bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bacterial Cell Enlargement Requires Control of Cell Wall Stiffness Mediated by Peptidoglycan Hydrolases
Authors: Wheeler Richard , Turner Robert D. , Bailey Richard G. , Salamaga Bartłomiej , Mesnage Stéphane , Mohamad Sharifah A. S. , Hayhurst Emma J. , Horsburgh Malcolm , Hobbs Jamie K. , Foster Simon J. 
Published: July 2015

ABSTRACT

Most bacterial cells are enclosed in a single macromolecule of the cell wall polymer, peptidoglycan, which is required for shape determination and maintenance of viability, while peptidoglycan biosynthesis is an important antibiotic target. It is hypothesized that cellular enlargement requires regional expansion of the cell wall through coordinated insertion and hydrolysis of peptidoglycan. Here, a group of (apparent glucosaminidase) peptidoglycan hydrolases are identified that are together required for cell enlargement and correct cellular morphology of
Staphylococcus aureus
, demonstrating the overall importance of this enzyme activity. These are Atl, SagA, ScaH, and SagB. The major advance here is the explanation of the observed morphological defects in terms of the mechanical and biochemical properties of peptidoglycan. It was shown that cells lacking groups of these hydrolases have increased surface stiffness and, in the absence of SagB, substantially increased glycan chain length. This indicates that, beyond their established roles (for example in cell separation), some hydrolases enable cellular enlargement by making peptidoglycan easier to stretch, providing the first direct evidence demonstrating that cellular enlargement occurs via modulation of the mechanical properties of peptidoglycan.

IMPORTANCE
Understanding bacterial growth and division is a fundamental problem, and knowledge in this area underlies the treatment of many infectious diseases. Almost all bacteria are surrounded by a macromolecule of peptidoglycan that encloses the cell and maintains shape, and bacterial cells must increase the size of this molecule in order to enlarge themselves. This requires not only the insertion of new peptidoglycan monomers, a process targeted by antibiotics, including penicillin, but also breakage of existing bonds, a potentially hazardous activity for the cell. Using
Staphylococcus aureus
, we have identified a set of enzymes that are critical for cellular enlargement. We show that these enzymes are required for normal growth and define the mechanism through which cellular enlargement is accomplished, i.e., by breaking bonds in the peptidoglycan, which reduces the stiffness of the cell wall, enabling it to stretch and expand, a process that is likely to be fundamental to many bacteria.
Pediatric Cystic Fibrosis Sputum Can Be Chemically Dynamic, Anoxic, and Extremely Reduced Due to Hydrogen Sulfide Formation
Authors: Cowley Elise S. , Kopf Sebastian H. , LaRiviere Alejandro , Ziebis Wiebke , Newman Dianne K. 
Published: July 2015

ABSTRACT

Severe and persistent bacterial lung infections characterize cystic fibrosis (CF). While several studies have documented the microbial diversity within CF lung mucus, we know much less about the inorganic chemistry that constrains microbial metabolic processes and their distribution. We hypothesized that sputum is chemically heterogeneous both within and between patients. To test this, we measured microprofiles of oxygen and sulfide concentrations as well as pH and oxidation-reduction potentials in 48 sputum samples from 22 pediatric patients with CF. Inorganic ions were measured in 20 samples from 12 patients. In all cases, oxygen was depleted within the first few millimeters below the sputum-air interface. Apart from this steep oxycline, anoxia dominated the sputum environment. Different sputum samples exhibited a broad range of redox conditions, with either oxidizing (16 mV to 355 mV) or reducing (−300 to −107 mV) potentials. The majority of reduced samples contained hydrogen sulfide and had a low pH (2.9 to 6.5). Sulfide concentrations increased at a rate of 0.30 µM H
2
S/min. Nitrous oxide was detected in only one sample that also contained sulfide. Microenvironmental variability was observed both within a single patient over time and between patients. Modeling oxygen dynamics within CF mucus plugs indicates that anoxic zones vary as a function of bacterial load and mucus thickness and can occupy a significant portion of the mucus volume. Thus, aerobic respiration accounts only partially for pathogen survival in CF sputum, motivating research to identify mechanisms of survival under conditions that span fluctuating redox states, including sulfidic environments.

IMPORTANCE
Microbial infections are the major cause of morbidity and mortality in people living with CF, and yet microbial growth and survival in CF airways are not well understood. Insufficient information about the chemistry of the
in vivo
environment contributes to this knowledge gap. Our documentation of variable redox states corresponding to the presence or absence of sulfide begins to fill this void and motivates understanding of how different opportunistic pathogens adapt in these dynamic environments. Given the changing chemical state of CF sputum over time, it is important to consider a spectrum of aerobic and anaerobic lifestyles when studying CF pathogens in the laboratory. This work not only provides relevant constraints that can shape the design of laboratory experiments, it also suggests that sulfide might be a useful proxy for assessing the redox state of sputum in the clinic.
Genomic Adaptations to the Loss of a Conserved Bacterial DNA Methyltransferase
Authors: Gonzalez Diego , Collier Justine 
Published: July 2015

ABSTRACT

CcrM is an orphan DNA methyltransferase nearly universally conserved in a vast group of
Alphaproteobacteria.
In
Caulobacter crescentus
, it controls the expression of key genes involved in the regulation of the cell cycle and cell division. Here, we demonstrate, using an experimental evolution approach, that
C. crescentus
can significantly compensate, through easily accessible genetic changes like point mutations, the severe loss in fitness due to the absence of CcrM, quickly improving its growth rate and cell morphology in rich medium. By analyzing the compensatory mutations genome-wide in 12 clones sampled from independent Δ
ccrM
populations evolved for ~300 generations, we demonstrated that each of the twelve clones carried at least one mutation that potentially stimulated
ftsZ
expression, suggesting that the low intracellular levels of FtsZ are the major burden of Δ
ccrM
mutants. In addition, we demonstrate that the phosphoenolpyruvate-carbohydrate phosphotransfer system (PTS) actually modulates
ftsZ
and
mipZ
transcription, uncovering a previously unsuspected link between metabolic regulation and cell division in
Alphaproteobacteria
. We present evidence that point mutations found in genes encoding proteins of the PTS provide the strongest fitness advantage to Δ
ccrM
cells cultivated in rich medium despite being disadvantageous in minimal medium. This environmental sign epistasis might prevent such mutations from getting fixed under changing natural conditions, adding a plausible explanation for the broad conservation of CcrM.

IMPORTANCE
In bacteria, DNA methylation has a variety of functions, including the control of DNA replication and/or gene expression. The cell cycle-regulated DNA methyltransferase CcrM modulates the transcription of many genes and is critical for fitness in
Caulobacter crescentus
. Here, we used an original experimental evolution approach to determine which of its many targets make CcrM so important physiologically. We show that populations lacking CcrM evolve quickly, accumulating an excess of mutations affecting, directly or indirectly, the expression of the
ftsZ
cell division gene. This finding suggests that the most critical function of CcrM in
C. crescentus
is to promote cell division by enhancing FtsZ intracellular levels. During this work, we also discovered an unexpected link between metabolic regulation and cell division that might extend to other
Alphaproteobacteria
.
Diagnostic outcomes following childhood non-specific abdominal pain: a record-linkage study
Authors: Thornton G C D , Goldacre M J , Goldacre R , Howarth L J 
Published: July 2015

AimsNon-specific abdominal pain (NSAP) is the most common diagnosis on discharge following admission for abdominal pain in childhood. Our aim was to determine the risk of subsequent hospital diagnosis of organic and functional gastroenterological conditions following a diagnosis of NSAP, and to assess the persistence of this risk.MethodsAn NSAP cohort of 268 623 children aged 0–16 years was constructed from linked English Hospital Episode Statistics from 1999 to 2011. The control cohort (1 684 923 children, 0–16 years old) comprised children hospitalised with unrelated conditions. Clinically relevant outcomes were selected and standardised rate ratios were calculated.ResultsFrom the NSAP cohort, 15 515 (5.8%) were later hospitalised with bowel pathology and 13 301 (5%) with a specific functional disorder. Notably, there was a 4.84 (95% CI 4.45 to 5.27) times greater risk of Crohn's disease following NSAP and a 4.23 (4.13 to 4.33) greater risk of acute appendicitis than in the control cohort. The risk of irritable bowel syndrome (IBS) was 7.22 (6.65 to 7.85) times greater following NSAP. The risks of inflammatory bowel disease (IBD), IBS and functional disorder (unspecified) were significantly increased in all age groups except <2-year-olds. The risk of underlying bowel pathology remained raised up to 10 years after first diagnosis with NSAP.ConclusionsOnly a small proportion of those with NSAP go on to be hospitalised with underlying bowel pathology. However, their risk is increased even at 10 years after the first hospital admission with NSAP. Diagnostic strategies need to be assessed and refined and active surveillance employed for children with NSAP.
How well do health professionals interpret diagnostic information? A systematic review
Authors: Whiting Penny F , Davenport Clare , Jameson Catherine , Burke Margaret , Sterne Jonathan A C , Hyde Chris , Ben-Shlomo Yoav 
Published: July 2015

ObjectiveTo evaluate whether clinicians differ in how they evaluate and interpret diagnostic test information.DesignSystematic review.Data sourcesMEDLINE, EMBASE and PsycINFO from inception to September 2013; bibliographies of retrieved studies, experts and citation search of key included studies.Eligibility criteria for selecting studiesPrimary studies that provided information on the accuracy of any diagnostic test (eg, sensitivity, specificity, likelihood ratios) to health professionals and that reported outcomes relating to their understanding of information on or implications of test accuracy.ResultsWe included 24 studies. 6 assessed ability to define accuracy metrics: health professionals were less likely to identify the correct definition of likelihood ratios than of sensitivity and specificity. –25 studies assessed Bayesian reasoning. Most assessed the influence of a positive test result on the probability of disease: they generally found health professionals’ estimation of post-test probability to be poor, with a tendency to overestimation. 3 studies found that approaches based on likelihood ratios resulted in more accurate estimates of post-test probability than approaches based on estimates of sensitivity and specificity alone, while 3 found less accurate estimates. 5 studies found that presenting natural frequencies rather than probabilities improved post-test probability estimation and speed of calculations.ConclusionsCommonly used measures of test accuracy are poorly understood by health professionals. Reporting test accuracy using natural frequencies and visual aids may facilitate improved understanding and better estimation of the post-test probability of disease.
Effectiveness and cost-effectiveness of telephone-based support versus usual care for treatment of pressure ulcers in people with spinal cord injury in low-income and middle-income countries: study protocol for a 12-week randomised controlled trial
Authors: Arora Mohit , Harvey Lisa Anne , Hayes Alison Joy , Chhabra Harvinder Singh , Glinsky Joanne Valentina , Cameron Ian Douglas , Lavrencic Lucija , Arumugam Narkeesh , Hossain Sohrab , Bedi Parneet Kaur 
Published: July 2015

IntroductionPressure ulcers are a common and severe complication of spinal cord injury, particularly in low-income and middle-income countries where people often need to manage pressure ulcers alone and at home. Telephone-based support may help people in these situations to manage their pressure ulcers. The aim of this study is to determine the effectiveness and cost-effectiveness of telephone-based support to help people with spinal cord injury manage pressure ulcers at home in India and Bangladesh.Methods and analysisA multicentre (3 sites), prospective, assessor-blinded, parallel, randomised controlled trial will be undertaken. 120 participants with pressure ulcers on the sacrum, ischial tuberosity or greater trochanter of the femur secondary to spinal cord injury will be randomly assigned to a Control or Intervention group. Participants in the Control group will receive usual community care. That is, they will manage their pressure ulcers on their own at home but will be free to access whatever healthcare support they can. Participants in the Intervention group will also manage their pressure ulcers at home and will also be free to access whatever healthcare support they can, but in addition they will receive weekly telephone-based support and advice for 12 weeks (15–25 min/week). The primary outcome is the size of the pressure ulcer at 12 weeks. 13 secondary outcomes will be measured reflecting other aspects of pressure ulcer resolution, depression, quality of life, participation and satisfaction with healthcare provision. An economic evaluation will be run in parallel and will include a cost-effectiveness and a cost-utility analysis.Ethics and disseminationEthical approval was obtained from the Institutional Ethics Committee at each site. The results of this study will be disseminated through publications and presented at national and international conferences.Trial registration numberACTRN12613001225707.
Prediction and prognostication of neurological deterioration in patients with acute ICH: a hospital-based cohort study
Authors: Ovesen Christian , Christensen Anders Fogh , Havsteen Inger , Krarup Hansen Christine , Rosenbaum Sverre , Kurt Engin , Christensen Hanne 
Published: July 2015

ObjectivePatients with intracerebral haemorrhage (ICH) are at high risk of neurological deterioration (ND). We aimed at establishing predictors of early ND (END) as well as late ND (LND) and at exploring the impact of neurological stability during the first week on long-term prognosis.DesignWe conducted this study as a retrospective cohort study. ND was evaluated based on the consciousness and severity of neurological symptoms. ND during the first 24 h after admission was defined as early ND and from 24 h to 7 days as LND. Patients were followed up until February 2015.ParticipantsWe included 300 patients with acute ICH (≤4.5 h from symptom onset) who were admitted to our institution from March 2009 to January 2015.SettingSection of Acute Neurology, Department of Neurology, Bispebjerg Hospital is a specialised referral centre receiving patients with acute stroke from the entire capital region of Denmark.ResultsWe found that a spot sign on CT angiography (OR 10.7 CI 4.79 to 24.3) and extensive degree of interventricular haemorrhage (IVH) (OR 8.73 CI 2.87 to 26.5) were independent predictors of END, whereas a degree of comorbidity (Charlton Index), admission stroke severity and degree of IVH predicted LND. On follow-up imaging, haematoma expansion was independently associated with END (OR 6.1 CI 2.2 to 17.3), and expansion of IVH was independently associated with both END (OR 1.7 CI 1.2 to 2.3 per point increase) and LND (OR 2.3 CI 1.3 to 4.2 per point increase). ND during the first week was associated with a 1-year mortality of 60.5%, compared with 9.2% among the patients who remained stable.ConclusionsThese results suggest that stability during the first week entails an optimistic prognosis. A relatively easy and effective risk stratification of END and LND is possible on admission based on the spot sign, IVH and clinical parameters.
Social inequality in pre-pregnancy BMI and gestational weight gain in the first and second pregnancy among women in Sweden
Authors: Holowko Natalie , Chaparro M Pia , Nilsson Karina , Ivarsson Anneli , Mishra Gita , Koupil Ilona , Goodman Anna 
Published: July 2015

BackgroundHigh pre-pregnancy body mass index (BMI) and inappropriate gestational weight gain (GWG) are associated with adverse short and long-term maternal and neonatal outcomes and may act as modifiable risk factors on the path to overweight/obesity, but their social patterning is not well established. This study investigates the association of education with BMI and GWG across two consecutive pregnancies.MethodsThe study includes 163 352 Swedish women, having their first and second singleton birth in 1982–2010. In both pregnancies, we investigated the association of women's education with (1) pre-pregnancy weight status and (2) adequacy of GWG. We used multinomial logistic regression, adjusting for child's birth year, mother's age and smoking status.ResultsOverall, the odds of starting either pregnancy at an unhealthy BMI were higher among women with a low education compared to more highly-educated women. Lower education also predicted a greater increase in BMI between pregnancies, with this effect greatest among women with excessive GWG in the first pregnancy (p<0.0001 for interaction). Education was also inversely associated with odds of excessive GWG in both pregnancies among healthy weight status women, but this association was absent or even weakly reversed among overweight and obese women.ConclusionsLower educated women had the largest BMI increase between pregnancies, and these inequalities were greatest among women with excessive GWG in the first pregnancy. The importance of a healthy pre-pregnancy BMI, appropriate GWG and a healthy postpartum weight should be communicated to all women, which may assist in reducing existing social inequalities in body weight.
The association between individual-level social capital and health: cross-sectional, prospective cohort and fixed-effects models
Authors: Oshio Takashi 
Published: July 2015

BackgroundIt is well known that individual-level social capital is positively associated with health, but most preceding studies have not fully controlled for an individual's time-invariant attributes, especially unobserved ones. The current study attempted to address how the association between individual-level social capital and health is confounded by an individual's unobserved time-invariant attributes.MethodsData were collected from six-wave nationwide panel surveys conducted from 2005 to 2010, with 162 720 observations from 30 590 individuals. Individual-level bonding and bridging social capital, as well as their associations with self-rated health (SRH) and psychological distress (measured by Kessler 6 scores), were considered. Estimation results of cross-sectional, prospective cohort and fixed-effects logistic models were compared.ResultsThe OR of reporting poor SRH responding to high bonding social capital rose from 0.64 (95% CI 0.62 to 0.65) in the pooled cross-sectional model to 0.77 (0.75 to 0.80) in the prospective cohort model and 0.87 (0.82 to 0.92) in the fixed-effects model. Similar patterns were observed for bridging social capital, but the OR of reporting poor SRH became non-significant in the fixed-effects model. Similar results were obtained for psychological distress.ConclusionsThe results suggest that the association between individual-level social capital and health is overstated by an individual's unobserved time-invariant attributes. The relevance of health in individual-level social capital should be assessed cautiously.
Endovascular stroke therapy with the Aperio thrombectomy device
Authors: Kallenberg Kai , Solymosi Laszlo , Taschner Christian A , Berkefeld Joachim , Schlamann Marc , Jansen Olav , Arnold Sebastian , Tomandl Bernd , Knauth Michael , Turowski Bernd 
Published: July 2015

BackgroundThe pharmaceutical therapy for acute ischemic stroke has shortcomings in reopening large vessels and dissolving long thrombi, and endovascular treatment has been found to provide added value. The Aperio thrombectomy device showed promising results in an experimental study. The purpose of this study was to evaluate the device clinically.Methods119 patients with acute stroke were treated in nine centers using the Aperio thrombectomy device. Target vessel, diameter, thrombus length, procedure time, recanalization, number of deployments, additional use of anticoagulants, complications, and the use of additional devices were assessed.ResultsThe median thrombus length was 15 mm (range 1.5–20 mm) and the average time from device insertion to recanalization was 30 min (range 5–120 min). Blood flow restoration (Thrombolysis In Cerebral Infarction (TICI) 2–3) was achieved in 85%. In the majority of cases complete clot removal was achieved (TICI 0, 12%; TICI 1, 2%; TICI 2a, 14%; TICI 2b, 18%; TICI 3, 53%). The median number of deployments was 2 (range 1–6). Twelve procedural complications (10%) occurred.ConclusionsThe Aperio thrombectomy device seems to be an effective and adequately safe tool for reopening occluded cerebral arteries in the setting of acute stroke.
Identifying patients with rheumatoid arthritis with moderate disease activity at risk of significant radiographic progression despite methotrexate treatment
Authors: Fautrel B , Nab H W , Brault Y , Gallo G 
Published: July 2015

ObjectivesTo determine the baseline factors predictive of significant radiographic progression (SRP) in patients with moderately active rheumatoid arthritis (RA) despite receiving methotrexate (MTX).MethodsPatients from the MTX arm of the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) trial with sustained moderate RA (defined as ≥3.2 mean disease activity score in 28 joints ≤5.1 during the last 6 months of the first year) were analysed for SRP (mTSS >3.0 overall) after 2 and 3 years. Baseline predictors for SRP were identified by univariate and multivariate analyses. All variables shown to be significantly associated with SRP were categorised based on clinically relevant cut-offs and tertiles and were included in a matrix risk model.Results228 patients were assigned MTX treatment, 210 patients were in the radiographic intention-to-treat population, and 96 of these had sustained moderate RA. SRP occurred in 25 (26%) and 33 (34%) patients after 2 and 3 years of MTX treatment, respectively. Univariate and multivariate analyses found that C reactive protein (CRP) and rheumatoid factor (RF) positivity at baseline were predictive of SRP after 2 and 3 years (p<0.05 for all). The matrix risk model showed that RF positivity and CRP levels >40 mg/L at baseline were significantly associated with SRP after 2 (p<0.05 for both; R2=0.24) and 3 years (p<0.05 for both; R2=0.22). The baseline erosion score was not found to be predictive of SRP.ConclusionsPatients with sustained moderate RA despite receiving MTX treatment are at risk of SRP, with both RF positivity and high CRP levels shown to be predictive of this.