LRG1-Targeted Nintedanib Delivery for Enhanced Renal Fibrosis Mitigation.

Renal fibrosis lacks effective nephroprotective drugs in clinical settings due to poor accumulation of therapeutic agents in damaged kidneys, underscoring the urgent need for advanced renal-targeted delivery systems. Herein, we exploited the significantly increased expression of the leucine-rich α-2 glycoprotein 1 (LRG1) protein during renal fibrosis to develop a novel drug delivery system. Our engineered nanocarrier, DENNM, preferentially targets fibrotic kidneys via the decorated ET peptide's high affinity for LRG1. Once internalized by damaged renal cells, DENNM releases its encapsulated nintedanib, triggered by the active caspase-3 protease, disrupting the nanomedicine's structural integrity. The released nintedanib effectively reduces the level of expression of the extracellular matrix and impedes the progression of renal fibrosis by inhibiting the transforming growth factor-ß (TGF-ß)-Smad2/3 pathway. Our comprehensive in vitro and in vivo studies validate DENNM's antifibrotic efficacy, emphasizing LRG1's potential in renal targeted drug delivery and introducing an innovative approach to nanomedicine for treating renal fibrosis.

Effect of a Mobile Health-Based Remote Interaction Management Intervention on the Quality of Life and Self-Management Behavior of Patients With Low Anterior Resection Syndrome: Randomized Controlled Trial.

BACKGROUND: People who undergo sphincter-preserving surgery have high rates of anorectal functional disturbances, known as low anterior resection syndrome (LARS). LARS negatively affects patients' quality of life (QoL) and increases their need for self-management behaviors. Therefore, approaches to enhance self-management behavior and QoL are vital. OBJECTIVE: This study aims to assess the effectiveness of a remote digital management intervention designed to enhance the QoL and self-management behavior of patients with LARS. METHODS: From July 2022 to May 2023, we conducted a single-blinded randomized controlled trial and recruited 120 patients with LARS in a tertiary hospital in Hefei, China. All patients were randomly assigned to the intervention group (using the "e-bowel safety" applet and monthly motivational interviewing) or the control group (usual care and an information booklet). Our team provided a 3-month intervention and followed up with all patients for an additional 3 months. The primary outcome was patient QoL measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. The secondary outcomes were evaluated using the Bowel Symptoms Self-Management Behaviors Questionnaire, LARS score, and Perceived Social Support Scale. Data collection occurred at study enrollment, the end of the 3-month intervention, and the 3-month follow-up. Generalized estimating equations were used to analyze changes in all outcome variables. RESULTS: In the end, 111 patients completed the study. In the intervention group, 5 patients withdrew; 4 patients withdrew in the control group. Patients in the intervention group had significantly larger improvements in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 total score (mean difference 11.51; 95% CI 10.68-12.35; Cohen d=1.73) and Bowel Symptoms Self-Management Behaviors Questionnaire total score (mean difference 8.80; 95% CI 8.28-9.32; Cohen d=1.94) than those in the control group. This improvement effect remained stable at 3-month follow-up (mean difference 14.47; 95% CI 13.65-15.30; Cohen d=1.58 and mean difference 8.85; 95% CI 8.25-9.42; Cohen d=2.23). The LARS score total score had significantly larger decreases after intervention (mean difference -3.28; 95% CI -4.03 to -2.54; Cohen d=-0.39) and at 3-month follow-up (mean difference -6.69; 95% CI -7.45 to -5.93; Cohen d=-0.69). The Perceived Social Support Scale total score had significantly larger improvements after intervention (mean difference 0.47; 95% CI 0.22-0.71; Cohen d=1.81). CONCLUSIONS: Our preliminary findings suggest that the mobile health-based remote interaction management intervention significantly enhanced the self-management behaviors and QoL of patients with LARS, and the effect was sustained. Mobile health-based remote interventions become an effective method to improve health outcomes for many patients with LARS. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200061317; https://tinyurl.com/tmmvpq3.

Forkhead box A1 induces angiogenesis through activation of the S100A8/p38 MAPK axis in cutaneous wound healing.

BACKGROUND: The association between S100 calcium-binding protein A8 (S100A8) and angiogenesis has been reported in previous reports. This study focuses on the roles of S100A8 in the angiogenesis of human dermal microvascular endothelial cells (HDMECs) and in cutaneous wound healing in mice. METHODS: Candidate genes related to angiogenesis activity were screened using a GSE83582 dataset. The overexpression DNA plasmid of S100A8 was transfected into HDMECs to analyze its effect on cell proliferation, migration, and angiogenesis. Full-thickness skin wounds were induced on mice, followed by adenovirus treatments to analyze the function of gene alteration in wound healing and pathological changes. The upstream regulator of S100A8 was predicted by bioinformatics analysis and verified by luciferase and immunoprecipitation assays. The role of the forkhead box A1 (FOXA1)-S100A8 interaction in p38 MAPK activation and angiogenesis were validated by rescue experiments. RESULTS: S100A8 was identified as a gene significantly correlated with angiogenesis. The S100A8 upregulation promoted the proliferation, migration, and angiogenesis of HDMECs, and it promoted p38 MAPK phosphorylation. Treatment of SB203580, a p38 MAPK inhibitor, blocked the promoting effect of S100A8. FOXA1 was identified as an upstream factor of S100A8 promoting its transcription. FOXA1 overexpression in HDMECs increased p38 MAPK phosphorylation and enhanced the activity of cells, which were blocked by the S100A8 inhibition. Similar results were reproduced in vivo where FOXA1 overexpression accelerated whereas the S100A8 knockdown retarded the cutaneous wound healing in mice. CONCLUSION: FOXA1 mediates the phosphorylation of p38 MAPK through transcription activation of S100A8, thereby inducing angiogenesis and promoting cutaneous wound healing.

Probiotics-Fermented Grifola frondosa Total Active Components: Better Antioxidation and Microflora Regulation for Alleviating Alcoholic Liver Damage in Mice.

Alcoholic liver damage is caused by long-term drinking, and it further develops into alcoholic liver diseases. In this study, we prepared a probiotic fermentation product of Grifola frondosa total active components (PFGF) by fermentation with Lactobacillus acidophilus, Lactobacillus rhamnosus, and Pediococcus acidilactici. After fermentation, the total sugar and protein content in the PFGF significantly decreased, while the lactic acid level and antioxidant activity of the PFGF increased. Afterward, we investigated the alleviating effect of PFGF on alcoholic liver injury in alcohol-fed mice. The results showed that the PFGF intervention reduced the necrosis of the liver cells, attenuated the inflammation of the liver and intestines, restored the liver function, increased the antioxidant factors of the liver, and maintained the cecum tissue barrier. Additionally, the results of the 16S rRNA sequencing analysis indicated that the PFGF intervention increased the relative abundance of beneficial bacteria, such as Lactobacillus, Ruminococcaceae, Parabacteroids, Parasutterella, and Alistipes, to attenuate intestinal inflammation. These results demonstrate that PFGF can potentially alleviate alcoholic liver damage by restoring the intestinal barrier and regulating the intestinal microflora.

Pro-angiogenic role of ZEB1 in skin wound healing by upregulating VEGFA via microRNA-206 suppression.

Angiogenesis has been identified to assume a critical role in skin wound healing. Moreover, zinc finger E-box binding homeobox 1 (ZEB1) was capable of promoting skin wound healing. Herein, cell and animal experiments were implemented in this study to figure out whether ZEB1 orchestrated angiogenesis during skin wound healing. Subsequent to gain- and loss-of-function approaches in human dermal microvascular endothelial cells (HDMECs), HDMEC proliferation, migration and angiogenesis were evaluated by CCK8, EdU, wound healing, Transwell and angiogenesis in vitro assays. The relationship among ZEB1, microRNA (miR)-206 and vascular endothelial growth factor A (VEGFA) was assessed by microarray analysis, dual-luciferase, ChIP and RIP assays. Finally, the mechanism of ZEB1 in skin wound healing was confirmed by in vivo experiments. Mechanically, ZEB1 upregulation resulted in miR-206 downregulation by binding to miR-206 promoter, and miR-206 repressed VEGFA expression by directly targeting. ZEB1 overexpression enhanced HDMEC proliferation, migration and angiogenesis, which was neutralized by miR-206 upregulation or VEGFA inhibition. Moreover, ZEB1 significantly promoted skin wound healing in mice, which was negated by overexpression of miR-206. Conclusively, ZEB1 augmented angiogenesis to promote skin wound healing by elevating VEGFA expression via miR-206 repression.

[Screening and identification of potassium-dissolving bacteria from different rhizosphere soil of Paris polyphylla var. yunnanensis].

The study aiming at exploring the potassium-dissolving capacity of rhizosphere potassium-dissolving bacteria from diffe-rent sources and screen the strains with high potassium-dissolving ability, so as to lay a theoretical foundation for cultivation and quality improvement of Paris polyphylla var. yunnanensis sources. The rhizosphere soil of 10 wild and transplanted species from Yunnan, Sichuan and Guizhou provinces was used as the research object. Potassium-dissolving bacteria were isolated and purified, and their potassium-dissolving capacity was determined by flame spectrophotometry, and identified by physiological, biochemical and molecular biological methods. Twenty-six potassium-dissolving bacteria were purified and 13 were obtained from wild and transplanted strains respectively. It was found through the determination of potassium-dissolving capacity that the potassium-dissolving capacity of 26 strains was significantly different, and the mass concentration of K~+ in the fermentation broth were 1.04-2.75 mg·L~(-1), the mcentration of potassium were 0.01-1.82 mg·L~(-1). The strains were identified as Bacillus, Agrobacterium rhizome and Staphylococcus by physiological, biochemical and 16 S rDNA molecular methods, among them Bacillus amylolyticus(4 strains) was the dominant bacterium of Bacillus. The physiology and biochemistry of rhizosphere potassium-dissolving bacteria in P. polyphylla var. yunnanensis rhizosphere were diffe-rent, and the living environment were different, so the potassium-dissolving capacity also changed. Strain Y4-1 with the highest potassium decomposability was Bacillus amylolytic with a potassium increase of 1.82 mg·L~(-1). The potassium-dissolving ability and the distribution of potassium-dissolving bacteria were different in various habitats. The screening of potassium-dissolving bacteria provided a new strain for the preparation of microbial fertilizer. It is expected that B. amyloidococcus Y4-1 can be used as an ideal strain to cultivate mycorrhizal seedlings of P. polyphylla var. yunnanensis.

[Isolation and identification of phosphatolytic bacteria in Paris polyphylla var. yunnanensis].

The wild resources of Paris polyphylla var. yunnanensis, a secondary endangered medicinal plant, are severely scarce. Introduction and cultivation can alleviate market demand. To screen phosphatolytic bacteria in the rhizosphere soil of P. polyphylla var. yunnanensis and provide data support for the development of high-efficiency microbial fertilizer, in this study, the dilution plate coating method was used to isolate and screen the phosphorus solubilizing bacteria with the ability of mineralizing organic phosphorus from the rhizosphere soil of wild and transplanted varieties of P. polyphylla var. yunnanensis in 10 different locations in Yunnan, Sichuan and Guizhou. After separation and purification, the phosphatolytic capacity was analyzed by qualitative and quantitative analysis. Combined with physiological and biochemical experiments, the strains were identified using 16 S rDNA sequencing analysis. Forty one strains were selected from the rhizosphere soil of P. polyphylla var. yunnanensis from 10 different habitats. Among them, 21 strains were obtained from the rhizosphere soil of the wild variety P. polyphylla var. yunnanensis and 20 strains were obtained from the rhizosphere soil of the transplanted variety. And significance analysis found that 41 organophosphate solubilizing strains had significant differences in their ability to solubilize phosphorus. The amount of phosphate solubilizing was 0.08-67.61 mg·L~(-1), the pH value was between 4.27 and 6.82. The phosphatolytic amount of strain Y3-5 was 67.61 mg·L~(-1), and the phosphorus increase amount was 57.57 mg·L~(-1). All 41 strains were identified as Gram-positive Bacillus. Combining physiological characteristic and phylogenetic trees, Bacillus mobilis Y3-5 was finally selected as the candidate rhizosphere phosphatolytic bacteria of P. polyphylla var. yunnanensis. The distribution of phosphorus solubilizing bacteria in the rhizosphere soil of P. polyphylla var. yunnanensis was different, and there were significant diffe-rences in phosphorus solubility. Organophosphate-dissolving strain Y3-5 is expected to be a candidate strain of P. polyphylla var. yunnanensis microbial fertilizer.

Toxicity of cooking oil fume derived particulate matter: Vitamin D3 protects tubule formation activation in human umbilical vein endothelial cells.

Cooking oil fumes-derived PM2.5 (COFs-derived PM2.5) is the main source of indoor pollution. Exposure to COFs-derived PM2.5 can cause oxidative stress and affect angiogenesis. Here we investigated the roles of vitamin D3 (VD3) in protecting tubule formation injury induced by COFs-derived PM2.5, and the roles of ROS/NLRP3/VEGF signaling pathway in the effects. Human umbilical vein endothelial cells (HUVECs) were exposed to 0 (1‰ DMSO), 1000 nmol/l VD3, 100 µg/ml PM2.5, and 1000 nmol/l VD3 + 100 µg/ml PM2.5, respectively. Cell viability and tube formation, as well as protein and mRNA levels were measured. The results showed that exposure of COFs-derived PM2.5 dose-and time-dependently reduced the viability of HUVECs, increased the levels of mitochondrial and intracellular ROS, and changed the mitochondrial membrane potential level. While co-incubation with VD3 rescued these adverse effects. Both Western blot and real-time PCR (RT-PCR) showed that the expressions of NLRP3, caspase-1, Interleukin (IL)-1ß, and IL-18 in COFs-derived PM2.5 exposure group increased significantly, which could be effectively decreased by co-incubation with VD3. COFs-derived PM2.5 exposure could also reduce the expression of VEGF, while co-incubating HUVECs with VD3 evidently up-regulated the protein level of VEGF in HUVECs. In addition, COFs-derived PM2.5 could also inhibit the tube formation of HUVECs in vitro, which could be effectively rescued by the co-incubation of VD3. Our study proved that COFs-derived PM2.5 could damage the tubule formation of HUVECs in vitro, which could be effectively rescue by co-incubation with VD3, in which processes the ROS/NLRP3/VEGF signaling pathway played a crucial role. It provides a new theoretical basis for further study on the toxicity of PM2.5 to umbilical cord blood vessels.

Region-specific insular volumetric decreases in drug-naive, first-episode schizophrenia and their unaffected siblings.

Decreased insular volume may be one of the anatomical alterations caused by schizophrenia. The possibility of region-specific insular volumetric reduction as an endophenotype and/or a possible treatment predictor is a critical issue with great implications for the diagnosis and prognosis of the disease. The sample of the current study comprised 44 drug-naive and first-episode patients, 42 unaffected siblings, and 44 healthy controls. A computational anatomy toolbox (CAT12) was applied to analyze the structural images with a fine-grained, cross-validated brainnetome atlas. Correlation analysis and support vector regression (SVR) were used to determine the relationship between insular deficits and symptomatic severity among patients. The gray matter volume (GMV) values in the left hypergranular insula (G) exhibited the following pattern: patients < siblings < controls. GMV values in the right ventral agranular insula (vIa) and baseline Positive and Negative Syndrome Scale negative symptoms subscale scores among patients showed a positive correlation (r = 0.384, p = .010). Further SVR analysis exhibited a significantly positive correlation between GMV values in the right vIa and negative symptomatic improvement among patients (r = 0.537, p < .001). Results suggested the presence of region-specific insular volumetric decreases in first-episode schizophrenia. Thus, volumetric decrease in left G might be a potential endophenotype for schizophrenia, and GMV values in right vIa might be used to predict negative symptomatic improvement in schizophrenia.

The effects of cooking oil fumes-derived PM2.5 on blood vessel formation through ROS-mediated NLRP3 inflammasome pathway in human umbilical vein endothelial cells.

BACKGROUND: Cooking oil fumes (COFs), a main pollutant in kitchen air, is a major risk to human health. In our previous research, exposure to COFs-derived PM2.5 could cause umbilical vascular endothelial dysfunction, leading to decreased fetal weight. Here, to test the role of ROS-mediated NLRP3 inflammasome pathway in blood vessel formation of human umbilical vein endothelial cells (HUVECs) caused by COFs-derived PM2.5, the cells were exposed to COFs-derived PM2.5 at different concentrations with and without N-acetyl-L-cysteine (NAC). METHODS: MTT assay was used to determine HUVECs viability. Intracellular ROS and mitochondrial ROS levels were assessed with DCFH-DA and MitoSOX™ assay. The levels of proteins and mRNA involved in NLRP3 inflammasome signaling pathway and VEGF were measured by western blot and real-time PCR (RT-PCR). Tube formation in HUVECs was detected by tube formation assay. RESULTS: The results revealed that COFs-derived PM2.5 exposure reduced HUVECs viability, increased the intracellular and mitochondrial ROS levels in cells, and up-regulated the levels of proteins and mRNA involved in NLRP3 inflammasome signaling pathway. However, the protein and mRNA expression of VEGF were reduced with the increasing exposure concentrations. In addition, COFs-derived PM2.5 also affected the tube formation. However, co-incubation with NAC effectively rescued the damages caused by COFs-derived PM2.5 exposure. CONCLUSIONS: This study proved that COFs-derived PM2.5 could significantly reduce HUVECs viability, induce the overproduction of ROS, lead to inflammation and inhibit VEGF expression, thus affect angiogenesis of HUVECs in vitro. It was revealed that the impact caused by COFs-derived PM2.5 on blood vessel formation through a ROS-mediated NLRP3 inflammasome pathway.

Associations of ambient PM2.5 and O3 with cardiovascular mortality: a time-series study in Hefei, China.

China is among the countries with the worst air quality throughout the world. As PM2.5 was not included in the national air quality monitoring network before January 2013 in China, no study has investigated the associations of ambient PM2.5 and O3 with cardiovascular mortality in Hefei, China. In this time-series analysis, Poisson regression in generalized additive model was adopted to assess the associations between the air pollutants and cardiovascular mortality during the 2013-2015 in Hefei, China. The findings showed that the daily average level of PM2.5 and O3 was 77.8 µg/m3 and 60.1 µg/m3 in the study period, respectively. PM2.5 and O3 exposure tended to increase cardiovascular mortality, but the associations were statistically insignificant. Further stratified analyses by seasons showed that with every 10 µg/m3 increase of PM2.5 in the cold season (October-March), the risk of cardiovascular death increased by 0.22% (95% CI 0.05%, 0.39%); while every 10 µg/m3 increase of O3 in the warm season (April-September), the risk of cardiovascular death increased by 1.29% (95% CI 0.26%, 2.33%) on Lag0. Interestingly, stratified analysis by gender showed that the associations of PM2.5, but not O3 exposure, could significantly increase cardiovascular mortality in females, but not males. The findings of this study especially underscored the adverse associations of PM2.5 and O3 exposure with females in specific seasons. More studies are needed to verify our findings and further investigate the underlying mechanisms. Graphical Abstract.

A comparative study of magnetic resonance imaging on the gray matter and resting-state function in prodromal and first-episode schizophrenia.

It is very difficult to predict the future development possibility of schizophrenia through the clinical symptoms of the high-risk cases. Therefore, how to determine the possibility of developing into schizophrenia individuals before the onset of the diseases are particularly important. The study investigated cerebral gray matter volume differences and resting-state functional connections among patients with psychosis risk syndrome (PRS), patients with first-episode schizophrenic (FES), and healthy controls (HC), aiming to provide scientific clinical evidence for schizophrenia early identification and intervention. A total of 19 PRS patients, 18 FES patients, and 29 HC were recruited. Gray matter volume and amplitude of low-frequency fluctuation (fALFF) during resting-state functional studies were measured. Comparison of gray matter volumes showed that PRS and FES groups had common reduced gray matter volume in the right caudate. PRS and FES patients showed altered connectivity mainly in the semantic processing-related brain areas. fALFF analysis found that PRF and FES patients had significant differences in fALFF values of the brain region mainly located in the subcortical network, visual recognition network, and auditory network. In addition, PRF individuals had a higher fALFF value and a lower fALFF value in the anterior wedge of the cerebral network than the HC group. Gray matter volume loss between related brain areas might appear prior to illness onset. Similar fALFF values occurred in PRS and FES groups indicated that multiple brain regions of neuronal activity abnormalities and unconventional neural network mechanism have been existed in PRS patients.

Solution-processable organic-inorganic hybrid hole injection layer for high efficiency phosphorescent organic light-emitting diodes.

The presence of a solution-processed hybrid PEDOT: PSS-MoO3-based hole injection layer (HIL) promotes a good interfacial contact between the indium tin oxide anode and hole-transporting layer for efficient operation of organic light-emitting diodes (OLEDs). This work reveals that the use of the hybrid HIL benefits the performance of phosphorescent OLEDs in two ways: (1) to assist in efficient hole injection, thereby improving power efficiency of OLEDs, and (2) to improve electron-hole current balance and suppression of interfacial defects at the organic/anode interface. The combined effects result in the power efficiency of 89.2 lm/W and external quantum efficiency of 23.9% for phosphorescent green OLEDs. The solution-processed hybrid PEDOT: PSS-MoO3-based HIL is beneficial for application in solution-processed organic electronic devices.

Effective medium analysis of absorption enhancement in short-pitch metal grating incorporated organic solar cells.

The effective medium theory is applied to analyze the absorption enhancement in organic solar cells with a short-pitch metal grating. A 37% improvement in the absorption of the active layer is achieved with respect to that of a planar control cell. It is inspired that the propagating surface plasmon modes are excited at the interface between the effective medium layer and the flat metal plate, resulting in a reduction of light reflection. In real structure, the electric field redistributes with its intensity in the region with active materials infiltrated in the grooves increases significantly, exhibiting like hot spots to assist in achieving broadband absorption enhancement. Moreover, the localized surface plasmon resonances excited at the top of the metal ridges also contribute to the absorption enhancement in the cells.

Emission behavior of dual-side emissive transparent white organic light-emitting diodes.

White organic light-emitting diodes (WOLEDs) resemble light more naturally, with emission spectrum that is comfortable to the human eye. The transparent WOLEDs can be almost invisible by day and can emit a pleasant diffused light at night, allowing the surface light source to shine in both directions, an exciting new lighting technology that could bring new device concepts. However, undesirable angular-dependent emission in transparent WOLEDs is often observed, due to the microcavity effect. In this work, the emission behavior of dual-side emissive transparent WOLEDs was studied experimentally and theoretically. It is found that avoidance of the overlap between the peak wavelengths of the emitters and the resonant wavelength of the organic microcavity moderates the angular-dependent electroluminescence emission behavior, thereby improving the color stability of the transparent white WOLEDs over a broad range of the viewing angle.

Broad autism phenotype features of Chinese parents with autistic children and their associations with severity of social impairment in probands.

BACKGROUND: Parents of children with autism have higher rates of broad autism phenotype (BAP) features than parents of typically developing children (TDC) in Western countries. This study was designed to examine the rate of BAP features in parents of children with autism and the relationship between parental BAP and the social impairment of their children in a Chinese sample. METHODS: A total of 299 families with autistic children and 274 families with TDC participated in this study. Parents were assessed using the Broad Autism Phenotype Questionnaire (BAPQ), which includes self-report, informant-report, and best-estimate versions. Children were assessed using the Chinese version of the Social Responsiveness Scale (SRS). RESULTS: Parents of children with autism were significantly more likely to have BAP features than were parents of TDC; mothers and fathers in families with autistic children had various BAP features. The total scores of the informant and best-estimate BAPQ versions for fathers were significantly associated with their children's SRS total scores in the autism group, whereas the total scores of the three BAPQ versions for mothers were significantly associated with their children's SRS total scores in the TDC group. In the autism group, the total SRS scores of children with "BAP present" parents (informant and best-estimate) were higher than the total SRS scores of children with"BAP absent" parents. In the TDC group, the total SRS scores of children with "BAP present" parents were higher than the total SRS scores of children with"BAP absent" parents (best-estimate). CONCLUSIONS: Parents of autistic children were found to have higher rates of BAP than parents of TDC in a sample of Chinese parents. The BAP features of parents are associated with their children's social functioning in both autism families and TDC families, but the patterns of the associations are different.

Correlation between FMR1 expression and clinical phenotype in discordant dichorionic-diamniotic monozygotic twin sisters with the fragile X mutation.

BACKGROUND: The clinical phenotypes of females with fragile X full mutations vary drastically. Comparisons of discordant monozygotic twins provide opportunities to ascertain crucial factors that influence disease phenotype penetrance. OBJECTIVE: To identify crucial factors influencing the phenotypic expression of fragile X syndrome (FXS). METHODS AND RESULTS: We describe a pair of discordant monozygotic female twins (dichorionic-diamniotic, Di-Di) with full mutation. The degrees of their phenotypic discordance regarding physical, psychiatric and behavioural features were quantified in a series of neuropsychological tests that varied significantly. Their FMR1 expression levels and whole genome DNA methylation profiling in blood were similar. Their similar life experiences also suggested that environmental factors had limited influence. However, the skewed inactivation of the normal X chromosome in the hair roots of twin A, resulting in large reduction in FMR1 expression compared to that of twin B, could adequately explain their widely variable phenotypes. CONCLUSIONS: The sixfold variation in hair root FMR1 expression, which reflected FMRP (fragile X mental retardation protein) expression in the brain, accounted for the disparate phenotypes in IQ, cognition, and social capability between the twins. Additionally, considering the Di-Di type twinning and different CGG repeat sizes, CGG expansion should occur before splitting at day 3 of gestation.

Neonatal intrahippocampal injection of lipopolysaccharide induces deficits in social behavior and prepulse inhibition and microglial activation in rats: Implication for a new schizophrenia animal model.

Several lines of evidence have suggested that the dysregulation of immune system is involved in the pathogenesis of schizophrenia. Microglia are the resident macrophage of the brain and the major player in innate immunity in the brain. We hypothesized that microglia activation may be closely associated with the neuropathology of schizophrenia. Neonatal intrahippocampal injection of lipopolysaccharide (LPS), an activator of microglia, was performed in rats at postnatal day 7 (PD7), and they were separately treated with saline or minocycline for consecutive 3days. Behavioral changes (locomotor activity, social interaction and prepulse inhibition) were examined in adulthood, and the number of microglia was assessed using immunohistochemistry at PD9, PD21 and PD67. The adult rats in LPS-injected group showed obvious behavioral alterations (deficits in social behavior and prepulse inhibition) and a persistently dramatic increase of number of activated microglial cells in the hippocampus, cerebral cortex and thalamus compared to those in saline-injected group. Interestingly, pretreatment with minocycline could significantly rescue the behavioral deficits and prevent microglia activation. Our results suggest that neonatal intrahippocampal LPS injection may serve as a potential schizophrenia animal model, and inhibition of microglia activation may be a potential treatment strategy for schizophrenia.

Association of TLR4 polymorphisms (Asp299Gly and Thr399Ile) with sepsis: a meta-analysis and trial sequence analysis.

Several investigations have been carried out to explore the genetic association of TLR4 codon variants, specifically Asp299Gly and Thr399Ile, and susceptibility to sepsis, but the results have been contradictory. The present study aimed to conduct a meta-analysis to draw a definitive conclusion regarding the role of TLR4 genetic variants (Asp299Gly and Thr399Ile) in sepsis. A thorough literature search was conducted using the PubMed, Scopus, and Science Direct databases. The inclusion and exclusion criteria were established to ensure the accuracy of the data. The Comprehensive Meta-Analysis Software v4 was utilized to perform the meta-analysis and related analyses. A total of 13 studies were analyzed, including 2328 sepsis cases and 2495 healthy controls for the TLR4 Asp299Gly variant. Eight studies provided genotype data for the rs4986791 polymorphism. The Asp299Gly variant showed a marginal protective effect in the allele (p = 0.08, odds ratio = 0.71) and dominant (p = 0.09, odds ratio = 0.71) genetic models, although it was not statistically significant. The trial sequential analysis indicated that further case-control studies are necessary to draw definitive conclusions about the TLR4 polymorphisms in sepsis. The TLR4 Asp299Gly variant may have a protective effect against sepsis. However, additional research with larger sample sizes across diverse populations is required to validate this finding.

Validation of the Chinese version of the 'caring ability of family caregivers of patients with cancer scale (CAFCPCS)' in family caregivers of elderly patients with cancer: A study protocol.

AIM: This study aims to translate the English version of the 'caring ability of family caregivers of patients with cancer scale (CAFCPCS)' into Chinese and validate its psychometric properties in the family caregivers of elderly patients with cancer. DESIGN: A methodological study. METHODS: Based on the Brislin translation model, the original scale will be translated and back-translated, the Delphi expert consultation method will be adopted for cross-cultural adaptation, and the pilot will be carried out in 20-30 family caregivers of elderly patients with cancer. Then, a dual-centre prospective study will be conducted by recruiting 371-542 family caregivers of elderly patients with cancer to validate the psychometric properties of the Chinese version of CAFCPCS. RESULTS: The scale's content validity will be evaluated using the Delphi expert inquiry method, and the face validity will be evaluated using a pre-experiment. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) will be used to assess structural validity, while internal consistency reliability and split-half reliability will be used to assess reliability. PATIENT OR PUBLIC CONTRIBUTION: Public involvement is of great significance for this study. Participants will be used in a pre-test to give feedback on whether the contents of the clinical pilot version of CAFCPCS after expert consultation can reflect real problems and whether the sentences can be well understood. Based on their opinions, the research group will further refine the scale.