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Background and Purpose: Inhibitors of voltage-gated sodium channels (Na V s) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Na v channels as a means of informing the development of improved antiseizure drugs., Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of Na V 1.6 alone or together with Na V 1.2. These novel Na V inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding Na V 1.6) and in wild-type mice., Key Results: Pharmacologic inhibition of Na V 1.6 in Scn8a N1768D/+ mice prevented seizures evoked by a 6-Hz shock. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. Na V 1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS Na V isoforms., Conclusions and Implications: Our data suggest Na V 1.6 inhibition is a driver of efficacy for Na V inhibitor anti-seizure medicines. Sparing the Na V 1.1 channels of inhibitory interneurons did not compromise efficacy. Selective Na V 1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: The aim of this study was to examine whether ACTN3 rs1815739 polymorphism, which causes the deficiency of the alpha-actinin-3 muscle protein, is related to the formation of open bite malocclusion., Materials and Methods: Fifty-eight participants (18.5 ± 3.6 years old) with anterior open bite (n = 29) and normal overbite (n = 29) who presented to Marmara University, Department of Orthodontics for treatment were included in the study. Initial cephalometric radiographs were used for the diagnosis of malocclusion. The case group was divided into three subgroups according to degree of open bite. For DNA isolation, oral epithelial cells were collected with buccal swabs (Van Allen Way, Carlsbad, USA), and the real-time PCR method was used for the genotyping of all polymorphisms. The results were statistically analysed, and the threshold for statistical significance was set at p < 0.05., Results: The frequencies of RR, RX and XX genotypes of ACTN3 rs1815739 polymorphism were found as 6 (20.7%), 14 (48.3%) and 9 (31.0%) in the control group and 8 (8%), 9 (31.0%) and 12 (41.4%) in the case group, respectively. There was no statistically significant difference between the groups in terms of the presence of the examined polymorphism (p > 0.05). However, the intra-group evaluation of case group revealed a significant difference in the prevalence of XX genotype (83.3%) for the subgroup with an open bite of -5 mm or above., Conclusion: Although no significant difference was observed between the case and control groups, a possible association was identified between ACTN3 rs1815739 polymorphism and an increased severity of open bite malocclusion., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder primarily linked with mutations in Exostosin-1 (EXT1) and Exostosin-2 (EXT2) genes. However, not all HME cases can be explained by these mutations, and its pathogenic mechanisms are not fully understood. Herein, utilizing whole-exome sequencing and genetic screening with a family trio design, we identify two novel rare mutations co-segregating with HME in a Chinese family, including a nonsense mutation (c.204G>A, p.Trp68*) in EXT1 and a missense mutation (c.893T>G, p.Phe298Cys) in FUT7. Functional assays reveal that the FUT7 mutation affects the cellular localization of FUT7 protein and regulates cell proliferation. Notably, the simultaneous loss of fut7 and ext1 in a zebrafish model results in severe chondrodysplasia, indicating a functional link between FUT7 and EXT1 in chondrocyte regulation. Additionally, we unveil that FUT7 p.Phe298Cys reduces EXT1 expression through IL6/STAT3/SLUG axis at the transcription level and through ubiquitination-related proteasomal degradation at the protein level. Together, our findings not only identify novel germline mutations in FUT7 and EXT1 genes, but also highlight the critical interaction between these genes, suggesting a potential 'second-hit' mechanism over EXT1 mutations in HME pathogenesis. This insight enhances our understanding of the mechanisms underlying HME and opens new avenues for potential therapeutic interventions., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All methods used in the present study were in accordance with the relevant guidelines and regulations. This study was approved by the Ethics Committee for Clinical Research and Animal Trials of the First Affiliated Hospital of Sun Yat-sen University (permit NO. [2020]363). Informed consent was obtained from all the participants. All work involving zebrafish was reviewed and approved by the Animal Research Advisory Committee of the South China University of Technology., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The permeability of blood vessels plays a crucial role in the spread of cancer cells, facilitating their metastasis at distant sites. Small extracellular vesicles (sEVs) are known to contribute to the metastasis of various cancers by crossing the blood vessel wall. However, the role of abnormal glycoconjugates on sEVs in tumor blood vessels remains unclear. Our study found elevated levels of fucosyltransferase VII (FUT7) and its product sialyl Lewis X (sLeX) in muscle-invasive bladder cancer (BLCA), with high levels of sLeX promoting the growth and invasion of BLCA cells. Further investigation revealed that sLeX was enriched in sEVs derived from BLCA. sLeX-decorated sEVs increased blood vessel permeability by disrupting the tight junctions of human umbilical vein endothelial cells (HUVECs). Using the glycoproteomics approach, we identified integrin α3 (ITGA3) as a sLeX-bearing glycoprotein in BLCA cells and their sEVs. Mechanically, sLeX modification stabilized ITGA3 by preventing its degradation in lysosomes. sEVs carrying sLeX-modified ITGA3 can be effectively internalized by HUVECs, leading to a decrease in the expression of tight junction protein. Conversely, silencing ITGA3 in sLeX-decorated sEVs restored tight junction proteins and reduced blood vessel permeability by inhibiting the MAPK pathway. Moreover, sLeX-modification of ITGA3 at Asn 265 in HUVECs promoted occludin dephosphorylation at Ser/Thr residues, followed by inducing its importin α1-mediated nuclear translocation, which resulted in the disruption of tight junctions. Our findings suggest a potential strategy for disrupting the formation of a metastatic microenvironment and preventing the spread of malignant bladder cancer., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethical approval With the approval of the Ethics Committee of Northwest University, we obtained human plasma from bladder cancer patients and healthy volunteers in the First Affiliated Hospital of Xi’an Jiaotong University and the Shaanxi Provincial People's Hospital. All animal experiments are approved by the Institutional Animal Care and Use Committee of Northwest University., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background and Objectives: Schools play a crucial role in facilitating physical activity among children, but the COVID-19 pandemic has affected both children's physical activity and the school environment. It is essential to understand between-school differences in children's physical activity post lockdown, to determine if and how the role of schools has changed., Design and Participants: Active-6 is a natural experiment comparing postlockdown accelerometer-estimated physical activity to a pre-COVID-19 comparator group. Accelerometer and individual data were collected on 1296 children aged 10-11 pre-COVID-19 (2017-8), with school characteristics collected from the 50 schools they attended. Post lockdown, we collected accelerometer, individual and school data from 393 children in 23 of the same schools and 436 children in 27 of the same schools in 2021 (Wave 1) and 2022 (Wave 2), respectively., Methods: Sources of variation (between-school, between-pupil and within-pupil) in child weekday moderate to vigorous physical activity at each wave were modelled using linear mixed-effects models with school-level wave random coefficients. We extended the model to estimate the proportion of between-school variation explained by school policy, curriculum and physical environment factors and school-aggregated pupil characteristics. We also explored the extent to which postlockdown differences in moderate to vigorous physical activity were mediated by individual or school factors., Results: Between-school variation comprised 13% of the total variation pre-COVID-19, 7% in Wave 1 and 13% in Wave 2. School factors associated with moderate to vigorous physical activity were the following: whether physical education was compromised due to space (often: 9 minutes lower moderate to vigorous physical activity; sometimes: 5.4 minutes lower); high after-school club attendance (7 minutes higher moderate to vigorous physical activity for each additional club attended on average in the school); cycle training policy (4 minutes higher moderate to vigorous physical activity); and higher prevalence of active travel (1 minute higher moderate to vigorous physical activity for each 10% point increase in prevalence). These factors explained 22% of the between-school variation pre-COVID-19, and 72% at Wave 2. The relative importance changed, with cycle training policy and active travel being the most important pre-COVID-19 and cycle training policy, active after-school clubs and compromised physical education space most important in Wave 2. No factors were found to mediate the postlockdown differences in moderate to vigorous physical activity, except compromised physical education space, which had a suppressor effect in Wave 2., Limitations: Only 27 of the initial 50 schools participated post lockdown, limiting our ability to make comparisons across waves. Sample sizes were additionally affected by missing data for some variables., Conclusions and Future Work: While schools continue to play an important role in facilitating children's physical activity, the factors that contribute to this have changed post-COVID-19, with cycle training, active after-school clubs and ensuring physical education is prioritised even when space is limited now explaining nearly three-quarters of the between-school variation in children's moderate to vigorous physical activity. School-level interventions that focus on these areas, and policies that support them, may offer the potential to increase children's physical activity., Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme as award number NIHR131847.

Objectives: We report the effect of quality of therapy delivery on outcomes in a randomized, controlled trial of behavioural activation (BA) and guided self-help (GSH) for depression in adults with intellectual disabilities., Methods: A study specific measure of quality was used in a linear mixed effect model to determine the effects therapy and therapy quality on therapy outcome., Results: There was a significant interaction between quality and treatment type, with lower quality therapy associated with better outcome for GSH but poorer outcome for BA, with little difference in outcomes at higher levels of therapy quality., Conclusions: Factors suggesting high quality in individualized BA may indicate problematic engagement for GSH. More research into processes in therapy for people with intellectual disabilities is required., (© 2024 The Author(s). British Journal of Clinical Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Introduction Studies show that changes to dental incentive structures and treatment timings impact behaviour among UK general dental practitioners (GDP). Since 1980, the British Dental Association (BDA) has conducted panel inquiries to understand the time taken to complete dental treatments, the most recent of these being the 1999 Heathrow Timings study.Aims Given significant changes to the UK general dental service (GDS) since 1999, this research aims to gain a refreshed understanding of the time involved to complete clinical treatments in the UK and gain insight into working hours.Materials and methods This study adopted a mixed-method research design, adapted from the BDA's Heathrow Timings study. Averages for 34 adult and 12 children's treatments were found using an online survey and group discussion with 15 GDPs.Results Overall, GDPs worked 35.23 hours per week, at an hourly rate of £39.94. Comparison to the Heathrow study in 1999 shows an increase in time to deliver multiple treatments, including clinical examinations, root canals, extractions, composite fillings, porcelain veneers, acrylic full dentures and children's extractions.Conclusion Overall, this study provides a current and updated insight into dental treatment times performed by GDPs in the UK and highlights a decrease in working hours and real-term earnings of GDPs over the past 20 years., (© 2024. The Author(s), under exclusive licence to the British Dental Association.)

The recent, rapid spreading of non-native pink salmon Oncorhynchus gorbuscha in the North Atlantic area has raised concerns about their possible negative impacts on native salmonid species. Potential interactions include competition for food resources during the short freshwater phase of juvenile O. gorbuscha, but little is known about their feeding behavior in the newly occupied North Atlantic rivers. Using stable isotope and stomach content analyses, patterns of freshwater feeding of non-native O. gorbuscha fry were studied in a large Fennoscandian river, the Teno, that discharges to the Barents Sea. Changes in stable isotope values (δ 13 C, δ 15 N, δ 34 S) and stomach contents from the period of emergence (April to mid-May) to estuarine entry (late May/June) were examined and provided both temporally integrated and short-term indicators of freshwater feeding dependency. In addition, the occurrence of juvenile O. gorbuscha and changes in their length and weight during their emergence/migration period were investigated. Juvenile O. gorbuscha were at the spawning grounds from April through to mid-May with abundance peaking in mid-May. Fish moved to the estuary by late May and their abundance decreased toward June, and their body size increased concurrently. Stomach analyses indicated no feeding activity in April-early May in the spawning areas, but the stomach fullness indices increased markedly in fish sampled in the estuary in May and June. The most important prey items in stomachs were Chironomidae and Ephemeroptera larvae. Significant changes in all analysed stable isotopes were detected among sample periods, with a peak in mid-May and June showing significantly lower values than other sample periods. A change from the higher values reflective of parental marine feeding to the lower values reflective of freshwater feeding indicated active in-river feeding by juveniles during the study period. The documented active freshwater feeding of non-native juvenile O. gorbuscha suggests potential resource competition with native fluvial fishes, particularly salmonids., (© 2023 The Authors. Journal of Fish Biology published by John Wiley & Sons Ltd on behalf of Fisheries Society of the British Isles.)

Background: Endings in therapy are discussed widely in mainstream literature, however, there is only a small amount of research that considers endings in therapy for people with intellectual disabilities., Methods: Eight therapists were interviewed about their experience of ending therapy with people with intellectual disabilities. Interviews were analysed using Interpretative Phenomenological Analysis (IPA)., Results: Four superordinate themes associated with endings that go well were identified: 'recognising', 'readying', 'reframing' and reflecting', with a fifth theme reflecting endings that were less successful. Participants worked hard to offer transformative experiences of endings and an overarching 'super-superordinate' theme of 'facilitating transformative endings' encompassed the findings., Conclusions: Endings are a multi-faceted component of psychological therapy with people with intellectual disabilities and are significant for both client and therapist. We discuss implications for therapy adaptations and future research., (© 2023 The Authors. Journal of Applied Research in Intellectual Disabilities published by John Wiley & Sons Ltd.)

Background: The COVID-19 lockdowns and social distancing measures, including school closures, had a major impact on children's physical activity in England, with data showing an initial reduction in activity in the short-term post-lockdown phase of the pandemic followed by a recovery on average in the medium-term post-lockdown period. The school environment is an important context for child physical activity. The purpose of this study is to understand the changes that took place to school physical activity environments once schools reopened after lockdowns. This information will improve understanding of why changes to children's physical activity have occurred over the course of the pandemic and the implications for future promotion of physical activity in schools., Methods: Interviews with parents ( n  = 43), school staff ( n  = 18) and focus groups with 10- to 11-year-old children (participant n  = 92) were conducted at two time points: between September-December 2021 and February-July 2022. Interview and focus group guides covered the impact of the pandemic on child physical activity and changes to this over time. The framework method was used for analysis., Results: Three themes and three subthemes were generated: (1) the return to school; (2) over-pressured staff and environment and (3) the uneven impact of the pandemic. Theme 3 consists of three subthemes: (a) retained pandemic policies, (b) impact on physical activity culture and (c) different children need different things., Limitations and Future Work: Conducting this research in schools during ongoing COVID-19 disruptions was a challenge and may have limited school and participant participation, particularly school staff. The parent interview sample is predominantly female, active and of higher socioeconomic status, so the experiences of male, less active and lower socioeconomic parents are limited. This study suggests that the impact of COVID-19 on child physical activity is uneven, affecting some children more than others. Future work is therefore needed to explore the details of this potential diverging experience., Conclusion: The COVID-19 pandemic, school closures and post-lockdown school policies have impacted upon primary school physical activity environments. The post-lockdown school environment is highly pressured, impacting the extent to which schools can support and encourage child physical activity. Future research is needed to further explore the impact of post-lockdown changes on physical activity environments in schools, particularly over the longer term, as schools continue to adapt post lockdowns. Strategies required to support school physical activity environments must be context specific and sensitive to these changes, pressures and needs., Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme as award number NIHR131847.

Purpose: Guanfacine is an α 2A -adrenergic receptor agonist, FDA-approved to treat attention-deficit hyperactivity disorder and high blood pressure, typically as an extended-release formulation up to 7 mg/day. In our dysautonomia clinic, we observed that off-label use of short-acting guanfacine at 1 mg/day facilitated symptom relief in two families with multiple members presenting with severe generalized anxiety. We also noted anecdotal improvements in associated dysautonomia symptoms such as hyperhidrosis, cognitive impairment, and palpitations. We postulated that a genetic deficit existed in these patients that might augment guanfacine susceptibility., Methods: We used whole-exome sequencing to identify mutations in patients with shared generalized anxiety and dysautonomia symptoms. Guanfacine-induced changes in the function of voltage-gated Na + channels were investigated using voltage-clamp electrophysiology., Results: Whole-exome sequencing uncovered the p.I739V mutation in SCN9A in the proband of two nonrelated families. Moreover, guanfacine inhibited ionic currents evoked by wild-type and mutant Na V 1.7 encoded by SCN9A, as well as other Na V channel subtypes to a varying degree., Conclusion: Our study provides further evidence for a possible pathophysiological role of Na V 1.7 in anxiety and dysautonomia. Combined with off-target effects on Na V channel function, daily administration of 1 mg short-acting guanfacine may be sufficient to normalize Na V channel mutation-induced changes in sympathetic activity, perhaps aided by partial inhibition of Na V 1.7 or other channel subtypes. In a broader context, expanding genetic and functional data about ion channel aberrations may enable the prospect of stratifying patients in which mutation-induced increased sympathetic tone normalization by guanfacine can support treatment strategies for anxiety and dysautonomia symptoms., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

GALNT7 is a glycosyltransferase enzyme transferring N-acetylgalactosamine to initiate O-linked glycosylation in the Golgi apparatus. Breast cancer is the most common cancer in women globally. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2; ERBB2) are important biomarkers in the prognosis and molecular subtyping of breast cancer. Here, we showed that ER-positive, PR-positive or HER2-positive breast tumors have higher expression of GALNT7 compared to ER-negative, PR-negative or HER2-negative breast tumors, respectively. We found that CpG-aggregated methylation of GALNT7 gene is decreased, and in parallel, its transcript levels are increased in breast cancer compared to healthy breast tissue. We observed that the difference in the expression of GALNT7 between negative and positive status of the receptors is the highest for HER2, followed by ER and PR, pointing that HER2 might be relatively more influential than ER and PR on the expression of GALNT7 in breast cancer. We reported that basal-like breast tumors have decreased expression of GALNT7 compared to non-basal-like tumors, and that high GALNT7 expression is associated with favorable relapse-free and distant metastasis-free survival in HER2 status-dependent manner in breast cancer patients. Moreover, we showed that GALNT7 expression in breast cancer is cell type- (epithelial vs stromal cells), tumor grade- and ethnicity-dependent. Combined, we propose that GALNT7 might contribute to different clinical outcomes depending on the receptor status in breast cancer, and that a better understanding of GALNT7 and its function in the context of breast cancer is needed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The dynamics of physico-chemical, nutrient, and chlorophyll-a variables were studied in the bloom and non-bloom locations along the off-Gujarat coastal waters to understand the variability in biogeochemistry using multivariate analytical tests. The dissolved oxygen was significantly lower in the bloom stations (3.89 ± 0.44 mgL -1 ) than in the non-bloom stations (5.50 ± 0.70 mg L -1 ), due to the biological degradation of organic matter in addition to anaerobic microbial respiration. Nutrients (PO 4 and NO 3 ) and Chl-a concentrations were recorded higher in the bloom locations at 0.83 ± 0.21 µmol L -1 , 4.47 ± 0.69 µmol L -1 , 4.14 ± 1.49 mg m -3 , respectively. PO 4 and NO 3 have shown a significantly higher positive correlation of r = 0.73 and r = 0.69 with Chl-a for bloom data than the non-bloom data. The percentage variance contributed by PC1 and PC2 for both bloom and non-bloom locations were estimated at 52.33%. The variable PO 4 explains the highest 24.19% variability in PC1, followed by Chl-a (19.89%). The PO 4 triggers the bloom formation and also correlates to the higher concentrations of Chl-a in the bloom locations. The bloom concentration ranges from 9553 to 12,235 trichomes L -1 . The bloom intensity has shown a significant positive correlation with Chl-a (r = 0.77), NO 3 (r = 0.56), and PO 4 (r = 0.30), but a negative correlation was noticed with DO (r =  - 0.63) and pH (r =  - 0.49). The study also initiates a way forward research investigation on ocean-color technologies to identify and monitor blooms and climate change-driven factors for bloom formation. The occurrence of bloom and its influence on fishery resources and other marine biotas will open many research windows in marine fisheries, oceanography, remote sensing, marine biology, and trophodynamics., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction Devon and Cornwall have been identified as 'dental deserts' with limited NHS dental access and high levels of oral health inequality. Challenges around recruitment and retention of the dental workforce have been acknowledged as an important contributory factor.Aims The aim of this research was to explore the experiences of dental practices within Devon and Cornwall in relation to recruitment and retention of the dental workforce.Method A self-administered, online questionnaire was used to explore various aspects of workforce recruitment and retention. The questionnaire included categorical rating scale and free-text question formats providing quantitative and qualitative data.Results In total, 106 dental practices responded to the survey, providing a response rate of 36%. The vast majority of respondents (94%) considered recruitment and retention to be a major barrier to delivering NHS services. Additionally, 77% of practices had a current staff vacancy, 57% had a dentist vacancy and 48% had a vacancy for dental nurses. Thematic analysis led to identification of four main themes which were considered to influence recruitment and retention: NHS system; economic challenges; logistics; and support networks.Conclusion A large number of dental practices in Devon and Cornwall are failing to operate at capacity due to workforce shortages, which is affecting access to services in both NHS and private practices. Recruitment and retention of dentists and dental nurses appears to be the most challenging factor, with NHS practices affected more than the private sector., (© 2023. The Author(s), under exclusive licence to the British Dental Association.)

Background: Various interventions, programs and policies have been implemented to improve physical activity (PA) levels worldwide. However, countries continue to face barriers and challenges in achieving their targets. To date, there is a lack of study on the evaluation of physical activity (PA) promotion and how it's associated with public participation., Methods: This study assessed PA promotion in eight different settings in terms of policy availability, policy implementation, and public participation in PA programs. Policy availability was assessed by reviewing 384 policy and strategy documents, rules, regulations, legislation, and guidelines on PA. We scored the documents by using the Comprehensive Analysis of Policy on Physical Activity (CAPPA) framework. Data to assess policy implementation and public participation were taken from the Thailand Report Card Survey 2021 (TRC2021), and the Thailand Surveillance on Physical Activity (SPA) 2021. Both surveys comprised over 5,000 nationally-representative samples from on-screen, face-to-face interviews, and an online self-administered survey. We scored the policy implementation and public participation based on respondents' response towards policy implementation and participation indicators. A grading scheme was applied to indicate how successful an investment has been made., Results: Public education and mass media received the highest average score in policy availability, implementation and public participation in PA program (67.9%, grade B), followed by active urban design (66.1%, grade B-) and active transport (63.7%, grade B-). Workplace, whole-of-school, and community-wide initiatives were the investments with the lowest scores, implying low availability, limited implementation, and less accessibility to public. Females were less likely to participate in active transport, active urban design, sports/recreation for all, workplace activity, and community-wide initiatives. Age and educational attainment were consistent predictors of utilization in all investments., Conclusions: With varying degrees of policy availability and accessibility, public participation in PA investments is likely to be constrained by biological and socioeconomic inequality. Future investments should aim at providing generalized or tailored interventions to ensure equal access and participation for all segments of the population., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Mercury (Hg) is a serious concern for aquatic ecosystems because it may biomagnify to harmful concentrations within food webs and consequently end up in humans that eat fish. However, the trophic transfer of mercury through the aquatic food web may be impacted by several factors related to network complexity and the ecology of the species present. The present study addresses the interplay between trophic ecology and mercury contamination in the fish communities of two lakes in a pollution-impacted subarctic watercourse, exploring the role of both horizontal (feeding habitat) and vertical (trophic position) food web characteristics as drivers for the Hg contamination in fish. The lakes are located in the upper and lower parts of the watercourse, with the lower site located closer to, and downstream from, the main pollution source. The lakes have complex fish communities dominated by coregonids (polymorphic whitefish and invasive vendace) and several piscivorous species. Analyses of habitat use, stomach contents, and stable isotope signatures (δ 15 N, δ 13 C) revealed similar food web structures in the two lakes except for a few differences chiefly related to ecological effects of the invasive vendace. The piscivores had higher Hg concentrations than invertebrate-feeding fish. Concentrations increased with size and age for the piscivores and vendace, whereas habitat differences were of minor importance. Most fish species showed significant differences in Hg concentrations between the lakes, the highest values typically found in the downstream site where the biomagnification rate also was higher. Mercury levels in piscivorous fish included concentrations that exceed health authorization limits, with possible negative implications for fishing and human consumption. Our findings accentuate the importance of acquiring detailed knowledge of the drivers that can magnify Hg concentrations in fish and how these may vary within and among aquatic systems, to provide a scientific basis for adequate management strategies. Environ Toxicol Chem 2023;42:873-887. © 2023 SETAC., (© 2023 SETAC.)

It has been well documented that periphyton communities play a key role in primary productivity, nutrient cycling, and food web interactions. However, a worldwide overview of research on the key themes, current situation, and major trends within the field is lacking. In this study, we applied the machine learning technique (latent Dirichlet allocation, LDA) to analyze the abstracts of 6690 publications related to periphyton from 1991 to 2020 based on the Web of Science database. The relative frequency of classical and basic research on periphyton related to colonization, biomass, growth rate, and habitats has been clearly decreasing. The increasing trends of research on periphyton are embodied in the periphyton function in freshwater ecosystems (e.g., application as ecological indicators, function in the removal of nutrients, and application in paleolimnology), the research at macroscales (e.g., spatial-temporal variation, and functional and taxonomic diversity), and the anthropogenic themes (e.g., climate warming, response to multiple stressors, and land use type). The keyword and title analysis showed that the periphyton studies are concentrated mainly on diatom aspects, especially with respect to streams relative to lakes. The thematic space based on non-metric multidimensional scaling (NMDS) showed that the classical themes such as growth rate, colonization, and environmental factors (e.g., multiple stressors and climate warming) were most linked to other research themes. We proposed that future trends in the periphyton should focus on the function of periphyton in lakes and their response to multiple environmental pressures with the increasingly extensive eutrophication in lakes and the increasingly significant change in the climate., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Numerous studies reported a significant decline in physical activity level in adolescents as a result of the COVID-19 lockdown. Physical fitness is recognized as a powerful marker of health in youth. The aim of this study was to evaluate the impact of the COVID-19 pandemic lockdown on health-related physical fitness in French adolescents. Two cross-sectional studies were performed comparing two different groups of French adolescents, before (sample 1) and after the first lockdown (sample 2). A total of 1231 adolescents (aged to 16.5 ± 1.5 years) participated in the two cross-sectional studies. Complete data for physical fitness and anthropometrics data were obtained. Adolescents from sample 2 showed lower physical fitness levels compared to adolescents from sample 1. Regarding physical fitness for boys and girls, physical fitness levels were significantly lower in both sex between adolescents from the sample 1 and adolescents from the sample 2, except for cardiorespiratory fitness and flexibility for boys and girls, respectively. The physical fitness global score was also significantly lower between adolescents from the sample 1 and 2 for boys (-9.8%, p < 0.01) and girls (-16.2%; p < 0.01), respectively. Overall, the higher difference was found for performance in the speed body displacement test (-30%). A difference of 12.8% and 25% was observed for boys and girls, respectively.   Conclusion: COVID-19 pandemic lockdown had a negative impact on physical fitness in French youth. This study highlights the need to develop, in a near future, prevention programmes in order to improve the physical fitness in youth. What is Known: • COVID-19 pandemic deeply impacted lifestyle habits. A worrying decrease of physical activity, associated to a dramatic increase of time spent in sedentary behaviors was found in many coutries. What is New: • Our study bring first data on the health-related physical fitness consequences due to lockdown in French adolescents. Our study demonstrate the negative impact of COVID-19 pandemic lockdown on health-related physical fitness in French adolescents., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Acquired and inherited dysfunction in voltage-gated sodium channels underlies a wide range of diseases. In addition to defects in trafficking and expression, sodium channelopathies are caused by dysfunction in one or several gating properties, for instance activation or inactivation. Disruption of channel inactivation leads to increased late sodium current, which is a common defect in seizure disorders, cardiac arrhythmias skeletal muscle myotonia and pain. An increase in late sodium current leads to repetitive action potentials in neurons and skeletal muscles, and prolonged action potential duration in the heart. In this Topical Review, we compare the effects of late sodium current in brain, heart, skeletal muscle and peripheral nerves., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Purpose: This study aimed to investigate the long-term clinical outcomes after surgical decompression in cauda equina syndrome (CES) and see if any preoperative patient-related factors contributed to this outcome., Methods: A systematic literature search was conducted in the electronic databases of PubMed, Embase, Scopus, and Ovid. Data regarding outcome parameters from eligible studies were extracted. Meta-analysis was performed using a random-effect model., Results: A total of 852 patients (492 males and 360 females), with a mean age of 44.6 ± 5.5 years from 22 studies diagnosed with cauda equina syndrome and undergoing surgical decompression, were included in the meta-analysis; however, not all studies reported every outcome. The mean follow-up period was 39.2 months, with a minimum follow-up of 12 months in all included studies. Meta-analysis showed that on long-term follow-up, 43.3% [29.1, 57.5] (n=708) of patients had persistent bladder dysfunction. Persistent bowel dysfunction was observed in 31.1% [14.7, 47.6] (n=439) cases, sensory deficit in 53.3% [37.1, 69.6] (n=519), motor weakness in 38.4% [22.4, 54.4] (n=490), and sexual dysfunction in 40.1% [28.0, 52.1] (n=411). Decompression within 48 hours of the onset of symptoms was associated with a favourable outcome in terms of bladder function with 24.6% [1.6, 50.9] (n=75) patients having persistent dysfunction, whereas 50.3% [10.3, 90.4] (n=185) of patients in studies with a mean time to decompression after 48 hours had persistent bladder dysfunction. Other factors such as speed of onset and sex of the patients were not found to significantly impact long-term bladder outcomes., Conclusion: The long-term outcomes of CES after decompression are enumerated. Decompression within 48 hours of the onset of symptoms appears to result in fewer patients with persistent bladder dysfunction. However, a randomized controlled trial is required to conclusively determine whether early decompression leads to better outcomes., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

High blood glucose has long been established as a risk factor for tumor metastasis, yet the molecular mechanisms underlying this association have not been elucidated. Here we describe that hyperglycemia promotes tumor metastasis via increased platelet activity. Administration of glucose, but not fructose, reprogrammed the metabolism of megakaryocytes to indirectly prime platelets into a prometastatic phenotype with increased adherence to tumor cells. In megakaryocytes, a glucose metabolism-related gene array identified the mitochondrial molecular chaperone glucose-regulated protein 75 (GRP75) as a trigger for platelet activation and aggregation by stimulating the Ca 2+ -PKCα pathway. Genetic depletion of Glut1 in megakaryocytes blocked MYC-induced GRP75 expression. Pharmacologic blockade of platelet GRP75 compromised tumor-induced platelet activation and reduced metastasis. Moreover, in a pilot clinical study, drinking a 5% glucose solution elevated platelet GRP75 expression and activated platelets in healthy volunteers. Platelets from these volunteers promoted tumor metastasis in a platelet-adoptive transfer mouse model. Together, under hyperglycemic conditions, MYC-induced upregulation of GRP75 in megakaryocytes increases platelet activation via the Ca 2+ -PKCα pathway to promote cancer metastasis, providing a potential new therapeutic target for preventing metastasis. SIGNIFICANCE: This study provides mechanistic insights into a glucose-megakaryocyte-platelet axis that promotes metastasis and proposes an antimetastatic therapeutic approach by targeting the mitochondrial protein GRP75., (©2021 American Association for Cancer Research.)

Aims To provide information on the demographics and work patterns of the UK special care dentistry (SCD) specialist workforce.Design A self-administered electronic questionnaire.Setting All UK-based SCD specialists on the membership of the British Society for Disability and Oral Health and the British Society of Gerodontology.Materials and methods An electronic questionnaire was distributed to a potential 301 SCD specialists. Responses were descriptively analysed.Results One hundred responses (33%) were received. The majority of respondents were female (74%) and/or of white ethnicity (86%). Three-quarters (78%) were based in England and a third (37%) were based in South East England. Two-thirds (66%) worked in the community dental service. Forty-eight percent work part-time and 32% have had a career break. Forty-three percent are planning to retire by 2026 and approximately half (53%) plan to retire by 2031. A significant minority (44%) do not feel appropriately paid.Conclusions Workforce planners should anticipate the impact on specialist provision due to a combination of a predominantly female workforce with associated working patterns, an anticipated loss of numbers and experience, and the effect financial dissatisfaction may have on attracting trainees. Efforts should be made to increase racial diversity.

Exposure to indoor air pollutants released from traditional cookstoves in rural Indian households is a matter of great concern. While there are various studies over several decades focused towards intervention strategies for reducing air pollutants, limited literature exists towards the identification of appropriate methodology for feasible intervention, adoption and usage of improved cookstoves (ICS). In the present study, PM 2.5 and CO microenvironment concentrations are estimated in households using traditional and improved cookstove (NEERDHUR). The reduction in PM 2.5 and CO microenvironment concentrations after the introduction of ICS was found to be 89-94% and 35-57%, respectively. Information-education-communication (IEC) activity was used as a tool to increase the adoption and usage rate in the ICS using households. The cost-benefit analysis was also performed to check the benefits of ICS use, and the benefit-cost ratio was found to be 3 to 4 times. Findings of the study suggest that, although the ICS intervention could significantly improve the indoor air quality, however, it fails to comply with the permissible safe limits; further focus on greener fuels and ventilation characteristics is suggested. The outcomes from the study can help decision-makers, corporate social responsibility fund mobilizers and policymakers for effective policy advocacy to design efforts by promoting clean cooking interventions and linking and mapping these with national missions and flagship programs.

Subsequent to their introduction in the 1950s, Arctic charr Salvelinus alpinus have been able to establish a self-sustaining population that has adapted to the unique conditions of the sub-Antarctic Kerguelen Islands. Here, 48 individuals (198-415 mm) were caught with gillnets and their basic biology and feeding ecology were examined using stable isotope analysis. The Lac des Fougères population split use of littoral and pelagic resources evenly, although larger fish relied more heavily on littoral production and appear to follow the size-dependent life history habitat template seen in many Scandinavian lakes where smaller sized individuals occupy the pelagic zone and larger individuals dominate the littoral habitat. In Kerguelen, Arctic charr mature at the same ages (5.6 years) as Arctic charr in both sub-Arctic and Arctic lakes. Although mortality was average in comparison to comparator sub-Arctic lakes, it was high in comparison to Arctic lakes. Maximal age (>7+) was at the lower end of the range typically seen in sub-Arctic lakes. Although they inhabit a resource-poor environment, Kerguelen Arctic charr showed no evidence of cannibalism. Thus, while Arctic charr can survive and reproduce in the relatively unproductive Kerguelen lake environments, survival and growth nevertheless appear to be traded off against survival and longevity. The uniqueness of the population location and the recency of its introduction suggest that further monitoring of the population has the potential to yield valuable insights into both the adaptability of the species and its likely responses to ongoing large-scale environmental change as represented by climate change., (© 2020 Fisheries Society of the British Isles.)

Glycosylation is one of the most common posttranslational modifications of proteins and lipids. In the case of tumors, cell transformation accompanied by aberrant glycosylation results in the expression of tumor-associated glycans that promote tumor invasion. As part of the innate immunity, anti-glycan antibodies recognize tumor-associated glycans, and these antibodies can be present in the bloodstream in the early stages of cancer. Recently, anti-glycan antibody profiles have been of interest in various cancer studies. Novel advantages in the field of analytical techniques have simplified the analysis of anti-glycan antibodies and made it easier to have more comprehensive knowledge about their functions. One of the robust approaches for studying anti-glycan antibodies engages in microarray technology. The analysis of glycan microarrays can provide more expanded information to simultaneously specify or suggest the role of antibodies to a wide variety of glycans in the progression of different diseases, therefore making it possible to identify new biomarkers for diagnosing cancer and/or the state of the disease. Thus, in this review, we discuss antibodies to various glycans, their application for diagnosing cancer and one of the most promising tools for the investigation of these molecules, microarrays.

Health and performance impairments provoked by thermal stress are societal challenges geographically spreading and intensifying with global warming. Yet, science may be underestimating the true impact, since no study has evaluated effects of sunlight exposure on human brain temperature and function. Accordingly, performance in cognitively dominated and combined motor-cognitive tasks and markers of rising brainstem temperature were evaluated during exposure to simulated sunlight (equal to ~1000 watt/m 2 ). Acute exposure did not affect any performance measures, whereas prolonged exposure of the head and neck provoked an elevation of the core temperature by 1 °C and significant impairments of cognitively dominated and motor task performances. Importantly, impairments emerged at considerably lower hyperthermia levels compared to previous experiments and to the trials in the presents study without radiant heating of the head. These findings highlight the importance of including the effect of sunlight radiative heating of the head and neck in future scientific evaluations of environmental heat stress impacts and specific protection of the head to minimize detrimental effects.

Three-coordinate main group Lewis acids are exceedingly important reagents in chemical synthesis. In contrast to the well-established chemistries of neutral group 13 and cationic group 14 species, isoelectronic group 15 element dications are unknown. In this work, we use stabilizing N-heterocyclic imine substituents to isolate and characterize phosphorandiylium dications ([R 3 P] 2+ ) and show that the electrophilicity at the phosphorus atoms is controlled by the π-electron-donating ability of these subtituents. Structural, spectroscopic and theoretical results reveal that the phosphorus dications adopt a perfectly trigonal-planar geometry with the electron-deficient phosphorus centres being well separated from the borate anions. The reactivity of the dications reveal their exceptional Lewis acidity at phosphorus; the adjacent nitrogen atoms, however, are weakly basic, resulting in transformations such as chloride ion abstraction from Me 3 SiCl and the selective monodefluorination of trifluoromethyl groups.

Background: Knowing breast volumes before certain surgeries helps the surgeon to obtain breast symmetry. Calculating breast volumes from three-dimensional surface images is possible with specialized software applications. However, limited data exist concerning the accuracy of such volume calculations. The purpose of this study was to investigate the accuracy of breast volume calculations performed with the 3D BreAST, 3dMD Vultus, and VECTRA software applications., Methods: Twenty-six subjects who underwent 44 mastectomies were enrolled. Preoperative three-dimensional surface images were acquired with a VECTRA-XT stereophotogrammetry device. Breast volumes were calculated from these images with the three software applications. The mastectomy specimens were weighed to derive their actual volume and compared with the software calculations., Results: For all three methods, a positive correlation between the breast volume and absolute calculation error was found (p < 0.001), but not for the errors as a percentage of the breast volume (p = 0.17, p = 0.80, and p = 0.42). The 3D BreAST, 3dMD Vultus, and VECTRA applications provided mean volume calculation errors of 21, 186, and -32 ml (p = 0.27, p < 0.001, and p = 0.14) or 2 ± 25, 48 ± 26, and -6 ± 27 percent of the breast volume (p = 0.67, p < 0.001, and p = 0.16), respectively., Conclusions: Despite that two applications calculated accurate mean breast volumes, all applications showed a high standard deviation in terms of the percentage of the breast volume. Therefore, the usefulness of absolute breast volume calculations from three-dimensional surface images seems limited., Clinical Question/level of Evidence: Diagnostic, II.

Triple negative breast cancer (TNBC) is a major global public health problem. The lack of targeted therapy and the elevated mortality evidence the need for better knowledge of the tumor biology. Hypoxia and aberrant glycosylation are associated with advanced stages of malignancy, tumor progression and treatment resistance. Importantly, serum deprivation regulates the invasive phenotype and favors TNBC cell survival. However, in TNBC, the role of hypoxia and serum deprivation in the regulation of glycosylation remains largely unknown. The effects of hypoxia and serum deprivation on the expression of glycosyltransferases and glycan profile were evaluated in the MDA-MB-231 cell line. We showed that the overexpression of HIF-1α was accompanied by acquisition of epithelial-mesenchimal transition features. Significant upregulation of fucosyl- and sialyltransferases involved in the synthesis of tumor-associated carbohydrate antigens was observed together with changes in fucosylation and sialylation detected by Aleuria aurantia lectin and Sambucus nigra agglutinin lectin blots. Bioinformatic analysis further indicated a mechanism by which HIF-1α can regulate ST3GAL6 expression and the relationship within the intrinsic characteristics of TNBC tumors. In conclusion, our results showed the involvement of hypoxia and serum deprivation in glycosylation profile regulation of TNBC cells triggering breast cancer aggressive features and suggesting glycosylation as a potential diagnostic and therapeutic target.

Lectins are sugar-binding proteins that can recognize and bind to carbohydrates conjugated to proteins and lipids. Coupled with mass spectrometry technologies, lectin affinity chromatography is becoming a popular approach for identification and quantification of glycoproteins in complex samples such as blood, tumor tissues, and cell lines. Given the commercial availability of a large number of lectins that recognize diverse sugar structures, it is now possible to isolate and study glycoproteins for biological and medical research. This unit provides a general guide to single-lectin-based enrichment of glycoproteins from serum-free conditioned media. Due to the unique carbohydrate specificity of most lectins and the complexity of the samples, optimization steps may be required to evaluate different elution buffers and methods as well as binding conditions, for each lectin, for optimal recovery of bound glycoproteins., (Copyright © 2015 John Wiley & Sons, Inc.)