bluuebunny/crossref_metadata_2025_split huggingface dataset:
RalF-Mediated Activation of Arf6 Controls Rickettsia typhi Invasion by Co-Opting Phosphoinositol Metabolism
Authors: Rennoll-Bankert Kristen E. , Rahman M. Sayeedur , Guillotte Mark L. , Lehman Stephanie S. , Beier-Sexton Magda , Gillespie Joseph J. , Azad Abdu F. 
Published: October 2016

ABSTRACT

Rickettsiae are obligate intracellular pathogens that induce their uptake into nonphagocytic cells; however, the events instigating this process are incompletely understood. Importantly, diverse
Rickettsia
species are predicted to utilize divergent mechanisms to colonize host cells, as nearly all adhesins and effectors involved in host cell entry are differentially encoded in diverse
Rickettsia
species. One particular effector, RalF, a Sec7 domain-containing protein that functions as a guanine nucleotide exchange factor of ADP-ribosylation factors (Arfs), is critical for
Rickettsia typhi
(typhus group rickettsiae) entry but pseudogenized or absent from spotted fever group rickettsiae. Secreted early during
R. typhi
infection, RalF localizes to the host plasma membrane and interacts with host ADP-ribosylation factor 6 (Arf6). Herein, we demonstrate that RalF activates Arf6, a process reliant on a conserved Glu within the RalF Sec7 domain. Furthermore, Arf6 is activated early during infection, with GTP-bound Arf6 localized to the
R. typhi
entry foci. The regulation of phosphatidylinositol 4-phosphate 5-kinase (PIP5K), which generates PI(4,5)P
2
, by activated Arf6 is instrumental for bacterial entry, corresponding to the requirement of PI(4,5)P
2
for
R. typhi
entry. PI(3,4,5)P
3
is then synthesized at the entry foci, followed by the accumulation of PI(3)P on the short-lived vacuole. Inhibition of phosphoinositide 3-kinases, responsible for the synthesis of PI(3,4,5)P
3
and PI(3)P, negatively affects
R. typhi
infection. Collectively, these results identify RalF as the first bacterial effector to directly activate Arf6, a process that initiates alterations in phosphoinositol metabolism critical for a lineage-specific
Rickettsia
entry mechanism.
Macrophages Promote Oxidative Metabolism To Drive Nitric Oxide Generation in Response to Trypanosoma cruzi
Authors: Koo Sue-jie , Chowdhury Imran H. , Szczesny Bartosz , Wan Xianxiu , Garg Nisha J. 
Published: October 2016

ABSTRACTTrypanosoma cruziis the causative agent of chronic chagasic cardiomyopathy. Why macrophages (mφs), the early responders to infection, fail to achieve parasite clearance is not known. Mouse (RAW 264.7) and human (THP-1 and primary) mφs were infected for 3 h and 18 h withT. cruziTcI isolates, SylvioX10/4 (SYL, virulent) and TCC (nonpathogenic), which represent mφ stimulation and infection states, respectively. Mφs incubated with lipopolysaccharide and gamma interferon (LPS/IFN-γ) and with interleukin-4 (IL-4) were used as controls. We monitored the cytokine profile (using enzyme-linked immunosorbent assay [ELISA]), reactive oxygen species (ROS; fluorescent probes), nitric oxide (·NO; Griess assay), and metabolic state using a custom-designed mitoxosome array and Seahorse XF24 Analyzer. LPS/IFN-γ treatment of mφs elicited a potent increase in production of tumor necrosis alpha (TNF-α) at 3 h and of ROS and ·NO by 18 h. Upon SYL infection, murine mφs elicited an inflammatory cytokine profile (TNF-α ≫ TGF-β + IL-10) and low levels of ·NO and ROS production. LPS/IFN-γ treatment resulted in the inhibition of oxidative metabolism at the gene expression and functional levels and a switch to the glycolytic pathway in mφs, while IL-4-treated mφs utilized oxidative metabolism to meet energy demands. SYL infection resulted in an intermediate functional metabolic state with increased mitoxosome gene expression and glycolysis, and IFN-γ addition shut down the oxidative metabolism in SYL-infected mφs. Further, TCC- and SYL-stimulated mφs exhibited similar levels of cell proliferation and production of TNF-α and ROS, while TCC-stimulated mφs exhibited up to 2-fold-higher levels of oxidative metabolism and ·NO production than SYL-infected mφs. Inhibiting ATP-coupled O2consumption suppressed the ·NO generation in SYL-infected mφs. Mitochondrial oxygen consumption constitutes a mechanism for stimulating ·NO production in mφs duringT. cruziinfection. Enhancing the oxidative metabolism provides an opportunity for increased ·NO production and pathogen clearance by mφs to limit disease progression.
The Phosphorolytic Exoribonucleases Polynucleotide Phosphorylase and RNase PH Stabilize sRNAs and Facilitate Regulation of Their mRNA Targets
Authors: Cameron Todd A. , De Lay Nicholas R. 
Published: October 2016

ABSTRACT

Gene regulation by base pairing between small noncoding RNAs (sRNAs) and their mRNA targets is an important mechanism that allows bacteria to maintain homeostasis and respond to dynamic environments. In Gram-negative bacteria, sRNA pairing and regulation are mediated by several RNA-binding proteins, including the sRNA chaperone Hfq and polynucleotide phosphorylase (PNPase). PNPase and its homolog RNase PH together represent the two 3′ to 5′ phosphorolytic exoribonucleases found in
Escherichia coli
; however, the role of RNase PH in sRNA regulation has not yet been explored and reported. Here, we have examined in detail how PNPase and RNase PH interact to support sRNA stability, activity, and base pairing in exponential and stationary growth conditions. Our results indicate that these proteins facilitate the stability and regulatory function of the sRNAs RyhB, CyaR, and MicA during exponential growth. PNPase further appears to contribute to pairing between RyhB and its mRNA targets. During stationary growth, each sRNA responded differently to the absence or presence of PNPase and RNase PH. Finally, our results suggest that PNPase and RNase PH stabilize only Hfq-bound sRNAs. Taken together, these results confirm and extend previous findings that PNPase participates in sRNA regulation and reveal that RNase PH serves a similar, albeit more limited, role as well. These proteins may, therefore, act to protect sRNAs from spurious degradation while also facilitating regulatory pairing with their targets.

IMPORTANCE
In many bacteria, Hfq-dependent base-pairing sRNAs facilitate rapid changes in gene expression that are critical for maintaining homeostasis and responding to stress and environmental changes. While a role for Hfq in this process was identified more than 2 decades ago, the identity and function of the other proteins required for Hfq-dependent regulation by sRNAs have not been resolved. Here, we demonstrate that PNPase and RNase PH, the two phosphorolytic RNases in
E. coli
, stabilize sRNAs against premature degradation and, in the case of PNPase, also accelerate regulation by sRNA-mRNA pairings for certain sRNAs. These findings are the first to demonstrate that RNase PH influences and supports sRNA regulation and suggest shared and distinct roles for these phosphorolytic RNases in this process.
Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract
Authors: Birder Lori A. , Klumpp David J. 
Published: October 2016

ABSTRACT
Urinary tract infection (UTI) pathogenesis is understood increasingly at the level of the uropathogens and the cellular and molecular mediators of host inflammatory responses. However, little is known about the mediators of symptoms during UTI and what distinguishes symptomatic events from asymptomatic bacteriuria. Here, we review bladder physiology and sensory pathways in the context of an emerging literature from murine models dissecting the host and pathogen factors mediating pain responses during UTI. The bladder urothelium is considered a mediator of sensory responses and appears to play a role in UTI pain responses. Virulence factors of uropathogens induce urothelial damage that could trigger pain due to compromised bladder-barrier function. Instead, bacterial glycolipids are the major determinants of UTI pain independent of urothelial damage, and the O-antigen of lipopolysaccharide modulates pain responses. The extent of pain modulation by O-antigen can have profound effects, from abolishing pain responses to inducing chronic pain that results in central nervous system features reminiscent of neuropathic pain. Although these effects are largely dependent upon Toll-like receptors, pain is independent of inflammation. Surprisingly, some bacteria even possess analgesic properties, suggesting that bacteria exhibit a wide range of pain phenotypes in the bladder. In summary, UTI pain is a complex form of visceral pain that has significant potential to inform our understanding of bacterial pathogenesis and raises the specter of chronic pain resulting from transient infection, as well as novel approaches to treating pain.
Evidence from prospective cohort studies does not support current dietary fat guidelines: a systematic review and meta-analysis
Authors: Harcombe Zoë , Baker Julien S , Davies Bruce 
Published: October 2016

ObjectivesNational dietary guidelines were introduced in 1977 and 1983, by the US and UK governments to reduce coronary heart disease (CHD) mortality by reducing dietary fat intake. Our 2016 systematic review examined the epidemiological evidence available to the dietary committees at the time; we found no support for the recommendations to restrict dietary fat. The present investigation extends our work by re-examining the totality of epidemiological evidence currently available relating to dietary fat guidelines.MethodsA systematic review and meta-analysis of prospective cohort studies currently available, which examined the relationship between dietary fat, serum cholesterol and the development of CHD, were undertaken.ResultsAcross 7 studies, involving 89 801 participants (94% male), there were 2024 deaths from CHD during the mean follow-up of 11.9±5.6 years. The death rate from CHD was 2.25%. Eight data sets were suitable for inclusion in meta-analysis; all excluded participants with previous heart disease. Risk ratios (RRs) from meta-analysis were not statistically significant for CHD deaths and total or saturated fat consumption. The RR from meta-analysis for total fat intake and CHD deaths was 1.04 (95% CI 0.98 to 1.10). The RR from meta-analysis for saturated fat intake and CHD deaths was 1.08 (95% CI 0.94 to 1.25).ConclusionsEpidemiological evidence to date found no significant difference in CHD mortality and total fat or saturated fat intake and thus does not support the present dietary fat guidelines. The evidence per se lacks generalisability for population-wide guidelines.
Prevalence, discomfort and self-relief behaviours of painful diabetic neuropathy in Taiwan: a cross-sectional study
Authors: Jane Sui-Whi , Lin Ming-Shyan , Chiu Wen-Nan , Beaton Randal D , Chen Mei-Yen 
Published: October 2016

ObjectivesTo explore the prevalence, discomfort, and self-relief behaviours of painful diabetic neuropathy (PDN) among rural community residents with type 2 diabetes.DesignA community-based, cross-sectional study.SettingThis study was part of a longitudinal cohort study of a nurse-led health promotion programme for preventing foot ulceration in Chiayi County, Taiwan.ParticipantsSix hundred and twenty-eight community adults with type 2 diabetes participated in this study.Outcome measuresParameters assessed included peripheral neuropathy, peripheral vasculopathy, glycaemic control and metabolic biomarkers. Statistical analyses included descriptive statistics and a multivariate logistic regression model.ResultsAbout 30.6% of participants (192/628) had PDN. Factors associated with PDN included an abnormal ankle brachial index (ABI; OR=3.4; 95% CI 1.9 to 6.2; p<0.001), Michigan neuropathy screening index (OR=1.69; 95% CI 1.0 to 2.6; p=0.021), triglyceride level (OR=1.61; 95% CI 1.0 to 2.4; p=0.036) and being female (OR=1.68; 95% CI 1.1 to 2.4; p=0.022). PDN was characterised by uncomfortable feelings of prickling, stinging or burning pain and inexplicable dullness around the base or dorsal areas of the feet, but received little attention or treatment from primary healthcare providers.ConclusionsA high prevalence of PDN was found in rural community residents with type 2 diabetes and the healthcare workers provided little attention to, or treatment of, discomfort. It is important to identify high-risk groups with PDN early in order to prevent foot ulceration and reduce the incidence of amputation of the extremities. It is also urgent to develop appropriate treatment and self-relief behaviours to halt or reverse the progression of PDN for this population living in rural areas.
Current practices in patient-reported outcome (PRO) data collection in clinical trials: a cross-sectional survey of UK trial staff and management
Authors: Kyte Derek , Ives Jonathan , Draper Heather , Calvert Melanie 
Published: October 2016

ObjectivesPatient-reported outcome measures (PROMs) collected in clinical trials should be administered in a standardised way across sites and routinely screened for avoidable missing data in order to maximise data quality/minimise risk of bias. Recent qualitative findings, however, have raised concerns about the consistency of PROM administration in UK trials. The purpose of this study was to determine the generalisability of these findings across the wider community of trial personnel.DesignOnline cross-sectional survey.SettingParticipants were recruited from 55 UK Clinical Research Collaboration Registered Clinical Trials Units and 19 Comprehensive Local Research Networks.ParticipantsResearch nurses, data managers/coordinators, trial managers and chief/principal investigators involved in clinical trials collecting PROMs.AnalysisWe undertook descriptive analyses of the quantitative data and directed thematic analysis of free-text comments. Factors associated with the management of missing PRO data were explored using logistic regression.ResultsSurvey data from 767 respondents supported the generalisability of qualitative study findings, suggesting inconsistencies in PROM administration with regard to: the level of assistance given to trial participants; the timing of PROM completion in relation to the clinical consultation; and the management of missing data. Having ≥10 years experience in a research role was significantly associated with the appropriate management of missing PROM data (OR 2.26 (95% CI 1.06 to 4.82), p=0.035). There was a consensus that more PROM guidance was needed in future trials and agreement between professional groups about the necessary components.ConclusionsThere are inconsistencies in the way PROMs are administered by trial staff. Such inconsistencies may reduce the quality of data and have the potential to introduce bias. There is a need for improved guidance in future trials that support trial personnel in conducting optimal PROM data collection to inform patient care.
Community-based Rehabilitation Training after stroke: protocol of a pilot randomised controlled trial (ReTrain)
Authors: Dean Sarah G , Poltawski Leon , Forster Anne , Taylor Rod S , Spencer Anne , James Martin , Allison Rhoda , Stevens Shirley , Norris Meriel , Shepherd Anthony I , Calitri Raff 
Published: October 2016

IntroductionThe Rehabilitation Training (ReTrain) intervention aims to improve functional mobility, adherence to poststroke exercise guidelines and quality of life for people after stroke. A definitive randomised controlled trial (RCT) is required to assess the clinical and cost-effectiveness of ReTrain, which is based on Action for Rehabilitation from Neurological Injury (ARNI). The purpose of this pilot study is to assess the feasibility of such a definitive trial and inform its design.Methods and analysisA 2-group, assessor-blinded, randomised controlled external pilot trial with parallel mixed-methods process evaluation and economic evaluation. 48 participants discharged from clinical rehabilitation despite residual physical disability will be individually randomised 1:1 to ReTrain (25 sessions) or control (exercise advice booklet). Outcome assessment at baseline, 6 and 9 months include Rivermead Mobility Index; Timed Up and Go Test; modified Patient-Specific Functional Scale; 7-day accelerometry; Stroke Self-efficacy Questionnaire, exercise diary, Fatigue Assessment Scale, exercise beliefs and self-efficacy questionnaires, SF-12, EQ-5D-5L, Stroke Quality of Life, Carer Burden Index and Service Receipt Inventory. Feasibility, acceptability and process outcomes include recruitment and retention rates; with measurement burden and trial experiences being explored in qualitative interviews (20 participants, 3 intervention providers). Analyses include descriptive statistics, with 95% CI where appropriate; qualitative themes; intervention fidelity from videos and session checklists; rehearsal of health economic analysis.Ethics and disseminationNational Health Service (NHS) National Research Ethics Service approval granted in April 2015; recruitment started in June. Preliminary studies suggested low risk of serious adverse events; however (minor) falls, transitory muscle soreness and high levels of postexercise fatigue are expected. Outputs include pilot data to inform whether to proceed to a definitive RCT and support a funding application; finalised Trainer and Intervention Delivery manuals for multicentre replication of ReTrain; presentations at conferences, public involvement events; internationally recognised peer-reviewed journal publications, open access sources and media releases.Trial registration numberNCT02429180; Pre-results.
Study protocol of the YP Face IT feasibility study: comparing an online psychosocial intervention versus treatment as usual for adolescents distressed by appearance-altering conditions/injuries
Authors: Williamson Heidi , Hamlet Claire , White Paul , Marques Elsa M R , Cadogan Julia , Perera Rohan , Rumsey Nichola , Hayward Leighton , Harcourt Diana 
Published: October 2016

IntroductionA significant number of adolescents suffer extensive and enduring difficulties such as social anxiety, body image dissatisfaction, low self-esteem and bullying as a result of conditions or injuries that affect their appearance (eg, craniofacial and skin conditions, treatment side effects and scarring). Evidence-based psychosocial interventions to meet their specific needs are currently lacking. YP Face IT, developed by the UK's Centre for Appearance Research in collaboration with clinical experts and young people, is an innovative online psychosocial intervention designed to offer this group immediate support, advice and coping strategies. It has been endorsed by young people, their parents/carers, GPs, clinical psychologists and health professionals working with those affected by appearance-related conditions.Methods and analysisYoung people aged 12–17 with an appearance-altering condition/injury that self-identify as experiencing appearance-related distress, teasing or bullying will be invited to participate via GP practices and UK charities. Consenting participants will be randomised to the intervention (YP Face IT) or the treatment as usual (TAU) control group. Outcome measures will be completed by young people and their parents/carers at baseline, 13, 26 and 52 weeks. Primary outcome measures will be the Body Esteem Scale and the Social Anxiety Scale for Adolescents. Participants will complete other health-related outcome measures and resource use questionnaires for health economic analysis. We will assess recruitment rates, acceptability of the YP Face IT programme, adherence and retention to treatment, questionnaire completion rates, variation of TAU in Primary Care and the feasibility of GP practice staff supervising young people's use of YP Face IT.Ethics and disseminationThis feasibility trial protocol (V.1, 3 March 2014), received a favourable ethical opinion from the NRES Committee South West-Frenchay (reference number 14/SW/0058). Findings will be disseminated through academic peer-reviewed publications, conferences and to participating GP practices and charities supporting those with conditions affecting appearance.Trial registration numberISRCTN40650639; Pre-results.
Developing Quality Improvement capacity and capability across the Children in Fife partnership
Authors: Morris Craig , Alexander Ingrid 
Published: October 2016

A Project Manager from the Fife Early Years Collaborative facilitated a large-scale Quality Improvement (herein QI) project to build organisational capacity and capability across the Children in Fife partnership through three separate, eight month training cohorts.This 18 month QI project enabled 32 practitioners to increase their skills, knowledge, and experiences in a variety of QI tools including the Model for Improvement which then supported the delivery of high quality improvement projects and improved outcomes for children and families. Essentially growing the confidence and capability of practitioners to deliver sustainable QI.27 respective improvement projects were delivered, some leading to service redesign, reduced waiting times, increased uptake of health entitlements, and improved accessibility to front-line health services. 13 improvement projects spread or scaled beyond the initial site and informal QI mentoring took place with peers in respective agencies. Multiple PDSA cycles were conducted testing the most efficient and effective support mechanisms during and post training, maintaining regular contact, and utilising social media to share progress and achievements.
Presentation of neurogenic shock within the emergency department
Authors: Taylor Matthew Pritam , Wrenn Paul , O'Donnell Andrew David 
Published: October 2016

BackgroundInjury to the spinal cord can result in loss of sympathetic innervation causing a drop in BP and HR, this condition is known as neurogenic shock. There is debate among the literature on how and when neurogenic shock presents and what values of HR and BP should be used to define it. Previous studies do not take into account multiple prehospital and emergency department recordings.ObjectiveTo improve understanding of how neurogenic shock presents in humans, allowing better identification and treatment.MethodsThe Trauma Audit and Research Network database for an adult major trauma centre was used to isolate patients with a spinal cord injury. Qualifying patients had all available BPs and HRs collated into a database. Patients with neurogenic shock were isolated, allowing data analysis.ResultsOut of 3069 trauma patients, 33 met the inclusion criteria, of which 15 experienced neurogenic shock. 87% of the patients who had neurogenic shock experienced it within 2 hours of injury. Neurogenic shock below the T6 level was less common (p=0.009); however, there were still four cases in the cohort. More patients with complete spinal cord injury had neurogenic shock (p=0.039).ConclusionsNeurogenic shock is variable and unpredictable. It can present in the prehospital environment and without warning in a patient with previously normal vital signs. The medical team should be aware of it in all patients with spinal cord injury regardless of injury level.