A multicenter randomized controlled trial comparing short- and medium-term outcomes of novel biologics and lightweight synthetic mesh for laparoscopic inguinal hernia repair.

INTRODUCTION: The use of biological graft in laparoscopic inguinal hernia repair (LIHR) has been controversial, and there is a lack of high-level evidence to confirm the value of biological graft in LIHR. The purpose of this study is to evaluate the effectiveness of a novel composite biologics in LIHR. METHODS: A multicenter, single-blinded, randomized controlled clinical trial was designed. Fifty patients with unilateral primary inguinal hernia were randomly assigned to the experimental and control group (1:1). The experimental group was repaired with a non-crosslinked composite extracellular matrix from porcine urinary bladder matrix and small intestinal submucosa (UBM/SIS). The control group was repaired with a lightweight, large-pore, synthetic mesh. The primary endpoint was the effectiveness rate of hernia repair. RESULTS: The patients were followed up for four years. No significant difference was found between the experimental group and the control group in the effective rate of hernia repair (24/24[100%] vs 21/22[95.45%], RR, 0.4667; 95%CI, 0.3294-2.304; P = 0.4783). There was no fever, seroma, infection, groin pain, foreign body discomfort or recurrence in the experimental group during the follow-up. In the control group, there were 2 cases of seroma 14 days after operation, 1 case of groin discomfort 60 days after operation and one case of recurrence 410 days after surgery. CONCLUSION: Compared with the lightweight synthetic mesh, the novel UBM/SIS graft has comparable short-term and medium-term effectiveness in LIHR, and the incidence of postoperative complications such as seroma groin discomfort is lower. Trial registration Clinical Trials Registry: ChiCTR1800020173.

[Exploratory analysis of gut microbiota differences in patients with bronchial asthma of different inflammatory types].

Objective: To observe the characteristics and differences of gut microbiota in asthma patients with different inflammatory types through metagenomic analysis. Methods: Adults aged ≥18 years who visited the Respiratory Clinic of Peking University Third Hospital from August 1, 2021 to August 31, 2022 and were primarily diagnosed with asthma were selected as the study subjects. Finally, 29 patients with stable asthma were included. Fresh fecal samples were collected and the fecal DNA was extracted for high-throughput 16sRNA sequencing of gut microbiota. The diversity and community structure of gut microbiota in different groups of asthma patients were compared, and the species differences were analyzed through random forest and LEfSe analysis. Results: There were sex-based differences in asthma patients with different types of inflammation, and the proportion of female patients was higher in neutrophilic asthma patients (χ2=4.14, P=0.042). There was no significant intergroup difference in the alpha diversity of gut microbiota among asthma patients with different inflammatory types, but there were significant differences in the microbiome. Patients with neutrophilic asthma had higher relative abundance of Bacillales (P=0.029) and Oscillospiraceae (P=0.015). In species LEfSe analysis, patients with eosinophilic asthma had a higher relative abundance of fungi. Conclusion: There are intergroup differences in the gut microbiota of asthma patients with different inflammation types, and fungi are biomarkers that distinguish the differences in gut microbiota between patients with eosinophilic asthma and neutrophilic asthma.

Comprehensive profiling of cancer neoantigens from aberrant RNA splicing.

BACKGROUND: Cancer neoantigens arise from protein-altering somatic mutations in tumor and rank among the most promising next-generation immuno-oncology agents when used in combination with immune checkpoint inhibitors. We previously developed a computational framework, REAL-neo, for identification, quality control, and prioritization of both class-I and class-II human leucocyte antigen (HLA)-presented neoantigens resulting from somatic single-nucleotide mutations, small insertions and deletions, and gene fusions. In this study, we developed a new module, SPLICE-neo, to identify neoantigens from aberrant RNA transcripts from two distinct sources: (1) DNA mutations within splice sites and (2) de novo RNA aberrant splicings. METHODS: First, SPLICE-neo was used to profile all DNA splice-site mutations in 11,892 tumors from The Cancer Genome Atlas (TCGA) and identified 11 profiles of splicing donor or acceptor site gains or losses. Transcript isoforms resulting from the top seven most frequent profiles were computed using novel logic models. Second, SPLICE-neo identified de novo RNA splicing events using RNA sequencing reads mapped to novel exon junctions from either single, double, or multiple exon-skipping events. The aberrant transcripts from both sources were then ranked based on isoform expression levels and z-scores assuming that individual aberrant splicing events are rare. Finally, top-ranked novel isoforms were translated into protein, and the resulting neoepitopes were evaluated for neoantigen potential using REAL-neo. The top splicing neoantigen candidates binding to HLA-A*02:01 were validated using in vitro T2 binding assays. RESULTS: We identified abundant splicing neoantigens in four representative TCGA cancers: BRCA, LUAD, LUSC, and LIHC. In addition to their substantial contribution to neoantigen load, several splicing neoantigens were potent tumor antigens with stronger bindings to HLA compared with the positive control of antigens from influenza virus. CONCLUSIONS: SPLICE-neo is the first tool to comprehensively identify and prioritize splicing neoantigens from both DNA splice-site mutations and de novo RNA aberrant splicings. There are two major advances of SPLICE-neo. First, we developed novel logic models that assemble and prioritize full-length aberrant transcripts from DNA splice-site mutations. Second, SPLICE-neo can identify exon-skipping events involving more than two exons, which account for a quarter to one-third of all skipping events.

CSF biomarkers of immune activation and Alzheimer's disease for predicting cognitive impairment risk in the elderly.

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aß42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aß42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aß42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

[Reference values of skeletal muscle mass for children in Nanjing area].

Objective: To establish the reference values and growth curves of skeletal muscle mass among children in the Nanjing area. Methods: A cross-sectional study was conducted with children who underwent physical examination at the Department of Child Health Care, Children's Hospital of Nanjing Medical University from 2020 January to 2022 September. Their height, weight, body fat mass and skeletal muscle mass were measured. Body mass index, percentage of body fat mass, percentage of skeletal muscle mass, relative skeletal muscle mass index and the ratio of skeletal muscle to body fat were calculated. The associations between skeletal muscle mass indices and physical measurements index were analyzed through the Spearman correlation test. The Mann-Kendall test was used to assess the trend for skeletal muscle mass. Generalized additive models for location, scale and shape were used to construct percentile reference values and growth curves of male and female skeletal muscle mass indices at different ages. Results: A total of 32 690 children aged 4-14 years were enrolled in this study, including 19 912 boys (60.91%). Skeletal muscle mass, percentage of skeletal muscle mass, relative skeletal muscle mass index and the ratio of skeletal muscle to body fat of boys and girls was 11.10 (8.40, 14.90) and 10.30 (7.90, 13.20) kg, 40.36% (37.01%, 43.13%) and 39.38% (36.43%, 41.88%), 6.70 (6.07, 7.52) and 6.33 (5.79, 7.00), 2.39 (1.46, 3.47) and 2.14 (1.45, 3.00) kg/m2, respectively. Skeletal muscle mass of both boys and girls was all positively associated with weight (r=0.97, 0.96), body mass index (r=0.68, 0.63) and percentage of body fat mass (r=0.40, 0.43) (all P<0.01). The reference values and growth curves showed that the percentage of skeletal muscle mass P50 ranged from 37.75%-44.61% in boys and from 36.22%-40.55% in girls. The relative skeletal muscle mass index P50 ranged from 5.80-9.68 kg/m2 in boys and from 5.57-7.98 kg/m2 in girls. The ratio of skeletal muscle to body fat P50 ranged from 1.86-2.67 in boys and from 1.29-2.41 in girls. There was an increasing trend with age for both boys and girls in the growth of skeletal muscle mass (Z=4.20, 3.75, both Ptrend<0.01), and increased slightly before 9 years of age and then increased rapidly until 14 years of age in both boys and girls. Conclusions: The skeletal muscle mass indices change with age and gender during childhood. Percentile reference values for pediatric skeletal muscle mass indices can be used to evaluate the muscular growth and development in children in the Nanjing area.

Prediction of hospital mortality among critically ill patients in a single centre in Asia: comparison of artificial neural networks and logistic regression-based model.

INTRODUCTION: This study compared the performance of the artificial neural network (ANN) model with the Acute Physiologic and Chronic Health Evaluation (APACHE) II and IV models for predicting hospital mortality among critically ill patients in Hong Kong. METHODS: This retrospective analysis included all patients admitted to the intensive care unit of Pamela Youde Nethersole Eastern Hospital from January 2010 to December 2019. The ANN model was constructed using parameters identical to the APACHE IV model. Discrimination performance was assessed using area under the receiver operating characteristic curve (AUROC); calibration performance was evaluated using the Brier score and Hosmer-Lemeshow statistic. RESULTS: In total, 14 503 patients were included, with 10% in the validation set and 90% in the ANN model development set. The ANN model (AUROC=0.88, 95% confidence interval [CI]=0.86-0.90, Brier score=0.10; P in Hosmer-Lemeshow test=0.37) outperformed the APACHE II model (AUROC=0.85, 95% CI=0.80-0.85, Brier score=0.14; P<0.001 for both comparisons of AUROCs and Brier scores) but showed performance similar to the APACHE IV model (AUROC=0.87, 95% CI=0.85-0.89, Brier score=0.11; P=0.34 for comparison of AUROCs, and P=0.05 for comparison of Brier scores). The ANN model demonstrated better calibration than the APACHE II and APACHE IV models. CONCLUSION: Our ANN model outperformed the APACHE II model but was similar to the APACHE IV model in terms of predicting hospital mortality in Hong Kong. Artificial neural networks are valuable tools that can enhance real-time prognostic prediction.

[Clinical effect of anterolateral thigh flow-through chimeric perforator free flap transplantation in the treatment of upper limb complex tissue defects with main artery injury].

Objective: To investigate the clinical effect of anterolateral thigh flow-through chimeric perforator free flap transplantation in the treatment of upper limb complex tissue defects with main artery injury. Methods: The study was a retrospective observational study. From May 2019 to January 2022, 11 patients with upper limb complex tissue defects combined with main artery injury who met the inclusion criteria were admitted to the Department of Hand, Foot and Ankle Surgery of General Hospital of Ningxia Medical University, including 7 males and 4 females, aged from 18 to 56 years. After debridement, the area of skin and soft tissue defects was from 20 cm×6 cm to 32 cm×10 cm, and the exposed area of dead cavity or deep tissue was from 7 cm×4 cm to 10 cm×7 cm. Three patients had radial artery defects with a length of 4 to 7 cm; two patients had ulnar artery defects with a length of 5 to 8 cm; 4 patients had defects in both ulnar and radial arteries with a length of 3 to 7 cm; and in two patients, the ulnar, radial and brachial arteries were all defective with a length of 4 to 8 cm. The anterolateral thigh flow-through chimeric perforator flap was designed and cut. The skin flap area was from 22 cm×7 cm to 32 cm×11 cm, the chimeric muscle flap area was from 7 cm×4 cm to 10 cm×7 cm, and the length of the flow-through vessel in the "T" shaped vessel pedicle was from 4 to 8 cm. When transplanting the skin flap, the proximal end of the vascular pedicle was anastomosed with the proximal end of the recipient site, and the distal end of the vascular pedicle was anastomosed with the more normal blood vessel at the distal end of the forearm; the invalid cavity was filled with the muscle flap. The donor site wounds of tissue flap were closed directly or treated with skin grafting. After operation, the blood supply and survival of the flap, the survival of the distal limb, and the survival of the skin graft at the flap donor site were observed. Computed tomography angiography (CTA) was performed to observe the patency of the proximal and distal anastomotic arteries from 2 to 4 weeks after surgery. During follow-up, the texture of the flap, the survival of the grafted skin and the healing of the donor area were observed. Results: One patient (complete forearm disconnection) developed distal limb blood disorder on 5 days after surgery. CTA examination suggested embolization of the distal anastomosis of the flow-through artery. more muscle and skin and soft tissue necrosis of the distal limb showed in emergency exploration. So, amputation was performed ultimately. No vascular crisis occurred in the skin flaps of the remaining 10 patients, and all skin flaps, distal limbs and the skin grafts in flap donor sites survived well. Two to 4 weeks after surgery, the proximal and distal ends of the anastomosed arteries were good in the patency. Follow-up for 11-37 months, the flap texture was good, and all donor site wounds healed well. Conclusions: The use of anterolateral thigh flow-through chimeric perforator flap to repair upper limb complex tissue defects accompanied by main artery injury can improve the success rate of limb salvage, which can be promoted in clinical practice.

Determinants of depressive symptoms at individual, school and province levels: a national survey of 398,520 Chinese children and adolescents.

OBJECTIVES: The aims of this study were to describe the national distribution of depressive symptoms in Chinese children and adolescents, to examine the determinants of depressive symptoms at individual, school and province levels and to assess the gender and age differences in the effect of school factors on depressive symptoms. STUDY DESIGN: This was a national cross-sectional study. METHODS: A school-based online survey was conducted in mainland China from between December 1, 2021, and January 1, 2022. A total of 398,520 eligible participants were included in the analysis. School-level data were drawn from students, headteachers and Baidu Maps, and province-level data were obtained from the national human development report. The Patient Health Questionnaire-2 was used to measure depressive symptoms. RESULTS: Areas with the highest mean scores for depressive symptoms were in the northeastern, inner central and southwestern regions of China. At the individual level, younger age, male sex, being an only child, Han ethnicity, lower body mass index, more days of exercise, less drinking and smoking behaviours, higher subjective family socio-economic status (SES) and popularity in school were related to fewer depressive symptoms; however, objective family SES and maternal education were not related to fewer depressive symptoms. The school-level variables of public status, psychological activities and psychological courses and province-level variable of higher Human Development Index were associated with fewer depressive symptoms. The effect of psychological courses and activities on depressive symptoms was greater in females. CONCLUSIONS: The results showed multilevel factors related to depressive symptoms and emphasised the importance of implementing school-based psychological activities to ameliorate depressive symptoms in Chinese children and adolescents across age and gender.

[Periconceptional maternal homocysteine and birth weight outcomes in offspring: a prospective cohort study].

Objective: To quantify the associations between periconceptional maternal homocysteine (HCY) and offspring's birth weight and risk of small for gestational age (SGA) infant. Methods: The 19 984 mother-child pairs in this prospective cohort study were recruited from the Shanghai preconception cohort; the infants were delivered from 1st September 2016 to 11th November 2022. A standardized questionnaire was used to collect the mothers' demographic information, medical history, dietary supplement use, and maternal complications during pregnancy, and their serum samples were collected. Serum HCY, folate, and vitamin B12 were measured using chemiluminescent microparticle immunoassay based on serum sample drawn at enrollment. Birth weight data were obtained from medical records. Multiple imputation methods were applied to handle missing data in key variables. Multivariable linear regression and Poisson regression models were used to analyze the relationship between maternal HCY concentration during the periconceptional period and the birth weight and SGA risk of the offspring. Results: A total of 9 452 pairs were enrolled preconceptionally and the remaining 10 532 pairs were enrolled in early pregnancy. The proportion of mothers whose pregnancy age was greater than 35 years was 9.2% (1 832/19 984), the proportion of primiparous women was 76.5% (15 283/19 984), the proportion of pre-pregnancy overweight and obesity was 14.0% (2 804/19 984), the proportion of using folic acid supplements before pregnancy was 21.4% (4 272/19 984), and the proportion of those who supplemented with folic acid during early pregnancy was 85.2% (8 976/10 532); gestational diabetes mellitus was in 6.2% (1 245/19 984), gestational hypertensive syndrome in 3.6% (711/19 984). The birth weight of the offspring was (3 297±468) g, and there were 1 962 SGA children (9.8%). The HCY concentration in the overall population in appropriate for gestational age during the periconceptional period was (7.9±3.2) µmol/L, with (8.3±3.7) µmol/L in the preconception subgroup and (7.3±2.4) µmol/L in the early pregnancy subgroup. After adjustment for the covariates of perinatal demographic information, adverse pregnancy outcomes, serum folate and vitamin B12, increased maternal periconceptional HCY was significantly associated with lower offspring birth weight (ß=-2.30, 95%CI -4.43--0.16, P=0.035). Only the early pregnancy subgroup was significantly associated with lower offspring birth weight (ß=-7.39, 95%CI-11.50--3.21, P<0.001). No association was found between peripregnancy HCY and offspring SGA risk. However, elevated HCY in early pregnancy was associated with an increased risk of SGA in the offspring (RR=1.05, 95%CI 1.01-1.08, P=0.002). Periconceptional vitamin B12 was a mediator of the association between HCY and offspring birth weight, accounting for 16.5%, 41.2% and 5.4% of its total effect in the overall periconceptional population, the pre-pregnancy subgroup and the early pregnancy subgroup, respectively. Conclusions: Maternal periconceptional HCY level is associated with lower birth weight in offspring, but not with the risk of SGA. Elevated maternal HCY in early pregnancy subgroup may be associated with increased risk of SGA in offspring.

Causal effects of diabetic retinopathy on depression, anxiety and bipolar disorder in the European population: a Mendelian randomization study.

PURPOSE: To verify the causal effects of diabetic retinopathy (DR) on depression, anxiety and bipolar disorder (BD). METHODS: Mendelian randomization (MR) analysis was performed to identify the causal relationships between DR and depression or anxiety or BD via using DR-related GWAS data (14,584 cases and 176,010 controls), depression-related GWAS data (59,851 cases and 113,154 controls), anxiety-related GWAS data (7016 cases and 14,745 controls) and BD-related GWAS data (41,917 cases and 371,549 controls). The inverse-variance weighted (IVW) model was adopted to estimate the causal relationship. The outcome was expressed as odds ratio (OR) with 95% confidence intervals (CI). RESULTS: The MR analysis results presented that DR was causally associated with a significantly increased risk of BD in the European population (IVW, OR = 1.06, 95%CI [1.03, 1.08], P = 2.44 × 10-6), while DR was unable to causally influence the risk of depression (IVW, OR = 1.01, 95%CI [0.99, 1.04], P = 0.32) and anxiety (IVW, OR = 0.97, 95%CI [0.89, 1.06], P = 0.48) in the European population. Subgroup analysis based on BD identified DR causally increased the risk of bipolar I disorder (BD I) but not bipolar II disorder (BD II). Sensitivity analysis results did not show any pleiotropy and heterogeneity in both groups of analyses, indicating that the results were stable and reliable. CONCLUSIONS: The results of the current MR analysis indicated a causal relationship between DR and BD in the European population, while there was no causal connection between DR and depression or anxiety. However, further research is needed to confirm these conclusions.

Deconvolution reveals cell-type-specific transcriptomic changes in the aging mouse brain.

Mounting evidence highlights the crucial role of aging in the pathogenesis of Alzheimer's disease (AD). We have previously explored human apoE-targeted replacement mice across different ages and identified distinct molecular pathways driven by aging. However, the specific contribution of different brain cell types to the gene modules underlying these pathways remained elusive. To bridge this knowledge gap, we employed a computational deconvolution approach to examine cell-type-specific gene expression profiles in major brain cell types, including astrocytes (AS), microglia (MG), oligodendroglia (OG), neurons (NEU), and vascular cells (VC). Our findings revealed that immune module genes were predominantly expressed in MG, OG, and VC. The lipid metabolism module genes were primarily expressed in AS, MG, and OG. The mitochondria module genes showed prominent expression in VC, and the synapse module genes were primarily expressed in NEU and VC. Furthermore, we identified intra- and inter-cell-type interactions among these module genes and validated their aging-associated expression changes using published single cell studies. Our study dissected bulk brain transcriptomics data at the cellular level, providing a closer examination of the cell-type contributions to the molecular pathways driven by aging.

Cell-specific crosstalk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone.

Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially due to subventricular zone (SVZ) contact. Despite this, crosstalk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. Additionally, GBM brain tumor initiating cells (BTICs) increase expression of CTSB upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Finally, we show LV-proximal CTSB upregulation in patients, showing the relevance of this crosstalk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM. Highlights: Periventricular GBM is more malignant and disrupts neurogenesis in a rodent model.Cell-specific proteomics elucidates tumor-promoting crosstalk between GBM and NPCs.NPCs induce upregulated CTSB expression in GBM, promoting tumor progression.GBM stalls neurogenesis and promotes NPC senescence via CTSB.

[The triglyceride glucose index predicts the risk of nonfatal cardio-cerebrovascular disease in the Beijing community: a prospective cohort study].

Objective: To explore the characteristics of the association between the triglyceride glucose (TyG) index and nonfatal cardio-cerebrovascular disease risk in a community population. Method: This was a prospective cohort study. From December 2011 to April 2012, the first investigation was conducted among subjects with more than 40-year old who were from Shijingshan district and Pingguoyuan community in Beijing. The second investigation was conducted from April to October 2015. All the subjects were divided into three groups according to the tertile of the TyG index at baseline. The multivariate Cox proportional risk regression model was established to explore the correlation between the TyG index and nonfatal cardio-cerebrovascular disease risk and the Kaplan-Meier survival curve of the TyG index group was drawn. Subgroup analyses were performed according to age, gender, body mass index, type 2 diabetes mellitus (T2DM), hypertension, and hyperlipidemia to determine the correlation characteristics between the TyG index and nonfatal cardio-cerebrovascular disease among subgroups. Results: A total of 9 577 subjects were finally included to analyze. The mean follow-up time of this study was (34.14±3.84) months. During the follow-up, 363 subjects (3.8%) occurred nonfatal cardio-cerebrovascular disease. The multivariate Cox regression analysis results showed that the hazard ratio (HR) of nonfatal cardio-cerebrovascular disease in the high TyG index group was 1.54 (95%CI 1.19-1.98), 1.60 (95%CI 1.23-2.10), and 1.57 (95%CI 1.20-2.05) in the three models, compared with the low TyG index group. The Kaplan-Meier analysis showed that the risk of nonfatal cardio-cerebrovascular disease increased from the low-TyG index group to the high-TyG index group (P=0.015). In the six subgroups analysis, only gender was shown to have a significant interaction effect with the TyG index and nonfatal cardio-cerebrovascular disease risk. In the female population, the risk of nonfatal cardio-cerebrovascular disease is significantly increased with the increase in the TyG index level (P<0.001). Conclusions: A high TyG index is independently related to the increased risk of nonfatal cardio-cerebrovascular disease in the Beijing community population. Gender has a significant interaction with the TyG index and nonfatal cardio-cerebrovascular disease risk. Therefore, the TyG index may be a useful marker to predict the nonfatal cardio-cerebrovascular disease risk of a community population.

APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids.

BACKGROUND: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types. METHODS: We generated three-dimensional (3-D) cerebral organoids from human parental iPSC lines and its isogenic APOE-deficient (APOE-/-) iPSC line. To elucidate the cell-type-specific effects of APOE deficiency in the cerebral organoids, we performed scRNA-seq in the parental and APOE-/- cerebral organoids at Day 90. RESULTS: We show that APOE deficiency in human iPSC-derived cerebral organoids impacts brain lipid homeostasis by modulating multiple cellular and molecular pathways. Molecular profiling through single-cell RNA sequencing revealed that APOE deficiency leads to changes in cellular composition of isogenic cerebral organoids likely by modulating the eukaryotic initiation factor 2 (EIF2) signaling pathway as these events were alleviated by the treatment of an integrated stress response inhibitor (ISRIB). APOE deletion also leads to activation of the Wnt/ß-catenin signaling pathway with concomitant decrease of secreted frizzled-related protein 1 (SFRP1) expression in glia cells. Importantly, the critical role of apoE in cell-type-specific lipid homeostasis was observed upon APOE deletion in cerebral organoids with a specific upregulation of cholesterol biosynthesis in excitatory neurons and excessive lipid accumulation in astrocytes. Relevant to human AD, APOE4 cerebral organoids show altered neurogenesis and cholesterol metabolism compared to those with APOE3. CONCLUSIONS: Our work demonstrates critical roles of apoE in brain homeostasis and offers critical insights into the APOE4-related pathogenic mechanisms.

[Developmental effects of TCIPP and TnBP on zebrafish (Danio rerio) embryos].

Objective: To investigate the toxicity of tris (2-chloropropyl) phosphate (TCIPP) and tributyl phosphate (TnBP) on the growth and development of zebrafish embryos, as well as to explore the underlying mechanisms at the transcriptional level. Methods: With zebrafish as a model, two hpf zebrafish embryos were exposed to TCIPP and TnBP (0.1, 1, 10, 100, 500, and 1 000 µmol/L) using the semi-static method, and their rates of lethality and hatchability were determined. The transcriptome changes of 120 hpf juvenile zebrafish exposed to environmentally relevant concentrations of 0.1 and 1 µmol/L were measured. Results: The 50% lethal concentrations (LC50) of TCIPP and TnBP for zebrafish embryos were 155.30 and 27.62 µmol/L (96 hpf), 156.5 and 26.05 µmol/L (120 hpf), respectively. The 72 hpf hatching rates of TCIPP (100 µmol/L) and TnBP (10 µmol/L) were (23.33±7.72)% and (91.67±2.97)%, which were significantly decreased compared with the control group (P<0.05). Transcriptome analysis showed that TnBP had more differential genes (DEGs) than TCIPP, with a dose-response relationship. These DEGs were enriched in 32 pathways in total, including those involved in oxidative stress, energy metabolism, lipid metabolism, and nuclear receptor-related pathways, using the IPA pathway analysis. Among them, three enriched pathways overlapped between TCIPP and TnBP, including TR/RXR activation and CAR/RXR activation. Additionally, DEGs were also mapped onto pathways of LXR/RXR activation and oxidative stress for TnBP exposure only. Conclusion: Both TCIPP and TnBP have growth and developmental toxicities in zebrafish embryos, with distinct biomolecular mechanisms, and TnBP has a stronger effect than TCIPP.

LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4.

Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer's disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell-specific Lrp1-KO mice (smLrp1-/-) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1-/- mice but not in the APOE3 smLrp1-/- mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1-/- mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1-/- mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype-dependent manner.

Dual-channel compressed ultrafast photography for Z-pinch dynamic imaging.

The compressed ultrafast photography (CUP) can capture non-repetitive time-evolving events at 7 × 1013 fps, which is anticipated to find a diverse range of applications in physics, biomedical imaging, and materials science. The feasibility of diagnosing ultrafast phenomenon of Z-pinch by using the CUP has been analyzed in this article. Specifically, a dual-channel CUP design has been adopted for acquiring high quality reconstructed images and the strategies of identical masks, uncorrelated masks, and complementary masks have been compared. Furthermore, the image of the first channel was rotated by 90° to balance the spatial resolution between the sweep direction and the non-sweep direction. Both five synthetic videos and two simulated Z-pinch videos were chosen as the ground truth to validate this approach. The average peak signal to noise ratio of the reconstruction results is 50.55 dB for the self-emission visible light video and 32.53 dB for the laser shadowgraph video with unrelated masks (rotated channel 1). The simulation results show that the time-space-evolving process of plasma distribution can be well retold, and the phenomenon of plasma instability can be accurately diagnosed by the dual-channel CUP with unrelated masks (rotated channel 1). This study may promote the practical applications of the CUP in the field of accelerator physics.