Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8+ T cell effector functions.

Concentrations of the secondary bile acid, deoxycholic acid (DCA), are aberrantly elevated in colorectal cancer (CRC) patients, but the consequences remain poorly understood. Here, we screened a library of gut microbiota-derived metabolites and identified DCA as a negative regulator for CD8+ T cell effector function. Mechanistically, DCA suppressed CD8+ T cell responses by targeting plasma membrane Ca2+ ATPase (PMCA) to inhibit Ca2+-nuclear factor of activated T cells (NFAT)2 signaling. In CRC patients, CD8+ T cell effector function negatively correlated with both DCA concentration and expression of a bacterial DCA biosynthetic gene. Bacteria harboring DCA biosynthetic genes suppressed CD8+ T cells effector function and promoted tumor growth in mice. This effect was abolished by disrupting bile acid metabolism via bile acid chelation, genetic ablation of bacterial DCA biosynthetic pathway, or specific bacteriophage. Our study demonstrated causation between microbial DCA metabolism and anti-tumor CD8+ T cell response in CRC, suggesting potential directions for anti-tumor therapy.

Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition.

The gut microbiota play a pivotal role in human health. Emerging evidence indicates that gut microbes participate in the progression of tumorigenesis through the generation of carcinogenic metabolites. However, the underlying molecular mechanism is largely unknown. In the present study we show that a tryptophan metabolite derived from Peptostreptococcus anaerobius, trans-3-indoleacrylic acid (IDA), facilitates colorectal carcinogenesis. Mechanistically, IDA acts as an endogenous ligand of an aryl hydrocarbon receptor (AHR) to transcriptionally upregulate the expression of ALDH1A3 (aldehyde dehydrogenase 1 family member A3), which utilizes retinal as a substrate to generate NADH, essential for ferroptosis-suppressor protein 1(FSP1)-mediated synthesis of reduced coenzyme Q10. Loss of AHR or ALDH1A3 largely abrogates IDA-promoted tumour development both in vitro and in vivo. It is interesting that P. anaerobius is significantly enriched in patients with colorectal cancer (CRC). IDA treatment or implantation of P. anaerobius promotes CRC progression in both xenograft model and ApcMin/+ mice. Together, our findings demonstrate that targeting the IDA-AHR-ALDH1A3 axis should be promising for ferroptosis-related CRC treatment.

A lncRNA from an inflammatory bowel disease risk locus maintains intestinal host-commensal homeostasis.

Inflammatory bowel diseases (IBD) are known to have complex, genetically influenced etiologies, involving dysfunctional interactions between the intestinal immune system and the microbiome. Here, we characterized how the RNA transcript from an IBD-associated long non-coding RNA locus ("CARINH-Colitis Associated IRF1 antisense Regulator of Intestinal Homeostasis") protects against IBD. We show that CARINH and its neighboring gene coding for the transcription factor IRF1 together form a feedforward loop in host myeloid cells. The loop activation is sustained by microbial factors, and functions to maintain the intestinal host-commensal homeostasis via the induction of the anti-inflammatory factor IL-18BP and anti-microbial factors called guanylate-binding proteins (GBPs). Extending these mechanistic insights back to humans, we demonstrate that the function of the CARINH/IRF1 loop is conserved between mice and humans. Genetically, the T allele of rs2188962, the most probable causal variant of IBD within the CARINH locus from the human genetics study, impairs the inducible expression of the CARINH/IRF1 loop and thus increases genetic predisposition to IBD. Our study thus illustrates how an IBD-associated lncRNA maintains intestinal homeostasis and protects the host against colitis.

Specific white matter connectomic changes in schizophrenia compared with psychotic bipolar disorder.

BACKGROUND: Schizophrenia (SZ) and bipolar disorder with psychosis (BDP) can be clinically confusing. The specific connectomic changes in SZ compared with BDP may lead to a deeper comprehension of the pathophysiological core of SZ. Therefore, this study explored the common and distinct white matter (WM) structural connectomic alterations between these two diseases. METHOD: Diffusion tensor imaging data were collected from 19 drug-naïve patients with first episode SZ, 19 drug-naïve patients with BDP, and 19 healthy controls (HC). A graph theoretical approach was used to assess the brain WM network properties. RESULTS: Except for the clustering coefficients, no significant differences in the global parameters was found between SZ and BDP. Five brain regions, the right precentral, right post-cingulum, right insula, left superior occipital, and left inferior temporal gyri, showed specific differences in the nodal parameters in SZ compared with BDP and HC. Nine brain regions, the left rectus, left lingual, right inferior parietal, left superior temporal, right precentral, right postcentral, bilateral middle frontal, and right post-cingulum gyri, showed specific differences in the nodal parameters in BDP. Significant correlations between clinical symptoms and connectomic changes were detected in the right insula and left superior occipital gyrus in patients with SZ but in the left lingual gyrus in patients with BDP. CONCLUSIONS: Identifying shared and distinct WM structural networks between SZ and BDP may improve the understanding of the neuroanatomy of mental diseases. Specifically, the insula, the inferior temporal, superior temporal, and the lingual gyri may help to distinguish between SZ and BDP.

The correlation between metabolic syndrome and neurocognitive and social cognitive performance of patients with schizophrenia.

Cognitive impairment is one of the core symptoms of schizophrenia, and patients with schizophrenia are at increased risk of metabolic syndrome (MS). However, the role of MS in cognitive impairment of schizophrenia is not established. This study investigated the correlation between neurocognitive, social cognitive performance and MS with schizophrenia. One hundred and fifty eight (158) schizophrenia patients were divided into 3 groups with ① normal metabolism, ② metabolic disorder (only meeting 1 or 2 MS criteria), and ③ metabolic syndrome (meeting 3 or more MS criteria). MATRICS Consensus Cognitive Battery)MCCB(and the Brief Psychiatric Rating Scale)BPRS(were used to evaluate cognitive performance and clinical symptoms. Blood samples were obtained to detect glucose and lipid metabolic levels. Overall MCCB and subscale T scores in the normal metabolism and metabolic disorder groups were better than in the MS group. After controlling for the confounding factors including age, sex, the usage of hypolipidemic and hypoglycemic drugs, and disease duration, metabolic deficits had effects on the symbol coding and spatial span scores. The results suggest that a defective metabolic state might play a role in neurocognitive performance of schizophrenia patients.

The role of altered brain structural connectivity in resilience, vulnerability, and disease expression to schizophrenia.

BACKGROUND: Schizophrenia (SCZ) is a highly heritable disorder associated with brain connectivity changes. Although the mechanism of disease expression and vulnerability of SCZ have been reported by previous studies, the mechanism of resilience to SCZ based on the brain structural connectivity is poorly understood. The goal of the present study was to identify the structural brain connectivity related with the resilience to SCZ, which is defined here as the capacity to avoid or delay the onset of SCZ in unaffected siblings of SCZ probands. METHOD: We collected diffusion tensor imaging (DTI) data of 49 medication-naive, first-episode SCZ (FE-SCZ) patients, 56 unaffected siblings of SCZ probands (SIB-SCZ), and 90 healthy controls. Then we used graph theoretical approach to calculate the topological properties of the brain structural network, including global, subnetwork, and regional parameters. Finally, we compared the parameters between the three groups, and identified the brain structural network related to the resilience, vulnerability and disease expression to SCZ. RESULTS: With respect to resilience, only the SIB-SCZ showed significantly increased connectivity in the subnetworks of the left cuneus-precuneus and left posterior cingulate gyrus-precuneus, and in brain areas of right supramarginal gyrus and right inferior temporal gyrus. With respect to vulnerability, both the FE-SCZ and SIB-SCZ had decreased cluster coefficients and local efficiency, and decreased nodal efficiency in the right medial superior frontal gyrus and right medial orbital superior frontal gyrus compared with the healthy controls. With respect to disease expression, only the FE-SCZ group showed decreased or increased global, subnetwork, and nodal connectivity in broader brain regions compared with the healthy controls. CONCLUSION: Difference in the topological properties of brain structural connectivity not only reflect the underlying mechanism of vulnerability but also that of resilience to schizophrenia. Alteration in the brain structural connectivity associating with resilience and disease expression may contribute to the onset of SCZ.

The relationship of individual social activity and cognitive function of community Chinese elderly: a cross-sectional study.

BACKGROUND: The prevention of cognitive impairment is a crucial public health issue, and leisure activities have been studied as the strategy of the cognitive preservation. The aim of the study was to explore the possible relationship between social activity and cognitive function among community-dwelling Chinese elderly in two big cities of Southern China. PARTICIPANTS AND METHODS: Altogether, 557 nondemented older adults aged 60 years and older (73.4±6.5 years) were recruited in the social centers in Hong Kong and Guangzhou. A leisure activity questionnaire was used to measure the social activity participation. Cognitive function was examined using a neuropsychological battery. The association between social activity and cognitive function was analyzed using the multiple linear regression analysis. RESULTS: Social activities had a weak relationship with cognitive performance when measured in terms of overall participation. Attending an interest class had significant association with the Cantonese version of Mini Mental State Examination, the word list learning test, the delayed recall test, and the trail making test. Religious activity showed significant association with the word list learning test and the digit vigilance test. Singing had significant association with the Category Verbal Fluency Test (CVFT) and the trail making test. CONCLUSION: Some individual social activity items may be associated with better cognitive function among the community Chinese elderly independently of other factors.

Kesterite Cu2ZnSn(S,Se)4 Solar Cells with beyond 8% Efficiency by a Sol-Gel and Selenization Process.

A facile sol-gel and selenization process has been demonstrated to fabricate high-quality single-phase earth abundant kesterite Cu2ZnSn(S,Se)4 (CZTSSe) photovoltaic absorbers. The structure and band gap of the fabricated CZTSSe can be readily tuned by varying the [S]/([S] + [Se]) ratios via selenization condition control. The effects of [S]/([S] + [Se]) ratio on device performance have been presented. The best device shows 8.25% total area efficiency without antireflection coating. Low fill factor is the main limitation for the current device efficiency compared to record efficiency device due to high series resistance and interface recombination. By improving film uniformity, eliminating voids, and reducing the Mo(S,Se)2 interfacial layer, a further boost of the device efficiency is expected, enabling the proposed process for fabricating one of the most promising candidates for kesterite solar cells.

[The resting-state functional connectivity of the hypothalamus and its relationships with gonadal steroid hormones and depression symptoms in perimenopausal women].

OBJECTIVE: This study aimed to investigate the resting-state functional connectivity of the hypothalamus and its relationships with gonadal steroid hormones and depression symptoms in perimenopausal women. METHODS: Total 66 perimenopausal women voluntarily participated in this study from October 2012 to June 2013. Zung Self-rating Depression Scale (ZSDS) was used to assess depression symptoms. Plasma gonadal steroid hormones including estradiol, testosterone, and progesterone were determined by the chemiluminescence immunoassay. A 3.0 Tesla magnetic resonance imaging (MRI) scanner was utilized to acquire resting-state functional MRI data. The z-value functional connectivity map of each participant was calculated voxel-wisely based on the seed region of the hypothalamus. One sample t test of Statistical Parametric Mapping (SPM) were used to determine the brain areas with statistically significant functional connectivity to the hypothalamus, then multiple regression of SPM was used to calculate the correlated areas with 3 gonadal steroid hormones, respectively. Finally, Pearson correlation was performed to analyze bivariate correlations between mean z-values and ZSDS scores. RESULTS: Significant functional connectivity to the hypothalamus were found in brain areas as follows:the lateral inferior frontal gyrus, medial prefrontal cortex, dorsal lateral prefrontal cortex, orbitofrontal cortex, subgenual cortex, anterior cingulate cortex, posterior cingulate cortex, cuneus and precuneus, hippocampus and parahippocampal gyrus, and angular gyrus (False Discovery Rate q<0.05). Among these areas, the plasma testosterone level was positively related to the functional connectivity strength of the right angular gyrus, and negatively related to the strengths of the right subgenual cortex and bilateral medial superior frontal gyrus to the hypothalamus (PAlphaSim<0.05). Especially, mean z-value in the subgenual cortex was positively related to the ZSDS index score (r=0.279, P=0.023), and factor scores of the core depression symptoms (r=0.278, P=0.024) and somatic symptoms (r=0.357, P=0.003). CONCLUSION: In perimenopausal women, the hypothalamus has resting-state functional connectivity with widespread areas involved in the brain depression-related network and default mode network, and the plasma androgen level may modulate the functional connectivity strengths of the hypothalamus and decrease the susceptibility of perimenopausal women to depression.

The comparison of glucose and lipid metabolism parameters in drug-naïve, antipsychotic-treated, and antipsychotic discontinuation patients with schizophrenia.

BACKGROUND: Although many studies have reported that glucose and lipid metabolism disorders are a significant side effect associated with the use of antipsychotic drugs, the characteristics of glucose and lipid metabolism disorders in patients with schizophrenia who are taking antipsychotic drugs remain poorly understood, and the possible effects that antipsychotic discontinuation may have on glucose and lipid metabolism remain unclear. METHODS: The sample consisted of 131 Chinese patients with schizophrenia, including 70 first-episode, drug-naïve patients; 33 patients who had received continuous antipsychotic drug treatment for ≥1 year prior to the beginning of the study; and 28 patients who had discontinued antipsychotic drug treatment for ≥3 months prior to the beginning of study. We compared the glucose and lipid metabolic parameter levels among the three groups of patients with schizophrenia. All assessments were performed upon hospital admission. RESULTS: The characteristics of glucose and lipid metabolism disorders in Chinese patients with schizophrenia who are taking antipsychotic drugs included significant augmentation of the body mass index and waist circumference, significantly higher levels of fasting plasma insulin and insulin resistance, and significantly lower plasma high-density lipoprotein cholesterol levels. Antipsychotic discontinuation appeared to not significantly improve any plasma glucose and lipid metabolic parameter levels. CONCLUSION: The results suggest that antipsychotic drugs aggravate glucose and lipid metabolism disorders and that antipsychotic discontinuation is generally not associated with improvements in the parameters that indicate glucose and lipid metabolism disorders in Chinese patients with schizophrenia.

Validity of the Chinese version of the brief index of sexual functioning for women with a new scoring algorithm and comparison of normative and recurrently depressed Han Chinese population.

INTRODUCTION: The Brief Index of Sexual Functioning for Women (BISF-W) is proved to be a useful instrument to assess female sexual function, but the validation information of its Chinese version is still unavailable. It has not been used to assess female sexual function among Han Chinese women with recurrent depression. AIM: This study aims to validate the Chinese version of BISF-W (C-BISF-W) with a new scoring algorithm and evaluate the impact of recurrent depression on sexual function among Han Chinese women. METHODS: Three groups of subjects, 63 unmedicated patients with recurrent depression, 50 medicated remitted patients with recurrent depression, and 92 healthy controls were enrolled in this study. Sexual function was assessed with C-BISF-W. A new scoring algorithm was developed to provide an overall composite score (G) and seven dimension scores: desire (D1), arousal (D2), frequency of sexual activity (D3), orgasm (D4), sexual interaction (D5), relationship dissatisfaction (D6), and problems affecting sexual function (D7). MAIN OUTCOME MEASURES: Psychometric analyses were conducted. RESULTS: Four factors whose Eigenvalues were higher than 1 were extracted, explaining 61.426% of the total variance. Compared with healthy age-matched control, unmedicated cases scored significantly lower in G, D1, D2, D3, D4 and D5, whereas these were higher in D6 and D7. No significant difference was found in the scores of G, D1, D2, D3, D4, and D5 between remitted cases and control, but the former scored higher in D6 and D7 than the latter. In comparison with unmedicated cases, medicated remitted cases got a higher score in G, D1, D2, and D5. For the healthy control, sexual function (G) was negatively correlated with age. CONCLUSIONS: With the new scoring algorithm, C-BISF-W is proved to be a validated instrument to assess female sexual function. The impact of recurrent depression on female sexual function is negatively profound and extensive.

The effect of DISC1 on regional gray matter density of schizophrenia in Han Chinese population.

Schizophrenia is thought to arise in part from abnormal gray matter (GM), which are partly shared by the relatives of the probands. DISC1 is one of the most promising susceptibility genes of schizophrenia and a SNP rs821597 (A) in the gene was associated with schizophrenia in Han Chinese population. In this study, 61 healthy controls and 72 with schizophrenic patients were genotyped at rs821597, and underwent T1-weighted MRI for the density of GM. The results showed that the risk allele (A) carriers had higher GM density in regional left parahippocampal gyrus and right orbitofrontal cortex in schizophrenic patients, but had reduced GM density of these brain regions in healthy controls. The DISC1 variant rs821597 may confer risk for schizophrenia by its effects on the regional GM in left parahippocampal gyrus and right orbitofrontal cortex with other risk factors for schizophrenia.

Validation of the Chinese version of the "Mood Disorder Questionnaire" for screening bipolar disorder among patients with a current depressive episode.

BACKGROUND: The Mood Disorder Questionnaire (MDQ) is a well-recognized screening tool for bipolar disorder, but its Chinese version needs further validation. This study aims to measure the accuracy of the Chinese version of the MDQ as a screening instrument for bipolar disorder (BPD) in a group of patients with a current major depressive episode. METHODS: 142 consecutive patients with an initial DSM-IV-TR diagnosis of a major depressive episode were screened for BPD using the Chinese translation of the MDQ and followed up for one year. The final diagnosis, determined by a special committee consisting of three trained senior psychiatrists, was used as a 'gold standard' and ROC was plotted to evaluate the performance of the MDQ. The optimal cut-off was chosen by maximizing the Younden's index. RESULTS: Of the 142 patients, 122 (85.9%) finished the one year follow-up. On the basis of a semi-structured clinical interview 48.4% (59/122) received a diagnosis of unipolar depression (UPD), 36.9% (45/122) BPDII and 14.8% (18/122) BPDI. At the end of the one year follow-up,9 moved from UPD to BPD, 2 from BPDII to UPD, 1 from BPDII to BPDI, the overall rate of initial misdiagnosis was 16.4%. MDQ showed a good accuracy for BPD: the optimal cut-off was 4, with a sensitivity of 0.72 and a specificity of 0.73. When BPDII and BPDI were calculated independently, the optimal cut-off for BPDII was 4, with a sensitivity of 0.70 and a specificity of 0.73; while the optimal cut-off for BPDI was 5, with a sensitivity of 0.67 and a specificity of 0.86. CONCLUSIONS: Our results show that the Chinese version of MDQ is a valid tool for screening BPD in a group of patients with current depressive episode on the Chinese mainland.

Psychosis and Dandy-Walker complex: report of four cases.

Concurrence of psychosis and Dandy-Walker complex (DWC) has been reported in some medical literature. Here, we reported four patients with concurrent psychosis and DWC of all four subtypes. Some clinical features found were juvenile or young adult age onset, high frequency of family history of psychosis, atypical psychotic symptoms, and high prevalence of cognitive deficit and refractoriness to treatment, in line with the cases in previous reports. These findings might help further illuminate the role that the cerebellum plays in the etiology of schizophrenia or bipolar disorder.

[Comparison of white matter integrity of schizophrenic patients with and without impulsive behaviors by diffusion tensor magnetic resonance imaging].

OBJECTIVE: To compare the regional white matter integrity of schizophrenics with impulsive behaviors versus those without. METHODS: Seventeen patients with first-episode-schizophrenia impulsive behaviors and 24 patients with first-episode-schizophrenia non-impulsive behaviors underwent diffusion weighted magnetic resonance imaging with a single-shot echo planar imaging (EPI) sequence aligned to straight axial plane. The fractional anisotropy (FA) images of two groups received two-sample t-test with SPM5 software. RESULTS: The patients with impulsive behaviors demonstrated a significant decrement of white matter FA values in left precentral gyrus (MNI: x = -28.00, y = -28.72, z = -54.71; cluster = 79 voxels), left cerebellum anterior lobe (MNI: x = -22, y = -56, z = -28; cluster = 130 voxels) and left occipital lobe (MNI: x = -6, y = -72, z = 6; cluster = 54 voxels). CONCLUSION: The altered white matter integrity of left precentral gyrus, cerebellum anterior lobe and occipital lobe may be involved in the neural mechanism of impulsive behaviors in schizophrenia.