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Liver metabolites are involved in the progression of rheumatoid arthritis (RA), indicating a connection between the liver and joints. However, the impact and mechanism of Hepatitis B virus (HBV), a hepatotropic virus, on RA are still unclear. We investigated the correlation between HBV and RA using Mendelian randomization analysis. Single-cell transcriptome analysis was conducted to investigate changes in cell subtypes in synovial tissue of HBV-RA patients. Fibroblast-like synoviocytes (FLS) were used to create a cell model, and the transcriptome was examined to identify the key downstream molecules of FMT regulated by HBx. CIA model was constructed using HBV transgenic, HBx transgenic, and TRADF1 knockout mice to investigate the impact and mechanism of HBV on CIA. The results of our study revealed a significant positive correlation between HBV and RA. The functional studies identified a crucial role of fibroblast-myofibroblast transition (FMT) in the progression of RA. The results suggest that HBV-encoded HBx may promote FMT in RA by upregulating TRAFD1. Furthermore, trans-ferulic acid (TFA) was identified by screening for common metabolites in the liver, joints, and peripheral blood using the metabolome and WGCNA. Interestingly, we found that TFA ameliorated HBx-induced RA by suppressing TRAFD1 expression. Our study demonstrates that hidden liver-joint axis, an imbalance between TFA and HBx, plays a critical role in HBV-induced RA, which could be a potential strategy for preventing RA development.

BACKGROUND: Trigeminal neuralgia (TN) is a severe facial pain condition often associated with a neurovascular conflict. However, neuroinflammation has also been implicated in TN, as it frequently co-occurs with multiple sclerosis (MS). METHODS: We analysed protein expression levels of TN patients compared to MS patients and controls. Proximity Extension Assay technology was used to analyse the levels of 92 proteins with the Multiplex Neuro-Exploratory panel provided by SciLifeLab, Uppsala, Sweden. Serum and CSF samples were collected from TN patients before (n = 33 and n = 27, respectively) and after (n = 28 and n = 8, respectively) microvascular decompression surgery. Additionally, we included samples from MS patients (n = 20) and controls (n = 20) for comparison. RESULTS: In both serum and CSF, several proteins were found increased in TN patients compared to either MS patients, controls, or both, including EIF4B, PTPN1, EREG, TBCB, PMVK, FKBP5, CD63, CRADD, BST2, CD302, CRIP2, CCL27, PPP3R1, WWP2, KLB, PLA2G10, TDGF1, SMOC1, RBKS, LTBP3, CLSTN1, NXPH1, SFRP1, HMOX2, and GGT5. The overall expression of the 92 proteins in postoperative TN samples seems to shift towards the levels of MS patients and controls in both serum and CSF, as compared to preoperative samples. Interestingly, there was no difference in protein levels between MS patients and controls. CONCLUSIONS: We conclude that TN patients showed increased serum and CSF levels of specific proteins and that successful surgery normalizes these protein levels, highlighting its potential as an effective treatment. However, the similarity between MS and controls challenges the idea of shared pathophysiology with TN, suggesting distinct underlying mechanisms in these conditions. SIGNIFICANCE: This study advances our understanding of trigeminal neuralgia (TN) and its association with multiple sclerosis (MS). By analysing 92 protein biomarkers, we identified distinctive molecular profiles in TN patients, shedding lig

Aim: To test the hypothesis that liver-expressed antimicrobial peptide 2 (LEAP2) genetic variants might influence the susceptibility to human obesity. Methods: Using data from the UK Biobank, we identified independent LEAP2 gene single nucleotide polymorphisms (SNPs) and examined their associations with obesity traits and serum insulin-like growth factor-1 (IGF-1) concentration. These associations were evaluated for both individual SNPs and after combining them into a genetic risk score (GRSLEAP2) using linear and logistic regression models. Sex-stratified analyses were also conducted. Results: Five SNPs showed positive associations with obesity-related traits. rs57880964 was associated with body mass index (BMI) and waist-to-hip ratio adjusted for BMI (WHRadjBMI), in the total population and among women. Four independent SNPs were positively associated with higher serum IGF-1 concentrations in both men and women. GRSLEAP2 was associated with BMI and WHRadjBMI only in women and with serum IGF-1 concentration in both sexes. Conclusions: These findings reveal sex-specific associations between key LEAP2 gene variants and several obesity traits, while also indicating a strong independent association of LEAP2 variants with serum IGF-1 concentration.

Efficient drug delivery remains a critical challenge for treating neurodegenerative diseases, such as Alzheimer's disease (AD). Using innovative nanomaterials, delivering current medications like acetylcholinesterase inhibitors to the brain through the intranasal route is a promising strategy for managing AD. Here, we developed a unique combinational drug delivery system based on N,N,N-trimethyl chitosan nanoparticles (NPs). These NPs encapsulate rivastigmine, the most potent acetylcholinesterase inhibitor, along with insulin, a complementary therapeutic agent. The spherical NPs exhibited a zeta potential of 17.6 mV, a size of 187.00 nm, and a polydispersity index (PDI) of 0.29. Our findings demonstrate significantly improved drug transport efficiency through sheep nasal mucosa using the NPs compared to drug solutions. The NPs exhibited transport efficiencies of 73.3% for rivastigmine and 96.9% for insulin, surpassing the efficiencies of the drug solutions, which showed transport efficiencies of 52% for rivastigmine and 21% for insulin ex vivo. These results highlight the potential of a new drug delivery system as a promising approach for enhancing nasal transport efficiency. These combinational mucoadhesive NPs offer a novel strategy for the simultaneous cerebral delivery of rivastigmine and insulin, which could prove helpful in developing effective treatments of AD and other neurodegenerative conditions.

Increased knowledge about sex differences is important for development of individualized treatments against many diseases as well as understanding behavioral and pathological differences. This review summarizes sex chromosome effects on gene expression, epigenetics, and hormones in relation to the brain. We explore neuroanatomy, neurochemistry, cognition, and brain pathology aiming to explain the current state of the art. While some domains exhibit strong differences, others reveal subtle differences whose overall significance warrants clarification. We hope that the current review increases awareness and serves as a basis for the planning of future studies that consider both sexes equally regarding similarities and differences.

Background: Numerous studies have consistently demonstrated a decline in sleep quality during the COVID-19 pandemic. The primary objective of this study is to explore the impact of engaging with pertinent epidemic information through the media amid the COVID-19 crisis on individuals’ sleep quality and the underlying mechanisms through which this influence operates. Methods: An online cross-sectional study design was employed. A total of 1,063 British adults (36.2% males; Mage = 38.85, SDage = 13.36, ranging from 18 to 77 years old) participated in the study and completed our questionnaires, which included media usage frequency during the pandemic, the 10-item Kessler Psychological Distress Scale (K10), the Insomnia Severity Index (ISI), and the Ten-item Personality Inventory (TIPI). Results: Pearson’s correlation analyses indicated that there was no significant correlation between COVID-19-related traditional media use (television, radio, newspaper) and psychological distress or sleep quality. However, exposure to information related to COVID-19 through new media use (Facebook, Tik Tok, Twitter) was correlated with greater psychological distress and poorer sleep quality. A moderated mediation analysis showed that psychological distress fully mediated the relationship between new media use and poor sleep, which was moderated by age, with the association between psychological distress and poor sleep quality being stronger among older adults. Conclusion: Exposure to information of COVID-19 via new (but not traditional) media use deteriorated sleep quality through greater psychological distress, and this relationship was stronger among older adults.

Circulating proteins can reveal key pathways to cancer and identify therapeutic targets for cancer prevention. We investigate 2,074 circulating proteins and risk of nine common cancers (bladder, breast, endometrium, head and neck, lung, ovary, pancreas, kidney, and malignant non-melanoma) using cis protein Mendelian randomisation and colocalization. We conduct additional analyses to identify adverse side-effects of altering risk proteins and map cancer risk proteins to drug targets. Here we find 40 proteins associated with common cancers, such as PLAUR and risk of breast cancer [odds ratio per standard deviation increment: 2.27, 1.88-2.74], and with high-mortality cancers, such as CTRB1 and pancreatic cancer [0.79, 0.73-0.85]. We also identify potential adverse effects of protein-altering interventions to reduce cancer risk, such as hypertension. Additionally, we report 18 proteins associated with cancer risk that map to existing drugs and 15 that are not currently under clinical investigation. In sum, we identify protein-cancer links that improve our understanding of cancer aetiology. We also demonstrate that the wider consequence of any protein-altering intervention on well-being and morbidity is required to interpret any utility of proteins as potential future targets for therapeutic prevention.

Introduction: In the last few years, several models trying to calculate the biological brain age have been proposed based on structural magnetic resonance imaging scans (T1-weighted MRIs, T1w) using multivariate methods and machine learning. We developed and validated a convolutional neural network (CNN)-based biological brain age prediction model that uses one T1w MRI preprocessing step when applying the model to external datasets to simplify implementation and increase accessibility in research settings. Our model only requires rigid image registration to the MNI space, which is an advantage compared to previous methods that require more preprocessing steps, such as feature extraction. Methods: We used a multicohort dataset of cognitively healthy individuals (age range = 32.0-95.7 years) comprising 17,296 MRIs for training and evaluation. We compared our model using hold-out (CNN1) and cross-validation (CNN2-4) approaches. To verify generalisability, we used two external datasets with different populations and MRI scan characteristics to evaluate the model. To demonstrate its usability, we included the external dataset's images in the cross-validation training (CNN3). To ensure that our model used only the brain signal on the image, we also predicted brain age using skull-stripped images (CNN4). Results: The trained models achieved a mean absolute error of 2.99, 2.67, 2.67, and 3.08 years for CNN1-4, respectively. The model's performance in the external dataset was in the typical range of mean absolute error (MAE) found in the literature for testing sets. Adding the external dataset to the training set (CNN3), overall, MAE is unaffected, but individual cohort MAE improves (5.63-2.25 years). Salience maps of predictions reveal that periventricular, temporal, and insular regions are the most important for age prediction. Discussion: We provide indicators for using biological (predicted) brain age as a metric for age correction in neuroimaging studies as an alternati

Introduction Depression is a major global burden with unclear pathophysiology and poor treatment outcomes. Diagnosis of depression continues to rely primarily on behavioral rather than biological methods. Investigating tools that might aid in diagnosing and treating early-onset depression is essential for improving the prognosis of the disease course. While there is increasing evidence of possible biomarkers in adult depression, studies investigating this subject in adolescents are lacking.Methods In the current study, we analyzed protein levels in 461 adolescents assessed for depression using the Development and Well-Being Assessment (DAWBA) questionnaire as part of the domestic Psychiatric Health in Adolescent Study conducted in Uppsala, Sweden. We used the Proseek Multiplex Neuro Exploratory panel with Proximity Extension Assay technology provided by Olink Bioscience, followed by transcriptome analyses for the genes corresponding to the significant proteins, using four publicly available cohorts.Results We identified a total of seven proteins showing different levels between DAWBA risk groups at nominal significance, including RBKS, CRADD, ASGR1, HMOX2, PPP3R1, CD63, and PMVK. Transcriptomic analyses for these genes showed nominally significant replication of PPP3R1 in two of four cohorts including whole blood and prefrontal cortex, while ASGR1 and CD63 were replicated in only one cohort.Discussion Our study on adolescent depression revealed protein-level and transcriptomic differences, particularly in PPP3R1, pointing to the involvement of the calcineurin pathway in depression. Our findings regarding PPP3R1 also support the role of the prefrontal cortex in depression and reinforce the significance of investigating prefrontal cortex-related mechanisms in depression.

Anorexia nervosa (AN) is an eating disorder often highly resistant to treatment, characterised by restrictive eating and/or compensatory behaviours such as purging or excessive exercising, leading to low body weight and dysregulated appetite. The recovery rate is low for those with AN in standard treatment, including cognitive behavioural therapy (CBT), enhanced-CBT, and anti-depressant medication, and risk of relapse is high (Muratore, Attia, 2021; Monteleone et al., 2022; Dalle Grave et al., 2023) estimated at around an annual global rate of 50% (Steinhausen, 2002, Frostad et al., 2022). Moreover, longitudinal studies show that for those with over twenty years lived experience of AN, recovery rate is only 40–63% (Eddy et al., 2017, Fichter et al., 2017). And for the last five years in the UK (2017–2022), an alarming 84% rise in AN admissions to the National Health Service was reported (Royal College of Psychiatrists, 2022), a rise echoed around the world, especially in high-income countries (Zipfel et al., 2022). Given this alarming rise, some clinicians are dividing opinion by suggesting palliative care and medically assisted death for treatment resistant AN (Royal College of Psychiatrists, 2023). Considering the dangerous nature of AN and heightened risk of death, new approaches are urgently needed to examine novel neurobiological mechanisms maintaining the disorder that may improve global treatment resistance.

Introduction: The COVID-19 pandemic led to a surge in mental health issues and psychological distress, disruption to work/studying conditions, and social isolation particularly among young adults. Changes in these factors are differentially associated with alcohol use. Moreover, the relationship between these factors are bidirectional and may have fluctuated throughout the different phases of the pandemic. However, studies focusing on young adults had conflicting results, short follow-up periods, and lacked comprehensive data to describe underlying mechanisms. Methods: 1067 young adults participated in repetitive measures termed wave 4 (2021) of the Survey of Adolescent Life in Västmanland Cohort “SALVe” Cohort. Of these, 889 also completed pre-pandemic measurements termed wave 3 (2018). Participants completed the Alcohol Use Disorders Identification Test (AUDIT) to evaluate alcohol consumption and harmful use. Cross-sectional associations between perceived changes in alcohol use and shift in individual, mental health, and work environment factors were examined using Chi-square tests. Logistic regression was utilized to identify pre-pandemic predictors of harmful consumption during the pandemic. Results: Harmful consumption decreased only in females following the COVID-19 pandemic. Participants who reported increased feelings of depression, anxiety, and loneliness were more likely to increase their alcohol use. Interestingly, the subgroup who felt less lonely and met their friends more often, as well as those who continued working/studying from their regular workplace also had an increased likelihood of higher consumption. Only pre-pandemic ADHD and delinquency symptoms predicted harmful alcohol consumption following the pandemic. Conclusion: Females reduced harmful alcohol consumption during the COVID-19 pandemic. While those who suffered the burden of social isolation and distress were more likely to increase their alcohol use, young adults who felt less lonely an