ANK3 rs10994336 and ZNF804A rs7597593 polymorphisms: genetic interaction for emotional and behavioral symptoms of alcohol withdrawal syndrome.

OBJECTIVE: Alcohol withdrawal syndrome (AWS) is a complex condition associated with alcohol use disorder (AUD), characterized by significant variations in symptom severity among patients. The psychological and emotional symptoms accompanying AWS significantly contribute to withdrawal distress and relapse risk. Despite the importance of neural adaptation processes in AWS, limited genetic investigations have been conducted. This study primarily focuses on exploring the single and interaction effects of single-nucleotide polymorphisms in the ANK3 and ZNF804A genes on anxiety and aggression severity manifested in AWS. By examining genetic associations with withdrawal-related psychopathology, we ultimately aim to advance understanding the genetic underpinnings that modulate AWS severity. METHODS: The study involved 449 male patients diagnosed with alcohol use disorder. The Self-Rating Anxiety Scale (SAS) and Buss-Perry Aggression Questionnaire (BPAQ) were used to assess emotional and behavioral symptoms related to AWS. Genomic DNA was extracted from peripheral blood, and genotyping was performed using PCR. RESULTS: Single-gene analysis revealed that naturally occurring allelic variants in ANK3 rs10994336 (CC homozygous vs. T allele carriers) were associated with mood and behavioral symptoms related to AWS. Furthermore, the interaction between ANK3 and ZNF804A was significantly associated with the severity of psychiatric symptoms related to AWS, as indicated by MANOVA. Two-way ANOVA further demonstrated a significant interaction effect between ANK3 rs10994336 and ZNF804A rs7597593 on anxiety, physical aggression, verbal aggression, anger, and hostility. Hierarchical regression analyses confirmed these findings. Additionally, simple effects analysis and multiple comparisons revealed that carriers of the ANK3 rs10994336 T allele experienced more severe AWS, while the ZNF804A rs7597593 T allele appeared to provide protection against the risk associated with the ANK3 rs10994336 mutation. CONCLUSION: This study highlights the gene-gene interaction between ANK3 and ZNF804A, which plays a crucial role in modulating emotional and behavioral symptoms related to AWS. The ANK3 rs10994336 T allele is identified as a risk allele, while the ZNF804A rs7597593 T allele offers protection against the risk associated with the ANK3 rs10994336 mutation. These findings provide initial support for gene-gene interactions as an explanation for psychiatric risk, offering valuable insights into the pathophysiological mechanisms involved in AWS.

Development and validation of prognostic nomograms based on De Ritis ratio and clinicopathological features for patients with stage II/III colorectal cancer.

BACKGROUND: Metabolic derangements and systemic inflammation are related to the progression of colorectal cancer (CRC) and the prognoses of these patients. The survival of stage II and III CRC patients existed considerable heterogeneity highlighting the urgent need for new prediction models. This study aimed to develop and validate prognostic nomograms based on preoperative serum liver enzyme as well as evaluate the clinical utility. METHODS: A total of 4014 stage II/III primary CRC patients pathologically diagnosed from January 2007 to December 2013 were included in this study. These patients were randomly divided into a training set (n = 2409) and a testing set (n = 1605). Univariate and multivariate Cox analyses were used to select the independent factors for predicting overall survival (OS) and disease-free survival (DFS) of stage II/III CRC patients. Next, nomograms were constructed and validated to predict the OS and DFS of individual CRC patients. The clinical utility of nomograms, tumor-node-metastasis (TNM), and the American Joint Committee on Cancer (AJCC) system was evaluated using time-dependent ROC and decision curve analyses. RESULTS: Among seven preoperative serum liver enzyme markers, aspartate aminotransferase-to-alanine aminotransferase ratio (De Ritis ratio) was identified as an independent factor for predicting both OS and DFS of stage II/III CRC patients. The nomograms incorporated De Ritis ratio and significant clinicopathological features achieved good accuracy in terms of OS and DFS prediction, with C-index of 0.715 and 0.692, respectively. The calibration curve showed good agreement between prediction by nomogram and actual observation. The results of time-dependent ROC and decision curve analyses suggested that the nomograms had improved discrimination and greater clinical benefits compared with TNM and AJCC staging. CONCLUSIONS: De Ritis ratio was an independent predictor in predicting both the OS and DFS of patients with stage II/III CRC. Nomograms based on De Ritis ratio and clinicopathological features showed better clinical utility, which is expected to help clinicians develop appropriate individual treatment strategies for patients with stage II /III CRC.

A chromosome-scale genome sequence of sudangrass (Sorghum sudanense) highlights the genome evolution and regulation of dhurrin biosynthesis.

KEY MESSAGE: Sudangrass is more similar to US commercial sorghums than to cultivated sorghums from Africa sequence-wise and contain significantly lower dhurrin than sorghums. CYP79A1 is linked to dhurrin content in sorghum. Sudangrass [Sorghum sudanense (Piper) Stapf] is a hybrid between grain sorghum and its wild relative S. bicolor ssp. verticilliflorum and is grown as a forage crop due to its high biomass production and low dhurrin content compared to sorghum. In this study, we sequenced the sudangrass genome and showed that the assembled genome was 715.95 Mb with 35,243 protein-coding genes. Phylogenetic analysis with whole genome proteomes demonstrated that the sudangrass genome was more similar to US commercial sorghums than to its wild relatives and cultivated sorghums from Africa. We confirmed that at seedling stage, sudangrass accessions contained significantly lower dhurrin as measured by hydrocyanic acid potential (HCN-p) than cultivated sorghum accessions. Genome-wide association study identified a QTL most tightly associated with HCN-p and the linked SNPs were located in the 3' UTR of Sobic.001G012300 which encodes CYP79A1, the enzyme that catalyzes the first step of dhurrin biosynthesis. As in other grasses such as maize and rice, we also found that copia/gypsy long terminal repeat (LTR) retrotransposons were more abundant in cultivated than in wild sorghums, implying that crop domestication in the grasses was accompanied by increased copia/gypsy LTR retrotransposon insertions in the genomes.

Tracking of Protein Adsorption on Poly(l-lactic acid) Film Surfaces: The Role of Molar Mass.

Poly(l-lactic acid) (PLLA) has been extensively utilized as a biomaterial for various biomedical applications. The first and one of the most critical steps upon contact with biological fluids is the adsorption of proteins on the material's surface. Understanding the behavior of protein adsorption is vital for guiding the synthesis and preparation of PLLA for biomedical purposes. In this study, total internal reflection fluorescence microscopy was employed to investigate the adsorption of human serum albumin (HSA) on PLLA films with different molar masses. We found that molar mass affects HSA adsorption in such a way that it affects only the adsorption rate constants, but not the desorption rate constants. Additionally, we observed that HSA adsorption is spatially heterogeneous and exhibits many strong binding sites regardless of the molar mass of the PLLA films. We found that the free volume of PLLA plays a crucial role in determining its water uptake capacity and surface hydration, consequently impacting the adsorption of HSA.

Design, synthesis and biological evaluation of novel N-(methyl-d3) pyridazine-3-carboxamide derivatives as TYK2 inhibitors.

As a mediator of pro-inflammatory cytokines, TYK2 is an attractive target to treat autoimmunity diseases. Herein, we reported the design, synthesis, and structure-activity relationships (SARs) of N-(methyl-d3) pyridazine-3-carboxamide derivatives as TYK2 inhibitors. Among them, compound 24 exhibited acceptable inhibition activity against STAT3 phosphorylation. Furthermore, 24 showed satisfactory selectivities toward other members of JAK family and performed a good stability profile in liver microsomal assay. Pharmacokinetics (PK) study indicated that compound 24 has reasonable PK exposures. In anti-CD40-induced colitis models, compound 24 was orally highly effective with no significant hERG and CYP isozymes inhibition. These results indicated that compound 24 was worthy of further investigation for the development of anti-autoimmunity diseases agents.

Spectral Classification of Large-Scale Blended (Micro)Plastics Using FT-IR Raw Spectra and Image-Based Machine Learning.

Microplastics (MPs) are currently recognized as emerging pollutants; their identification and classification are therefore essential during their monitoring and management. In contrast to most studies based on small datasets and library searches, this study developed and compared four machine learning-based classifiers and two large-scale blended plastic datasets, where a 1D convolutional neural network (CNN), decision tree, and random forest (RF) were fed with raw spectral data from Fourier transform infrared spectroscopy, while a 2D CNN used the corresponding spectral images as the input. With an overall accuracy of 96.43% on a small dataset and 97.44% on a large dataset, the 1D CNN outperformed other models. The 1D CNN was the best at predicting environment samples, while the RF was the most robust with less spectral data. Overall, RF and 2D CNNs might be evaluated for plastic identification with fewer spectral data; however, 1D CNNs were thought to be the most effective with sufficient spectral data. Accordingly, an open-source MP spectroscopic analysis tool was developed to facilitate a quick and accurate analysis of existing MP samples.

RETN gene polymorphisms interact with alcohol dependence in association with depression.

BACKGROUND: Previous studies suggest that alcohol dependence is associated with increased risk of depression. The occurrence of depressive symptoms is related to polymorphisms in various genetic regions. This study aimed to investigate the interaction of RETN gene polymorphisms (rs1477341, rs3745368) with alcohol dependence on depressive symptoms in adult male during acute alcohol withdrawal. METHODS: A total of 429 male adults were recruited in this study. Alcohol dependence was assessed using the Michigan alcoholism screening test (MAST). Depression was assessed using the 20-item self-rating depression scale (SDS). Hierarchical regression analysis was used to evaluate the interaction between genes and alcohol dependence on depression. Region of significance (ROS) test was used to explain the interaction effect. The strong and weak forms of the differential susceptibility and diathesis models were used to determine which fits the data better. RESULTS: Our results showed that MAST scores were significantly positively associated with SDS scores (r = 0.23, p < 0.01) in alcohol-dependent patients during alcohol withdrawal. The interaction between genotype and alcohol dependence was significant (ß = -0.14, p < 0.05) in a strong diathesis-stress model. Susceptibility for depression symptoms was associated with alcohol dependence in RETN rs1477341 A carriers. Specifically, those that showed more alcohol dependence and the A allele of RETN rs1477341 exhibited more depression symptoms. However, RETN rs3745368 had no significant interaction with alcohol dependence. CONCLUSIONS: The A allele of RETN rs1477341 may correlate with susceptibility to depression symptoms in alcohol-dependent individuals during acute alcohol withdrawal.

Positive effects of the COVID-19 pandemic on depression and anxiety in Chinese adolescents.

The potential impact on mental health of home schooling and social isolation due to COVID-19 lockdowns has led to widespread concern, particularly for adolescents. However, studies including pre-pandemic data from longitudinal cohorts with an assessment of the longer-term impact of the Covid-19 pandemic beyond the first months of 2020 are scarce. This longitudinal study of 1534 adolescents attending a secondary school in Hunan province investigated self-reported symptoms of anxiety and depression using two validated scales (Screen for Child Anxiety Related Disorders, Child Mood and Feelings Questionnaire) at six time points before, during, and after the 2020 national lockdown restrictions in China. Perceived COVID-related stress was assessed by an author-developed scale at two timepoints during the lockdown. We investigated trends in symptoms over time with a fixed effects model and multiple imputations of missing data. Counter to our expectations, depressive and anxiety symptoms were reduced during the 2020 lockdown relative to pre-lockdown (depression: b = - 3.37, SE = 0.345, Cohen's d = - 0.25, p < 0.0001; anxiety: b = - 4.55, SE = 0.382, Cohen's d = - 0.30, p < 0.0001). Symptoms remained significantly reduced even after lockdown restrictions eased. Higher symptom levels during lockdown were associated with greater self-reported COVID-related stress (depression: b = 0.11, SE = 0.026, p < 0.0001; anxiety: b = 0.11, SE = 0.036, p < 0.0001). Although COVID-related stresses correlated with higher levels of anxiety and depression, the lockdown period was associated with improved symptom levels in the adolescents taking part in our study. School closures may have improved the mental health of adolescents in China. We speculate this beneficial effect of lockdown can be explained by the adverse effects of attending school itself such as exposure to bullying and achievement pressures.

Internet-based cognitive behavioural therapy combined with attentional bias modification training in generalized anxiety disorder: a randomized, controlled multi-session experiment.

BACKGROUND: Although attentional bias modification training (ABM) and cognitive behavioural therapy (CBT) are two effective methods to decrease the symptoms of generalized anxiety disorders (GAD), to date, no randomized controlled trials have yet evaluated the effectiveness of an intervention combining internet-based cognitive behavioural therapy (ICBT) and ABM for adults with GAD. AIMS: This study aimed to investigate the effectiveness of an intervention combining ICBT and ABM for adults with GAD. METHOD: Sixty-three participants diagnosed with GAD were randomly assigned to the treatment group (ICBT with ABM; 31 participants) or the control group (ICBT with ABM placebo; 32 participants), and received 8 weeks of treatment and three evaluations. The CBT, ABM and ABM-placebo training were conducted via the internet. The evaluations were conducted at baseline, 8 weeks later, and 1 month later, respectively. RESULTS: Both the treatment and control groups reported significantly reduced anxiety symptoms and attentional bias, with no clear superiority of either intervention. However, the treatment group showed a greater reduction in negative automatic thoughts than the control group after treatment and at 1-month follow-up (η2 = 0.123). CONCLUSION: The results suggest that although not differing in therapeutic efficacy, the intervention combining ICBT and ABM is superior to the intervention combining ICBT and ABM-placebo in the reduction of negative automatic thoughts. ABM may be a useful augmentation of ICBT on reducing anxiety symptoms.

Identification and quantification of immune infiltration landscape on therapy and prognosis in left- and right-sided colon cancer.

BACKGROUND: The left-sided and right-sided colon cancer (LCCs and RCCs, respectively) have unique molecular features and clinical heterogeneity. This study aimed to identify the characteristics of immune cell infiltration (ICI) subtypes for evaluating prognosis and therapeutic benefits. METHODS: The independent gene datasets, corresponding somatic mutation and clinical information were collected from The Cancer Genome Atlas and Gene Expression Omnibus. The ICI contents were evaluated by "ESTIMATE" and "CIBERSORT." We performed two computational algorithms to identify the ICI landscape related to prognosis and found the unique infiltration characteristics. Next, principal component analysis was conducted to construct ICI score based on three ICI patterns. We analyzed the correlation between ICI score and tumor mutation burden (TMB), and stratified patients into prognostic-related high- and low- ICI score groups (HSG and LSG, respectively). The role of ICI scores in the prediction of therapeutic benefits was investigated by "pRRophetic" and verified by Immunophenoscores (IPS) (TCIA database) and an independent immunotherapy cohort (IMvigor210). The key genes were preliminary screened by weighted gene co-expression network analysis based on ICI scores. And they were further identified at various levels, including single cell, protein and immunotherapy response. The predictive ability of ICI score for prognosis was also verified in IMvigor210 cohort. RESULTS: The ICI features with a better prognosis were marked by high plasma cells, dendritic cells and mast cells, low memory CD4+ T cells, M0 macrophages, M1 macrophages, as well as M2 macrophages. A high ICI score was characterized by an increased TMB and genomic instability related signaling pathways. The prognosis, sensitivities of targeted inhibitors and immunotherapy, IPS and expression of immune checkpoints were significantly different in HSG and LSG. The genes identified by ICI scores and various levels included CA2 and TSPAN1. CONCLUSION: The identification of ICI subtypes and ICI scores will help gain insights into the heterogeneity in LCC and RCC, and identify patients probably benefiting from treatments. ICI scores and the key genes could serve as an effective biomarker to predict prognosis and the sensitivity of immunotherapy.

Genome-wide association mapping identifies an SNF4 ortholog that impacts biomass and sugar yield in sorghum and sugarcane.

Sorghum is a feed/industrial crop in developed countries and a staple food elsewhere in the world. This study evaluated the sorghum mini core collection for days to 50% flowering (DF), biomass, plant height (PH), soluble solid content (SSC), and juice weight (JW), and the sorghum reference set for DF and PH, in 7-12 testing environments. We also performed genome-wide association mapping with 6 094 317 and 265 500 single nucleotide polymorphism markers in the mini core collection and the reference set, respectively. In the mini core panel we identified three quantitative trait loci for DF, two for JW, one for PH, and one for biomass. In the reference set panel we identified another quantitative trait locus for PH on chromosome 6 that was also associated with biomass, DF, JW, and SSC in the mini core panel. Transgenic studies of three genes selected from the locus revealed that Sobic.006G061100 (SbSNF4-2) increased biomass, SSC, JW, and PH when overexpressed in both sorghum and sugarcane, and delayed flowering in transgenic sorghum. SbSNF4-2 encodes a γ subunit of the evolutionarily conserved AMPK/SNF1/SnRK1 heterotrimeric complexes. SbSNF4-2 and its orthologs will be valuable in genetic enhancement of biomass and sugar yield in plants.

Predictive molecular markers for the treatment with immune checkpoint inhibitors in colorectal cancer.

Colorectal cancer is one of the most common malignant tumors and, hence, has become one of the most important public health issues in the world. Treatment with immune checkpoint inhibitors (ICIs) successfully improves the survival rate of patients with melanoma, non-small-cell lung cancer, and other malignancies, and its application in metastatic colorectal cancer is being actively explored. However, a few patients develop drug resistance. Predictive molecular markers are important tools to precisely screen patient groups that can benefit from treatment with ICIs. The current article focused on certain important predictive molecular markers for ICI treatment in colorectal cancer, including not only some of the mature molecular markers, such as deficient mismatch repair (d-MMR), microsatellite instability-high (MSI-H), tumor mutational burden (TMB), programmed death-ligand-1 (PD-L1), tumor immune microenvironment (TiME), and tumor-infiltrating lymphocytes (TILs), but also some of the novel molecular markers, such as DNA polymerase epsilon (POLE), polymerase delta 1 (POLD1), circulating tumor DNA (ctDNA), and consensus molecular subtypes (CMS). We have reviewed these markers in-depth and presented the results from certain important studies, which suggest their applicability in CRC and indicate their advantages and disadvantages. We hope this article is helpful for clinicians and researchers to systematically understand these markers and can guide the treatment of colorectal cancer.

A panel of differentially methylated regions enable prognosis prediction for colorectal cancer.

We aim to identify a panel of differentially methylated regions (DMRs) for predicting survival outcomes for patients with CRC from the TCGA (n = 393). Four DMRs (MUC12, TBX20, CHN2, and B3GNT7) were selected as candidate prognostic markers for CRC. The prediction potential of selected DMRs was validated by the targeted bisulfite sequencing method in an independent cohort with 251 Chinese CRC patients. DMR methylation scores (DMSs) were constructed to evaluate the prognosis of CRC. Results of the validation cohort confirmed that higher DMSs were associated with poor overall survival (OS) of CRC, with hazard ratio (HR) value ranged from 1.445 to 2.698 in multivariable Cox models. Patients in the high prognostic index (high-PI) group showed a markedly unfavorable prognosis compared to the low-PI group in both TCGA discovery cohort (HR = 3.508, 95%CI: 2.196-5.604, P < 0.001) and independent validation cohort (HR = 1.912, 95%CI: 1.258-2.907, P = 0.002).

Synthesis of Cyclopentene Derivatives via Electrochemically Induced Intermolecular Selective (3+2) Annulation.

Cyclopentenes are common cores in many natural products, and in bioactive and functional molecules. However, their synthesis remains challenging in terms of harsh conditions, poor selectivity, prefunctionalization of the substrates, over-reliance on volatile activating reagents and the use of noble metals. Herein, we develop an electrochemical mediator-induced intermolecular selective (3+2) annulation of readily available alkenes and alkynes/alkenes, which provides a simple and efficient method for the synthesis of a library of decorated cyclopentenes and cyclopentanes. This protocol features high efficiency, mild reaction conditions, broad substrate scope, good functional group tolerance, and high regioselectivity. Potential applications are demonstrated by gram-scale synthesis as well as the construction of structural diversity and complexity. A preliminary mechanistic investigation was performed, which indicated that an iodine radical and carbon radicals are involved in this transformation.

Fibroblast growth factor 21 associating with serotonin and dopamine in the cerebrospinal fluid predicts impulsivity in healthy subjects.

BACKGROUND: Impulsivity is more commonly reported in subjects with mental disorders compared to healthy subjects, suggesting a potential application of impulsivity in predicting impulsivity-related mental disorders. However, no biomarker of impulsivity available so far. This study explored the association between cerebrospinal fluid (CSF) fibroblast growth factor 21 (FGF21), a key hormonal mediator of the stress response, and impulsivity in healthy subjects. METHODS: A total of 126 healthy persons subjected to surgery of anterior cruciate ligament were recruited in the present study. The impulsiveness of the subjects was evaluated by the Chinese version of the Barratt Impulsiveness Scale (BIS)-11 before surgery. CSF and blood samples of the subjects were collected before spinal anesthesia for surgery. The levels of FGF21, serotonin and dopamine in CSF and the level of FGF21 in blood of the subjects were measured by ELISA using commercial kits. RESULTS: Negative correlations were found between BIS-11 total score and either FGF21, serotonin or dopamine in CSF. However, BIS-11 total score was not correlated with FGF21 in blood. In addition, FGF21 was positively correlated with serotonin and dopamine in CSF, respectively. Multivariable linear regression models indicated that the decrease of FGF21 level associating with the decrease of serotonin and dopamine level in CSF contributed to the higher impulsivity. Furthermore, receiver operating characteristic curve (ROC) analysis indicated an important role of CSF FGF21 predicting high impulsivity. CONCLUSIONS: FGF21, serotonin and dopamine in CSF associate with impulsivity in opposite directions. The decrease of CSF FGF21 is related to higher impulsivity, and indicate that CSF FGF21 may predict impulsivity in healthy subjects.

Prediction Model Combining Clinical and MR Data for Diagnosis of Lymph Node Metastasis in Patients With Rectal Cancer.

BACKGROUND: Determining the status of lymph node (LN) metastasis in rectal cancer patients preoperatively is crucial for the treatment option. However, the diagnostic accuracy of current imaging methods is low. PURPOSE: To develop and test a model for predicting metastatic LNs of rectal cancer patients based on clinical data and MR images to improve the diagnosis of metastatic LNs. STUDY TYPE: Retrospective. SUBJECTS: In all, 341 patients with histologically confirmed rectal cancer were divided into one training set (120 cases) and three validation sets (69, 103, 49 cases). FIELD STRENGTH/SEQUENCE: 3.0T, axial and sagittal T2 -weighted turbo spin echo and diffusion-weighted imaging (b = 0 s/mm2 , 800 s/mm2 ) ASSESSMENT: In the training dataset, univariate logistic regression was used to identify the clinical factors (age, gender, and tumor markers) and MR data that correlated with LN metastasis. Then we developed a prediction model with these factors by multiple logistic regression analysis. The accuracy of the model was verified using three validation sets and compared with the traditional MRI method. STATISTICAL TESTS: Univariate and multivariate logistic regression. The area under the curve (AUC) value was used to quantify the diagnostic accuracy of the model. RESULTS: Eight factors (CEA, CA199, ADCmean, mriT stage, mriN stage, CRM, EMVI, and differentiation degree) were significantly associated with LN metastasis in rectal cancer patients (P<0.1). In the training set (120) and the three validation sets (69, 103, 49), the AUC values of the model were much higher than the diagnosis by MR alone (training set, 0.902 vs. 0.580; first validation set, 0.789 vs. 0.743; second validation set, 0.774 vs. 0.573; third validation set, 0.761 vs. 0.524). DATA CONCLUSION: For the diagnosis of metastatic LNs in rectal cancer patients, our proposed logistic regression model, combining clinical and MR data, demonstrated higher diagnostic efficiency than MRI alone. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

Discovery of potent and selective Bcl-2 inhibitors with acyl sulfonamide skeleton.

The antiapoptotic protein B-cell lymphoma 2 (Bcl-2), overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, a series of novel derivatives with acyl sulfonamide skeleton was designed, synthesized, and evaluated as Bcl-2 inhibitors by means of bioisosteric replacement. Among them, compound 24g demonstrated equal efficient inhibition activity against RS4;11 cell line compared to positive control ABT-199. Moreover, it showed improved selectivity for Bcl-2/Bcl-xL inhibitory effects, the result of which was consistent with platelet toxicity studies. In vitro and in vivo pharmacokinetic properties of compound 24g had a significantly improved profiles. Taken together, those results suggested it as a promising candidate for development of novel therapeutics targeting Bcl-2 in cancer.

Valproic acid affects neuronal fate and microglial function via enhancing autophagic flux in mice after traumatic brain injury.

In recent years, many studies have focused on autophagy, an evolutionarily conserved mechanism that relies on lysosomes to achieve cellular metabolic requirements and organelle turnover, and revealed its important role in animal models of traumatic injury. Autophagy is a double-edged sword. Appropriate levels of autophagy can promote the removal of abnormal proteins or damaged organelles, while hyperactivated autophagy can induce autophagic apoptosis. However, recent studies suggest that autophagic flux seems to be blocked after traumatic brain injury (TBI), which contributes to the apoptosis of brain cells. In this study, valproic acid (VPA), which was clinically used for epilepsy treatment, was used to treat TBI. The Morris water maze test, hematoxylin & eosin staining and Nissl staining were first conducted to confirm that VPA treatment had a therapeutic effect on mice after TBI. Western blotting, enzyme-linked immunosorbent assay and immunofluorescence staining were then performed to reveal that VPA treatment reversed TBI-induced blockade of autophagic flux, which was accompanied by a reduced inflammatory response. In addition, the variations in activation and phenotypic polarization of microglia were observed after VPA treatment. Nevertheless, the use of the autophagy inhibitor 3-methyladenine partially abolished VPA-induced neuroprotection and the regulation of microglial function after TBI, resulting in the deterioration of the central nervous system microenvironment and neurological function. Collectively, VPA treatment reversed the TBI-induced blockade of autophagic flux in the mouse brain cortex, subsequently inhibiting brain cell apoptosis and affecting microglial function to achieve the promotion of functional recovery in mice after TBI. Cover Image for this issue: doi: 10.1111/jnc.14755.

Colorectal cancer-derived exosomal miR-106b-3p promotes metastasis by down-regulating DLC-1 expression.

Cancer-derived exosomal miRNAs play an important role in the development of metastasis, but the effects and underlying mechanisms remain unclear. In the present study, we investigated the miRNA expression profiles of 5 paired serum exosomal samples from metastatic colorectal cancer (mCRC) and non-mCRC patients via RNA sequencing. After we evaluated the differentially expressed miRNAs in 80 CRC patients, miR-106b-3p was selected as a metastasis-associated miRNA of CRC. We showed that the expression level of serum exosomal miR-106b-3p was significantly higher in CRC patients with metastasis than those without metastasis. Additionally, high serum exosomal miR-106b-3p expression in patients was correlated with a poor prognosis. Coculture of low-metastatic CRC cells with high-metastatic CRC cell-derived exosomes promoted cell migration, invasion, and epithelial-to-mesenchymal transition (EMT), which was caused by the transport and transduction of miR-106b-3p in vitro. Moreover, exosomal miR-106b-3p promoted lung metastasis of CRC cells in vivo. In addition, we demonstrated that miR-106b-3p regulated metastasis by targeting deleted in liver cancer-1 (DLC-1). A negative correlation was also identified between miR-106b-3p and DLC-1 expression in human CRC tumour tissues and in mouse lung metastatic lesions. Collectively, our study indicated that metastasis-associated miR-106b-3p from serum exosomes could be used as a potential prognostic biomarker and therapeutic target for CRC patients.

Active smoking, sleep quality and cerebrospinal fluid biomarkers of neuroinflammation.

BACKGROUNDS: Cigarette smoking has been shown to be associated with sleep disorders and the related neuropathogenesis including neuroinflammation. Previous studies showed that pro- and anti-inflammatory cytokines are physiologically important in maintaining circadian function. In addition, sleep deprivation leads to immune dysregulations. However, no study has been published yet by using cerebrospinal fluid (CSF) biomarkers of neuroinflammation to investigate the relationship between active cigarette smoking and sleep disorders. METHODS: CSF tissues from subjects of 191 male subjects (non-smokers n = 104; active smokers n = 87) receiving local anesthesia before surgery for anterior cruciate ligament injuries were obtained after the assessment of clinical information and Pittsburgh Sleep Quality Index (PSQI). The levels of tumor necrosis factor alpha (TNFα), Interleukin (IL) 1 beta (IL1ß), IL2, IL4, IL6 and IL10 were measured using radioimmunoassay and ELISA. RESULTS: PSQI scores were significantly higher in active smokers than that in non-smokers (p < 0.001, Cohen's d = 0.63). Significantly higher levels of CSF TNFα were found in active smokers compared to non-smokers (28 ± 1.97 vs. 22.97 ± 2.48, p < 0.05, Cohen's d = 2.23). There was a positive correlation between CSF IL1ß levels and PSQI scores in non-smokers (r = 0.31, p = 0.01, adjustment R-Squared = 0.11). DISCUSSION: This is the first study to reveal the association between higher CSF TNFα levels and poorer sleep quality in active smoking. In addition, CSF IL1ß levels might be a potential biomarker in central nervous system for circadian dysregulation.