hexasome. Our results indicate that nucleosome composition has the potential to regulate chromatin signaling at the histone tails and ultimately help shape the chromatin landscape.
Investigating the accuracy of imputed genotypes in Nellore cattle using the ARS-UCD1.2 assembly of the bovine genome
Authors: da Costa Hermisdorff Isis , Costa Raphael Bermal , de Albuquerque Lucia Galvão , Pausch Hubert , Kadri Naveen Kumar 
Published: June 2020

AbstractBackgroundImputation accuracy among other things depends on the size of the reference panel, the marker’s minor allele frequency (MAF), and the correct placement of variants on the reference genome assembly. Using high-density genotypes of 3938 Nellore cattle from Brazil, we investigated the accuracy of imputation from 50K to 777K SNP density, using map positions determined according to the bovine genome assemblies UMD3.1 and ARS-UCD1.2. We assessed the effect of reference and target panel sizes on the pre-phasing-based imputation quality using ten-fold cross-validation. Further, we compared the reliability of the model-based imputation quality score (Rsq) from Minimac3 to empirical imputation accuracy.ResultsThe overall accuracy of imputation measured as the squared correlation between true and imputed allele dosages (R2dose) was virtually identical using either the UMD3.1 or ARS-UCD1.2 genome assembly. When the size of the reference panel increased from 250 to 2000, R2doseincreased from 0.845 to 0.917, and the number of polymorphic markers in the imputed data set increased from 586,701 to 618,660. Advantages in both accuracy and marker density were also observed when larger target panels were imputed, likely resulting from more accurate haplotype inference. Imputation accuracy and the marker density in the imputed data increased from 0.903 to 0.913 and from 593,239 to 595,570 when haplotypes were inferred in 500 and 2900 target animals, respectively. The model-based imputation quality scores from Minimac3 (Rsq) were highly correlated to but systematically higher than empirically estimated accuracies. The correlation between these metrics increased with the size of the reference panel and MAF of imputed variants.ConclusionsAccurate imputation of BovineHD BeadChip markers is possible in Nellore cattle using the new bovine reference genome assembly ARS-UCD1.2. The use of large reference and target panels improves the accuracy of the imputed genotypes and provides genotypes for more markers segregating at low frequency for downstream genomic analyses. The model-based imputation quality score from Minimac3 (Rsq) can be used to detect poorly imputed variants but its reliability depends on the size of the reference panel used and MAF of the imputed variants.
Preferred endocytosis of amyloid precursor protein from cholesterol-enriched lipid raft microdomains
Authors: Cho Yoon Young , Kwon Oh-Hoon , Chung Sungkwon 
Published: June 2020

AbstractAmyloid precursor protein (APP) at the plasma membrane is internalized via endocytosis, and delivered to endosomes and lysosomes, where neurotoxic amyloid-β (Aβ) is produced via β-, γ-secretases. Hence, endocytosis plays a key role in the processing of APP and subsequent Aβ generation. β-, γ-secretases as well as APP are localized in cholesterol-enriched lipid raft microdomains. However, it is still unclear whether lipid rafts are the site where APP undergoes endocytosis and whether cholesterol levels affect this process. In this study, we found that localization of APP in lipid rafts was increased by elevated cholesterol level. We also showed that increasing or decreasing cholesterol levels increased or decreased APP endocytosis, respectively. When we labeled cell surface APP, APP localized in lipid rafts preferentially underwent endocytosis compared to non-raft localized APP. In addition, APP endocytosis from lipid rafts was regulated by cholesterol levels. Our results indicate that cholesterol levels regulate the localization of APP in lipid rafts affecting raft-dependent APP endocytosis. Thus, regulating the microdomain localization of APP could offer a new therapeutic strategy for Alzheimer’s disease.
Transparency and open science reporting guidelines in sleep research and chronobiology journals
Authors: Spitschan Manuel , Schmidt Marlene H. , Blume Christine 
Published: June 2020

Abstract“Open science” is an umbrella term describing various aspects of transparent and open science principles. The adoption of open science principles at different levels of the scientific process (e.g., individual researchers, laboratories, institutions) has been rapidly changing the scientific research landscape in the past years, but uptake of these principles differ from discipline to discipline. Here, we asked to what extent journals in the field of sleep and chronobiology research encourage or even require following transparent and open science principles in their author guidelines. To this end, we scored the author guidelines of a comprehensive set of 28 sleep and chronobiology journals, including the major outlets in the field, using the standardised Transparency and Openness (TOP) Factor. This instrument rates the extent to which journals encourage or require following various aspects of open science, including data citation, data transparency, analysis code transparency, materials transparency, design and analysis guidelines, study pre-registration, analysis plan pre-registration, replication, registered reports, and the use of open science badges. Across the 28 journals, we find low values on the TOP Factor (median [25th, 75thpercentile] 2.5 [1, 3], min. 0, max. 9, out of a total possible score of 28). This suggests an opportunity for sleep and chronobiology journals to further support the recent developments by implementing transparency and openness principles in their guidelines and making adherence to them mandatory.
TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS
Authors: Cunningham Kathleen M. , Zhang Ke , Ruan Kai , Maulding Kirstin , Senturk Mumine , Grima Jonathan , Sung Hyun , Zuo Zhongyuan , Song Helen , Rothstein Jeffrey D. , Bellen Hugo J. , Lloyd Thomas E. 
Published: June 2020

AbstractDisrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which impaired NCT causes neurodegeneration remain unclear. In aDrosophilascreen, we identified Ref(2)p/p62, a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in C9orf72 that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron microscopy ofDrosophilatissues demonstrate an accumulation of lysosome-like organelles that precedes neurodegeneration. These phenotypes are partially caused by cytoplasmic mislocalization of Mitf/TFEB, a key transcriptional regulator of autophagolysosomal function. Additionally, TFEB is mislocalized and downregulated in human cells expressing GGGGCC repeats and in C9-ALS patient motor cortex. Our data suggest that the C9orf72-HRE impairs Mitf/TFEB nuclear import, thereby disrupting autophagy and exacerbating proteostasis defects in C9-ALS/FTD.
Identification of regulatory microRNAs for hypoxia induced coagulation mechanism byIn-silicoanalysis
Authors: Hembrom Anju A. , Srivastava Swati , Garg Iti , Kumar Bhuvnesh 
Published: June 2020

AbstractBackgroundHypoxia (oxygen deprivation) is known to induce a prothrombotic state by activating the process of coagulation. Hypoxia inducible factor (HIF), is a major transcription factor involved in cellular response to low oxygen tension. MicroRNAs (miRNAs) are non-coding regulatory sequences capable of post-translational modification of multiple genes. Present study aimed to identify common regulatory miRNAs of HIF gene family and coagulation pathway byIn-silicoapproach in order to understand the molecular mechanism underlying the process of hypoxia induced coagulation.MethodsHIF family and Coagulation pathway genes along with their receptors and mediators were enlisted after comprehensive literature review. Thorough search of three highly cited database was done to identify the miRNAs targeting these genes. The extracted miRNA list was then prioritized on the basis of number and functional relevance of genes targeted. The target genes of all prioritized miRNAs were listed and subjected to followed by gene ontology (GO) study and pathway analysis.ResultPresentIn-silicoanalysis identified five candidate miRNAs, viz., hsa-mir-4433a-3p, hsa-mir-4667-5p, hsa-mir-6735-5p, hsa-mir-6777-3p and hsa-mir-6815-3p that co-regulate genes of HIF family and coagulation pathway. GO and pathway analysis revealed that genes regulated by these five microRNAs, predominantly modulate genes facilitating coagulation and hypoxic response.ConclusionWe identified five key microRNAs involved in body’s response to hypoxia and potentially involved in the blood coagulation cascade as well. These five candidate miRNAs may serve as putative epigenetic biomarkers and therapeutic targets to modulate the process of hypoxia induced coagulation.
The immune-opioid axis in prediabetes: prediction of prediabetes with insulin resistance by plasma interleukin-10 and Endomorphin-2 to kappa-opioid receptors ratio
Authors: Moustafa Shatha Rouf 
Published: June 2020

AbstractBackgroundPrediabetes is characterized by a hemoglobin A1c of 5.7%–6.4% and fasting blood glucose of 100–125 mg/dl. A high percentage of prediabetes subjects develops into type 2 diabetes mellitus in the following years. The effect of opioid peptides and their receptors, in addition to immunological cytokines on prediabetes, is not well understood.ObjectiveWe hypothesize that opioid peptides and their receptors affect the insulin and the insulin resistance (IR) in patients with prediabetes and that the immune cytokines, IL-6 (inflammatory factor) and IL-10 (anti-inflammatory factor), influence the opioid system.MethodsA total of 60 patients with prediabetes and IR (prediabetes+IR), 60 patients with prediabetes without IR (prediabetes-IR), and 60 controls participated in the study. The IR state was HOMAIR > 2.5. The enzyme linked immunosorbent assay was used to measure interleukin (IL)-6, IL-10, μ- and κ-opioid receptors (MOR and KOR), endomorphin-2 (EM2), and β- endorphin (βEP).ResultsThe subjects with prediabetes had dyslipidemia, and not all of them underwent the IR state. The IL-6, IL-10, β-endorphin, MOR, and endomorphin-2 were higher in the prediabetes subgroups compared with the control group. MOR was correlated with IL-10 and KOR. Prediabetes+IR can be predicted by the increased levels of the combination of IL-10, βEP, and EM2 and by the combination of IL-10 and endomorphin-2/KOR with good sensitivity and specificity.ConclusionOpioid peptides and their receptors were upregulated in patients with prediabetes depending on the significance of IR. These changes in the opioid system depend on the immune cytokines. Both systems need to be normalized to prevent further development into diabetes mellitus.
What happens after a blood meal? A transcriptome response from the main tissues involved in egg production inRhodnius prolixus, an insect vector of Chagas disease
Authors: Leyria Jimena , Orchard Ian , Lange Angela B. 
Published: June 2020

AbstractThe blood-sucking hemipteranRhodnius prolixusis a vector of Chagas disease, one of the most neglected tropical diseases affecting several million people, mostly in Latin America. The blood meal is an event with a high epidemiological impact since in adult mated females it initiates the production of hundreds of eggs. By means of RNA-Sequencing (RNA-Seq) we have examined how a blood meal influences mRNA expression in the central nervous system (CNS), fat body and ovaries in order to promote egg production, focusing on tissue-specific responses under controlled nutritional conditions. We illustrate the cross talk between reproduction and a) lipids, proteins and trehalose metabolism, b) neuropeptide and neurohormonal signaling, and c) the immune system. Overall, our molecular evaluation confirms and supports previous studies and provides an invaluable molecular resource for future investigations on different tissues involved in successful reproductive events. Analyses like this can be used to increase the chances of developing novel strategies of vector population control by translational research, with less impact on the environment and more specificity for a particular organism.Author summaryThe blood-sucking hemipteranRhodnius prolixusis one of the main vectors of Chagas disease. The blood meal is an event with a high epidemiological impact since in adult mated females, blood-gorging leads to the production of hundreds of eggs. This work describes an in-depth central nervous system (CNS), ovary and fat body transcriptome analysis, focusing on transcripts related to blood intake which may be relevant in promoting egg production. To date, the principle focus in Chagas disease prevention is on the elimination of triatomine vectors and their progeny. This work will serve as a starting point for initiating novel investigations on targets identified with a potential for use in vector control; for example using specific genes to generated symbiont-mediated RNAi, a powerful technology which provides a novel means in biocontrol against tropical disease vectors.
Food-Poisoning Bacteria Employ a Citrate Synthase and a Type II NRPS to Synthesize Bolaamphiphilic Lipopeptide Antibiotics
Authors: Dose Benjamin , Ross Claudia , Niehs Sarah P. , Scherlach Kirstin , Bauer Johanna P. , Hertweck Christian 
Published: June 2020

AbstractMining the genome of the food-spoiling bacteriumBurkholderia gladiolipv.cocovenenansrevealed five non-ribosomal peptide synthetase (NRPS) gene clusters, including an orphan gene locus(bol).Gene inactivation and metabolic profiling linked thebolgene cluster to novel bolaamphiphilic lipopeptides with antimycobacterial activity. A combination of chemical analyses and bioinformatics elucidated the structures of bolagladin A and B, lipocyclopeptides featuring an unusual dehydro-β-alanine enamide linker fused to an unprecedented tricarboxylic fatty acid tail. Through a series of targeted gene deletions we proved the involvement of a designated citrate synthase (CS), priming ketosynthases (KS III), a type II NRPS including a novel desaturase for enamide formation, and a multimodular NRPS generating the cyclopeptide. Network analyses revealed the evolutionary origin of the CS and identified cryptic CS/NRPS gene loci in various bacterial genomes.
Urbanization promotes specific bacteria in freshwater microbiomes including potential pathogens
Authors: Numberger Daniela , Zoccarato Luca , Woodhouse Jason , Ganzert Lars , Sauer Sascha , Grossart Hans-Peter , Greenwood Alex 
Published: June 2020

ABSTRACTFreshwater ecosystems are characterized by complex and highly dynamic microbial communities that are strongly structured by their local environment and biota. Growing city populations and the process of urbanization substantially alter freshwater environments. To determine the changes in freshwater microbial communities associated with urbanization, full-length 16S rRNA gene PacBio sequencing was performed from surface water and sediments from a wastewater treatment plant, urban and rural lakes in the Berlin-Brandenburg region, Northeast Germany. Water samples exhibited highly habitat specific bacterial communities with multiple genera showing clear urban signatures. We identified potentially harmful bacterial groups associated with environmental parameters specific to urban habitats such asAlistipes, Escherichia/Shigella, RickettsiaandStreptococcus. We demonstrate that urbanization alters natural microbial communities in lakes and, via simultaneous eutrophication, creates favorable conditions that promote specific bacterial genera including potential pathogens. Our findings are of global relevance highlighting a long-term health risk in urbanized waterbodies, at a time of accelerated global urbanization. The results demonstrate the urgency for undertaking mitigation measures such as targeted lake restoration projects and sustainable water management efforts.
A neural surveyor to map touch on the body
Authors: Miller Luke E. , Fabio Cécile , Azaroual Malika , Muret Dollyane , van Beers Robert J. , Farnè Ales-sandro , Medendorp W. Pieter 
Published: June 2020

AbstractPerhaps the most recognizable sensory map in all of neuroscience is the somatosensory homunculus. Though it seems straightforward, this simple representation belies the complex link between an activation in a somatotopic map and the associated touch location on the body. Any isolated activation is spatially ambiguous without a neural decoder that can read its position within the entire map, but how this is computed by neural networks is unknown. We propose that the somatosensory system implements multilateration, a common computation used by surveying and GPS systems to localize objects. Specifically, to decode touch location on the body, multilateration estimates the relative distance between the afferent input and the boundaries of a body part (e.g., the joints of a limb). We show that a simple feedforward neural network, which captures several fundamental receptive field properties of cortical somatosensory neurons, can implement a Bayes-optimal multilateral computation. Simulations demonstrated that this decoder produced a pattern of localization variability between two boundaries that was unique to multilateration. Finally, we identify this computational signature of multilateration in actual psychophysical experiments, suggesting that it is a candidate computational mechanism underlying tactile localization.
Activation of the Integrated Stress Response in drug-tolerant melanoma cells confers vulnerability to mitoribosome-targeting antibiotics
Authors: Vendramin Roberto , Konnova Angelina , Adnane Sara , Cinque Sonia , Katopodi Vicky , Knezevic Zorica , Karras Panangiotis , Demesmaeker Ewout , Bosisio Francesca M , Rizzotto Lara , Bechter Oliver , Marine Jean-Christophe , Leucci Eleonora 
Published: June 2020

SummaryTherapy resistance remains a major clinical challenge for the management of metastatic melanoma. Here we show that activation of the Integrated Stress Response (ISR), which we show is common in drug-tolerant and resistant melanoma, promotes selective synthesis of mitochondrial proteins in the cytosol. Since mitochondrial translation adapts to the influx of nuclear-encoded mitochondrial proteins, ISR activation indirectly enhances mitochondrial translation and makes these cells highly vulnerable to mitochondrial translation inhibitors. Treatment of melanoma with mitoribosome-targeting antibiotics, induces proteotoxic stress and significantly compromises the growth ofNRAS-mutant and immunotherapy-resistant skin melanoma as well as uveal melanoma. Additionally, a triple BRAFi/MEKi/Tigecycline combination reduces intratumour heterogeneity by abrogating emergence of dedifferentiated drug-tolerant cells, and delayed or even prevented the development of resistance in BRAFV600EPDX models. Consistently, a melanoma patient exposed to Doxycycline, a mitoribosome-targeting antibiotic commonly used to treat infections, experienced a complete and long-lasting response of a treatment-resistant lesion.SignificanceOur study indicates that the repurposing of mitoribosome-targeting antibiotics offers a rational salvage strategy for targeted therapy inBRAF-mutant melanoma, and a therapeutic option to targetNRAS-driven and immunotherapy-resistant cutaneous melanoma and uveal melanomas.
Adhesive Contact Between Cylindrical (Ebola) and Spherical (SARS-CoV-2) Viral Particles and a Cell Membrane
Authors: Wang Jiajun , Lapinski Nicole , Zhang X. Frank , Jagota Anand 
Published: June 2020

AbstractA critical event during the process of cell infection by a viral particle is attachment, which is driven by adhesive interactions and resisted by bending and tension. The biophysics of this process has been studied extensively but the additional role of externally applied force or displacement has generally been neglected. In this work we study the adhesive force-displacement response of viral particles against a cell membrane. We have built two models: one in which the viral particle is cylindrical (say, representative of filamentous virus such as Ebola) and another in which it is spherical (such as SARS-CoV-2 and Zika). Our interest is in initial adhesion, in which case deformations are small and the mathematical model for the system can be simplified considerably. The parameters that characterize the process combine into two dimensionless groups that represent normalized membrane bending stiffness and tension. In the limit where bending dominates, for sufficiently large values of normalized bending stiffness, there is no adhesion between viral particles and the cell membrane without applied force. (The zero-external-force contact width and pull-off force are both zero.) For large values of normalized membrane tension, the adhesion between virus and cell membrane is weak but stable. (The contact width at zero external force has a small value.) Our results for pull-off force and zero force contact width help to quantify conditions that could aid the development of therapies based on denying the virus entry into the cell by blocking its initial adhesion.