bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advanced Human Immunodeficiency Virus Disease at Diagnosis in Mozambique and Swaziland
Authors: Kujawski Stephanie A , Lamb Matthew R , Lahuerta Maria , McNairy Margaret L , Ahoua Laurence , Abacassamo Fatima , Nuwagaba-Biribonwoha Harriet , Gachuhi Averie , El-Sadr Wafaa M , Elul Batya 
Published: July 2017

Abstract

Background
Early diagnosis of human immunodeficiency virus (HIV) is a prerequisite to maximizing individual and societal benefits of antiretroviral therapy.

Methods
Adults ≥18 years of age testing HIV positive at 10 health facilities in Mozambique and Swaziland received point-of-care CD4+ cell count testing immediately after diagnosis. We examined median CD4+ cell count at diagnosis, the proportion diagnosed with advanced HIV disease (CD4+ cell count ≤350 cells/μL) and severe immunosuppression (CD4+ cell count ≤100 cells/μL), and determinants of the latter 2 measures.

Results
Among 2333 participants, the median CD4+ cell count at diagnosis was 313 cells/μL (interquartile range, 164–484), more than half (56.5%) had CD4+ ≤350 cells/μL, and 13.9% had CD4+ ≤100 cells/μL. The adjusted relative risk (aRR) of both advanced HIV disease and severe immunosuppression at diagnosis was higher in men versus women (advanced disease aRR = 1.31; 95% confidence interval [CI] = 1.16–1.48; severe immunosuppression aRR = 1.54, 95% CI = 1.17–2.02) and among those who sought HIV testing because they felt ill (advanced disease aRR = 1.30, 95% CI = 1.08–1.55; severe immunosuppression aRR = 2.10, 95% CI = 1.35–2.26). Age 18–24 versus 25–39 was associated with a lower risk of both outcomes (advanced disease aRR = 0.70, 95% CI = 0.59–0.84; severe immunosuppression aRR = 0.62, 95% CI = 0.41–0.95).

Conclusions
More than 10 years into the global scale up of comprehensive HIV services, the majority of adults diagnosed with HIV at health facilities in 2 high-prevalence countries presented with advanced disease and 1 in 7 had severe immunosuppression. Innovative strategies for early identification of HIV-positive individuals are urgently needed.
HID-1 controls cargo sorting and dense core formation by influencingtrans-Golgi network acidification in neuroendocrine cells
Authors: Hummer Blake H. , de Leeuw Noah F. , Hosford Bethany , Burns Christian , Joens Matthew S. , Fitzpatrick James A.J. , Asensio Cedric S. 
Published: July 2017

AbstractLarge dense core vesicles (LDCVs) mediate the regulated release of neuropeptides and peptide hormones. They form at thetrans-Golgi network (TGN) where their soluble content aggregates to form a dense core, but the mechanisms controlling biogenesis are still not completely understood. Recent studies have implicated the peripheral membrane protein HID-1 in neuropeptide sorting and insulin secretion. Using CRISPR/Cas9, we generated HID-1 KO rat neuroendocrine cells, and show that the absence of HID-1 results in specific defects in peptide hormone and monoamine storage and regulated secretion. Loss of HID-1 causes a reduction in the number of LDCVs and affects their morphology and biochemical properties due to impaired cargo sorting and dense core formation. HID-1 KO cells also exhibit defects in TGN acidification together with mislocalization of the Golgi-enriched vacuolar H+-ATPase subunit isoform a2. We propose that HID-1 influences early steps in LDCV formation by controlling dense core formation at the TGN.
Hierarchical Analysis of Multi-mapping RNA-Seq Reads Improves the Accuracy of Allele-specific Expression
Authors: Raghupathy Narayanan , Choi Kwangbom , Vincent Matthew J. , Beane Glen L. , Sheppard Keith , Munger Steven C. , Korstanje Ron , de Villena Fernando Pardo-Manual , Churchill Gary A. 
Published: July 2017

AbstractAllele-specific expression (ASE) refers to the differential abundance of the allelic copies of a transcript. Direct RNA sequencing (RNA-Seq) can provide quantitative estimates of ASE for genes with transcribed polymorphisms. However, estimating ASE is challenging due to ambiguities in read alignment. Current approaches do not account for the hierarchy of multiple read alignments to genes, isoforms, and alleles. We have developed EMASE (Expectation-Maximization for Allele Specific Expression), an integrated approach to estimate total gene expression, ASE, and isoform usage based on hierarchical allocation of multi-mapping reads. In simulations, EMASE outperforms standard ASE estimation methods. We apply EMASE to RNA-Seq data from F1 hybrid mice where we observe widespread ASE associated with cis-acting polymorphisms and a small number of parent-of-origin effects at known imprinted genes. The EMASE software is freely available under GNU license athttps://github.com/churchill-lab/emaseand it can be adapted to other sequencing applications.
Maternal obesity alters uterine NK cell activity through a functional KIR2DL1/S1 imbalance
Authors: Castellana Barbara , Perdu Sofie , Kim Yoona , Chan Kathy , Atif Jawairia , Marziali Megan , Beristain Alexander G. 
Published: July 2017

ABSTRACTIn pregnancy, uterine natural killer cells (uNK) play essential roles in coordinating uterine angiogenesis, blood vessel remodeling, and promoting maternal tolerance to fetal tissue. Deviances from a normal uterine microenvironment are thought to modify uNK function(s), limiting their ability to establish a healthy pregnancy. While maternal obesity has become a major health concern due to associations with adverse effects on fetal and maternal health, our understanding into how obesity contributes to poor pregnancy disorders is essentially unknown. Given the importance of uNK in pregnancy, this study sets out to examine if obesity affects uNK function. Using a cohort of pregnant women, we show that baseline activity of uNK from obese women is elevated, but that enhanced activity does not equate to increased killing potential. Instead, obesity associates with altered uNK production of angiogenic VEGF-A and PlGF. These changes coincide with alterations in NKp46+and NKG2A+uNK subsets and elevated expression of KIR2D(L1/S1/S3/S5) receptors. Detailed examination revealed that obesity leads to imbalances in KIR2DL1/S1 expression that together instruct altered responses to HLA-C2 antigen, including increased production of TNFα. Together, these findings suggest that maternal obesity modulates uNK function by altering angiokine/cytokine production and the response to HLA-C2 antigen.
The transcriptionally permissive chromatin state of ES cells is acutely tuned to translational output
Authors: Bulut-Karslioglu Aydan , Macrae Trisha A. , Oses-Prieto Juan A. , Covarrubias Sergio , Percharde Michelle , Ku Gregory , Diaz Aaron , McManus Michael T. , Burlingame Alma L. , Ramalho-Santos Miguel 
Published: July 2017

SUMMARYA permissive chromatin environment coupled to hypertranscription is critical to drive the rapid proliferation of Embryonic Stem (ES) cells and peri-implantation embryos. We carried out a genome-wide screen to systematically dissect the regulation of the euchromatic state of ES cells. The results reveal that activity of cellular growth pathways, prominently protein synthesis, perpetuates the euchromatic state and hypertranscription of ES cells. Acute, mild inhibition of translation results in rapid depletion of euchromatic marks in ES cells and blastocysts, concurrent with delocalization of RNA polymerase II and reduction in nascent transcription. Remarkably, reduced translational output leads to rewiring of open chromatin within 3 hours, including decreased accessibility at a subset of active developmental enhancers and increased accessibility at histone genes and transposable elements. Using a proteome-scale analysis, we show that several euchromatin regulators are unstable proteins and thus continuously depend on a high translational output. We propose that this mechanistic interdependence of euchromatin, transcription and translation sets the pace of proliferation at peri-implantation and may be employed generally by stem/progenitor cells.
Modest static pressure suppresses columnar epithelial cell proliferation in association with cell shape and cytoskeletal modifications
Authors: Hagiyama Man , Yabuta Norikazu , Okuzaki Daisuke , Inoue Takao , Takashima Yasutoshi , Kimura Ryuichiro , Ri Aritoshi , Ito Akihiko 
Published: July 2017

AbstractIntraluminal pressure elevation can cause degenerative disorders, such as ileus and hydronephrosis, and the threshold is fairly low and constant, 20–30 cm H2O. We previously devised a novel two-chamber culture system subjecting cells cultured on a semipermeable membrane to increased culture medium height (water pressure up to 60 cm H2O). Here, we cultured several different cell lines using the low static pressure-loadable two-chamber system, and examined cell growth, cell cycle, and cell morphology. Madin–Darby canine kidney (MDCK) columnar epithelial cells were growth-suppressed in a manner dependent on static water pressure ranging from 2–50 cm H2O, without cell cycle arrest at any specific phase. Two other types of columnar epithelial cells exhibited similar phenotypes. By contrast, spherical epithelial and mesenchymal cells were not growth-suppressed, even at 50 cm H2O. Phalloidin staining revealed that 50 cm H2O pressure load vertically flattened and laterally widened columnar epithelial cells and made actin fiber distribution sparse, without affecting total phalloidin intensity per cell. When the mucosal protectant irsogladine maleate (100 nM) was added to 50-cm-high culture medium, MDCK cells were reduced in volume and their doubling time shortened. Cell proliferation and morphology are known to be regulated by the Hippo signaling pathway, but a pressure load of 50 cm H2O did not alter the expression levels of Hippo signaling molecules in columnar epithelial cells, suggesting that this pathway was not involved in the pressure-induced phenotypes. RNA sequencing of MDCK cells showed that a 50 cm H2O pressure load upregulatedkeratin 14, an intermediate filament, 12-fold. This upregulation was confirmed at the protein level by immunofluorescence, suggesting a role in cytoskeletal reinforcement. These results provide evidence that cell morphology and the cytoskeleton are closely linked to cell growth. Pathological intraluminal pressure elevation may cause mucosal degeneration by acting directly on this linkage.SummaryWe provide evidence that columnar epithelial cells are growth-suppressed by pressure loads as low as 30 cm H2O, in association with cell-shape flattening and cytoskeletal alterations.
Correlated gene expression and anatomical communication support synchronized brain activity in the mouse functional connectome
Authors: Mills Brian D. , Grayson David S. , Shunmugavel Anandakumar , Miranda-Dominguez Oscar , Feczko Eric , Earl Eric , Neve Kim , Fair Damien A. 
Published: July 2017

AbstractCognition and behavior depend on synchronized intrinsic brain activity which is organized into functional networks across the brain. Research has investigated how anatomical connectivity both shapes and is shaped by these networks, but not how anatomical connectivity interacts with intra-areal molecular properties to drive functional connectivity. Here, we present a novel linear model to explain functional connectivity in the mouse brain by integrating systematically obtained measurements of axonal connectivity, gene expression, and resting state functional connectivity MRI. The model suggests that functional connectivity arises from synergies between anatomical links and inter-areal similarities in gene expression. By estimating these interactions, we identify anatomical modules in which correlated gene expression and anatomical connectivity cooperatively, versus distinctly, support functional connectivity. Along with providing evidence that not all genes equally contribute to functional connectivity, this research establishes new insights regarding the biological underpinnings of coordinated brain activity measured by BOLD fMRI.
Experimental evolution ofCandida albicansunder hypoxia and heat shock reveals nuclear genome variants and mitochondrial methylome alterations
Authors: Bartelli Thais Fernanda , Bruno Danielle do Carmo Ferreira , Lichtenstein Flavio , Briones Marcelo R. S. 
Published: July 2017

ABSTRACTInfection byCandida albicansrequires its adaption to physical constraints in the human body, such as low oxygen tension (hypoxia), increased temperature (37°C) and different carbon sources. Previous studies demonstrated that the genetic variability ofC. albicansisolates is an important adaptive mechanism, although little is known about the dynamics of this genetic diversity, and the influence of these environmental conditions on its mitochondrial genome (mtDNA). To test the synergistic effect of these stress conditions onC. albicansgenome, reference strain SC5314 was subjected to anin vitroevolution scheme under hypoxia and 37°C, with two different carbon sources (glycerol and dextrose) for up to 48 weeks (approximately 4,000 generations). Experimental evolution results showed no sequence or copy number changes in the mtDNA, although sequence variants were detected on its nuclear genome by Multilocus sequence typing (MLST) and whole genome sequencing (WGS). After 12 weeks of experimental evolution, sample GTH12, grown under hypoxia at 37°C in glycerol, showed inferior growth and respiratory rates as compared to other conditions tested. Although WGS of GTH12 revealed no variants in its mtDNA, WGS with sodium bisulfite showed a significant reduction in mtDNA methylation in GTH12 in both non-coding and coding regions. Our results provide the first whole mitochondrial genome methylation map ofC. albicansand show that environmental conditions promote the selective growth of specific variants and affect the methylation patterns of the mtDNA in a strain-specific manner.
A novel flatworm-specific gene family implicated in reproduction inMacrostomum lignano
Authors: Grudniewska Magda , Mouton Stijn , Grelling Margriet , Wolters Anouk H. G. , Kuipers Jeroen , Giepmans Ben N. G. , Berezikov Eugene 
Published: July 2017

AbstractFree-living flatworms, such as the planarianSchmidtea mediterranea, are extensively used as model organisms to study stem cells and regeneration. The majority of studies in planarians so far focused on broadly conserved genes. However, investigating what makes these animals different might be equally informative for understanding its biology. Here, we present a re-analysis of neoblast and germline transcriptional signatures in the flatwormM. lignanoand combine it with the whole-animal electron microscopy atlas (nanotomy) as a reference platform for ultrastructural studies inM. lignano. We show that germline-enriched genes have a high fraction of flatworm-specific genes and identifyMlig-sperm1gene as a member of a novel gene family conserved only in free-living flatworms and essential for producing healthy spermatozoa. This work demonstrates that investigation of flatworm-specific genes is crucial for understanding flatworm biology and establishes a basis for future research in this direction inM. lignano.
Functional Diversification of Tripeptidyl Peptidase and Endopeptidase Sedolisins in Fungi
Authors: Orts Facundo , Have Arjen ten 
Published: July 2017

AbstractSedolisins are acid proteases that are related to the basic subtilisins. They have been identified in all three superkingdoms but are not ubiquitous, although fungi that secrete acids as part of their lifestyle can have up to six paralogs. Both tripeptidyl peptidase (TPP) and endopeptidase activity have been identified and it has been suggested that these correspond to separate subfamilies.We studied eukaryotic sedolisins by computational analysis. A maximum likelihood tree shows three major clades of which two contain only fungal sequences. One fungal clade contains all known TPPs whereas the other contains the endosedolisins. We identified four cluster specific inserts (CSIs) in endosedolisins, of which CSIs 1, 3 and 4 appear as solvent exposed according to structure modeling. Part of CSI2 is exposed but a short stretch forms a novel and partially buried α-helix that induces a conformational change near the binding pocket. We also identified a total of 12 specificity determining positions (SDPs) divided over three SDP sub-networks. The major SDP network contains eight directly connected SDPs and modeling of virtual mutants suggests a key role for the W307A or F307A substitution. This substitution is accompanied by a group of four SDPs that physically interact at the interface of the catalytic domain and the enzyme’s prosegment. Modeling of virtual mutants suggests these SDPs are indeed required to compensate the conformational change induced by CSI2 and the A307. The additional major network SDPs as well as the two small SDP networks appear to be linked to this major substitution, all together explaining the hypothesized functional diversification of fungal sedolisins.HighlightsThere are two sedolisin subfamilies in fungi: tripeptidyl peptidases and endopeptidasesFunctional Diversification of fungal sedolisins led to a conformational change in the pocketFunctional Diversification centers around buried SDP307SDP307 is aromatic in TPPs and Alanine in endosedolisinsAdditional SDPs affect the interaction between core and chaperone-like prosegment
ESCRT-Independent Surface Receptor And Transporter Protein Degradation By The ILF Pathway
Authors: McNally Erin Kate , Brett Christopher Leonard 
Published: July 2017

SUMMARYSurface receptor and transporter protein down-regulation drives cell signaling, quality control and metabolism underlying diverse physiology. After endocytosis, proteins are delivered to endosomes where ESCRTs package them into intralumenal vesicles, which are degraded by acid hydrolases upon fusion with lysosomes. However, reports of ESCRT-independent surface protein degradation are emerging suggesting that alternative, non-canonical pathways exist. UsingSaccharomyces cerevisiaeas a model, here we show that in response to substrates, protein misfolding or TOR signaling, some internalized surface transporters (Hxt3, Itr1, Aqr1) bypass ESCRTs en route to the lysosome membrane where they are sorted into an area that is internalized as an intralumenal fragment (ILF) and degraded upon organelle fusion. This ILF pathway also degrades typical ESCRT client proteins (Mup1, Can1, Ste3) when ESCRT function is impaired. As the underlying machinery is conserved, we speculate that the ILF pathway is an important contributor to receptor and transporter down-regulation in all eukaryotes.
The mitotic spindle is chiral due to torques generated by motor proteins
Authors: Novak Maja , Polak Bruno , Simunić Juraj , Boban Zvonimir , Kuzmić Barbara , Thomae Andreas W. , Tolić Iva M. , Pavin Nenad 
Published: July 2017

AbstractMitosis relies on forces generated in the spindle, a micro-machine composed of microtubules and associated proteins1,2. Forces are required for the congression of chromosomes to the metaphase plate and separation of chromatids in anaphase3-6. However, torques may also exist in the spindle, yet they have not been investigated. Here we show that the spindle is chiral. Chirality is evident from the finding that microtubule bundles follow a left-handed helical path, which cannot be explained by forces but rather by torques acting in the bundles. STED super-resolution microscopy, as well as confocal microscopy, of human spindles shows that the bundles have complex curved shapes. The average helicity of the bundles with respect to the spindle axis is 1.2°/μm. Inactivation of kinesin-5 (Eg5/Kif11) abolished the chirality of the spindle, suggesting that this motor generates the helical shape of microtubule bundles. To explain the observed shapes, we introduce a theoretical model for the balance of forces and torques acting in the spindle, and show that torque is required to generate the helical shapes. We conclude that torques generated by motor proteins, in addition to forces, exist in the spindle and determine its architecture.
Closing the strategy execution gap through business simulations
Authors: Monauni Max 
Published: July 2017

Purpose
The purpose of this paper is to outline the relevance of a well-defined and well-led strategy execution process with respect to corporate success. It proposes customized business simulations as an effective solution for a smooth strategy execution.

Design/methodology/approach
Business simulations can help to bridge the strategy–execution gap. To illustrate this, three representative real-life business cases from different industries are described and analyzed, which successfully utilized simulation-based strategy implementation.

Findings
Recent studies have shown that poor alignment between the executive board and the operational business levels, insufficient understanding as well as a lack of accountability within the process are the key reasons for faulty strategy execution. Bespoke business simulations can address these issues.

Originality/value
There are several existing tools for strategy execution at hand. However, business simulations strongly increase the personal involvement of the employees by fostering high interactivity and gamification to boost the strategy transformation process.
Ways of working between third sector organizations and UK universities: are we getting it right?
Authors: Fearon Colm , Sama Antonio , van Vuuren Wim 
Published: July 2017

Purpose
The purpose of this paper is to offer strategic advice and identify ways in which third sector organizations can work with United Kingdom (UK) universities for promoting business education and enterprise skills development.

Design/methodology/approach
The authors’ strategic advice is based on analysis of qualitative interviews, focus groups, interactive seminars/workshops, and working with third sector support agencies.

Findings
Advice for third sector organizations includes the following points: build your efficacy – share the burden, do not attempt everything on your own; partner, or own the business skills yourself – you decide upon your strategy; develop your “social mission” and be “business oriented”; develop applied student projects – everyone wins; think about student volunteers; and local universities are there for you – check and see.

Originality/value
This is the first article of Development and Learning in Organization (DLO) to consider relationships between UK’s third sector organizations and regional universities. The authors deal with important education, skills, and business development issues for the third sector. There are new opportunities in 2016 (and beyond) for universities to build closer relationships with their third sector communities.