bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards Genotype-Specific Care for Chronic Hepatitis B: The First 6 Years Follow Up From the CHARM Cohort Study
Authors: Davies Jane , Smith Emma L , Littlejohn Margaret , Edwards Rosalind , Sozzi Vitina , Jackson Kathy , Mcguire Katie , Binks Paula , Cowie Benjamin C , Locarnini Stephen , Davis Joshua S , Tong Steven Y C 
Published: November 2019

Abstract

Objective
There is increasing evidence to suggest that, among those with chronic hepatitis B virus infection, the natural history and rate of progression to cirrhosis and hepatocellular carcinoma is influenced by hepatitis B virus genotype. The unique hepatitis B virus genotype C4 circulates among Indigenous Australians. The aim of this work is to describe the process of establishing this cohort and review the first 6 years of available data in an effort to understand the real-world clinical care and natural history of this subgenotype.

Method
We followed a longitudinal cohort of Indigenous Australians from the Northern Territory of Australia with established subgenotype C4 infections. We assigned phases of disease according to Gastroenterological Society of Australia and Asian Pacific Association for the Study of the Liver criteria using clinical and laboratory information that had been collected for clinical management.

Results
Of 193 patients followed over a median of 38 months, 58 (30%) individuals transitioned from 1 disease phase to another, 10 (5%) cleared hepatitis B e antigen, and 6 cleared hepatitis B surface antigen (3%). In this relatively young cohort (median age 40.3 years), 26 (13%) had cirrhosis by the end of the follow up period, with the majority of these being in the immune control phase of disease.

Conclusions
In this cohort of hepatitis B subgenotype C4 patients, we report an aggressive and dynamic clinical phenotype. High rates of cirrhosis at a young age appear to occur in the early phases of disease.
Patient experiences with outpatient parenteral antibiotic therapy: results of a patient survey comparing skilled nursing facilities and home infusion
Authors: Mansour Omar , Arbaje Alicia I , Townsend Jennifer L 
Published: November 2019

Abstract

Background
Outpatient parenteral antibiotic therapy (OPAT) is prescribed for patients with serious infections requiring prolonged therapy. Most patients requiring OPAT are discharged either home with home healthcare companies (HHCs) or to skilled nursing facilities (SNFs). Few data are available regarding patient experiences in these different sites of care.

Objectives
(1) Compare overall patient satisfaction with OPAT care across the SNF and HHC settings; (2) Identify barriers to patient satisfaction in OPAT; and (3) Develop a model for OPAT patient satisfaction that can help programs improve the patient experience across both sites of care.

Methods
We developed and administered a patient experience survey to 100 patients returning to a single clinic for follow up. The survey consisted of 15 items (Likert scale, multiple choice, and free text responses). Patient characteristics and responses to the survey for patients who received care at home and at SNFs were analyzed and compared.

Results
Of the 100 patients surveyed, 98 completed the survey. Overall, HHC patients were more satisfied with their care than patients in SNFs, with a greater proportion stating they would recommend the site to others (71.7% for HHC and 32.7% for SNFs, p<0.01). Patients in SNFs had a larger number of complaints about lapses in medical care, infection prevention, and the physical environment than HHC patients.

Conclusion
OPAT patient satisfaction is higher for home infusion than SNFs. In order to improve the patient experience, OPAT programs need to engage stakeholders in HHCs and SNFs to improve communication and care delivery.
Effects of sleep on a high-heat capacity mattress on sleep stages, EEG power spectra, cardiac interbeat intervals and body temperatures in healthy middle-aged men‡
Authors: Herberger Sebastian , Kräuchi Kurt , Glos Martin , Lederer Katharina , Assmus Lisa , Hein Julia , Penzel Thomas , Fietze Ingo 
Published: November 2019

Abstract

Study Objectives
This study deals with the question whether a slow (non-disturbing) reduction of core body temperature (CBT) during sleep increases sleep stage N3 and EEG slow wave energy (SWE) and leads to a slowing of heart rate in humans.

Participants
Thirty-two healthy male subjects with a mean ± SD age 46 ± 4 years and body mass index 25.2 ± 1.8 kg/m2.

Methods
A high-heat capacity mattress (HM) was used to lower body temperatures in sleep and was compared to a conventional low-heat capacity mattress (LM) in a double-blinded fashion. Polysomnography was performed accompanied by measurements of skin-, core body- and mattress surface-temperatures, and heart rate. EEG power spectral analyses were carried out using Fast Fourier Transform. Interbeat intervals were derived from the electrocardiogram.

Results
The HM led to a larger decline in CBT, mediated through higher heat conduction from the core via the proximal back skin onto the mattress together with reduced heart rate. These effects occurred together with a significant increase in sleep stage N3 and standardized slow wave energy (sSWE, 0.791–4.297 Hz) accumulated in NREM sleep. In the 2nd half of the night sSWE increase was significantly correlated with body temperature changes, for example with CBT decline in the same phase.

Conclusions
A HM subtly decreases CBT, leading to an increased amount of sleep stage N3 and of sSWE, as well as a slowing of heart rate.
Single cell transcriptomic analysis revealed long-lasting adverse effects of prenatal tamoxifen administration on neurogenesis in prenatal and adult brains
Authors: Lee Chia-Ming , Zhou Liqiang , Liu Jiping , Shi Jiayu , Geng Yanan , Wang Jiaruo , Su Xinjie , Barad Nicholas , Wang Junbang , Sun Yi E. , Lin Quan 
Published: November 2019

SummaryCreER/LoxP system has enabled precise gene manipulation in distinct cell subpopulations at any specific time point upon tamoxifen (TAM) administration. This system is widely accepted to track neural lineages and study gene functions. We have observed prenatal TAM treatment caused high rate of delayed delivery and mortality of pups. These substances could promote undesired results, leading to data misinterpretation. Here, we report that TAM administration during early stages of cortical neurogenesis promoted precocious neural differentiation, while inhibited neural progenitor cell (NPC) proliferation. The TAM-induced inhibition of NPC proliferation led to deficits in cortical neurogenesis, dendritic morphogenesis, and cortical patterning in neonatal and postnatal offspring. Mechanistically, single cell RNA sequencing (scRNA-seq) analysis combined with in vivo and in vitro assays showed TAM could exert these drastic effects mainly through dysregulating the expression of Dmrta2 and Wnt8b. In adult mice, administration of TAM significantly attenuated NPC proliferation in both the subventricular zone and the dentate gyrus. This study revealed the cellular and molecular mechanisms for the adverse effects of prenatal tamoxifen administration on corticogenesis, suggesting that tamoxifen-induced CreER/LoxP system may not be suitable for neural lineage tracing and genetic manipulation studies in both embryonic and adult brains.SignificantFor the first time, our study revealed the molecular mechanisms underlying tamoxifen activities on cortical development. This study also clearly showed that care must be taken when using tamoxifen-induced CreER/LoxP system for neural lineage tracing and genetic manipulation studies.
Global kinome silencing combined with 3D invasion screening of the tumor microenvironment identifies fibroblast-expressed PIK3Cδ involvement in triple-negative breast cancer progression
Authors: Gagliano Teresa , Shah Kalpit , Gargani Sofia , Lao Liyan , Alsaleem Mansour , Chen Jianing , Ntafis Vasileios , Huang Penghan , Ditsiou Angeliki , Vella Viviana , Yadav Kritika , Bienkowska Kamila , Bresciani Giulia , Kang Kai , Li Leping , Carter Philip , Benstead-Hum Graeme , O’Hanlon Timothy , Dean Michael , Pearl Frances M.G. , Lee Soo-Chin , Rakha Emad A , Green Andrew R , Kontoyiannis Dimitris L. , Song Erwei , Stebbing Justin , Giamas Georgios 
Published: November 2019

AbstractAs there is growing evidence for the tumor microenvironment’s (TME) role in tumorigenesis, we sought to investigate the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of progression. Although PIK3Cδ has been mainly described in leucocytes, we detected high expression in primary fibroblasts derived from TNBC patients, while PIK3Cδ was undetectable in cancer epithelial cell lines. Genetic and pharmacologic gain- and loss-of functions experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. By employing an integrated secretomics and transcriptomics analysis, we revealed a paracrine mechanism via which f-PIK3Cδ confers its pro-tumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, which subsequently led to upregulation of NR4A1 in TNBC cells where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, in addition to a decrease on tumor metastasis emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA datasets identified f-PIK3Cδ (protein and mRNA levels) as an independent prognostic factor for overall and disease free survival, highlighting it as a therapeutic target for TNBC.
MutateX: an automated pipeline forin-silicosaturation mutagenesis of protein structures and structural ensembles
Authors: Tiberti Matteo , Terkelsen Thilde , Cremers Tycho Canter , Di Marco Miriam , da Piedade Isabelle , Maiani Emiliano , Papaleo Elena 
Published: November 2019

AbstractMutations resulting in amino acid substitution influence the stability of proteins along with their binding to other biomolecules. A molecular understanding of the effects induced by protein mutations are both of biotechnological and medical relevance. The availability of empirical free energy functions that quickly estimate the free energy change upon mutation (ΔΔG) can be exploited for systematic screenings of proteins and protein complexes. Indeed,in silicosaturation mutagenesis can guide the design of new experiments or rationalize the consequences of already-known mutations at the atomic level. Often software such as FoldX, while fast and reliable, lack the necessary automation features to make them useful in high-throughput scenarios. Here we introduce MutateX, a software which aims to automate the prediction of ΔΔGs associated with the systematic mutation of each available residue within a protein or protein complex to all other possible residue types, by employing the FoldX energy function. MutateX also supports ΔΔG calculations over protein ensembles and the estimation of the changes in free energy upon post-translational modifications. At the heart of MutateX lies an automated pipeline engine that handles input preparation, performs parallel runs with FoldX and outputs publication-ready figures. We here illustrate the MutateX protocol applied to the study of the mutational landscape of cancer-related proteins, industrial enzymes and protein-protein interfaces. The results of the high-throughput scan provided by our tools could help in different applications, such as the analysis of disease-associated mutations, or in the design of protein variants for experimental studies or industrial applications. MutateX is a collection of Python tools that relies on Open Source libraries and requires the FoldX software to be installed beforehand. It is available free of charge and under the GNU General Public License fromhttps://github.com/ELELAB/mutatex.
A novel microRNA-based strategy to expand the differentiation potency of stem cells
Authors: Salazar-Roa María , Trakala Marianna , Álvarez-Fernández Mónica , Valdés-Mora Fátima , Zhong Cuiqing , Muñoz Jaime , Yu Yang , Peters Timothy J. , Graña Osvaldo , Serrano Rosa , Zapatero-Solana Elisabet , Abad María , Bueno María José , de Cedrón Marta Gómez , Fernández-Piqueras José , Serrano Manuel , Blasco María A. , Wang Da-Zhi , Clark Susan J. , Izpisua-Belmonte Juan Carlos , Ortega Sagrario , Malumbres Marcos 
Published: November 2019

SUMMARYFull differentiation potential along with self-renewal capacity is a major property of pluripotent stem cells (PSCs). However, the differentiation capacity frequently decreases during expansion of PSCs in vitro. We show here that transient exposure to a single microRNA, expressed at early stages during normal development, improves the differentiation capacity of already-established murine and human PSCs. Short exposure to miR-203 in PSCs (miPSCs) results in expanded differentiation potency as well as improved efficiency in stringent assays such as tetraploid complementation and human-mouse interspecies chimerism. Mechanistically, these effects are mediated by direct repression ofde novoDNA methyltransferases Dnmt3a and Dnmt3b, leading to transient and reversible erasing of DNA methylation. As a proof of concept, miR-203 improves differentiation and maturation of PSCs into cardiomyocytes in vitro as well as cardiac regeneration in vivo, after cardiac injury. These data support the use of transient exposure to miR-203 as a general and single method to reset the epigenetic memory in PSCs, and improve their use in regenerative medicine.
Leveraging correlations between polygenic risk score predictors to detect heterogeneity in GWAS cohorts
Authors: Yuan Jie , Xing Henry , Lamy Alexandre ,   The Schizophrenia Working Group of the Psychiatric Genomics Consortium, Lencz Todd , Pe’er Itsik 
Published: November 2019

AbstractEvidence from both GWAS and clinical observation has suggested that certain psychiatric, metabolic, and autoimmune diseases are heterogeneous, comprising multiple subtypes with distinct genomic etiologies and Polygenic Risk Scores (PRS). However, the presence of subtypes within many phenotypes is frequently unknown. We present CLiP (Correlated Liability Predictors), a method to detect heterogeneity in single GWAS cohorts. CLiP calculates a weighted sum of correlations between SNPs contributing to a PRS on the case/control liability scale. We demonstrate mathematically and through simulation that among i.i.d. homogeneous cases, significant anti-correlations are expected between otherwise independent predictors due to ascertainment on the hidden liability score. In the presence of heterogeneity from distinct etiologies, confounding by covariates, or mislabeling, these correlation patterns are altered predictably. We further extend our method to two additional association study designs: CLiP-X for quantitative predictors in applications such as transcriptome-wide association, and CLiP-Y for quantitative phenotypes, where there is no clear distinction between cases and controls. Through simulations, we demonstrate that CLiP and its extensions reliably distinguish between homogeneous and heterogeneous cohorts when the PRS explains as low as 5% of variance on the liability scale and cohorts comprise 50, 000 − 100, 000 samples, an increasingly practical size for modern GWAS. We apply CLiP to heterogeneity detection in schizophrenia cohorts totaling > 50, 000 cases and controls collected by the Psychiatric Genomics Consortium. We observe significant heterogeneity in mega-analysis of the combined PGC data (p-value 8.54e-4), as well as in individual cohorts meta-analyzed using Fisher’s method (p-value 0.03), based on significantly associated variants.
Lipid Specificity of the Fusion of Bacterial Extracellular Vesicles with the Host Membrane
Authors: Prince Ashutosh , Tiwari Anuj , Mandal Titas , Koiri Debraj , Meher Geetanjali , Sinha Deepak Kumar , Saleem Mohammed 
Published: November 2019

AbstractBacterial membrane vesicles (MVs) facilitate long-distance delivery of virulence factors crucial for pathogenicity. The entry and trafficking mechanisms of virulence factors inside host cells are recently emerging, however, if bacterial MVs can fuse and modulate the physicochemical properties of the host lipid membrane and membrane lipid parameter for fusion remains unknown. Here we reconstitute the interaction of bacterial MV with host cell lipid membranes and quantitatively show that bacterial MV interaction increases the fluidity, dipole potential, and Compressibility of a biologically relevant multi-component host membrane upon fusion. The presence of cylindrical lipids such as phosphatidylcholine and a moderate acyl chain length of C16 helps the MV interaction. While significant binding of bacterial MVs to the raft-like lipid membranes with phase-separated regions of the membrane was observed, however, MVs prefer binding to the liquid-disordered regions of the membrane. Further, the elevated levels of cholesterol tend to hinder the interaction of bacterial MVs as evident from the favorable excess Gibbs free energy of mixing of bacterial MVs with host lipid membranes. The findings provide new insights that might have implications for the regulation of host machinery by bacterial pathogens through the manipulation of host membrane properties.
Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements
Authors: Henderson Rory , Lu Maolin , Zhou Ye , Mu Zekun , Parks Robert , Han Qifeng , Hsu Allen L. , Carter Elizabeth , Blanchard Scott C. , Edwards RJ , Wiehe Kevin , Saunders Kevin O. , Borgnia Mario J. , Bartesaghi Alberto , Mothes Walther , Haynes Barton F. , Acharya Priyamvada , Alam S. Munir 
Published: November 2019

AbstractThe trimeric HIV-1 Envelope protein (Env) mediates viral-host cell fusionviaa network of conformational transitions, with allosteric elements in each protomer orchestrating host receptor-induced exposure of the co-receptor binding site and fusion elements. To understand the molecular details of this allostery, we introduced Env mutations aimed to prevent CD4-induced rearrangements in the HIV-1 BG505 Env trimer. Binding analysis performed on the soluble ectodomain BG505 SOSIP Env trimers, cell-surface expressed BG505 full-length trimers and single-molecule Förster Resonance Energy Transfer (smFRET) performed on the full-length virion-bound Env confirmed that these mutations prevented CD4-induced transitions of the HIV-1 Env. Structural analysis by single-particle cryo-electron microscopy performed on the BG505 SOSIP mutant Env proteins revealed rearrangements in the gp120 topological layer contacts with gp41. Specifically, a conserved tryptophan at position 571 (W571) was displaced from its typical pocket at the interface of gp120 topological layers 1 and 2 by lysine 567, disrupting key gp120-gp41 contacts and rendering the Env insensitive to CD4 binding. Vector based analysis of closed Env SOSIP structures revealed the newly designed trimers exhibited a quaternary structure distinct from that typical of SOSIPs and residing near a cluster of Env trimers bound to vaccine-induced fusion peptide-directed antibodies (vFP Mabs). These results reveal the critical function of W571 as a conformational switch in Env allostery and receptor-mediated viral entry and provide insights on Env conformation that are relevant for vaccine design.
qPaLM: quantifying occult microarchitectural relationships in histopathological landscapes
Authors: Kendall Timothy J , Duff Catherine M , Thomson Andrew M , Iredale John P 
Published: November 2019

AbstractOptimal tissue imaging methods should be easy to apply, not require use-specific algorithmic training, and should leverage feature relationships central to subjective gold-standard assessment. We reinterpret histological images as landscapes to describe quantitative pathological landscape metrics (qPaLM), a generalisable framework defining topographic relationships in tissue using geoscience approaches. qPaLM requires no user-dependent training to operate on all image datasets in a classifier-agnostic manner to quantify occult abnormalities, derive mechanistic insights, and define a new feature class for machine-learning diagnostic classification.
Mapping the micro-proteome of the nuclear lamina and lamin associated domains
Authors: Cutler Jevon A. , Wong Xianrong , Hoskins Victoria E. , Gordon Molly , Madugundu Anil K. , Pandey Akhilesh , Reddy Karen L. 
Published: November 2019

AbstractThe nuclear lamina is a proteinaceous network of filaments that provide both structural and gene regulatory functions by tethering proteins and large domains of DNA, so-called lamin associated domains (LADs), to the periphery of the nucleus. LADs are a large fraction of the mammalian genome that are repressed, in part, by their association to the nuclear periphery. The genesis and maintenance of LADs is poorly understood as are the proteins that participate in these functions. In an effort to identify proteins that reside at the nuclear periphery and potentially interact with LADs, we have taken a two-pronged approach. First, we have undertaken an interactome analysis of the inner nuclear membrane bound LAP2β to further characterize the nuclear lamina proteome. To accomplish this, we have leveraged the BioID system, which previously has been successfully used to characterize the nuclear lamina proteome. Second, we have established a system to identify proteins that bind to LADs by developing a chromatin directed BioID system. We combined the BioID system with the m6A-tracer system which binds to LADs in live cells to identify both LAD proximal and nuclear lamina proteins. In combining these datasets, we have further characterized the protein network at the nuclear lamina, identified putative LAD proximal proteins and found several proteins that appear to interface with both micro-proteomes. Importantly, several proteins essential for LAD function, including heterochromatin regulating proteins related to H3K9 methylation, were identified in this study.
Elucidating cryptic sympatric speciation in terrestrial orchids
Authors: Pansarin Emerson R. , Ferreira Alessandro W.C. 
Published: November 2019

ABSTRACTPREMISECryptic sympatric speciation occurs when closely related species arises with no geographic or spatial isolation. Since cryptic species can not usually be detected when investigations are based exclusively on classical plant taxonomy, molecular markers and integrative taxonomy are important tools to elucidate the identity of cryptic taxa.METHODSIn this paper we aimed to provide a detailed investigation based on molecular data and experimental taxonomy conducted on populations of a plant model occurring inside mesophytic forests and a supposed cryptic sympatric species that is found in marshy areas. Furthermore, a phylogeny was reconstructed by using nrDNA and cpDNA sequences in order to ascertain the position of both sympatric species withinLiparis. The divergence among sequences of the putative cryptic sympatric species and related taxa was also verified based on DNA barcoding.KEY RESULTSOur results reveal cryptic sympatric speciation in the orchid genusLiparis. Differences in microhabitat, flowering phenology, morphology of leaves and flowers, and reproductive strategies support the taxon occurring in marshy areas is a cryptic species. The molecular analyses reveal the cryptic species is closely related toL. nervosa.CONCLUSIONSPaludalLiparisis a sympatric cryptic species distinguishable fromL. nervosaby differences in habitat, phenology and breeding system. Our conclusions are supported by the molecular investigations. The crypticLiparisemerges as sister toL. nervosa, within a clade with terrestrial habitat and plicate leaves. The discovery of sympatric cryptic speciation in orchids provides increase on the knowledge of diversification and reproductive isolation in flowering plants.