Sex Differences in Cognitive Flexibility and Resting Brain Networks in Middle-Aged Marmosets

Sex differences in human cognitive performance are well characterized. However, the neural correlates of these differences remain elusive. This issue may be clarified using nonhuman primates, for which sociocultural influences are minimized. We used the marmoset (Callithrix jacchus) to investigate sex differences in two aspects of executive function: reversal learning and intradimensional/extradimensional (ID/ED) set shifting. Stress reactivity and motor function were also assessed. In agreement with human literature, females needed more trials than males to acquire the reversals. No sex differences in ED set shifting or motivational measures were observed. The findings suggest enhanced habit formation in females, perhaps due to striatal estrogenic effects. Both sexes showed increased urinary cortisol during social separation stressor, but females showed an earlier increase in cortisol and a greater increase in agitated locomotion, possibly indicating enhanced stress reactivity. Independent of sex, basal cortisol predicted cognitive performance. No sex differences were found in motor performance. Associations between brain networks and reversal learning performance were investigated using resting state fMRI. Resting state functional connectivity (rsFC) analyses revealed sex differences in cognitive networks, with differences in overall neural network metrics and specific regions, including the prefrontal cortex, caudate, putamen, and nucleus accumbens. Correlations between cognitive flexibility and neural connectivity indicate that sex differences in cognitive flexibility are related to sex-dependent patterns of resting brain networks. Overall, our findings reveal sex differences in reversal learning, brain networks, and their relationship in the marmoset, positioning this species as an excellent model to investigate the biological basis of cognitive sex differences

Subject Lines as Sensors:Co-word Analysis of Email to Support the Management of Collaborative Engineering Work

This paper presents a topic-based analysis of email subject line data from a large-scale engineering project and explores its utility for supporting the management of collaborative work. The main contributions of the paper are a novel interpretation of the co-word network analysis method for application within an engineering project management context, and the appraisal of the method for d=finding patterns within subject line data. Our findings suggest that the approach has the potential to contribute to monitoring work complexity, tracking progress, recognizing synergy and divergence, detecting scope creep, and supporting knowledge capture

Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of randomised controlled trials

BACKGROUND: Chlorpromazine (CPZ) remains one of the most common drugs used for people with schizophrenia worldwide, and a benchmark against which other treatments can be evaluated. Quantitative reviews are rare; this one evaluates the effects of chlorpromazine in the treatment of schizophrenia in comparison with placebo. METHODS: We sought all relevant randomised controlled trials (RCT) comparing chlorpromazine to placebo by electronic and reference searching, and by contacting trial authors and the pharmaceutical industry. Data were extracted from selected trials and, where possible, synthesised and random effects relative risk (RR), the number needed to treat (NNT) and their 95% confidence intervals (CI) calculated. RESULTS: Fifty RCTs from 1955–2000 were included with 5276 people randomised to CPZ or placebo. They constitute 2008 person-years spent in trials. Meta-analysis of these trials showed that chlorpromazine promotes a global improvement (n = 1121, 13 RCTs, RR 0.76 CI 0.7 to 0.9, NNT 7 CI 5 to 10), although a considerable placebo response is also seen. People allocated to chlorpromazine tended not to leave trials early in both the short (n = 945, 16 RCTs, RR 0.74 CI 0.5 to 1.1) and medium term (n = 1861, 25 RCTs, RR 0.79 CI 0.6 to 1.1). There were, however, many adverse effects. Chlorpromazine is sedating (n = 1242, 18 RCTs, RR 2.3 CI 1.7 to 3.1, NNH 6 CI 5 to 8), increases a person's chances of experiencing acute movement disorders, Parkinsonism and causes low blood pressure with dizziness and dry mouth. CONCLUSION: It is understandable why the World Health Organization (WHO) have endorsed and included chlorpromazine in their list of essential drugs for use in schizophrenia. Low- and middle-income countries may have more complete evidence upon which to base their practice compared with richer nations using recent innovations

Marine heatwaves threaten global biodiversity and the provision of ecosystem services

The global ocean has warmed substantially over the past century, with far-reaching implications for marine ecosystems 1 . Concurrent with long-term persistent warming, discrete periods of extreme regional ocean warming (marine heatwaves, MHWs) have increased in frequency 2 . Here we quantify trends and attributes of MHWs across all ocean basins and examine their biological impacts from species to ecosystems. Multiple regions in the Pacific, Atlantic and Indian Oceans are particularly vulnerable to MHW intensification, due to the co-existence of high levels of biodiversity, a prevalence of species found at their warm range edges or concurrent non-climatic human impacts. The physical attributes of prominent MHWs varied considerably, but all had deleterious impacts across a range of biological processes and taxa, including critical foundation species (corals, seagrasses and kelps). MHWs, which will probably intensify with anthropogenic climate change 3 , are rapidly emerging as forceful agents of disturbance with the capacity to restructure entire ecosystems and disrupt the provision of ecological goods and services in coming decades. © 2019, The Author(s), under exclusive licence to Springer Nature Limited

Estimating encounter location distributions from animal tracking data

1. Ecologists have long been interested in linking individual behaviour with higher level processes. For motile species, this ‘upscaling’ is governed by how well any given movement strategy maximizes encounters with positive factors and minimizes encounters with negative factors. Despite the importance of encounter events for a broad range of ecological processes, encounter theory has not kept pace with developments in animal tracking or movement modelling. Furthermore, existing work has focused primarily on the relationship between animal movement and encounter rates while the relationship between individual movement and the spatial locations of encounter events in the environment has remained conspicuously understudied. 2. Here, we bridge this gap by introducing a method for describing the long-term encounter location probabilities for movement within home ranges, termed the conditional distribution of encounters (CDE). We then derive this distribution, as well as confidence intervals, implement its statistical estimator into open-source software and demonstrate the broad ecological relevance of this distribution. 3. We first use simulated data to show how our estimator provides asymptotically consistent estimates. We then demonstrate the general utility of this method for three simulation-based scenarios that occur routinely in biological systems: (a) a population of individuals with home ranges that overlap with neighbours; (b) a pair of individuals with a hard territorial border between their home ranges; and (c) a predator with a large home range that encompassed the home ranges of multiple prey individuals. Using GPS data from white-faced capuchins Cebus capucinus, tracked on Barro Colorado Island, Panama, and sleepy lizards Tiliqua rugosa, tracked in Bundey, South Australia, we then show how the CDE can be used to estimate the locations of territorial borders, identify key resources, quantify the potential for competitive or predatory interactions and/or identify any changes in behaviour that directly result from location-specific encounter probability. 4. The CDE enables researchers to better understand the dynamics of populations of interacting individuals. Notably, the general estimation framework developed in this work builds straightforwardly off of home range estimation and requires no specialized data collection protocols. This method is now openly available via the ctmm R package

The Binding Effect of Proteins on Medications and Its Impact on Electrochemical Sensing: Antipsychotic Clozapine as a Case Study

Partial funding for Open Access provided by the UMD Libraries' Open Access Publishing Fund.Clozapine (CLZ), a dibenzodiazepine, is demonstrated as the optimal antipsychotic for patients suffering from treatment-resistant schizophrenia. Like many other drugs, understanding the concentration of CLZ in a patient’s blood is critical for managing the patients’ symptoms, side effects, and overall treatment efficacy. To that end, various electrochemical techniques have been adapted due to their capabilities in concentration-dependent sensing. An open question associated with electrochemical CLZ monitoring is whether drug–protein complexes (i.e., CLZ bound to native blood proteins, such as serum albumin (SA) or alpha-1 acid-glycoprotein (AAG)) contribute to electrochemical redox signals. Here, we investigate CLZ-sensing performance using fundamental electrochemical methods with respect to the impact of protein binding. Specifically, we test the activity of bound and free fractions of a mixture of CLZ and either bovine SA or human AAG. Results suggest that bound complexes do not significantly contribute to the electrochemical signal for mixtures of CLZ with AAG or SA. Moreover, the fraction of CLZ bound to protein is relatively constant at 31% (AAG) and 73% (SA) in isolation with varying concentrations of CLZ. Thus, electrochemical sensing can enable direct monitoring of only the unbound CLZ, previously only accessible via equilibrium dialysis. The methods utilized in this work offer potential as a blueprint in developing electrochemical sensors for application to other redox-active medications with high protein binding more generally. This demonstrates that electrochemical sensing can be a new tool in accessing information not easily available previously, useful toward optimizing treatment regimens

Opposite temperature effect on transport activity of KCC2/KCC4 and N(K)CCs in HEK-293 cells

<p>Abstract</p> <p>Background</p> <p>Cation chloride cotransporters play essential roles in many physiological processes such as volume regulation, transepithelial salt transport and setting the intracellular chloride concentration in neurons. They consist mainly of the inward transporters NCC, NKCC1, and NKCC2, and the outward transporters KCC1 to KCC4. To gain insight into regulatory and structure-function relationships, precise determination of their activity is required. Frequently, these analyses are performed in HEK-293 cells. Recently the activity of the inward transporters NKCC1 and NCC was shown to increase with temperature in these cells. However, the temperature effect on KCCs remains largely unknown.</p> <p>Findings</p> <p>Here, we determined the temperature effect on KCC2 and KCC4 transport activity in HEK-293 cells. Both transporters demonstrated significantly higher transport activity (2.5 fold for KCC2 and 3.3 fold for KCC4) after pre-incubation at room temperature compared to 37°C.</p> <p>Conclusions</p> <p>These data identify a reciprocal temperature dependence of cation chloride inward and outward cotransporters in HEK-293 cells. Thus, lower temperature should be used for functional characterization of KCC2 and KCC4 and higher temperatures for N(K)CCs in heterologous mammalian expression systems. Furthermore, if this reciprocal effect also applies to neurons, the action of inhibitory neurotransmitters might be more affected by changes in temperature than previously thought.</p

A non-synonymous coding change in the CYP19A1 gene Arg264Cys (rs700519) does not affect circulating estradiol, bone structure or fracture

Background The biosynthesis of estrogens from androgens is catalyzed by aromatase P450 enzyme, coded by the CYP19A1 gene on chromosome 15q21.2. Genetic variation within the CYP19A1 gene sequence has been shown to alter the function of the enzyme. The aim of this study is to investigate whether a non-synonymous Arg264Cys (rs700519) single nucleotide polymorphism (SNP) is associated with altered levels of circulating estradiol, areal bone mineral density or fracture. Methods This population- based study of 1,022 elderly Caucasian women (mean age 74.95 ± 2.60 years) was genotyped for the rs700519 SNP were analyzed to detect any association with endocrine and bone phenotypes. Results The genotype frequencies were 997 wildtype (97.6%), 24 heterozygous (2.3%) and 1 homozygous (0.1%). When individuals were grouped by genotype, there was no association between the polymorphism and serum estradiol (wildtype 27.5 ± 16.0; variants 31.2 ± 18.4, P = 0.27). There was also no association seen on hip bone mineral density (wildtype 0.81 ± 0.12; 0.84 ± 0.14 for variants, P = 0.48) or femoral neck bone mineral density (0.69 ± 0.10 for wildtype; 0.70 ± 0.12 for variants, P = 0.54) before or after correction of the data with age, height, weight and calcium therapy. There were also no associations with quantitative ultrasound measures of bone structure (broadband ultrasound attenuation, speed of sound and average stiffness). Conclusions In a cohort of 1,022 elderly Western Australian women, the presence of Arg264Cys (rs700519) polymorphism was not found to be associated with serum estradiol, bone structure or phenotypes

Intracellular chloride concentration influences the GABAA receptor subunit composition

GABAA receptors (GABAARs) exist as different subtype variants showing unique functional properties and defined spatio-temporal expression pattern. The molecular mechanisms underlying the developmental expression of different GABAAR are largely unknown. The intracellular concentration of chloride ([Cl−]i), the main ion permeating through GABAARs, also undergoes considerable changes during maturation, being higher at early neuronal stages with respect to adult neurons. Here we investigate the possibility that [Cl−]i could modulate the sequential expression of specific GABAARs subtypes in primary cerebellar neurons. We show that [Cl−]i regulates the expression of α3-1 and δ-containing GABAA receptors, responsible for phasic and tonic inhibition, respectively. Our findings highlight the role of [Cl−]i in tuning the strength of GABAergic responses by acting as an intracellular messenger

Identifying inequitable healthcare in older people: systematic review of current research practice

$\textbf{Background:}$ There is growing consensus on the importance of identifying age-related inequities in the receipt of public health and healthcare interventions, but concerns regarding conceptual and methodological rigour in this area of research. Establishing age inequity in receipt requires evidence of a difference that is not an artefact of poor measurement of need or receipt; is not warranted on the grounds of patient preference or clinical safety; and is judged to be unfair. $\textbf{Method:}$ A systematic, thematic literature review was undertaken with the objective of characterising recent research approaches. Studies were eligible if the population was in a country within the Organisation for Economic Co-operation and Development and analyses included an explicit focus on age-related patterns of healthcare receipt including those 60 years or older. A structured extraction template was applied. Extracted material was synthesised in thematic memos. A set of categorical codes were then defined and applied to produce summary counts across key dimensions. This process was iterative to allow reconciliation of discrepancies and ensure reliability. $\textbf{Results:}$ Forty nine studies met the eligibility criteria. A wide variety of concepts, terms and methodologies were used across these studies. Thirty five studies employed multivariable techniques to produce adjusted receipt-need ratios, though few clearly articulated their rationale, indicating the need for great conceptual clarity. Eighteen studies made reference to patient preference as a relevant consideration, but just one incorporated any kind of adjustment for this factor. Twenty five studies discussed effectiveness among older adults, with fourteen raising the possibility of differential effectiveness, and one differential cost-effectiveness, by age. Just three studies made explicit reference to the ethical nature of healthcare resource allocation by age. While many authors presented suitably cautious conclusions, some appeared to over-stretch their findings concluding that observed differences were ‘inequitable’. Limitations include possible biases in the retrieved material due to inconsistent database indexing and a focus on OECD country populations and studies with English titles. $\textbf{Conclusions:}$ Caution is needed among clinicians and other evidence-users in accepting claims of healthcare ‘ageism’ in some published papers. Principles for improved research practice are proposed.This research was funded by the National Institute for Health Research’s School for Public Health Research