bluuebunny/crossref_metadata_2025_split huggingface dataset:
The PP2A‐interactor TIP41 modulates ABA responses in Arabidopsis thaliana
Authors: Punzo Paola , Ruggiero Alessandra , Possenti Marco , Nurcato Roberta , Costa Antonello , Morelli Giorgio , Grillo Stefania , Batelli Giorgia 
Published: March 2018

SummaryModulation of growth in response to environmental cues is a fundamental aspect of plant adaptation to abiotic stresses. TIP41 (TAP42 INTERACTING PROTEIN OF 41 kDa) is the Arabidopsis thaliana orthologue of proteins isolated in mammals and yeast that participate in the Target‐of‐Rapamycin (TOR) pathway, which modifies cell growth in response to nutrient status and environmental conditions. Here, we characterized the function of TIP41 in Arabidopsis. Expression analyses showed that TIP41 is constitutively expressed in vascular tissues, and is induced following long‐term exposure to NaCl, polyethylene glycol and abscisic acid (ABA), suggesting a role of TIP41 in adaptation to abiotic stress. Visualization of a fusion protein with yellow fluorescent protein indicated that TIP41 is localized in the cytoplasm and the nucleus. Abolished expression of TIP41 results in smaller plants with a lower number of rosette leaves and lateral roots, and an increased sensitivity to treatments with chemical TOR inhibitors, indicating that TOR signalling is affected in these mutants. In addition, tip41 mutants are hypersensitive to ABA at germination and seedling stage, whereas over‐expressing plants show higher tolerance. Several TOR‐ and ABA‐responsive genes are differentially expressed in tip41, including iron homeostasis, senescence and ethylene‐associated genes. In yeast and mammals, TIP41 provides a link between the TOR pathway and the protein phosphatase 2A (PP2A), which in plants participates in several ABA‐mediated mechanisms. Here, we showed an interaction of TIP41 with the catalytic subunit of PP2A. Taken together, these results offer important insights into the function of Arabidopsis TIP41 in the modulation of plant growth and ABA responses.
Tomatidine Is a Lead Antibiotic Molecule That Targets Staphylococcus aureus ATP Synthase Subunit C
Authors: Lamontagne Boulet Maxime , Isabelle Charles , Guay Isabelle , Brouillette Eric , Langlois Jean-Philippe , Jacques Pierre-Étienne , Rodrigue Sébastien , Brzezinski Ryszard , Beauregard Pascale B. , Bouarab Kamal , Boyapelly Kumaraswamy , Boudreault Pierre-Luc , Marsault Éric , Malouin François 
Published: March 2018

ABSTRACT

Methicillin-resistant
Staphylococcus aureus
(MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti-
Staphylococcus
antibiotics and new classes of drugs not susceptible to the mechanisms of resistance shared among bacteria is imperative. We recently showed that tomatidine (TO), a steroidal alkaloid from solanaceous plants, possesses potent antibacterial activity against
S. aureus
small-colony variants (SCVs), the notoriously persistent form of this bacterium that has been associated with recurrence of infections. Here, using genomic analysis of
in vitro
-generated TO-resistant
S. aureus
strains to identify mutations in genes involved in resistance, we identified the bacterial ATP synthase as the cellular target. Sequence alignments were performed to highlight the modified sequences, and the structural consequences of the mutations were evaluated in structural models. Overexpression of the
atpE
gene in
S. aureus
SCVs or introducing the mutation found in the
atpE
gene of one of the high-level TO-resistant
S. aureus
mutants into the
Bacillus subtilis atpE
gene provided resistance to TO and further validated the identity of the cellular target. FC04-100, a TO derivative which also possesses activity against non-SCV strains, prevents high-level resistance development in prototypic strains and limits the level of resistance observed in SCVs. An ATP synthesis assay allowed the observation of a correlation between antibiotic potency and ATP synthase inhibition. The selectivity index (inhibition of ATP production by mitochondria versus that of bacterial ATP synthase) is estimated to be >10
5
-fold for FC04-100.
Hypervirulent Group A Streptococcus of Genotypeemm3 Invades the Vascular System in Pulmonary Infection of Mice
Authors: Lei Benfang , Minor Dylan , Feng Wenchao , Liu Mengyao 
Published: March 2018

ABSTRACTNatural mutations of the two-component regulatory system CovRS are frequently associated with invasive group AStreptococcus(GAS) isolates and lead to the enhancement of virulence gene expression, innate immune evasion, systemic dissemination, and virulence. How CovRS mutations enhance systemic dissemination is not well understood. A hypervirulent GAS isolate of theemm3 genotype, MGAS315, was characterized using a mouse model of pulmonary infection to understand systemic dissemination. This strain has a G1370T mutation in the sensor kinasecovSgene of CovRS. Intratracheal inoculation of MGAS315 led to the lung infection that displayed extensive Gram staining at the alveolar ducts, alveoli, and peribronchovascular and perivascular interstitium. The correction of thecovSmutation did not alter the infection at the alveolar ducts and alveoli but prevented GAS invasion of the peribronchovascular and perivascular interstitium. Furthermore, thecovSmutation allowed MGAS315 to disrupt and degrade the smooth muscle and endothelial layers of the blood vessels, directly contributing to systemic dissemination. It is concluded that hypervirulentemm3 GAScovSmutants can invade the perivascular interstitium and directly attack the vascular system for systemic dissemination.
Antimicrobial Resistance inStreptococcusspp
Authors: Haenni Marisa , Lupo Agnese , Madec Jean-Yves 
Published: March 2018

ABSTRACTThe genusStreptococcusincludes Gram-positive organisms shaped in cocci and organized in chains. They are commensals, pathogens, and opportunistic pathogens for humans and animals. MostStreptococcusspecies of veterinary relevance have a specific ecological niche, such asS. uberis, which is almost exclusively an environmental pathogen causing bovine mastitis. In contrast,S. suiscan be considered as a true zoonotic pathogen, causing specific diseases in humans after contact with infected animals or derived food products. Finally,Streptococcusspecies such asS. agalactiaecan be sporadically zoonotic, even though they are pathogens of both humans and animals independently. For clarification, a short taxonomical overview will be given here to highlight the diversity of streptococci that infect animals. Several families of antibiotics are used to treat animals for streptococcal infections. First-line treatments are penicillins (alone or in combination with aminoglycosides), macrolides and lincosamides, fluoroquinolones, and tetracyclines. Because of the selecting role of antibiotics, resistance phenotypes have been reported in streptococci isolated from animals worldwide. Globally, the dynamic of resistance acquisition in streptococci is slower than what is experienced inEnterobacteriaceae, probably due to the much more limited horizontal spread of resistance genes. Nonetheless, transposons or integrative and conjugative elements can disseminate resistance determinants among streptococci. Besides providing key elements on the prevalence of resistance in streptococci from animals, this article will also largely consider the mechanisms and molecular epidemiology of the major types of resistance to antimicrobials encountered in the most important streptococcal species in veterinary medicine.
From Malawi to Middlesex: the case of the Arbutus Drill Cover System as an example of the cost-saving potential of frugal innovations for the UK NHS
Authors: Prime Matthew , Attaelmanan Ibtehal , Imbuldeniya Arjuna , Harris Matthew , Darzi Ara , Bhatti Yasser 
Published: March 2018

BackgroundMusculoskeletal disease is one of the leading clinical and economic burdens of the UK health system, and the resultant demand for orthopaedic care is only set to increase. One commonly used and one of the most expensive hardware in orthopaedic surgery is the surgical drill and saw. Given financial constraints, the National Health Service (NHS) needs an economic way to address this recurring cost. We share evidence of one frugal innovation with potential for contributing to the NHS’ efficiency saving target of £22 billion by 2020.MethodsExploratory case study methodology was used to develop insights and understanding of the innovations potential for application in the NHS. Following a global search for potential frugal innovations in surgery, the Arbutus Drill Cover System was identified as an innovation with potential to deliver significant cost savings for the NHS in the UK.ResultsThe Arbutus Drill Cover System is up to 94% cheaper than a standard surgical drill available in the UK. Clinical and laboratory tests show that performance, safety and usability are as good as current offerings in high-income countries and significantly better than hand drills typically used in low-and-middle-income countries. The innovation meets all regulatory requirements to be a medical device in the Europe and North America.ConclusionsThe innovation holds promise in reducing upfront and life span costs for core equipment used in orthopaedic surgery without loss of effectiveness or safety benchmarks. However, the innovation needs to navigate complicated and decentralised procurement processes and clinicians and healthcare leaders need to overcome cognitive bias.
Trends in initiation of direct oral anticoagulant therapies for atrial fibrillation in a national population-based cross-sectional study in the French health insurance databases
Authors: Huiart Laetitia , Ferdynus Cyril , Renoux Christel , Beaugrand Amélie , Lafarge Sophie , Bruneau Léa , Suissa Samy , Maillard Olivier , Ranouil Xavier 
Published: March 2018

ObjectiveUnlike several other national health agencies, French health authorities recommended that the newer direct oral anticoagulant (DOAC) agents only be prescribed as second choice for the treatment of newly diagnosed non-valvular atrial fibrillation (NVAF), with vitamin K antagonists (VKA) remaining the first choice. We investigated the patterns of use of DOACs versus VKA in the treatment of NVAF in France over the first 5 years of DOAC availability. We also identified the changes in patient characteristics of those who initiated DOAC treatment over this time period.MethodsBased on the French National Health Administrative Database, we constituted a population-based cohort of all patients who were newly treated for NVAF between January 2011 and December 2015. Trends in drug use were described as the percentage of patients initiating each drug at the time of treatment initiation. A multivariate analysis using logistic regression model was performed to identify independent sociodemographic and clinical predictors of initial anticoagulant choice.ResultsThe cohort comprised 814 446 patients who had received a new anticoagulant treatment for NVAF. The proportion of patients using DOACs as initial anticoagulant therapy reached 54% 3 months after the Health Ministry approved the reimbursement of dabigatran for NVAF, and 61% by the end of 2015, versus VKA use. In the multivariate analysis, we found that DOAC initiators were younger and healthier overall than VKA initiators, and this tendency was reinforced over the 2011–2014 period. DOACs were more frequently prescribed by cardiologists in 2012 and after (adjusted OR in 2012: 2.47; 95% CI 2.40 to 2.54).ConclusionDespite recommendations from health authorities, DOACs have been rapidly and massively adopted as initial therapy for NVAF in France. Observational studies should account for the fact that patients selected to initiate DOAC treatment are healthier overall, as failure to do so may bias the risk–benefit assessment of DOACs.
Association of allergic diseases with children’s life satisfaction: population-based study in Finland
Authors: Haanpää Leena , af Ursin Piia , Nermes Merja , Kaljonen Anne , Isolauri Erika 
Published: March 2018

ObjectiveTo assess the impact of allergic diseases on the subjective well-being and life satisfaction of primary-school children.DesignPopulation-based cohort.SettingFinnish sample of children ages 10 and 12 from the International Survey of Children’s Well-Being.ParticipantsNationally representative sample of 1947 school children.Main outcome measureTwo different instruments to assess the child’s own perception of well-being, the short version of the Student Life Satisfaction Scale (SLSS) and the Brief Multidimensional Student Life Satisfaction Scale (BMSLSS).ResultsAltogether, 51.4% of children reported having at least one allergic condition (10.1% asthma, 23.8% eczema and 40.3% seasonal allergic rhinitis). A statistically significant distinction in life satisfaction emerged between non-allergic and allergic children (inferior in the latter). In particular, children with eczema were more likely to report a reduction in life satisfaction compared with non-allergic children (SLSS β=−128.220; BMSLSS β=−90.694; p<0.01). Apart from freedom from eczema, good life satisfaction was associated with a physically active lifestyle.ConclusionsActive allergic disease reduces the child’s own perception of well-being. During clinical visits, more attention should be paid to the child’s psychosocial status and impairments, which may differ substantially from those of parents or medical authorities.
Vitamin D, obesity and leptin in relation to bladder cancer incidence and survival: prospective protocol study
Authors: Gislefoss Randi Elin , Stenehjem Jo Steinson , Hektoen Helga Helseth , Andreassen Bettina Kulle , Langseth Hilde , Axcrona Karol , Weiderpass Elisabete , Mondul Alison , Robsahm Trude Eid 
Published: March 2018

IntroductionBladder cancer (BC) (including renal pelvis, ureter and urethra) is one of the most common urogenital cancers and the fourth most frequent cancer in men in the USA. In Norway, the incidence of BC has increased over the last decades. The age-standardised incidence rates per 100 000 for 2011-2015 were 53.7 in men and 16.5 in women. Compared to the 5-year period 2006–2010, the percentage increase in incidence was 6.1% in men and 12.3% in women. The recurrence rate of BC is over 50%, the highest recurrence rate of any malignancy. Smoking and occupational exposure to aromatic amines are recognised as the major risk factors. Recently, low-serum level of 25-hydroxy vitamin D (25(OH)D) and obesity have been suggested to increase the BC risk, and leptin, which is important in weight regulation, may be involved in bladder carcinogenesis. More knowledge on potential risk factors for BC is necessary for planning and implementing primary prevention measures.Methods and analysesCohort and nested case–control studies will be carried out using the population-based Janus Serum Bank Cohort consisting of prediagnostic sera, clinical measurement data (body height and weight, body surface area and weight change over time, blood pressure, cholesterol and triglycerides) and self-reported information on lifestyle factors (smoking, physical activity). Participants were followed from cohort inclusion (1972–2003) through 2014. The cohort will be linked to the Cancer Registry of Norway (cancer data), the National Cause of Death Registry (date and cause of death), National Population Registry (vital status) and Statistic Norway (education and occupation). Serum samples will be analysed for 25(OH)D, vitamin D binding protein, leptin, albumin, calcium and parathyroid hormone. Cox regression and conditional logistic regression models and mediation analysis will be used to estimate association between the exposures and BC.Ethics and disseminationThe study has been approved by the Regional Committee for Medical Research Ethics and is funded by the Norwegian Cancer Society. Results will be published in peer-reviewed journals, at scientific conferences and through press releases.
Thyroid disorders and breast cancer risk in Asian population: a nationwide population-based case–control study in Taiwan
Authors: Weng Chien-Hsiang , Chen Yi-Huei , Lin Ching-Heng , Luo Xun , Lin Tseng-Hsi 
Published: March 2018

ObjectiveTo evaluate whether hyperthyroidism or hypothyroidism increases the risk of subsequent breast cancer in an Asian population.DesignNationwide population-based case–control study.SettingAll healthcare facilities in Taiwan.ParticipantsA total of 103 466 women (mean age 53.3 years) were enrolled.Methods51 733 adult women with newly diagnosed primary breast cancer without a previous cancer history between 2006 and 2011 were identified and included in our study. 51 733 women with no cancer diagnosis prior to the index date were age matched as controls. Diagnosis of hyperthyroidism or hypothyroidism prior to the diagnosis of breast cancer or the same index date was identified, age, histories of thyroid disease treatment, oestrogen use and radioactive iodine treatment were adjusted.Main outcome measuresTo identify risk differences in developing breast cancer among patients with a medical history of hyperthyroidism or hypothyroidism.ResultsThere was a significantly increased risk of breast cancer in women with hyperthyroidism under the age of 55 years (age <45: OR 1.16, P=0.049; age 45–55: OR 1.15, P=0.019). Patients with hypothyroidism also showed an increased risk of breast cancer (OR 1.19, P=0.029) without statistical significance after stratification by age group (age <45, 45–55, >55 years). Treatment for thyroid disorders did not alter the association in subgroup analyses (P=0.857; 0.262, respectively).ConclusionsAsian women under 55 years of age with history of hyperthyroidism have a significantly increased risk of breast cancer regardless of treatment. Women with history of hypothyroidism may also have an increased risk.
Patient perspectives on the HIV continuum of care in London: a qualitative study of people diagnosed between 1986 and 2014
Authors: Bruton Jane , Rai Tanvi , Day Sophie , Ward Helen 
Published: March 2018

ObjectivesTo describe the experiences of the HIV treatment cascade of diagnosis, engagement with care and initiation of treatment from the perspective of patients; we explored whether this differed according to the year of their diagnosis, for example, whether they had experienced HIV care in the pretreatment era.DesignQualitative interview study with framework analysis.SettingTwo large HIV adult outpatient clinics in central London.Participants52 HIV-positive individuals, 41 men, 11 women, purposively sampled to include people who had been diagnosed at different stages in the history of the epidemic classified as four ‘generations’: pre-1996 (preantiretroviral therapy (ART)), 1997–2005 (complex ARTs), 2006–2012 (simpler ARTs) and 2013 onwards (recent diagnoses).ResultsSome important differences were identified; for earlier generations, the visible illness and deaths from AIDS made it harder to engage with care following diagnosis. Subsequent decisions about starting treatment were deeply influenced by the fear of severe side effects from early ART. However, despite improvements in ART and life expectancy over the epidemic, we found a striking similarity across participants’ accounts of the key stages of the care continuum, regardless of when they were diagnosed. Diagnosis was a major traumatic life event for almost everyone. Fear of testing positive or having low self-perceived risk affected the timing of testing and diagnosis. Engaging with care was facilitated by a flexible approach from services/clinicians. Initiating treatment was a major life decision.ConclusionWe found patients’ experiences are influenced by when they were diagnosed, with earliest cohorts facing substantial challenges. However, being diagnosed with HIV and starting treatment continue to be significant life-altering events even in the era of effective, simple treatments. Despite the advances of biomedical treatment, services should continue to recognise the needs of patients for whom the diagnosis and treatment remain significant challenges.
Opportunities and challenges to improving antibiotic prescribing practices through a One Health approach: results of a comparative survey of doctors, dentists and veterinarians in Australia
Authors: Zhuo Annie , Labbate Maurizio , Norris Jacqueline M , Gilbert Gwendolyn L , Ward Michael P , Bajorek Beata V , Degeling Chris , Rowbotham Samantha J , Dawson Angus , Nguyen Ky-Anh , Hill-Cawthorne Grant A , Sorrell Tania C , Govendir Merran , Kesson Alison M , Iredell Jonathan R , Dominey-Howes Dale 
Published: March 2018

ObjectivesTo explore and compare the knowledge, attitudes and experiences of doctors, dentists and veterinarians (as prescribers) in relation to antibiotic use and antibiotic resistance (AbR), and to consider the implications of these for policy-making that support a One Health approach.DesignA cross-sectional survey conducted online.SettingDoctors, dentists and veterinarians practising in primary, secondary or tertiary care in Australia.Participants547 doctors, 380 dentists and 403 veterinarians completed the survey.Main outcome measuresPrescribers’ knowledge, attitudes and perceptions of AbR, the extent to which a range of factors are perceived as barriers to appropriate prescribing practices, and perceived helpfulness of potential strategies to improve antibiotic prescribing in practice.ResultsThere was substantial agreement across prescriber groups that action on AbR is required by multiple sectors and stakeholders. However, prescribers externalised responsibility to some extent by seeing the roles of others as more important than their own in relation to AbR. There were common and context-specific barriers to optimal prescribing across the prescriber groups. Prescriber groups generally perceived restrictive policies as unhelpful to supporting appropriate prescribing in their practice.ConclusionsThe results have implications for implementing a One Health approach that involves doctors, dentists and veterinarians as key players to tackling the crisis of AbR. The findings are that (1) prescribers understand and are likely receptive to a One Health policy approach to AbR, (2) policy development should be sensitive to barriers that are specific to individual prescriber groups and (3) the development and introduction of interventions that might be perceived as reducing prescriber autonomy will need to be carefully designed and implemented.
Maternal iron status during pregnancy and respiratory and atopic outcomes in the offspring: a Mendelian randomisation study
Authors: Bédard Annabelle , Lewis Sarah J , Burgess Stephen , Henderson A John , Shaheen Seif O 
Published: March 2018

IntroductionLimited evidence from birth cohort studies suggests that lower prenatal iron status may be a risk factor for childhood respiratory and atopic outcomes, but these observational findings may be confounded. Mendelian randomisation (MR) can potentially provide unconfounded estimates of causal effects by using common genetic variants as instrumental variables. We aimed to study the relationship between prenatal iron status and respiratory and atopic outcomes in the offspring using MR.MethodsIn the Avon Longitudinal Study of Parents and Children birth cohort, we constructed four maternal genotypic risk scores by summing the total number of risk alleles (associated with lower iron status) across single nucleotide polymorphisms known to be associated with at least one of four iron biomarkers (serum iron, ferritin, transferrin and transferrin saturation). We used MR to study their associations with respiratory and atopic outcomes in children aged 7–9 years (n=6002).ResultsWhen analyses were restricted to mothers without iron supplementation during late pregnancy, negative associations were found between the maternal transferrin saturation score and childhood forced expiratory volume in 1 s and forced vital capacity (difference in age, height and gender-adjusted SD units per SD increase in genotypic score: −0.05 (−0.09, −0.01) p=0.03, and −0.04 (−0.08, 0.00) p=0.04, respectively).ConclusionUsing MR we have found weak evidence suggesting that low maternal iron status during pregnancy may cause impaired childhood lung function.