Systematic review and meta-analysis: multimodal functional and anatomical neural alterations in autism spectrum disorder.

BACKGROUND: This meta-analysis aimed to explore the most robust findings across numerous existing resting-state functional imaging and voxel-based morphometry (VBM) studies on the functional and structural brain alterations in individuals with autism spectrum disorder (ASD). METHODS: A whole-brain voxel-wise meta-analysis was conducted to compare the differences in the intrinsic functional activity and gray matter volume (GMV) between individuals with ASD and typically developing individuals (TDs) using Seed-based d Mapping software. RESULTS: A total of 23 functional imaging studies (786 ASD, 710 TDs) and 52 VBM studies (1728 ASD, 1747 TDs) were included. Compared with TDs, individuals with ASD displayed resting-state functional decreases in the left insula (extending to left superior temporal gyrus [STG]), bilateral anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC), left angular gyrus and right inferior temporal gyrus, as well as increases in the right supplementary motor area and precuneus. For VBM meta-analysis, individuals with ASD displayed decreased GMV in the ACC/mPFC and left cerebellum, and increased GMV in the left middle temporal gyrus (extending to the left insula and STG), bilateral olfactory cortex, and right precentral gyrus. Further, individuals with ASD displayed decreased resting-state functional activity and increased GMV in the left insula after overlapping the functional and structural differences. CONCLUSIONS: The present multimodal meta-analysis demonstrated that ASD exhibited similar alterations in both function and structure of the insula and ACC/mPFC, and functional or structural alterations in the default mode network (DMN), primary motor and sensory regions. These findings contribute to further understanding of the pathophysiology of ASD.

Large-scale network abnormality in behavioral addiction.

BACKGROUND: Researchers have endeavored to ascertain the network dysfunction associated with behavioral addiction (BA) through the utilization of resting-state functional connectivity (rsFC). Nevertheless, the identification of aberrant patterns within large-scale networks pertaining to BA has proven to be challenging. METHODS: Whole-brain seed-based rsFC studies comparing subjects with BA and healthy controls (HC) were collected from multiple databases. Multilevel kernel density analysis was employed to ascertain brain networks in which BA was linked to hyper-connectivity or hypo-connectivity with each prior network. RESULTS: Fifty-six seed-based rsFC publications (1755 individuals with BA and 1828 HC) were included in the meta-analysis. The present study indicate that individuals with BAs exhibit (1) hypo-connectivity within the fronto-parietal network (FN) and hypo- and hyper-connectivity within the ventral attention network (VAN); (2) hypo-connectivity between the FN and regions of the VAN, hypo-connectivity between the VAN and regions of the FN and default mode network (DMN), hyper-connectivity between the DMN and regions of the FN; (3) hypo-connectivity between the reward system and regions of the sensorimotor network (SS), DMN and VAN; (4) hypo-connectivity between the FN and regions of the SS, hyper-connectivity between the VAN and regions of the SS. CONCLUSIONS: These findings provide impetus for a conceptual framework positing a model of BA characterized by disconnected functional coordination among large-scale networks.

A Multimodal Meta-Analytical Evidence of Functional and Structural Brain Abnormalities Across Alzheimer's Disease Spectrum.

BACKGROUND: Numerous neuroimaging studies have reported that Alzheimer's disease (AD) spectrum have been linked to alterations in intrinsic functional activity and cortical thickness (CT) of some brain areas. However, the findings have been inconsistent and the correlation with the transcriptional profile and neurotransmitter systems remain largely unknown. METHODS: We conducted a meta-analysis to identify multimodal differences in the amplitude of low-frequency fluctuation (ALFF)/fractional ALFF (fALFF) and CT in patients with AD and preclinical AD compared to healthy controls (HCs), using the Seed-based d Mapping with Permutation of Subject Images software. Transcriptional data were retrieved from the Allen Human Brain Atlas. The atlas-based nuclear imaging-derived neurotransmitter maps were investigated by JuSpace toolbox. RESULTS: We included 26 ALFF/fALFF studies comprising 884 patients with AD and 1,020 controls, along with 52 studies comprising 2,046 patients with preclinical AD and 2,336 controls. For CT, we included 11 studies comprising 353 patients with AD and 330 controls. Overall, compared to HCs, patients with AD showed decreased ALFF/fALFF in the bilateral posterior cingulate gyrus (PCC)/precuneus and right angular gyrus, as well as increased ALFF/fALFF in the bilateral parahippocampal gyrus (PHG). Patients with peclinical AD showed decreased ALFF/fALFF in the left precuneus. Additionally, patients with AD displayed decreased CT in the bilateral PHG, left PCC, bilateral orbitofrontal cortex, sensorimotor areas and temporal lobe. Furthermore, gene sets related to brain structural and functional changes in AD and preclincal AD were enriched for G protein-coupled receptor signaling pathway, ion gated channel activity, and components of biological membrane. Functional and structural alterations in AD and preclinical AD were spatially associated with dopaminergic, serotonergic, and GABAergic neurotransmitter systems. CONCLUSIONS: The multimodal meta-analysis demonstrated that patients with AD exhibited convergent functional and structural alterations in the PCC/precuneus and PHG, as well as cortical thinning in the primary sensory and motor areas. Furthermore, patients with preclinical AD showed reduced functional activity in the precuneus. AD and preclinical AD showed genetic modulations/neurotransmitter deficits of brain functional and structural impairments. These findings may provide new insights into the pathophysiology of the AD spectrum.

The perioperative experience and needs of hepatocellular carcinoma patients in interventional therapy: a phenomenological qualitative study.

OBJECTIVE: This study aims to investigate the perioperative experience and needs of patients with liver cancer for interventional therapy, in order to provide the basis for further improving a patient's medical experience and satisfaction. METHODS: A semi-structured in-depth interview was conducted for 16 patients with liver cancer in interventional therapy using the phenomenological research method of qualitative research. The themes were analyzed, summarized, refined and extracted using the Colaizzi analytical procedure. RESULTS: The study results revealed that the perioperative experience and needs of patients with liver cancer for interventional therapy could mainly be summarized into seven themes: anxiety, fear and helplessness; not understanding the specific procedures of interventional therapy; worrying that the disease would not be treated as expected; lack of understanding of perioperative adverse reactions and the inability to cope with these; concern on the financial burden of health care costs on families; concerned on the physical and mental health of the dependent; the further improvement of diagnosis and treatment procedures. CONCLUSION: Patients with liver cancer undergo a complex psychological experience during interventional therapy. In clinical practice, a patient's psychological needs and changes should be valued, in order to provide a targeted psychological intervention, health guidance and social support, thereby improving the medical experience and satisfaction of patients.

Real-world data of China: Analysis of HPV vaccine coverage and post-vaccination adverse reaction monitoring in Western Chinese provinces from 2018 to 2021.

To investigate the HPV vaccine coverage and post-vaccination adverse reactions in Gansu Province, Western China, from 2018 to 2021. Data on suspected adverse reactions to HPV vaccines were collected from the Chinese Vaccine Adverse Event Following Immunization (AEFI). Estimate the incidence rates of Common Adverse Reaction and Rare Adverse Reaction. HPV vaccine coverage among females in different age groups was calculated using data from the Gansu Provincial Immunization Information Platform. The first-dose HPV vaccine coverage rate among females aged 9 to 45 was 2.02%, with the lowest rate of less than 1% observed in females aged 9 to 14. From 2018 to 2021, the incidence rates of Common Adverse Reaction and Rare Adverse Reaction reported in females after HPV vaccination were 11.82 and 0.39 per 100,000 doses, respectively. Common Adverse Reaction included fever (5.52 per 100,000 doses), local redness and swelling (3.33 per 100,000 doses), fatigue (3.15 per 100,000 doses), headache (2.76 per 100,000 doses), as well as local induration and nausea/vomiting (1.97 per 100,000 doses). Adverse reactions mainly occurred within 1 day after vaccination, followed by 1 to 3 days after vaccination. The HPV vaccine coverage rate among females aged 9 to 14 in Gansu Province is remarkably low, and there is an urgent need to enhance vaccine coverage. From 2018 to 2021, the incidence of Adverse reaction Following Immunization HPV vaccination fell within the expected range, indicating the vaccine's safety profile.

α-Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3-Mediated Pyroptosis of Granulosa Cells.

SCOPE: Premature ovarian insufficiency (POI) is a common female infertility problem, with its pathogenesis remains unknown. The NOD-like receptor family pyrin domain-containing 3 (NLRP3)-mediated pyroptosis has been proposed as a possible mechanism in POI. This study investigates the therapeutic effect of α-ketoglutarate (AKG) on ovarian reserve function in POI rats and further explores the potential molecular mechanisms. METHODS AND RESULTS: POI rats are caused by administration of cyclophosphamide (CTX) to determine whether AKG has a protective effect. AKG treatment increases the ovarian index, maintains both serum hormone levels and follicle number, and improves the ovarian reserve function in POI rats, as evidence by increased the level of lactate and the expression of rate-limiting enzymes of glycolysis in the ovaries, additionally reduced the expression of NLRP3, Gasdermin D (GSDMD), Caspase-1, Interleukin-18 (IL-18), and Interleukin-1 beta (IL-1ß). In vitro, KGN cells are treated with LPS and nigericin to mimic pyroptosis, then treated with AKG and MCC950. AKG inhibits inflammatory and pyroptosis factors such as NLRP3, restores the glycolysis process in vitro, meanwhile inhibition of NLRP3 has the same effect. CONCLUSION: AKG ameliorates CTX-induced POI by inhibiting NLRP3-mediated pyroptosis, which provides a new therapeutic strategy and drug target for clinical POI patients.

[Distribution Characteristics of Arsenic in Drinking Water in China and Its Health Risk Based on Disability-adjusted Life Years].

Long-term exposure to arsenic can lead to functional damage to many organs and can be life-threatening. It is of great significance to analyze the distribution characteristics of arsenic in water and evaluate its potential risk for preventing and controlling human health hazards caused by water-derived arsenic. Based on the published data from 2000 to 2022, the geographical distribution characteristics of arsenic in drinking water across China were systematically analyzed in detail, and the health risk of arsenic in drinking water was quantitatively assessed using disability-adjusted life years (DALYs), which represent the burden of disease. The results showed that the average concentration of arsenic in drinking water in China was (2.88 ±0.33) µg·L-1, which was lower than the limit of 10 µg·L-1 set by the standard for drinking water quality (GB 5749-2022). Nevertheless, the arsenic in drinking water in some provinces, including Shanxi, Inner Mongolia, and Ningxia, was still higher than the limit. The arsenic concentration in drinking water in northern China was higher than that in southern China, and that in rural areas was higher than that in cities. The estimated health risk of arsenic in drinking water (1.63×10-6 DALYs per person-year) was higher than the acceptable risk level of waterborne exposure of 1.0×10-6 DALYs per person-year set by the World Health Organization. The personal health risks related to arsenic in drinking water in the six geographical regions were ranked as follows:North China > Northeast China > Central South China > Northwest China > Southwest China > East China. Almost all (99.4%) of the health burden associated with water arsenic was attributable to skin and lung cancer, which caused 2 905.25 and 1 513.96 DALYs per year, respectively. Most (78.0%) of the health burden was borne by people aged 45 years or older. In addition, given the proportion of each age group in the total population, older persons over the age of 60 bear a higher drinking-water-associated arsenic burden at the individual level than others, and attention should be consequently paid to them when controlling the risk of arsenic in water.

Identification of a novel m6A-related lncRNAs signature and immunotherapeutic drug sensitivity in pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) ranks as the fourth leading cause for cancer-related deaths worldwide. N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) are closely related with poor prognosis and immunotherapeutic effect in PDAC. The aim of this study is to construct and validate a m6A-related lncRNAs signature and assess immunotherapeutic drug sensitivity in PDAC. METHODS: RNA-seq data for 178 cases of PDAC patients and 167 cases of normal pancreatic tissue were obtained from TCGA and GTEx databases, respectively. A set of 21 m6A-related genes were downloaded based on the previous report. Co-expression network was conducted to identify m6A-related lncRNAs in PDAC. Cox analyses and least absolute shrinkage and selection operator (Lasso) regression model were used to construct a risk prognosis model. The relationship between signature genes and immune function was explored by single-sample GSEA (ssGSEA). The tumor immune dysfunction and exclusion (TIDE) score and tumor mutation burden (TMB) were utilized to evaluate the response to immunotherapy. Furthermore, the expression levels of 4 m6A-related lncRNAs on PDAC cell lines were measured by the quantitative real-time PCR (qPCR). The drug sensitivity between the high- and low-risk groups was validated using PDAC cell lines by Cell-Counting Kit 8 (CCK8). RESULTS: The risk prognosis model was successfully constructed based on 4 m6A-related lncRNAs, and PDAC patients were divided into the high- and low-risk groups. The overall survival (OS) of the high-risk groups was more unfavorable compared with the low-risk groups. Receiver operating characteristic (ROC) curves demonstrated that the risk prognosis model reasonably predicted the 2-, 3- and 5-year OS of PDAC patients. qPCR analysis confirmed the decreased expression levels of 4 m6A-related lncRNAs in PDAC cells compared to the normal pancreatic cells. Furthermore, CCK8 assay revealed that Phenformin exhibited higher sensitivity in the high-risk groups, while Pyrimethamine exhibited higher sensitivity in the low-risk groups. CONCLUSION: The prognosis of patients with PDAC were well predicted in the risk prognosis model based on m6A-related lncRNAs, and selected immunotherapy drugs have potential values for the treatment of pancreatic cancer.

A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.

Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

A multimodal meta-analysis of regional functional and structural brain abnormalities in obsessive-compulsive disorder.

Numerous neuroimaging studies of resting-state functional imaging and voxel-based morphometry (VBM) have revealed abnormalities in specific brain regions in obsessive-compulsive disorder (OCD), but results have been inconsistent. We conducted a whole-brain voxel-wise meta-analysis on resting-state functional imaging and VBM studies that investigated differences of functional activity and gray matter volume (GMV) between patients with OCD and healthy controls (HCs) using seed-based d mapping (SDM) software. A total of 41 independent studies (51 datasets) for resting-state functional imaging and 42 studies (46 datasets) for VBM were included by a systematic literature search. Overall, patients with OCD displayed increased spontaneous functional activity in the bilateral inferior frontal gyrus (IFG) (extending to the bilateral insula) and bilateral medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC), as well as decreased spontaneous functional activity in the bilateral paracentral lobule, bilateral cerebellum, left caudate nucleus, left inferior parietal gyri, and right precuneus cortex. For the VBM meta-analysis, patients with OCD displayed increased GMV in the bilateral thalamus (extending to the bilateral cerebellum), right striatum, and decreased GMV in the bilateral mPFC/ACC and left IFG (extending to the left insula). The conjunction analyses found that the bilateral mPFC/ACC, left IFG (extending to the left insula) showed decreased GMV with increased intrinsic function in OCD patients compared to HCs. This meta-analysis demonstrated that OCD exhibits abnormalities in both function and structure in the bilateral mPFC/ACC, insula, and IFG. A few regions exhibited only functional or only structural abnormalities in OCD, such as the default mode network, striatum, sensorimotor areas, and cerebellum. It may provide useful insights for understanding the underlying pathophysiology of OCD and developing more targeted and efficacious treatment and intervention strategies.

Object detection: A novel AI technology for the diagnosis of hepatocyte ballooning.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has reached epidemic proportions worldwide and is the most frequent cause of chronic liver disease in developed countries. Within the spectrum of liver disease in MAFLD, steatohepatitis is a progressive form of liver disease and hepatocyte ballooning (HB) is a cardinal pathological feature of steatohepatitis. The accurate and reproducible diagnosis of HB is therefore critical for the early detection and treatment of steatohepatitis. Currently, a diagnosis of HB relies on pathological examination by expert pathologists, which may be a time-consuming and subjective process. Hence, there has been interest in developing automated methods for diagnosing HB. This narrative review briefly discusses the development of artificial intelligence (AI) technology for diagnosing fatty liver disease pathology over the last 30 years and provides an overview of the current research status of AI algorithms for the identification of HB, including published articles on traditional machine learning algorithms and deep learning algorithms. This narrative review also provides a summary of object detection algorithms, including the principles, historical developments, and applications in the medical image analysis. The potential benefits of object detection algorithms for HB diagnosis (specifically those combined with a transformer architecture) are discussed, along with the future directions of object detection algorithms in HB diagnosis and the potential applications of generative AI on transformer architecture in this field. In conclusion, object detection algorithms have huge potential for the identification of HB and could make the diagnosis of MAFLD more accurate and efficient in the near future.

Meta-analysis of cortical thickness reduction in adult schizophrenia.

BACKGROUND: Numerous neuroimaging studies using surface-based morphometry analyses have reported altered cortical thickness among patients with schizophrenia, but the results have been inconsistent. We sought to provide a whole-brain meta-analysis, which may help enhance the spatial accuracy of identification. METHODS: We conducted a meta-analysis of whole-brain studies that explored cortical thickness alteration among adult patients with schizophrenia, including first-episode patients with schizophrenia, and patients with chronic schizophrenia, compared with healthy controls by using the seed-based d mapping with permutation of subject images (SDM-PSI) software. RESULTS: A systematic literature search identified 25 studies (33 data sets) of cortical thickness, including 2008 patients with schizophrenia and 2004 healthy controls. Overall, patients with schizophrenia showed decreased cortical thickness in the right inferior frontal gyrus (IFG) and bilateral insula extending to the superior temporal gyrus (STG). Subgroup meta-analysis reported that patients with chronic schizophrenia showed decreased cortical thickness in the right insula extending to the right IFG. There was no significant cortical thickness difference between first-episode patients with schizophrenia and healthy controls. LIMITATIONS: The results of meta-regression analyses should be viewed cautiously since they were driven by a small number of studies or did not overlap with the between-group differences found in the primary analyses. CONCLUSION: The meta-analysis suggested robust cortical thickness reduction in the IFG, insula and STG among adult patients with schizophrenia, particularly in those with chronic schizophrenia. The results provide useful insights to understanding the underlying pathophysiology of schizophrenia.

Anti-Glioma Effects of Ligustilide or n-Butylphthalide on Their Own and the Synergistic Effects with Temozolomide via PI3K/Akt Signaling Pathway.

Background: Ligustilide (LIG) and n-butylphthalide (NBP) have neuroprotective effects in cerebral ischemia; however, their roles in gliomas are not well-known.This study aimed to explore the anti-glioma effects of LIG and NBP individually and the synergistic effects of temozolomide (TMZ) via the PI3K/Akt Signaling Pathway. Materials and Methods: Cytotoxicity of LIG and NBP alone and in combination with TMZ in U251 cells was determined using the CCk-8. The effect of compounds alone or in combination on cell migration was detected using the wound healing assay, and the invasion was evaluated by transwell assays, respectively. Cell apoptosis was quantified by flow cytometry and the changed expressions of proteins were detected by Western blotting. Results: The results showed that LIG and NBP significantly inhibited the growth of U251 cells at concentrations of 4-10 µg/mL and 1.5-6 µg/mL in a dose-dependent manner (p<0.05, p<0.01). The combination of 20 µg/mL TMZ with LIG in the concentration range of 4-10 µg/mL or with NBP of 0.5-6 µg/mlachieved synergistic effect towardsU251 cells. LIG and NBP, alone or in combination with TMZ, markedly inhibited cell invasion (p< 0.001) and enhanced apoptosis (p< 0.05). The combination of TMZ with LIG or NBP markedly inhibited cell migration (p< 0.001). Western blot analysis showed that LIG, NBP, and TMZ, alone and in combination, significantly decreased the expression of Bcl-2, p-PI3K, and p-Akt, and increased the expression of Bax. Conclusion: Both LIG and NBP exert anti-glioma effects on their own through the PI3K/Akt pathway and enhance TMZ-mediated anti-glioma efficiency via the same pathway.

Effects of Enterotoxigenic Escherichia coli Challenge on Jejunal Morphology and Microbial Community Profiles in Weaned Crossbred Piglets.

Pathogenic enterotoxigenic Escherichia coli (ETEC) is a major cause of bacterial diarrhea in weaning piglets, which are vulnerable to changes in environment and feed. This study aimed to determine the effects of the ETEC challenge on piglet growth performance, diarrhea rate, jejunal microbial profile, jejunal morphology and goblet cell distribution. A total of 13 piglets from one litter were selected on postnatal day 21 and assigned to treatments with or without ETEC challenge at 1 × 108 CFUs, as ETEC group or control group, respectively. On postnatal day 28, samples were collected, followed by the detection of serum biochemical indexes and inflammatory indicators, HE staining, PAS staining and 16S rDNA gene amplicon sequencing. Results showed that the growth performance decreased, while the diarrhea rate increased for the ETEC group. The jejunum is the main segment of the injured intestine during the ETEC challenge. Compared with the control, the ETEC group displayed fewer goblet cells in the jejunum, where goblet cells are more distributed at the crypt and less distributed at the villus. In addition, ETEC piglets possessed higher abundances of the genus Desulfovibrio, genus Oxalobacter and genus Peptococus and lower abundances of the genus Prevotella 2, genus Flavonifractor and genus Blautra. In terms of alpha diversity, Chao 1 and observed features indexes were both increased for the ETEC group. Our study provides insights into jejunal histopathological impairment and microbial variation in response to ETEC infection for weaned piglets and is a valuable reference for researchers engaged in animal health research to select stress models.

[Relationship of Cognitive Function With Menarche Age,Menopause Age, and Reproductive Period in Female Patients With Hypertension].

Objective To explore the relationship of menarche age,menopause age,and reproductive period with cognitive function in the female patients with hypertension.Methods Hypertension screening was carried out in Wuyuan county of Jiangxi province from July to August in 2018.Data were collected through a face-to-face questionnaire survey,physical measurement,and biochemical tests.The cognitive function was scored according to the mini-mental state examination(MMSE)scale.Multiple linear regression and Logistic regression were employed to analyze the effects of menarche age,menopause age,and reproductive period on cognitive function,and the penalized spline regression to fit the curves.Results A total of 4595 postmenopausal women with hypertension were included in the analysis,with the mean age of(65.1±8.4)years,mean menarche age of(16.6±2.2)years,mean menopause age of(48.2±5.0)years,mean reproductive period of(31.7±5.5)years,mean MMSE score of(19.0±6.3)points,and total cognitive impairment detection rate of 40.4%(1859/4595).The detection rates of cognitive impairment were 28.4%,39.1%,and 45.8% in the females with the menarche ages of <15,15-16,and ≥17 years,47.9%,39.7%,and 38.3% in the females with the menopausal ages of <45,45-49,and ≥50 years,and 56.0%,44.4%,40.6%,and 32.6% in the females with the reproductive periods of <25,25-29,30-34,and ≥35 years,respectively.Moreover,the detection rates of cognitive impairment among different age groups were statistically significant(all P<0.05).Compared with the group with the menarche age <15 years,the groups with the menarche ages of 15-16 years and ≥17 years showed increased detection rates of cognitive impairment(OR=1.45,95%CI=1.19-1.75,P<0.001;OR=1.65,95%CI=1.37-1.98,P<0.001).Compared with the group with the menopausal age <45 years,the groups with the menopausal ages of 45-49 years and ≥50 years showed decreased detection rates of cognitive impairment(OR=0.80,95%CI=0.66-0.95,P=0.013;OR=0.78,95%CI=0.65-0.93,P<0.001).Compared with the group with the reproductive period <25 years,the groups with the reproductive periods of 25-29,30-34,and ≥35 years showed decreased detection rates of cognitive impairment(OR=0.66,95%CI=0.52-0.84,P<0.001;OR=0.62,95%CI=0.50-0.76,P<0.001;OR=0.51,95%CI=0.41-0.63,P<0.001).Conclusion The detection rate of cognitive impairment had a positive correlation with menarche age and negative correlations with menopause age and reproductive period in the female patients with hypertension.

CD24+LCN2+ liver progenitor cells in ductular reaction contributed to macrophage inflammatory responses in chronic liver injury.

BACKGROUND: CD24+CK19+/CD24+SOX9+ resident liver cells are activated and expanded after chronic liver injury in a ductular reaction. However, the sources and functions of these cells in liver damage remain disputed. RESULTS: The current study combined genetic lineage tracing with in vitro small-molecule-based reprogramming to define liver progenitor cells (LPCs) derived from hepatic parenchymal and non-parenchymal tissues. tdTom+ hepatocytes were isolated from ROSA26tdTomato mice following AAV8-Tbg-Cre-mediated recombination, EpCAM+ biliary epithelial cells (BECs) from wild-type intrahepatic bile ducts and ALB/GFP-EpCAM- cells were isolated from AlbCreERT/R26GFP mice. A cocktail of small molecules was used to convert the isolated cells into LPCs. These in vitro cultured LPCs with CD24 and SOX9 expression regained the ability to proliferate. Transcriptional profiling showed that the in-vitro cultured LPCs derived from the resident LPCs in non-parenchymal tissues expressed Lipocalin-2 (Lcn2) at high levels. Accordingly, endogenous Cd24a+Lcn2+ LPCs were identified by integration of sc-RNA-sequencing and pathological datasets of liver dysfunction which indicates that LPCs produced by ductular reactions might also originate from the resident LPCs. Transplantation of in-vitro cultured Cd24a+Lcn2+ LPCs into CCl4-induced fibrotic livers exacerbated liver damage and dysfunction, possibly due to LCN2-dependent macrophage inflammatory response. CONCLUSIONS: CD24+LCN2+ LPCs constituted the expanding ductular reaction and contributed to macrophage-mediated inflammation in chronic liver damage. The current findings highlight the roles of LPCs from distinct origins and expose the possibility of targeting LPCs in the treatment of chronic hepatic diseases.

GPC3-IL7-CCL19-CAR-T primes immune microenvironment reconstitution for hepatocellular carcinoma therapy.

BACKGROUND: Chimeric antigen receptor (CAR)-T-cell therapy is a revolutionary treatment that has become a mainstay of advanced cancer treatment. Conventional glypican-3 (GPC3)-CAR-T cells have not produced ideal clinical outcomes in advanced hepatocellular carcinoma (HCC), and the mechanism is unclear. This study aims to investigate the clinical utility of novel GPC3-7-19-CAR-T cells constructed by our team and to explore the mechanisms underlying their antitumor effects. METHODS: We engineered a novel GPC3-targeting CAR including an anti-GPC3 scFv, CD3ζ, CD28 and 4-1BB that induces co-expression of IL-7 at a moderate level (500 pg/mL) and CCL19 at a high level (15000 pg /mL) and transduced it into human T cells. In vitro, cell killing efficacy was validated by the xCELLigence RTCA system, LDH nonradioactive cytotoxicity assay and was confirmed in primary HCC organoid models employing a 3D microfluid chip. In vivo, the antitumor capacity was assessed in a humanized NSG mouse xenograft model. Finally, we initiated a phase I clinical trial to evaluate the safety and effect of GPC3-7-19-CAR-T cells in the clinic. RESULTS: GPC3-7-19-CAR-T cells had 1.5-2 times higher killing efficiency than GPC3-CAR-T cells. The tumor formation rates in GPC3-7-19-CAR-T cells treated model were reduced (3/5vs.5/5), and the average tumor volumes were 0.74 cm3 ± 1.17 vs. 0.34 cm3 ± 0.25. Of note, increased proportion of CD4+ TEM and CD8+ TCM cells was infiltrated in GPC3-7-19-CAR-T cells group. GPC3-7-19-CAR-T cells obviously reversed the immunosuppressive tumor microenvironment (TME) by reducing polymorphonuclear (PMN)-myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells infiltration and recruiting more dendritic cells (DCs) to HCC xenograft tumor tissues. In one patient with advanced HCC, GPC3-7-19-CAR-T-cell treatment resulted in tumor reduction 56 days after intravenous infusion. CONCLUSIONS: In conclusion, GPC3-7-19-CAR-T cells achieved antitumor effects superior to those of conventional GPC3-CAR-T cells by reconstructing the TME induced by the dominant CD4+ TEM and CD8+ TCM cell subsets. Most importantly, GPC3-7-19-CAR-T cells exhibited good safety and antitumor efficacy in HCC patients in the clinic. ► Novel GPC3-7-19-CAR-T cells designed with mediate level of IL-7 secretion and high level of CCL19 secretion, which could recruit more mature DCs to assist killing on GPC3+HCCs. ►DC cells recruited by CCL19 could interact with CD4+ T cells and promote the differentiation of CD4+TEFF cells into CD4+TEM and CD8+TCM subsets, leading a better anti-tumor effect on GPC3+HCCs. ►Compared with conventional GPC3-CAR-T, GPC3-7-CCL19-CAR-T cells could reverse tumor immunosuppressive microenvironment by reducing PMN-MDSC and Treg cell infiltration.

Understanding the degradation mechanism of TTA-based blue fluorescent OLEDs by exciton dynamics and transient electroluminescence measurements.

The lifetime of blue organic light-emitting diodes (OLEDs) has always been a big challenge in practical applications. Blue OLEDs based on triplet-triplet annihilation (TTA) up-conversion materials have potential to achieve long lifetimes due to fusing two triplet excitons to one radiative singlet exciton, but there is a lack of an in-depth understanding of exciton dynamics on degradation mechanisms. In this work, we established a numerical model of exciton dynamics to study the impact factors in the stability of doped blue OLEDs based on TTA up-conversion hosts. By performing transient electroluminescence experiments, the intrinsic parameters related to the TTA up-conversion process of aging devices were determined. By combining the change of excess charge density in the emitting layer (EML) with aging time, it is concluded that the TTA materials are damaged by the excess electrons in the EML during ageing, which is the main degradation mechanism of OLEDs. This work provides a theoretical basis for preparing long-lifetime blue fluorescent OLEDs.

Ultra-Low Intensity Post-Pulse Affects Cellular Responses Caused by Nanosecond Pulsed Electric Fields.

High-intensity nanosecond pulse electric fields (nsPEF) can preferentially induce various effects, most notably regulated cell death and tumor elimination. These effects have almost exclusively been shown to be associated with nsPEF waveforms defined by pulse duration, rise time, amplitude (electric field), and pulse number. Other factors, such as low-intensity post-pulse waveform, have been completely overlooked. In this study, we show that post-pulse waveforms can alter the cell responses produced by the primary pulse waveform and can even elicit unique cellular responses, despite the primary pulse waveform being nearly identical. We employed two commonly used pulse generator designs, namely the Blumlein line (BL) and the pulse forming line (PFL), both featuring nearly identical 100 ns pulse durations, to investigate various cellular effects. Although the primary pulse waveforms were nearly identical in electric field and frequency distribution, the post-pulses differed between the two designs. The BL's post-pulse was relatively long-lasting (~50 µs) and had an opposite polarity to the main pulse, whereas the PFL's post-pulse was much shorter (~2 µs) and had the same polarity as the main pulse. Both post-pulse amplitudes were less than 5% of the main pulse, but the different post-pulses caused distinctly different cellular responses. The thresholds for dissipation of the mitochondrial membrane potential, loss of viability, and increase in plasma membrane PI permeability all occurred at lower pulsing numbers for the PFL than the BL, while mitochondrial reactive oxygen species generation occurred at similar pulsing numbers for both pulser designs. The PFL decreased spare respiratory capacity (SRC), whereas the BL increased SRC. Only the PFL caused a biphasic effect on trans-plasma membrane electron transport (tPMET). These studies demonstrate, for the first time, that conditions resulting from low post-pulse intensity charging have a significant impact on cell responses and should be considered when comparing the results from similar pulse waveforms.

Copper enhanced arsenic-accumulation in As-hyperaccumulator Pteris vittata by upregulating its gene expression for As uptake, translocation, and sequestration.

In contaminated soils, arsenic (As) often co-exists with copper (Cu). However, its effects on As accumulation and the related mechanisms in As-hyperaccumulator Pteris vittata remain unclear. In this study, P. vittata plants were exposed to 50 µM As and/or 50 µM Cu under hydroponics to investigate the effects of Cu on plant growth and As accumulation, as well as gene expression related to arsenic uptake (P transporters), reduction (arsenate reductases), and translocation and sequestration (arsenite antiporters). After 14 d of growth and compared to the As treatment, the As concentration in P. vittata fronds increased by 1.4-times from 793 to 1131 mg·kg-1 and its biomass increased by 1.2-fold from 18.0 to 21.1 g·plant-1 in the As+Cu treatment. Copper-enhanced As accumulation was probably due to upregulated gene expressions related to As-metabolisms including As uptake (1.9-fold in P transporter PvPht1;3), translocation (2.1-2.4 fold in arsenite antiporters PvACR3/3;2) and sequestration (1.5-2.0 fold in arsenite antiporters PvACR3;1/3;3). Our results suggest that moderate amount of Cu can help to increase the As accumulation efficiency in P. vittata, which has implication in its application in phytoremedation in As and Cu co-contaminated soils.