bluuebunny/crossref_metadata_2025_split huggingface dataset:
PPE Surface Proteins Are Required for Heme Utilization by
Mycobacterium tuberculosis
Authors: Mitra Avishek , Speer Alexander , Lin Kan , Ehrt Sabine , Niederweis Michael 
Published: January 2017

ABSTRACT

Iron is essential for replication of
Mycobacterium tuberculosis
, but iron is efficiently sequestered in the human host during infection. Heme constitutes the largest iron reservoir in the human body and is utilized by many bacterial pathogens as an iron source. While heme acquisition is well studied in other bacterial pathogens, little is known in
M. tuberculosis
. To identify proteins involved in heme utilization by
M. tuberculosis
, a transposon mutant library was screened for resistance to the toxic heme analog gallium(III)-porphyrin (Ga-PIX). Inactivation of the
ppe36
,
ppe62
, and
rv0265c
genes resulted in resistance to Ga-PIX. Growth experiments using isogenic
M. tuberculosis
deletion mutants showed that PPE36 is essential for heme utilization by
M. tuberculosis
, while the functions of PPE62 and Rv0265c are partially redundant. None of the genes restored growth of the heterologous
M. tuberculosis
mutants, indicating that the proteins encoded by the genes have separate functions. PPE36, PPE62, and Rv0265c bind heme as shown by surface plasmon resonance spectroscopy and are associated with membranes. Both PPE36 and PPE62 proteins are cell surface accessible, while the Rv0265c protein is probably located in the periplasm. PPE36 and PPE62 are, to our knowledge, the first proline-proline-glutamate (PPE) proteins of
M. tuberculosis
that bind small molecules and are involved in nutrient acquisition. The absence of a virulence defect of the
ppe36
deletion mutant indicates that the different iron acquisition pathways of
M. tuberculosis
may substitute for each other during growth and persistence in mice. The emerging model of heme utilization by
M. tuberculosis
as derived from this study is substantially different from those of other bacteria.

IMPORTANCE
Tuberculosis is caused by
Mycobacterium tuberculosis
and is a devastating disease affecting eight million people each year. Iron is an essential nutrient for replication of
M. tuberculosis
in the human host. More than 70% of iron in the human body is bound in heme. Not surprisingly, many bacterial pathogens, including
M. tuberculosis
, are able to acquire iron from heme. However, the mechanism of heme uptake by
M. tuberculosis
is poorly understood. We have identified two novel surface proteins that bind heme and are required for heme utilization by
M. tuberculosis
. These findings constitute a major advancement of our understanding of iron acquisition by
M. tuberculosis
and show that
M. tuberculosis
has evolved heme uptake systems different from the paradigms established by other bacteria.
Autoinducer 2 Signaling via the Phosphotransferase FruA Drives Galactose Utilization by
Streptococcus pneumoniae
, Resulting in Hypervirulence
Authors: Trappetti Claudia , McAllister Lauren J. , Chen Austen , Wang Hui , Paton Adrienne W. , Oggioni Marco R. , McDevitt Christopher A. , Paton James C. 
Published: January 2017

ABSTRACT

Communication between bacterial cells is crucial for the coordination of diverse cellular processes that facilitate environmental adaptation and, in the case of pathogenic species, virulence. This is achieved by the secretion and detection of small signaling molecules called autoinducers, a process termed quorum sensing. To date, the only signaling molecule recognized by both Gram-positive and Gram-negative bacteria is autoinducer 2 (AI-2), synthesized by the metabolic enzyme LuxS (
S
-ribosylhomocysteine lyase) as a by-product of the activated methyl cycle. Homologues of LuxS are ubiquitous in bacteria, suggesting a key role in interspecies, as well as intraspecies, communication. Gram-negative bacteria sense and respond to AI-2 via the Lsr ABC transporter system or by the LuxP/LuxQ phosphorelay system. However, homologues of these systems are absent from Gram-positive bacteria and the AI-2 receptor is unknown. Here we show that in the major human pathogen
Streptococcus pneumoniae
, sensing of exogenous AI-2 is dependent on FruA, a fructose-specific phosphoenolpyruvate-phosphotransferase system that is highly conserved in Gram-positive pathogens. Importantly, AI-2 signaling via FruA enables the bacterium to utilize galactose as a carbon source and upregulates the Leloir pathway, thereby leading to increased production of capsular polysaccharide and a hypervirulent phenotype.

IMPORTANCE
S. pneumoniae
is a Gram-positive bacterium frequently carried asymptomatically in the human nasopharynx. However, in a proportion of cases, it can spread to other sites of the body, causing life-threatening diseases that translate into massive global morbidity and mortality. Our data show that AI-2 signaling via FruA promotes the transition of the pneumococcus from colonization to invasion by facilitating the utilization of galactose, the principal sugar available in the upper respiratory tract. AI-2-mediated upregulation of Leloir pathway enzymes results in increased production of capsular polysaccharide and hypervirulence in a murine intranasal challenge model. This identifies the highly conserved FruA phosphotransferase system as a target for new antimicrobials based on the disruption of this generic quorum-sensing system.
α-Defensin HD5 Inhibits Human Papillomavirus 16 Infection via Capsid Stabilization and Redirection to the Lysosome
Authors: Wiens Mayim E. , Smith Jason G. 
Published: January 2017

ABSTRACT

α-Defensins are an important class of abundant innate immune effectors that are potently antiviral against a number of nonenveloped viral pathogens; however, a common mechanism to explain their ability to block infection by these unrelated viruses is lacking. We previously found that human defensin 5 (HD5) blocks a critical host-mediated proteolytic processing step required for human papillomavirus (HPV) infection. Here, we show that bypassing the requirement for this cleavage failed to abrogate HD5 inhibition. Instead, HD5 altered HPV trafficking in the cell. In the presence of an inhibitory concentration of HD5, HPV was internalized and reached the early endosome. The internalized capsid became permeable to antibodies and proteases; however, HD5 prevented dissociation of the viral capsid from the genome, reduced viral trafficking to the
trans
-Golgi network, redirected the incoming viral particle to the lysosome, and accelerated the degradation of internalized capsid proteins. This mechanism is equivalent to the mechanism by which HD5 inhibits human adenovirus. Thus, our data support capsid stabilization and redirection to the lysosome during infection as a general antiviral mechanism of α-defensins against nonenveloped viruses.

IMPORTANCE
Although the antiviral activity of α-defensins against enveloped viruses can be largely explained by interference with receptor binding and fusion, a common mechanism for inhibition of nonenveloped viruses remains elusive. In studies of a prominent human α-defensin that is expressed in the gut and in the male and female genitourinary tract, we discovered striking parallels between the mechanisms of inhibition of HPV and human adenovirus infection. Thus, detailed studies of the impact of α-defensins on the intracellular trafficking of two disparate viruses support a general mechanism of α-defensin antiviral activity against nonenveloped viruses.
Are age-appropriate antibiotic formulations missing from the WHO list of essential medicines for children? A comparison study
Authors: Ivanovska Verica , Leufkens Hubert G , Rademaker Carin MA , Zisovska Elizabeta , Pijnenburg Mariëlle W , van Dijk Liset , Mantel-Teeuwisse Aukje K 
Published: January 2017

ObjectiveThere is a global call for formulations, which are better suited for children of different age categories and in a variety of settings. One key public health area of interest is age-appropriate paediatric antibiotics. We aimed to identify clinically relevant paediatric formulations of antibiotics listed on pertinent formularies that were not on the WHO Essential Medicines List for Children (EMLc).MethodsWe compared four medicines lists versus the EMLc and contrasted paediatric antibiotic formulations in relation to administration routes, dosage forms and/or drug strengths. The additional formulations on comparator lists that differed from the EMLc formulations were evaluated for their added clinical values and costs.ResultsThe analysis was based on 26 EMLc antibiotics. Seven oral and two parenteral formulations were considered clinically relevant for paediatric use. Frequently quoted benefits of oral formulations included: filling the gap of unmet therapeutic needs in certain age/weight groups (phenoxymethylpenicillin and metronidazole oral liquids, and nitrofurantoin capsules), and simplified administration and supply advantages (amoxicillin dispersible tablets, clyndamycin capsules, cloxacillin tablets, and sulfamethoxazole+trimethoprim tablets). Lower doses of ampicillin and cefazolin powder for injection could simplify the dosing in newborns and infants, reduce the risk of medical errors, and decrease the waste of medicines, but may target only narrow age/weight groups.ConclusionsThe identified additional formulations of paediatric antibiotics on comparator lists may offer clinical benefits for low-resource settings, including simplified administration and increased dosing accuracy. The complexity of both procuring and managing multiple strengths and formulations also needs to be considered.
Anaesthesia modalities during laser photocoagulation for retinopathy of prematurity: a retrospective, longitudinal study
Authors: Jiang Jing-bo , Strauss Randy , Luo Xian-qiong , Nie Chuan , Wang Yan-li , Zhang Jia-wen , Zhang Zhi-wei 
Published: January 2017

ObjectivesLaser photocoagulation surgery is a routine treatment for threshold retinopathy of prematurity (ROP). However, little is known about which anaesthesia protocols provide efficient pain control while minimising exposure risk to vulnerable infants. In this study, therefore, we assessed the efficacy and tolerability of multiple anaesthesia techniques used on premature infants during laser therapy.Design and main outcome measuresAnaesthesia modalities consisted of topical eye drops anaesthesia, general anaesthesia and intravenous fentanyl sedation with mechanical ventilation. Laser treatment efficacy and detailed operative information were retrospectively and consecutively analysed. Cardiorespiratory stability was assessed and compared. The Neonatal Pain Agitation and Sedation Scale (N-PASS) was used to evaluate tolerability in infants that underwent intravenous fentanyl sedation.Results97 cases of prematurity were included in this study. In 94/97 (96.9%) cases, vascular proliferation regressed. In the topical anaesthesia groups, the ophthalmologist needed 12–16 min more to complete the treatment. During the 3 postoperative days, topical anaesthesia demonstrated the greatest instability; 4/31 (12.90%) infants in this group suffered from life threatening events requiring resuscitation. The only instability observed in general anaesthesia and fentanyl sedation was attributed to difficulty in extubating within 24 hours after surgery. During laser therapy, the N-PASS score increased to 1.8 in the fentanyl sedation group.ConclusionsTopical anaesthesia was associated with more cardiorespiratory instability during ROP laser treatment. While general anaesthesia and fentanyl sedation had similar postoperative cardiorespiratory results, the latter demonstrated acceptable pain stress control. However, the difficulty of weaning off mechanical ventilation in some cases after surgery needs to be addressed in future studies.
Survival prospects after acute myocardial infarction in the UK: a matched cohort study 1987–2011
Authors: Gitsels Lisanne A , Kulinskaya Elena , Steel Nicholas 
Published: January 2017

ObjectivesEstimate survival after acute myocardial infarction (AMI) in the general population aged 60 and over and the effect of recommended treatments.DesignCohort study in the UK with routinely collected data between January 1987 and March 2011.Setting310 general practices that contributed to The Health Improvement Network (THIN) database.Participants4 cohorts who reached the age of 60, 65, 70, or 75 years between 1987 and 2011 included 16 744, 43 528, 73 728, and 76 392 participants, respectively. Participants with a history of AMI were matched on sex, year of birth, and general practice to 3 controls each.Outcome measuresThe hazard of all-cause mortality associated with AMI was calculated by a multilevel Cox's proportional hazards regression, adjusted for sex, year of birth, socioeconomic status, angina, heart failure, other cardiovascular conditions, chronic kidney disease, diabetes, hypertension, hypercholesterolaemia, alcohol consumption, body mass index, smoking status, coronary revascularisation, prescription of β-blockers, ACE inhibitors, calcium-channel blockers, aspirin, or statins, and general practice.ResultsCompared with no history of AMI by age 60, 65, 70, or 75, having had 1 AMI was associated with an adjusted hazard of mortality of 1.80 (95% CI 1.60 to 2.02), 1.71 (1.59 to 1.84), 1.50 (1.42 to 1.59), or 1.45 (1.38 to 1.53), respectively, and having had multiple AMIs with a hazard of 1.92 (1.60 to 2.29), 1.87 (1.68 to 2.07), 1.66 (1.53 to 1.80), or 1.63 (1.51 to 1.76), respectively. Survival was better after statins (HR range across the 4 cohorts 0.74–0.81), β-blockers (0.79–0.85), or coronary revascularisation (in first 5 years) (0.72–0.80); unchanged after calcium-channel blockers (1.00–1.07); and worse after aspirin (1.05–1.10) or ACE inhibitors (1.10–1.25).ConclusionsThe hazard of death after AMI is less than reported by previous studies, and standard treatments of aspirin or ACE inhibitors prescription may be of little benefit or even cause harm.
Sing Your Lungs Out—a community singing group for chronic obstructive pulmonary disease: a 1-year pilot study
Authors: McNaughton Amanda , Weatherall Mark , Williams Mathew , McNaughton Harry , Aldington Sarah , Williams Gayle , Beasley Richard 
Published: January 2017

ObjectiveSinging group participation may benefit patients with chronic obstructive pulmonary disease (COPD). Previous studies are limited by small numbers of participants and short duration of generally hospital-based singing group intervention. This study examines the feasibility of long-term participation in a community singing group for patients with COPD who had completed pulmonary rehabilitation (PR).MethodsThis was a feasibility cohort study. Patients with COPD who had completed PR and were enrolled in a weekly community exercise group were recruited to a new community-based singing group which met weekly for over 1 year. Measurements at baseline, 4 months and 1 year comprised comprehensive pulmonary function tests including lung volumes, 6 min walk test (6MWT), Clinical COPD Questionnaire (CCQ), Hospital Anxiety and Depression Scale (HADS) and hospital admission days for acute exacerbation of COPD (AECOPD) for 1 year before and after the first singing group session.FindingsThere were 28 participants with chronic lung disease recruited from 140 people approached. Five withdrew in the first month. 21 participants meeting Global Initiative for Chronic Obstructive Lung Disease criteria for COPD completed 4-month and 18 completed 1-year assessments. The mean attendance was 85%. For the prespecified primary outcome measure, total HADS score, difference between baseline and 12 months was −0.9, 95% CI −3.0 to 1.2, p=0.37. Of the secondary measures, a significant reduction was observed for HADS anxiety score after 1 year of −0.9 (95% CI −1.8 to −0.1) points, p=0.038 and an increase in the 6MWT at 1 year, of 65 (95% CI 35 to 99) m compared with baseline p<0.001.ConclusionsOur findings support the feasibility of long-term participation in a community singing group for adults with COPD who have completed PR and are enrolled in a weekly community exercise group and provide evidence of improved exercise capacity and a reduction in anxiety.Trial registration numberACTRN12615000736549; Results.
A systematic review of management strategies for children’s mental health care in the emergency department: update on evidence and recommendations for clinical practice and research
Authors: Newton Amanda S , Hartling Lisa , Soleimani Amir , Kirkland Scott , Dyson Michele P , Cappelli Mario 
Published: January 2017

ObjectiveChildren with mental health crises require access to specialised resources and services which are not yet standard in general and paediatric EDs. In 2010, we published a systematic review that provided some evidence to support the use of specialised care models to reduce hospitalisation, return ED visits and length of ED stay. We perform a systematic review to update the evidence base and inform current policy statements.MethodsTwelve databases and the grey literature were searched up to January 2015. Seven studies were included in the review (four newly identified studies). These studies compared ED-based strategies designed to assess, treat and/or therapeutically support or manage a mental health presentation. The methodological quality of six studies was assessed using the Cochrane Effective Practice and Organization of Care Risk of Bias tool (one interrupted time series study) and a modified Newcastle-Ottawa Scale (three retrospective cohort and two before–after studies). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was applied to rate overall evidence quality (high, moderate, low or very low) for individual outcomes from these six studies. An additional study evaluated the psychometric properties of a clinical instrument and was assessed using criteria developed by the Society of Pediatric Psychology Assessment Task Force (well-established, approaching well-established or promising assessment).ResultsThere is low to very low overall evidence quality that: (1) use of screening laboratory tests to medically clear mental health patients increases length of ED stay and costs, but does not increase the risk of clinical management or disposition change if not conducted; and (2) specialised models of ED care reduce lengths of ED stay, security man-hours and restraint orders. One mental health assessment tool of promising quality, the home, education, activities and peers, drugs and alcohol, suicidality, emotions and behaviour, discharge resources (HEADS-ED), has had good accuracy in predicting admission to inpatient psychiatry.ConclusionsLower-quality data suggest benefits to the use of specialised resources and services for paediatric mental health care in general and paediatric EDs. Experimental evaluation of strategies and the inclusion of patient-reported outcomes will improve confidence in these findings. Additional psychometric studies are needed for the HEADS-ED tool to be considered well established.
Risk factors associated with unintentional house fire incidents, injuries and deaths in high-income countries: a systematic review
Authors: Turner Samantha L , Johnson Rhodri D , Weightman Alison L , Rodgers Sarah E , Arthur Geri , Bailey Rowena , Lyons Ronan A 
Published: January 2017

ObjectiveTo identify the distinguishing risk factors associated with unintentional house fire incidents, injuries and deaths.Study designSystematic review.MethodsA range of bibliographical databases and grey literature were searched from their earliest records to January 2016. To ensure the magnitude of risk could be quantified, only those study types which contained a control group, and undertook appropriate statistical analyses were included. A best evidence synthesis was conducted instead of a meta-analysis due to study heterogeneity.ResultsEleven studies investigating a variety of risk factors and outcomes were identified. Studies ranged from medium to low quality with no high quality studies identified. Characteristics commonly associated with increased risk of house fire incidents, injuries and fatalities included: higher numbers of residents, male, children under the age of 5 years, non-working households, smoking, low income, non-privately owned properties, apartments and buildings in poor condition. Several risk factors were only associated with one outcome (eg, living alone was only associated with increased risk of injurious fires), and households with older residents were at increased risk of injurious fires, but significantly less likely to experience a house fire in the first place.ConclusionsThis best evidence synthesis indicates that several resident and property characteristics are associated with risk of experiencing house fire incidents, injuries or death. These findings should be considered by the Fire and Rescue Services and others with a role in fire prevention. Future research should adopt robust, standardised study designs to permit meta-analyses and enable stronger conclusions to be drawn.
Interpreting 750 GeV diphoton excess with R-parity violating supersymmetry
Authors: Ding Ran , Huang Li , Li Tianjun , Zhu Bin 
Published: January 2017

We propose a supersymmetric explanation of the diphoton excess in the Minimal Supersymmetric Standard Model (MSSM) with the leptonic R-parity violation. In our model, sneutrino serves as the 750 GeV resonance and produced through quark–antiquark annihilation. With introducing appropriate trilinear soft parameters, we show that the diphoton branching ratio is significantly enhanced compared with the conventional MSSM. For current dijet and W-pair LHC constraints, we can successfully fit the observed diphoton signal rate in sizeable parameter regions, the resulting parameter space strongly favor the masses of light smuon and stau within the range from 375–500 GeV, which depends on the choice of electroweakino masses and soft trilinear terms. While after taking into account the compatibility of diphoton excess between the 8 TeV and 13 TeV LHC, only the coupling involved with the second generation quarks is survived. In this case, the corresponding parameter space favors a narrow mass range of smuon and stau with [Formula: see text]. Even if the 750 GeV diphoton excesses were not confirmed by the ATLAS and CMS experiments, we point out that our proposal can still be used to explain the current and future tentative diphoton excesses.
Constraining capability of Zγh production at the ILC
Authors: Alam Sher , Behera Subhasish , Kumar Satendra , Sahoo Shibananda 
Published: January 2017

Higgs boson couplings with gauge bosons are probed through [Formula: see text] in an effective Lagrangian framework. For this study, the beam polarization facility at the ILC along with the typical center-of-mass energy of 500 GeV is considered. The reach of the ILC with an integrated luminosity of 300 fb[Formula: see text] in the determination of CP-conserving parameters is obtained. Sensitivity of the probe of each of these couplings in the presence of other couplings is investigated. The most influential coupling parameters are [Formula: see text]. Other parameters of significant effect are [Formula: see text] and [Formula: see text]. A detailed study of the various kinematic distributions represents possibilities to disentangle the effect of some of these couplings.