Lipidomics of homeoviscous adaptation to low temperatures in Staphylococcus aureus utilizing exogenous straight-chain unsaturated fatty acids.

It is well established that Staphylococcus aureus can incorporate exogenous straight-chain unsaturated fatty acids (SCUFAs) into membrane phospho- and glyco-lipids from various sources in supplemented culture media and when growing in vivo during infection. Given the enhancement of membrane fluidity when oleic acid (C18:1Δ9) is incorporated into lipids, we were prompted to examine the effect of medium supplementation with C18:1Δ9 on growth at low temperatures. C18:1Δ9 supported the growth of a cold-sensitive, branched-chain fatty acid (BCFA)-deficient mutant at 12°C. Interestingly, we found similar results in the BCFA-sufficient parental strain, supported by the fact that the incorporation of C18:1Δ9 into the membrane increased membrane fluidity in both strains. We show that the incorporation of C18:1Δ9 and its elongation product C20:1Δ11 into membrane lipids was required for growth stimulation and relied on a functional FakAB incorporation system. Lipidomics analysis of the phosphatidylglycerol and diglycosyldiacylglycerol lipid classes revealed major impacts of C18:1Δ9 and temperature on lipid species. Growth at 12°C in the presence of C18:1Δ9 also led to increased production of the carotenoid pigment staphyloxanthin. The enhancement of growth by C18:1Δ9 is an example of homeoviscous adaptation to low temperatures utilizing an exogenous fatty acid. This may be significant in the growth of S. aureus at low temperatures in foods that commonly contain C18:1Δ9 and other SCUFAs in various forms. IMPORTANCE: We show that Staphylococcus aureus can use its known ability to incorporate exogenous fatty acids to enhance its growth at low temperatures. Individual species of phosphatidylglycerols and diglycosyldiacylglycerols bearing one or two degrees of unsaturation derived from the incorporation of C18:1Δ9 at 12°C are described for the first time. In addition, enhanced production of the carotenoid staphyloxanthin occurs at low temperatures. The studies describe a biochemical reality underlying membrane biophysics. This is an example of homeoviscous adaptation to low temperatures utilizing exogenous fatty acids over the regulation of the biosynthesis of endogenous fatty acids. The studies have likely relevance to food safety in that unsaturated fatty acids may enhance the growth of S. aureus in the food environment.

A membrane-associated conveyor belt controls the rotational direction of the bacterial type 9 secretion system.

Many bacteria utilize the type 9 secretion system (T9SS) for gliding motility, surface colonization, and pathogenesis. This dual-function motor supports both gliding motility and protein secretion, where rotation of the T9SS plays a central role. Fueled by the energy of the stored proton motive force and transmitted through the torque of membrane-anchored stator units, the rotary T9SS propels an adhesin-coated conveyor belt along the bacterial outer membrane like a molecular snowmobile, thereby enabling gliding motion. However, the mechanisms controlling the rotational direction and gliding motility of T9SS remain elusive. Shedding light on this mechanism, we find that in the gliding bacterium Flavobacterium johnsoniae , deletion of the C-terminus of a conveyor belt protein controls, and in fact, reverses the rotational direction of T9SS from counterclockwise (CCW) to clockwise (CW). Largescale conformational changes at the interface of the T9SS ring with the C-terminus of the conveyer belt, as well as those of the ring protein themselves, in concert with a CW bias of the stators general rotation brings forth a 'tri-component gearset' model: the conveyor belt controls the conformation of the T9SS ring, and thereby its rotational direction. Consequently, the CW rotating stator either push the outer edge of the T9SS rings, causing its CCW rotation or press against the inner surface of the rings, resulting in CW rotation. This regulatory mechanism exemplifies how an outer membrane associated conveyor belt adjusts the rotational direction of its driver, the T9SS, thus providing adaptive sensory feedback to control the motility of a molecular snowmobile.

Lipidomics of homeoviscous adaptation to low temperatures in Staphylococcus aureus utilizing exogenous straight-chain unsaturated fatty acids over biosynthesized endogenous branched-chain fatty acids.

It is well established that Staphylococcus aureus can incorporate exogenous straight-chain unsaturated fatty acids (SCUFAs) into membrane phospho- and glyco-lipids from various sources in supplemented culture media, and when growing in vivo in an infection. Given the enhancement of membrane fluidity when oleic acid (C18:1Δ9) is incorporated into lipids, we were prompted to examine the effect of medium supplementation with C18:1Δ9 on growth at low temperatures. C18:1Δ9 supported the growth of a cold-sensitive, branched-chain fatty acid (BCFA)-deficient mutant at 12°C. Interestingly, we found similar results in the BCFA-sufficient parental strain. We show that incorporation of C18:1Δ9 and its elongation product C20:1Δ9 into membrane lipids was required for growth stimulation and relied on a functional FakAB incorporation system. Lipidomics analysis of the phosphatidylglycerol (PG) and diglycosyldiacylglycerol (DGDG) lipid classes revealed major impacts of C18:1Δ9 and temperature on lipid species. Growth at 12°C in the presence of C18:1Δ9 also led to increased production of the carotenoid pigment staphyloxanthin; however, this was not an obligatory requirement for cold adaptation. Enhancement of growth by C18:1Δ9 is an example of homeoviscous adaptation to low temperatures utilizing an exogenous fatty acid. This may be significant in the growth of S. aureus at low temperatures in foods that commonly contain C18:1Δ9 and other SCUFAs in various forms.

UK Reproducibility Network open and transparent research practices survey dataset.

Openness and transparency in the research process are a prerequisite to the production of high quality research outputs. Efforts to maximise these features have substantially accelerated in recent years, placing open and transparent research practices at the forefront of funding and related priorities, and encouraging investment in resources and infrastructure to enable such practices. Despite these efforts, there has been no systematic documentation of current practices, infrastructure, or training and resources that support open and transparent research in the UK. To address this gap, we developed and conducted the Open and Transparent Research Practices survey, a large-scale audit study completed by research-active staff in UK research institutions to better understand existing practices, needs, support, and barriers faced when implementing open and transparent research. The data presented here capture responses from over 2,500 research-active staff based at 15 institutions affiliated with the UK Reproducibility Network. The data provide a snapshot of open research practices that can be used to identify barriers, training needs, and areas that require greater investments.

Treatment of polymyalgia rheumatica: British Society for Rheumatology guideline scope.

The last British Society for Rheumatology (BSR) guideline on PMR was published in 2009. The guideline needs to be updated to provide a summary of the current evidence for pharmacological and non-pharmacological management of adults with PMR. This guideline is aimed at healthcare professionals in the UK who directly care for people with PMR, including general practitioners, rheumatologists, nurses, physiotherapists, occupational therapists, pharmacists, psychologists and other health professionals. It will also be relevant to people living with PMR and organisations that support them in the public and third sector, including charities and informal patient support groups. This guideline will be developed using the methods and processes outlined in the BSR Guidelines Protocol. Here we provide a brief summary of the scope of the guideline update in development.

The DiSCPersal model: A simple model for the small-scale atmospheric transport of spheroidal carbonaceous particles (SCPs).

Spheroidal carbonaceous particles (SCPs) are atmospherically mobile by-products of anthropogenic, high-temperature fossil fuel combustion. Since they are preserved in many geologic archives across the globe, SCPs have been identified as a potential marker for the onset of the Anthropocene. Our ability to reliably model the atmospheric dispersal of SCPs remains limited to coarse spatial scales (i.e., 102-103 km). We address this gap by developing the DiSCPersal model, a multi-iterative and kinematics-based model for dispersal of SCPs at local spatial scales (i.e., 10°-102 km). Although simple and limited by available measurements of SCPs, the model is nonetheless corroborated by empirical data of the spatial distribution of SCPs from Osaka, Japan. We find that particle diameter and injection height are the primary controls of dispersal distance, whereas particle density is of secondary importance. Further, stark differences in the modelled dispersal distances of SCPs between non-point vs. smokestack sources could explain the ambiguity of dispersal distances and the relative magnitude of long-range vs. localized sourcing of SCPs reported in the literature. This research underscores the need to incorporate understanding of the localized dispersal patterns of SCPs when interpreting their preservation in geologic archives. By extension, our findings have implications for the reliability of SCPs as a globally synchronous marker for the onset of the Anthropocene.

Beware 'persuasive communication devices' when writing and reading scientific articles.

Authors rely on a range of devices and techniques to attract and maintain the interest of readers, and to convince them of the merits of the author's point of view. However, when writing a scientific article, authors must use these 'persuasive communication devices' carefully. In particular, they must be explicit about the limitations of their work, avoid obfuscation, and resist the temptation to oversell their results. Here we discuss a list of persuasive communication devices and we encourage authors, as well as reviewers and editors, to think carefully about their use.

A reproducible systematic map of research on the illusory truth effect.

People believe information more if they have encountered it before, a finding known as the illusory truth effect. But what is the evidence for the generality and pervasiveness of the illusory truth effect? Our preregistered systematic map describes the existing knowledge base and objectively assesses the quality, completeness and interpretability of the evidence provided by empirical studies in the literature. A systematic search of 16 bibliographic and grey literature databases identified 93 reports with a total of 181 eligible studies. All studies were conducted at Western universities, and most used convenience samples. Most studies used verbatim repetition of trivia statements in a single testing session with a minimal delay between exposure and test. The exposure tasks, filler tasks and truth measures varied substantially across studies, with no standardisation of materials or procedures. Many reports lacked transparency, both in terms of open science practices and reporting of descriptive statistics and exclusions. Systematic mapping resulted in a searchable database of illusory truth effect studies ( https://osf.io/37xma/ ). Key limitations of the current literature include the need for greater diversity of materials as stimuli (e.g., political or health contents), more participants from non-Western countries, studies examining effects of multiple repetitions and longer intersession intervals, and closer examination of the dependency of effects on the choice of exposure task and truth measure. These gaps could be investigated using carefully designed multi-lab studies. With a lack of external replications, preregistrations, data and code, verifying replicability and robustness is only possible for a small number of studies.

A network of change: united action on research integrity.

The last decade has seen renewed concern within the scientific community over the reproducibility and transparency of research findings. This paper outlines some of the various responsibilities of stakeholders in addressing the systemic issues that contribute to this concern. In particular, this paper asserts that a united, joined-up approach is needed, in which all stakeholders, including researchers, universities, funders, publishers, and governments, work together to set standards of research integrity and engender scientific progress and innovation. Using two developments as examples: the adoption of Registered Reports as a discrete initiative, and the use of open data as an ongoing norm change, we discuss the importance of collaboration across stakeholders.

Prescribing in pregnancy and during breast feeding: using principles in clinical practice.

Prescribing in pregnancy often causes uncertainty and anxiety for the clinician and may lead to the omission of necessary treatment. Many drugs have inadequate data to assure safety, and therefore the clinician is left with a dilemma as to where the balance of risks and benefits lie with respect to the mother and her fetus. Understanding under what circumstances women can be prescribed medication and using principles of prescribing in pregnancy to further clarify the potential risks will aid good clinical decision-making. An appreciation of the available resources and the conviction to find the best available evidence will best serve the patient and her fetus. Teratogenicity refers to the potential for a drug to cause fetal malformations and affects the embryo 3-8 weeks after conception. Teratogenic drugs are associated with an increased risk of malformations, but the majority of babies are born with no abnormalities. In addition, approximately 2-3% of infants are born with major malformations with no association with maternal medication, and this and other confounding factors need to be addressed during counselling of a woman. Fetotoxicity refers to the functional changes that can occur to the fetus as a result of medication in the second and third trimesters. These effects are more subtle and more difficult to assess and therefore there are fewer data to support or refute these types of associations. For the majority of drugs, the neonatal dose from breast feeding is a fraction of the dose exposure in utero.

The Trajectory of Truth: A Longitudinal Study of the Illusory Truth Effect.

Repeated statements are rated as subjectively truer than comparable new statements, even though repetition alone provides no new, probative information (the illusory truth effect). Contrary to some theoretical predictions, the illusory truth effect seems to be similar in magnitude for repetitions occurring after minutes or weeks. This Registered Report describes a longitudinal investigation of the illusory truth effect (n = 608, n = 567 analysed) in which we systematically manipulated intersession interval (immediately, one day, one week, and one month) in order to test whether the illusory truth effect is immune to time. Both our hypotheses were supported: We observed an illusory truth effect at all four intervals (overall effect: χ 2(1) = 169.91; M repeated = 4.52, M new = 4.14; H1), with the effect diminishing as delay increased (H2). False information repeated over short timescales might have a greater effect on truth judgements than repetitions over longer timescales. Researchers should consider the implications of the choice of intersession interval when designing future illusory truth effect research.

Cell-targeted PD-1 agonists that mimic PD-L1 are potent T cell inhibitors.

The PD-1/PD-L1 pathway is a key immune checkpoint that regulates T cell activation. There is strong rationale to develop PD-1 agonists as therapeutics against autoimmunity, but progress in this area has been limited. Here, we generated T cell receptor (TCR) targeting, PD-1 agonist bispecifics called ImmTAAI molecules that mimic the ability of PD-L1 to facilitate the colocalization of PD-1 with the TCR complex at the target cell-T cell interface. PD-1 agonist ImmTAAI molecules specifically bound to target cells and were highly effective in activating the PD-1 receptor on interacting T cells to achieve immune suppression. Potent PD-1 antibody ImmTAAI molecules closely mimicked the mechanism of action of endogenously expressed PD-L1 in their localization to the target cell-T cell interface, inhibition of proximal TCR signaling events, and suppression of T cell function. At picomolar concentrations, these bispecifics suppressed cytokine production and inhibited CD8+ T cell-mediated cytotoxicity in vitro. Crucially, in soluble form, the PD-1 ImmTAAI molecules were inactive and, hence, could avoid systemic immunosuppression. This study outlines a promising new route to generate more effective, potent, tissue-targeted PD-1 agonists that can inhibit T cell function locally with the potential to treat autoimmune and chronic inflammatory diseases of high unmet need.

Methylphenidate amplifies long-term plasticity in the hippocampus via noradrenergic mechanisms.

Methylphenidate treatment is used for Attention Deficit Hyperactivity Disorder and can improve learning and memory. Previously, improvements were considered a by-product of increased attention; however, we hypothesize that methylphenidate directly alters mechanisms underlying learning and memory, and therefore examined its effects on hippocampal long-term potentiation and long-term depression. Methylphenidate enhanced both mechanisms in the absence of presynaptic changes and in a noradrenalin beta-receptor-dependent manner. These findings can explain both the improved learning and memory and decreased learning selectivity found with methylphenidate treatment and constitute the first demonstration of direct actions of methylphenidate on mechanisms implicated in cognition.

Reducing inappropriate urine testing at Hutt Valley District Health Board using Choosing Wisely principles.

AIM: Unnecessary treatment of asymptomatic bacteriuria is a concern. Hutt Valley District Health Board sought to reduce clinically inappropriate urine culture requests through removal of urine dipsticks from wards and education of staff using Choosing Wisely principles. The purpose of this research is to quantitatively evaluate the success of these initiatives. METHODS: The numbers and results of urine cultures performed for Hutt Valley DHB were analysed, for the period from January 2015 to October 2017. Urinalyses were compared between those designated as 'inpatient' and those as 'outpatient', with the latter being the control of this study. The numbers of primary and secondary coded discharge diagnoses of UTIs were used as a measure of the negative impact of the interventions. RESULTS: There was a 28% reduction in monthly urine culture requests for inpatients, after staff education and removal of urine dipsticks, with no change in those for outpatients (the negative control). After the intervention, a higher proportion of urine cultures were positive for urinary pathogens (25.2% compared to 23.0%) and the average number of diagnoses of UTI in hospital discharges decreased 17% (from 161 to 134). CONCLUSION: The removal of urine dipsticks from wards and the education of staff significantly reduced the number of urine culture requests and is a useful strategy to reduce the overuse of antibiotics for asymptomatic bacteriuria without an increase in the number of UTIs. These simple interventions could be used at other hospitals as part of measures to reduce unnecessary care and overdiagnosis.

Enumeration in Alzheimer's disease and other late life psychiatric syndromes.

Previous studies suggest that visual enumeration is spared in normal aging but impaired in abnormal aging (late stage Alzheimer's disease, AD), raising the task's potential as a marker of dementia. Experiment 1 compared speeded enumeration of 1-9 random dots in early stage AD, vascular dementia (VAD), depression, and age-matched controls. Previous deficits were replicated but they were not specific to AD, with the rate of counting larger numerosities similarly slowed relative to controls by both AD and VAD. Determination of subitizing span was complicated by the surprisingly slower enumeration of one than of two items, especially in AD patients. Experiment 2 showed that AD patients' relative difficulty with one item persisted with further practice and extended to the enumeration of targets among distractors. However, it was abolished when pattern recognition was possible (enumerating dots on a die). Although an enumeration test is unlikely to help differentiate early AD from other common dementias, the unexpected pattern of patients' performance challenges current models of enumeration and requires further investigation.

Attitude of medical students towards general practice and general practitioners.

BACKGROUND: The stimuli for this work came from the need to identify and understand the origin of students' attitudes towards general practice in the context of undergraduate curriculum reform and concerns about recruitment. AIM: To evaluate attitudes of medical students towards general practice as a specialty and general practitioners (GPs) as doctors and explore factors influencing students' attitudes and intended career choice. DESIGN OF STUDY: Cross-sectional survey. SETTING: Final-year students at two London medical schools. METHOD: Questionnaires were distributed to 984 students and the results analysed using SPSS analysis. RESULTS: The mean response rate was 72% (700/984). Medical students had a positive attitude towards general practice as a specialty (mean Likert score = 3.90/5, 95% confidence interval [CI] = 3.86 to 3.94) and towards GPs as doctors (mean Likert score = 3.62/5, 95% CI = 3.59 to 3.66). They rated personal experience of GPs as the most important factor influencing their attitude. Students' attitudes towards general practice and GPs were more positive (P<0.001) in the fifth year. First-year students perceived the media to have a more important role in influencing their attitude than those in the fifth year(P<0.001). General practice was the only career option to significantly increase in popularity between the first and final year(P < 0.001). CONCLUSIONS: Medical students end their undergraduate years with a more positive attitude towards general practice than has been reported elsewhere recently. This may be partially explained by the greater contact with GPs and suggests that efforts by medical schools to ensure a more balanced, community-based curriculum promotes positive attitudes to general practice. The influence of the media on the first years of medical school requiresfurther investigation.