Genetic variants of m6A modification genes are associated with survival of HBV-related hepatocellular carcinoma.

N6-methyladenosine (m6A) is a dynamic and reversible modification process involving in a series of important biological and pathophysiological processes, including the progression of cancers. Herein, we aimed to assess the relationships of genetic variants in m6A modification genes with the survival of hepatitis B virus -related hepatocellular carcinoma (HBV-HCC). We performed a two-stage survival analysis to investigate the associations of 4425 single nucleotide polymorphisms (SNPs) in 36 m6A modification genes with the overall survival (OS) of HBV-HCC patients. Then, the identified SNPs were further used to functionally annotate. We identified that METTL3 rs1263790 (A > G) and ADARB1 rs57884102 (C > T) were significantly associated with the HBV-HCC OS (hazard ratios [HR] = 0.68, 95% confidence interval [CI] = 0.52-0.89, p = 0.004; and HR = 1.70, 95% CI = 1.33-2.18, p < 0.001, respectively). Combined analysis revealed that patients carrying more risk genotypes of two variants had a progressively poorer OS. Moreover, the expression quantitative trait loci (eQTL) analysis indicated that rs1263790 G allele decreased mRNA expression levels of METTL3 in 483 cell-cultured fibroblasts samples. And we found the mRNA expression levels of METTL3 and ADARB1 in HCC tissues were higher than in normal tissues, and the higher METTL3 and the lower ADARB1 were associated with poorer HCC OS. Our results demonstrated that two novel genetic variants (METTL3 rs1263790 and ADARB1 rs57884102) may be potential prognostic markers for HBV-HCC, but these results need larger different ethnic cohorts and functional experiments to validate in the future.

Rheumatoid arthritis patients harbour aberrant enteric bacteriophages with autoimmunity-provoking potential: a paired sibling study.

OBJECTIVES: Viruses have been considered as important participants in the development of rheumatoid arthritis (RA). However, the profile of enteric virome and its role in RA remains elusive. This study aimed to investigate the atlas and involvement of virome in RA pathogenesis. METHODS: Faecal samples from 30 pairs of RA and healthy siblings that minimise genetic interferences were collected for metagenomic sequencing. The α and ß diversity of the virome and the virome-bacteriome interaction were analysed. The differential bacteriophages were identified, and their correlations with clinical and immunological features of RA were analysed. The potential involvement of these differential bacteriophages in RA pathogenesis was further investigated by auxiliary metabolic gene annotation and molecular mimicry study. The responses of CD4+ T cells and B cells to the mimotopes derived from the differential bacteriophages were systemically studied. RESULTS: The composition of the enteric bacteriophageome was distorted in RA. The differentially presented bacteriophages correlated with the immunological features of RA, including anti-CCP autoantibody and HLA-DR shared epitope. Intriguingly, the glycerolipid and purine metabolic genes were highly active in the bacteriophages from RA. Moreover, peptides of RA-enriched phages, in particular Prevotella phage and Oscillibacter phage could provoke the autoimmune responses in CD4+ T cells and plasma cells via molecular mimicry of the disease-associated autoantigen epitopes, especially those of Bip. CONCLUSIONS: This study provides new insights into enteric bacteriophageome in RA development. In particular, the aberrant bacteriophages demonstrated autoimmunity-provoking potential that would promote the occurrence of the disease.

Combination of scavenger receptor-A with anti-cyclic citrullinated peptide antibody for the diagnosis of rheumatoid arthritis.

OBJECTIVES: The routine biomarkers for rheumatoid arthritis (RA), including anticyclic citrullinated peptide antibody (anti-CCP), rheumatoid factor (RF), immunoglobulin M (IgM), erythrocyte sedimentation rate (ESR), and C-reaction protein (CRP) have limited sensitivity and specificity. Scavenger receptor-A (SR-A) is a novel RA biomarker identified by our group recently, especially for seronegative RA. Here, we performed a large-scale multicentre study to further assess the diagnostic value of SR-A in combination with other biomarkers for RA. METHODS: The performance of SR-A in combination with other biomarkers for RA diagnosis was first revealed by a pilot study, and was further elucidated by a large-scale multicentre study. A total of 1129 individuals from 3 cohorts were recruited in the study, including RA patients, healthy controls, and patients with other common rheumatic diseases. Diagnostic properties were evaluated by the covariate-adjusted receiver-operating characteristic (AROC) curve, sensitivity, specificity and clinical association, respectively. RESULTS: Large-scale multicentre analysis showed that SR-A and anti-CCP dual combination was the optimal method for RA diagnosis, increasing the sensitivity of anti-CCP by 13% (87% vs 74%) while maintaining a specificity of 90%. In early RA patients, SR-A and anti-CCP dual combination also showed promising diagnostic value, increasing the sensitivity of anti-CCP by 7% (79% vs 72%) while maintaining a specificity of 94%. Moreover, SR-A and anti-CCP dual combination was correlated with ESR, IgM, and autoantibodies of RA patients, further revealing its clinical significance. CONCLUSION: SR-A and anti-CCP dual combination could potentially improve early diagnosis of RA, thus improving the prognosis and reducing mortality.

Pharmacological USP2 targeting suppresses ovarian cancer growth by potentiating apoptosis and ferroptosis.

Ovarian cancer is a frequently observed type of gynaecologic malignancy generally associated with poor prognosis around the world. Ubiquitin-specific proteases (USPs) form the largest subfamily of deubiquitylating enzymes and have emerged as potential therapeutic targets against human cancers. Through a systematic analysis of the prognostic significance of USP expression, USP2 was found to be inversely correlated with patient survival in ovarian cancer. Accordingly, we investigated the effects of pharmacological inhibition of USP2 on ovarian cancer by exploiting its small molecule inhibitor ML364. Our findings show that ML364 effectively hindered ovarian cancer growth and migration using a series of in vitro assays. In addition to apoptosis induction, ML364 also sensitized ovarian cancer cells to ferroptosis. Mechanistically, ML364 treatment resulted in cyclin D1 downregulation, increased poly (ADP-ribose) polymerase (PARP) cleavage, and elevated ROS levels in ovarian cancer cells. Collectively, our findings suggest USP2 as a potential therapeutic target in ovarian cancer, and hence, its pharmacological inhibition warrants further investigation.

The effects of immune checkpoint inhibitors vs. chemotherapy combined with brain radiotherapy in non-small cell lung cancer patients with brain metastases.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a prevalent form of cancer, often leading to brain metastases (BM) and a significant decline in patient prognosis. Whether immune checkpoint inhibitors (ICIs) combined with brain radiotherapy is superior to conventional chemotherapy combined with brain radiotherapy in those patients remains to be explored. MATERIALS AND METHODS: Our study enrolled 161 NSCLC patients with BM who underwent either ICIs combined with brain radiotherapy or chemotherapy combined with brain radiotherapy. End points included overall survival (OS), progression-free survival (PFS), intracranial PFS (IPFS), and extracranial PFS (EPFS). Univariate and multivariate Cox regressions were employed to identify prognostic risk variables. RESULTS: Patients receiving ICIs combined with brain radiotherapy exhibited significantly longer OS compared to those receiving chemotherapy combined with brain radiotherapy (34.80 months vs. 17.17 months, P = 0.005). In the Cox regression analysis, chemotherapy combined with brain radiotherapy (HR, 1.82; 95% CI, 1.09-3.05; P = 0.023), smoking (HR, 1.75; 95% CI, 1.02-2.99; P = 0.043) and squamous cell carcinoma (HR, 2.59; 95% CI, 1.31-5.13; P = 0.006) were associated with a worse prognosis. After propensity score matching (PSM), this finding remained consistent with before PSM (43.73 months vs. 17.17 months, P = 0.018). Squamous cell carcinoma (HR, 2.46; 95% CI, 1.15-5.26; P = 0.021) and CT + RT (HR, 2.11; 95% CI, 1.15-3.88; P = 0.016) were associated with a less favorable prognosis. CONCLUSION: The study suggests that the combination of ICIs and brain radiotherapy provides superior OS for NSCLC patients with BM, compared to the chemotherapy combined with brain radiotherapy.

High-mind wandering correlates with high risk for problematic alcohol use in China and Germany.

Everyone experiences the natural ebb and flow of task-unrelated thoughts. Given how common the fluctuations in these thoughts are, surprisingly, we know very little about how they shape individuals' responses to alcohol use. Here, we investigated if mind wandering is associated with a risk of developing problematic alcohol use. We undertook an online survey among the general population in China (N = 1123) and Germany (N = 1018) from December 2021 to February 2022 and examined the subjective experience of mind wandering and problematic alcohol use through the Mind Wandering Questionnaire (MWQ) and the Alcohol Use Disorders Identification Test (AUDIT). We compared mind wandering and problematic alcohol use between two countries and investigated the association between MWQ scores with AUDIT scores. We found higher scores on the MWQ and a high percentage of problematic alcohol use (i.e., AUDIT score ≥ 8) in Germany (22.5%) as compared to in China (14.5%). Higher self-reported mind wandering was associated with higher AUDIT scores. AUDIT scores were increased mostly in male, elder, and high-mind wandering people. Our findings highlight that mind wandering and problematic alcohol use enhanced in Germany as compared to in China. Our study sheds light on the relationship between mind wandering and problematic alcohol use that may help to further investigate causal effects of interventions.

Involuntary social isolation and alcohol consumption: an ecological momentary assessment in Germany amid the COVID-19 pandemic.

AIMS: Alcohol consumption often occurs in a social setting, which was affected by social distancing measures amid the coronavirus disease-2019 (COVID-19) pandemic. In this study, we examine how involuntary social isolation (i.e. comparing a no-lockdown stage with a lockdown stage) affects the association between loneliness, social activities, and drinking behavior. METHOD: We performed an ecological momentary assessment eight times per day for 7 days amid the COVID-19 pandemic in Germany. We recruited 280 participants and assessed their trait loneliness, daily state loneliness, social activities, and drinking behaviors. RESULTS: We found that a lockdown condition moderates the association between trait and daily state loneliness and alcohol consumption. During a lockdown stage, trait loneliness was positively associated, whereas state loneliness was negatively associated with alcohol consumption. During a no-lockdown stage, trait and state loneliness were both negatively associated with alcohol consumption. For both no-lockdown and lockdown stages, duration of social interaction, male gender, and weekends was positively associated with alcohol consumption. CONCLUSION: Our study suggests that an involuntary social isolation condition (i.e. a lockdown stage) changes how trait loneliness is associated with alcohol consumption.

The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

Therapeutic Strategies for Ischemic Stroke: Modulating the Adult Neural Stem Cell Niche through the Wnt/ß-catenin Pathway.

Stroke is a prominent contributor to mortality and impairment on a global scale. Ischemic stroke accounts for approximately 80% of stroke cases and is caused by occlusion of cerebral blood vessels. Enhancing neurogenesis through the modulation of the neural stem cell niche in the adult brain is a promising therapeutic strategy for individuals afflicted with ischemic stroke. Neurogenesis results in the generation of newborn neurons that serve as replacements for deceased neural cells within the ischemic core, thereby playing a significant role in the process of neural restoration subsequent to cerebral ischemia. Research has shown that activation of the Wnt/ß-catenin pathway can augment neurogenesis following cerebral ischemia, suggesting that this pathway is a potentially beneficial therapeutic target for managing ischemic stroke. This review provides an extensive analysis of the current knowledge regarding the involvement of the Wnt/ß-catenin pathway in promoting neurogenesis, thereby offering a promising avenue for therapeutic intervention in the context of ischemic stroke or other neurological impairments.

CircTAOK1 regulates high glucose induced inflammation, oxidative stress, ECM accumulation, and apoptosis in diabetic nephropathy via targeting miR-142-3p/SOX6 axis.

BACKGROUND: Diabetic nephropathy (DN) is a complication caused by diabetes. Circular RNAs (circRNAs) are a kind of RNA with a closed circular structure, which has high stability and is involved in many disease-related processes. The mechanism of circRNA TAO kinase 1 (circTAOK1) in the pathogenesis and development of DN is unclear. METHODS: CircTAOK1, microRNA (miR)-142-3p, and sex-determining region Y-box transcription factor 6 (SOX6) mRNA levels were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). Cell counting kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used to analyze cell proliferation. Cell cycle distribution was detected by flow cytometry. Western blot assay was performed to test B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X (Bax), cleaved-caspase 3, and fibronectin (FN), collagen I (Col I), and collagen IV (Col IV) protein levels. ELISA assay was used to measure interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor (TNF-α) levels. The reactive oxygen species (ROS) and malondialdehyde (MDA) levels and the superoxide dismutase (SOD) activity were assessed by the corresponding kits. And the correlation between miR-142-3p and circTAOK1 or SOX6 was confirmed by dual luciferase reporter assay, RNA immunoprecipitation assay and RNA pull down assay. RESULTS: CircTAOK1 and SOX6 expression levels were up-regulated, while miR-142-3p expression was down-regulated in DN serum and HG-treated HK-2 cells. Knockdown of circTAOK1 could inhibit cell injury of HG-induced HK-2 cells. The inhibitory effect of circTAOK1 knockdown on HG-induced HK-2 cell injury was restored by miR-142-3p downregulation. CircTAOK1 acted as a sponge for miR-142-3p, and SOX6 was targeted by miR-142-3p. The overexpression of SOX6 could recover the effect of miR-142-3p overexpression on HG-induced HK-2 cell injury. CircTAOK1 regulated the expression of SOX6 by targeting miR-142-3p. CONCLUSION: CircTAOK1 knockdown inhibited HG-induced HK-2 cell damage in DN by the miR-142-3p/SOX6 axis.

[Structures, aims and needs of early career scientists at the German Center for Mental Health]. / Strukturen, Ziele und Bedürfnisse der Early Career Scientists am Deutschen Zentrum für Psychische Gesundheit.

BACKGROUND: Early career scientists (ECS) are agents of change and driving forces in the promotion of mental health. The German Center for Mental Health (DZPG) is a powerful initiative to guide and support careers in the field of mental health. OBJECTIVE: The DZPG aims to make investments to educate, engage, excite, and empower ECS in an interdisciplinary and interinstitutional scientific community. STRUCTURES, TOPICS AND INITIATIVES: To achieve this, the ECS Board at the DZPG plays a central role and consists of 18 elected ECS representatives. The ECS culture gives members the right of voice and embraces bottom-to-top ideas and acknowledges autonomy and co-determination. The DZPG academy was developed to facilitate communication and networking and encourage collaboration among ECS members. The DZPG also navigates several key issues, such as equality, diversity, inclusion, family friendliness and work-life balance, which are essential for a functioning research landscape. The DZPG also extends opportunities to ECS to develop skills and competencies that are essential for contemporary ECS. It complements nationwide support for ECS with funding opportunities, mental health support at work, careers advice and guidance activities. Importantly, the ECS Board is committed to patient and public involvement and engagement, scientific communication and knowledge transfer to multiple settings. CONCLUSION: The DZPG will contribute to fostering ECS training programs for student and academic exchanges, collaborative research, and pooling of resources to acquire grants and scholarships. It will also support the establishment of hubs for ECS networks and promote the expansion of international competence of ECS in Germany.

Neoerysiphe leontopodii sp. nov., a new powdery mildew from China.

A powdery mildew was found on Leontopodium leontopodioides (Asteraceae) in China. Phylogenetic analyses using a combination of internal transcribed spacer and 28S rDNA sequences showed that this species, which clusters as sister to Neoerysiphe joerstadii, is allied to N. galii, N. geranii, and N. nevoi. This species differs from the closely allied N. joerstadii in the number and size of asci (3-10 asci, 55-75 × 20-40 µm versus 16-32 asci, 40-60 × 20-30 µm). This species is morphologically very similar to N. gnaphalii, but clearly differs from this species in having larger chasmothecia and colorless appendages. Therefore, the powdery mildew on L. leontopodioides is described as N. leontopodii sp. nov.

Detection of methyltransferase activity and inhibitor screening based on rGO-mediated silver enhancement signal amplification strategy.

DNA methylation refers to the chemical modification process of obtaining a methyl group by the covalent bonding of a specific base in DNA sequence with S-adenosyl methionine (SAM) as a methyl donor under the catalysis of methyltransferase (MTase), which is related to the occurrence of multiple diseases. Therefore, the detection of MTase activity is of great significance for disease diagnosis and drug screening. Because reduced graphene oxide (rGO) has a unique planar structure and remarkable catalytic performance, it is not clear whether rGO can rapidly catalyze silver deposition as an effective way of signal amplification. However, in this study, we were pleasantly surprised to find that using H2O2 as a reducing agent, rGO can rapidly catalyze silver deposition, and its catalytic efficiency of silver deposition is significantly better than that of GO. Therefore, based on further verifying the mechanism of catalytic properties of rGO, we constructed a novel electrochemical biosensor (rGO/silver biosensor) for the detection of dam MTase activity, which has high selectivity and sensitivity to MTase in the range of 0.1 U/mL to 10.0 U/mL, and the detection limit is as low as 0.07 U/mL. Besides, this study also used Gentamicin and 5-Fluorouracil as inhibitor models, confirming that the biosensor has a good application prospect in the high-throughput screening of dam MTase inhibitors.

Environmental stress, minority status, and local poverty: risk factors for mental health in Berlin's inner city.

This study examines whether climate change-associated environmental stressors, including air and noise pollution, local heat levels, as well as a lack of surrounding greenspace, mediate the effects of local poverty on mental health, using the 28-item General Health Questionnaire. We recruited 478 adults who were representative of eleven of Berlin's inner-city neighborhoods. The relationship of individual-level variables, neighborhood-level sociodemographic and environmental data from the Berlin Senate (Department for Urban Development, Building and Housing) to mental health was assessed in a multilevel model using SPSS. We found that neither local exposure to environmental stressors, nor available greenspace as a protective factor, mediated the effects of local poverty on variance in mental health (all p values > 0.2). However, surrounding greenspace (r = -0.24, p < 0.001), nitrogen dioxide levels (r = 0.10, p < 0.05), noise pollution (rho = 0.15, p < 0.01), and particle pollution (r = 0.12, p < 0.001) were associated with local poverty, which, more strongly than individual factors, accounted for variance in mental health (ß = 0.47, p < 0.001). Our analysis indicates that the effects of local poverty on mental health are not mediated by environmental factors. Instead, local poverty was associated with both an increased mental health burden and the exposure to climate-related environmental stressors.

Revisiting the World's Strictest COVID-19 Lockdown: Formidable Mental Health Challenges.

INTRODUCTION: Many nations have implemented lockdowns to prevent and minimize the spread of infections in healthcare settings. However, the impact of lockdown duration on mental health remains controversial. METHODS: We conducted a retrospective study using online questionnaires to assess the mental health status of the general population during the Shanghai lockdown period from March to May 2022. The mental health of the participants was evaluated by the 12-item General Health Questionnaire (GHQ-12), in which a cut-off score of 12 or more indicated psychological distress. A logistic regression model was used to evaluate the relationship between lockdown duration and mental health. RESULTS: Among 2139 participants (mean age: 26.12 years, standard deviation: 6.37, 731 females; 1378 unmarried; 1099 Shanghai residents), approximately 47% reported psychological distress (GHQ-12≥12). Participants exposed to lockdown reported significantly higher GHQ-12 scores (11.93±6.81 vs. 8.73±6.35, p<0.001). In our logistic regression model, participants who experienced the longest lockdown (43-61 days) had a significantly higher risk of psychological distress compared with those who did not (odds ratio: 3.10, 95% confidence interval: 2.06-4.70, p<0.001). DISCUSSION: Lockdown duration significantly affects mental health, with longer lockdown duration being associated with worse mental health status. The relationship between lockdown and mental health should not be neglected in case of lockdown in response to future pandemics.

Urinary orosomucoid and retinol binding protein levels as early diagnostic markers for diabetic kidney Disease.

BACKGROUND: Diabetic kidney disease (DKD) is the most common microvascular complication of diabetes, which has been a major cause of end-stage renal failure. Diagnosing diabetic kidney disease is important to prevent long-term kidney damage and determine the prognosis of patients with diabetes. In this study, we investigated the clinical significance of combined detection of urine orosomucoid and retinol-binding protein for early diagnosis of diabetic kidney disease. METHODS: We recruited 72 newly diagnosed patients with type 2 diabetes and 34 healthy persons from August 2016 to July 2018 at the First Affiliated Hospital of Henan Polytechnic University (Jiaozuo Second People's Hospital). Using the Mogensen grading criteria, participants were classified as having diabetes or diabetic kidney disease, and healthy persons constituted the control group. Urine orosomucoid and retinol-binding protein levels were measured and correlated with other variables. RESULTS: With the aggravation of renal damage, the level of urinary mucoid protein gradually increased. Urinary retinol-binding protein and microalbumin levels were significantly higher in the diabetes group than in control and nephropathy groups. Orosomucoid and retinol-binding protein might be independent risk factors for diabetes and diabetic kidney disease. Urinary orosomucoid significantly correlated with retinol-binding protein and microalbumin levels in the diabetic kidney disease group. CONCLUSION: Elevated urine orosomucoid and retinol-binding protein levels can be detected in the early stages of type 2 diabetic kidney disease. Both of these markers are important for diabetic kidney disease detection and early treatment.

Efficacy of erector spinae plane block for postoperative analgesia lumbar surgery: a systematic review and meta-analysis.

OBJECTIVES: The erector spinae plane (ESP) block is a newly defined regional anesthesia technique first described in 2016. The aim of this meta-analysis is to assess the efficacy of ESP block in improving analgesia following lumbar surgery. METHODS: PubMed, EMBASE, Cochrane Library, and Web of Science were searched for randomized controlled trials (RCTs) that compared the analgesic efficacy of the ESP block with non-block care for lumbar surgery from inception 3 August 2021. The primary outcomes were postoperative opioid consumption and pain scores during the first 24 h. Postoperative pain was measured as pain at rest and on movement at postoperative 0, 4, 8, 12, and 24 h expressed on a visual analog scale (VAS), where 0 = no pain and 10 = the most severe pain. RESULTS: 11 studies involving 775 patients were included in our analysis. The use of ESP block significantly decreased 24-h opioid consumption (WMD, -8.70; 95% CI, -10.48 to -6.93; I2 = 97.5%; P < 0.001) compared with the non-block. Moreover, ESP block reduced pain scores at postoperative time-points up to 24 h. ESP block also prolonged the time to first analgesic request (WMD = 6.93; 95% CI: 3.44 to 10.43, I2 = 99.8%; P < 0.001). There was less PONV with ESP block versus non-block group (RR, 0.354; 95% CI, 0.23 to 0.56; I2 = 25.2%; P < 0.001), but no difference in pruritus. CONCLUSIONS: ESP block provides less opioid consumption and PONV, lower pain scores, and longer time to first analgesic request in patients undergoing lumbar surgery compared to general anesthesia alone.

Measuring self-regulation in everyday life: Reliability and validity of smartphone-based experiments in alcohol use disorder.

Self-regulation, the ability to guide behavior according to one's goals, plays an integral role in understanding loss of control over unwanted behaviors, for example in alcohol use disorder (AUD). Yet, experimental tasks that measure processes underlying self-regulation are not easy to deploy in contexts where such behaviors usually occur, namely outside the laboratory, and in clinical populations such as people with AUD. Moreover, lab-based tasks have been criticized for poor test-retest reliability and lack of construct validity. Smartphones can be used to deploy tasks in the field, but often require shorter versions of tasks, which may further decrease reliability. Here, we show that combining smartphone-based tasks with joint hierarchical modeling of longitudinal data can overcome at least some of these shortcomings. We test four short smartphone-based tasks outside the laboratory in a large sample (N = 488) of participants with AUD. Although task measures indeed have low reliability when data are analyzed traditionally by modeling each session separately, joint modeling of longitudinal data increases reliability to good and oftentimes excellent levels. We next test the measures' construct validity and show that extracted latent factors are indeed in line with theoretical accounts of cognitive control and decision-making. Finally, we demonstrate that a resulting cognitive control factor relates to a real-life measure of drinking behavior and yields stronger correlations than single measures based on traditional analyses. Our findings demonstrate how short, smartphone-based task measures, when analyzed with joint hierarchical modeling and latent factor analysis, can overcome frequently reported shortcomings of experimental tasks.

Association Between Functional Nucleotide Polymorphisms Up-regulating Transforming Growth Factor ß1 Expression and Increased Tuberculosis Susceptibility.

Previous studies demonstrated that transforming growth factor (TGT) ß1 plays an immunosuppressive role in clinical tuberculosis. However, the contribution of TGF-ß1 gene polymorphisms to human tuberculosis susceptibility remains undetermined. In this study, we showed that single-nucleotide polymorphisms (SNPs) in TGF-ß1 gene were associated with increased susceptibility to tuberculosis in the discovery cohort (1533 case patients and 1445 controls) and the validation cohort (832 case patients and 1084 controls), and 2 SNPs located in the promoter region (rs2317130 and rs4803457) are in strong linkage disequilibrium. The SNP rs2317130 was associated with the severity of tuberculosis. Further investigation demonstrated that rs2317130 CC genotype is associated with higher TGF-ß1 and interleukin 17A production. The mechanistic study showed that rs2317130 C allele affected TGF-ß1 promoter activity by regulating binding activity to nuclear extracts. These findings provide insights into the pathogenic role of TGF-ß1 in human tuberculosis and reveal a function for the TGF-ß1 promoter SNPs in regulating immune responses during Mycobacterium tuberculosis infection.

Untargeted metabolomics analysis reveals Mycobacterium tuberculosis strain H37Rv specifically induces tryptophan metabolism in human macrophages.

BACKGROUND: Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) remains a global health issue. The characterized virulent M. tb H37Rv, avirulent M. tb H37Ra and BCG strains are widely used as reference strains to investigate the mechanism of TB pathogenicity. Here, we attempted to determine metabolomic signatures associated with the Mycobacterial virulence in human macrophages through comparison of metabolite profile in THP-1-derived macrophages following exposure to the M. tb H37Rv, M. tb H37Ra and BCG strains. RESULTS: Our findings revealed remarkably changed metabolites in infected macrophages compared to uninfected macrophages. H37Rv infection specifically induced 247 differentially changed metabolites compared to H37Ra or BCG infection. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed H37Rv specifically induces tryptophan metabolism. Moreover, quantitative PCR (qPCR) results showed that indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) which converts the tryptophan to a series of biologically second metabolites were up-regulated in H37Rv-infected macrophages compared to H37Ra- or BCG-infected macrophages, confirming the result of enhanced tryptophan metabolism induced by H37Rv infection. These findings indicated that targeting tryptophan (Trp) metabolism may be a potential therapeutic strategy for pulmonary TB. CONCLUSIONS: We identified a number of differentially changed metabolites that specifically induced in H37Rv infected macrophages. These signatures may be associated with the Mycobacterial virulence in human macrophages. The present findings provide a better understanding of the host response associated with the virulence of the Mtb strain.