bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences in the Importance of Mast Cells, Basophils, IgE, and IgG versus That of CD4+T Cells and ILC2 Cells in Primary and Secondary Immunity to Strongyloides venezuelensis
Authors: Mukai Kaori , Karasuyama Hajime , Kabashima Kenji , Kubo Masato , Galli Stephen J. 
Published: March 2017

ABSTRACTThere is evidence that mast cells, basophils, and IgE can contribute to immune responses to parasites; however, the relative levels of importance of these effector elements in parasite immunity are not fully understood. Previous work inIl3-deficient and c-kitmutantKitW/W-vmice indicated that interleukin-3 and c-Kit contribute to expulsion of the intestinal nematodeStrongyloides venezuelensisduring primary infection. Our findings in mast cell-deficientKitW-sh/W-shmice and two types of mast cell-deficient mice that have normal c-kit(“HelloKitty” and MasTRECK mice) confirmed prior work inKitW/W-vmice that suggested that mast cells play an important role inS. venezuelensisegg clearance in primary infections. We also assessed a possible contribution of basophils in immune responses toS. venezuelensis. By immunohistochemistry, we found that numbers of basophils and mast cells were markedly increased in the jejunal mucosa during primary infections withS. venezuelensis. Studies in basophil-deficientMcpt8DTRmice revealed a small but significant contribution of basophils toS. venezuelensisegg clearance in primary infections. Studies in mice deficient in various components of immune responses showed that CD4+T cells and ILC2 cells, IgG, FcRγ, and, to a lesser extent, IgE and FcεRI contribute to effective immunity in primaryS. venezuelensisinfections. These findings support the conclusion that the hierarchy of importance of immune effector mechanisms in primaryS. venezuelensisinfection is as follows: CD4+T cells/ILC2 cells, IgG, and FcRγ>mast cells>IgE and FcεRI>basophils. In contrast, in secondaryS. venezuelensisinfection, our evidence indicates that the presence of CD4+T cells is of critical importance but mast cells, antibodies, and basophils have few or no nonredundant roles.
Inactivation ofNMB0419, Encoding a Sel1-Like Repeat (SLR) Protein, in Neisseria meningitidis Is Associated with Differential Expression of Genes Belonging to the Fur Regulon and Reduced Intraepithelial Replication
Authors: Li Ming-Shi , Langford Paul R. , Kroll J. Simon 
Published: March 2017

ABSTRACTNeisseria meningitidisis a commensal microbe that colonizes the human nasopharynx but occasionally invades the bloodstream to cause life-threatening infection.N. meningitidisMC58NMB0419encodes a Sel1-like repeat (SLR)-containing protein, previously implicated in invasion of epithelial cells. A gene-regulatory function was revealed inEscherichia coliexpressing plasmid-borneNMB0419and showing significantly increased epithelial adherence compared to the wild type, due to increased expression of mannose-sensitive type 1 pili. While a meningococcalNMB0419mutant did not have altered epithelial adherence, in a transcriptome-wide comparison of the wild type and anNMB0419mutant, a large proportion of genes differentially regulated in the mutant were involved in iron acquisition and metabolism. Fifty-one percent and 38% of genes, respectively, up- and downregulated in theNMB0419mutant had previously been identified as being induced and repressed by meningococcal Fur. Anin vitrogrowth defect of theNMB0419mutant under iron restriction was consistent with the downregulation oftbpABandhmbR, while an intraepithelial replication defect was consistent with the downregulation oftonB,exbB, andexbD, based on a known phenotype of a meningococcaltonBmutant. Disruption of the N-terminal NMB0419 signal peptide, predicted to export the protein beyond the cytoplasmic membrane, resulted in loss of functional traits inN. meningitidisandE. coli. Our study indicates that the expression ofNMB0419is associated with transcriptional changes counterbalancing the regulatory function of Fur, offering a new perspective on regulatory mechanisms involved in meningococcal interaction with epithelial cells, and suggests new insights into the roles of SLR-containing genes in other bacteria.
Going Outside the TonB Box: Identification of Novel FepA-TonB Interactions
In Vivo
Authors: Gresock Michael G. , Postle Kathleen 
Published: March 2017

ABSTRACT

In Gram-negative bacteria, the cytoplasmic membrane protein TonB transmits energy derived from proton motive force to energize transport of important nutrients through TonB-dependent transporters in the outer membrane. Each transporter consists of a beta barrel domain and a lumen-occluding cork domain containing an essential sequence called the TonB box. To date, the only identified site of transporter-TonB interaction is between the TonB box and residues ∼158 to 162 of TonB. While the mechanism of ligand transport is a mystery, a current model based on site-directed spin labeling and molecular dynamics simulations is that, following ligand binding, the otherwise-sequestered TonB box extends into the periplasm for recognition by TonB, which mediates transport by pulling or twisting the cork. In this study, we tested that hypothesis with the outer membrane transporter FepA using
in vivo
photo-cross-linking to explore interactions of its TonB box and determine whether additional FepA-TonB interaction sites exist. We found numerous specific sites of FepA interaction with TonB on the periplasmic face of the FepA cork in addition to the TonB box. Two residues, T32 and A33, might constitute a ligand-sensitive conformational switch. The facts that some interactions were enhanced in the absence of ligand and that other interactions did not require the TonB box argued against the current model and suggested that the transport process is more complex than originally conceived, with subtleties that might provide a mechanism for discrimination among ligand-loaded transporters. These results constitute the first study on the dynamics of TonB-gated transporter interaction with TonB
in vivo
.

IMPORTANCE
The TonB system of Gram-negative bacteria has a noncanonical active transport mechanism involving signal transduction and proteins integral to both membranes. To achieve transport, the cytoplasmic membrane protein TonB physically contacts outer membrane transporters such as FepA. Only one contact between TonB and outer membrane transporters has been identified to date: the TonB box at the transporter amino terminus. The TonB box has low information content, raising the question of how TonB can discriminate among multiple different TonB-dependent transporters present in the bacterium if it is the only means of contact. Here we identified several additional sites through which FepA contacts TonB
in vivo
, including two neighboring residues that may explain how FepA signals to TonB that ligand has bound.
Changing trends in reproductive/lifestyle factors in UK women: descriptive study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)
Authors: Gentry-Maharaj Aleksandra , Glazer Clara , Burnell Matthew , Ryan Andy , Berry Hannah , Kalsi Jatinderpal , Woolas Robert , Skates Steve J , Campbell Stuart , Parmar Mahesh , Jacobs Ian , Menon Usha 
Published: March 2017

ObjectiveThere has been considerable interest in the impact of reproductive factors on health but there are little data on how these have varied over time. We explore trends in reproductive/lifestyle factors of postmenopausal British women by analysing self-reported data from participants of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).DesignProspective birth cohort analysis.SettingPopulation cohort invited between 2001 and 2005 from age-sex registers of 27 Primary Care Trusts in England, Wales and Northern Ireland and recruited through 13 National Health Service Trusts.Participants202 638 postmenopausal women aged 50–74 years at randomisation to UKCTOCS between April 2001 and October 2005.InterventionsWomen were stratified into the following six birth cohorts (1925–1929, 1930–1934, 1935–1939, 1940–1944, 1945–1949, 1950–1955) based on year of birth. Self-reported data on reproductive factors provided at recruitment were explored using tabular and graphical summaries to examine for differences between the birth cohorts.Outcome measuresTrends in mean age at menarche and menopause, use of oral contraceptives, change in family size, infertility treatments, tubal ligation and hysterectomy rates.ResultsWomen born between 1935 and 1955 made up 86% of the cohort. Median age at menarche decreased from 13.4 for women born between 1925 and 1929 to 12.8 for women born between 1950 and 1955. Increased use of the oral contraceptives, infertility treatments and smaller family size was observed in the younger birth cohorts. Tubal ligation rates increased for those born between 1925 and 1945, but this increase did not persist in subsequent cohorts. Hysterectomy rates (17–20%) did not change over time.ConclusionsThe trends seen in this large cohort are likely to reflect the reproductive history of the UK female postmenopausal population of similar age. Since these are risk factors for hormone-related cancers, these trends are important in understanding the changing incidence of these cancers.Trial registration numberInternational Standard Randomised Controlled Trial Number: 22488978.
Computer-determined dosage of insulin in the management of neonatal hyperglycaemia (HINT2): protocol of a randomised controlled trial
Authors: Alsweiler Jane , Williamson Kathryn , Bloomfield Frank , Chase Geoffrey , Harding Jane 
Published: March 2017

IntroductionNeonatal hyperglycaemia is frequently treated with insulin, which may increase the risk of hypoglycaemia. Computer-determined dosage of insulin (CDD) with the STAR-GRYPHON program uses a computer model to predict an effective dose of insulin to treat hyperglycaemia while minimising the risk of hypoglycaemia. However, CDD models can require more frequent blood glucose testing than common clinical protocols. The aim of this trial is to determine if CDD using STAR-GRYPHON reduces hypoglycaemia in hyperglycaemic preterm babies treated with insulin independent of the frequency of blood glucose testing.Methods and analysisDesign: Multicentre, non-blinded, randomised controlled trial. Setting: Neonatal intensive care units in New Zealand and Australia. Participants: 138 preterm babies ≤30 weeks' gestation or ≤1500 g at birth who develop hyperglycaemia (two consecutive blood glucose concentrations ≥10 mmol/L, at least 4 hours apart) will be randomised to one of three groups: (1) CDD using the STAR-GRYPHON model-based decision support system: insulin dose and frequency of blood glucose testing advised by STAR-GRYPHON, with a maximum testing interval of 4 hours; (2) bedside titration: insulin dose determined by medical staff, maximum blood glucose testing interval of 4 hours; (3) standard care: insulin dose and frequency of blood glucose testing determined by medical staff. The target range for blood glucose concentrations is 5–8 mmol/L in all groups. A subset of babies will have masked continuous glucose monitoring. Primary outcome: is the number of babies with one or more episodes of hypoglycaemia (blood glucose concentration <2.6 mmol/L), during treatment with insulin.Ethics and disseminationThis protocol has been approved by New Zealand's Health and Disability Ethics Committee: 14/STH/26. A data safety monitoring committee has been appointed to oversee the trial. Findings will be disseminated to participants and carers, peer-reviewed journals, guideline developers and the public.Trial registration number12614000492651
Diagnosing malignant melanoma in ambulatory care: a systematic review of clinical prediction rules
Authors: Harrington Emma , Clyne Barbara , Wesseling Nieneke , Sandhu Harkiran , Armstrong Laura , Bennett Holly , Fahey Tom 
Published: March 2017

ObjectivesMalignant melanoma has high morbidity and mortality rates. Early diagnosis improves prognosis. Clinical prediction rules (CPRs) can be used to stratify patients with symptoms of suspected malignant melanoma to improve early diagnosis. We conducted a systematic review of CPRs for melanoma diagnosis in ambulatory care.DesignSystematic review.Data sourcesA comprehensive search of PubMed, EMBASE, PROSPERO, CINAHL, the Cochrane Library and SCOPUS was conducted in May 2015, using combinations of keywords and medical subject headings (MeSH) terms.Study selection and data extractionStudies deriving and validating, validating or assessing the impact of a CPR for predicting melanoma diagnosis in ambulatory care were included. Data extraction and methodological quality assessment were guided by the CHARMS checklist.ResultsFrom 16 334 studies reviewed, 51 were included, validating the performance of 24 unique CPRs. Three impact analysis studies were identified. Five studies were set in primary care. The most commonly evaluated CPRs were the ABCD, more than one or uneven distribution of Colour, or a large (greater than 6 mm) Diameter (ABCD) dermoscopy rule (at a cut-point of >4.75; 8 studies; pooled sensitivity 0.85, 95% CI 0.73 to 0.93, specificity 0.72, 95% CI 0.65 to 0.78) and the 7-point dermoscopy checklist (at a cut-point of ≥1 recommending ruling in melanoma; 11 studies; pooled sensitivity 0.77, 95% CI 0.61 to 0.88, specificity 0.80, 95% CI 0.59 to 0.92). The methodological quality of studies varied.ConclusionsAt their recommended cut-points, the ABCD dermoscopy rule is more useful for ruling out melanoma than the 7-point dermoscopy checklist. A focus on impact analysis will help translate melanoma risk prediction rules into useful tools for clinical practice.
KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1
Authors: Kapplinger Jamie D , Erickson Anders , Asuri Sirisha , Tester David J , McIntosh Sarah , Kerr Charles R , Morrison Julie , Tang Anthony , Sanatani Shubhayan , Arbour Laura , Ackerman Michael J 
Published: March 2017

BackgroundVariable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymousKCNQ1p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, inKCNQ1-encoded Kv7.1.Methods419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (KCNH2-p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overallKCNQ1transcript levels to assess the effect on splicing.ResultsFor women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the totalKCNQ1transcript levels.ConclusionsOur results provide the first evidence that synonymous variants outside the canonical splice sites inKCNQ1can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants.
Venous collateral drainage patterns predict clinical worsening in dural venous sinus thrombosis
Authors: Sheth Sunil A , Trieu Harry , Liebeskind David S , Saver Jeffrey L , Szeder Viktor , Jahan Reza , Tateshima Satoshi , Duckwiler Gary 
Published: March 2017

BackgroundDural venous sinus thrombosis (DVST) is an increasingly recognized cause of a wide array of neurological symptoms, with outcomes that range from complete recovery to death. The condition of approximately 23% of patients with DVST will worsen after initial presentation, as a result of restricted venous outflow and venous hypertension, but early identification of this subset is challenging. A venous collateral scale (VCS) that grades alternative drainage routes may improve prediction of clinical deterioration.ObjectiveTo examine the ability of the VCS system to accurately identify patients with DVST who will experience clinical worsening, based on their imaging at presentation.MethodsFrom our institutional database, we identified patients with DVST on dedicated venous imaging between January 2010 and July 2016. A VCS was created and calculated from venous imaging at presentation by two reviewers blinded to subsequent data.ResultsThe 27 patients who met the inclusion criteria for this study had a median age of 42 years and 14 (52%) were female. Initial symptoms included headache without hemorrhage in 30% and focal deficit in 30%. Transverse sinus occlusion was present in 70% and superior sagittal sinus occlusion in 41%. VCS was 0 in 11%, 1 in 37%, and 2 in 52%. A lower VCS was significantly associated with clinical worsening both from time of initial symptom onset (77% vs 29%, VCS 0–1 vs 2, p<0.05) and during hospitalization (62% vs 0%, VCS 0–1 vs 2, p<0.01). In multivariate analysis, VCS but no other presenting features was significantly associated with in-hospital worsening (OR=2, p<0.01).ConclusionsThe type and quality of venous collaterals influence outcome in DVST. VCS helps to identify patients whose condition is likely to deteriorate and may need additional aggressive interventions.
Scalable and Efficient Flow-Based Community Detection for Large-Scale Graph Analysis
Authors: Bae Seung-Hee , Halperin Daniel , West Jevin D. , Rosvall Martin , Howe Bill 
Published: March 2017

Community detection is an increasingly popular approach to uncover important structures in large networks. Flow-based community detection methods rely on communication patterns of the network rather than structural properties to determine communities. The Infomap algorithm in particular optimizes a novel objective function called the map equation and has been shown to outperform other approaches in third-party benchmarks. However, Infomap and its variants are inherently sequential, limiting their use for large-scale graphs.
In this article, we propose a novel algorithm to optimize the map equation called RelaxMap. RelaxMap provides two important improvements over Infomap: parallelization, so that the map equation can be optimized over much larger graphs, and prioritization, so that the most important work occurs first, iterations take less time, and the algorithm converges faster. We implement these techniques using OpenMP on shared-memory multicore systems, and evaluate our approach on a variety of graphs from standard graph clustering benchmarks as well as real graph datasets. Our evaluation shows that both techniques are effective: RelaxMap achieves 70% parallel efficiency on eight cores, and prioritization improves algorithm performance by an additional 20--50% on average, depending on the graph properties. Additionally, RelaxMap converges in the similar number of iterations and provides solutions of equivalent quality as the serial Infomap implementation.
Main Memory in HPC
Authors: Zivanovic Darko , Pavlovic Milan , Radulovic Milan , Shin Hyunsung , Son Jongpil , Mckee Sally A. , Carpenter Paul M. , Radojković Petar , Ayguadé Eduard 
Published: March 2017

An important aspect of High-Performance Computing (HPC) system design is the choice of main memory capacity. This choice becomes increasingly important now that 3D-stacked memories are entering the market. Compared with conventional Dual In-line Memory Modules (DIMMs), 3D memory chiplets provide better performance and energy efficiency but lower memory capacities. Therefore, the adoption of 3D-stacked memories in the HPC domain depends on whether we can find use cases that require much less memory than is available now.
This study analyzes the memory capacity requirements of important HPC benchmarks and applications. We find that the High-Performance Conjugate Gradients (HPCG) benchmark could be an important success story for 3D-stacked memories in HPC, but High-Performance Linpack (HPL) is likely to be constrained by 3D memory capacity. The study also emphasizes that the analysis of memory footprints of production HPC applications is complex and that it requires an understanding of application scalability and target category, i.e., whether the users target capability or capacity computing. The results show that most of the HPC applications under study have per-core memory footprints in the range of hundreds of megabytes, but we also detect applications and use cases that require gigabytes per core. Overall, the study identifies the HPC applications and use cases with memory footprints that could be provided by 3D-stacked memory chiplets, making a first step toward adoption of this novel technology in the HPC domain.
Promoter Methylation Modulates Indoleamine 2,3-Dioxygenase 1 Induction by Activated T Cells in Human Breast Cancers
Authors: Noonepalle Satish K. , Gu Franklin , Lee Eun-Joon , Choi Jeong-Hyeon , Han Qimei , Kim Jaejik , Ouzounova Maria , Shull Austin Y. , Pei Lirong , Hsu Pei-Yin , Kolhe Ravindra , Shi Fang , Choi Jiseok , Chiou Katie , Huang Tim H.M. , Korkaya Hasan , Deng Libin , Xin Hong-Bo , Huang Shuang , Thangaraju Muthusamy , Sreekumar Arun , Ambs Stefan , Tang Shou-Ching , Munn David H. , Shi Huidong 
Published: March 2017

Abstract
Triple-negative breast cancer (TNBC) cells are modulated in reaction to tumor-infiltrating lymphocytes. However, their specific responses to this immune pressure are unknown. In order to address this question, we first used mRNA sequencing to compare the immunophenotype of the TNBC cell line MDA-MB-231 and the luminal breast cancer cell line MCF7 after both were cocultured with activated human T cells. Despite similarities in the cytokine-induced immune signatures of the two cell lines, MDA-MD-231 cells were able to transcribe more IDO1 than MCF7 cells. The two cell lines had similar upstream JAK/STAT1 signaling and IDO1 mRNA stability. However, using a series of breast cancer cell lines, IFNγ stimulated IDO1 protein expression and enzymatic activity only in ER−, not ER+, cell lines. Treatment with 5-aza-deoxycytidine reversed the suppression of IDO1 expression in MCF7 cells, suggesting that DNA methylation was potentially involved in IDO1 induction. By analyzing several breast cancer datasets, we discovered subtype-specific mRNA and promoter methylation differences in IDO1, with TNBC/basal subtypes exhibiting lower methylation/higher expression and ER+/luminal subtypes exhibiting higher methylation/lower expression. We confirmed this trend of IDO1 methylation by bisulfite pyrosequencing breast cancer cell lines and an independent cohort of primary breast tumors. Taken together, these findings suggest that IDO1 promoter methylation regulates anti-immune responses in breast cancer subtypes and could be used as a predictive biomarker for IDO1 inhibitor–based immunotherapy. Cancer Immunol Res; 5(4); 330–44. ©2017 AACR.