TET1 and TDG Suppress Inflammatory Response in Intestinal Tumorigenesis: Implications for Colorectal Tumors With the CpG Island Methylator Phenotype.

BACKGROUND & AIMS: Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathologic consequences are poorly understood. METHODS: We disrupted active DNA demethylation genes Tet1 and/or Tdg from ApcMin mice and characterized the methylome and transcriptome of colonic adenomas. Data were compared to human colonic adenocarcinomas (COAD) in The Cancer Genome Atlas. RESULTS: There were increased numbers of small intestinal adenomas in ApcMin mice expressing the TdgN151A allele, whereas Tet1-deficient and Tet1/TdgN151A-double heterozygous ApcMin colonic adenomas were larger with features of erosion and invasion. We detected reduction in global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-mutant ApcMin mice and hypermethylation of CpG islands in Tet1-mutant ApcMin adenomas. Up-regulation of inflammatory, immune, and interferon response genes was present in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. This up-regulation was also seen in murine colonic organoids and human CRC lines infected with lentiviruses expressing TET1 or TDG short hairpin RNA. A 127-gene inflammatory signature separated colonic adenocarcinomas into 4 groups, closely aligned with their microsatellite or chromosomal instability and characterized by different levels of DNA methylation and DNMT1 expression that anticorrelated with TET1 expression. Tumors with the CpG island methylator phenotype (CIMP) had concerted high DNMT1/low TET1 expression. TET1 or TDG knockdown in CRC lines enhanced killing by natural killer cells. CONCLUSIONS: Our findings reveal a novel epigenetic regulation, linked to the type of genomic instability, by which TET1/TDG-mediated DNA demethylation decreases methylation levels and inflammatory/interferon/immune responses. CIMP in CRC is triggered by an imbalance of methylating activities over demethylating activities. These mice represent a model of CIMP CRC.

Sequential Activation of Two Pathogen-Sensing Pathways Required for Type I Interferon Expression and Resistance to an Acute DNA Virus Infection.

Toll-like receptor 9 (TLR9), its adaptor MyD88, the downstream transcription factor interferon regulatory factor 7 (IRF7), and type I interferons (IFN-I) are all required for resistance to infection with ectromelia virus (ECTV). However, it is not known how or in which cells these effectors function to promote survival. Here, we showed that after infection with ECTV, the TLR9-MyD88-IRF7 pathway was necessary in CD11c(+) cells for the expression of proinflammatory cytokines and the recruitment of inflammatory monocytes (iMos) to the draining lymph node (dLN). In the dLN, the major producers of IFN-I were infected iMos, which used the DNA sensor-adaptor STING to activate IRF7 and nuclear factor κB (NF-κB) signaling to induce the expression of IFN-α and IFN-ß, respectively. Thus, in vivo, two pathways of DNA pathogen sensing act sequentially in two distinct cell types to orchestrate resistance to a viral disease.

Correlation between the changes of brain amplitude of low-frequency fluctuation and cognitive impairment in patients with neuropsychiatric lupus.

PURPOSE: To explore the relationship between brain function changes and clinical serological indicators and behavioral cognitive assessment in patients with neuropsychiatric systemic lupus erythematosus (NPSLE), and understand the pathogenesis of NPSLE from the perspective of imaging. METHODS: The resting-state functional imaging data, clinical serological, and behavioral cognitive assessment scores of 28 patients with NPSLE and 22 healthy controls (HC) were prospectively collected. The resting-state amplitude of low-frequency fluctuation (ALFF) values obtained from the analysis and processing were correlated with the serological data and behavioral cognitive assessment scores to determine the relationship between these data. RESULTS: The average age of the patients of the NPSLE group was older than that of the HC group; significant differences in education level, Auditory Verbal Learning Test Hua Shan Version (AVLT-H), and Trail Making Test scores were observed between the two groups. The NPSLE group demonstrated increased brain activity in the insula, precentral gyrus, and superior temporal gyrus, and decreased brain activity in the superior parietal gyrus. The ALFF value of the insula positively correlated with the Anti-ß2gp1 antibody and negatively correlated with the anti-nucleosome antibody and the AVL-recall (RC) score. The ALFF of the precentral gyrus negatively correlated with the AVL-immediate recall (I). The ALFF value of the superior temporal gyrus negatively correlated with the AVL-RC score. The left superior parietal gyrus positively correlated with the c-reactive protein. The right superior parietal gyrus positively correlated with the System Lupus Erythematosus Disease Activity Index and negatively correlated with the AVL-I score. CONCLUSION: Patients with NPSLE show different brain activity changes in different brain regions, and the abnormal brain regions are correlated with certain lupus antibodies, inflammatory factors, and cognitive assessment, thereby suggesting that the correlation between the three could provide novel insights into the pathogenesis of NPSLE.

Synergistic cooperation between the ß-catenin and SF1 regulates progesterone synthesis in laying hen ovarian granulosa cells.

The development of ovarian follicles in poultry is a key factor affecting the performance of egg production. Ovarian follicle development is regulated via the Wnt/ß-catenin signaling pathway, and ß-catenin, encoded by CTNNB1, is a core component of this pathway. In this study, using ovary GCs from laying hens, we investigated the regulatory role of CTNNB1 in steroid synthesis. We found that CTNNB1 significantly regulates the expression of StAR and CYP11A1 (key genes related to progesterone synthesis) and the secretion of progesterone (P4). Furthermore, simultaneous overexpression of CTNNB1 and SF1 resulted in significantly higher levels of CYP11A1 and secretion of P4 than in cells overexpressing CTNNB1 or SF1 alone. We also found that in GCs overexpressing SF1, levels of CYP11A1 and secreted P4 were significantly greater than in controls. Silencing of CYP11A1 resulted in the inhibition of P4 secretion while overexpression of SF1 in CYP11A1-silenced cells restored P4 secretion to normal levels. Together, these results indicate that synergistic cooperation between the ß-catenin and SF1 regulates progesterone synthesis in laying hen ovarian hierarchical granulosa cells to promote CYP11A1 expression.

Aesthetic impact of resin infiltration and its mechanical effect on ceramic bonding for white spot lesions.

BACKGROUND: Treating white spot lesions (WSLs) with resin infiltration alone may not be sufficient, raising questions about its compatibility with other treatments amid controversial or incomplete data. Therefore, this study aimed to assess the aesthetic feasibility of resin infiltration combined with bleaching, as well as its potential mechanical effect on ceramic bonding to WSLs. METHODS: One hundred and fifty flat enamel surfaces of bovine incisors were prepared. Ninety specimens were deminerailized and randomly assigned to three groups(n = 30): post-bleaching resin infiltration (Bl-R), pre-bleaching resin infiltration (R-Bl), and only resin infiltration (R). Color, surface roughness and microhardness were assessed in immediate, thermocycling and pigmentation tests. The remaining sixty samples were randomly assigned to three groups (n = 20): control (Ctrl), bonding (Bo), pre-bonding resin infiltration (R-Bo). Shear bonding strength, failure mode, micro-leakage depth and interface morphology were evaluated after ceramic bonding. The Tukey test and analysis of variance (ANOVA) were used for statistical analysis. RESULTS: For the effect of resin infiltration and bleaching on WSLs, the R-Bl group showed the worst chromic masking ability, with the highest |ΔL|, |Δa|, |Δb|, and ΔE values after treatment. Compared with those in the Bl-R group, the R-Bl and R groups showed significant time-dependent staining, which is possibly attributed to their surface roughness. For the effect of resin infiltration on the adhesive properties of WSLs, resin infiltration reduced the staining penetration depth of WSLs from 2393.54 ± 1118.86 µm to 188.46 ± 89.96 µm (P < 0.05) while reducing WSLs porosity in SEM observation. CONCLUSIONS: Post-bleaching resin infiltration proved to be advantageous in the aesthetic treatment of WSLs. Resin infiltration did not compromise bonding strength but it did reduce microleakage and enhance marginal sealing. Overall, resin infiltration can effectively enhance the chromatic results of treated WSLs and prevent long-term bonding failure between ceramics and enamel. Based on these findings, the use of post-bleaching resin infiltration is recommended, and resin infiltration before ceramic bonding is deemed viable in clinical practice.

Tandem Synergistic Effect of Cu-In Dual Sites Confined on the Edge of Monolayer CuInP2 S6 toward Selective Photoreduction of CO2 into Multi-Carbon Solar Fuels.

One-unit-cell, single-crystal, hexagonal CuInP2 S6 atomically thin sheets of≈0.81 nm in thickness was successfully synthesized for photocatalytic reduction of CO2 . Exciting ethene (C2 H4 ) as the main product was dominantly generated with the yield-based selectivity reaching ≈56.4 %, and the electron-based selectivity as high as ≈74.6 %. The tandem synergistic effect of charge-enriched Cu-In dual sites confined on the lateral edge of the CuInP2 S6 monolayer (ML) is mainly responsible for efficient conversion and high selectivity of the C2 H4 product as the basal surface site of the ML, exposing S atoms, can not derive the CO2 photoreduction due to the high energy barrier for the proton-coupled electron transfer of CO2 into *COOH. The marginal In site of the ML preeminently targets CO2 conversion to *CO under light illumination, and the *CO then migrates to the neighbor Cu sites for the subsequent C-C coupling reaction into C2 H4 with thermodynamic and kinetic feasibility. Moreover, ultrathin structure of the ML also allows to shorten the transfer distance of charge carriers from the interior onto the surface, thus inhibiting electron-hole recombination and enabling more electrons to survive and accumulate on the exposed active sites for CO2 reduction.

Reversal of neurovascular decoupling and cognitive impairment in patients with end-stage renal disease during a hemodialysis session: Evidence from a comprehensive fMRI analysis.

Neurovascular (NV) decoupling is a potential neuropathologic mechanism of cognitive impairment in patients with end-stage renal disease (ESRD). Hemodialysis improves cognitive impairment at 24 h post-dialysis, which suggests a potential neuroprotective effect of hemodialysis treatment on the brain. We investigated the effects of hemodialysis treatment on the reversal of NV decoupling associated with cognitive improvement. A total of 39 patients with ESRD and 39 healthy controls were enrolled. All patients were imaged twice during a dialysis session: before hemodialysis (T1pre-dialysis ) and at 24 h after dialysis (T2post-dialysis ). The healthy controls were imaged once. NV coupling was characterized based on correlation coefficients between four types of blood oxygen level-dependent signals and cerebral blood flow (CBF). A battery of neuropsychological and blood tests was performed before the imaging. Patients with ESRD showed improvements in memory and executive function at T2post-dialysis compared with that at T1pre-dialysis . At both T1pre-dialysis and T2post-dialysis , patients with ESRD had lower amplitude of low-frequency fluctuation (ALFF)-CBF coupling than healthy controls. Additionally, patients with ESRD had higher ALFF-CBF coupling at T2post-dialysis than at T1pre-dialysis . Higher memory scores, higher hemoglobin level, lower total plasma homocysteine level, lower systolic blood pressure variance, and lower ultrafiltration volume were associated with higher ALFF-CBF coupling in patients with ESRD after a hemodialysis session. These findings indicate that partial correction of anemia and hyperhomocysteinemia, stable systolic blood pressure, and fluid restriction may be closely linked to the reversal of NV decoupling and improvement in cognition in patients with ESRD.

Matching CP@NCOH/NF Cathode and GH/FNP/NF Anode for High-Performance Asymmetric Supercapacitor.

It is extremely crucial to design and match high-quality cathode and anode for achieving high-performance asymmetric supercapacitors (ASCs). Herein, Co3 (PO4 )2 @NiCo-LDH/Ni foam (CP@NCOH/NF) cathode with hierarchical morphology and graphene hydrogel/Fe-Ni phosphide/Ni foam (GH/FNP/NF) anode with the robust and porous structure are elaborately designed and prepared, respectively. Owing to their unique and profitable structures, both CP@NCOH/NF and GH/FNP/NF electrodes yield the superior capacity (10760 and 2236 mC cm-2 at 2 mA cm-2 , respectively), good rate capability (63% retention at 200 mA cm-2 and 52% retention at 50 mA cm-2 , respectively), and excellent cycling stability (72% and 74% retention after 10 000 cycles, respectively). Benefiting from their matchable electrochemical performances, the configured solid-state CP@NCOH/NF//GH/FNP/NF ASC outputs both competitive energy density (80.2 Wh kg-1 /4.1 mWh cm-3 ) and power density (14563 W kg-1 /750 mW cm-3 ), companied by remarkable cyclability (71% retention after 10 000 cycles), manifesting its great promise for large-scale integrated energy-storage system.

Evaluation of diffuse glioma grade and proliferation activity by different diffusion-weighted-imaging models including diffusion kurtosis imaging (DKI) and mean apparent propagator (MAP) MRI.

PURPOSE: To evaluate two advanced diffusion models, diffusion kurtosis imaging and the newly proposed mean apparent propagation factor-magnetic resonance imaging, in the grading of gliomas and the assessing of their proliferative activity. METHODS: Fifty-nine patients with clinically diagnosed and pathologically proven gliomas were enrolled in this retrospective study. All patients underwent DKI and MAP-MRI scans. Manually outline the ROI of the tumour parenchyma. After delineation, the imaging parameters were extracted using only the data from within the ROI including mean diffusion kurtosis (MK), return-to-origin probability (RTOP), Q-space inverse variance (QIV) and non-Gaussian index (NG), and the differences in each parameter in the classification of glioma were compared. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of these parameters. RESULTS: MK, NG, RTOP and QIV were significantly different amongst the different grades of glioma. MK, NG and RTOP had excellent diagnostic value in differentiating high-grade from low-grade glioma, with largest areas under the curve (AUCs; 0.929, 0.933 and 0.819, respectively; P < 0.01). MK and NG had the largest AUCs (0.912 and 0.904) when differentiating grade II tumours from III tumours (P < 0.01) and large AUCs (0.791 and 0.786) when differentiating grade III from grade IV tumours. Correlation analysis of tumour proliferation activity showed that MK, NG and QIV were strongly correlated with the Ki-67 LI (P < 0.001). CONCLUSION: MK, RTOP and NG can effectively represent the microstructure of these altered tumours. Multimodal diffusion-weighted imaging is valuable for the preoperative evaluation of glioma grade and tumour proliferative activity.

Abnormal grey matter structural changes in patients with end-stage kidney disease and mild cognitive impairment: correlations with clinical features.

End-stage kidney disease and mild cognitive impairment (ESKD-MCI) affect the quality of life and long-term treatment outcomes of patients affected by these diseases. Clarifying the morphological changes from brain injuries in ESKD-MCI and their relationship with clinical features is helpful for the early identification and intervention of MCI before it progresses to irreversible dementia. This study gathered data from 23 patients with ESKD-MCI, 24 patients with ESKD and non-cognitive impairment (NCI), and 27 health controls (HCs). Structural magnetic resonance studies, cognitive assessments, and general clinical data were collected from all participants. Voxel-based morphometry analysis was performed to compare grey matter (GM) volume differences between the groups. The patients' GM maps and clinical features were subjected to univariate regression to check for possible correlations. Patients with ESKD-MCI displayed significantly more impairments in multiple cognitive domains, including global cognition, visuospatial and executive function, and memory, compared to patients with ESKD-NCI. Using a more liberal threshold (P < 0.001, uncorrected), we found that compared to patients with ESKD-NCI, patients with ESKD-MCI exhibited clusters of regions with lower GM volumes, including the right hippocampus (HIP), parahippocampal gyrus (PHG), Rolandic operculum, and supramarginal gyrus. The volumes of the right HIP and PHG were negatively correlated with serum calcium levels. ESKD-MCI was associated with a subtle volume reduction of GM in several brain areas known to be involved in memory, language, and auditory information processing. We speculate that these slight morphometric impairments may be associated with disturbed calcium metabolism.

Dyadic psycho-social interventions for stroke survivors and family caregivers: A systematic review and meta-analysis of randomized controlled trials.

AIMS AND OBJECTIVES: To describe dyadic psycho-social intervention measures and to evaluate their influence on stroke survivors and caregiver's functional independence, quality of life, depression, anxiety, self-efficacy and coping ability. BACKGROUND: Because of the importance of dyadic intervention and the seriousness of the psycho-social problems of stroke survivors and caregivers, understanding the influence of dyadic psycho-social interventions is vital. DESIGN: A systematic review and meta-analysis based on PRISMA guidelines. DATA SOURCES: Nine databases were systematically searched for randomized controlled trials submitted from 1910 to 4 July 2022. METHODS: The included papers were evaluated for quality, and quantitative data were standardly extracted and analysed by meta-analysis, followed by synthesis. The meta-analysis was carried out using Review Manager 5.4 software. RESULTS: Fifteen randomized controlled trials were included (n = 2190 for patients, and n = 1933 for caregivers). Study results showed that dyadic psycho-social interventions significantly alleviated the depressive symptoms of patients, obviously improved the ability to function independently of patients and more quickly alleviated the care burden of caregivers. CONCLUSIONS: This study provided moderate support for the benefits of dyadic psycho-social intervention in improving survivor and caregiver's functional independence, quality of life, depression, anxiety, self-efficacy and care burden. Nevertheless, due to limitations of the study, it was deemed necessary that this topic is studied further. RELEVANCE TO CLINICAL PRACTICE: This review suggests that dyadic psycho-social interventions should be considered as effective strategies for decreasing psycho-social problems of stroke survivors and caregivers, and provides evidence for the formulation of targeted intervention programs. The personalized implementation of such interventions should be the focus of clinical practice. NO PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public contribution.

Health promoting properties and sensory characteristics of phytochemicals in berries and leaves of sea buckthorn (Hippophaë rhamnoides).

Sea buckthorn (Hippophaë rhamnoides L., SB), as a multi-functional plant, is widely grown in Asia, Europe and Canada. The berries and leaves of SB contain a diverse array of health-supporting phytochemicals, which are also related to the sensory qualities of berry and berry products. This review summarizes the biologically active key-compounds of the berries and leaves of SB, their health-promoting effects, as well as the contributions to the sensory quality of the berries. The target compounds consist of sugars, sugar derivatives, organic acids, phenolic compounds and lipophilic compounds (mainly carotenoids and tocopherols), which play an important role in anti-inflammatory and antioxidant functions, as well as in metabolic health. In addition, these compounds contribute to the orosensory qualities of SB berries, which are closely related to consumer acceptance and preference of the products. Studies regarding the bioavailability of the compounds and the influence of the processing conditions are also part of this review. Finally, the role of the sensory properties is emphasized in the development of SB products to increase utilization of the berry as a common meal component and to obtain value-added products to support human health.

Simple and effective serum biomarkers potential for predicting status epilepticus in anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: Patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis who also present with status epilepticus (SE) often have a poor prognosis. The aim of this study is to explore simple and effective predictors for anti-NMDAR encephalitis accompanied with SE. METHODS: We retrospectively analyzed 65 anti-NMDAR encephalitis patients from January 2015 to December 2018 who admitted to the Third Affiliated Hospital of Sun Yat-sen University. Patients were divided into SE group and non-SE groups. Their pre-treatment data and 3-month follow-up data were retrospectively analyzed. RESULTS: The results showed that compared with the non-SE group, the levels of serum uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) in anti-NMDAR encephalitis patients with SE decreased significantly before treatment. Additionally, the levels of serum UA and HDL-C increased while the level of C-reactive protein (CRP) decreased 3 months after treatment in the SE group. Compared with the non-SE group, the SE patients had higher modified Rankin scale (mRS) scores before (mRS1) and after treatment (mRS2). Serum UA concentrations before treatment showed significantly negative correlations with mRS1 (r = - 0.407, p < 0.01) and mRS2 (r = - 0.458, p < 0.001), while the level of serum CRP before treatment had strong positive correlations with mRS1 (r = 0.304, p < 0.05) and mRS2 (r = 0.301, p < 0.05) in anti-NMDAR encephalitis patients. The receiver operating characteristic curve demonstrated that the combined detection of UA, HDL-C and CRP before treatment had a significantly higher value (the area under the curve = 0.848; 95% confidence interval [CI], 0.74-0.957; p < 0.001) to predict anti-NMDAR encephalitis accompanied with SE than that of single detection. CONCLUSIONS: Hence, the combined detection of serum UA, HDL-C and CRP before treatment may be simple and effective indicators for predicting SE in anti-NMDAR encephalitis, which may be helpful in early stages to remind clinicians to be alert to the emergence of SE.

Multiparametric MR radiomics in brain glioma: models comparation to predict biomarker status.

BACKGROUND: Genotype status of glioma have important significance to clinical treatment and prognosis. At present, there are few studies on the prediction of multiple genotype status in glioma by method of multi-sequence radiomics. The purpose of the study is to compare the performance of clinical features (age, sex, WHO grade, MRI morphological features etc.), radiomics features from multi MR sequence (T2WI, T1WI, DWI, ADC, CE-MRI (contrast enhancement)), and a combined multiple features model in predicting biomarker status (IDH, MGMT, TERT, 1p/19q of glioma. METHODS: In this retrospective analysis, 81 glioma patients confirmed by histology were enrolled in this study. Five MRI sequences were used for radiomic feature extraction. Finally, 107 features were extracted from each sequence on Pyradiomics software, separately. These included 18 first-order metrics, such as the mean, standard deviation, skewness, and kurtosis etc., 14 shape features and second-order metrics including 24 grey level run length matrix (GLCM), 16 grey level run length matrix (GLRLM), 16 grey level size zone matrix (GLSZM), 5 neighboring gray tone difference matrix (NGTDM), and 14 grey level dependence matrix (GLDM). Then, Univariate analysis and LASSO (Least absolute shrinkage and selection operator regression model were used to data dimension reduction, feature selection, and radiomics signature building. Significant features (p < 0.05 by multivariate logistic regression were retained to establish clinical model, T1WI model, T2WI model, T1 + C (T1WI contrast enhancement model, DWI model and ADC model, multi sequence model. Clinical features were combined with multi sequence model to establish a combined model. The predictive performance was validated by receiver operating characteristic curve (ROC analysis and decision curve analysis (DCA). RESULTS: The combined model showed the better performance in some groups of genotype status among some models (IDH AUC = 0.93, MGMT AUC = 0.88, TERT AUC = 0.76). Multi sequence model performed better than single sequence model in IDH, MGMT, TERT. There was no significant difference among the models in predicting 1p/19q status. Decision curve analysis showed combined model has higher clinical benefit than multi sequence model. CONCLUSION: Multi sequence model is an effective method to identify the genotype status of cerebral glioma. Combined with clinical models can better distinguish genotype status of glioma. KEY POINTS: The combined model showed the higher performance compare with other models in predicting genotype status of IDH, MGMT, TERT. Multi sequence model showed a better predictive model than that of a single sequence model. Compared with other models, the combined model and multi sequence model show no advantage in prediction of 1p/19q status.

Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice.

BACKGROUND: Constipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). METHODS: Constipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood-brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-ß, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups. RESULTS: Compared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood-brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-ß, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota. CONCLUSIONS: Our results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice.

Cutting Edge: Protection by Antiviral Memory CD8 T Cells Requires Rapidly Produced Antigen in Large Amounts.

Numerous attempts to produce antiviral vaccines by harnessing memory CD8 T cells have failed. A barrier to progress is that we do not know what makes an Ag a viable target of protective CD8 T cell memory. We found that in mice susceptible to lethal mousepox (the mouse homolog of human smallpox), a dendritic cell vaccine that induced memory CD8 T cells fully protected mice when the infecting virus produced Ag in large quantities and with rapid kinetics. Protection did not occur when the Ag was produced in low amounts, even with rapid kinetics, and protection was only partial when the Ag was produced in large quantities but with slow kinetics. Hence, the amount and timing of Ag expression appear to be key determinants of memory CD8 T cell antiviral protective immunity. These findings may have important implications for vaccine design.

Abnormal rich club organization in end-stage renal disease patients before dialysis initiation and undergoing maintenance hemodialysis.

BACKGROUND: End-stage renal disease (ESRD) patients are at a substantially higher risk for developing cognitive impairment compared with the healthy population. Dialysis is an essential way to maintain the life of ESRD patients. Based on previous research, there isn't an uncontested result whether cognition was improved or worsened during dialysis. METHODS: To explore the impact of dialysis treatment on cognitive performance, we recruited healthy controls (HCs), predialysis ESRD patients (predialysis group), and maintenance hemodialysis ESRD patients (HD group). All ESRD patients performed six blood biochemistry tests (hemoglobin, urea, cystatin C, Na+, K+, and parathyroid hormone). Neuropsychological tests were used to measure cognitive function. By using diffusion tensor imaging and graph-theory approaches, the topological organization of the whole-brain structural network was investigated. Generalized linear models (GLMs) were performed to investigate blood biochemistry predictors of the neuropsychological tests and the results of graph analyses in the HD group and predialysis group. RESULTS: Neuropsychological analysis showed the HD group exhibited better cognitive function than the predialysis group, but both were worse than HCs. Whole-brain graph analyses revealed that increased global efficiency and normalized shortest path length remained in the predialysis group and HD group than the HCs. Besides, a lower normalized clustering coefficient was found in the predialysis group relative to the HCs and HD group. For the GLM analysis, only the Cystatin C level was significantly associated with the average fiber length of rich club connections in the predialysis group. CONCLUSIONS: Our study revealed that dialysis had a limited effect on cognitive improvement.

Groundwater hydrogeochemical formation and evolution in a karst aquifer system affected by anthropogenic impacts.

Karst groundwater, an important water source, is often highly influenced by human impacts, causing environmental damage and threats to human health. However, studies on the anthropogenic influences on the hydrogeochemical evolution of karst groundwater are relatively rare. To assess hydrogeochemical formation and evolution, we focused on a typical karst groundwater system (Jinan, China) which is composed of cold groundwater (av. temperature 13-17 °C), springs and geothermal water (av. temperature > 30 °C) and is significantly affected by human activities. The study was performed by means of water samples collecting and analyzing and isotope analysis (2H, 18O and 14C). The statistical analysis and inverse models were also applied to further understand geochemical processes and anthropogenic influences. The 2H, 18O and 14C results indicate that the cold karst groundwater is easily influenced and contaminated by the local environment, while geothermal water is relatively old with a slow rate of recharge. The hydrochemical types of cold karst groundwater are mainly HCO3-Ca and HCO3·SO4-Ca, while geothermal water hydrochemical types are SO4-Ca·Na and SO4-Ca. Groundwater Ca2+, Mg2+, HCO3- and SO42- are mainly controlled by carbonate equilibrium, gypsum dissolution and dedolomitization. Groundwater Na+, K+ and Cl- are mainly derived from halite dissolution, and in geothermal water, they are also affected by incongruent dissolution of albite and K-feldspar. Anthropogenic nitrogen produces ammonium resulting in nitrification and reduction in CO2(g) consumption and HCO3- release from carbonate dissolution. Principal component analysis and inverse models also indicate that nitrification and denitrification have significantly affected water-rock interactions. Our study suggests that karst groundwater quality is dominated by water-rock interactions and elucidates the influence of anthropogenic nitrogen. We believe that this paper will be a good reference point to study anthropogenic influences on the groundwater environment and to protect karst groundwater globally.

Altered white matter microstructure mediates the relationship between hemoglobin levels and cognitive control deficits in end-stage renal disease patients.

The brain-kidney crosstalk theory suggested that the brain and kidneys may be considered end organs on parallel trajectories and subject to shared risk factors, which are receiving increasing attention. Cognitive control deficits were frequently presented in patients with end-stage renal disease (ESRD). Whether or not cognitive control impairment is concerned with brain-kidney crosstalk is in need of further research. To detect the relationship between ESRD and cognitive control impairment, diffusion tensor imaging was collected in 64 healthy controls (HCs) and 64 patients with ESRD. Tract-based spatial statistics and fixel-based analysis were used to detect the difference of white matter (WM) microstructure and morphology between ESRD patients and HCs in the whole brain. Tractography atlas-based analysis was also used to investigate the difference of diffusional characteristics along fiber bundles of interest between the two groups. For the whole-brain analysis, ESRD patients showed WM microstructural alteration and fiber density variation in the cingulum. In addition, ESRD patients exhibited higher MD and RD than HCs along the anterior cingulum. Among all of the blood biochemistry tests that represent kidney disease to a degree, the stepwise regression analysis showed that only hemoglobin significantly contributed to the cognitive control deficits in ESRD patients. Mediation analysis proved that the relationship between hemoglobin and cognitive control deficits of ESRD patients was mediated by WM microstructural alteration of the cingulum. Our results indicated that the anterior cingulum was correlated with cognitive control deficits and mediated the impact of hemoglobin on cognitive control.

Association between abnormal thalamic metabolites and sleep disturbance in patients with end-stage renal disease.

Sleep disturbances are common in end-stage renal disease (ESRD) patients. However, the underlying neuropathological mechanisms are largely unclear. Previous studies have revealed the important role of the thalamus in the potential mechanisms of sleep disorders. We hypothesized that the sleep disturbances in ESRD patients may correspond to metabolic changes of thalamus and the uremic factors may have a vital contribution on these changes. We performed multi-voxel 1H-MRS of bilateral thalami in 27 ESRD patients who currently receiving hemodialysis treatment and 21 age-matched healthy volunteers. ESRD patients underwent Pittsburgh Sleep Quality Index (PSQI) scale and restless legs syndrome (RLS) rating scale assessment. Laboratory blood tests including serum creatinine, serum urea, cystatin-C, serum parathyroid hormone (PTH), calcium and phosphorus levels, hemoglobin and hematocrit were performed in all ESRD patients close to the time of the MR examination. We found correlations among elevated PTH, higher PSQI score and RLS rating score in ESRD patients. ESRD patients displayed decreased N-acetylaspartate and creatine ratio (NAA/Cr) of thalami compared with controls. There were significantly negative correlation between NAA/Cr and serum PTH level or PSQI score. The metabolic changes of thalami played an important role in the neuropathological mechanisms of lower sleep quality in ESRD patients. Secondary hyperparathyroidism as one of the main uremia-related factors was closely related to abnormal metabolites of the thalamus in patients with ESRD, revealing the crosstalk procedure between renal impairment and brain function.