Arsenite oxidase in complex with antimonite and arsenite oxyanions: Insights into the catalytic mechanism.

Arsenic contamination of groundwater is among one of the biggest health threats affecting millions of people in the world. There is an urgent need for efficient arsenic biosensors where the use of arsenic metabolizing enzymes can be explored. In this work, we have solved four crystal structures of arsenite oxidase (Aio) in complex with arsenic and antimony oxyanions and the structures determined correspond to intermediate states of the enzymatic mechanism. These structural data were complemented with density-functional theory calculations providing a unique view of the molybdenum active site at different time points that, together with mutagenesis data, enabled to clarify the enzymatic mechanism and the molecular determinants for the oxidation of As(III) to the less toxic As(V) species.

Cognitive domains affected post-COVID-19; a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: This review aims to characterize the pattern of post-COVID-19 cognitive impairment, allowing better prediction of impact on daily function to inform clinical management and rehabilitation. METHODS: A systematic review and meta-analysis of neurocognitive sequelae following COVID-19 was conducted, following PRISMA-S guidelines. Studies were included if they reported domain-specific cognitive assessment in patients with COVID-19 at >4 weeks post-infection. Studies were deemed high-quality if they had >40 participants, utilized healthy controls, had low attrition rates and mitigated for confounders. RESULTS: Five of the seven primary Diagnostic and Statistical Manual of Mental Disorders (DSM-5) cognitive domains were assessed by enough high-quality studies to facilitate meta-analysis. Medium effect sizes indicating impairment in patients post-COVID-19 versus controls were seen across executive function (standardised mean difference (SMD) -0.45), learning and memory (SMD -0.55), complex attention (SMD -0.54) and language (SMD -0.54), with perceptual motor function appearing to be impacted to a greater degree (SMD -0.70). A narrative synthesis of the 56 low-quality studies also suggested no obvious pattern of impairment. CONCLUSIONS: This review found moderate impairments across multiple domains of cognition in patients post-COVID-19, with no specific pattern. The reported literature was significantly heterogeneous, with a wide variety of cognitive tasks, small sample sizes and disparate initial disease severities limiting interpretability. The finding of consistent impairment across a range of cognitive tasks suggests broad, as opposed to domain-specific, brain dysfunction. Future studies should utilize a harmonized test battery to facilitate inter-study comparisons, whilst also accounting for the interactions between COVID-19, neurological sequelae and mental health, the interplay between which might explain cognitive impairment.

The significance of the library's physical space: how COVID-19 impacted a consumer health service.

Background: During the beginning of the COVID-19 pandemic, many consumer health libraries were forced to close their doors to patrons. At the Health Information Center in Knoxville, Tennessee, the physical space closed, while health information services continued to be provided via phone and email. To examine the impact of lack of access to a physical library for consumer health information, researchers analyzed the number of health information requests pre-COVID-19 pandemic compared to during the initial phase of the pandemic. Case Presentation: Data from an internal database was collected and analyzed. Researchers divided the data into three time periods: March 2018 to February 2019 (Phase 1), March 2019 to February 2020 (Phase 2), and March 2020 to February 2021 (Phase 3). Data was de-identified and duplicate entries were removed. The type of interaction and request topics were reviewed in each phase. Conclusion: In Phase 1, there were 535 walk-ins to request health information and 555 walk-ins in Phase 2. In Phase 3, there were 40 walk-ins. The number of requests through phone and email varied but remained steady. There was a 61.56% decrease in requests between Phase 1 and Phase 3 while there was a 66.27% decrease between Phase 2 and Phase 3 due to the lack of walk-in requests. The number of phone and email requests did not increase despite the closure of the physical library space to the public. Access to the physical space plays a significant role in providing health information requests to patients and family members.

Neurology and neuropsychiatry of COVID-19: a systematic review and meta-analysis of the early literature reveals frequent CNS manifestations and key emerging narratives.

There is accumulating evidence of the neurological and neuropsychiatric features of infection with SARS-CoV-2. In this systematic review and meta-analysis, we aimed to describe the characteristics of the early literature and estimate point prevalences for neurological and neuropsychiatric manifestations.We searched MEDLINE, Embase, PsycINFO and CINAHL up to 18 July 2020 for randomised controlled trials, cohort studies, case-control studies, cross-sectional studies and case series. Studies reporting prevalences of neurological or neuropsychiatric symptoms were synthesised into meta-analyses to estimate pooled prevalence.13 292 records were screened by at least two authors to identify 215 included studies, of which there were 37 cohort studies, 15 case-control studies, 80 cross-sectional studies and 83 case series from 30 countries. 147 studies were included in the meta-analysis. The symptoms with the highest prevalence were anosmia (43.1% (95% CI 35.2% to 51.3%), n=15 975, 63 studies), weakness (40.0% (95% CI 27.9% to 53.5%), n=221, 3 studies), fatigue (37.8% (95% CI 31.6% to 44.4%), n=21 101, 67 studies), dysgeusia (37.2% (95% CI 29.8% to 45.3%), n=13 686, 52 studies), myalgia (25.1% (95% CI 19.8% to 31.3%), n=66 268, 76 studies), depression (23.0% (95% CI 11.8% to 40.2%), n=43 128, 10 studies), headache (20.7% (95% CI 16.1% to 26.1%), n=64 613, 84 studies), anxiety (15.9% (5.6% to 37.7%), n=42 566, 9 studies) and altered mental status (8.2% (95% CI 4.4% to 14.8%), n=49 326, 19 studies). Heterogeneity for most clinical manifestations was high.Neurological and neuropsychiatric symptoms of COVID-19 in the pandemic's early phase are varied and common. The neurological and psychiatric academic communities should develop systems to facilitate high-quality methodologies, including more rapid examination of the longitudinal course of neuropsychiatric complications of newly emerging diseases and their relationship to neuroimaging and inflammatory biomarkers.

Migration, cultural capital and acculturation.

Migration is not a recent phenomenon. Human beings have moved around the globe for numerous reasons over past millennia and will continue to do so. Moving to a new culture, especially if there are differences in primary language, diet, dress etc can create difficulties in acculturation. Migrant experience is not homogenous during the process or in settling down post-migration. Individuals migrate alone, with families or in groups and do so for a number of reasons, e.g. educational, economic, socio-political or as a result of natural or manmade disasters. Each individual has their own culture and cultural capital which they carry with them wherever they go. Cultural capital needs to be differentiated from social capital although some common features persist. Cultural capital is shown to have three sources - objective, institutionalized and embodied. Each of these is likely to play a role in acculturation though some sources may be more effective than others. It is important to understand the role cultural capital plays in acculturation and positive settling down. It should be possible to use strengths of cultural capital to reduce post-migration distress. In this paper we present a potential model in understanding the role cultural capital can play in the acculturative processes.

Psychiatric disorders in older adults: a naturalistic study from North India.

The number of older adults is increasing, especially among low- and middle-income countries. This raises specific issues related to healthcare since, as people are living longer, it is much more likely they will be living with complex co-morbidities, both physical and mental. In a naturalistic study from a private healthcare clinic from an industrial town in North India, details of 52 patients (mean age 72.4 years) were collected. Two thirds were male, and a vast majority attended the clinic accompanied by a family member. Those with different types of dementias were much more likely to present with sleep disturbances. A significant number of patients were illiterate or poorly educated, and a large number dropped out of healthcare. Reasons for this are discussed and detailed presentations regarding symptoms are described. Healthcare policies must take into account rural urban factors and ensure that policies take into account healthcare needs of older adults across geographical areas and complex co-morbidities.

CAPE Vulnerability Index.

The Compassion, Assertive action, Pragmatism and Evidence (CAPE) Vulnerability Index is a global foreign policy index which has been used to identify countries which require foreign aid and how that can be prioritized. The Index offers an evidenced, structured, and reasoned approach to using aid in bi-lateral agreements with mental health as a foundation. This study used 26 internationally available and validated indicators to explore and perform the analysis leading to the development of the Index. As with many summary statistics used to describe matters across the globe there has to be a fundamental reliance on national reporting or gathering of the underlying information used in their derivation, although their reliability may be in question and, in addition, such an exercise can be refined and repeated every year. It is concluded that the countries which score worse on the Index are likely to be failed states or fragile states: countries where the governments do not have complete control or authority. Such governments can often be repressive and corrupt, may participate in serious human rights abuses, and are characterized by conflict of various forms. These governments are also likely to suffer disadvantage as a result of extremes of climate changes, extreme poverty, inequality, social and ethnic divisions, the inability to provide basic services, and suffer from pockets of insurgency in the form of terrorism, which are often violent and brutal.

Magna Carta for individuals living with mental illness.

There is considerable evidence to suggest that individuals with mental illness as well as their carers and families are discriminated against across a number of domains. It is also well recognized that people with mental illness are likely to die younger than their counterparts who do not have mental illness. We propose that a Magna Carta is urgently needed to protect the rights of people with mental illness and help reduce discrimination. In this paper a background and rationale for this is offered alongside suggestions for reducing discrimination. The simple message is this; progress in health, economic, environmental and global development will not be made without improvements in mental health. The reasons are equally straightforward as mental illnesses cause more disability than any other health condition and bring enormous pain and suffering to individuals, their families and communities. These impacts lead to early death, damage to the economy and restrain individual progress. Every country needs to take urgent responsibility for defending the rights of individuals with mental illness.

Influence of library relocation and marketing: examining zip codes and health disparities to serve consumers in East Tennessee.

BACKGROUND: In 2014, the Preston Medical Library underwent a radical change, moving from an academic office building to the main floor of a regional medical center. While the library had previously served the public, health information requests have substantially increased in volume due to the new location. Researchers analyzed request data to see if the service's reach has expanded to counties that previously had not used the service, to see which counties have requested the most health information, and to ascertain whether more requests are from counties with higher poverty rates. CASE PRESENTATION: Each health information request is logged with the subject nature and patron contact information. Consumer health request data were downloaded from the library database. Names and other identifying data were removed. Request forms were sorted and reviewed by zip code and county, comparing number of requests as well as poverty levels. Tableau was utilized to create maps, visually showing patron concentrations and poverty levels. CONCLUSIONS: There were 3,141 health information requests from September 21, 2014, to May 31, 2019. The majority of requests were from local counties. Requests were also received from counties that had not been previously reached and counties with elevated poverty levels. Collecting data on patron interactions is not only critical for institutional reporting, but also for community outreach. Understanding that data require taking additional steps to filter the information, assess local demographics, and customize library services. Researchers anticipate being able to better tailor services to the community based on the results.

Electron transfer through arsenite oxidase: Insights into Rieske interaction with cytochrome c.

Arsenic is a widely distributed environmental toxin whose presence in drinking water poses a threat to >140 million people worldwide. The respiratory enzyme arsenite oxidase from various bacteria catalyses the oxidation of arsenite to arsenate and is being developed as a biosensor for arsenite. The arsenite oxidase from Rhizobium sp. str. NT-26 (a member of the Alphaproteobacteria) is a heterotetramer consisting of a large catalytic subunit (AioA), which contains a molybdenum centre and a 3Fe-4S cluster, and a small subunit (AioB) containing a Rieske 2Fe-2S cluster. Stopped-flow spectroscopy and isothermal titration calorimetry (ITC) have been used to better understand electron transfer through the redox-active centres of the enzyme, which is essential for biosensor development. Results show that oxidation of arsenite at the active site is extremely fast with a rate of >4000s-1 and reduction of the electron acceptor is rate-limiting. An AioB-F108A mutation results in increased activity with the artificial electron acceptor DCPIP and decreased activity with cytochrome c, which in the latter as demonstrated by ITC is not due to an effect on the protein-protein interaction but instead to an effect on electron transfer. These results provide further support that the AioB F108 is important in electron transfer between the Rieske subunit and cytochrome c and its absence in the arsenite oxidases from the Betaproteobacteria may explain the inability of these enzymes to use this electron acceptor.

An origin-of-life reactor to simulate alkaline hydrothermal vents.

Chemiosmotic coupling is universal: practically all cells harness electrochemical proton gradients across membranes to drive ATP synthesis, powering biochemistry. Autotrophic cells, including phototrophs and chemolithotrophs, also use proton gradients to power carbon fixation directly. The universality of chemiosmotic coupling suggests that it arose very early in evolution, but its origins are obscure. Alkaline hydrothermal systems sustain natural proton gradients across the thin inorganic barriers of interconnected micropores within deep-sea vents. In Hadean oceans, these inorganic barriers should have contained catalytic Fe(Ni)S minerals similar in structure to cofactors in modern metabolic enzymes, suggesting a possible abiotic origin of chemiosmotic coupling. The continuous supply of H2 and CO2 from vent fluids and early oceans, respectively, offers further parallels with the biochemistry of ancient autotrophic cells, notably the acetyl CoA pathway in archaea and bacteria. However, the precise mechanisms by which natural proton gradients, H2, CO2 and metal sulphides could have driven organic synthesis are uncertain, and theoretical ideas lack empirical support. We have built a simple electrochemical reactor to simulate conditions in alkaline hydrothermal vents, allowing investigation of the possibility that abiotic vent chemistry could prefigure the origins of biochemistry. We discuss the construction and testing of the reactor, describing the precipitation of thin-walled, inorganic structures containing nickel-doped mackinawite, a catalytic Fe(Ni)S mineral, under prebiotic ocean conditions. These simulated vent structures appear to generate low yields of simple organics. Synthetic microporous matrices can concentrate organics by thermophoresis over several orders of magnitude under continuous open-flow vent conditions.

Imputing Single-Cell Protein Abundance in Multiplex Tissue Imaging.

Multiplex tissue imaging are a collection of increasingly popular single-cell spatial proteomics and transcriptomics assays for characterizing biological tissues both compositionally and spatially. However, several technical issues limit the utility of multiplex tissue imaging, including the limited number of molecules (proteins and RNAs) that can be assayed, tissue loss, and protein probe failure. In this work, we demonstrate how machine learning methods can address these limitations by imputing protein abundance at the single-cell level using multiplex tissue imaging datasets from a breast cancer cohort. We first compared machine learning methods' strengths and weaknesses for imputing single-cell protein abundance. Machine learning methods used in this work include regularized linear regression, gradient-boosted regression trees, and deep learning autoencoders. We also incorporated cellular spatial information to improve imputation performance. Using machine learning, single-cell protein expression can be imputed with mean absolute error ranging between 0.05-0.3 on a [0,1] scale. Finally, we used imputed data to predict whether single cells were more likely to come from pre-treatment or post-treatment biopsies. Our results demonstrate (1) the feasibility of imputing single-cell abundance levels for many proteins using machine learning; (2) how including cellular spatial information can substantially enhance imputation results; and (3) the use of single-cell protein abundance levels in a use case to demonstrate biological relevance.

A Scoping Review on the Influence of Contextual Factors on Training Load in Adolescent Soccer Players: What Do We Know?

This scoping review aimed to systematically explore the breadth and extent of the literature regarding the relationship between contextual factors (CFs) and training load (TL) in adolescent soccer players. Further aims included comprehending potential underlying mechanisms and identifying knowledge gaps. CFs were defined as factors not part of the main training process, such as the coach-athlete relationship and educational responsibilities. PubMed, EBSCO APA PsycINFO, Web of Science, ProQuest Dissertations & Theses A&I, and SportRxiv were searched. Studies involving adolescent soccer players that investigated the CF-TL relationship and measured TL indicators were deemed eligible. Seventeen studies were included, reflecting the limited number of articles published regarding the CF-TL relationship. CFs were mostly related to match-play (N = 13) and phase of the season (N = 7). Moreover, these factors appeared to affect TL. CF related to players' personal environment (N = 3) were underrepresented in the reviewed studies. Overall, the CF-TL relationship appears to be rarely scrutinized. A likely cause for this lack of research is the segregation of the physiological and psychological research domains, where the CF-TL relationship is often speculated upon but not measured. Therefore, a holistic approach is warranted which also investigates the effect of personal environment, such as stressful life stress events, on TL.

Exposure to Low-Intensity Blast Increases Clearance of Brain Amyloid Beta.

The long-term effects of exposure to blast overpressure are an important health concern in military personnel. Increase in amyloid beta (Aß) has been documented after non-blast traumatic brain injury (TBI) and may contribute to neuropathology and an increased risk for Alzheimer's disease. We have shown that Aß levels decrease following exposure to a low-intensity blast overpressure event. To further explore this observation, we examined the effects of a single 37 kPa (5.4 psi) blast exposure on brain Aß levels, production, and clearance mechanisms in the acute (24 h) and delayed (28 days) phases post-blast exposure in an experimental rat model. Aß and, notably, the highly neurotoxic detergent soluble Aß42 form, was reduced at 24 h but not 28 days after blast exposure. This reduction was not associated with changes in the levels of Aß oligomers, expression levels of amyloid precursor protein (APP), or increase in enzymes involved in the amyloidogenic cleavage of APP, the ß- and ϒ-secretases BACE1 and presenilin-1, respectively. The levels of ADAM17 α-secretase (also known as tumor necrosis factor α-converting enzyme) decreased, concomitant with the reduction in brain Aß. Additionally, significant increases in brain levels of the endothelial transporter, low-density related protein 1 (LRP1), and enhancement in co-localization of aquaporin-4 (AQP4) to perivascular astrocytic end-feet were observed 24 h after blast exposure. These findings suggest that exposure to low-intensity blast may enhance endothelial clearance of Aß by LRP1-mediated transcytosis and alter AQP4-aided glymphatic clearance. Collectively, the data demonstrate that low-intensity blast alters enzymatic, transvascular, and perivascular clearance of Aß.

Comparative physiological effects of antipsychotic drugs in children and young people: a network meta-analysis.

BACKGROUND: The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the effects of various antipsychotic medications on physiological variables in children and adolescents with neuropsychiatric and neurodevelopmental conditions. METHODS: For this network meta-analysis, we searched Medline, EMBASE, PsycINFO, Web of Science, and Scopus from database inception until Dec 22, 2023, and included randomised controlled trials comparing antipsychotics with placebo in children or adolescents younger than 18 years with any neuropsychiatric and neurodevelopmental condition. Primary outcomes were mean change from baseline to end of acute treatment in bodyweight, BMI, fasting glucose, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, prolactin, heart rate, systolic blood pressure (SBP), and QT interval corrected for heart rate (QTc) for patients receiving either active treatment or placebo. For multigroup trials reporting several doses, we calculated a summary value for each physiological variable for all doses. After transitivity assessment, we fitted frequentist random-effects network meta-analyses for all comparisons in the network. A Kilim plot was used to summarise the results for all treatments and outcomes, providing information regarding the strength of the statistical evidence of treatment effects, using p values. Network heterogeneity was assessed with τ, risk of bias of individual trials was assessed with the Cochrane Collaboration's Tool for Assessing Risk of Bias, and the credibility of findings from each network meta-analysis was assessed with the Confidence in Network Meta-Analysis (CINEMA) app. This study is registered on PROSPERO (CRD42021274393). FINDINGS: Of 6676 studies screened, 47 randomised controlled trials were included, which included 6500 children (mean age 13·29 years, SD 2·14) who received treatment for a median of 7 weeks (IQR 6-8) with either placebo (n=2134) or one of aripiprazole, asenapine, blonanserin, clozapine, haloperidol, lurasidone, molindone, olanzapine, paliperidone, pimozide, quetiapine, risperidone, or ziprasidone (n=4366). Mean differences for bodyweight change gain compared with placebo ranged from -2·00 kg (95% CI -3·61 to -0·39) with molindone to 5·60 kg (0·27 to 10·94) with haloperidol; BMI -0·70 kg/m2 (-1·21 to -0·19) with molindone to 2·03 kg/m2 (0·51 to 3·55) with quetiapine; total cholesterol -0·04 mmol/L (-0·39 to 0·31) with blonanserin to 0·35 mmol/L (0·17 to 0·53) with quetiapine; LDL cholesterol -0·12 mmol/L (-0·31 to 0·07) with risperidone or paliperidone to 0·17 mmol/L (-0·06 to 0·40) with olanzapine; HDL cholesterol 0·05 mmol/L (-0·19 to 0·30) with quetiapine to 0·48 mmol/L (0·18 to 0·78) with risperidone or paliperidone; triglycerides -0·03 mmol/L (-0·12 to 0·06) with lurasidone to 0·29 mmol/L (0·14 to 0·44) with olanzapine; fasting glucose from -0·09 mmol/L (-1·45 to 1·28) with blonanserin to 0·74 mmol/L (0·04 to 1·43) with quetiapine; prolactin from -2·83 ng/mL (-8·42 to 2·75) with aripiprazole to 26·40 ng/mL (21·13 to 31·67) with risperidone or paliperidone; heart rate from -0·20 bpm (-8·11 to 7·71) with ziprasidone to 12·42 bpm (3·83 to 21·01) with quetiapine; SBP from -3·40 mm Hg (-6·25 to -0·55) with ziprasidone to 10·04 mm Hg (5·56 to 14·51) with quetiapine; QTc from -0·61 ms (-1·47 to 0·26) with pimozide to 0·30 ms (-0·05 to 0·65) with ziprasidone. INTERPRETATION: Children and adolescents show varied but clinically significant physiological responses to individual antipsychotic drugs. Treatment guidelines for children and adolescents with a range of neuropsychiatric and neurodevelopmental conditions should be updated to reflect each antipsychotic drug's distinct profile for associated metabolic changes, alterations in prolactin, and haemodynamic alterations. FUNDING: UK Academy of Medical Sciences, Brain and Behaviour Research Foundation, UK National Institute of Health Research, Maudsley Charity, the Wellcome Trust, Medical Research Council, National Institute of Health and Care Research Biomedical Centre at King's College London and South London and Maudsley NHS Foundation Trust, the Italian Ministry of University and Research, the Italian National Recovery and Resilience Plan, and Swiss National Science Foundation.