Do Individual Differences And Aging Effects In The Estimation Of Geographical Slant Reflect Cognitive Or Perceptual Effects?

Several individual differences including age have been suggested to affect the perception of slant. A cross-sectional study of outdoor hill estimation (N = 106) was analyzed using individual difference measures of age, experiential knowledge, fitness, personality traits, and sex. Of particular note, it was found that for participants who reported any experiential knowledge about slant, estimates decreased (i.e., became more accurate) as conscientiousness increased, suggesting that more conscientious individuals were more deliberate about taking their experiential knowledge (rather than perception) into account. Effects of fitness were limited to those without experiential knowledge, suggesting that they, too, may be cognitive rather than perceptual. The observed effects of age, which tended to produce lower, more accurate estimates of hill slant, provide more evidence that older adults do not see hills as steeper. The main effect of age was to lower slant estimates; such effects may be due to implicit experiential knowledge acquired over a lifetime. The results indicate the impact of cognitive, rather than perceptual factors on individual differences in slant estimation

Allostery and inhibition of Psychrobacter arcticus adenosine 5'-triphosphate phosphoribosyltransferase

Allostery is the regulation of a protein by binding in an area distinct from the enzyme active site, but despite having clear applications in biotechnology and in drug discovery, elucidation of its complexities is still ongoing. Allostery can be either activating or inhibiting and the allosteric site is often distant to the one affected. The enzyme Psychrobacter arcticus ATP phosphoribosyl transferase (ATPPRT) is both allosterically activated and inhibited and is therefore useful as a model organism for understanding allostery. P. arcticus, ATPPRT is a Type IV ATPPRT, catalyzes the first step in histidine biosynthesis, and is comprised of two subunits: a short form HisG[sub]S and HisZ. HisG[sub]S is the catalytic domain and is allosterically activated by HisZ. HisZ also contains an allosteric binding site for inhibition by histidine. Short form HisG[sub]S alone is catalytically active but insensitive to histidine. This work establishes the kinetic mechanism of histidine inhibition in PaATPPRT, with histidine binding non-competitively with respect to both substrates (ATP and PRPP). AMP was confirmed as a competitive inhibitor with respect to both substrates for both PaATPPRT and PaHisGS and ADP was determined to be an alternative substrate. This work demonstrates the first example of histidine binding in a site analogous to that of HisRS in a short-form ATPPRT. It also highlights an interaction between two loops in PaHisZ, mediated by a hydrogen bond between Tyr263 and His104, that is likely to greatly reduce the probability of the complex sampling the activated conformation necessary for successful reaction. Additionally, a clear distinction between the activated form of PaATPPRT with ATP bound compared to all other structures is observed. Overall, this work demonstrates a clear reliance on key structural changes for the allosteric regulation of PaATPPRT. Attempts to purify Staphylococcus aureus ATPPRT were unsuccessful

Child relationships in the middle grades

Thesis (Ed.M.)--Boston Universit

Investigation into the role of the germline epigenome in the transmission of glucocorticoid-programmed effects across generations.

BACKGROUND: Early life exposure to adverse environments affects cardiovascular and metabolic systems in the offspring. These programmed effects are transmissible to a second generation through both male and female lines, suggesting germline transmission. We have previously shown that prenatal overexposure to the synthetic glucocorticoid dexamethasone (Dex) in rats reduces birth weight in the first generation (F1), a phenotype which is transmitted to a second generation (F2), particularly through the male line. We hypothesize that Dex exposure affects developing germ cells, resulting in transmissible alterations in DNA methylation, histone marks and/or small RNA in the male germline. RESULTS: We profile epigenetic marks in sperm from F1 Sprague Dawley rats expressing a germ cell-specific GFP transgene following Dex or vehicle treatment of the mothers, using methylated DNA immunoprecipitation sequencing, small RNA sequencing and chromatin immunoprecipitation sequencing for H3K4me3, H3K4me1, H3K27me3 and H3K9me3. Although effects on birth weight are transmitted to the F2 generation through the male line, no differences in DNA methylation, histone modifications or small RNA were detected between germ cells and sperm from Dex-exposed animals and controls. CONCLUSIONS: Although the phenotype is transmitted to a second generation, we are unable to detect specific changes in DNA methylation, common histone modifications or small RNA profiles in sperm. Dex exposure is associated with more variable 5mC levels, particularly at non-promoter loci. Although this could be one mechanism contributing to the observed phenotype, other germline epigenetic modifications or non-epigenetic mechanisms may be responsible for the transmission of programmed effects across generations in this model

Mapping the structural path for allosteric inhibition of a short-form ATP phosphoribosyltransferase by histidine

Funding: This work was supported by a Wellcome Trust Institutional Strategic Support Fund to the University of St Andrews and the Biotechnology and Biological Sciences Research Council (BBSRC) [grant number BB/M010996/1] via an EASTBIO Doctoral Training Partnership studentship to GF. X-ray diffraction data were collected at Diamond Light Source in the UK.ATP phosphoribosyltransferase (ATPPRT) catalyses the first step of histidine biosynthesis, being allosterically inhibited by the final product of the pathway. Allosteric inhibition of long-form ATPPRTs by histidine has been extensively studied, but inhibition of short-form ATPPRTs is poorly understood. Short-form ATPPRTs are hetero-octamers formed by four catalytic subunits (HisGS) and four regulatory subunits (HisZ). HisGS alone is catalytically active and insensitive to histidine. HisZ enhances catalysis by HisGS in the absence of histidine but mediates allosteric inhibition in its presence. Here, steady-state and pre-steady-state kinetics establish that histidine is a non-competitive inhibitor of short-form ATPPRT, and that inhibition does not occur by dissociating HisGS from the hetero-octamer. The crystal structure of ATPPRT in complex with histidine and the substrate 5-phospho-α-D-ribosyl-1-pyrophosphate (PRPP) was solved, showing histidine bound solely to HisZ, with four histidine molecules per hetero-octamer. Histidine binding involves the repositioning of two HisZ loops. The histidine-binding loop moves closer to histidine to establish polar contacts. This leads to a hydrogen bond between its Tyr263 and His104 in the Asp101–Leu117 loop. The Asp101–Leu117 loop leads to the HisZ/HisGS interface, and in the absence of histidine its motion prompts HisGS conformational changes responsible for catalytic activation. Following histidine binding, interaction with the histidine-binding loop may prevent the Asp101–Leu117 loop from efficiently sampling conformations conducive to catalytic activation. Tyr263Phe-PaHisZ-containing PaATPPRT, however, is less susceptible though not insensitive to histidine inhibition, suggesting the Tyr263-His104 interaction may be relevant to, yet not solely responsible for transmission of the allosteric signal.Publisher PDFPeer reviewe

Protocol of a randomised controlled trial of real-time continuous glucose monitoring in neonatal intensive care 'REACT'.

INTRODUCTION: Hyperglycaemia is common in the very preterm infant and has been associated with adverse outcomes. Preventing hyperglycaemia without increasing the risk of hypoglycaemia has proved challenging. The development of real-time continuous glucose monitors (CGM) to inform treatment decisions provides an opportunity to reduce this risk. This study aims to assess the feasibility of CGM combined with a specifically designed paper guideline to target glucose control in the preterm infant. METHODS AND ANALYSES: The Real Time Continuous Glucose Monitoring in Neonatal Intensive Care (REACT) trial is an international multicentre randomised controlled trial. 200 preterm infants ≤1200 g and ≤24 hours of age will be randomly allocated to either real-time CGM or standard care (with blinded CGM data collection). The primary outcome is time in target 2.6-10 mmol/L during the study intervention assessed using CGM. Secondary outcomes include efficacy relating to glucose control, utility including staff acceptability, safety outcomes relating to incidence and prevalence of hypoglycaemia and health economic analyses. ETHICS AND DISSEMINATION: The REACT trial has been approved by the National Health Service Health Research Authority National Research Ethics Service Committee East of England (Cambridge Central); Medical Ethics Review Committee, VU University Medical Centre, Amsterdam, The Netherlands and the Research Ethics Committee, Sant Joan de Déu Research Foundation, Barcelona, Spain. Recruitment began in July 2016 and will continue until mid-2018. The trial has been adopted by the National Institute of Health Research Clinical Research Network portfolio (ID: 18826) and is registered with anInternational Standard Randomised Control Number (ISRCTN registry ID: 12793535). Dissemination plans include presentations at scientific conferences, scientific publications and efforts at stakeholder engagement. TRIAL REGISTRATION NUMBER: ISRCTN12793535; Pre-results

‘You can’t start a car when there’s no petrol left’: a qualitative study of patient, family and clinician perspectives on implantable cardioverter defibrillator deactivation

Objective: To explore the attitudes towards implantable cardioverter defibrillator (ICD) deactivation and initiation of deactivation discussions among patients, relatives and clinicians. Design: A multiphase qualitative study consisting of in situ hospital ICD clinic observations, and semistructured interviews of clinicians, patients and relatives. Data were analysed using a constant comparative approach. Setting: One tertiary and two district general hospitals in England. Participants: We completed 38 observations of hospital consultations prior to ICD implantation, and 80 interviews with patients, family members and clinicians between 2013 and 2015. Patients were recruited from preimplantation to postdeactivation. Clinicians included cardiologists, cardiac physiologists, heart failure nurses and palliative care professionals. Results: Four key themes were identified from the data: the current status of deactivation discussions; patients’ perceptions of deactivation; who should take responsibility for deactivation discussions and decisions; and timing of deactivation discussions. We found that although patients and doctors recognised the importance of advance care planning, including ICD deactivation at an early stage in the patient journey, this was often not reflected in practice. The most appropriate clinician to take the lead was thought to be dependent on the context, but could include any appropriately trained member of the healthcare team. It was suggested that deactivation should be raised preimplantation and regularly reviewed. Identification of trigger points postimplantation for deactivation discussions may help ensure that these are timely and inappropriate shocks are avoided. Conclusions: There is a need for early, ongoing and evolving discussion between ICD recipients and clinicians regarding the eventual need for ICD deactivation. The most appropriate clinician to instigate deactivation discussions is likely to vary between patients and models of care. Reminders at key trigger points, and routine discussion of deactivation at implantation and during advance care planning could prevent distressing experiences for both the patient and their family at the end of life

Loss of microbial diversity and pathogen domination of the gut microbiota in critically ill patients

Among long-stay critically ill patients in the adult intensive care unit (ICU), there are often marked changes in the complexity of the gut microbiota. However, it remains unclear whether such patients might benefit from enhanced surveillance or from interventions targeting the gut microbiota or the pathogens therein. We therefore undertook a prospective observational study of 24 ICU patients, in which serial faecal samples were subjected to shotgun metagenomic sequencing, phylogenetic profiling and microbial genome analyses. Two-thirds of the patients experienced a marked drop in gut microbial diversity (to an inverse Simpson's index of <4) at some stage during their stay in the ICU, often accompanied by the absence or loss of potentially beneficial bacteria. Intravenous administration of the broad-spectrum antimicrobial agent meropenem was significantly associated with loss of gut microbial diversity, but the administration of other antibiotics, including piperacillin/tazobactam, failed to trigger statistically detectable changes in microbial diversity. In three-quarters of ICU patients, we documented episodes of gut domination by pathogenic strains, with evidence of cryptic nosocomial transmission of Enterococcus faecium. In some patients, we also saw an increase in the relative abundance of apparent commensal organisms in the gut microbiome, including the archaeal species Methanobrevibacter smithii. In conclusion, we have documented a dramatic absence of microbial diversity and pathogen domination of the gut microbiota in a high proportion of critically ill patients using shotgun metagenomics