Factor analysis of the Chinese version of the Autism Spectrum Quotient 10 and its association with schizotypal traits in adolescents and young adults in Hong Kong.

BACKGROUND: There is evidence suggesting that autistic traits are associated with schizotypal traits. This study examined the factor structure of the Autism Spectrum Quotient 10 (AQ-10) and its associations with schizotypal traits (measured by the Schizotypal Personality Questionnaire-Brief [SPQ-B]) in a cohort of Chinese adolescents and young adults. METHODS: Invitation letters, stratified by locations and housing types, were randomly sent to individuals aged 15 to 24 years for participation. Assessments were made using face-to-face or online interviews. Autistic traits were assessed using the Chinese version of the AQ-10. Schizotypal personality traits were assessed using the Chinese version of the 22-item SPQ-B. RESULTS: In total, 395 male and 536 female participants (mean age, 19.93 years) were recruited between July 2020 and May 2021. Exploratory factor analysis of the AQ-10 yielded three factors (theory of mind, task switching, and attention deficits) explaining 55.11% of the total variance. Autistic traits were positively correlated with schizotypal traits of disorganised features (r = 0.21, p < 0.001), interpersonal relationship deficits (r = 0.19, p < 0.001), and cognitive-perceptual deficits (r = 0.11, p = 0.001). CONCLUSION: In Chinese adolescents and young adults, autistic traits, especially task switching and attention deficits (compared with theory of mind) are more closely correlated with schizotypal personality traits. Disentangling the overlapping and diametrical structure of autistic traits and schizotypal traits may help understand their aetiologies, assessment, and interventions.

Women's engagement with community perinatal mental health services: a realist evaluation.

BACKGROUND: In recognition of the burden of Perinatal Mental Health problems, NHS England invested £365 million to transform women's access to mental health care, including investment in Community Perinatal Mental Health Services. This study examined how elements of provider care affected women's engagement with these services. METHODS: Semi-structured interviews were conducted with 139 women and explored their experiences of care from 10 different Community Perinatal Mental Health Teams; including which service components participants believed made a difference to their initial and continued engagement. Realist analysis was used to create context-mechanism-outcome configurations (CMOCs) across interviews, since not all parts of the configurations were always articulated within singular interviews. RESULTS: Four key pillars for engagement were identified: perinatal competence, relationship building, accurate reassurance, and reliability. The way perinatal competencies were relayed to women mattered; compassion, understanding and consistency were critical interactional styles. The extent to which these factors affected women's engagement varied by their context and personal characteristics. CONCLUSIONS: As mental health problems increase, disproportionately affecting vulnerable populations, it is critical to continue to ensure support is not only available, but appropriately meets the needs of those individuals. Our findings suggest that key staff behaviours applied at the right time can support women's engagement and potentially contribute to better treatment outcomes.

A bacterial sense of touch: T4P retraction motor as a means of surface sensing by Pseudomonas aeruginosa PA14.

Most microbial cells found in nature exist in matrix-covered, surface-attached communities known as biofilms. This mode of growth is initiated by the ability of the microbe to sense a surface on which to grow. The opportunistic pathogen Pseudomonas aeruginosa (Pa) PA14 utilizes a single polar flagellum and type 4 pili (T4P) to sense surfaces. For Pa, T4P-dependent "twitching" motility is characterized by effectively pulling the cell across a surface through a complex process of cooperative binding, pulling, and unbinding. T4P retraction is powered by hexameric ATPases. Pa cells that have engaged a surface increase production of the second messenger cyclic AMP (cAMP) over multiple generations via the Pil-Chp system. This rise in cAMP allows cells and their progeny to become better adapted for surface attachment and activates virulence pathways through the cAMP-binding transcription factor Vfr. While many studies have focused on mechanisms of T4P twitching and regulation of T4P production and function by the Pil-Chp system, the mechanism by which Pa senses and relays a surface-engagement signal to the cell is still an open question. Here we review the current state of the surface sensing literature for Pa, with a focus on T4P, and propose an integrated model of surface sensing whereby the retraction motor PilT senses and relays the signal to the Pil-Chp system via PilJ to drive cAMP production and adaptation to a surface lifestyle.

Assessment of an AI-based tool for population-wide collection of placental morphological data.

OBJECTIVES: Automated placental assessment could allow accurate and timely morphological/pathological measurements at scale. We undertook a pilot study using an artificial intelligence-based assessment system (AI-PLAX) to ascertain the potential of a state-wide rollout as part of Generation Victoria, assessing the impact of time post-delivery, user, and technology used for image capture, on a range of derived placental data. STUDY DESIGN: Ten placentas were imaged by three different users and imaging technologies (iPad, iPhone, Samsung) at (0 h), 24 h, and 48 h post-delivery. Using AI-PLAX, disc size (short and long length, perimeter, area), shape (normal, abnormal), cord insertion type (central, eccentric), cord coiling, abruption (retroplacental hematoma), and meconium staining were determined. RESULTS: When analysing the maternal surface of the placenta, time in cold storage post-delivery had modest effects on placental dimensions, with decreases in the short length (24-48 h: -3.7 %), disc area (0-24 h: 4.7 % and 0-48 h: -7.4 %), and perimeter (0-48 h: -3.8 %) observed. There was marginal impact on placental dimensions when the placenta was imaged by different users, including long length (+1.9 %), disc area (+2.9 %), and perimeter (+2.0 %). Measures of placental size were not impacted by the type of technology used to capture the images. When analysing the fetal surface of the placenta, more variance in placental size measures were observed between users. Abruption detection was not affected by any parameter. Time between delivery and imaging impacted apparent meconium staining - likely reflecting changes in fetal surface colour over time. Meconium staining was not affected by technology or user. CONCLUSIONS: This study supports the feasibility of the collection of placenta images for later morphological analysis by AI-PLAX, with measures obtained minimally influenced by time in cold storage, user imaging the placenta, or technology to capture the images.

Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.

Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanisms underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: 1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; 2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; 3) age is a dominant factor affecting mitochondrial activity, especially across different fat depots and skeletal muscle groups, and most brain regions; 4) age-effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and 5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.

Cell-Surface ZnT8 Antibody Prevents and Reverses Autoimmune Diabetes in Mice.

Type 1 diabetes (T1D) is an autoimmune disease in which pathogenic lymphocytes target autoantigens expressed in pancreatic islets, leading to the destruction of insulin-producing ß-cells. Zinc transporter 8 (ZnT8) is a major autoantigen abundantly present on the ß-cell surface. This unique molecular target offers the potential to shield ß-cells against autoimmune attacks in T1D. Our previous work showed that a monoclonal antibody (mAb43) against cell-surface ZnT8 could home in on pancreatic islets and prevent autoantibodies from recognizing ß-cells. This study demonstrates that mAb43 binds to exocytotic sites on the ß-cell surface, masking the antigenic exposure of ZnT8 and insulin after glucose-stimulated insulin secretion. In vivo administration of mAb43 to NOD mice selectively increased the proportion of regulatory T cells in the islet, resulting in complete and sustained protection against T1D onset as well as reversal of new-onset diabetes. The mAb43-induced self-tolerance was reversible after treatment cessation, and no adverse effects were exhibited during long-term monitoring. Our findings suggest that mAb43 masking of the antigenic exposure of ß-cells suppresses the immunological cascade from B-cell antigen presentation to T cell-mediated ß-cell destruction, providing a novel islet-targeted and antigen-specific immunotherapy to prevent and reverse clinical T1D.

Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition.

Genome-wide association studies (GWAS) have identified a large number of candidate genes believed to affect longitudinal bone growth and bone mass. One of these candidate genes, TMEM263, encodes a poorly characterized plasma membrane protein. Single nucleotide polymorphisms in TMEM263 are associated with bone mineral density in humans and mutations are associated with dwarfism in chicken and severe skeletal dysplasia in at least one human fetus. Whether this genotype-phenotype relationship is causal, however, remains unclear. Here, we determine whether and how TMEM263 is required for postnatal growth. Deletion of the Tmem263 gene in mice causes severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. Mice lacking Tmem263 show no differences in body weight within the first 2 weeks of postnatal life. However, by P21 there is a dramatic growth deficit due to a disrupted growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, which is critical for longitudinal bone growth. Tmem263-null mice have low circulating IGF-1 levels and pronounced reductions in bone mass and growth plate length. The low serum IGF-1 in Tmem263-null mice is associated with reduced hepatic GH receptor (GHR) expression and GH-induced JAK2/STAT5 signaling. A deficit in GH signaling dramatically alters GH-regulated genes and feminizes the liver transcriptome of Tmem263-null male mice, with their expression profile resembling wild-type female, hypophysectomized male, and Stat5b-null male mice. Collectively, our data validates the causal role for Tmem263 in regulating postnatal growth and raises the possibility that rare mutations or variants of TMEM263 may potentially cause GH insensitivity and impair linear growth.

CTRP6 promotes the macrophage inflammatory response, and its deficiency attenuates LPS-induced inflammation.

Macrophages play critical roles in inflammation and tissue homeostasis, and their functions are regulated by various autocrine, paracrine, and endocrine factors. We have previously shown that CTRP6, a secreted protein of the C1q family, targets both adipocytes and macrophages to promote obesity-linked inflammation. However, the gene programs and signaling pathways directly regulated by CTRP6 in macrophages remain unknown. Here, we combine transcriptomic and phosphoproteomic analyses to show that CTRP6 activates inflammatory gene programs and signaling pathways in mouse bone marrow-derived macrophages (BMDMs). Treatment of BMDMs with CTRP6 upregulated proinflammatory, and suppressed the antiinflammatory, gene expression. We also showed that CTRP6 activates p44/42-MAPK, p38-MAPK, and NF-κB signaling pathways to promote inflammatory cytokine secretion from BMDMs, and that pharmacologic inhibition of these signaling pathways markedly attenuated the effects of CTRP6. Pretreatment of BMDMs with CTRP6 also sensitized and potentiated the BMDMs response to lipopolysaccharide (LPS)-induced inflammatory signaling and cytokine secretion. Consistent with the metabolic phenotype of proinflammatory macrophages, CTRP6 treatment induced a shift toward aerobic glycolysis and lactate production, reduced oxidative metabolism, and elevated mitochondrial reactive oxygen species production in BMDMs. Importantly, in accordance with our in vitro findings, BMDMs from CTRP6-deficient mice were less inflammatory at baseline and showed a marked suppression of LPS-induced inflammatory gene expression and cytokine secretion. Finally, loss of CTRP6 in mice also dampened LPS-induced inflammation and hypothermia. Collectively, our findings suggest that CTRP6 regulates and primes the macrophage response to inflammatory stimuli and thus may have a role in modulating tissue inflammatory tone in different physiological and disease contexts.

Loss of CTRP10 results in female obesity with preserved metabolic health.

Obesity is a major risk factor for type 2 diabetes, dyslipidemia, cardiovascular disease, and hypertension. Intriguingly, there is a subset of metabolically healthy obese (MHO) individuals who are seemingly able to maintain a healthy metabolic profile free of metabolic syndrome. The molecular underpinnings of MHO, however, are not well understood. Here, we report that CTRP10/C1QL2-deficient mice represent a unique female model of MHO. CTRP10 modulates weight gain in a striking and sexually dimorphic manner. Female, but not male, mice lacking CTRP10 develop obesity with age on a low-fat diet while maintaining an otherwise healthy metabolic profile. When fed an obesogenic diet, female Ctrp10 knockout (KO) mice show rapid weight gain. Despite pronounced obesity, Ctrp10 KO female mice do not develop steatosis, dyslipidemia, glucose intolerance, insulin resistance, oxidative stress, or low-grade inflammation. Obesity is largely uncoupled from metabolic dysregulation in female KO mice. Multi-tissue transcriptomic analyses highlighted gene expression changes and pathways associated with insulin-sensitive obesity. Transcriptional correlation of the differentially expressed gene (DEG) orthologous in humans also show sex differences in gene connectivity within and across metabolic tissues, underscoring the conserved sex-dependent function of CTRP10. Collectively, our findings suggest that CTRP10 negatively regulates body weight in females, and that loss of CTRP10 results in benign obesity with largely preserved insulin sensitivity and metabolic health. This female MHO mouse model is valuable for understanding sex-biased mechanisms that uncouple obesity from metabolic dysfunction.

CTRP13 ablation improves systemic glucose and lipid metabolism.

OBJECTIVE: Tissue crosstalk mediated by secreted hormones underlies the integrative control of metabolism. We previously showed that CTRP13/C1QL3, a secreted protein of the C1q family, can improve glucose metabolism and insulin action in vitro and reduce food intake and body weight in mice when centrally delivered. A role for CTRP13 in regulating insulin secretion in isolated islets has also been demonstrated. It remains unclear, however, whether the effects of CTRP13 on cultured cells and in mice reflect the physiological function of the protein. Here, we use a loss-of-function mouse model to address whether CTRP13 is required for metabolic homeostasis. METHODS: WT and Ctrp13 knockout (KO) mice fed a standard chow or a high-fat diet were subjected to comprehensive metabolic phenotyping. Transcriptomic analyses were carried out on visceral and subcutaneous fat, liver, and skeletal muscle to identify pathways altered by CTRP13 deficiency. RNA-seq data was further integrated with the Metabolic Syndrome in Man (METSIM) cohort data. Adjusted regression analysis was used to demonstrate that genetic variation of CTRP13 expression accounts for a significant proportion of variance between differentially expressed genes (DEGs) in adipose tissue and metabolic traits in humans. RESULTS: Contrary to expectation, chow-fed Ctrp13-KO male mice had elevated physical activity, lower body weight, and improved lipid handling. On a high-fat diet (HFD), Ctrp13-KO mice of either sex were consistently more active and leaner. Loss of CTRP13 reduced hepatic glucose output and improved glucose tolerance, insulin sensitivity, and triglyceride clearance, though with notable sex differences. Consistent with the lean phenotype, transcriptomic analyses revealed a lower inflammatory profile in visceral fat and liver. Reduced hepatic steatosis was correlated with the suppression of lipid synthesis and enhanced lipid catabolism gene expression. Visceral fat had the largest number of DEGs and mediation analyses on the human orthologs of the DEGs suggested the potential causal contribution of CTRP13 to human metabolic syndrome. CONCLUSIONS: Our results suggest that CTRP13 is a negative metabolic regulator, and its deficiency improves systemic metabolic profiles. Our data also suggest the reduction in circulating human CTRP13 levels seen in obesity and diabetes may reflect a compensatory physiologic response to counteract insulin resistance.

Adiponectin and resistin modulate the progression of Alzheimer´s disease in a metabolic syndrome model.

Metabolic syndrome (MetS), a cluster of metabolic conditions that include obesity, hyperlipidemia, and insulin resistance, increases the risk of several aging-related brain diseases, including Alzheimer's disease (AD). However, the underlying mechanism explaining the link between MetS and brain function is poorly understood. Among the possible mediators are several adipose-derived secreted molecules called adipokines, including adiponectin (ApN) and resistin, which have been shown to regulate brain function by modulating several metabolic processes. To investigate the impact of adipokines on MetS, we employed a diet-induced model to induce the various complications associated with MetS. For this purpose, we administered a high-fat diet (HFD) to both WT and APP/PSN1 mice at a pre-symptomatic disease stage. Our data showed that MetS causes a fast decline in cognitive performance and stimulates Aß42 production in the brain. Interestingly, ApN treatment restored glucose metabolism and improved cognitive functions by 50% while decreasing the Aß42/40 ratio by approximately 65%. In contrast, resistin exacerbated Aß pathology, increased oxidative stress, and strongly reduced glucose metabolism. Together, our data demonstrate that ApN and resistin alterations could further contribute to AD pathology.

Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition.

Genome-wide association studies (GWAS) have identified a large number of candidate genes believed to affect longitudinal bone growth and bone mass. One of these candidate genes, TMEM263, encodes a poorly characterized plasma membrane protein. Single nucleotide polymorphisms in TMEM263 are associated with bone mineral density in humans and mutations are associated with dwarfism in chicken and severe skeletal dysplasia in at least one human fetus. Whether this genotype-phenotype relationship is causal, however, remains unclear. Here, we determine whether and how TMEM263 is required for postnatal growth. Deletion of the Tmem263 gene in mice causes severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. Mice lacking Tmem263 show no differences in body weight within the first two weeks of postnatal life. However, by P21 there is a dramatic growth deficit due to a disrupted GH/IGF-1 axis, which is critical for longitudinal bone growth. Tmem263-null mice have low circulating IGF-1 levels and pronounced reductions in bone mass and growth plate length. The low serum IGF-1 in Tmem263-null mice is associated with reduced hepatic GH receptor (GHR) expression and GH-induced JAK2/STAT5 signaling. A deficit in GH signaling dramatically alters GH-regulated genes and feminizes the liver transcriptome of Tmem263-null male mice, with their expression profile resembling a wild-type female, hypophysectomized male, and Stat5b-null male mice. Collectively, our data validates the causal role for Tmem263 in regulating postnatal growth and raises the possibility that rare mutations or variants of TMEM263 may potentially cause GH insensitivity and impair linear growth.

Hypermetabolism in mice carrying a near-complete human chromosome 21.

The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model (TcMAC21) carrying a near-complete human chromosome 21. Independent of diets and housing temperatures, TcMAC21 mice consume more calories, are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have a higher body temperature. The hypermetabolism and elevated thermogenesis are likely due to a combination of increased activity level and sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) activity and energy dissipation. Mitochondrial respiration is also markedly increased in skeletal muscle to meet the high ATP demand created by the futile cycle and hyperactivity. This serendipitous discovery provides proof-of-concept that sarcolipin-mediated thermogenesis via uncoupling of the SERCA pump can be harnessed to promote energy expenditure and metabolic health.

Study protocol for The GOAL Trial: comprehensive geriatric assessment for frail older people with chronic kidney disease to increase attainment of patient-identified goals-a cluster randomised controlled trial.

BACKGROUND: An increasing number of older people are living with chronic kidney disease (CKD). Many have complex healthcare needs and are at risk of deteriorating health and functional status, which can adversely affect their quality of life. Comprehensive geriatric assessment (CGA) is an effective intervention to improve survival and independence of older people, but its clinical utility and cost-effectiveness in frail older people living with CKD is unknown. METHODS: The GOAL Trial is a pragmatic, multi-centre, open-label, superiority, cluster randomised controlled trial developed by consumers, clinicians, and researchers. It has a two-arm design, CGA compared with standard care, with 1:1 allocation of a total of 16 clusters. Within each cluster, study participants ≥ 65 years of age (or ≥ 55 years if Aboriginal or Torres Strait Islander (First Nations Australians)) with CKD stage 3-5/5D who are frail, measured by a Frailty Index (FI) of > 0.25, are recruited. Participants in intervention clusters receive a CGA by a geriatrician to identify medical, social, and functional needs, optimise medication prescribing, and arrange multidisciplinary referral if required. Those in standard care clusters receive usual care. The primary outcome is attainment of self-identified goals assessed by standardised Goal Attainment Scaling (GAS) at 3 months. Secondary outcomes include GAS at 6 and 12 months, quality of life (EQ-5D-5L), frailty (Frailty Index - Short Form), transfer to residential aged care facilities, cost-effectiveness, and safety (cause-specific hospitalisations, mortality). A process evaluation will be conducted in parallel with the trial including whether the intervention was delivered as intended, any issue or local barriers to intervention delivery, and perceptions of the intervention by participants. The trial has 90% power to detect a clinically meaningful mean difference in GAS of 10 units. DISCUSSION: This trial addresses patient-prioritised outcomes. It will be conducted, disseminated and implemented by clinicians and researchers in partnership with consumers. If CGA is found to have clinical and cost-effectiveness for frail older people with CKD, the intervention framework could be embedded into routine clinical practice. The implementation of the trial's findings will be supported by presentations at conferences and forums with clinicians and consumers at specifically convened workshops, to enable rapid adoption into practice and policy for both nephrology and geriatric disciplines. It has potential to materially advance patient-centred care and improve clinical and patient-reported outcomes (including quality of life) for frail older people living with CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04538157. Registered on 3 September 2020.