Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-ß clearance in animal models of Alzheimer's disease.

Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer's disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance. First, we used gene ontology analysis of microglia from young and old mice to identify differential expression of cyclin-dependent kinase inhibitor 2A (p16ink4a), a cell cycle factor related to aging. We found that p16ink4a expression was increased in microglia near amyloid plaques in brain tissue from patients with AD and 5XFAD mice, a model of AD. In BV2 microglia, small interfering RNA (siRNA)-mediated p16ink4a downregulation transformed microglia with enhanced amyloid phagocytic capacity through regulated the cell cycle and increased cell proliferation. To regulate microglial phagocytosis by gene transduction, we used poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which predominantly target microglia, to deliver the siRNA and to control microglial reactivity. Nanoparticle-based delivery of p16ink4a siRNA reduced amyloid plaque formation and the number of aged microglia surrounding the plaque and reversed learning deterioration and spatial memory deficits. We propose that downregulation of p16ink4a in microglia is a promising strategy for the treatment of Alzheimer's disease.

Disease Course of Korean African Swine Fever Virus in Domestic Pigs Exposed Intraorally, Intranasally, Intramuscularly, and by Direct Contact with Infected Pigs.

African swine fever (ASF) is a fatal contagious disease affecting swine. The first Korean ASF virus (ASFV) isolate (Korea/Pig/Paju1/2019) was used to compare the disease course of ASFV in pigs inoculated via the four routes. In the challenge experiment, domestic pigs were infected via the intraoral (IO) and intranasal (IN) routes with a 106 50% hemadsorbing dose (HAD50) and an intramuscular (IM) injection of 103 HAD50. In the direct contact (DC) group, five naïve pigs were brought into direct contact with two IM-ASFV-infected pigs. IO-, IN-, and IM-inoculated pigs showed similar disease courses, whereas DC pigs had comparable ASF syndrome after a 7-day latent period. The disease course in the DC route, one of the most common routes of infection, was not significantly different from that in the IO and IN routes. IM and DC groups differed in terms of the severity of fever and hemorrhagic lesions in the lymph nodes and spleen, indicating that the IM route, suitable for early vaccine development trials, is not appropriate for studying the ASFV infection mechanism, including early stage of infection, and IO and IN challenges with a designated dose can be alternatives in trials for assessing ASFV pathogenicity and vaccine efficacy investigations.

Long-term cardiovascular outcome in women with preeclampsia in Korea: a large population-based cohort study and meta-analysis.

Recent studies reported the long-term cardiovascular risk of preeclampsia. However, only a few studies have investigated the association between preeclampsia and long-term cardiovascular disease in Asian populations, although there could be racial/ethnic differences in the risk of cardiovascular diseases. Therefore, we aimed to evaluate the long-term effects of preeclampsia on cardiovascular disease in an Asian population. This study included 68,658 parous women in the Health Examinees Study (HEXA) cohort of South Korea and compared the risk of long-term cardiovascular disease, including ischemic heart disease and stroke, according to the history of preeclampsia. We also performed a meta-analysis combining current study data with data from existing literature in the Asian population. Among the study population, 3413 (5.23%) women had a history of preeclampsia, and 767 (1.12%) and 404 (0.59%) women developed ischemic heart disease and stroke for 22 years. Women with a history of preeclampsia were at a higher risk for both ischemic heart disease (adjusted hazard ratio 1.66 [1.19-2.04]) and stroke (adjusted hazard ratio 1.48 [1.02-2.16]) than those without. In the meta-analysis, the pooled hazard ratio of ischemic heart disease and stroke were also increased in women with a history of preeclampsia (ischemic heart disease 1.65 [1.51-1.82]; stroke 1.78 [1.52-2.10]).

N-cadherin dynamically regulates pediatric glioma cell migration in complex environments.

Pediatric high-grade gliomas are highly invasive and essentially incurable. Glioma cells migrate between neurons and glia, along axon tracts, and through extracellular matrix surrounding blood vessels and underlying the pia. Mechanisms that allow adaptation to such complex environments are poorly understood. N-cadherin is highly expressed in pediatric gliomas and associated with shorter survival. We found that intercellular homotypic N-cadherin interactions differentially regulate glioma migration according to the microenvironment, stimulating migration on cultured neurons or astrocytes but inhibiting invasion into reconstituted or astrocyte-deposited extracellular matrix. N-cadherin localizes to filamentous connections between migrating leader cells but to epithelial-like junctions between followers. Leader cells have more surface and recycling N-cadherin, increased YAP1/TAZ signaling, and increased proliferation relative to followers. YAP1/TAZ signaling is dynamically regulated as leaders and followers change position, leading to altered N-cadherin levels and organization. Together, the results suggest that pediatric glioma cells adapt to different microenvironments by regulating N-cadherin dynamics and cell-cell contacts.

Age-Related Gut Microbiota Transplantation Disrupts Myocardial Energy Homeostasis and Induces Oxidative Damage.

BACKGROUND: Aging-related energy homeostasis significantly affects normal heart function and disease development. The relationship between the gut microbiota and host energy metabolism has been well established. However, the influence of an aged microbiota on energy metabolism in the heart remains unclear. OBJECTIVE: The objective of this was to explore the effects of age-related microbiota composition on energy metabolism in the heart. METHODS: In this study, we used the fecal microbiota transplantation (FMT) method. The fecal microbiota from young (2-3 mo) and aged (18-22 mo) donor mice were transplanted into separate groups of young (2-3 mo) recipient mice. The analysis utilized whole 16S rRNA sequencing and plasma metabolomics to assess changes in the gut microbiota composition and metabolic potential. Energy changes were monitored by performing an oral glucose tolerance test, biochemical testing, body composition analysis, and metabolic cage measurements. Metabolic markers and markers of DNA damage were assessed in heart samples. RESULTS: FMT of an aged microbiota changed the composition of the recipient's gut microbiota, leading to an elevated Firmicutes-to-Bacteroidetes ratio. It also affected overall energy metabolism, resulting in elevated plasma glucose concentrations, impaired glucose tolerance, and epididymal fat accumulation. Notably, FMT of an aged microbiota increased the heart weight and promoted cardiac hypertrophy. Furthermore, there were significant associations between heart weight and cardiac hypertrophy indicators, epididymal fat weight, and fasting glucose concentrations. Mechanistically, FMT of an aged microbiota modulated the glucose metabolic pathway and induced myocardial oxidative damage. CONCLUSIONS: Our findings suggested that an aged microbiota can modulate metabolism and induce cardiac injury. This highlights the possible role of the gut microbiota in age-related metabolic disorders and cardiac dysfunction.

Actinidia polygama Water Extract (APWE) Protects Against UVB-Induced Photoaging via MAPK/AP-1 and TGFß-Smad Pathway.

BACKGROUND: Actinidia polygama (silver vine) has been used in oriental medicine to treat gout, rheumatoid arthritis, and inflammation. Actinidia polygama water extract (APWE) is named PB203. OBJECTIVE: To investigate whether PB203 has anti-photoaging effects and to understand the molecular mechanism underlying such effects. METHODS: The antioxidant effect was assessed by 1,1-diphenyl-2-picrylhydrazyl assay and 2',7'-dichlorodihydrofluorescein diacetate staining in ultraviolet B (UVB)-irradiated HaCaT cells with or without PB203 treatment. Type I collagen, matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase (TIMP-1), hyaluronic acid (HA), hyaluronan synthase 1 (HAS1) and HAS2 levels were measuring by enzyme-linked immunosorbent assay or reverse transcription quantitative polymerase chain reaction. Also, we investigate the effects of PB203 on wrinkle formation, and the potential mechanisms underlying such effects were investigated in UVB-induced wrinkle mouse model mice. RESULTS: PB203 alleviated the UVB-induced reactive oxygen species production, phosphorylation of JNK, ERK, and p38, and formation of AP-1. In addition, PB203 inhibited the decreases in type I collagen and TIMP-1 levels, and the increase in MMP-1 levels in UVB-exposed HaCaT cells. In UVB-induced wrinkle mouse model, PB203 inhibited the decreases in elastin and type I collagen levels as well as the increases in MMP-1 expression, wrinkle formation, and skin dehydration. Furthermore, PB203 increased the expression of filaggrin, HAS1, and HAS2, improving the skin barrier function. CONCLUSION: Taken together, we found that PB203 is as a potent candidate to serve as a functional ingredient or therapeutic agent to improve UVB-mediated skin aging.

Evaluation of purine-nucleoside degrading ability and in vivo uric acid lowering of Streptococcus thermophilus IDCC 2201, a novel antiuricemia strain.

This study evaluated 15 lactic acid bacteria with a focus on their ability to degrade inosine and hypo-xanthine-which are the intermediates in purine metabolism-for the management of hyperuricemia and gout. After a preliminary screening based on HPLC, Lactiplantibacillus plantarum CR1 and Lactiplantibacillus pentosus GZ1 were found to have the highest nucleoside degrading rates, and they were therefore selected for further characterization. S. thermophilus IDCC 2201, which possessed the hpt gene encoding hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and exhibited purine degradation, was also selected for further characterization. These three selected strains were examined in terms of their probiotic effect on lowering serum uric acid in a Sprague-Dawley (SD) rat model of potassium oxonate (PO)-induced hyperuricemia. Among these three strains, the level of serum uric acid was most reduced by S. thermophilus IDCC 2201 (p < 0.05). Further, analysis of the microbiome showed that administration of S. thermophlilus IDCC 2201 led to a significant difference in gut microbiota composition compared to that in the group administered with PO-induced hyperuricemia. Moreover, intestinal short-chain fatty acids (SCFAs) were found to be significantly increased. Altogether, the results of this work indicate that S. thermophilus IDCC 2201 lowers uric acid levels by degrading purine-nucleosides and also restores intestinal flora and SCFAs, ultimately suggesting that S. thermophilus IDCC 2201 is a promising candidate for use as an adjuvant treatment in patients with hyperuricemia.

N-cadherin dynamically regulates pediatric glioma cell migration in complex environments.

Pediatric high-grade gliomas are highly invasive and essentially incurable. Glioma cells migrate between neurons and glia, along axon tracts, and through extracellular matrix surrounding blood vessels and underlying the pia. Mechanisms that allow adaptation to such complex environments are poorly understood. N-cadherin is highly expressed in pediatric gliomas and associated with shorter survival. We found that inter-cellular homotypic N-cadherin interactions differentially regulate glioma migration according to the microenvironment, stimulating migration on cultured neurons or astrocytes but inhibiting invasion into reconstituted or astrocyte-deposited extracellular matrix. N-cadherin localizes to filamentous connections between migrating leader cells but to epithelial-like junctions between followers. Leader cells have more surface and recycling N-cadherin, increased YAP1/TAZ signaling, and increased proliferation relative to followers. YAP1/TAZ signaling is dynamically regulated as leaders and followers change position, leading to altered N-cadherin levels and organization. Together, the results suggest that pediatric glioma cells adapt to different microenvironments by regulating N-cadherin dynamics and cell-cell contacts.

Blending Three Probiotics Alleviates Loperamide-Induced Constipation in Sprague-Dawley (SD)-Rats.

BIOVITA 3 bacterial species (BIOVITA 3), a probiotic blend powder containing Clostridium butyricum IDCC 1301, Weizmannia coagulans IDCC 1201 and Bacillus subtilis IDCC 1101, has been used as a food ingredient for gut health. However, its efficacy in improving constipation has not been reported. Therefore, we aimed to investigate the functional effects of oral administration of BIOVITA 3 as well as its component strains alone (at 1.0×109 CFU/day) in Sprague-Dawley (SD) rats with loperamide-induced constipation. The study included fecal analysis, gastrointestinal transit ratio, histopathological analysis, short chain fatty acids (SCFAs), and metagenome analysis. As results, the BIOVITA 3 group showed significant improvements in fecal number, water content, gastrointestinal transit ratio, and thickening of the mucosal layer. In the SCFAs analysis, all probiotic-treated groups showed an increase in total SCFAs compared to the loperamide-constipated group. Changes in microbial abundance and the diversity index of three groups (normal, constipated, and BIOVITA 3) were also defined. Of these, the BIOVITA 3 showed a significant improvement in loperamide-constipated SD-rats. This study suggests the possibility that BIOVITA 3 can be applied as an ingredient in functional foods to relieve constipation.

Roles of Human Gut Microbiota in Liver Cirrhosis Risk: A Two-Sample Mendelian Randomization Study.

BACKGROUND: Accumulating evidence suggests that alterations in gut microbiota composition and diversity are associated with liver cirrhosis. But whether gut microbiota promotes or hampers the genesis and development of liver cirrhosis remains vague. OBJECTIVES: This study aimed to establish a causal relationship between gut microbiota and the development of liver fibrosis and cirrhosis. To achieve this, we employed a 2-sample Mendelian randomization (MR) analysis utilizing genome-wide association study (GWAS) summary statistics. This approach enabled us to assess the potential impact of gut microbiota on liver cirrhosis. METHODS: The independent genetic instruments of gut microbiota were obtained from the MiBioGen (up to 18,340 participants), which is a large-scale genome-wide genotype and 16S fecal microbiome dataset. Cirrhosis data were derived from the FinnGen biobank analysis, which included 214,403 individuals of European ancestry (811 patients and 213,592 controls). To assess the causal relationship between gut microbiota and cirrhosis, we applied 4 different methods of MR analysis: the inverse-variance weighted method (IVW), the MR-Egger regression, the weighted median analysis (WME), and the weighted mode. Furthermore, sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy. RESULTS: Results of MR analyses provided evidence of a causal association between 4 microbiota features and cirrhosis, including 2 family [Lachnosiraceae: odds ratio (OR): 1.82626178; 95% confidence interval (CI): 1.05208209, 3.17012532; P = 0.0323194; Lactobacillaceae : OR: 0.62897502; 95% CI: 0.42513162, 0.93055788; P = 0.02033345] and 2 genus [Butyricicoccus: OR: 0.41432215; 95% CI: 0.22716865, 0.75566257; P = 0.0040564; Lactobacillus: OR: 0.6663767; 95% CI: 0.45679511, 0.97211616; P = 0.03513627]. CONCLUSIONS: Our findings offered compelling evidence of a causal association between gut microbiota and cirrhosis in European population and identified specific bacteria taxa that may regulate the genesis and progression of liver fibrosis and cirrhosis, may offer a new direction for the treatment of cirrhosis.

Adherence of PARP inhibitor for frontline maintenance therapy in primary epithelial ovarian cancer: a cross-sectional survey.

OBJECTIVE: To identify the adherence rate to poly (ADP-ribose) polymerase (PARP) inhibitors and identify factors contributing to the deterioration of adherence at our institution. METHODS: The adherence rate to PARP inhibitors was calculated using self-reported Adherence to Refills and Medications Scale questionnaires from a cross-sectional survey. Multivariable logistic regression analysis was performed to identify the factors that affected adherence. RESULTS: Of the 131 respondents, 32 (24.4%) showed non-adherence to PARP inhibitors. In the multivariable logistic regression analysis, unemployed or retired status (odds ratio [OR]=4.878; 95% confidence interval [CI]=1.528-15.572; p=0.008), patients receiving niraparib (OR=3.387; 95% CI=1.283-8.940; p=0.014), and a lower score on the quality-of-life assessment (EORTC-QLQ-OV28), which reflects a better quality of life (QOC) with a lower symptom burden (OR=1.056; 95% CI=1.027-1.086; p<0.001) were associated with high adherence to PARP inhibitors. CONCLUSION: Approximately one-fourth of patients with ovarian cancer are non-adherent to PARP inhibitors as maintenance treatment for newly diagnosed advanced ovarian cancer. The occupational status, type of PARP inhibitor, and QOC may affect adherence to PARP inhibitors.

Eight-year trajectories and predictors of cognitive function in community-dwelling Korean older adults with cardiovascular diseases.

PURPOSE: This study aims to identify longitudinal patterns and predictors of cognitive function trajectories among Korean older adults with cardiovascular diseases. DESIGN: This study is a longitudinal panel analysis based on secondary data. Data from the the Korean Longitudinal Study of Ageing (KLoSA) were used for analysis. METHODS: The KLoSA is a representative panel survey of older Koreans. We analyzed responses from 301 participants aged ≥65 years who completed the same survey more than three times out of five waves between 2012 and 2020. FINDINGS: Latent class growth modeling identified two trajectories of cognitive function in older people with cardiovascular diseases: "low and declining" (n = 81, 26.9%) and "high and declining" (n = 220, 73.1%). Participants in "the low and declining trajectory group" were more likely to have a low educational level, weak handgrip strength, depression, and low social participation at baseline than those in "the high and declining trajectory group." CONCLUSIONS: Our results indicate a need to develop community-based tailored interventions for improving handgrip strength, mental health, and social participation in delaying cognitive decline in older people with cardiovascular diseases considering their educational level. CLINICAL RELEVANCE: Healthcare providers should be more concerned about older people with a weaker handgrip, depression, and low social activities as a high-risk group for cognitive decline over time in cardiovascular care. Therefore, it is necessary to evaluate them early with standardized tools and make subsequent strategies for the older population with cardiovascular diseases.

Activation of Nrf2 by sulfuretin stimulates chondrocyte differentiation and increases bone lengths in zebrafish.

Elongation of most bones occur at the growth plate through endochondral ossification in postnatal mammals. The maturation of chondrocyte is a crucial factor in longitudinal bone growth, which is regulated by a complex network of paracrine and endocrine signaling pathways. Here, we show that a phytochemical sulfuretin can stimulate hypertrophic chondrocyte differentiation in vitro and in vivo. We found that sulfuretin stabilized nuclear factor (erythroid-derived 2)-like 2 (Nrf2), stimulated its transcriptional activity, and induced expression of its target genes. Sulfuretin treatment resulted in an increase in body length of zebrafish larvae and induced the expression of chondrocyte markers. Consistently, a clinically available Nrf2 activator, dimethyl fumarate (DMF), induced the expression of hypertrophic chondrocyte markers and increased the body length of zebrafish. Importantly, we found that chondrocyte gene expression in cell culture and skeletal growth in zebrafish stimulated by sulfuretin were significantly abrogated by Nrf2 depletion, suggesting that such stimulatory effects of sulfuretin were dependent on Nrf2, at least in part. Taken together, these data show that sulfuretin has a potential use as supporting ingredients for enhancing bone growth. [BMB Reports 2023; 56(9): 496-501].

Pathogenicity and Pathological Characteristics of African Swine Fever Virus Strains from Pig Farms in South Korea from 2022 to January 2023.

Since the first African swine fever (ASF) outbreak occurred at a pig farm in South Korea in September 2019, as of 31 January 2023, 31 ASF cases have occurred at pig farms, while 2799 ASF virus (ASFV)-infected wild boars have been identified. The circulation of ASFV in wild boar populations poses a high risk of spillover to pig farms in the country. However, information on the changes in the pathogenicity of Korean ASFV strains from wild boars is not available. Investigating the pathogenicity of ASFV strains from pig farms is the only way to predict their alterations. In a previous study, no changes in the pathogenicity of ASFV strains circulating during 2019-2021 were identified through animal experiments. In this study, we chose two ASFV strains with potentially reduced pathogenicity among ten viruses obtained from pig premises from 2022 to January 2023 and estimated their pathogenicities and pathological characteristics. All the inoculated pigs died 8-10 days post-inoculation after showing pyrexia, depression, anorexia, and recumbency together with the common pathological lesions of enlarged hemorrhagic lymph nodes and splenomegaly with infarction. These results support that the pathogenicity among ASFV isolates in South Korea still remained unchanged during the study period.

Genetic Profile of African Swine Fever Viruses Circulating at Pig Farms in South Korea during the Outbreaks between 2022 and April 2023.

Fifteen pig farms were affected by African swine fever (ASF) in South Korea during the outbreaks between 2022 and April 2023. The ASF virus (ASFV) genome was directly extracted from the blood and tissue samples of 15 ASFV-positive pig farms to analyze the genetic characteristics. Phylogenetic analysis revealed that the 15 strains belonged to p72 genotype II and CD2v serogroup 8, which were the central variable region (CVR) I variants of the B602L gene. Fourteen strains were intergenic region (IGR) II variants, containing an additional tandem repeat sequence (TRS), between I73L and I329R, with the exception of one strain from an ASFV-infected pig farm reported on 22 January 2023, which was an IGR I variant. In addition, a single-nucleotide polymorphism (SNP) was detected at position 107 from the start of the IGR between A179L and A137R in six isolates. The findings of this study suggest that the sources of the virus at the pig farms from which these variants originated differed from those of other pig farms.

SARS-CoV-2 RNAemia and Disease Severity in COVID-19 Patients.

OBJECTIVE: The clinical implications of SARS-CoV-2 RNA viremia in blood (RNAemia) remain uncertain despite gaining more prognostic implications for coronavirus disease 2019 (COVID-19). However, the clinical relevance of SARS-CoV-2 RNAemia has not been well documented. METHODS: We conducted a cohort study on 95 confirmed COVID-19 patients and explored the prospects with evidence of SARS-CoV-2 RNAemia in association with various clinical characteristics. We performed reverse transcription-polymerase chain reaction and studied the risk factors of SARS-CoV-2 RNAemia using logistic regression analysis. RESULTS: The presence of SARS-CoV-2 RNAemia in critical or fatal cases was the highest (66.7%), followed by severe (12.5%) and mild to moderate (1.7%) in admission samples. SARS-CoV-2 viral RNAemia was detected on admission and 1st week samples; however, RNAemia was not detected on the samples collected on the second week post-symptom onset. Multiple regression analysis showed that the severity of the disease was an independent predictor of RNAemia (p < 0.021), and the Kaplan-Meier survival curve estimated an increased mortality rate in SARS-CoV-2 RNAemia cases (p < 0.001). CONCLUSIONS: Our study demonstrated that SARS-CoV-2 RNAemia is a predictive risk factor for clinical severity in COVID-19 patients. Hence, we showed that blood RNAemia might be a critical marker for disease severity and mortality.

Epidemiology of Chronic Inflammatory Demyelinating Polyneuropathy in South Korea: A Population-Based Study.

BACKGROUND AND PURPOSE: We performed a population-based study to determine the prevalence and incidence of chronic inflammatory demyelinating polyneuropathy (CIDP) in South Korea using data from the Korean Health Insurance Review and Assessment Service (HIRA) database. METHODS: Data recorded in the HIRA database between January 2016 and December 2020 were analyzed. The inclusion criteria in this study for patients with CIDP were a diagnostic code of G61.8 in the seventh and eighth revision of the Korean Standard Classification of Disease and a >3-month history of oral immunosuppressant use. The age-adjusted incidence rate and prevalence of CIDP in South Korea were also analyzed. RESULTS: CIDP was newly diagnosed in 953 patients during the study period. The mean age at diagnosis was 58.36 years, and the male-to-female ratio was 1.74. The age-adjusted incidence rates were 0.22, 0.21, 0.23, 0.30, and 0.25 per 100,000 person-years in 2016, 2017, 2018, 2019, and 2020, respectively. The age-adjusted prevalence was estimated at 1.16 per 100,000 persons in 2020. Age and the Elixhauser Comorbidity Index were associated with the in-hospital mortality of patients with CIDP. Infection and cardiovascular disease (CVD) were also significantly associated with the in-hospital mortality of those patients. Acute-onset CIDP was initially diagnosed in an estimated 101 out of 953 patients with CIDP. CONCLUSIONS: The prevalence and incidence rates of CIDP in South Korea were comparable between this nationwide cohort study and previous studies. Common comorbidities such as CVD and diabetes should be appropriately monitored in patients with CIDP to prevent a poor prognosis and socioeconomic burden.

The Gender-Diversity and Autism Questionnaire: A Community-Developed Clinical, Research, and Self-Advocacy Tool for Autistic Transgender and Gender-Diverse Young Adults.

Background: Autistic transgender people face unique risks in society, including inequities in accessing needed care and related mental health disparities. Given the need for specific and culturally responsive accommodations/supports, the characterization of key experiences, challenges, needs, and resilience factors within this population is imperative. This study developed a structured self-report tool for autistic transgender young adults to communicate their experiences and needs in a report format attuned to common autistic thinking and communication styles. Methods: This cross-nation project developed and refined the Gender-Diversity and Autism Questionnaire through an iterative community-based approach using Delphi panel methodology. This proof-of-principle project defined "expertise" broadly, employing a multi-input expert search approach to balance academic-, community-, and lived experience-based expertise. Results: The expert collaborators (N = 24 respondents) completed a two-round Delphi study, which developed 85 mostly closed-ended items based on 90% consensus. Final item content falls within six topic areas: the experience of identities; the impact of experienced or anticipated discrimination, bias, and violence toward autistic people and transgender people; tasks and experiences of everyday life; gender diversity- or autism-related care needs and history; the experience of others doubting an individual's gender identity and/or autism; and the experience of community and connectedness. The majority of retained items relate to tasks and experiences of everyday life or the impact of experienced or anticipated discrimination, bias, and violence. Conclusions: This study employed a multipronged multimodal search approach to maximize equity in representation of the expert measure development team. The resulting instrument, designed for clinical, research, and self-advocacy applications, has parallel Dutch and English versions and is available for immediate use. Future cross-cultural research with this instrument could help identify contextual risk and resilience factors to better understand and address inequities faced by this large intersectional population.

Why is this an important issue?: Transgender and gender-diverse are words used to describe people whose gender varies from their assigned sex at birth. Many autistic people identify as being transgender/gender-diverse. Autistic gender-diverse/transgender young adults often describe difficulties getting the care they need, which can increase their chances of experiencing stress and mental health challenges. This study created a self-report questionnaire for autistic transgender/gender-diverse young adults to share about their health care, support needs, and broader experiences. What were the results of the study?: A diverse group of experts in the autism and gender diversity co-occurrence, including autistic transgender people, worked together to develop the questionnaire. The researchers found experts by searching the internet and talking to people in the community and research field. The questionnaire is called the Gender-Diversity and Autism Questionnaire and has 85 questions that are grouped into 6 different areas: the experience of identities; the impact of experienced or anticipated discrimination, bias, and violence toward autistic people and transgender people; tasks and experiences of everyday life; gender diversity- or autism-related care needs and history; the experience of others doubting an individual's gender identity and/or autism; and the experience of community and connectedness. The questionnaire has English and Dutch versions so it can be used for research in different countries. What do the authors recommend for future research on this topic?: Researchers are currently using the new questionnaire to compare the experiences and needs of autistic transgender young adults in the Netherlands and the United States. The results may help explain why some outcomes are different between autistic transgender young people in the two countries and how culture and society play a role. How will these findings help autistic adults now or in the future?: We created the questionnaire to be used in different settings, including clinics and in research. The questionnaire gives autistic transgender young adults a structured way to communicate their experiences, needs, challenges, and areas of strength. The answers that an autistic transgender young adult gives on the questionnaire could help other people understand the clinical and community supports that the young adult wants and needs. Future studies may use the questionnaire to understand obstacles that autistic transgender young adults may face.

The effects of a 24-week interactive text message-based mobile health intervention for enhancing self-care behaviours of patients with heart failure: A quasi-experimental study.

AIMS: The aim of this study was to identify the effects of a 24-week interactive text message-based mobile health intervention (called) on enhancing the self-care behaviours of patients with heart failure. BACKGROUND: Whether text message-based mobile health intervention can be used to improve long-term adherence to self-care behaviours among heart failure patients remains unclear. DESIGN: A quasi-experimental study with a pretest-post-test design and repeated measures. METHODS: Data from 100 patients (mean age, 58.78 years; 83.0% men) were analysed. The intervention group (n = 50) used the program over 24 weeks, which consisted of weekly goal setting and interactive text messaging, while the control group (n = 50) received usual care. Trained research assistants collected data using self-reported Likert questionnaires. Primary (self-care behaviours) and secondary (health literacy, eHealth literacy, and disease knowledge) outcome variables were measured at baseline and at 1, 3 and 6 months after intervention for follow-up. RESULTS: The findings showed that the intervention group demonstrated significantly better self-care behaviours than the control group during the 6 months. Notably, the trajectory of self-care behaviours of the patients in the intervention group showed a steep rise between the first- and third-month follow-up, followed by high stability between the third- and sixth-month follow-up. In addition, the intervention group had significantly higher disease knowledge than the control group at the first- and sixth-month follow-up. CONCLUSIONS: We found that the program, as an interactive text messaging service, may be an optimal strategy for improving long-term adherence to self-care behaviours through motivating and providing social support. RELEVANCE TO THE NURSING PRACTICE: The WithUs program can help nurses and other healthcare professionals to track patients' health indicators such as symptom severity, diet and physical activity. In addition, nurses can take an important role in evaluating the efficacy of the app in relation to patients' health outcome. PATIENT OR PUBLIC CONTRIBUTION: Patients have completed a self-reported questionnaire after providing informed consent.

MSH2-MSH3 promotes DNA end resection during homologous recombination and blocks polymerase theta-mediated end-joining through interaction with SMARCAD1 and EXO1.

DNA double-strand break (DSB) repair via homologous recombination is initiated by end resection. The extent of DNA end resection determines the choice of the DSB repair pathway. Nucleases for end resection have been extensively studied. However, it is still unclear how the potential DNA structures generated by the initial short resection by MRE11-RAD50-NBS1 are recognized and recruit proteins, such as EXO1, to DSB sites to facilitate long-range resection. We found that the MSH2-MSH3 mismatch repair complex is recruited to DSB sites through interaction with the chromatin remodeling protein SMARCAD1. MSH2-MSH3 facilitates the recruitment of EXO1 for long-range resection and enhances its enzymatic activity. MSH2-MSH3 also inhibits access of POLθ, which promotes polymerase theta-mediated end-joining (TMEJ). Collectively, we present a direct role of MSH2-MSH3 in the initial stages of DSB repair by promoting end resection and influencing the DSB repair pathway by favoring homologous recombination over TMEJ.