Complete absence of GLUT1 does not impair human terminal erythroid differentiation.

The Glucose transporter 1 (GLUT1) is one of the most abundant proteins within the erythrocyte membrane and is required for glucose and dehydroascorbic acid (Vitamin C precursor) transport. It is widely recognized as a key protein for red cell structure, function, and metabolism. Previous reports highlighted the importance of GLUT1 activity within these uniquely glycolysis-dependent cells, in particular for increasing antioxidant capacity needed to avoid irreversible damage from oxidative stress in humans. However, studies of glucose transporter roles in erythroid cells are complicated by species-specific differences between humans and mice. Here, using CRISPR-mediated gene editing of immortalized erythroblasts and adult CD34+ hematopoietic progenitor cells, we generate committed human erythroid cells completely deficient in expression of GLUT1. We show that absence of GLUT1 does not impede human erythroblast proliferation, differentiation, or enucleation. This work demonstrates for the first-time generation of enucleated human reticulocytes lacking GLUT1. The GLUT1-deficient reticulocytes possess no tangible alterations to membrane composition or deformability in reticulocytes. Metabolomic analyses of GLUT1-deficient reticulocytes reveal hallmarks of reduced glucose import, downregulated metabolic processes and upregulated AMPK-signalling, alongside alterations in antioxidant metabolism, resulting in increased osmotic fragility and metabolic shifts indicative of higher oxidant stress. Despite detectable metabolic changes in GLUT1 deficient reticulocytes, the absence of developmental phenotype, detectable proteomic compensation or impaired deformability comprehensively alters our understanding of the role of GLUT1 in red blood cell structure, function and metabolism. It also provides cell biological evidence supporting clinical consensus that reduced GLUT1 expression does not cause anaemia in GLUT1 deficiency syndrome.

Mechanisms accounting for gendered differences in mental health status among young Canadians: A novel quantitative analysis.

Adolescent girls consistently report worse mental health than boys. This study used reports from a 2018 national health promotion survey (n = 11,373) to quantitatively explore why such gender-based differences exist among young Canadians. Using mediation analyses and contemporary social theory, we explored mechanisms that may explain differences in mental health between adolescents who identify as boys versus girls. The potential mediators tested were social supports within family and friends, engagement in addictive social media use, and overt risk-taking. Analyses were performed with the full sample and in specific high-risk groups, such as adolescents who report lower family affluence. Higher levels of addictive social media use and lower perceived levels of family support among girls mediated a significant proportion of the difference between boys and girls for each of the three mental health outcomes (depressive symptoms, frequent health complaints, and diagnosis of mental illness). Observed mediation effects were similar in high-risk subgroups; however, among those with low affluence, effects of family support were somewhat more pronounced. Study findings point to deeper, root causes of gender-based mental health inequalities that emerge during childhood. Interventions designed to reduce girls' addictive social media use or increase their perceived family support, to be more in line with their male peers, could help to reduce differences in mental health between boys and girls. Contemporary focus on social media use and social supports among girls, especially those with low affluence, warrant study as the basis for public health and clinical interventions.

Supervised physical activity and the incidence of gestational diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Gestational diabetes mellitus (GDM) characterized by dysfunction in maintaining glucose homeostasis is recognized as the most common metabolic complication associated with pregnancy leading to adverse clinical outcomes for maternal and fetal health. Although previous analysis of the findings from randomized controlled trials (RCTs) support that regular physical activity reduces the incidence of GDM during pregnancy, less is known about the optimal timing of intervention with respect to trimester stage. OBJECTIVES: To examine the interaction between both the timing and volume of supervised physical activity interventions on reducing the incidence of GDM during pregnancy. STUDY DESIGN: Electronic databases including CINAHL, Embase, Medline and the Cochrane library were searched for records up to 29 September 2022. Eligibility criteria were RCTs including standard antenatal care + supervised physical activity intervention without dietary modification vs. those receiving standard antenatal care alone in women with no previous diagnosis of GDM, type 1 or type 2 diabetes mellitus. RESULTS: Of the 3411 records identified, 20 RCTs comprising 6732 participants were included. It was found that supervised physical activity interventions decreased GDM risk when started within the first trimester (RR: 0.57, 95% CI: 0.41-0.79; p = .001) and by accumulating >600 MET·min·wk-1 of exercise (RR: 0.77, 95% CI: 0.60-0.98; p = .03) compared with standard antenatal care alone. Women with a BMI ≤25 kg/m2 experienced the greatest risk reduction in GDM following supervised exercise training (RR: 0.51, 95% CI: 0.34-0.75; p = .001). CONCLUSION: Supervised physical activity reduces the incidence of GDM during pregnancy. It is recommended that pregnant individuals achieve a minimum of 600 MET·min·wk-1 of physical activity during the first trimester in order to reduce their odds of developing GDM. Attaining a healthy pre-pregnancy BMI is also an important determinant for the prevention of GDM with exercise.

Domains of spirituality and their importance to the health of 75 533 adolescents in 12 countries.

Spirituality is an ancient concept with many contemporary applications to the field of health promotion. While recognized in the UN Convention on the Rights of the Child as a basic human right, definitional misunderstandings about what spirituality is, and is not, and the mechanisms by which it affects the health of young people, remain. In this cross-national analysis involving >75 000 adolescents from 12 countries, we examined the relative importance of each of four spiritual health domains (connections to self, others, nature and the transcendent) in the lives of young people, and how these connections relate to a standard indicator of positive mental health status. Descriptive and applied regression analyses confirmed two major findings: (i) boys and girls in all 12 countries ranked the importance of each of the four domains in the same order, with 'connections to self' identified as most important; and (ii) both direct and indirect pathways are evident that connect the remaining three domains to positive mental health status, but through strong connections to self. Based on our scale items, fostering a strong connection to self, which involves cultivating a sense of meaning, purpose and joy in the lives of adolescents, appears most fundamental to fostering optimal mental health. This may be achieved directly or, dependent upon context and culture, indirectly with emphasis on the connections afforded by the other three domains. Such findings provide important insights to guide the content of adolescent health promotion interventions.

Spirituality is considered by many to be an important domain of health. It is sometimes measured in four domains of connections: to oneself, to others, to nature and to the transcendent. While the importance of such connections is recognized as a fundamental human right for children, few international studies have studied their impacts on the health and well-being of young people. In this study of young people conducted over 4 years in 12 countries, we examined the perceived importance of each of four spiritual health domains and how they each related to positive mental health status in >75 000 adolescents. 'Connections to self' were consistently viewed as most important among boys and girls in all 12 countries. Fostering of strong connections to self, which involves cultivating a sense of meaning, purpose and joy in the lives of adolescents, appears most fundamental to achieving mental health and well-being. This may be achieved directly through a focus on connections to self, or indirectly by focusing on the indirect effects of the other three domains on mental health. This opens up many opportunities for health promotion in child populations, internationally.

Mental health and academic outcomes over the first year at university in international compared to domestic Canadian students.

OBJECTIVE: To compare risk factors and associated mental health and academic outcomes between international and domestic students. PARTICIPANTS: Canadian university undergraduate students. METHODS: Electronic surveys were completed at university entry and the end of first year. Surveys assessed demographics, risk factors, symptoms of mental disorders, and access to support. Academic outcomes were obtained from university databases. RESULTS: International students had comparable or lower rates of clinically significant anxiety, depression, and insomnia. Domestic female students reported the highest screening rates for common mental disorders. However, international students were more likely to report having attempted suicide. International students felt less connected to the university community and had lower academic performance. Psychosocial risk factor profiles and proportions accessing mental health services were similar. CONCLUSIONS: The scope of mental health need appears more similar than different between international and domestic students; however, international students may benefit from targeted academic and social support initiatives.

Robust deep learning-based protein sequence design using ProteinMPNN.

Although deep learning has revolutionized protein structure prediction, almost all experimentally characterized de novo protein designs have been generated using physically based approaches such as Rosetta. Here, we describe a deep learning-based protein sequence design method, ProteinMPNN, that has outstanding performance in both in silico and experimental tests. On native protein backbones, ProteinMPNN has a sequence recovery of 52.4% compared with 32.9% for Rosetta. The amino acid sequence at different positions can be coupled between single or multiple chains, enabling application to a wide range of current protein design challenges. We demonstrate the broad utility and high accuracy of ProteinMPNN using x-ray crystallography, cryo-electron microscopy, and functional studies by rescuing previously failed designs, which were made using Rosetta or AlphaFold, of protein monomers, cyclic homo-oligomers, tetrahedral nanoparticles, and target-binding proteins.

Unveiling new perspective of phylogeography, genetic diversity, and population dynamics of Southeast Asian and Pacific chickens.

The complex geographic and temporal origins of chicken domestication have attracted wide interest in molecular phylogeny and phylogeographic studies as they continue to be debated up to this day. In particular, the population dynamics and lineage-specific divergence time estimates of chickens in Southeast Asia (SEA) and the Pacific region are not well studied. Here, we analyzed 519 complete mitochondrial DNA control region sequences and identified 133 haplotypes with 70 variable sites. We documented 82.7% geographically unique haplotypes distributed across major haplogroups except for haplogroup C, suggesting high polymorphism among studied individuals. Mainland SEA (MSEA) chickens have higher overall genetic diversity than island SEA (ISEA) chickens. Phylogenetic trees and median-joining network revealed evidence of a new divergent matrilineage (i.e., haplogroup V) as a sister-clade of haplogroup C. The maximum clade credibility tree estimated the earlier coalescence age of ancestral D-lineage (i.e., sub-haplogroup D2) of continental chickens (3.7 kya; 95% HPD 1985-4835 years) while island populations diverged later at 2.1 kya (95% HPD 1467-2815 years). This evidence of earlier coalescence age of haplogroup D ancestral matriline exemplified dispersal patterns to the ISEA, and thereafter the island clade diversified as a distinct group.

The feasibility and effectiveness of a novel online mental health literacy course in supporting university student mental health: a pilot study.

BACKGROUND: There is a need for effective universal approaches to promote and support university student mental health that are scalable and sustainable. In this pilot study we assess the feasibility and acceptability of a fully-digitalized, comprehensive mental health literacy course co-created with and tailored to the needs of undergraduate students. We also explore preliminary associations with mental health and positive behaviour change. METHODS: An accredited online mental health literacy course was developed using state-of-the-art pedagogical principles and a reverse mentorship approach. The course was offered as an interdisciplinary undergraduate elective. Students completed an online survey before and after the 12-week course that collected demographic information and assessed mental health knowledge, emotional self-awareness, mental health, stigma, and health-related behaviors using validated measures. Dependent group t-tests were used to compare pre- and post-course levels of knowledge, mental health, sleep quality and substance use. Mental health outcomes of students who completed the course were compared to an age and sex-matched sample of students not enrolled in the course and who completed the same survey measures over the same academic year. Multivariable linear regression was used to examine the effect of course participation on outcomes at follow-up. RESULTS: The course had good uptake and was positively reviewed by participants. Specifically, students found the course engaging, relevant, and applicable, and agreed they would recommend it to their peers. Among course participants there was improvement in mental health knowledge (p < 0.001) and emotional self-awareness (p = 0.02) at course completion. Compared to the matched comparison group, taking the course was associated with reduced alcohol (ß = - 0.41, p = 0.01) and cannabis use (ß = - 0.35, p = 0.03), and improved sleep quality (ß = 1.56, p = 0.09) at the end of the term. CONCLUSIONS: Findings suggest that delivering mental health literacy as an online accredited course may be an acceptable and effective way of promoting university student mental health through improved knowledge, emotional self-awareness, and healthy lifestyle choices. As the course is expanded to larger and more diverse student cohorts we will be able to further examine the short and long-term effectiveness of the course in supporting student mental health and the underlying mechanisms.

Computational design of mechanically coupled axle-rotor protein assemblies.

Natural molecular machines contain protein components that undergo motion relative to each other. Designing such mechanically constrained nanoscale protein architectures with internal degrees of freedom is an outstanding challenge for computational protein design. Here we explore the de novo construction of protein machinery from designed axle and rotor components with internal cyclic or dihedral symmetry. We find that the axle-rotor systems assemble in vitro and in vivo as designed. Using cryo-electron microscopy, we find that these systems populate conformationally variable relative orientations reflecting the symmetry of the coupled components and the computationally designed interface energy landscape. These mechanical systems with internal degrees of freedom are a step toward the design of genetically encodable nanomachines.

Insights on the historical biogeography of Philippine domestic pigs and its relationship with continental domestic pigs and wild boars.

The Philippine archipelago was believed to have never been connected to the Asian continent even during the severe Quaternary sea-level drops. As a result, the history of domestic pig (Sus scrofa) dispersal in the Philippines remains controversial and must have some anthropogenic origin associated with human migration events. In this study, the context of origin, dispersal, and the level of genetic introgression in Philippine domestic pigs were deduced using mitochondrial DNA D-loop analysis altogether with domestic pigs and wild boar corresponding to their geographic origin. The results revealed considerable genetic diversity (0.900±0.016) and widespread Asian pig-ancestry (94.60%) in the phylogenetic analysis, with admixed European pig-origin (5.10%) harboring various fractions of ancestry from Berkshire and Landrace. The close genetic connection between the continental wild boars and domestic pigs present in the Philippine domestic pigs corroborates our hypothesis of a genetic signal that may be associated with the recently reported multiple waves of human migrations to the Philippines. The Haplogroup D7, reported to occur only in Indo-Burma Biodiversity Hotspots, included a high frequency of Philippine domestic pig haplotypes (54.08%), which poses an interesting challenge because its distribution is not consistent with the hypothesized migration route of Neolithic Austronesian-speaking populations. We detected the first Pacific Clade signature and ubiquitously distributed D2 haplotypes (Asian major) on several Philippine islands. The analyses of mismatch distribution and neutrality test were consistent with the Bayesian skyline plot which showed a long stationary period of effective population size. The population decline was consistent with the pronounced population bottleneck in Asian and European pigs during the interglacial periods of the Pleistocene. The results of this study will support the conservation strategies and improvements of economically important genetic resources in the Philippines.

A novel application of a data mining technique to study intersections in the social determinants of mental health among young Canadians.

OBJECTIVES: Adolescent mental health is an emergent clinical and public health priority in Canada. Gender-based differences in mental health are well established. The objective of this study was to evaluate a new data mining technique to identify social locations of young Canadians where differences in mental health between adolescent males and females were most pronounced. METHODS: We examined reports from 21,221 young Canadians aged 11-15 years (10,349 males, 10,872 females) who had responded to a 2018 national health and health behaviours survey. Using recursive partitioning for subgroup identification (SIDES), we identified social locations that were associated with the strongest differences between males and females for three reported mental health outcomes: positive psychosomatic health, symptoms of depression, and having a diagnosed mental illness. RESULTS: The SIDES algorithm identified both established and new intersections of social factors that were associated with gender-based differences in mental health experiences, most favouring males. DISCUSSION: This analysis represents a novel proof-of-concept to demonstrate the utility of a subgroup identification algorithm to reveal important differences in mental health experiences between adolescent males and females. The algorithm detected new social locations (i.e., where gender intersected with other characteristics) associated with poor mental health outcomes. These findings set the stage for further intersectional research, involving both quantitative and qualitative analyses, to explore how axes of discrimination may intersect to shape potential gender-based health inequalities that emerge during childhood.

Clinical effectiveness of gasless laparoscopic surgery for abdominal conditions: systematic review and meta-analysis.

BACKGROUND: In high-income countries, laparoscopic surgery is the preferred approach for many abdominal conditions. Conventional laparoscopy is a complex intervention that is challenging to adopt and implement in low resource settings. This systematic review and meta-analysis evaluate the clinical effectiveness of gasless laparoscopy compared to conventional laparoscopy with CO2 pneumoperitoneum and open surgery for general surgery and gynaecological procedures. METHODS: A search of the MEDLINE, EMBASE, Global Health, AJOL databases and Cochrane Library was performed from inception to January 2021. All randomised (RCTs) and comparative cohort (non-RCTs) studies comparing gasless laparoscopy with open surgery or conventional laparoscopy were included. The primary outcomes were mortality, conversion rates and intraoperative complications. SECONDARY OUTCOMES: operative times and length of stay. The inverse variance random-effects model was used to synthesise data. RESULTS: 63 studies were included: 41 RCTs and 22 non-RCTs (3,620 patients). No procedure-related deaths were reported in the studies. For gasless vs conventional laparoscopy there was no difference in intraoperative complications for general RR 1.04 [CI 0.45-2.40] or gynaecological surgery RR 0.66 [0.14-3.13]. In the gasless laparoscopy group, the conversion rates for gynaecological surgery were high RR 11.72 [CI 2.26-60.87] when compared to conventional laparoscopy. For gasless vs open surgery, the operative times were longer for gasless surgery in general surgery RCT group MD (mean difference) 10 [CI 0.64, 19.36], but significantly shorter in the gynaecology RCT group MD - 18.74 [CI - 29.23, - 8.26]. For gasless laparoscopy vs open surgery non-RCT, the length of stay was shorter for gasless laparoscopy in general surgery MD - 3.94 [CI - 5.93, - 1.95] and gynaecology MD - 1.75 [CI - 2.64, - 0.86]. Overall GRADE assessment for RCTs and Non-RCTs was very low. CONCLUSION: Gasless laparoscopy has advantages for selective general and gynaecological procedures and may have a vital role to play in low resource settings.

Origin and Demographic History of Philippine Pigs Inferred from Mitochondrial DNA.

The Philippines is a mega-diverse country that lies at the crossroads of past human migrations in the Asia-Pacific region and is believed to have never been connected to the Asian continent, even during the major sea-level subsidence of the Quaternary. As a result, the history of pig dispersal in the Philippines remains controversial, due to limited molecular studies and absence of archaeological evidence of pig domestication. This study provides the first comprehensive analysis of 184 complete mitochondrial DNA D-loop region from Philippine pigs to elucidate their early dispersal history by performing a phylogenetic comparison with wild boars and domestic pigs worldwide. The results showed a demographic signal of the ancestry of Philippine pigs that had a close genetic relationship with those from the mainland Southeast Asia and Northeast Asia, suggesting gene flow that may have resulted from human migration and trade. Here we have suggested two possible dispersal routes. One parallels the Neolithic expansion in Island Southeast Asia and Oceania via Northeast Asia, the other from the mainland Southeast Asia, into Palawan and Sulu Archipelago as early as prehistoric times via the Sundaic Region. Despite geographic barriers to migration, numerous genetic lineages have persisted across the Philippine islands, even justifying the recognition of a Philippine Lanyu subclade. The prehistoric population history suggests a demographic expansion that coincided with the interglacial periods of the Pleistocene and may have spread from the southern regions into the eastern and central regions of the Philippines. The intriguing signal of discrepancy discovered between the ancestral pattern and distribution range of the numerous endemic Philippine wild pigs opens a challenging new approach to illuminate complexity among these animals. Our study has contributed significantly towards completing the sparse molecular studies on Philippine pigs, an essential for creating win-win conservation measures.

Correlating spacing in the primary dentition and caries experience in preschool children.

PURPOSE: To evaluate the correlation between spacing in the primary dentition and caries experience. METHODS: One hundred seventy-four clinical records, including photographs during 2017-2019 were assessed for primate, generalised and interdental spaces. The mean of decayed, missing or filled teeth and surfaces (dmft and dmfs) were recorded to quantify the caries experience. Linear regression analyses were used to ascertain correlations between spacing and dental caries. The strength of the associations was quantified using odds ratio (OR) and 95% confidence interval (CI). RESULTS: Ninety-seven boys and 77 girls were included in the final analysis. Approximately 41% of children had primate space in all four quadrants, and 15% of children had no primate spaces in all four quadrants. 50% of children did not exhibit generalised spacing, while 39% of children showed interdental spacing. Children with no primate space had approximately five surfaces higher dmfs score compared to those with primate space in all four quadrants (95% CI - 9.27 to - 1.23; p < 0.05). Similarly, children with no primate space in the mandible had 6.12 surfaces higher dmfs score compared to those with primate space in the mandibular arch (95% CI - 10.07 to - 2.17; p < 0.05). CONCLUSIONS: Preschool children with no primate space exhibited a 50% increase in dmfs scores compared to children with primate space.

Predictors of mental health and academic outcomes in first-year university students: Identifying prevention and early-intervention targets.

BACKGROUND: Although there is growing interest in mental health problems in university students there is limited understanding of the scope of need and determinants to inform intervention efforts. AIMS: To longitudinally examine the extent and persistence of mental health symptoms and the importance of psychosocial and lifestyle factors for student mental health and academic outcomes. METHOD: Undergraduates at a Canadian university were invited to complete electronic surveys at entry and completion of their first year. The baseline survey measured important distal and proximal risk factors and the follow-up assessed mental health and well-being. Surveys were linked to academic grades. Multivariable models of risk factors and mental health and academic outcomes were fit and adjusted for confounders. RESULTS: In 1530 students surveyed at entry to university 28% and 33% screened positive for clinically significant depressive and anxiety symptoms respectively, which increased to 36% and 39% at the completion of first year. Over the academic year, 14% of students reported suicidal thoughts and 1.6% suicide attempts. Moreover, there was persistence and overlap in these mental health outcomes. Modifiable psychosocial and lifestyle factors at entry were associated with positive screens for mental health outcomes at completion of first year, while anxiety and depressive symptoms were associated with lower grades and university well-being. CONCLUSIONS: Clinically significant mental health symptoms are common and persistent among first-year university students and have a negative impact on academic performance and well-being. A comprehensive mental health strategy that includes a whole university approach to prevention and targeted early-intervention measures and associated research is justified.

Potential of genomic selection for improvement of resistance to ostreid herpesvirus in Pacific oyster (Crassostrea gigas).

In genomic selection (GS), genome-wide SNP markers are used to generate genomic estimated breeding values for selection candidates. The application of GS in shellfish looks promising and has the potential to help in dealing with one of the main issues currently affecting Pacific oyster production worldwide, which is the 'summer mortality syndrome'. This causes periodic mass mortality in farms worldwide and has mainly been attributed to a specific variant of the ostreid herpesvirus (OsHV-1). In the current study, we evaluated the potential of genomic selection for host resistance to OsHV-1 in Pacific oysters, and compared it with pedigree-based approaches. An OsHV-1 disease challenge was performed using an immersion-based virus exposure treatment for oysters for 7 days. A total of 768 samples were genotyped using the medium-density SNP array for oysters. A GWAS was performed for the survival trait using a GBLUP approach in blupf90 software. Heritability ranged from 0.25 ± 0.05 to 0.37 ± 0.05 (mean ± SE) based on pedigree and genomic information respectively. Genomic prediction was more accurate than pedigree prediction, and SNP density reduction had little impact on prediction accuracy until marker densities dropped below approximately 500 SNPs. This demonstrates the potential for GS in Pacific oyster breeding programmes, and importantly, demonstrates that a low number of SNPs might suffice to obtain accurate genomic estimated breeding values, thus potentially making the implementation of GS more cost effective.

Root canal morphology of hypomineralised first permanent molars using micro-CT.

AIM: To investigate the root canal morphology of hypomineralised first permanent molars (FPMs) using micro-CT (µCT). METHODOLOGY: Twenty-four hypomineralised FPMs and five clinically sound FPMs were scanned using µCT and assessed using the following parameters: (i) root canal configuration, (ii) connecting canal frequency, (iii) enamel, dentin, and pulp volumes, (iv) cusp tip to pulp horn distance, root canal length, root canal width, and dentin thickness, and (v) the influence of the root canal system landmarks on access cavity outline forms and canal curvature. A two-way repeated-measures analysis of variance was employed with the statistical significance set at p < 0.05. RESULTS: The frequency of accessory and connecting canals was higher in hypomineralised FPMs. Mesio-buccal cusp horn was found to be the closest to its corresponding cusp tip in both groups. There was no significant difference between the root lengths, dentine widths, and pulp space measurements of hypomineralised FPMs compared to clinically sound FPMs. The best angulation to access FPMs was straight-line radicular, along the pulp horn. CONCLUSIONS: This study illustrates some variations in the root canal morphology in hypomineralised FPMs compared to clinically sound FPMs. Future studies should focus on assessing these parameters in larger samples.