bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of the Protein Kinase A-Regulated Proteome of Cryptococcus neoformans Identifies a Role for the Ubiquitin-Proteasome Pathway in Capsule Formation
Authors: Geddes J. M. H. , Caza M. , Croll D. , Stoynov N. , Foster L. J. , Kronstad J. W. 
Published: January 2016

ABSTRACT

The opportunistic fungal pathogen
Cryptococcus neoformans
causes life-threatening meningitis in immunocompromised individuals. The expression of virulence factors, including capsule and melanin, is in part regulated by the cyclic-AMP/protein kinase A (cAMP/PKA) signal transduction pathway. In this study, we investigated the influence of PKA on the composition of the intracellular proteome to obtain a comprehensive understanding of the regulation that underpins virulence. Through quantitative proteomics, enrichment and bioinformatic analyses, and an interactome study, we uncovered a pattern of PKA regulation for proteins associated with translation, the proteasome, metabolism, amino acid biosynthesis, and virulence-related functions. PKA regulation of the ubiquitin-proteasome pathway in
C. neoformans
showed a striking parallel with connections between PKA and protein degradation in chronic neurodegenerative disorders and other human diseases. Further investigation of proteasome function with the inhibitor bortezomib revealed an impact on capsule production as well as hypersusceptibility for strains with altered expression or activity of PKA. Parallel studies with tunicamycin also linked endoplasmic reticulum stress with capsule production and PKA. Taken together, the data suggest a model whereby expression of PKA regulatory and catalytic subunits and the activation of PKA influence proteostasis and the function of the endoplasmic reticulum to control the elaboration of the polysaccharide capsule. Overall, this study revealed both broad and conserved influences of the cAMP/PKA pathway on the proteome and identified proteostasis as a potential therapeutic target for the treatment of cryptococcosis.

IMPORTANCE
Fungi cause life-threatening diseases, but very few drugs are available to effectively treat fungal infections. The pathogenic fungus
Cryptococcus neoformans
causes a substantial global burden of life-threatening meningitis in patients suffering from HIV/AIDS. An understanding of the mechanisms by which fungi deploy virulence factors to cause disease is critical for developing new therapeutic approaches. We employed a quantitative proteomic approach to define the changes in the protein complement that occur upon modulating the cAMP signaling pathway that regulates virulence in
C. neoformans
. This approach identified a conserved role for cAMP signaling in the regulation of the ubiquitin-proteasome pathway and revealed a link between this pathway and elaboration of a major virulence determinant, the polysaccharide capsule. Targeting the ubiquitin-proteasome pathway opens new therapeutic options for the treatment of cryptococcosis.
Herpesviral ICP0 Protein Promotes Two Waves of Heterochromatin Removal on an Early Viral Promoter during Lytic Infection
Authors: Lee Jennifer S. , Raja Priya , Knipe David M. 
Published: January 2016

ABSTRACT
Herpesviruses must contend with host cell epigenetic silencing responses acting on their genomes upon entry into the host cell nucleus. In this study, we confirmed that unchromatinized herpes simplex virus 1 (HSV-1) genomes enter primary human foreskin fibroblasts and are rapidly subjected to assembly of nucleosomes and association with repressive heterochromatin modifications such as histone 3 (H3) lysine 9-trimethylation (H3K9me3) and lysine 27-trimethylation (H3K27me3) during the first 1 to 2 h postinfection. Kinetic analysis of the modulation of nucleosomes and heterochromatin modifications over the course of lytic infection demonstrates a progressive removal that coincided with initiation of viral gene expression. We obtained evidence for three phases of heterochromatin removal from an early gene promoter: an initial removal of histones and heterochromatin not dependent on ICP0, a second ICP0-dependent round of removal of H3K9me3 that is independent of viral DNA synthesis, and a third phase of H3K27me3 removal that is dependent on ICP0 and viral DNA synthesis. The presence of ICP0 in transfected cells is also sufficient to promote removal of histones and H3K9me3 modifications of cotransfected genes. Overall, these results show that ICP0 promotes histone removal, a reduction of H3K9me3 modifications, and a later indirect reduction of H3K27me3 modifications following viral early gene expression and DNA synthesis. Therefore, HSV ICP0 promotes the reversal of host epigenetic silencing mechanisms by several mechanisms.

IMPORTANCE
The human pathogen herpes simplex virus (HSV) has evolved multiple strategies to counteract host-mediated epigenetic silencing during productive infection. However, the mechanisms by which viral and cellular effectors contribute to these processes are not well defined. The results from this study demonstrate that HSV counteracts host epigenetic repression in a dynamic stepwise process to remove histone 3 (H3) and subsequently target specific heterochromatin modifications in two distinct waves. This provides the first evidence of a stepwise reversal of host epigenetic silencing by viral proteins. This work also suggests that targets capable of disrupting the kinetics of epigenetic regulation could serve as potential antiviral therapeutic agents.
Targeting Autophagy in Dendritic Cells as a Mechanism to Limit Immunopathogenesis in Herpetic Stromal Keratitis
Authors: Blaho John A. 
Published: January 2016

ABSTRACT

In a recent
mBio
article, Y. Jiang, X. Yin, P. M. Stuart, and D. A. Lieb [mBio 6(6):e01426-15, 2015, doi:10.1128/mBio.01426-15] presented an elegant set of experiments that utilized a transgenic, knockout strain of mice whose dendritic cells (DCs) are incapable of undergoing autophagy, to dissect out the aspects of the chronic inflammatory response following viral infection of corneal epithelial cells. The authors’ results provide a potential proof of concept that the DC autophagy pathway may be a valid target for therapeutic drug design in certain inflammatory pathologies.
Small Intestine Bacterial Overgrowth and Environmental Enteropathy in Bangladeshi Children
Authors: Donowitz Jeffrey R. , Haque Rashidul , Kirkpatrick Beth D. , Alam Masud , Lu Miao , Kabir Mamun , Kakon Shahria Hafiz , Islam Bushra Zarin , Afreen Sajia , Musa Abu , Khan Shaila Sharmeen , Colgate E. Ross , Carmolli Marya P. , Ma Jennie Z. , Petri William A. 
Published: January 2016

ABSTRACTRecent studies suggest small intestine bacterial overgrowth (SIBO) is common among developing world children. SIBO’s pathogenesis and effect in the developing world are unclear. Our objective was to determine the prevalence of SIBO in Bangladeshi children and its association with malnutrition. Secondary objectives included determination of SIBO’s association with sanitation, diarrheal disease, and environmental enteropathy. We performed a cross-sectional analysis of 90 Bangladeshi 2-year-olds monitored since birth from an impoverished neighborhood. SIBO was diagnosed via glucose hydrogen breath testing, with a cutoff of a 12-ppm increase over baseline used for SIBO positivity. Multivariable logistic regression was performed to investigate SIBO predictors. Differences in concomitant inflammation and permeability between SIBO-positive and -negative children were compared with multiple comparison adjustment. A total of 16.7% (15/90) of the children had SIBO. The strongest predictors of SIBO were decreased length-for-ageZ score since birth (odds ratio [OR], 0.13; 95% confidence interval [CI], 0.03 to 0.60) and an open sewer outside the home (OR, 4.78; 95% CI, 1.06 to 21.62). Recent or frequent diarrheal disease did not predict SIBO. The markers of intestinal inflammation fecal Reg 1β (116.8 versus 65.6 µg/ml;P= 0.02) and fecal calprotectin (1,834.6 versus 766.7 µg/g;P= 0.004) were elevated in SIBO-positive children. Measures of intestinal permeability and systemic inflammation did not differ between the groups. These findings suggest linear growth faltering and poor sanitation are associated with SIBO independently of recent or frequent diarrheal disease. SIBO is associated with intestinal inflammation but not increased permeability or systemic inflammation.IMPORTANCEA total of 165 million children worldwide are considered stunted, which is associated with increased risk of death prior to age 5 years and cognitive disability. Stunting has, in part, been attributed to the presence of environmental enteropathy. Environmental enteropathy is a poorly understood condition leading to chronic intestinal inflammation. It has been postulated that small intestine bacterial overgrowth contributes to the pathogenesis of environmental enteropathy as overgrowth has been associated with intestinal inflammation and micronutrient malabsorption when it develops in other clinical contexts. This study confirms the finding that overgrowth occurs at high rates in the developing world. This is the first study to show that overgrowth is associated with intestinal inflammation and linear growth delay in this setting and is the first to examine why children with no known gastrointestinal dysfunction develop overgrowth from the developing world environment.
The training—injury prevention paradox: should athletes be training smarterandharder?
Authors: Gabbett Tim J 
Published: January 2016

BackgroundThere is dogma that higher training load causes higher injury rates. However, there is also evidence that training has a protective effect against injury. For example, team sport athletes who performed more than 18 weeks of training before sustaining their initial injuries were at reduced risk of sustaining a subsequent injury, while high chronic workloads have been shown to decrease the risk of injury. Second, across a wide range of sports, well-developed physical qualities are associated with a reduced risk of injury. Clearly, for athletes to develop the physical capacities required to provide a protective effect against injury, they must be prepared to train hard. Finally, there is also evidence thatunder-trainingmay increase injury risk. Collectively, these results emphasise that reductions in workloads may not always be the best approach to protect against injury.Main thesisThis paper describes the ‘Training-Injury Prevention Paradox’ model; a phenomenon whereby athletes accustomed to high training loads havefewerinjuries than athletes training at lower workloads. The Model is based on evidence that non-contact injuries are not caused by training per se,but more likely by an inappropriate training programme. Excessive and rapid increases in training loads are likely responsible for a large proportion of non-contact, soft-tissue injuries. If training load is an important determinant of injury, it must be accurately measured up to twice daily and over periods of weeks and months (a season). This paper outlines ways of monitoring training load (‘internal’ and ‘external’ loads) and suggests capturing both recent (‘acute’) training loads and more medium-term (‘chronic’) training loads to best capture the player's training burden. I describe the critical variable—acute:chronic workload ratio—as a best practice predictor of training-related injuries. This provides the foundation for interventions to reduce players risk, and thus, time-loss injuries.SummaryThe appropriately graded prescription of high training loads should improve players’ fitness, which in turn mayprotectagainst injury, ultimately leading to (1) greater physical outputs and resilience in competition, and (2) a greater proportion of the squad available for selection each week.
Models of antenatal care to reduce and prevent preterm birth: a systematic review and meta-analysis
Authors: Fernandez Turienzo Cristina , Sandall Jane , Peacock Janet L 
Published: January 2016

ObjectiveTo assess the effectiveness of models of antenatal care designed to prevent and reduce preterm birth (PTB) in pregnant women.MethodsWe conducted a search of seven electronic databases and reference lists of retrieved studies to identify trials from inception up to July 2014 where pregnant women, regardless of risk factors for pregnancy complications, were randomly allocated to receive an alternative model of antenatal care or routine care. We pooled risks of PTB to determine the effect of alternative care models in all pregnant women. We also assessed secondary maternal and infant outcomes, women's satisfaction and economic outcomes.Results15 trials involving 22 437 women were included. Pregnant women in alternative care models were less likely to experience PTB (risk ratio 0.84, 95% CI 0.74 to 0.96). The subgroup of women randomised to midwife-led continuity models of antenatal care were less likely to experience PTB (0.78, 0.66 to 0.91) but there was no significant difference between this group and women allocated to specialised care (0.92, 0.76 to 1.12) (interaction test for subgroup differences p=0.20). Overall low-risk women in alternative care models were less likely to have PTB (0.74, 0.59 to 0.93), but this effect was not significantly different from that in mixed-risk populations (0.91, 0.79 to 1.05) (subgroup p=0.13).ConclusionsAlternative models of antenatal care for all pregnant women are effective in reducing PTB compared with routine care, but no firm conclusions could be drawn regarding the relative benefits of the two models. Future research should evaluate the impact of antenatal care models which include more recent interventions and predictive tests, and which also offer continuity of care by midwives throughout pregnancy.PROSPERO registration numberCRD42014007116.
Code Blue: methodology for a qualitative study of teamwork during simulated cardiac arrest
Authors: Clarke Samuel , Carolina Apesoa-Varano Ester , Barton Joseph 
Published: January 2016

IntroductionIn-hospital cardiac arrest (IHCA) is a particularly vexing entity from the perspective of preparedness, as it is neither common nor truly rare. Survival from IHCA requires the coordinated efforts of multiple providers with different skill sets who may have little prior experience working together. Survival rates have remained low despite advances in therapy, suggesting that human factors may be at play.Methods and analysisThis qualitative study uses a quasiethnographic data collection approach combining focus group interviews with providers involved in IHCA resuscitation as well as analysis of video recordings from in situ-simulated cardiac arrest events. Using grounded theory-based analysis, we intend to understand the organisational, interpersonal, cognitive and behavioural dimensions of IHCA resuscitation, and to build a descriptive model of code team functioning.Ethics and disseminationThis ongoing study has been approved by the IRB at UC Davis Medical Center.ResultsThe results will be disseminated in a subsequent manuscript.
Global dietary quality, undernutrition and non-communicable disease: a longitudinal modelling study
Authors: Green Rosemary , Sutherland Jennifer , Dangour Alan D , Shankar Bhavani , Webb Patrick 
Published: January 2016

ObjectivesTo determine the relationship between global dietary energy availability and dietary quality, and nutrition-related health outcomes.DesignA worldwide longitudinal modelling study using country-level data. Data on total dietary energy availability and dietary energy from 10 distinct food groups (as a proxy for dietary quality) were obtained from the FAO Food Balance Sheets database. Indicators of development were abstracted from the World Bank's World Development Indicators database. Data on nutrition and health outcomes were taken from the WHO mortality database and major cross-country analyses. We investigated associations of energy availability from food groups and health and nutrition outcomes in the combined data set using mixed effects models, while adjusting for measures of development.Population124 countries over the period 1980–2009.Main outcome measuresPrevalence of stunting in children under 5 years and mortality rate from ischaemic heart disease (IHD) in adults aged 55+ years.ResultsFrom 1980 to 2009, global dietary energy availability increased, and rates of child stunting and adult IHD mortality declined. After adjustment for measures of development, increased total dietary energy availability was significantly associated with reduced stunting rates (−0.84% per 100 kcal increase in energy, 95% CI −0.97 to −0.72) and non-significantly associated with increased IHD mortality rates (by 4.2 deaths per 100 000/100 kcal increase, 95% CI −1.85 to 10.2). Further analysis demonstrated that the changing availability of energy from food groups (particularly fruit, vegetables, starchy roots, meat, dairy and sugar) was important in explaining the associations with health outcomes.ConclusionsOur study has demonstrated that by combining large, publicly available data sets, important patterns underlying trends in diet-related health can be uncovered. These associations remain even after accounting for measures of development over a 30-year period. Further work and joined-up multisectoral thinking will be required to translate these patterns into policies that can improve nutrition and health outcomes globally.
Association study of TREM2 polymorphism rs75932628 with leucoaraiosis or Parkinson's disease in the Han Chinese population
Authors: Li Zhiming , Zhong Li , Gu Long , Huang Wenqing , Shi Xinzhen , Zhang Xilin , An Xingkai , Lin Qing , Tzeng Chi-Meng 
Published: January 2016

ObjectivesThe previously reported functional mutation rs75932628-T (p.R47H) in the triggering receptor expressed on myeloid cells 2 (TREM2) is a genetic risk factor for Alzheimer's disease, Parkinson's disease (PD) and frontotemporal dementia, in European populations. This study aims to assess the genetic association of the variant rs75932628-T with PD and leucoaraiosis (LA) in a Han Chinese population.SettingThis population-based study was conducted in China by Xiamen University and its affiliated hospital.Participants308 patients with LA, 342 patients with PD and 198 healthy blood donors were recruited from the First Affiliated Hospital of Xiamen University.Outcome measuresGenotyping was performed by molecular beacon real-time PCR and Sanger sequencing.ResultsNone of our participants carried the rs75932628-T mutation.ConclusionsOur results corroborate and extend previous findings, concluding that the variant rs75932628-T (p.R47H) in TREM2 is not a risk factor for LA or PD in the Han Chinese population.
Exploring general practitioners’ views and experiences on suicide risk assessment and management of young people in primary care: a qualitative study in the UK
Authors: Michail Maria , Tait Lynda 
Published: January 2016

ObjectiveTo explore general practitioner (GP) views and experiences of assessing, communicating with and managing suicidal young people with the aim of co-producing an educational intervention on youth suicide prevention tailored to GPs’ perceived needs.DesignQualitative focus group study using framework analysis.Setting5 inner city general practices in Nottingham.Participants28 GPs took part (9 males) with mean age of 37 years. The median number of years of professional experience was 13. Participants were recruited through convenience sampling based on accessibility, interest in the study and willingness to participate.Results3 themes emerged from the data in relation to GP's attitudes and beliefs towards suicide; the challenges GPs experience when it comes to the assessment and management of suicide risk in young people; and optimal ways of addressing some of these challenges through the provision of specialist education and training targeting GPs’ knowledge and clinical skills in this field.ConclusionsThe findings revealed wide variations in the understanding and operationalisation of risk among GPs, which has subsequent implications to how GPs perceive risk should be assessed. GP education on suicide risk assessment and management in youth should promote a holistic understanding and assessment of risk and its individual, social and contextual influences.
Preoperative prediction of potentially preventable morbidity after fast-track hip and knee arthroplasty: a detailed descriptive cohort study
Authors: Jørgensen Christoffer C , Petersen Morten Aa , Kehlet Henrik 
Published: January 2016

ObjectivesConstruction of a simple preoperative risk score for patients in high risk of potentially preventable ‘medical’ complications. Secondary objectives were to construct simple preoperative risk scores for ‘severe medical’, ‘surgical’ and ‘total’ potentially preventable complications.DesignProspective observational study.SettingElective primary unilateral total hip and knee arthroplasty with prospectively collected preoperative patient characteristics; similar standardised fast-track protocols; evaluation of complications through discharge and medical records; and complete 90 days follow-up through nationwide databases.Participants8373 consecutive unselected total hip arthroplasty (THA) and knee arthroplasty from January 2010 to November 2012.ResultsThere were 557 procedures (6.4%) followed by potentially preventable complications resulting in hospitalisation >4 days or readmission. Of 22 preoperative characteristics, 7 were associated with 379 (4.2%) potentially preventable ‘medical’ complications. Patients with ≥2 of the following, age ≥80 years, anticoagulant therapy, pulmonary disease, pharmacologically treated psychiatric disorder, anaemia and walking aids, composed 19.1% of the procedures; 55.7% constituted potentially preventable ‘medical’ complications that were mainly falls, mobilisation issues, pneumonias and cardiac arrhythmias. The number needed to be treated for a hypothetical intervention leading to 25% reduction in potentially preventable ‘medical’ complications was 34. THA, use of walking aids and cardiac disease were associated with 189 (2.2%) ‘surgical’ complications, but no clinically relevant preoperative prediction was possible.ConclusionsPreoperative identification of patients at high risk of preventable ‘medical’, but not ‘surgical’, complications is statistically possible. However, clinical relevance is limited. Future risk indices should differ between ‘medical’ and ‘surgical’ complications, and also consider ‘preventability’ of these.Trial registration numberNCT01515670.