NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion.

The progressive decline of CD8 T cell effector function-also known as terminal exhaustion-is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Texterm) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+TIM-3+) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states.

Detection of Endoleak after Endovascular Aortic Repair through Deep Learning Based on Non-contrast CT.

OBJECTIVES: To develop and validate a deep learning model for detecting post-endovascular aortic repair (EVAR) endoleak from non-contrast CT. METHODS: This retrospective study involved 245 patients who underwent EVAR between September 2016 and December 2022. All patients underwent both non-enhanced and enhanced follow-up CT. The presence of endoleak was evaluated based on computed tomography angiography (CTA) and radiology reports. First, the aneurysm sac was segmented, and radiomic features were extracted on non-contrast CT. Statistical analysis was conducted to investigate differences in shape and density characteristics between aneurysm sacs with and without endoleak. Subsequently, a deep learning model was trained to generate predicted segmentation of the endoleak. A binary decision was made based on whether the model produced a segmentation to detect the presence of endoleak. The absence of a predicted segmentation indicated no endoleak, while the presence of a predicted segmentation indicated endoleak. Finally, the performance of the model was evaluated by comparing the predicted segmentation with the reference segmentation obtained from CTA. Model performance was assessed using metrics such as dice similarity coefficient, sensitivity, specificity, and the area under the curve (AUC). RESULTS: This study finally included 85 patients with endoleak and 82 patients without endoleak. Compared to patients without endoleak, patients with endoleak had higher CT values and greater dispersion. The AUC in validation group was 0.951, dice similarity coefficient was 0.814, sensitivity was 0.877, and specificity was 0.884. CONCLUSION: This deep learning model based on non-contrast CT can detect endoleak after EVAR with high sensitivity.

LncRNA H19/miR-107 regulates endothelial progenitor cell pyroptosis and promotes flow recovery of lower extremity ischemia through targeting FADD.

BACKGROUND: Peripheral artery disease (PAD) is an ischemic disease with a rising incidence worldwide. The lncRNA H19 (H19) is enriched in endothelial progenitor cells (EPCs), and transplantation of pyroptosis-resistant H19-overexpressed EPCs (oe-H19-EPCs) may promote vasculogenesis and blood flow recovery in PAD, especially with critical limb ischemia (CLI). METHODS: EPCs isolated from human peripheral blood was characterized using immunofluorescence and flow cytometry. Cell proliferation was determined with CCK8 and EdU assays. Cell migration was assessed by Transwell and wound healing assays. The angiogenic potential was evaluated using tube formation assay. The pyroptosis pathway-related protein in EPCs was detected by western blot. The binding sites of H19 and FADD on miR-107 were analyzed using Luciferase assays. In vivo, oe-H19-EPCs were transplanted into a mouse ischemic limb model, and blood flow was detected by laser Doppler imaging. The transcriptional landscape behind the therapeutic effects of oe-H19-EPCs on ischemic limbs were examined with whole transcriptome sequencing. RESULTS: Overexpression of H19 in EPCs led to an increase in proliferation, migration, and tube formation abilities. These effects were mediated through pyroptosis pathway, which is regulated by the H19/miR-107/FADD axis. Transplantation of oe-H19-EPCs in a mouse ischemic limb model promoted vasculogenesis and blood flow recovery. Whole transcriptome sequencing indicated significant activation of vasculogenesis pathway in the ischemic limbs following treatment with oe-H19-EPCs. CONCLUSIONS: Overexpression of H19 increases FADD level by competitively binding to miR-107, leading to enhanced proliferation, migration, vasculogenesis, and inhibition of pyroptosis in EPCs. These effects ultimately promote the recovery of blood flow in CLI.

miR-181c-5p/DERL1 pathway controls breast cancer progression mediated by TRAF6-linked K63 ubiquitination of AKT.

BACKGROUND: Aberrant Derlin-1 (DERL1) expression is associated with an overactivation of p-AKT, whose involvement in breast cancer (BRCA) development has been widely speculated. However, the precise mechanism that links DERL1 expression and AKT activation is less well-studied. METHODS: Bioinformatic analyses hold a promising approach by which to detect genes' expression levels and their association with disease prognoses in patients. In the present work, a dual-luciferase assay was employed to investigate the relationship between DERL1 expression and the candidate miRNA by both in vitro and in vivo methods. Further in-depth studies involving immunoprecipitation-mass spectrum (IP-MS), co-immunoprecipitation (Co-IP), as well as Zdock prediction were performed. RESULTS: Overexpression of DERL1 was detected in all phenotypes of BRCA, and its knockdown showed an inhibitory effect on BRCA cells both in vitro and in vivo. The Cancer Genome Atlas (TCGA) database reported that DERL1 overexpression was correlated with poor overall survival in BRCA cases, and so the quantification of DERL1 expression could be a potential marker for the clinical diagnosis of BRCA. On the other hand, miR-181c-5p was downregulated in BRCA, suggesting that its overexpression could be a potent therapeutic route to improve the overall survival of BRCA cases. Prior bioinformatic analyses indicated a somewhat positive correlation between DERL1 and TRAF6 as well as between TRAF6 and AKT, but not between miR-181c-5p and DERL1. In retrospect, DERL1 overexpression promoted p-AKT activation through K63 ubiquitination. DERL1 was believed to directly interact with the E3 ligase TRAF6. As Tyr77Ala or Tyr77Ala/Gln81Ala/Arg85Ala/Val158Ala attempts to prevent the interaction between DERL1 and TRAF domain of TRAF6, resulted in a significant reduction in K63-ubiquitinated p-AKT production. However, mutations in Gln81Ala, Arg85Ala, or Val158Ala could possibly interrupt with these processes. CONCLUSIONS: Our data confirm that mediation of the miR-181c-5p/DERL1 pathway by TRAF6-linked AKT K63 ubiquitination holds one of the clues to set our focus on toward meeting the therapeutic goals of BRCA.

Jinlida for Diabetes Prevention in Impaired Glucose Tolerance and Multiple Metabolic Abnormalities: The FOCUS Randomized Clinical Trial.

Importance: Previous studies have shown that Jinlida (JLD) granules, an approved treatment for type 2 diabetes in China, can reduce blood glucose level, reduce glycated hemoglobin (HbA1c), and improve insulin resistance in people with type 2 diabetes. Objective: To evaluate the effect of long-term administration of JLD vs placebo on the incidence of diabetes in participants with impaired glucose tolerance (IGT) and multiple metabolic abnormalities. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled randomized clinical trial (FOCUS) was conducted across 35 centers in 21 cities in China from June 2019 to February 2023. Individuals aged 18 to 70 years with IGT and multiple metabolic abnormalities were enrolled. Intervention: Participants were randomly allocated 1:1 to receive JLD or placebo (9 g, 3 times per day, orally). They continued this regimen until they developed diabetes, withdrew from the study, were lost to follow-up, or died. Main Outcomes and Measures: The primary outcome was the occurrence of diabetes, which was determined by 2 consecutive oral glucose tolerance tests. Secondary outcomes included waist circumference; fasting and 2-hour postprandial plasma glucose levels; HbA1c; fasting insulin level; homeostatic model assessment for insulin resistance (HOMA-IR); total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels; ankle-brachial index; and carotid intima-media thickness. Results: A total of 889 participants were randomized, of whom 885 were in the full analysis set (442 in the JLD group; 443 in the placebo group; mean [SD] age, 52.57 [10.33] years; 463 [52.32%] female). Following a median observation period of 2.20 years (IQR, 1.27-2.64 years), participants in the JLD group had a lower risk of developing diabetes compared with those in the placebo group (hazard ratio, 0.59; 95% CI, 0.46-0.74; P < .001). During the follow-up period, the JLD group had a between-group difference of 0.95 cm (95% CI, 0.36-1.55 cm) in waist circumference, 9.2 mg/dL (95% CI, 5.4-13.0 mg/dL) in 2-hour postprandial blood glucose level, 3.8 mg/dL (95% CI, 2.2-5.6 mg/dL) in fasting blood glucose level, 0.20% (95% CI, 0.13%-0.27%) in HbA1c, 6.6 mg/dL (95% CI, 1.9-11.2) in total cholesterol level, 4.3 mg/dL (95% CI, 0.8-7.7 mg/dL) in low-density lipoprotein cholesterol level, 25.7 mg/dL (95% CI, 15.9-35.4 mg/dL) in triglyceride levels, and 0.47 (95% CI, 0.12-0.83) in HOMA-IR compared with the placebo group. After 24 months of follow-up, the JLD group had a significant improvement in ankle-brachial index and waist circumference compared with the placebo group. Conclusions and Relevance: The findings suggest that JLD can reduce the risk of diabetes in participants with IGT and multiple metabolic abnormalities. Trial Registration: Chinese Clinical Trial Register: ChiCTR1900023241.

Single-cell landscape of immunological responses in elderly patients with sepsis.

Sepsis is a dysregulated host response to severe infections, and immune dysfunction plays a crucial role in its pathogenesis. Elderly patients, a special population influenced by immunosenescence, are more susceptible to sepsis and have a worse prognosis. However, the immunopathogenic mechanisms underlying sepsis in elderly patients remain unclear. Here, we performed single-cell RNA sequencing of peripheral blood samples from young and old subjects and patients with sepsis. By exploring the transcriptional profiles of immune cells, we analyzed immune cell compositions, phenotype shifts, expression heterogeneities, and intercellular communication. In elderly patients with sepsis, innate immune cells (e.g., monocytes and DCs) exhibit decreased antigen presentation, presenting an overactive inflammatory and senescent phenotype. However, the immunophenotype of T cells shifted to characterize effector, memory, and exhaustion. Moreover, we identified strong interferon-γ responses of T cells in both aging and sepsis groups and a deranged inflammaging status in elderly sepsis patients. Tregs in elderly patients with sepsis showed increased abundance and enhanced immunosuppressive effects. In addition, metabolism-associated pathways were upregulated in T cells in elderly patients with sepsis, and the lysine metabolism pathway was enriched in Tregs. Cell-cell interaction analysis showed that the expression profile of ligand-receptor pairs was probably associated with aggravated immune dysfunction in elderly patients with sepsis. A novel HLA-KIR interaction was observed between Tregs and CD8 + T cells. These findings illustrate the immunological hallmarks of sepsis in elderly patients, and highlight that immunosuppressive and metabolic regulatory pathways may undergo important alterations in elderly patients with sepsis.

Development of a PAK4-targeting PROTAC for renal carcinoma therapy: concurrent inhibition of cancer cell proliferation and enhancement of immune cell response.

BACKGROUND: Finding the oncogene, which was able to inhibit tumor cells intrinsically and improve the immune answers, will be the future direction for renal cancer combined treatment. Following patient sample analysis and signaling pathway examination, we propose p21-activated kinase 4 (PAK4) as a potential target drug for kidney cancer. PAK4 exhibits high expression levels in patient samples and plays a regulatory role in the immune microenvironment. METHODS: Utilizing AI software for peptide drug design, we have engineered a specialized peptide proteolysis targeting chimera (PROTAC) drug with selectivity for PAK4. To address challenges related to drug delivery, we developed a nano-selenium delivery system for efficient transport of the peptide PROTAC drug, termed PpD (PAK4 peptide degrader). FINDINGS: We successfully designed a peptide PROTAC drug targeting PAK4. PpD effectively degraded PAK4 with high selectivity, avoiding interference with other homologous proteins. PpD significantly attenuated renal carcinoma proliferation in vitro and in vivo. Notably, PpD demonstrated a significant inhibitory effect on tumor proliferation in a fully immunocompetent mouse model, concomitantly enhancing the immune cell response. Moreover, PpD demonstrated promising tumor growth inhibitory effects in mini-PDX and PDO models, further underscoring its potential for clinical application. INTERPRETATION: This PAK4-targeting peptide PROTAC drug not only curtails renal cancer cell proliferation but also improves the immune microenvironment and enhances immune response. Our study paves the way for innovative targeted therapies in the management of renal cancer. FUNDING: This work is supported by Research grants from non-profit organizations, as stated in the Acknowledgments.

Deep brain stimulation of symptom-specific networks in Parkinson's disease.

Deep Brain Stimulation can improve tremor, bradykinesia, rigidity, and axial symptoms in patients with Parkinson's disease. Potentially, improving each symptom may require stimulation of different white matter tracts. Here, we study a large cohort of patients (N = 237 from five centers) to identify tracts associated with improvements in each of the four symptom domains. Tremor improvements were associated with stimulation of tracts connected to primary motor cortex and cerebellum. In contrast, axial symptoms are associated with stimulation of tracts connected to the supplementary motor cortex and brainstem. Bradykinesia and rigidity improvements are associated with the stimulation of tracts connected to the supplementary motor and premotor cortices, respectively. We introduce an algorithm that uses these symptom-response tracts to suggest optimal stimulation parameters for DBS based on individual patient's symptom profiles. Application of the algorithm illustrates that our symptom-tract library may bear potential in personalizing stimulation treatment based on the symptoms that are most burdensome in an individual patient.

Kaempferol efficacy in metabolic diseases: Molecular mechanisms of action in diabetes mellitus, obesity, non-alcoholic fatty liver disease, steatohepatitis, and atherosclerosis.

The incidence of metabolic diseases has progressively increased, which has a negative impact on human health and life safety globally. Due to the good efficacy and limited side effects, there is growing interest in developing effective drugs to treat metabolic diseases from natural compounds. Kaempferol (KMP), an important flavonoid, exists in many vegetables, fruits, and traditional medicinal plants. Recently, KMP has received widespread attention worldwide due to its good potential in the treatment of metabolic diseases. To promote the basic research and clinical application of KMP, this review provides a timely and comprehensive summary of the pharmacological advances of KMP in the treatment of four metabolic diseases and its potential molecular mechanisms of action, including diabetes mellitus, obesity, non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), and atherosclerosis. According to the research, KMP shows remarkable therapeutic effects on metabolic diseases by regulating multiple signaling transduction pathways such as NF-κB, Nrf2, AMPK, PI3K/AKT, TLR4, and ER stress. In addition, the most recent literature on KMP's natural source, pharmacokinetics studies, as well as toxicity and safety are also discussed in this review, thus providing a foundation and evidence for further studies to develop novel and effective drugs from natural compounds. Collectively, our manuscript strongly suggested that KMP could be a promising candidate for the treatment of metabolic diseases.

Deciphering smooth muscle cell heterogeneity in atherosclerotic plaques and constructing model: a multi-omics approach with focus on KLF15/IGFBP4 axis.

BACKGROUND: Ruptured atherosclerotic plaques often precipitate severe ischemic events, such as stroke and myocardial infarction. Unraveling the intricate molecular mechanisms governing vascular smooth muscle cell (VSMC) behavior in plaque stabilization remains a formidable challenge. METHODS: In this study, we leveraged single-cell and transcriptomic datasets from atherosclerotic plaques retrieved from the gene expression omnibus (GEO) database. Employing a combination of single-cell population differential analysis, weighted gene co-expression network analysis (WGCNA), and transcriptome differential analysis techniques, we identified specific genes steering the transformation of VSMCs in atherosclerotic plaques. Diagnostic models were developed and validated through gene intersection, utilizing the least absolute shrinkage and selection operator (LASSO) and random forest (RF) methods. Nomograms for plaque assessment were constructed. Tissue localization and expression validation were performed on specimens from animal models, utilizing immunofluorescence co-localization, western blot, and reverse-transcription quantitative-polymerase chain reaction (RT-qPCR). Various online databases were harnessed to predict transcription factors (TFs) and their interacting compounds, with determination of the cell-specific localization of TF expression using single-cell data. RESULTS: Following rigorous quality control procedures, we obtained a total of 40,953 cells, with 6,261 representing VSMCs. The VSMC population was subsequently clustered into 5 distinct subpopulations. Analyzing inter-subpopulation cellular communication, we focused on the SMC2 and SMC5 subpopulations. Single-cell subpopulation and WGCNA analyses revealed significant module enrichments, notably in collagen-containing extracellular matrix and cell-substrate junctions. Insulin-like growth factor binding protein 4 (IGFBP4), apolipoprotein E (APOE), and cathepsin C (CTSC) were identified as potential diagnostic markers for early and advanced plaques. Notably, gene expression pattern analysis suggested that IGFBP4 might serve as a protective gene, a hypothesis validated through tissue localization and expression analysis. Finally, we predicted TFs capable of binding to IGFBP4, with Krüppel-like family 15 (KLF15) emerging as a prominent candidate showing relative specificity within smooth muscle cells. Predictions about compounds associated with affecting KLF15 expression were also made. CONCLUSION: Our study established a plaque diagnostic and assessment model and analyzed the molecular interaction mechanisms of smooth muscle cells within plaques. Further analysis revealed that the transcription factor KLF15 may regulate the biological behaviors of smooth muscle cells through the KLF15/IGFBP4 axis, thereby influencing the stability of advanced plaques via modulation of the PI3K-AKT signaling pathway. This could potentially serve as a target for plaque stability assessment and therapy, thus driving advancements in the management and treatment of atherosclerotic plaques.

A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification.

Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.

Efficacy and safety of sympathetic mapping and ablation of renal nerves for the treatment of hypertension (SMART): 6-month follow-up of a randomised, controlled trial.

Background: Previous trials of renal denervation (RDN) have been designed to investigate reduction of blood pressure (BP) as the primary efficacy endpoint using non-selective RDN without intraoperatively verified RDN success. It is an unmet clinical need to map renal nerves, selectively denervate renal sympathetic nerves, provide readouts for the interventionalists and avoid futile RDN. We aimed to examine the safety and efficacy of renal nerve mapping/selective renal denervation (msRDN) in patients with uncontrolled hypertension (HTN) and determine whether antihypertensive drug burden is reduced while office systolic BP (OSBP) is controlled to target level (＜140 mmHg). Methods: We conducted a randomized, prospective, multicenter, single-blinded, sham-controlled trial. The study combined two efficacy endpoints at 6 months as primary outcomes: The control rate of patients with OSBP ＜140 mmHg (non-inferior outcome) and change in the composite index of antihypertensive drugs (Drug Index) in the treatment versus Sham group (superior outcome). This design avoids confounding from excess drug-taking in the Sham group. Antihypertensive drug burden was assessed by a composite index constructed as: Class N (number of classes of antihypertensive drugs) × (sum of doses). 15 hospitals in China participated in the study and 220 patients were enrolled in a 1:1 ratio (msRDN vs Sham). The key inclusion criteria included: age (18-65 years old), history of essential HTN (at least 6 months), heart rate (≥70 bpm), OSBP (≥150 mmHg and ≤180 mmHg), ambulatory BP monitoring (ABPM, 24-h SBP ≥130 mmHg or daytime SBP ≥135 mmHg or nighttime SBP ≥120 mmHg), renal artery stenosis (＜50%) and renal function (eGFR ＞45 mL/min/1.73 m2). The catheter with both stimulation and ablation functions was inserted in the distal renal main artery. The RDN site (hot spot) was selected if SBP increased (≥5 mmHg) by intra-renal artery (RA) electrical stimulation; an adequate RDN was confirmed by repeated electronic stimulation if no increase in BP otherwise, a 2nd ablation was performed at the same site. At sites where there was decreased SBP (≥5 mmHg, cold spot) or no BP response (neutral spot) to stimulation, no ablation was performed. The mapping, ablation and confirmation procedure was repeated until the entire renal main artery had been tested then either treated or avoided. After msRDN, patients had to follow a predefined, vigorous drug titration regimen in order to achieve target OSBP (＜140 mmHg). Drug adherence was monitored by liquid chromatography-tandem mass spectrometry analysis using urine. This study is registered with ClinicalTrials.gov (NCT02761811) and 5-year follow-up is ongoing. Findings: Between July 8, 2016 and February 23, 2022, 611 patients were consented, 220 patients were enrolled in the study who received standardized antihypertensive drug treatments (at least two drugs) for at least 28 days, presented OSBP ≥150 mmHg and ≤180 mmHg and met all inclusion and exclusion criteria. In left RA and right RA, mapped sites were 8.2 (3.0) and 8.0 (2.7), hot/ablated sites were 3.7 (1.4) and 4.0 (1.6), cold spots were 2.4 (2.6) and 2.0 (2.2), neutral spots were 2.0 (2.1) and 2.0 (2.1), respectively. Hot, cold and neutral spots was 48.0%, 27.5% and 24.4% of total mapped sites, respectively. At 6 M, the Control Rate of OSBP was comparable between msRDN and Sham group (95.4% vs 92.8%, p = 0.429), achieved non-inferiority margin -10% (2.69%; 95% CI -4.11%, 9.83%, p ＜ 0.001 for non-inferiority); the change in Drug Index was significantly lower in msRDN group compared to Sham group (4.37 (6.65) vs 7.61 (10.31), p = 0.010) and superior to Sham group (-3.25; 95% CI -5.56, -0.94, p = 0.003), indicating msRDN patients need significantly fewer drugs to control OSBP ＜140 mmHg. 24-hour ambulatory SBP decreased from 146.8 (13.9) mmHg by 10.8 (14.1) mmHg, and from 149.8 (12.8) mmHg by 10.0 (14.0) mmHg in msRDN and Sham groups, respectively (p < 0.001 from Baseline; p > 0.05 between groups). Safety profiles were comparable between msRDN and Sham groups, demonstrating the safety and efficacy of renal mapping/selective RDN to treat uncontrolled HTN. Interpretation: The msRDN therapy achieved the goals of reducing the drug burden of HTN patients and controlling OSBP <140 mmHg, with only approximately four targeted ablations per renal main artery, much lower than in previous trials. Funding: SyMap Medical (Suzhou), LTD, Suzhou, China.

Genetically determined type 1 diabetes mellitus and risk of osteoporosis.

BACKGROUND: Observational evidence suggests that type 1 diabetes mellitus (T1DM) is associated with the risk of osteoporosis (OP). Nevertheless, it is not apparent whether these correlations indicate a causal relationship. To elucidate the causal relationship, a two-sample Mendelian randomization (MR) analysis was performed. METHODS: T1DM data was obtained from the large genome-wide association study (GWAS), in which 6683 cases and 12,173 controls from 12 European cohorts were involved. Bone mineral density (BMD) samples at four sites were extracted from the GEnetic Factors for OSteoporosis (GEFOS) consortium, including forearm (FA) (n = 8,143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498), and heel (eBMD) (n = 426,824). The former three samples were from mixed populations and the last one was from European. Inverse variance weighting, MR-Egger, and weighted median tests were used to test the causal relationship between T1DM and OP. A series of sensitivity analyses were then conducted to verify the robustness of the results. RESULTS: Twenty-three independent SNPs were associated with FN-BMD and LS-BMD, twenty-seven were associated with FA-BMD, and thirty-one were associated with eBMD. Inverse variance-weighted estimates indicated a causal effect of T1DM on FN-BMD (odds ratio (OR) =1.033, 95 % confidence interval (CI): 1.012-1.054, p = 0.002) and LS-BMD (OR = 1.032, 95 % CI: 1.005-1.060, p = 0.022) on OP risk. Other MR methods, including weighted median and MR-Egger, calculated consistent trends. While no significant causation was found between T1DM and the other sites (FA-BMD: OR = 1.008, 95 % CI: 0.975-1.043, p = 0.632; eBMD: OR = 0.993, 95 % CI: 0.985-1.001, p = 0.106). No significant heterogeneity (except for eBMD) or horizontal pleiotropy was found for instrumental variables, suggesting these results were reliable and robust. CONCLUSIONS: This study shows a causal relationship between T1DM and the risk of some sites of OP (FN-BMD, LS-BMD), allowing for continued research to discover the clinical and experimental mechanisms of T1DM and OP. It also contributes to the recommendation if patients with T1DM need targeted care to promote bone health and timely prevention of osteoporosis.

Enhanced magnetic anisotropy of iridium dimers on antisite defects of two-dimensional transition-metal dichalcogenides.

The combination of transition-metal (TM) elements with two-dimensional (2D) transition-metal dichalcogenides (TMDs) provides an effective route to realizing a 2D controllable magnetic order, leading to significant applications in multifunctional nanospintronics. However, in most TM atoms@TMDs nanostructures, it is challenging for the magnetic anisotropy energy (MAE) to exceed 30 meV when affected by the crystal field. Hence, the stronger magnetic anisotropy of TMDs has yet to be developed. Here, utilizing first-principle calculations based on density functional theory (DFT), a feasible method to enhance the MAEs of TMDs via configurating iridium dimers (Ir2) on 2D traditional and Janus TMDs with antisite defects is reported. Calculations revealed that 28 of the 54 configurations considered possessed structure-dependent MAEs of >60 meV per Ir2 in the out-of-plane direction, suggesting the potential for applications at room temperature. We also showed the ability to tune the MAE further massively by applying a biaxial strain as well as the surface asymmetric polarization reversal of Janus-type substrates. This approach led to changes to >80 meV per Ir2. This work provides a novel strategy to achieve tunable large magnetic anisotropy in 2D TMDs. It also extends the functionality of antisite-defective TMDs, thereby providing theoretical support for the development of magnetic nanodevices.

Design, synthesis and biological evaluation of quinazoline and pyrrolo[3,2-d]pyrimidine derivatives as TLR7 agonists for antiviral agents.

Pattern recognition receptors (PRRs) play a critical role in the innate immune response, and toll-like receptor 7 (TLR7) is an important member of PRRs. Although several TLR7 agonists are available, most of them are being tested clinically, with only one available on the market. Thus, it is imperative to develop new TLR7 agonists. In this study, we designed and synthesized three kinds of quinazoline derivatives and five kinds of pyrrolo[3,2-d]pyrimidine derivatives targeting TLR7. The antiviral efficacy of these compounds was evaluated in vitro and in vivo. Our findings indicated that four kinds of compounds showed exceptional antiviral activity. Furthermore, molecular docking studies confirmed that compound 11 successfully positioned itself in the pocket of the TLR7 guanosine loading site with a binding energy of -4.45 kcal mol-1. These results suggested that these compounds might be potential antiviral agents.

Wearable Sensor Based on a Tough Conductive Gel for Real-Time and Remote Human Motion Monitoring.

The usage of a conductive hydrogel in wearable sensors has been thoroughly researched recently. Nonetheless, hydrogel-based sensors cannot simultaneously have excellent mechanical property, high sensitivity, comfortable wearability, and rapid self-healing performance, which result in poor durability and reusability. Herein, a robust conductive hydrogel derived from one-pot polymerization and subsequent solvent replacement is developed as a wearable sensor. Owing to the reversible hydrogen bonds cross-linked between polymer chains and clay nanosheets, the resulting conductive hydrogel-based sensor exhibits outstanding flexibility, self-repairing, and fatigue resistance performances. The embedding of graphene oxide nanosheets offers an enhanced hydrogel network and easy release of wearable sensor from the target position through remote irradiation, while Li+ ions incorporated by solvent replacement endow the wearable sensor with low detection limit (sensing strain: 1%), high conductivity (4.3 S m-1) and sensitivity (gauge factor: 3.04), good freezing resistance, and water retention. Therefore, the fabricated wearable sensor is suitable to monitor small and large human motions on the site and remotely under subzero (-54 °C) or room temperature, indicating lots of promising applications in human-motion monitoring, information encryption and identification, and electronic skins.

Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner.

Targeting C5aR1 modulates the function of infiltrated immune cells including tumor-associated macrophages (TAMs). The gut microbiome plays a pivotal role in colorectal cancer (CRC) tumorigenesis and development through TAM education. However, whether and how the gut flora is involved in C5aR1 inhibition-mediated TAMs remains unclear. Therefore, in this study, genetic deletion of C5ar1 or pharmacological inhibition of C5aR1 with anti-C5aR1 Ab or PMX-53 in the presence or absence of deletion Abs were utilized to verify if and how C5aR1 inhibition regulated TAMs polarization via affecting gut microbiota composition. We found that the therapeutic effects of C5aR1 inhibition on CRC benefited from programming of TAMs toward M1 polarization via driving AKT2-mediated 6-phosphofructokinase muscle type (PFKM) stabilization in a TLR5-dependent manner. Of note, in the further study, we found that C5aR1 inhibition elevated the concentration of serum IL-22 and the mRNA levels of its downstream target genes encoded antimicrobial peptides (AMPs), leading to gut microbiota modulation and flagellin releasement, which contributed to M1 polarization. Our data revealed that high levels of C5aR1 in TAMs predicted poor prognosis. In summary, our study suggested that C5aR1 inhibition reduced CRC growth via resetting M1 by AKT2 activation-mediated PFKM stabilization in a TLR5-dependent manner, which relied on IL-22-regulated gut flora.

PINK1 dominated mitochondria associated genes signature predicts abdominal aortic aneurysm with metabolic syndrome.

Abdominal aortic aneurysm (AAA) is typically asymptomatic but a devastating cardiovascular disorder, with overall mortality exceeding 80 % once it ruptures. Some patients with AAA may also have comorbid metabolic syndrome (MS), suggesting a potential common underlying pathogenesis. Mitochondrial dysfunction has been reported as a key factor contributing to the deterioration of both AAA and MS. However, the intricate interplay between metabolism and mitochondrial function, both contributing to the development of AAA, has not been thoroughly explored. In this study, we identified candidate genes related to mitochondrial function in AAA and MS. Subsequently, we developed a nomoscore model comprising hub genes (PINK1, ACSL1, CYP27A1, and SLC25A11), identified through the application of two machine learning algorithms, to predict AAA. We observed a marked disparity in immune infiltration profiles between high- and low-nomoscore groups. Furthermore, we confirmed a significant upregulation of the expression of the four hub genes in AAA tissues. Among these, ACSL1 showed relatively higher expression in LPS-treated RAW264.7 cell lines, while CYP27A1 exhibited a notable decrease. Moreover, SLC25A11 displayed a significant upregulation in AngII-treated VSMCs. Conversely, the expression level of PINK1 declined in LPS-stimulated RAW264.7 cell lines but significantly increased in AngII-treated VSMCs. In vivo experiments revealed that the activation of PINK1-mediated mitophagy inhibited the development of AAA in mice. In this current study, we have innovatively identified four mitochondrial function-related genes through integrated bioinformatic analysis. This discovery sheds light on the regulatory mechanisms and unveils promising therapeutic targets for the comorbidity of AAA and MS.