bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local structural dynamics of alpha-synuclein correlate with aggregation in different physiological conditions
Authors: Seetaloo Neeleema , Zacharopoulou Maria , Stephens Amberley D. , Kaminski Schierle Gabriele S. , Phillips Jonathan J. 
Published: February 2022

ABSTRACTIn Parkinson’s disease and other synucleinopathies, the intrinsically disordered, presynaptic protein alpha-synuclein misfolds and aggregates. We hypothesise that the exposure of alpha-synuclein to different cellular environments, with different chemical compositions, pH and binding partners, alters its biological and pathological function by inducing changes in molecular conformation. Our custom instrumentation and software enable measurement of the amide hydrogen exchange rates of wild-type alpha-synuclein at amino acid resolution under physiological conditions, mimicking those in the extracellular, intracellular, and lysosomal compartments of cells. We characterised the aggregation kinetics and morphology of the resulting fibrils and correlate these with structural changes in the monomer. Our findings reveal that the C-terminal residues of alpha-synuclein are driving its nucleation and thus its aggregation. Furthermore, the entire NAC region and specific other residues strongly promoted elongation of fibrils. This provides new detail on our current understanding of the relationship between the local chemical environment and monomeric conformations of alpha-synuclein.
The nature and chromosomal landscape of endogenous retroviruses (ERVs) integrated in the sheep nuclear genome
Authors: Mustafa Sarbast Ihsan , Schwarzacher Trude , Heslop-Harrison JS 
Published: February 2022

AbstractEndogenous retroviruses (ERVs) represent genomic components of retroviral origin that are found integrated in the genomes of various species of vertebrates. These genomic elements have been widely characterized in model organisms and humans. However, composition and abundances of ERVs have not been categorized fully in all domestic animals. The advent of next generation sequencing technologies, development of bioinformatics tools, availability of genomic databases and molecular cytogenetic techniques have revolutionized the exploration of the genome structure. Here, we investigated the nature, abundance, organization and assembly of ERVs and complete genomes of Jaagsiekte sheep retrovirus (JSRV) from high-throughput sequencing (HTS) data from two Iraqi domestic sheep breeds. We used graph-based read clustering (RepeatExplorer), frequency analysis of short motifs (k-mers), alignment to reference genome assemblies and fluorescent in situ hybridization (FISH). Three classes of ERVs were identified with the total genomic proportions of 0.55% from all analyzed whole genome sequencing raw reads, while FISH to ovine metaphase chromosomes exhibited abundant centromeric to dispersed distribution of these ERVs. Furthermore, the complete genomes of JSRV of two Iraqi sheep breeds were assembled and phylogenetically clustered with the known enJSRV proviruses in sheep worldwide. Characterization of partial and complete sequences of mammalian ERVs is valuable to provide insights into the genome landscape, to help with future genome assemblies and to identify potential sources of disease when ERVs become active.
The Genetics of Participation: Method and Analysis
Authors: Benonisdottir Stefania , Kong Augustine 
Published: February 2022

AbstractParticipation in a genetic study likely has a genetic component. Identifying such component is difficult as we cannot compare genetic information of participants with non-participants directly, the latter being unavailable. Here, we show that alleles that are more common in participants than non-participants would be further enriched in genetic segments shared by two related participants. Genome-wide analysis was performed by comparing allele frequencies in shared and not-shared genetic segments of first-degree relative pairs of the UK Biobank. A polygenic score constructed from that analysis, in non-overlapping samples, is associated with educational attainment (P = 2.1 × 10−52), body mass index (P = 1.5 × 10−19), and participation in a dietary study (P = 6.9 × 10−21). Further analysis shows that inclination to participate is a behavioural trait in its own right, and not simply a consequence of other established phenotypes. Understanding the basis of this trait is important for data analyses and the design of future surveys, genetic or otherwise.
Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice
Authors: Fleeman Rebecca M , Snyder Amanda M , Kuhn Madison K , Chan Dennis C , Smith Grace C , Crowley Nicole A , Arnold Amy C , Proctor Elizabeth A 
Published: February 2022

AbstractThe ε4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for Alzheimer’s disease (AD). While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease. Here we determined the concurrent effects of systemic metabolic changes and brain inflammation in young (3-month-old) and aged (18-month-old) male and female mice carrying theAPOE4gene. Using functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels, we found that brain cytokine signatures are predictive of systemic metabolic outcomes, independent of AD proteinopathies. Male and female mice each produce different cytokine signatures as they age and as their systemic metabolic phenotype declines, and these signatures areAPOEgenotype dependent. Ours is the first study to identify a quantitative and predictive link between systemic metabolism and specific pathological cytokine signatures in the brain. Our results highlight the effects of APOE4 beyond the brain and suggest the potential for bi-directional influence of risk factors in the brain and periphery.Abstract Figure
ClonoCluster: a method for using clonal origin to inform transcriptome clustering
Authors: Richman LP , Goyal Y , Jiang CL , Raj A 
Published: February 2022

AbstractClustering cells based on their high dimensional profiles is an important data reduction process by which researchers infer distinct categories of cellular state. The advent of cellular barcoding, however, provides an alternative means by which to group cells: by their clonal origin. We developed ClonoCluster, a computational method that combines both clone and transcriptome information to create hybrid clusters that weight both kinds of data with a tunable parameter. We generated hybrid clusters across six independent datasets and found that ClonoCluster generated qualitatively different clusters in all cases. The markers of these hybrid clusters were different but had equivalent fidelity to transcriptome-only clusters. The genes most strongly associated with the rearrangements in hybrid clusters were ribosomal function and extracellular matrix genes. We also developed the complementary tool Warp Factor that incorporates clone information in popular 2D visualization techniques like UMAP. Integrating ClonoCluster and Warp Factor revealed biologically relevant markers of cell identity.
Evolutionary trade-offs in osmotic and ionic regulation and the expression of gill ion transporter genes in high latitude, Neotropical cold clime crabs from the ‘end of the world’
Authors: McNamara John Campbell , Maraschi Anieli Cristina , Tapella Federico , Romero Maria Carolina 
Published: February 2022

AbstractSeeking to identify consequences of evolution at low temperature, we examine hyper/hypo-osmotic and ionic regulation and gill ion transporter gene expression in two sub-Antarctic Eubrachyura from the Beagle Channel, Tierra del Fuego. Despite sharing the same osmotic niche, Acanthocyclus albatrossis tolerates a wider salinity range (2-65 ‰S) than Halicarcinus planatus (5-60 ‰S); respective lower and upper critical salinities are 4 and 12 ‰S, and 63 and 50 ‰S. Acanthocyclus albatrossis is a weak hyperosmotic regulator, while H. planatus hyper-osmoconforms; isosmotic points are 1,380 and ≈1,340 mOsm kg−1 H2O. Both crabs hyper/hypo-regulate [Cl−] well with iso-chloride points at 452 and 316 mmol L−1 Cl−, respectively. [Na+] is hyper-regulated at all salinities. mRNA expression of gill Na+/K+-ATPase is salinity-sensitive in A. albatrossis, increasing ≈1.9-fold at 5 ‰S compared to 30 ‰S, decreasing at 40 to 60 ‰S. Expression in H. planatus is very low salinity-sensitive, increasing ≈4.7-fold over 30 ‰S, but decreasing at 50 ‰S. V(H+)-ATPase expression decreases in A. albatrossis at low and high salinities as in H. planatus. Na+-K+-2Cl− symporter expression in A. albatrossis increases 2.6-fold at 5 ‰S, but decreases at 60 ‰S compared to 30 ‰S. Chloride uptake may be mediated by increased Na+-K+-2Cl− expression but Cl− secretion is independent of symporter expression. These unrelated eubrachyurans exhibit similar systemic osmoregulatory characteristics and are better adapted to dilute media; however, the gene expressions underlying ion uptake and secretion show marked interspecific divergences. Cold clime crabs may have limited energy expenditure by regulating hemolymph [Cl−] alone, apportioning resources for other metabolic processes.Summary statementSub-Antarctic crabs may skimp on osmoregulatory capabilities to apportion energy for metabolic processes. They regulate chloride but not sodium or osmolality. Transporter gene expressions diverge markedly. Adaptive, differential ion regulation may characterize cold clime crabs.
Non-destructive chemical sensing within bulk soil using 1000 biosensors per gram of matrix
Authors: Fulk Emily M. , Gao Xiaodong , Lu Li Chieh , Redeker Kelly R. , Masiello Caroline A. , Silberg Jonathan J. 
Published: February 2022

ABSTRACTGene expression can be monitored in hard-to-image environmental materials using gas-reporting biosensors, but these outputs have only been applied in autoclaved matrices that are hydrated with rich medium. To better understand the compatibility of indicator gas reporting with environmental samples, we evaluated how matrix hydration affects the gas signal of an engineered microbe added to a sieved soil. A gas-reporting microbe presented a gas signal in a forest soil (Alfisol) when hydrated to an environmentally-relevant osmotic pressure. When the gas signal was concentrated prior to analysis, a biosensor titer of 103 cells/gram soil produced a significant signal when soil was supplemented with halides. A signal was also observed without halide amendment, but a higher cell titer (106 cells/gram soil) was required. A sugar-regulated gas biosensor was able to report with a similar level of sensitivity when added to an unsterilized soil matrix, illustrating how gas concentration enables biosensing within a soil containing environmental microbes. These results establish conditions where engineered microbes can report on gene expression in living environmental matrices with minimal perturbation, using biosensor titers that are orders of magnitude lower than the number of cells typically observed in a gram of soil.
Molecular signature of RV cardiac remodeling associated with Polymerase Gamma mutation
Authors: Gorr Matthew W. , Francois Ashley , Marcho Lynn M. , Saldana Ty , McGrail Erin , Sun Nuo , Stratton Matthew S. 
Published: February 2022

AbstractAging is associated with metabolic dysfunction and metabolic dysfunction accelerates the course of aging. This is well illustrated by aging-like phenotypes displayed in the Polymerase Gamma mutant mouse. Here, a key residue of the mitochondrial DNA polymerase is mutated (D257A) which hinders proof reading capacity, resulting in mitochondrial DNA mutation and instability. Given known cardiac phenotypes in the POLG mutant mouse, we sought to characterize the course of cardiac dysfunction in the POLG mutant to guide future intervention studies. Including both male and female animals allowed interrogation of sex-specific responses to severe metabolic dysfunction. We also conducted RNA-seq analysis on cardiac right ventricles to broadly identify mechanisms engaged by severe metabolic dysfunction that are associated with RV pathology. Several interesting sex differences were noted. Specifically, female POLG mutants died earlier than male POLG mutants and LV chamber diameters were impacted earlier in females than males. Moreover, male POLG mutants showed LV wall thinning while female POLG mutant LV walls were thicker. Both males and females displayed significant RV hypertrophy. Finally, RNA-seq analysis of the RV tissue indicated that POLG mutation significantly impacted canonical pathways associated with inflammation, fibrosis, and heart failure. Comparison of this RNA-seq dataset with other publically available datasets highlight 1) strong conservation among downregulated genes in models of accelerated cardiac aging, 2) the potential involvement of the mitochondrial unfolded protein response in the POLG mutant, and 3) the ability of zinc dependent HDAC inhibition to rescue the expression of genes downregulated in accelerated cardiac aging.
Induction of senescence upon loss of the Ash2l core subunit of H3K4 methyltransferase complexes
Authors: Bochyńska Agnieszka , Stenzel Alexander T. , Boroujeni Roksaneh Sayadi , Kuo Chao-Chung , Barsoum Mirna , Liang Weili , Bussmann Philip , Costa Ivan G. , Lüscher-Firzlaff Juliane , Lüscher Bernhard 
Published: February 2022

ABSTRACTGene expression is controlled in part by post-translational modifications of core histones. Methylation of lysine 4 of histone H3 (H3K4), associated with open chromatin and gene transcription, is catalyzed by type 2 lysine methyltransferase complexes that require WDR5, RBBP5, ASH2L and DPY30 as core subunits. Ash2l is essential during embryogenesis and for maintaining adult tissues. To expand on the mechanistic understanding of Ash2l, we generated mouse embryo fibroblasts (MEFs) with conditional Ash2l alleles. Upon loss of Ash2l, methylation of H3K4 and gene expression were downregulated, which correlated with inhibition of proliferation and cell cycle progression. Moreover, we observed induction of senescence concomitant with a set of downregulated signature genes but independent of SASP. Many of the signature genes are FoxM1 responsive. Indeed, exogenous FOXM1 was sufficient to delay senescence. Thus, although the loss of Ash2l in MEFs has broad and complex consequences, a distinct set of downregulated genes promotes senescence.
Differences in Ion-RNA binding modes due to charge density variations explain the stability of RNA in monovalent salts
Authors: Henning-Knechtel Anja , Thirumalai Devarajan , Kirmizialtin Serdal 
Published: February 2022

AbstractThe stability of RNA increases as the charge density of the alkali metal cations increases. The molecular mechanism for the stability does not exist. To fill this gap, we performed all-atom molecular dynamics (MD) pulling simulations to dissect the microscopic origin of this phenomenon. We first established that the free energy landscape obtained in the simulations is in excellent agreement with the single-molecule optical tweezer experiments. The origin of the stronger stability in Na+ compared to K+ is found to be due to the differences in the charge-density related binding modes. The smaller hydrated Na+ ion preferentially binds to the highly charged phosphates. In contrast, the larger K+ ions interact with the major grooves. As a result, the electrostatic repulsion between the phosphate groups is reduced more effectively by Na+ ions. Because the proposed mechanism is generic, we predict that the same conclusions are valid for divalent alkaline earth metal cations.
Enhanced sodium channel inactivation by temperature and FHF2 deficiency blocks heat nociception
Authors: Marra Christopher , Hartke Timothy V. , Ringkamp Matthias , Goldfarb Mitchell 
Published: February 2022

AbstractTransient voltage-gated sodium currents are essential for the initiation and conduction of action potentials in neurons and cardiomyocytes. The amplitude and duration of sodium currents are tuned by intracellular fibroblast growth factor homologous factors (FHFs/iFGFs) that associate with the cytoplasmic tails of voltage-gated sodium channels (Navs), and genetic ablation ofFhfgenes disturbs neurological and cardiac functions. Among reported phenotypes,Fhf2nullmice undergo lethal hyperthermia-induced cardiac conduction block attributable to the combined effects of FHF2 deficiency and elevated temperature on the cardiac sodium channel (Nav1.5) inactivation rate.Fhf2nullmice also display a lack of heat nociception, while retaining other somatosensory capabilities. Here, we use electrophysiological and computational methods to show that the heat nociception deficit can be explained by the combined effects of elevated temperature and FHF2 deficiency on the fast inactivation gating of Nav1.7 and tetrodotoxin-resistant sodium channels expressed in dorsal root ganglion C fibers. Hence, neurological and cardiac heat-associated deficits inFhf2nullmice derive from shared impacts of FHF deficiency and temperature towards Navinactivation gating kinetics in distinct tissues.
Metagenomic and Metabolomic Analyses Reveal Synergistic Effects of Fecal Microbiota Transplantation and Anti-PD-1 Therapy on Treating Colorectal Cancer
Authors: Huang Jiayuan , Zheng Xing , Kang Wanying , Hao Huaijie , Mao Yudan , Zhang Hua , Chen Yuan , Tan Yan , He Yulong , Zhao Wenjing , Yin Yiming 
Published: February 2022

AbstractAnti-PD-1 immunotherapy has saved numerous lives of cancer patients; however, it only exerts efficacy in 10-15% of patients with colorectal cancer. Fecal microbiota transplantation (FMT) is a potential approach to improving the efficacy of anti-PD-1 therapy, whereas the detailed mechanisms and the applicability of this combination therapy remain unclear. In this study, we evaluated the synergistic effect of FMT with anti-PD-1 in curing colorectal tumor-bearing mice using a multi-omics approach. Mice treated with the combination therapy showed superior survival rate and tumor control, compared to the mice received anti-PD-1 therapy or FMT alone. Metagenomic analysis showed that composition of gut microbiota in tumor-bearing mice treated with anti-PD-1 therapy was remarkably altered through receiving FMT. Particularly, Bacteroides genus, including FMT-increased B. thetaiotaomicron, B. fragilis, and FMT-decreased B. ovatus might contribute to the enhanced efficacy of anti-PD-1 therapy. Furthermore, metabolomic analysis upon mouse plasma revealed several potential metabolites that upregulated after FMT, including punicic acid and aspirin, might promote the response to anti-PD-1 therapy via their immunomodulatory functions. This work broadens our understanding of the mechanism by which FMT improves the efficacy of anti-PD-1 therapy, which may contribute to the development of novel microbiota-based anti-cancer therapies.
The effects of word-of-mouth and online review marketing strategies on students’ satisfaction with their housing selection during COVID-19 season
Authors: Avogo Florence Abugtane , Appau Williams Miller , Attakora-Amaniampong Elvis 
Published: February 2022

Purpose
This study aims to examine the effect of using word-of-mouth and online housing website strategies for student housing selection and building services satisfaction during COVID-19.

Design/methodology/approach
The study adopted mixed-methods research approach. An online survey of 975 public and private university students experience on room selection prior to school re-opening in Ghana was used. An exploratory factor analysis (EFA) and multiple regression model (MRM) were used to estimate the satisfaction of using online websites and word-of-mouth strategies (renting housing based on personal recommendation) on student room pricing and building services availability. Telephone interviews were further used to support the results of EFA and MRM.

Findings
The study reveals that most students were satisfied with the word-of-mouth strategy than online review marketing strategy for room selection during the COVID-19 pandemic. Secondly, online student housing review marketing strategy provided higher rent which did not reflect the services available. Furthermore, students were more interested in the nature of rooms, lavatories and kitchen in their choice of room than availability of internet, study area, television (TV) room and gym center.

Practical implications
The study suggest that student housing managers require to market their facilities as-it-is than to use one room as an advertising justification for all rooms which does not usually provide a true reflection of the existing situation of room. Again, housing which rely on online marketing strategies need to provide compensation for students who feel they have been misled by their advertisement.

Originality/value
The provision of compensation to students and availability of COVID-19 protection measures determine student room selection. Asides, the introduction of online marketing strategies in student housing in sub-Saharan student housing market is new, and, consequently, this study on it is a novelty.
Exploring the emancipatory role of entrepreneurship in a developing context
Authors: Zayadin Rana , Zucchella Antonella , Anand Amitabh 
Published: February 2022

PurposeThe aim of the study is to examine the reciprocal relation between context and emancipatory acts. Context is important in shaping the entrepreneurial action, particularly in a developing region, as it expounds its emancipatory role. At the same time emancipatory acts can affect context as well.Design/methodology/approachThe study employs an inductive research design, applying an open-ended exploratory research and conversation analysis, to elicit the stories of 25 entrepreneurs who are challenging their status quo.FindingsActs of emancipation were observed through a dynamic process centred around entrepreneurs' abilities to respond to policy debates. These debates introduced an individual level action towards social and institutional change. The findings present a model of entrepreneurial acts as an enabler in a socially constrained and challenging context.Originality/valueThrough contextual embeddedness, this study captured the entrepreneur's abilities to re-perform and negotiation with their context towards actions of emancipation. The study aims to capture individuals' narratives to enhance our understanding of the contextual and embedded factors that shape the entrepreneurial process towards emancipation. The study presents a model that theorises these narratives and actions.
Blockchain, logistics and omnichannel for last mile and performance
Authors: Naclerio Alessandro Gaetano , De Giovanni Pietro 
Published: February 2022

PurposeThis research investigates the effects that blockchain exerts on omnichannel solutions and logistics strategies with the aim of solving the last mile issues and improving performance.Design/methodology/approachResearch hypotheses are developed according to the literature review and the related gaps. Then, the hypotheses are tested using structural equation modelling and adopting a partial least squares – path modelling technique on a dataset composed of 157 firms.FindingsBlockchain technology alone is not an effective driver in solving last mile issues and improving performance. Rather, it exerts a positive contribution to both omnichannel and logistics. However, omnichannel is not effective in managing last mile problems and increasing performance without the support of other practices. Firms need to implement a strong logistics system to manage the last mile and get high performance, which can be then reinforced through blockchain and omnichannel solutions.Originality/valueThis research investigates the novel wave of research on blockchain and its impact on logistics management and omnichannel. It combines these ingredients to address the issues of last mile and improve the economic performance. The research provides an empirical verification of a new research stream that currently lacks empirical support.