bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cloud gazing: demonstrating paths for unlocking the value of cloud genomics through cross-cohort analysis
Authors: Deflaux Nicole , Selvaraj Margaret Sunitha , Condon Henry Robert , Mayo Kelsey , Haidermota Sara , Basford Melissa A. , Lunt Chris , Philippakis Anthony A. , Roden Dan M. , Denny Josh C. , Musick Anjene , Collins Rory , Allen Naomi , Effingham Mark , Glazer David , Natarajan Pradeep , Bick Alexander G. 
Published: December 2022

AbstractThe rapid growth of genomic data has led to a new research paradigm where data are stored centrally in Trusted Research Environments (TREs) such as theAll of UsResearcher Workbench (AoU RW) and the UK Biobank Research Analysis Platform (RAP). To characterize the advantages and drawbacks of different TRE attributes in facilitating cross-cohort analysis, we conducted a Genome-Wide Association Study (GWAS) of standard lipid measures on the UKB RAP and AoU RW using two approaches: meta-analysis and pooled analysis. We curated lipid measurements for 37,754All of Usparticipants with whole genome sequence (WGS) data and 190,982 UK Biobank participants with whole exome sequence (WES) data. For the meta-analysis, we performed a GWAS of each cohort in their respective platform and meta-analyzed the results. We separately performed a pooled GWAS on both datasets combined. We identified 490 and 464 significant variants in meta-analysis and pooled analysis, respectively. Comparison of full summary data from both meta-analysis and pooled analysis with an external study showed strong correlation of known loci with lipid levels (R2∼83-97%). Importantly, 90 variants met the significance threshold only in the meta-analysis and 64 variants were significant only in pooled analysis. These method-specific differences may be explained by differences in cohort size, ancestry, and phenotype distributions inAll of Usand UK Biobank. We noted approximately 20% of variants significant in only the pooled analysis or significant in only the meta-analysis were most prevalent in non-European, non-Asian ancestry individuals. Pooled analyses included more variants than meta-analyses. Pooled analysis required about half as many computational steps as meta-analysis. These findings have important implications for both platform implementations and researchers undertaking large-scale cross-cohort analyses, as technical and policy choices lead to cross-cohort analyses generating similar, but not identical results, particularly for non-European ancestral populations.
AAV-mediated Expression of a Novel Conformational Anti-Aggregated α-Synuclein Antibody Prolongs Survival in a Genetic Model of α-Synucleinopathies
Authors: Düchs Matthias , Blazevic Dragica , Rechtsteiner Philipp , Kenny Cynthia , Lamla Thorsten , Low Sarah , Savistchenko Jimmy , Neumann Manuela , Melki Ronald , Schönberger Tanja , Stierstorfer Birgit , Wyatt David , Igney Frederik , Ciossek Thomas 
Published: December 2022

AbstractPrion-like transmission of pathology in α-synucleinopathies like Parkinson’s disease or multiple system atrophy is increasingly recognized as one potential mechanism to address disease progression. Active and passive immunotherapies targeting insoluble, aggregated α-synuclein are already being actively explored in the clinic with mixed outcomes so far. Here, we report the identification of 306C7B3, a highly selective, aggregate-specific α-synuclein antibody with picomolar affinity devoid of binding to the monomeric, physiologic protein. 306C7B3 binding is Ser129-phosphorylation independent and shows high affinity to several different aggregated α-synuclein polymorphs, increasing the likelihood that it can also bind to the pathological seeds assumed to drive disease progression in patients. In support of this, highly selective binding to pathological aggregates in postmortem brains of MSA patients was demonstrated, with no staining in samples from other human neurodegenerative diseases.To achieve CNS exposure of 306C7B3, an Adeno-Associated Virus (AAV) based approach driving expression of the secreted antibody within the brain of (Thy-1)-[A30P]-hα-Synuclein mice was used. Widespread central transduction after intrastriatal inoculation was ensured by using the AAV2HBKO serotype, with transduction being spread to areas far away from the inoculation site. Treatment of (Thy-1)-[A30P]-hα-Synuclein mice at the age of 12 months demonstrated significantly increased survival, with 306C7B3 concentration reaching 3.9 nM in the cerebrospinal fluid.These results suggest that AAV-mediated expression of 306C7B3 has great potential as a disease-modifying therapy for α-synucleinopathies as it ensures CNS exposure of the antibody, thereby mitigating the selective permeability of the blood-brain barrier.
Tsetse flies choose birthing sites guided by environmental but not pheromonal cues
Authors: Adden Andrea K. , Haines Lee R. , Acosta-Serrano Álvaro , Prieto-Godino Lucia L. 
Published: December 2022

AbstractTsetse flies significantly impact public health and economic development in sub-Saharan African countries by transmitting the fatal disease African trypanosomiasis. Unusually, instead of laying eggs, tsetse birth a single larva that immediately burrows into the soil to pupate. Where the female chooses to larviposit is therefore crucial for offspring survival. Previous studies showed that a putative larval pheromone,n-pentadecane, attracts gravid femaleGlossina morsitans morsitansto appropriate larviposition sites. However, this attraction could not be reproduced in field experiments. Here, we resolve this disparity by designing naturalistic laboratory experiments that closely mimic the characteristics found in the wild. We show that gravid tsetse were neither attracted to the putative pheromone nor, interestingly, to pupae placed in the soil. In contrast, females appear to choose larviposition sites based on environmental cues. We conclude that it is the substrate, rather than larval pheromones, which drives larviposition site selection under naturalistic conditions.
Changes in gut microbiome composition drive fentanyl intake and striatal proteomic changes
Authors: Hofford Rebecca S. , Meckel Katherine R. , Wang Weiwei , Kim Michelle , Godino Arthur , Lam TuKiet T. , Kiraly Drew D. 
Published: December 2022

AbstractOpioid use disorder (OUD) is a public health crisis currently being exacerbated by increased rates of use and overdose of synthetic opioids, primarily fentanyl. Therefore, the identification of novel biomarkers and treatment strategies to reduce problematic fentanyl use and relapse to fentanyl taking is critical. In recent years, there has been a growing body of work demonstrating that the gut microbiome can serve as a potent modulator of the behavioral and transcriptional responses to both stimulants and opioids. Here, we advance this work to define how manipulations of the microbiome drive fentanyl intake and fentanyl seeking in a translationally relevant drug self-administration model. Additionally, we utilize global proteomic analysis of the nucleus accumbens following microbiome manipulation and fentanyl administration to define how microbiome status alters the functional proteomic landscape in this key limbic substructure. These findings establish clear relevance for gut-brain signaling in OUD, and lay foundations for further translational work in this space.
The telomere-to-telomere, gapless, phased diploid genome and methylome of the green algaScenedesmus obliquusUTEX 3031 reveals significant heterozygosity and functional separation of the haplotypes
Authors: Biondi Thomas C. , Kruse Colin P.S. , Koehler Samuel I. , Kwon Taehyung , Eng Wyatt , Kunde Yuliya , Gleasner Cheryl D. , Mak Kayley T. You , Polle Juergen , Hovde Blake T. , Hanschen Erik R. , Starkenburg Shawn R. 
Published: December 2022

AbstractRecent advances in sequencing technologies have improved contiguity of de novo genome assemblies. Nevertheless, the genomes of all eukaryotic organisms which are polyploid remain unfinished, limiting understanding of genetic and structural variation in diploid or polyploid organisms. Herein, we report the methodology and analysis of a 100% complete, gapless, phased, telomere-to-telomere diploid genome assembly of the eukaryote,Scenedesmus obliquusUTEX 3031 (DOE0152Z). Analysis of the fully assembled and resolved haplotypes revealed significant genomic rearrangements. Inter-haplotype heterogeneity was significant on most chromosomes yet one chromosome pair (Chromosome 15) was found to contain nearly no heterozygosity. Analysis of the 5mC methylation patterns revealed divergence in active gene content across haplotypes. Assembly of fully resolved chromosome pairs enabled complete resolution of genomic rearrangements and heterogeneity of haplotypes, the genomic basis of trait gain/loss, and evolutionary divergence across chromosome pairs. Further, when combined with 5mC methylation patterns, the assembly provides critical annotation information for genetic engineering approaches to achieve full knock-outs in allelic pairs.
Differential dysregulation of β-TrCP1 and -2 by HIV-1 Vpu leads to inhibition of canonical and non-canonical NF-κB pathways in infected cells
Authors: Pickering Suzanne , Sumner Jonathan , Kerridge Claire , Neil Stuart 
Published: December 2022

AbstractThe HIV-1 Vpu protein is expressed late in the virus lifecycle to promote infectious virus production and avoid innate and adaptive immunity. This includes the inhibition of the NF-κB pathway which, when activated, leads to the induction of inflammatory responses and the promotion of antiviral immunity. Here we demonstrate that Vpu can inhibit both canonical and non-canonical NF-κB pathways, through the direct inhibition of the F-box protein β-TrCP, the substrate recognition portion of the Skp1-Cul1-F-box (SCF)β-TrCPubiquitin ligase complex. There are two paralogues of β-TrCP (β-TrCP1/BTRC and β-TrCP2/FBXW11), encoded on different chromosomes, which appear to be functionally redundant. Vpu, however, is one of the few β-TrCP substrates to differentiate between the two paralogues. We have found that patient-derived alleles of Vpu, unlike those from lab-adapted viruses, trigger the degradation of β-TrCP1 while co-opting its paralogue β-TrCP2 for the degradation of cellular targets of Vpu, such as CD4. The potency of this dual inhibition correlates with stabilisation of the classical IκBα and the phosphorylated precursors of the mature DNA-binding subunits of canonical and non-canonical NF-κB pathways, p105/NFκB1 and p100/NFκB2, in HIV-1 infected CD4+ T cells. Both precursors act as alternative IκBs in their own right, thus reinforcing NF-κB inhibition at steady state and upon activation with either selective canonical or non-canonical NF-κB stimuli. These data reveal the complex regulation of NF-κB late in the viral replication cycle, with consequences for both the pathogenesis of HIV/AIDS and the use of NF-κB-modulating drugs in HIV cure strategies.
Are remote mental healthcare interventions cost-effective? A systematic review of economic evaluations of remote mental healthcare
Authors: Clark Amy , Appleton Rebecca , Kalocsanyiova Erika , Gkaintatzi Evdoxia , McCrone Paul 
Published: December 2022

AbstractBackgroundRemote interventions known as telemental health care increased in use due to the COVID-19 pandemic when social distancing requirements were in place. Whilst there is some evidence regarding the cost-effectiveness of telemental health prior to the pandemic, there is a need for further evaluation due to the increase in remote care.AimsTo systematically review the literature to explore whether remote mental health care interventions are cost-effective in terms of incremental cost per quality adjusted life year and in relation to condition specific outcomes compared to usual care or an alternative intervention.MethodA multilayer search strategy was conducted to build on the searches of a previous systematic review, as well as including grey literature and economic models. Six databases (PubMed, EMBASE, Cochrane Central, PsychINFO, CINAHL, and EconLit) were searched for literature relating to the cost effectiveness of telemental health. Quality appraisal was conducted for all included studies, and findings were synthesised using narrative synthesis.Results7386 studies were identified of which 59 met our inclusion criteria and were included in the synthesis of findings. 45 studies were rated as very good or excellent quality. Of the 59 included studies, 40 indicated that the telemental health intervention was cost-effective, whilst a further 16 suggested the intervention had potential to be cost-effective, but there was some uncertainty in the findings. Three studies reported that the intervention was not cost-effective.ConclusionsThis evidence will be used to inform practice in the UK as we respond to and recover from the COVID-19 pandemic.
Keratinocyte desmosomal cadherin Desmoglein 1 as a mediator and target of paracrine signaling in the melanoma niche
Authors: Burks Hope E. , Pokorny Jenny L. , Koetsier Jennifer L. , Roth-Carter Quinn R. , Arnette Christopher R. , Gerami Pedram , Seykora John T. , Johnson Jodi L. , Green Kathleen J. 
Published: December 2022

AbstractMelanoma is an aggressive cancer typically arising from transformation of melanocytes residing in the basal layer of the epidermis, where they are in direct contact with surrounding keratinocytes. The role of keratinocytes in shaping the melanoma tumor microenvironment remains understudied. We previously showed that temporary loss of the keratinocyte-specific cadherin, Desmoglein 1 (Dsg1) controls paracrine signaling between normal melanocytes and keratinocytes to stimulate the protective tanning response. Here, we provide evidence that melanoma cells hijack this intercellular communication by secreting factors that keep Dsg1 expression low in surrounding keratinocytes, which in turn generate their own paracrine signals that enhance melanoma spread through CXCL1/CXCR2 signaling. Evidence suggests a model whereby paracrine signaling from melanoma cells increases levels of the transcriptional repressorSnai2(Slug), and consequently decreases the Dsg1 transcriptional activatorGrhl1(Grainyhead like 1), a known promoter of epidermal differentiation and barrier function. Together, these data support the idea that paracrine crosstalk between melanoma cells and keratinocytes resulting in chronic keratinocyte Dsg1 reduction contributes to melanoma cell movement associated with tumor progression.
JMJD3 Deficiency in Midbrain Dopamine Neurons Disturbs Dopamine Synthesis and Aggravates Chronic Inflammatory Pain
Authors: He Xi-Biao , Guo Fang , Zhang Wei , Le Weidong , Zheng Yong , Ma Yongjun , Lee Sang-Hun , Wang Hui-Jing , Wu Yi , Zhou Qinming 
Published: December 2022

AbstractChronic pain is associated with midbrain dopamine levels. The molecules and mechanisms modulating this association remain to be elucidated. By using conditional knockout mice, we report that JMJD3 deficiency in midbrain dopamine neurons causes prolonged mechanical hyperalgesia regardless of sex and age. Both genetic defect and pharmaceutical inhibition of JMJD3 decrease dopamine level in midbrain and striatum, resulting from reduced tyrosine hydroxylase expression in midbrain dopamine neurons. Furthermore, epigenetic experiments reveal that JMJD3 is indispensable for the transcription of tyrosine hydroxylase through direct and indirect manners. These findings suggest JMJD3 and midbrain dopamine neurons as novel players and pharmaceutical targets for chronic pain regulation.
Porcine and human aortic valve endothelial and interstitial cell isolation and characterization
Authors: Nehl D. , Goody PR. , Maus K. , Pfeifer A. , Aikawa E. , Bakthiary F. , Zimmer S. , Nickenig G. , Jansen F. , Hosen MR. 
Published: December 2022

AbstractBackgroundCalcific aortic valve stenosis is defined by pathological changes in the aortic valve and their predominant cell types: valvular interstitial (VICs) and endothelial cells (VECs). Understanding the cellular and molecular mechanisms of this disease is a prerequisite to identify potential pharmacological treatment strategies. In this study, we present a unique aortic valve cell isolation technique to acquire specific human and porcine cell populations and compared VICs and VECs of these species with each other for the first time.Methods and ResultsAortic valve cells were isolated from human explants from patients undergoing surgical aortic valve replacement or porcine valvular tissue. Pure VEC and VIC populations could be verified by gene expression analysis and immunofluorescence staining showing a highly significant upregulation of endothelial markers in VECs and mesenchymal markers in VICs, respectively. Further analysis and comparison of cells inin vitroexperiments revealed that endothelial-to-mesenchymal transition could be induced in hVECs, leading to significant increase of mesenchymal markers.In vitrocalcification experiments of VICs induced by osteogenic medium or pro-calcifying medium demonstrated a pronounced calcification marker expression and visible calcific deposition in Alizarin red staining in both species.ConclusionThis study aims to initiate a first step towards standardization of a reproducible isolation technique for pure human and porcine VEC and VIC populations. Comparison of human and porcine aortic valve cells demonstrated that porcine cells might serve as an alternative cellular model system, in settings, where human tissues are difficult to obtain.Statements and DeclarationsThe authors declare no relevant financial or non-financial interests to disclose.
High-efficiency transfection ofAcanthamoeba castellaniiusing a cationic polymer
Authors: Moreno Anaísa B. , Ek Viktor , Eriksson Jens , Sellin Mikael E. , Guy Lionel 
Published: December 2022

AbstractThe free-living amoebaAcanthamoeba castellaniiis an ecologically, clinically, and evolutionarily important microorganism.A. castellaniiamoebae are directly pathogenic to humans and serve as reservoirs for bacterial pathogens (e.g.,Legionella pneumophila) but also regulate the proliferation of other microorganisms in the soil. Despite their importance, no reliable genetic system has been developed, hampering the use ofA. castellaniiand related species as model organisms. TransfectingA. castellaniiwith plasmids is possible with commercial kits, but it is expensive, inefficient, and vulnerable to product discontinuation. In this contribution, we present a method for efficient transfection ofA. castellaniiwith readily available and inexpensive polyethylenimines. We systematically explore the method’s parameters, obtaining up to 100-fold higher efficiency than currently used protocols. The method presented here provides a robust step towards a complete genetic toolbox forA. castellanii, hence expanding its use as a model organism.
Reconstruction of a potential coefficient in the Rayleigh–Love equation with non-classical boundary condition
Authors: Huntul M.J. , Tamsir Mohammad 
Published: December 2022

PurposeThe purpose of this paper is to reconstruct the potential numerically in the fourth-order Rayleigh–Love equation with boundary and nonclassical boundary conditions, from additional measurement.Design/methodology/approachAlthough, the aforesaid inverse identification problem is ill-posed but has a unique solution. The authors use the cubic B-spline (CBS) collocation and Tikhonov regularization techniques to discretize the direct problem and to obtain stable as well as accurate solutions, respectively. The stability, for the discretized system of the direct problem, is also carried out by means of the von Neumann method.FindingsThe acquired results demonstrate that accurate as well as stable solutions for the a(t) are accessed for λ∈ {10–8, 10–7, 10–6, 10–5}, when p ∈ {0.01%, 0.1%} for both linear and nonlinear potential coefficient a(t). The stability analysis shows that the discretized system of the direct problem is unconditionally stable.Research limitations/implicationsSince the noisy data are introduced, the investigation and analysis model real circumstances where the practical quantities are naturally infested with noise.Practical implicationsThe acquired results demonstrate that accurate as well as stable solutions for the a(t) are accessed for λ∈ {10–8, 10–7, 10–6, 10–5}, when p ∈ {0.01%, 0.1%} for both linear and nonlinear potential coefficient a(t). The stability analysis shows that the discretized system of the direct problem is unconditionally stable.Originality/valueThe potential term in the fourth-order Rayleigh–Love equation from additional measurement is reconstructed numerically, for the first time. The technique establishes that accurate, as well as stable solutions are obtained.
Factors affecting the construction quality in Bangladesh
Authors: Hoque Md. Ikramul , Hasan Muzamir 
Published: December 2022

PurposeQuality is a sensitive and high-priority issue in the global construction including in Bangladesh. This research is intended to provide necessary information to stakeholders and authorities for better management of the construction quality in Bangladesh. Therefore, this study seeks to find and prioritize the factors affecting the construction quality in Bangladesh.Design/methodology/approachIn total 65 factors were extracted and categorized from the literature and expert panel discussion. Subsequently, these factors were designed in a questionnaire under 13 major groups for a survey where 176 construction professionals participated and returned their completed survey form. Collected data were tested by the Cronbach Alpha to check the reliability before proceeding to the Relative Importance Index (RII) analysis for determining the relative ranks of identified factors.FindingsStatistical analysis of survey data represents that the most significant factors are: lack of management commitment, lack of technical skill and experience of the consultant, delays in progress investigation, political interference and contractor's desire for unrealistic profit. The most crucial major groups of factors influencing the construction quality are management, material, consultant, cost and time and contract-related major groups.Originality/valueIt will contribute to the body of knowledge, as it points out the impact of factors affecting quality in Bangladeshi construction. Authorities and stakeholders can be helped by the overview of the high and low ranks factors, understanding the diverse characteristics of factors and making more aware the industry about the quality issues which need to be a top concern to solve. Other developing countries that share the same socio-economic context as Bangladesh can be benefit from the results of this study to control quality issues in construction.