Hippocampal GPR35 Participates in the Pathogenesis of Cognitive Deficits and Emotional Alterations Induced by Aß1-42 in Mice.

The amyloid-beta (Aß) aggregation in Alzheimer's disease (AD) triggers neuroinflammation, and neurodegeneration, which lead to cognitive deficits along with other neuropsychiatric symptoms, including depression and anxiety. G protein-coupled receptor 35 (GPR35) is expressed in the brain and is involved in metabolic stresses. However, the role of GPR35 in AD pathogenesis remains unknown. Herein, pharmacological blockade, shRNA-mediated knockdown or knockout of GPR35 was performed to investigate the role and mechanisms of GPR35 in Aß1-42-induced cognitive impairment and emotional alterations in mice. A series of behavioral, histopathological, and biochemical tests were performed in mice. Our results showed that hippocampal GPR35 expression was significantly increased in Aß1-42-induced and APP/PS1 AD mouse models. Pharmacological blockade or knockdown of GPR35 ameliorated cognitive impairment and emotional alterations induced by Aß1-42 in mice. We also found that blockade or knockdown of GPR35 decreased the accumulation of Aß, and improved neuroinflammation, cholinergic system deficiency, and neuronal apoptosis via the RhoA/ROCK2 pathway in Aß1-42-treaed mice. However, activation of GPR35 aggravates Aß1-42-induced cognitive deficits and emotional alterations in mice. In addition, genetic deletion of GPR35 protects against the Aß1-42-induced cognitive deficits and emotional alterations in mice. Moreover, GPR35 could bind to TLR4. These results indicate that GPR35 participates in the pathogenesis of cognitive deficits and emotional alterations induced by Aß1-42 in mice, suggesting that GPR35 could be a potential therapeutic target for AD.

Contribution of crosstalk of mesothelial and tumoral epithelial cells in pleural metastasis of lung cancer.

Background: Tumor metastasis commonly affects pleura in advanced lung cancer and results in malignant pleural effusion (MPE). MPE is related to poor prognosis, but without systematic investigation on different cell types and their crosstalk at single cell resolution. Methods: We conducted single-cell RNA-sequencing (scRNA-seq) of lung cancer patients with pleural effusion. Next, our data were integrated with 5 datasets derived from individuals under normal, non-malignant disease and lung carcinomatous conditions. Mesothelial cells were re-clustered and their interactions with epithelial cells were comprehensively analyzed. Taking advantage of inferred ligand-receptor pairs, a prediction model of prognosis was constructed. The co-culture of mesothelial cells and malignant epithelial cells in vitro and RNA-seq was performed. Epidermal growth factor receptor (EGFR) antagonist cetuximab was utilized to prevent the lung cancer cells' invasiveness. Spatial distribution of cells in lung adenocarcinoma patients' samples were also analyzed to validate our findings. Results: The most distinctive transcriptome profiles between tumor and control were revealed in mesothelial cells, which is the predominate cell type of pleura. Five subtypes were divided, including one predominately identified in MPE which was characterized by enriched cancer-related pathways (e.g., cell migration) along evolutionary trajectory from normal mesothelial cells. Cancer-associated mesothelial cells (CAMCs) exhibited varied interactions with different subtypes of malignant epithelial cells, and multiple ligands/receptors exhibited significant correlation with poor prognosis. Experimentally, mesothelial cells can increase the migration ability of lung cancer cells through co-culturing. EGFR was the only affected gene in cancer cells that exhibited interaction with mesothelial cells and was associated with poor prognosis. Using EGFR antagonist cetuximab prevented the lung cancer cells' increased invasiveness caused by mesothelial cells. Moreover, epithelial mitogen (EPGN)-EGFR interaction was supported through spatial distribution analysis, revealing the significant proximity between EPGN+ mesothelial cells and EGFR+ epithelial cells. Conclusions: Our findings highlighted the important role of mesothelial cells and their interactions with cancer cells in pleural metastasis of lung cancer, providing potential targets for treatment.

Effect of dapagliflozin on ferroptosis through the gut microbiota metabolite TMAO during myocardial ischemia-reperfusion injury in diabetes mellitus rats.

Dapagliflozin (DAPA) demonstrates promise in the management of diabetic mellitus (DM) and cardiomyopathy. Trimethylamine N-oxide (TMAO) is synthesized by the gut microbiota through the metabolic conversion of choline and phosphatidylcholine. Ferroptosis may offer novel therapeutic avenues for the management of diabetes and myocardial ischemia-reperfusion injury (IRI). However, the precise mechanism underlying ferroptosis in cardiomyocytes and the specific role of TMAO generated by gut microbiota in the therapeutic approach for DM and myocardial IRI utilizing DAPA need to be further explored. Nine male SD rats with specific pathogen-free (SPF) status were randomly divided equally into the normal group, the DM + IRI (DIR) group, and the DAPA group. The diversity of the gut microbiota was analyzed using 16S rRNA gene sequencing. Additionally, the Wekell technique was employed to measure the levels of TMAO in the three groups. Application of network pharmacology to search for intersection targets of DAPA, DIR, and ferroptosis, and RT-PCR experimental verification. Ultimately, the overlapping targets that were acquired were subjected to molecular docking analysis with TMAO. The changes of Bacteroidetes and Firmicutes in the gut microbiota of DIR rats were most significantly affected by DAPA. Escherichia-Shigella and Prevotella_9 within the phylum Bacteroidetes could be identified as the primary effects of DAPA on DIR. Compared with the normal group, the TMAO content in the DIR group was significantly increased, while the TMAO content in the DAPA group was decreased compared to the DIR group. For the network pharmacology analysis, DAPA and DIR generated 43 intersecting target genes, and then further intersected with ferroptosis-related genes, resulting in 11 overlapping target genes. The mRNA expression of ALB, HMOX1, PPARG, CBS, LCN2, and PPARA decreased in the DIR group through reverse transcription polymerase chain reaction (RT-PCR) validation, while the opposite trend was observed in the DAPA group. The docking score between TMAO and DPP4 was - 5.44, and the MM-GBSA result of - 22.02 kcal/mol. It epitomizes the finest docking performance among all the target genes with the lowest score. DAPA could reduce the levels of metabolite TMAO produced by gut microbiota, thereby regulating related target genes to decrease ferroptosis in DIR cardiomyocytes.

Neuro-cardiac-guided transcranial magnetic stimulation: Unveiling the modulatory effects of low-frequency and high-frequency stimulation on heart rate.

Transcranial magnetic stimulation (TMS) is pivotal in the field of major depressive disorder treatment. Due to its unsatisfied response rate, an increasing number of researchers have turned their attention towards optimizing TMS site localization. Since the influence of TMS in reducing heart rate (HR) offers insights into its regulatory impact on the autonomic nervous system, a novel approach, called neurocardiac-guided TMS (NCG-TMS), has been proposed to pinpoint the brain region eliciting the maximal individual reduction in HR as a personalized optimal stimulation target. The present study intends to systematically explore the effects of stimulation frequency, left and right hemispheres, stimulation positions, and individual differences on HR modulation using the NCG-TMS method. In experiment 1, low-frequency TMS was administered to 30 subjects, and it was found that low-frequency NCG-TMS significantly downregulated HR, with more significant effects in the right hemisphere than in the left hemisphere and the prefrontal cortex than in other brain areas. In experiment 2, high-frequency NCG-TMS stimulation was administered to 30 subjects, showing that high-frequency NCG-TMS also downregulated HR and had the greatest modulatory effect in the right prefrontal region. Simultaneously, both experiments revealed sizeable individual variability in the optimal stimulation site, which in turn validated the feasibility of the NCG-TMS method. In conclusion, the present experiments independently replicated the effect of NCG-TMS, provided an effect of high-/low-frequency TMS stimulation to downregulate HR, and identified a right lateralization of the HR modulation effect.

Exploiting cell death and tumor immunity in cancer therapy: challenges and future directions.

Cancer remains a significant global challenge, with escalating incidence rates and a substantial burden on healthcare systems worldwide. Herein, we present an in-depth exploration of the intricate interplay between cancer cell death pathways and tumor immunity within the tumor microenvironment (TME). We begin by elucidating the epidemiological landscape of cancer, highlighting its pervasive impact on premature mortality and the pronounced burden in regions such as Asia and Africa. Our analysis centers on the pivotal concept of immunogenic cell death (ICD), whereby cancer cells succumbing to specific stimuli undergo a transformation that elicits robust anti-tumor immune responses. We scrutinize the mechanisms underpinning ICD induction, emphasizing the release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs) as key triggers for dendritic cell (DC) activation and subsequent T cell priming. Moreover, we explore the contributions of non-apoptotic RCD pathways, including necroptosis, ferroptosis, and pyroptosis, to tumor immunity within the TME. Emerging evidence suggests that these alternative cell death modalities possess immunogenic properties and can synergize with conventional treatments to bolster anti-tumor immune responses. Furthermore, we discuss the therapeutic implications of targeting the TME for cancer treatment, highlighting strategies to harness immunogenic cell death and manipulate non-apoptotic cell death pathways for therapeutic benefit. By elucidating the intricate crosstalk between cancer cell death and immune modulation within the TME, this review aims to pave the way for the development of novel cancer therapies that exploit the interplay between cell death mechanisms and tumor immunity and overcome Challenges in the Development and implementation of Novel Therapies.

THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation.

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus characterized by heart failure and cardiac remodeling. Previous studies show that tetrahydroberberrubine (THBru) retrogrades cardiac aging by promoting PHB2-mediated mitochondrial autophagy and prevents peritoneal adhesion by suppressing inflammation. In this study we investigated whether THBru exerted protective effect against DCM in db/db mice and potential mechanisms. Eight-week-old male db/db mice were administered THBru (25, 50 mg·kg-1·d-1, i.g.) for 12 weeks. Cardiac function was assessed using echocardiography. We showed that THBru administration significantly improved both cardiac systolic and diastolic function, as well as attenuated cardiac remodeling in db/db mice. In primary neonatal mouse cardiomyocytes (NMCMs), THBru (20, 40 µM) dose-dependently ameliorated high glucose (HG)-induced cell damage, hypertrophy, inflammatory cytokines release, and reactive oxygen species (ROS) production. Using Autodock, surface plasmon resonance (SPR) and DARTS analyses, we revealed that THBru bound to the domain of the receptor for advanced glycosylation end products (RAGE), subsequently leading to inactivation of the PI3K/AKT/NF-κB pathway. Importantly, overexpression of RAGE in NMCMs reversed HG-induced inactivation of the PI3K/AKT/NF-κB pathway and subsequently counteracted the beneficial effects mediated by THBru. We conclude that THBru acts as an inhibitor of RAGE, leading to inactivation of the PI3K/AKT/NF-κB pathway. This action effectively alleviates the inflammatory responses and oxidative stress in cardiomyocytes, ultimately leading to ameliorated DCM.

Prediction of pedicled flap survival preoperatively by operating indocyanine green angiography at 1,450 nm wavelength: an animal model study.

Background: Predicting flap viability benefits patients by reducing complications and guides flap design by reducing donor areas. Due to varying anatomy, obtaining individual vascular information preoperatively is fundamental for designing safe flaps. Although indocyanine green angiography (ICGA) is a conventional tool in intraoperative assessment and postoperative monitoring, it is rare in preoperative prediction. Methods: ICGA was performed on 20 male BALB/c mice under five wavelengths (900/1,000/1,100, /1,250/1,450 nm) to assess vascular resolution after ICG perfusion. A "mirrored-L" flap model with three angiosomes was established on another 20 male BALB/c mice, randomly divided into two equal groups. In Group A, a midline between angiosomes II and III was used as a border. In Group B, the points of the minimized choke vessel caliber marked according to the ICG signal at 1,450 nm wavelength (ICG1450) were connected. Necrotic area calculations, pathohistological testing, and statistical analysis were performed. Results: The vascular structure was clearly observed at 1,450 nm wavelength, while the 900 to 1,100 nm failed to depict vessel morphology. Necrosis was beyond the borderline in 60% of Group A. Conversely, 100% of Group B had necrosis distal to the borderline. The number of choke vessels between angiosomes II and III was positively correlated with the necrotic area (%). The pathohistological findings supported the gross observation and analysis. Conclusion: ICG1450 can delineate the vessel structure in vivo and predict the viability of pedicled skin flaps using the choke vessel as the border between angiosomes.

Qualifying P-glycoprotein in drug-resistant ovarian cancer cells: a dual-mode aptamer probe approach.

Drug resistance presents a significant obstacle in treating human ovarian cancer. The development of effective methods for detecting drug-resistant cancer cells is pivotal for tailoring personalized therapies and prognostic assessments. In this investigation, we introduce a dual-mode detection technique employing a fluorogenic aptamer probe for the qualification of P-glycoprotein (P-gp) in drug-resistant ovarian cancer cells. The probe, initially in an "off" state due to the proximity of a quencher to the fluorophore, exhibits increased fluorescence intensity upon binding with the target. The fluorescence enhancement shows a linear correlation with both the concentration of P-gp and the presence of P-gp in drug-resistant ovarian cancer cells. This correlation is quantifiable, with detection limits of 1.56 nM and 110 cells per mL. In an alternate mode, the optimized fluorophores, attached to the aptamer, form larger complexes upon binding to the target protein, which diminishes the rotation speed, thereby augmenting fluorescence polarization. The alteration in fluorescence polarization enables the quantitative analysis of P-gp in the cells, ranging from 100 to 1500 cells per milliliter, with a detection limit of 40 cells per mL. Gene expression analyses, protein expression studies, and immunofluorescence imaging further validated the reliability of our aptamer-based probe for its specificity towards P-gp in drug-resistant cancer cells. Our findings underscore that the dual-mode detection approach promises to enhance the diagnosis and treatment of multidrug-resistant ovarian cancer.

Helicobacter pylori Treatment and Gastric Cancer Risk Among Individuals With High Genetic Risk for Gastric Cancer.

Importance: Helicobacter pylori treatment and nutrition supplementation may protect against gastric cancer (GC), but whether the beneficial effects only apply to potential genetic subgroups and whether high genetic risk may be counteracted by these chemoprevention strategies remains unknown. Objective: To examine genetic variants associated with the progression of gastric lesions and GC risk and to assess the benefits of H pylori treatment and nutrition supplementation by levels of genetic risk. Design, Setting, and Participants: This cohort study used follow-up data of the Shandong Intervention Trial (SIT, 1989-2022) and China Kadoorie Biobank (CKB, 2004-2018) in China. Based on the SIT, a longitudinal genome-wide association study was conducted to identify genetic variants for gastric lesion progression. Significant variants were examined for incident GC in a randomly sampled set of CKB participants (set 1). Polygenic risk scores (PRSs) combining independent variants were assessed for GC risk in the remaining CKB participants (set 2) and in an independent case-control study in Linqu. Exposures: H pylori treatment and nutrition supplementation. Main Outcomes and Measures: Primary outcomes were the progression of gastric lesions (in SIT only) and the risk of GC. The associations of H pylori treatment and nutrition supplementation with GC were evaluated among SIT participants with different levels of genetic risk. Results: Our analyses included 2816 participants (mean [SD] age, 46.95 [9.12] years; 1429 [50.75%] women) in SIT and 100 228 participants (mean [SD] age, 53.69 [11.00] years; 57 357 [57.23%] women) in CKB, with 147 GC cases in SIT and 825 GC cases in CKB identified during follow-up. A PRS integrating 12 genomic loci associated with gastric lesion progression and incident GC risk was derived, which was associated with GC risk in CKB (highest vs lowest decile of PRS: hazard ratio [HR], 2.54; 95% CI, 1.80-3.57) and further validated in the analysis of 702 case participants and 692 control participants (mean [SD] age, 54.54 [7.66] years; 527 [37.80%] women; odds ratio, 1.83; 95% CI, 1.11-3.05). H pylori treatment was associated with reduced GC risk only for individuals with high genetic risk (top 25% of PRS: HR, 0.45; 95% CI, 0.25-0.82) but not for those with low genetic risk (HR, 0.81; 95% CI, 0.50-1.34; P for interaction = .03). Such effect modification was not found for vitamin (P for interaction = .93) or garlic (P for interaction = .41) supplementation. Conclusions and Relevance: The findings of this cohort study indicate that a high genetic risk of GC may be counteracted by H pylori treatment, suggesting primary prevention could be tailored to genetic risk for more effective prevention.

Choriocapillaris reduction accurately discriminates against early-onset Alzheimer's disease.

INTRODUCTION: This study addresses the urgent need for non-invasive early-onset Alzheimer's disease (EOAD) prediction. Using optical coherence tomography angiography (OCTA), we present a choriocapillaris model sensitive to EOAD, correlating with serum biomarkers. METHODS: Eighty-four EOAD patients and 73 controls were assigned to swept-source OCTA (SS-OCTA) or the spectral domain OCTA (SD-OCTA) cohorts. Our hypothesis on choriocapillaris predictive potential in EOAD was tested and validated in these two cohorts. RESULTS: Both cohorts revealed diminished choriocapillaris signals, demonstrating the highest discriminatory capability (area under the receiver operating characteristic curve: SS-OCTA 0.913, SD-OCTA 0.991; P < 0.001). A sparser SS-OCTA choriocapillaris correlated with increased serum amyloid beta (Aß)42, Aß42/40, and phosphorylated tau (p-tau)181 levels (all P < 0.05). Apolipoprotein E status did not affect choriocapillaris measurement. DISCUSSION: The choriocapillaris, observed in both cohorts, proves sensitive to EOAD diagnosis, and correlates with serum Aß and p-tau181 levels, suggesting its potential as a diagnostic tool for identifying and tracking microvascular changes in EOAD. HIGHLIGHTS: Optical coherence tomography angiography may be applied for non-invasive screening of Alzheimer's disease (AD). Choriocapillaris demonstrates high sensitivity and specificity for early-onset AD diagnosis. Microvascular dynamics abnormalities are associated with AD.

Study on Plant-blanket to reduce heavy metal migration caused by precipitation and to improve the soil environment of pyritic tailings.

The increasing demand for mineral resources due to industrial development has led to significant tailings pollution during the mineral extraction process. In the southwestern region of China, a large amount of pyritic tailings containing pyrite cinder easily leaches heavy metals and other pollutants when exposed to precipitation, resulting in widespread soil contamination. Effective remediation methods are urgently needed to address this issue. This study utilized naturally occurring Plant-blanket formed by the symbiosis of moss and herbaceous plants on pyritic tailings as restoration material. Through leaching experiments and staining tracer techniques, the study investigated the ability of Plant-blanket to reduce the migration of heavy metals from pyrite cinder to soil under the influence of precipitation and its role in improving the soil environment. The results showed that within 12 h, the Plant-blanket could absorb water equivalent to 206.9 % of its own weight and had good water retention ability. It reduced the stained area ratio of soil horizontal and vertical profiles after precipitation leaching by a maximum of 76.08 % and 46.41 %, respectively, and improved the pH, cation exchange capacity (CEC), bulk density, and water content of soil at different depths. In addition, after being covered by Plant-blanket, the migration of Cd and Cu was reduced by a maximum of 44.35 % and 55.77 % respectively, and it increased the diversity and abundance of bacterial communities, promoting the recovery of soil microbial ecological functions. These findings indicate that Plant-blanket can regulate water and improve soil environment, and has certain control ability on the migration of Cd and Cu produced by pyritic tailings. Meanwhile, Plant-blanket plays an important role in improving the soil environment in mining areas and promoting ecosystem restoration, providing valuable reference for further exploration of ecological restoration of tailings.

Preterm birth, a consequence of immune deviation mediated hyperinflammation.

Preterm birth represents a multifaceted syndrome with intricacies still present in our comprehension of its etiology. In the context of a semi-allograft, the prosperity from implantation to pregnancy to delivery hinges on the establishment of a favorable maternal-fetal immune microenvironment and a successful trilogy of immune activation, immune tolerance and then immune activation transitions. The occurrence of spontaneous preterm birth could be related to abnormalities within the immune trilogy, stemming from deviation in maternal and fetal immunity. These immune deviations, characterized by insufficient immune tolerance and early immune activation, ultimately culminated in an unsustainable pregnancy. In this review, we accentuated the role of both innate and adaptive immune reason in promoting spontaneous preterm birth, reviewed the risk of preterm birth from vaginal microbiome mediated by immune changes and the potential of vaginal microbiomes and metabolites as a new predictive marker, and discuss the changes in the role of progesterone and its interaction with immune cells in a preterm birth population. Our objective was to contribute to the growing body of knowledge in the field, shedding light on the immunologic reason of spontaneous preterm birth and effective biomarkers for early prediction, providing a roadmap for forthcoming investigations.

MEG3 in hematologic malignancies: from the role of disease biomarker to therapeutic target.

Maternally expressed gene 3 (MEG3) is a noncoding RNA that is known as a tumor suppressor in solid cancers. Recently, a line of studies has emphasized its potential role in hematological malignancies in terms of tumorigenesis, metastasis, and drug resistance. Similar to solid cancers, MEG3 can regulate various cancer hallmarks via sponging miRNA, transcriptional, or posttranslational regulation mechanisms, but may regulate different key elements. In contrast with solid cancers, in some subtypes of leukemia, MEG3 has been found to be upregulated and oncogenic. In this review, we systematically describe the role and underlying mechanisms of MEG3 in multiple types of hematological malignancies. Particularly, we highlight the role of MEG3 in drug resistance and as a novel therapeutic target.

Single-structure 3-axis Lorentz force magnetometer based on an AlN-on-Si MEMS resonator.

This work presents a single-structure 3-axis Lorentz force magnetometer (LFM) based on an AlN-on-Si MEMS resonator. The operation of the proposed LFM relies on the flexible manipulation of applied excitation currents in different directions and frequencies, enabling the effective actuation of two mechanical vibration modes in a single device for magnetic field measurements in three axes. Specifically, the excited out-of-plane drum-like mode at 277 kHz is used for measuring the x- and y-axis magnetic fields, while the in-plane square-extensional mode at 5.4 MHz is used for measuring the z-axis magnetic field. The different configurations of applied excitation currents ensure good cross-interference immunity among the three axes. Compared to conventional capacitive LFMs, the proposed piezoelectric LFM utilizes strong electromechanical coupling from the AlN layer, which allows it to operate at ambient pressure with a high sensitivity. To understand and analyze the measured results, a novel equivalent circuit model for the proposed LFM is also reported in this work, which serves to separate the effect of Lorentz force from the unwanted capacitive feedthrough. The demonstrated 3-axis LFM exhibits measured magnetic responsivities of 1.74 ppm/mT, 1.83 ppm/mT and 6.75 ppm/mT in the x-, y- and z-axes, respectively, which are comparable to their capacitive counterparts.

Pan-cancer single-cell landscape of drug-metabolizing enzyme genes.

OBJECTIVE: Varied expression of drug-metabolizing enzymes (DME) genes dictates the intensity and duration of drug response in cancer treatment. This study aimed to investigate the transcriptional profile of DMEs in tumor microenvironment (TME) at single-cell level and their impact on individual responses to anticancer therapy. METHODS: Over 1.3 million cells from 481 normal/tumor samples across 9 solid cancer types were integrated to profile changes in the expression of DME genes. A ridge regression model based on the PRISM database was constructed to predict the influence of DME gene expression on drug sensitivity. RESULTS: Distinct expression patterns of DME genes were revealed at single-cell resolution across different cancer types. Several DME genes were highly enriched in epithelial cells (e.g. GPX2, TST and CYP3A5) or different TME components (e.g. CYP4F3 in monocytes). Particularly, GPX2 and TST were differentially expressed in epithelial cells from tumor samples compared to those from normal samples. Utilizing the PRISM database, we found that elevated expression of GPX2, CYP3A5 and reduced expression of TST was linked to enhanced sensitivity of particular chemo-drugs (e.g. gemcitabine, daunorubicin, dasatinib, vincristine, paclitaxel and oxaliplatin). CONCLUSION: Our findings underscore the varied expression pattern of DME genes in cancer cells and TME components, highlighting their potential as biomarkers for selecting appropriate chemotherapy agents.

Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

Repression of YEATS2 induces cellular senescence in hepatocellular carcinoma and inhibits tumor growth.

Hepatocellular carcinoma (HCC) stands as the third leading cause of cancer-related fatalities globally. In this study, we observed a significant increase in the expression level of the YEATS2 gene in HCC patients, and it is negatively correlated with the patients' survival rate. While we have previously identified the association between YEATS2 and the survival of pancreatic cancer cells, the regulatory mechanisms and significance in HCC are still to be fully elucidated. Our study shows that knockdown (KD) of YEATS2 expression leads to DNA damage, which in turn results in an upregulation of γ-H2A.X expression and activation of the canonical senescence-related pathway p53/p21Cip1. Moreover, our transcriptomic analysis reveals that YEATS2 KD cells can enhance the expression of p21Cip1 via the c-Myc/miR-93-5p pathway, consequently fostering the senescence of HCC cells. The initiation of cellular senescence through dual-channel activation suggests that YEATS2 plays a pivotal regulatory role in the process of cell proliferation. Ultimately, our in vivo research utilizing a nude mouse tumor model revealed a notable decrease in both tumor volume and weight after the suppression of YEATS2 expression. This phenomenon is likely attributable to the attenuation of proliferative cell activity, coupled with a concurrent augmentation in the population of natural killer (NK) cells. In summary, our research results have supplemented the understanding of the regulatory mechanisms of HCC cell proliferation and indicated that targeting YEATS2 may potentially inhibit liver tumor growth.

Targeted depletion of PD-1-expressing cells induces immune tolerance through peripheral clonal deletion.

Thymic negative selection of the T cell receptor (TCR) repertoire is essential for establishing self-tolerance and acquired allograft tolerance following organ transplantation. However, it is unclear whether and how peripheral clonal deletion of alloreactive T cells induces transplantation tolerance. Here, we establish that programmed cell death protein 1 (PD-1) is a hallmark of alloreactive T cells and is associated with clonal expansion after alloantigen encounter. Moreover, we found that diphtheria toxin receptor (DTR)-mediated ablation of PD-1+ cells reshaped the TCR repertoire through peripheral clonal deletion of alloreactive T cells and promoted tolerance in mouse transplantation models. In addition, by using PD-1-specific depleting antibodies, we found that antibody-mediated depletion of PD-1+ cells prevented heart transplant rejection and the development of experimental autoimmune encephalomyelitis (EAE) in humanized PD-1 mice. Thus, these data suggest that PD-1 is an attractive target for peripheral clonal deletion and induction of immune tolerance.