Hippocampal excitation-inhibition balance underlies the 5-HT2C receptor in modulating depressive behaviours.

The implication of 5-hydroxytryptamine 2C receptor (5-HT2CR) in depression is a topic of debate, and the underlying mechanisms remain largely unclear. We now elucidate hippocampal excitation-inhibition (E/I) balance underlies the regulatory effects of 5-HT2CR in depression. Molecular biological analyses showed that chronic mild stress (CMS) reduced the expression of 5-HT2CR in hippocampus. We revealed that inhibition of 5-HT2CR induced depressive-like behaviors, reduced GABA release and shifted the E/I balance towards excitation in CA3 pyramidal neurons by using behavioral analyses, microdialysis coupled with mass spectrum, and electrophysiological recording. Moreover, 5-HT2CR modulated neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction through influencing intracellular Ca2+ release, as determined by fiber photometry and coimmunoprecipitation. Notably, disruption of nNOS-CAPON by specific small molecule compound ZLc-002 or AAV-CMV-CAPON-125C-GFP, abolished 5-HT2CR inhibition-induced depressive-like behaviors, as well as the impairment in soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly-mediated GABA vesicle release and a consequent E/I imbalance. Importantly, optogenetic inhibition of CA3 GABAergic neurons prevented the effects of AAV-CMV-CAPON-125C-GFP on depressive behaviors in the presence of 5-HT2CR antagonist. Conclusively, our findings disclose the regulatory role of 5-HT2CR in depressive-like behaviors and highlight the hippocampal nNOS-CAPON coupling-triggered E/I imbalance as a pivotal cellular event underpinning the behavioral consequences of 5-HT2CR inhibition.

Droplet Hi-C for Fast and Scalable Profiling of Chromatin Architecture in Single Cells.

Comprehensive analysis of chromatin architecture is crucial for understanding the gene regulatory programs during development and in disease pathogenesis, yet current methods often inadequately address the unique challenges presented by analysis of heterogeneous tissue samples. Here, we introduce Droplet Hi-C, which employs a commercial microfluidic device for high-throughput, single-cell chromatin conformation profiling in droplets. Using Droplet Hi-C, we mapped the chromatin architecture at single-cell resolution from the mouse cortex and analyzed gene regulatory programs in major cortical cell types. Additionally, we used this technique to detect copy number variation (CNV), structural variations (SVs) and extrachromosomal DNA (ecDNA) in cancer cells, revealing clonal dynamics and other oncogenic events during treatment. We further refined this technique to allow for joint profiling of chromatin architecture and transcriptome in single cells, facilitating a more comprehensive exploration of the links between chromatin architecture and gene expression in both normal tissues and tumors. Thus, Droplet Hi-C not only addresses critical gaps in chromatin analysis of heterogeneous tissues but also emerges as a versatile tool enhancing our understanding of gene regulation in health and disease.

Individualism, collectivism and conformity in nine countries: Relations with parenting and child adjustment.

This study investigated how individualism, collectivism and conformity are associated with parenting and child adjustment in 1297 families with 10-year-old children from 13 cultural groups in nine countries. With multilevel models disaggregating between- and within-culture effects, we examined between- and within-culture associations between maternal and paternal cultural values, parenting dimensions and children's adjustment. Mothers from cultures endorsing higher collectivism and fathers from cultures endorsing lower individualism engage more frequently in warm parenting behaviours. Mothers and fathers with higher-than-average collectivism in their culture reported higher parent warmth and expectations for children's family obligations. Mothers with higher-than-average collectivism in their cultures more frequently reported warm parenting and fewer externalising problems in children, whereas mothers with higher-than-average individualism in their culture reported more child adjustment problems. Mothers with higher-than-average conformity values in their culture reported more father-displays of warmth and greater mother-reported expectations for children's family obligations. Fathers with higher-than-average individualism in their culture reported setting more rules and soliciting more knowledge about their children's whereabouts. Fathers who endorsed higher-than-average conformity in their culture displayed more warmth and expectations for children's family obligations and granted them more autonomy. Being connected to an interdependent, cohesive group appears to relate to parenting and children's adjustment.

The impacts of early environmental adversity on cognitive functioning, body mass, and life-history behavioral profiles.

Early adverse experiences or exposures have a profound impact on neurophysiological, cognitive, and somatic development. Evidence across disciplines uncovers adversity-induced alternations in cortical structures, cognitive functions, and related behavioral manifestations, as well as an energetic trade-off between the brain and body. Based on the life history (LH) framework, the present research aims to explore the adversity-adapted cognitive-behavioral mechanism and investigate the relation between cognitive functioning and somatic energy reserve (i.e., body mass index; BMI). A structural equation modeling (SEM) analysis was performed with longitudinal self-reported, anthropometric, and task-based data drawn from a cohort of 2,607 8- to 11-year-old youths and their primary caregivers recruited by the Adolescent Brain Cognitive Development (ABCDSM) study. The results showed that early environmental adversity was positively associated with fast LH behavioral profiles and negatively with cognitive functioning. Moreover, cognitive functioning mediated the relationship between adversity and fast LH behavioral profiles. Additionally, we found that early environmental adversity positively predicted BMI, which was inversely correlated with cognitive functioning. These results revealed an adversity-adapted cognitive-behavioral mechanism and energy-allocation pathways, and add to the existing knowledge of LH trade-off and developmental plasticity.

The severity assessment of Parkinson's disease based on plasma inflammatory factors and third ventricle width by transcranial sonography.

BACKGROUND: Predicting Parkinson's disease (PD) can provide patients with targeted therapies. However, disease severity can be roughly evaluated in clinical practice based on the patient's symptoms and signs. OBJECTIVE: The current study attempted to explore the factors linked with PD severity and construct a predictive model. METHOD: The PD patients and healthy controls were recruited from our study center while recording their basic demographic information. The serum inflammatory markers levels, such as Cystatin C (Cys C), C-reactive protein (CRP), RANTES (regulated on activation, normal T cell expressed and secreted), Interleukin-10 (IL-10), and Interleukin-6 (IL-6) were determined for all the participants. PD patients were categorized into early and mid-advanced groups based on the Hoehn and Yahr (H-Y) scale and evaluated using PD-related scales. LASSO logistic regression analysis (Model C) helped select variables based on clinical scale evaluations, serum inflammatory factor levels, and transcranial sonography measurements. The optimal harmonious model coefficient λ was determined via 10-fold cross-validation. Moreover, Model C was compared with multivariate (Model A) and stepwise (Model B) logistic regression. The area under the curve (AUC) of a receiver operator characteristic (ROC), brier score, calibration curve, and decision curve analysis (DCA) helped determine the discrimination and calibration of the predictive model, followed by configuring a forest plot and column chart. RESULTS: The study included 113 healthy individuals and 102 PD patients, with 26 early and 76 mid-advanced patients. Univariate analysis of variance screened out statistically significant differences among inflammatory markers Cys C and RANTES. The average Cys C level in the mid-advanced stage was significantly higher than in the early stage (p < 0.001) but not for RANTES (p = 0.740). The LASSO logistic regression model (λ.1se = 0.061) associated with UPDRS-I, UPDRS-II, UPDRS-III, HAMA, PDQ-39, and Cys C as the included independent variables revealed that the Model C discrimination and calibration (AUC = 0.968, Brier = 0.049) were superior to Model A (AUC = 0.926, Brier = 0.079) and Model B (AUC = 0.929, Brier = 0.071) models. CONCLUSION: The study results show multiple factors are linked with PD assessment. Moreover, the inflammatory marker Cys C and transcranial sonography measurement could objectively predict PD symptom severity, helping doctors monitor PD evolution in patients while targeting interventions.

1-Pyrroline-5-carboxylate inhibit T cell glycolysis in prostate cancer microenvironment by SHP1/PKM2/LDHB axis.

BACKGROUND: Our previous studies demonstrated that 1-Pyrroline-5-carboxylate (P5C) released by prostate cancer cells inhibits T cell proliferation and function by increasing SHP1 expression. We designed this study to further explore the influence of P5C on T cell metabolism, and produced an antibody for targeting P5C to restore the functions of T cells. METHOD: We co-immunoprecipated SHP1 from T cells and analyzed the proteins that were bound to it using liquid chromatography mass spectrometry (LC/MS-MS). The influence of P5C on T cells metabolism was also detected by LC/MS-MS. Seahorse XF96 analyzer was further used to identify the effect of P5C on T cells glycolysis. We subsequently designed and produced an antibody for targeting P5C by monoclonal technique and verified its effectiveness to restore the function of T cells in vitro and in vivo. RESULT: PKM2 and LDHB bind SHP1 in T cells, and P5C could increase the levels of p-PKM2 while having no effect on the levels of PKM2 and LDHB. We further found that P5C influences T cell energy metabolism and carbohydrate metabolism. P5C also inhibits the activity of PKM2 and decreases the content of intracellular lactic acid while increasing the activity of LDH. Using seahorse XF96 analyzer, we confirmed that P5C remarkably inhibits glycolysis in T cells. We produced an antibody for targeting P5C by monoclonal technique and verified that the antibody could oppose the influence of P5C to restore the process of glycolysis and function in T cells. Meanwhile, the antibody also inhibits the growth of prostate tumors in an animal model. CONCLUSION: Our study revealed that P5C inhibits the process of glycolysis in T cells by targeting SHP1/PKM2/LDHB complexes. Moreover, it is important that the antibody for targeting P5C could restore the function of T cells and inhibit the growth of prostate tumors.

Single-cell analysis of isoform switching and transposable element expression during preimplantation embryonic development.

Alternative splicing is an essential regulatory mechanism for development and pathogenesis. Through alternative splicing one gene can encode multiple isoforms and be translated into proteins with different functions. Therefore, this diversity is an important dimension to understand the molecular mechanism governing embryo development. Isoform expression in preimplantation embryos has been extensively investigated, leading to the discovery of new isoforms. However, the dynamics of isoform switching of different types of transcripts throughout the development remains unexplored. Here, using single-cell direct isoform sequencing in over 100 single blastomeres from the mouse oocyte to blastocyst stage, we quantified isoform expression and found that 3-prime partial transcripts lacking stop codons are highly accumulated in oocytes and zygotes. These transcripts are not transcription by-products and might play a role in maternal to zygote transition (MZT) process. Long-read sequencing also enabled us to determine the expression of transposable elements (TEs) at specific loci. In this way, we identified 3,894 TE loci that exhibited dynamic changes along the preimplantation development, likely regulating the expression of adjacent genes. Our work provides novel insights into the transcriptional regulation of early embryo development.

Conserved mechanisms of self-renewal and pluripotency in mouse and human ESCs regulated by simulated microgravity using a 3D clinostat.

Embryonic stem cells (ESCs) exhibit unique attributes of boundless self-renewal and pluripotency, making them invaluable for fundamental investigations and clinical endeavors. Previous examinations of microgravity effects on ESC self-renewal and differentiation have predominantly maintained a descriptive nature, constrained by limited experimental opportunities and techniques. In this investigation, we present compelling evidence derived from murine and human ESCs, demonstrating that simulated microgravity (SMG)-induced stress significantly impacts self-renewal and pluripotency through a previously unidentified conserved mechanism. Specifically, SMG induces the upregulation of heat shock protein genes, subsequently enhancing the expression of core pluripotency factors and activating the Wnt and/or LIF/STAT3 signaling pathways, thereby fostering ESC self-renewal. Notably, heightened Wnt pathway activity, facilitated by Tbx3 upregulation, prompts mesoendodermal differentiation in both murine and human ESCs under SMG conditions. Recognizing potential disparities between terrestrial SMG simulations and authentic microgravity, forthcoming space flight experiments are imperative to validate the impact of reduced gravity on ESC self-renewal and differentiation mechanisms.

Acceleration Mechanism of Steel Slag Hydration Using THEED.

In this paper, the strength development of a pure steel slag (SS) system with various concentrations of N,N,N',N'-Tetrakis-(2-hydroxyethyl) ethylenediamine (THEED) was investigated. The hydration kinetics, pore structure and microstructure of SS pastes with and without THEED were characterized to underscore the working mechanism of THEED. Results show that THEED additions significantly increase the 3, 7 and 28 days compressive strength of hardened SS pastes. The enhancement effect increases with the dosage of THEED. At a concentration of 2000 ppm, THEED increased the compressive strength by 733%, 665%, and 545% at 3, 7 and 28 days, respectively. It is confirmed that THEED additions improve the hydration degree of SS by accelerating hydration of the aluminum phase (C3A, PDF-38-1429; C12A7, PDF-48-1882) and C2F,( PDF 38-0408) to generate Mc (PDF-41-0219) and Pa (PDF-30-0222) in the presence of CaCO3. Also, the hydration degree of silicates is increased by THEED. In this way, THEED additions refine the pore structure of hardened SS paste by increasing the pore volume with a diameter below 300 nm to achieve enhancement. The chelating effect of THEED results in promoting dissolution of SS, which provides the driving force for accelerating SS hydration.

ER: a critical hub for STING signaling regulation.

The Stimulator of Interferon Genes (STING) has a crucial role in mediating the immune response against cytosolic double-stranded DNA (dsDNA) and its activation is critically involved in various diseases. STING is synthesized, modified, and resides in the endoplasmic reticulum (ER), and its ER exit is intimately connected with its signaling. The ER, primarily known for its roles in protein folding, lipid synthesis, and calcium storage, has been identified as a pivotal platform for the regulation of a wide range of STING functions. In this review, we discuss the emerging factors that regulate STING in the ER and examine the interplay between STING signaling and ER pathways, highlighting the impacts of such regulations on immune responses and their potential implications in STING-related disorders.

Adolescents' relationships with parents and romantic partners in eight countries.

INTRODUCTION: Creating romantic relationships characterized by high-quality, satisfaction, few conflicts, and reasoning strategies to handle conflicts is an important developmental task for adolescents connected to the relational models they receive from their parents. This study examines how parent-adolescent conflicts, attachment, positive parenting, and communication are related to adolescents' romantic relationship quality, satisfaction, conflicts, and management. METHOD: We interviewed 311 adolescents at two time points (females = 52%, ages 15 and 17) in eight countries (China, Colombia, Italy, Kenya, the Philippines, Sweden, Thailand, and the United States). Generalized and linear mixed models were run considering the participants' nesting within countries. RESULTS: Adolescents with negative conflicts with their parents reported low romantic relationship quality and satisfaction and high conflicts with their romantic partners. Adolescents experiencing an anxious attachment to their parents reported low romantic relationship quality, while adolescents with positive parenting showed high romantic relationship satisfaction. However, no association between parent-adolescent relationships and conflict management skills involving reasoning with the partner was found. No associations of parent-adolescent communication with romantic relationship dimensions emerged, nor was there any effect of the country on romantic relationship quality or satisfaction. CONCLUSION: These results stress the relevance of parent-adolescent conflicts and attachment as factors connected to how adolescents experience romantic relationships.

Left atrial conduit strain derived from cardiac magnetic resonance is an independent predictor of left ventricular reverse remodeling in patients with nonischemic cardiomyopathy.

BACKGROUND: In some patients with nonischemic cardiomyopathy (NICM), left ventricular (LV) function improves with medical assistance, resulting in left ventricular reverse remodeling (LVRR). However, predictors of LVRR are not fully understood. The left atrium (LA) has been reported as a prognostic predictor in patients with heart failure (HF). The present study aimed to evaluate clinical predictors of LVRR related to LA function on cardiac magnetic resonance (CMR). METHODS: A total of 103 patients with reduced left ventricular ejection fraction (LVEF) were enrolled in this retrospective study between September 2015 and July 2021. CMR parameters, including strain data, were measured in all patients. Echocardiographic data obtained approximately 2 years after enrollment were analyzed to assess LVRR. RESULTS: LVRR occurred in 46 patients (44.7%) during follow-up. The value of LA conduit strain was higher in the LVRR group than in the non-LVRR group (6.6 [interquartile range (IQR): 5.6-9.3]% versus 5.0 [IQR: 3.0-6.2]%; p < 0.001). The multivariate logistic regression analysis showed that LA conduit strain was an independent predictor of LVRR (odds ratio [OR]: 1.216, 95% confidence interval [CI]: 1.050-1.408; p = 0.009). The area under the receiver operating characteristic (ROC) curve of the LA conduit strain was 0.746, and the cutoff value was 6.2%. The Kaplan‒Meier analysis revealed that the incidence of adverse cardiac events was significantly lower in patients with LA conduit strain > 6.2% compared to those with ⩽6.2%. (log-rank test, p = 0.019). CONCLUSIONS: LA conduit strain derived from CMR is an independent predictor of LVRR in patients with NICM.

How adolescents' lives were disrupted over the course of the COVID-19 pandemic: A longitudinal investigation in 12 cultural groups in 9 nations from March 2020 to July 2022.

It is unclear how much adolescents' lives were disrupted throughout the COVID-19 pandemic or what risk factors predicted such disruption. To answer these questions, 1,080 adolescents in 9 nations were surveyed 5 times from March 2020 to July 2022. Rates of adolescent COVID-19 life disruption were stable and high. Adolescents who, compared to their peers, lived in nations with higher national COVID-19 death rates, lived in nations with less stringent COVID-19 mitigation strategies, had less confidence in their government's response to COVID-19, complied at higher rates with COVID-19 control measures, experienced the death of someone they knew due to COVID-19, or experienced more internalizing, externalizing, and smoking problems reported more life disruption due to COVID-19 during part or all of the pandemic. Additionally, when, compared to their typical levels of functioning, adolescents experienced spikes in national death rates, experienced less stringent COVID-19 mitigation measures, experienced less confidence in government response to the COVID-19 pandemic, complied at higher rates with COVID-19 control measures, experienced more internalizing problems, or smoked more at various periods during the pandemic, they also experienced more COVID-19 life disruption. Collectively, these findings provide new insights that policymakers can use to prevent the disruption of adolescents' lives in future pandemics.

CRP, IL-1α, IL-1ß, and IL-6 levels and the risk of breast cancer: a two-sample Mendelian randomization study.

Epidemiological studies have reported a positive association between chronic inflammation and cancer risk. However, the causal association between chronic inflammation and breast cancer (BC) risk remains unclear. Here, we performed a Mendelian randomization study to investigate the etiological role of chronic inflammation in BC risk. We acquired data regarding C-reactive protein (CRP), interleukin (IL)-1a, IL-1b, and IL-6 expression and BC related to single nucleotide polymorphisms (SNPs) from two larger consortia (the genome-wide association studies and the Breast Cancer Association Consortium). Next, we conducted the two-sample Mendelian randomization study to investigate the relationship of the abovementioned inflammatory factors with the incidence of BC. We found that genetically predicted CRP, IL-6, and IL-1a levels did not increase BC incidence (odds ratio (OR)CRP 1.06, 95% confidence interval (CI) 0.98-1.12, P = 0.2059, ORIL-6 1.05, 95% CI 0.95-1.16, P = 0.3297 and ORIL-1a 1.01, 95% CI 0.99-1.03, P = 0.2167). However, in subgroup analysis, genetically predicted IL-1b levels increased ER + BC incidence (OR 1.15, 95% CI 1.03-1.27, P = 0.0088). Our study suggested that genetically predicted IL-1b levels were found to increase ER + BC susceptibility. However, due to the support of only one SNP, heterogeneity and pleiotropy tests cannot be performed, which deserves further research.

Evaluating the clinical performance of SDC2/NDRG4 methylation for colorectal cancer detection.

Purpose: The performance and clinical accuracy of combined SDC2/NDRG4 methylation were evaluated in diagnosing colorectal cancer (CRC) and advanced adenoma. Methods: A total of 2333 participants were enrolled to assess the sensitivity and specificity of biomarkers in diagnosing CRC in a multicenter clinical trial through feces DNA methylation tests. Results: SDC2/NDRG4 methylation showed excellent performance for CRC detection in biomarker research and the real world. Its sensitivity for detecting CRC, early CRC and advanced adenoma were 92.06%, 91.45% and 62.61%, respectively. Its specificity was 94.29%, with a total coincidence rate of 88.28%. When interference samples were included, the specificity was still good (82.61%). Therefore, the SDC2/NDRG4 methylation test showed excellent performance in detecting CRC and advanced adenoma under clinical application.

Colorectal cancer (CRC) is one of the most malignant tumors of the digestive system and second only to breast cancer and lung cancer in terms of global incidence. Early CRCs are challenging to determine given their atypical nature. In contrast, late CRC symptoms are affected by the type, location and range of the lesion and complications. Therefore, CRC patients are generally diagnosed late, present with a high degree of malignancy, and have poor prognosis and 5-year survival rates. The current study therefore evaluated whether SDC2 and NDRG4 methylation could be used for diagnosis CRCs at an early stage and whether it has the potential to detect asymptomatic patients with adenomas. The findings presented herein will certainly help support the early diagnosis of CRC and precancerous lesions in clinical practice.

The Ram Graft: Using One Complete Piece of Conchal Cartilage for Nasal Tip Reconstruction in East Asians.

SUMMARY: Adequate nasal tip projection remains a challenge in aesthetic rhinoplasty for East Asians. Various surgical techniques have been developed to reshape the nasal tip using auricular cartilage. In this article, we introduce the new ram graft to increase nasal tip projection by using one complete piece of conchal cartilage. Between 2019 and 2021, 19 patients who underwent nasal tip reconstruction using ram grafts were reviewed in a single hospital. The complication rate, satisfaction rate, and changes in nasolabial angle and nasal proportion were recorded. Nineteen patients with a mean age (± SD) of 28.9 ± 6.1 years underwent nasal tip reconstruction. The mean follow-up time was 15.4 ± 6.6 months. Nasolabial angle increased from 87.4 ± 10.0 degrees to 91.2 ± 10.2 degrees ( P > 0.05). Sixteen of 19 patients (84.2%) were satisfied with their results. The nasal length-to-nasal tip projection-to-dorsal height-to-radix height ratio is 2:0.8:0.62:0.19 preoperatively and 2:0.92:0.77:0.35 postoperatively. Complications including alloplast-related infection (two of 19) and septal extension graft-related decrease of nasal tip projection (one of 19) were recorded. By using one complete piece of conchal cartilage, the ram graft is a simple and effective approach to increase nasal tip projection for East Asians. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Developmental Trajectories of Parental Self-Efficacy as Children Transition to Adolescence in Nine Countries: Latent Growth Curve Analyses.

Little is known about the developmental trajectories of parental self-efficacy as children transition into adolescence. This study examined parental self-efficacy among mothers and fathers over 3 1/2 years representing this transition, and whether the level and developmental trajectory of parental self-efficacy varied by cultural group. Data were drawn from three waves of the Parenting Across Cultures (PAC) project, a large-scale longitudinal, cross-cultural study, and included 1178 mothers and 1041 fathers of children who averaged 9.72 years of age at T1 (51.2% girls). Parents were from nine countries (12 ethnic/cultural groups), which were categorized into those with a predominant collectivistic (i.e., China, Kenya, Philippines, Thailand, Colombia, and Jordan) or individualistic (i.e., Italy, Sweden, and USA) cultural orientation based on Hofstede's Individualism Index (Hofstede Insights, 2021). Latent growth curve analyses supported the hypothesis that parental self-efficacy would decline as children transition into adolescence only for parents from more individualistic countries; parental self-efficacy increased over the same years among parents from more collectivistic countries. Secondary exploratory analyses showed that some demographic characteristics predicted the level and trajectory of parental self-efficacy differently for parents in more individualistic and more collectivistic countries. Results suggest that declines in parental self-efficacy documented in previous research are culturally influenced.