A systematic review and meta-analysis of clinical efficacy of early and late rehabilitation interventions for ischemic stroke.

INTRODUCTION: At present, stroke has become the first cause of death and disability among Chinese adults. With the coming of the aging population in China, the disease burden brought by stroke will be increasingly aggravated. And stroke is a leading cause of disability. There is a golden plastic period after stroke, during which timely and safe intervention and rehabilitation therapy can effectively improve the disability status. However, there is still controversy about the duration of interventional rehabilitation after stroke. This study conducted a meta-analysis on the influence of intervention in early and late ischemic stroke rehabilitation. METHOD: Chinese language databases such as CNKI, Wanfang, and VIP, and English language databases such as Embase, PubMed, Web of Science, and The Cochrane Library were searched, and RCT related to early and late rehabilitation of ischemic stroke from the establishment of the database to October 2023 was collected. Review Manager 5.4.1 was used for relevant analysis. The main outcomes were Barthel Index or Modified Barthel Index, Fugl-Meyer Assessment scale, NIHSS, China Stroke Scale. Standardized Mean Difference (SMD) was used as an effective indicator of continuity variables, and the estimated interval was expressed by 95% confidence interval (CI). RESULTS: A total of 1908 patients were included in 16 studies. The results showed that, compared with late rehabilitation, early rehabilitation improved clinical efficacy. Barthel Index or Modified Barthel Index score was [SMD = 1.40, 95%CI(1.16,1.63), p < 0.001]; the score of Fugl-Meyer Assessment Scale was [SMD = 1.18, 95%Cl (0.85, 1.52), P < 0.001]; the score of NIHSS was [SMD= -0.44, 95% CI(-0.65, -0.24), P < 0.001]; the result of China Stroke Scale score was [SMD= -0.37, 95%CI(-0.56, -0.18), P < 0.001]. CONCLUSION: In comparison with late rehabilitation, early rehabilitation can significantly improve self-care abilities, daily activities, and neurological functions of ischemic stroke patients. TRIAL REGISTRATION: This meta-analysis has been registered with Prospero, and the registration number is CRD42022309911. The registration period is March 22, 2022.

Sexual Minority Identity and Risky Alcohol Use: the Moderating Role of Aggressive Behavior.

Adolescent alcohol use has significant consequences for concurrent and longitudinal health and wellbeing, with sexual minority youth consistently reporting higher levels of alcohol use than their heterosexual peers. Understanding how individual-difference variables like aggressive behavior are associated with variability in sexual minority adolescents' higher levels of alcohol use offers novel theoretical insight into this vulnerability. The 81,509 participants were drawn from the Profiles of Student life: Attitudes and Behavior Study. They were ages 14-17 years (M = 15.38, SD = 1.09) and 50.1% were cisgender girls. For sexual identity, 88% were heterosexual, 5% were mostly heterosexual, were 4% bisexual, were 1% mostly gay or lesbian, and were 1% being gay or lesbian. Participants reported on alcohol use, aggressive behavior, and sexual identity. Gay/lesbian and mostly gay/lesbian adolescents who reported higher aggressive behavior had higher levels of alcohol use than their heterosexual peers who also reported higher aggressive behavior. The way in which aggressive behavior amplified the link between mostly gay/lesbian and gay/lesbian identities and alcohol use suggests the need for more research examining how this trait may heighten both exposure and reaction to minority stressors among some subgroups of sexual minority youth.

HOGA1 variants in Chinese patients with primary hyperoxaluria type 3: genetic features and genotype-phenotype relationships.

PURPOSE: The aim of our study is to describe the genetic features and correlation between the genotype and phenotype of Chinese patients with primary hyperoxaluria type 3 (PH3). METHODS: The genetic and clinical data of PH3 patients in our cohort were collected and analyzed retrospectively. All published studies of Chinese PH3 populations between January 2010 and November 2022 were searched and enrolled based on inclusive standards. RESULTS: A total of 60 Chinese PH3 patients (21 cases from our cohort and 39 cases from previous studies) were included. The mean age of onset was 1.62 ± 1.35 (range 0.4-7) years. A total of 29 different variants in the HOGA1 gene were found. The mutations were most commonly clustered in exons 1, 6, and 7. Among the genotypes, exon 6 skipping (c.834G > A and c.834_834 + 1GG > TT mutations) was the most common, followed by c.769 T > G; the allele frequencies (AFs) were 48.76% and 12.40%, respectively. Patients homozygous for exon 6 skipping exhibited a median age of onset of 0.67 (0.58-1) years, which was significantly lower than that observed among heterozygotes and nonexon 6 skipping patients (p = 0.021). A total of 22.5% (9/40) of PH3 patients had a decreased estimated glomerular filtration rate, and one patient with homozygous exon 6 skipping developed end-stage renal disease. CONCLUSIONS: A hotspot mutation, potential hotspot mutation and genotype-phenotype correlation were found in Chinese PH3 patients. This study expands the mutational spectrum and contributes to the understanding of genotypic profiles of PH3, which may provide a potential diagnostic and therapeutic target.

Identification of mutations in 15 nephrolithiasis-related genes leading to a molecular diagnosis in 85 Chinese pediatric patients.

BACKGROUND: The aim of this study was to describe the genotypic and phenotypic characteristics of Chinese pediatric patients with hereditary nephrolithiasis. METHODS: Whole-exome sequencing (WES) was performed on 218 Chinese pediatric patients with kidney stones, and genetic and clinical data were collected and analyzed retrospectively. RESULTS: The median age at onset in our cohort was 2.5 years (age range, 0.3-13 years). We detected 79 causative mutations in 15 genes, leading to a molecular diagnosis in 38.99% (85/218) of all cases. Monogenic mutations were present in 80 cases, and digenic mutations were present in 5 cases; 34.18% (27/79) of mutations were not included in the databases. Six common mutant genes, i.e., HOGA1, AGXT, GRHPR, SLC3A1, SLC7A9, and SLC4A1, were found in 84.71% of the patients overall. Furthermore, three mutations (A278A, c.834_834 + 1GG > TT, and C257G) in HOGA1, two mutations (K12QfX156 and S275RfX28) in AGXT, and one mutation (C289DfX22) in GRHPR represented hotspot mutations. The patients with HOGA1 mutations had the earliest onset age (0.8 years), followed by those with SLC7A9 (1.8 years), SLC4A1 (2.7 years), AGXT (4.3 years), SLC3A1 (4.8 years), and GRHPR (8 years) mutations (p = 0.002). Nephrocalcinosis was most commonly observed in patients with AGXT gene mutations. CONCLUSIONS: Fifteen causative genes were detected in 85 Chinese pediatric patients with kidney stone diseases. The most common mutant genes, novel mutations, hotspot mutations, and genotype-phenotype correlations were also found. This study contributes to the understanding of genetic profiles and clinical courses in pediatric patients with hereditary nephrolithiasis. A higher resolution version of the Graphical abstract is available as Supplementary information.

Profiles of identity and discrimination and the psychological, health, and academic outcomes of Korean ethnic minority youth in China.

Korean Chinese is one of the 55 officially recognized ethnic minorities in China. The protective effects of strong bicultural (ethnic and national) identities and the detrimental effects of ethnic discrimination on adjustment outcomes are well documented for ethnic minority youth in W.E.I.R.D. societies. Yet, ethnic minority youth in non-W.E.I.R.D. societies, such as Korean Chinese, may experience a unique form of discrimination-national discrimination. It is not known how multiple social identities and experiences of dual discrimination may intersect to predict youth adjustment. Thus, this study explored profiles of ethnic and national identities and ethnic and national discrimination among Korean Chinese youth and examined their psychological, health, and academic adjustment. The analytic sample included 267 Korean Chinese youth aged from 12 to 18 (M = 15.21, SD = 1.65) residing in Northeast China. Three latent profiles were identified. The dominant profile of Korean Chinese youth was characterized by high bicultural identity and low ethnic and national discrimination (BILD; n = 171). The second profile was characterized by high bicultural identity and high national discrimination (BIND, n = 50). The third profile was characterized by moderate ethnic and national identities and moderate ethnic and national discrimination (MIMD, n = 46). Regression analyses found that the BILD profile showed fewer depressive symptoms compared to the BIND profile and showed better perceived physical health compared to the MIMD profile. The findings highlight strong bicultural identities as a cultural asset and discrimination-particularly national discrimination-as a contextual risk to Korean Chinese adolescents' well-being.

Racial-ethnic socialization, racial discrimination, and internalization of the model minority myth in East Asian families.

Guided by the integrative model, this study investigated the moderating effect of East Asian American youth-reported (N = 143) racial-ethnic socialization (RES) in the relationship between the youth's experiences of discrimination and internalization of the model minority myth. The results suggest that there was a significant interaction between youth's racial discrimination and youth-reported awareness of discrimination on youth's internalization of the model minority myth (b = 3.52, p < .05). No significant interaction effect emerged between racial discrimination and maintenance of heritage culture on internalization of model minority myth. The findings offer several contributions to inform research, family, and communities in understanding the ways caregivers respond to youth's racialized settings, which also contribute to youth's positive outcomes.

Development of a nonauxotrophic L-homoserine hyperproducer in Escherichia coli by systems metabolic engineering.

L-Homoserine is a valuable amino acid as a platform chemical in the synthesis of various important compounds. Development of microbial strains for high-level L-homoserine production is an attractive research direction in recent years. Herein, we converted a wild-type Escherichia coli to a non-auxotrophic and plasmid-free hyperproducer of L-homoserine using systematically metabolic engineer strategies. First, an initial strain was obtained through regulating L-homoserine degradation pathway and enhancing synthetic flow. To facilitate L-homoserine production, flux-control genes were tuned by optimizing the copy numbers in chromosome, and transport system was modified to promote L-homoserine efflux. Subsequently, a strategy of cofactors synergistic utilization was proposed and successfully applied to achieve L-homoserine hyperproduction. The final engineered strain could efficiently produce 85.29 g/L L-homoserine, which was the highest production level ever reported from a plasmid-free, antibiotic-free, inducer-free and nonauxotrophic strain. These strategies used here can be considered for developing microbial cell factory of other L-aspartate derivatives.

Sexual orientation disclosure to classmates among Latinx sexual minority high school and college youth.

This study examined how minority stressors mediate the association between sexual orientation disclosure to classmates and well-being in a sample of 238 Latinx sexual minority youth (SMY; age range: 14-24 years). Results indicated that sexual orientation disclosure to classmates was associated with higher levels of sexual orientation-based victimization, which contributed to higher levels of internalized homonegativity, which ultimately contributed to higher levels of depressive symptoms and lower self-esteem. Sexual orientation-based victimization and internalized homonegativity were positively associated with depressive symptoms and negatively associated with self-esteem but sexual orientation disclosure to classmates was only positively associated with depressive symptoms. Associations between sexual orientation-based victimization and internalized homonegativity were stronger among college Latinx SMY compared to SMY in high school.

Mesenchymal stem cells protect neurons against hypoxic-ischemic injury via inhibiting parthanatos, necroptosis, and apoptosis, but not autophagy.

Cellular therapy with mesenchymal stem cells (MSCs) protects cortical neurons against hypoxic-ischemic injury of stroke. Although sorts of efforts have been made to confirm the neuroprotective effect of MSCs on neurons against hypoxic-ischemic injury, the mechanism is until now far away from clear. Here in this study, oxygen-glucose deprivation (OGD)-injured neuron model was applied to mimic the neuronal hypoxic-ischemic injury in vitro. Co-culturing with MSCs in a transwell co-culture system, the OGD injured neurons were rescued by 75.0 %. Further data demonstrated that co-culturing with MSCs protected the cortical neurons from the OGD-induced parthanatos by alleviating apoptosis-inducing factor (AIF) nuclear translocation; attenuated the neuronal necroptosis by down-regulating the expression of the two essential kinases in necroptosis, receptor interacting protein kinase1 (RIP1) and 3 (RIP3); rescued the neurons from apoptosis by deactivating caspase-3; whilst performed no significant influence on OGD-induced neuronal autophagy, according to its failed regulation on Beclin1. In conclusion, MSCs potentially protect the cortical neurons from OGD-injury in vitro, through rescuing neurons from the cell death of parthanatos, necroptosis, and apoptosis, but not autophagy, which could provide some evidence to the mechanism explanation on stem cell treatment for ischemic stroke.

Sexual Orientation-Based Victimization and Internalized Homonegativity Among Latinx Sexual Minority Youth: The Moderating Effects of Social Support and School Level.

Latinx sexual minority adolescents and young adults experience sexual orientation-based victimization at school and may internalize these heterosexist experiences. However, social support may buffer the deleterious contributions of sexual orientation-based victimization. The current study explored associations between sexual orientation-based victimization and internalized homonegativity in different social contexts (family, peer, school adult) and across development (high school versus college) among 238 Latinx sexual minority adolescents and young adults (M = 19.03, SD = 2.28). Results indicated that sexual orientation-based victimization was positively associated with internalized homonegativity among Latinx sexual minority adolescents and young adults. Such associations were moderated by family support and the school level in the family context, such that in high school, family support exacerbated the association between sexual orientation-based victimization and internalized homonegativity. Yet, in college, family support mitigated that association. Findings also indicated that peer support exacerbated the association between sexual orientation-based victimization and internalized homonegativity in high school and college. No moderation of school adult support emerged in the context of school adults. Findings support the application of the minority stress model in Latinx sexual minority adolescents and young adults and highlight the complex moderating effect of social support across social contexts and development.

Ethnic/Racial Identity, Adolescent Sleep, and Somatic Health: Discrimination and Stress Responses as Mediating Mechanisms.

PURPOSE: This study sought to examine whether the daily associations between ethnic/racial discrimination and stress responses served as mediators linking ethnic/racial identity (ERI), adolescent sleep health, and somatic symptoms. METHODS: Data were drawn from 279 adolescents of color (69% female; 24% African Americans; 31% Asian Americans; 41% Latinx; and 4% unknown ethnicity/race; Mage = 14.31 years, SD = 0.65). Adolescents first completed an online survey about ERI exploration and commitment; and then 14-day diaries on ethnic/racial discrimination and stress responses (i.e., rumination and problem-solving coping), and finally, a post-diary survey about sleep and somatic health over the past two weeks. This study adopts slope-as-mediator mediation modeling, a novel approach highlighting the role of daily-level experiences in developmental processes by examining the day-to-day association between two variables as an explanatory mechanism. RESULTS: The daily associations between ethnic/racial discrimination and two stress responses significantly mediated the link between ERI exploration and adolescents' subsequent sleep and somatic health. For ERI commitment, only the mediating pathway of the association between ethnic/racial discrimination and problem-solving coping was significant. DISCUSSION: Daily responses to ethnic/racial discrimination, both adaptively and maladaptively, could in part explain the association between ERI exploration and adolescent health. Active participation in cultural activities may increase adaptive responses to ethnic/racial discrimination; meanwhile, uncertainty about ERI may lead to maladaptive reactions such as rumination. For ERI commitment, only problem-solving coping with ethnic/racial discrimination mediated the links to health outcomes, an observation possibly explained by the benefits of holding a strong sense of commitment to ERI.

Safety and efficacy of tirofiban treatment in the endovascular treatment of patients with acute ischaemic stroke - A meta-analysis.

OBJECT: The use of endovascular therapy (EVT) has become a widespread strategy for the clinical management of acute ischemic stroke (AIS). However, the combination of arterial injection of tirofiban with EVT for AIS continues to be a subject of controversy. This meta-analysis was conducted to assess the safety and efficacy of this treatment approach. METHODS: Relevant studies were identified through a systematic literature search in Pubmed, EMBASE, Web of Science, and Cochrane Library databases, covering articles published from January 2010 to January 2023. The efficacy outcomes included favorable functional outcomes, recanalization rates, and safety outcomes including mortality and symptomatic intracranial hemorrhage (sICH). RESULTS: The meta-analysis consisted of data from 13 studies, which included 1 randomized controlled trial (RCT), 7 prospective cohort studies, and 5 retrospective cohort studies, encompassing a total of 3477 patients. The study results indicate that the intra-arterial (IA) tirofiban+EVT for AIS is associated with significant improvements in favorable functional outcomes (OR, 1.21; 95%CI, 1.05-1.40; P = 0.009) and recanalization rate (OR, 1.33; 95%CI, 1.06-1.65; P = 0.01), as well as significant reductions in mortality rates (OR, 0.65; 95%CI, 0.53-0.79; P = 0.0001). Subgroup analysis revealed that administering a maintenance dose of intravenous (IV) tirofiban post-EVT was significantly associated with improved functional outcomes and reduced mortality in patients. In addition, there was no increase in the incidence of sICH (OR, 0.92; 95%CI, 0.71-1.20; P = 0.54). CONCLUSION: The administration of Intra-arterial tirofiban combined with EVT is an effective and safe treatment strategy for AIS, and postoperative maintenance doses of intravenous tirofiban may be more effective than IA only.

Two novel heterozygous ADCY10 variants identified in Chinese pediatric patients with absorptive hypercalciuria: case report and literature review.

Absorptive hypercalciuria (AH) is a prevalent cause of kidney stones, and the adenylate cyclase 10 (ADCY10) gene is a rare causative gene of AH. This study aims to investigate the genotypic and phenotypic characteristics of patients with AH caused by ADCY10 gene mutations. Whole-exome sequencing and Sanger sequencing were performed on the probands and their family members, respectively. Clinical and genetic data of patients with AH caused by ADCY10 gene mutations were collected and analysed retrospectively from the present study and published literature. Two female patients (6 years old and 1 year old) with multiple bilateral kidney stones were found to have a heterozygous c.3304T>C mutation and a heterozygous c.1726C>T mutation in the ADCY10 gene. Urinary metabolite analysis revealed that urine calcium / creatinine ratios were 0.95 mmol/mmol and 1.61 mmol/mmol, respectively. Both patients underwent thiazide intake postoperatively, and upon reexamination, urine calcium decreased to within the normal range. A total of 61 patients with AH were reported from previous and present studies. The sex ratio was 7:5 for males to females, and the mean age of onset was 23.61±20.08 years. A total of 16 ADCY10 gene mutations were identified, including seven missense (43.75%), five splicing (31.25%), two frameshift (12.50%) and two nonsense mutations (12.50%). Only two cases were identified as homozygous mutations (c.1205_1206del), and the others were heterozygous mutations. In summary, we identified two novel ADCY10 gene candidate pathogenic variants in Chinese pediatric patients, which expands the mutational spectrum of the ADCY10 gene and provides a potential diagnostic and therapeutic target.

Clinical features and mutational spectrum of Chinese patients with primary hyperoxaluria type 2.

Primary hyperoxaluria type 2 (PH2) is a rare hereditary disease that causes nephrolithiasis, nephrocalcinosis and kidney failure. This study aimed to investigate the clinical features and mutational spectrum of Chinese patients with PH2. A retrospective cohort study was performed on PH2 patients admitted to our center over seven years. We also systematically reviewed all the articles on Chinese PH2 patients published from January 2000 to May 2023 and conducted a meta-analysis. A total of 25 PH2 patients (10 from our center and 15 from published studies) were included in this study. The median age of onset in patients from our center was 8.50 (1.00, 24.00) years, and 50% were male. Among the full cohort of 25 Chinese patients, the median age of onset was 8.00 (0.40, 26.00) years, and 64% of them were male. Seven patients progressed to end-stage kidney disease, with a median age of 27.50 (12, 31) years. The cumulative renal survival rates were 100%, 91.67%, 45.83% and 30.56% at 10, 20, 30 and 40 years of age, respectively. A total of 18 different variants were identified, and c.864_865del was the dominant variant, accounting for 57.69% of the total alleles. Patients who were heterozygous for c.864_865del were more susceptible to nephrocalcinosis than those who were homozygous for c.864_865del and those harboring other mutations (83.33% versus 33.3% and 0%, respectively) (p = 0.025). The clinical features and mutational spectrum of Chinese PH2 patients were described. This study helps to expand awareness of the phenotypes and genotypes of Chinese PH2 patients and contributes to the improvement of diagnostic and treatment strategies for PH2 patients.

Engineering serine hydroxymethyltransferases for efficient synthesis of L-serine in Escherichia coli.

L-serine is a high-value amino acid widely used in the food, medicine, and cosmetic industries. However, the low yield of L-serine has limited its industrial production. In this study, a cellular factory for efficient synthesis of L-serine was obtained by engineering the serine hydroxymethyltransferases (SHMT). Firstly, after screening the SHMT from Alcanivorax dieselolei by genome mining, a mutant AdSHMTE266M with high thermal stability was identified through rational design. Subsequently, an iterative saturating mutant library was constructed by using coevolutionary analysis, and a mutant AdSHMTE160L/E193Q with enzyme activity 1.35 times higher than AdSHMT was identified. Additionally, the target protein AdSHMTE160L/E193Q/E266M was efficiently overexpressed by improving its mRNA stability. Finally, combining the substrate addition strategy and system optimization, the optimized strain BL21/pET28a-AdSHMTE160L/E193Q/E266M-5'UTR-REP3S16 produced 106.06 g/L L-serine, which is the highest production to date. This study provides new ideas and insights for the engineering design of SHMT and the industrial production of L-serine.

Everyday Discrimination and Sleep Among Migrant and Non-migrant Filipinos: Longitudinal Analyses from the Health of Philippine Emigrants Study (HoPES).

This study aimed to (1) identify differences in sleep patterns between Filipino migrants and non-migrants across 2 years and (2) explore the impact of discrimination trajectories on sleep trajectories. The Health of Philippine Emigrants Study (HoPES) consisted of a migrant (n = 832) and non-migrant cohort (n = 805), with baseline data collected in the Philippines. Both cohorts were followed longitudinally, with the non-migrants followed in the Philippines and the migrant cohort followed to the United States. Sleep duration, quality, and difficulty were assessed with the National Institutes of Health Patient-Reported Outcomes Information System (PROMIS) inventory, and discrimination was measured with an adapted version of the Everyday Discrimination scale. Migrants reported a faster decline in sleep duration (- 12 min a year) but higher sleep quality than non-migrants over 2 years. Migrants who reported high initial levels of everyday discrimination also reported faster declines in sleep duration and a slower decline in sleep difficulty. Further, migrants who reported stable (versus declining) levels of discrimination over 2 years reported a faster decline in sleep quality. These results speak to the complexity of immigrant health patterns and long-term associations between discrimination and sleep processes.

Sodium butyrate activates the KATP channels to regulate the mechanism of Parkinson's disease microglia model inflammation.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder. Microglia-mediated neuroinflammation has emerged as an involving mechanism at the initiation and development of PD. Activation of adenosine triphosphate (ATP)-sensitive potassium (KATP ) channels can protect dopaminergic neurons from damage. Sodium butyrate (NaB) shows anti-inflammatory and neuroprotective effects in some animal models of brain injury and regulates the KATP channels in islet ß cells. In this study, we aimed to verify the anti-inflammatory effect of NaB on PD and further explored potential molecular mechanisms. METHODS: We established an in vitro PD model in BV2 cells using 1-methyl-4-phenylpyridinium (MPP+ ). The effects of MPP+ and NaB on BV2 cell viability were detected by cell counting kit-8 assays. The morphology of BV2 cells with or without MPP+ treatment was imaged via an optical microscope. The expression of Iba-1 was examined by the immunofluorescence staining. The intracellular ATP content was estimated through the colorimetric method, and Griess assay was conducted to measure the nitric oxide production. The expression levels of pro-inflammatory cytokines and KATP channel subunits were evaluated by reverse transcription-quantitative polymerase chain reaction and western blot analysis. RESULTS: NaB (5 mM) activated the KATP channels through elevating Kir6.1 and Kir6.1 expression in MPP+ -challenged BV2 cells. Both NaB and pinacidil (a KATP opener) suppressed the MPP+ -induced activation of BV2 cells and reduced the production of nitrite and pro-inflammatory cytokines in MPP+ -challenged BV2 cells. CONCLUSION: NaB treatment alleviates the MPP+ -induced inflammatory responses in microglia via activation of KATP channels.

Racial-Ethnic Discrimination and Early Adolescents' Behavioral Problems: The Protective Role of Parental Warmth.

OBJECTIVE: The purpose of the study was to investigate the association between discrimination by multiple sources (ie, teachers, students, and other adults) and early adolescents' behavioral problems (ie, internalizing, externalizing, and attention problems), also considering the protective role of parental warmth in the association. METHOD: Cross-sectional analyses were conducted with 3,245 early adolescents of color obtained from the Adolescent Brain Cognitive Development Study (ABCD Study) at year 1 follow-up (Y1), a large and diverse sample of children (mean age = 9.48 years) in the United States. Racially-ethnically minoritized adolescents reported sources of discrimination, parental warmth, and symptoms of psychopathology. Regression with interaction terms was conducted to investigate the associations among sources of discrimination, parental warmth, and behavioral problems among racially-ethnically minority adolescents. Sensitivity analyses were conducted to examine (1) race/ethnicity and sex/gender variations; (2) whether the associations between different sources of discrimination and behavioral problems were reliably different; and (3) effects of discrimination, parental warmth, and their interplay at Y1 in predicting adolescents' behavioral problems at year 2 follow-up. RESULTS: Early adolescents experiencing interpersonal racial-ethnic discrimination by multiple sources, including teachers, students, and other adults, reported higher levels of attention, internalizing, and externalizing problems. Parental warmth was protective for the association between interpersonal racial-ethnic discrimination and early adolescents' behavioral problems. CONCLUSION: Experiencing interpersonal racial-ethnic discrimination from teachers, peers, and other adults is related to heightened attention, internalizing, and externalizing problems among racially-ethnically minoritized early adolescents. Parental warmth may reduce the risk of developing behavioral problems among early adolescents who experience interpersonal racial-ethnic discrimination from students, teachers, and other adults outside of school. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. We actively worked to promote sex and gender balance in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list.

GPR124 induces NLRP3 inflammasome-mediated pyroptosis in endothelial cells during ischemic injury.

OBJECTIVE: G protein-coupled receptor 124 (GPR124) regulates central nervous system angiogenesis and blood-brain barrier (BBB) integrity, and its deficiency aggravates BBB breakdown and hemorrhagic transformation in ischemic mice. However, excessive GPR124 expression promotes inflammation in atherosclerotic mice. In this study, we aimed to elucidate the role of GPR124 in hypoxia/ischemia-induced cerebrovascular endothelial cell injury. METHODS: bEnd.3 cells were exposed to oxygen-glucose deprivation (OGD), and time-dependent changes in GPR124 mRNA and protein expression were evaluated using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The effects of GPR124 overexpression or knockdown on the expression of pyroptosis-related genes were assessed at the mRNA and protein levels. Tadehaginoside (TA) was screened as a potential small molecule targeting GPR124, and its effects on pyroptosis-related signaling pathways were investigated. Finally, the therapeutic efficacy of TA was evaluated using a rat model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R). RESULTS: During OGD, the expression of GPR124 initially increased and then decreased over time, with the highest levels observed 1 h after OGD. The overexpression of GPR124 enhanced the OGD-induced expression of NLRP3, Caspase-1, and Gasdermin D (GSDMD) in bEnd.3 cells, whereas GPR124 knockdown reduced pyroptosis. Additionally, TA exhibited a high targeting ability to GPR124, significantly inhibiting its function and expression and suppressing the expression of pyroptosis-related proteins during OGD. Furthermore, TA treatment significantly reduced the cerebral infarct volume and pyroptotic signaling in tMCAO/R rats. CONCLUSIONS: Our findings suggest that GPR124 mediates pyroptotic signaling in endothelial cells during the early stages of hypoxia/ischemia, thereby exacerbating ischemic injury.

Multiple Discrimination and Substance Use Intention in Late Childhood: Findings From the Adolescent Brain Cognitive Development (ABCD) Study.

PURPOSE: The study aimed to investigate longitudinal, bidirectional associations between discrimination due to multiple reasons (race/ethnicity, sexual orientation, weight; termed multiple discrimination) and substance use (SU) intention in late childhood. These associations were compared across youth with no, single, and multiple (i.e., intersecting) marginalized identities based on race/ethnicity, sexual orientation, and overweight status. METHODS: Data were drawn from a national sample of youth in the Adolescent Brain Cognitive Development study (N = 8,530; 9-12 years old). Youth reported both their experiences of multiple discrimination (the number of forms of discrimination youth experienced) and SU intention at one-year and two-year follow-ups. Theoretically relevant covariates were included. RESULTS: Compared to non-marginalized youth (n = 2,689) and youth with single marginalized identities (n = 3,399), youth with intersecting marginalized identities (n = 2,442) reported the highest SU intention and multiple discrimination across waves. Only for this last group, multiple discrimination predicted stronger SU intention subsequently (ß = 0.07, 95% confidence interval [0.02, 0.11]), whereas stronger SU intention predicted lower levels of multiple discrimination over time (ß = -0.06, 95% confidence interval [-0.09, -0.02]). Sensitivity analyses yielded similar patterns with some nuances among subgroups of youth with varying intersecting marginalized identities. DISCUSSION: Multiple discrimination predicted stronger SU intention over time in late childhood, particularly among youth with intersecting marginalized identities. Policies and practices should consider addressing multiple discrimination to reduce SU disparities among diverse youth.