Antibody-activation of connexin hemichannels in bone osteocytes with ATP release suppresses breast cancer and osteosarcoma malignancy.

Bone tissue represents the most frequent site of cancer metastasis. We developed a hemichannel-activating antibody, Cx43-M2. Cx43-M2, directly targeting osteocytes in situ, activates osteocytic hemichannels and elevates extracellular ATP, thereby inhibiting the growth and migration of cultured breast and osteosarcoma cancer cells. Cx43-M2 significantly decreases breast cancer metastasis, osteosarcoma growth, and osteolytic activity, while improving survival rates in mice. The antibody's inhibition of breast cancer and osteosarcoma is dose dependent in both mouse and human cancer metastatic models. Furthermore, Cx43-M2 enhances anti-tumor immunity by increasing the population and activation of tumor-infiltrating immune-promoting effector T lymphocytes, while reducing immune-suppressive regulatory T cells. Our results suggest that the Cx43-M2 antibody, by activating Cx43 hemichannels and facilitating ATP release and purinergic signaling, transforms the cancer microenvironment from a supportive to a suppressive state. Collectively, our study underscores the potential of Cx43-M2 as a therapeutic for treating breast cancer bone metastasis and osteosarcoma.

Electrode switch-an efficient induced approach for self-activation of an electrode toward water splitting.

In this paper, we provide a novel electrode switch (ES) method to improve the stability of the alkaline electrolyzer toward water splitting. The voltage of the alkaline electrolyzer consisting of commercial Ni mesh electrodes utilizing the ES mode exhibits extreme stability because highly active Ni oxide(hydroxide) with oxygen defects is in situ formed during the hydrogen evolution reaction (HER) polarization process.

Contribution of copy number variants on antipsychotic treatment response in Han Chinese patients with schizophrenia.

BACKGROUND: Response to antipsychotic drugs (APD) varies greatly among individuals and is affected by genetic factors. This study aims to demonstrate genome-wide associations between copy number variants (CNVs) and response to APD in patients with schizophrenia. METHODS: A total of 3030 patients of Han Chinese ethnicity randomly received APD (aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, haloperidol and perphenazine) treatment for six weeks. This study is a secondary data analysis. Percentage change on the Positive and Negative Syndrome Scale (PANSS) reduction was used to assess APD efficacy, and more than 50% change was considered as APD response. Associations between CNV burden, gene set, CNV loci and CNV break-point and APD efficacy were analysed. FINDINGS: Higher CNV losses burden decreased the odds of 6-week APD response (OR = 0.66 [0.44, 0.98]). CNV losses in synaptic pathway involved in neurotransmitters were associated with 2-week PANSS reduction rate. CNV involved in sialylation (1p31.1 losses) and cellular metabolism (19q13.32 gains) associated with 6-week PANSS reduction rate at genome-wide significant level. Additional 36 CNVs associated with PANSS factors improvement. The OR of protective CNVs for 6-week APD response was 3.10 (95% CI: 1.33-7.19) and risk CNVs was 8.47 (95% CI: 1.92-37.43). CNV interacted with genetic risk score on APD efficacy (Beta = -1.53, SE = 0.66, P = 0.021). The area under curve to differ 6-week APD response attained 80.45% (95% CI: 78.07%-82.82%). INTERPRETATION: Copy number variants contributed to poor APD efficacy and synaptic pathway involved in neurotransmitter was highlighted. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, China Postdoctoral Science Foundation.

Comprehensive landscape of junctional genes and their association with overall survival of patients with lung adenocarcinoma.

Objectives: Junctional proteins are involved in tumorigenesis. Therefore, this study aimed to investigate the association between junctional genes and the prognosis of patients with lung adenocarcinoma (LUAD). Methods: Transcriptome, mutation, and clinical data were retrieved from The Cancer Genome Atlas (TCGA). "Limma" was used to screen differentially expressed genes. Moreover, Kaplan-Meier survival analysis was used to identify junctional genes associated with LUAD prognosis. The junctional gene-related risk score (JGRS) was generated based on multivariate Cox regression analysis. An overall survival (OS) prediction model combining the JGRS and clinicopathological properties was proposed using a nomogram and further validated in the Gene Expression Omnibus (GEO) LUAD cohort. Results: To our knowledge, this study is the first to demonstrate the correlation between the mRNA levels of 14 junctional genes (CDH15, CDH17, CDH24, CLDN6, CLDN12, CLDN18, CTNND2, DSG2, ITGA2, ITGA8, ITGA11, ITGAL, ITGB4, and PKP3) and clinical outcomes of patients with LUAD. The JGRS was generated based on these 14 genes, and a higher JGRS was associated with older age, higher stage levels, and lower immune scores. Thus, a prognostic prediction nomogram was proposed based on the JGRS. Internal and external validation showed the good performance of the prediction model. Mechanistically, JGRS was associated with cell proliferation and immune regulatory pathways. Mutational analysis revealed that more somatic mutations occurred in the high-JGRS group than in the low-JGRS group. Conclusion: The association between junctional genes and OS in patients with LUAD demonstrated by our "TCGA filtrating and GEO validating" model revealed a new function of junctional genes.

STEAP2 promotes hepatocellular carcinoma progression via increased copper levels and stress-activated MAP kinase activity.

Six Transmembrane Epithelial Antigen of Prostate 2 (STEAP2) belongs to a family of metalloreductases, which indirectly aid in uptake of iron and copper ions. Its role in hepatocellular carcinoma (HCC) remains to be characterized. Here, we report that STEAP2 expression was upregulated in HCC tumors compared with paired adjacent non-tumor tissues by RNA sequencing, RT-qPCR, Western blotting, and immunostaining. Public HCC datasets demonstrated upregulated STEAP2 expression in HCC and positive association with tumor grade. Transient and stable knockdown (KD) of STEAP2 in HCC cell lines abrogated their malignant phenotypes in vitro and in vivo, while STEAP2 overexpression showed opposite effects. STEAP2 KD in HCC cells led to significant alteration of genes associated with extracellular matrix organization, cell adhesion/chemotaxis, negative enrichment of an invasiveness signature gene set, and inhibition of cell migration/invasion. STEAP2 KD reduced intracellular copper levels and activation of stress-activated MAP kinases including p38 and JNK. Treatment with copper rescued the reduced HCC cell migration due to STEAP2 KD and activated p38 and JNK. Furthermore, treatment with p38 or JNK inhibitors significantly inhibited copper-mediated cell migration. Thus, STEAP2 plays a malignant-promoting role in HCC cells by driving migration/invasion via increased copper levels and MAP kinase activities. Our study uncovered a novel molecular mechanism contributing to HCC malignancy and a potential therapeutic target for HCC treatment.

Integrative multi-omics characterization of hepatocellular carcinoma in Hispanic patients.

Background: The incidence and mortality rates of hepatocellular carcinoma (HCC) among Hispanics in the United States are much higher than those of non-Hispanic whites. We conducted comprehensive multi-omics analyses to understand molecular alterations in HCC among Hispanic patients. Methods: Paired tumor and adjacent non-tumor samples were collected from 31 Hispanic HCC in South Texas (STX-Hispanic) for genomic, transcriptomic, proteomic, and metabolomic profiling. Additionally, serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed HCC. Results: Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in STX Hispanic HCCs, suggesting a predominant activation of the Wnt/ß-catenin pathway. The TERT promoter mutation frequency was also remarkably high in the Hispanic cohort. Cell cycles and liver functions were identified as positively- and negatively-enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in the serum samples of HCC patients. Two HCC subtypes from our Hispanic cohort were identified and validated with the TCGA liver cancer cohort. The subtype with better overall survival showed higher activity of immune and angiogenesis signatures, and lower activity of liver function-related gene signatures. It also had higher levels of immune checkpoint and immune exhaustion markers. Conclusions: Our study revealed some specific molecular features of Hispanic HCC and potential biomarkers for therapeutic management of HCC and provides a unique resource for studying Hispanic HCC.

Association of intestinal anti-inflammatory drug target genes with psychiatric Disorders: A Mendelian randomization study.

INTRODUCTION: Psychiatric disorders present a substantial global public health burden with limited drug options. The gut-brain axis connects inflammatory bowel diseases and psychiatric disorders, which often have comorbidities. While some evidence hints at anti-inflammatory drugs aiding in treating psychiatric conditions, the specific effects of intestinal anti-inflammatory drugs remain unclear. OBJECTIVES: This study investigates the causal effect of intestinal anti-inflammatory drug targets on psychiatric disorders. We hypothesize that these drug targets may offer new insights into the treatment and prevention of such disorders. Additionally, we explore gut microbiota's mediating role between drug target genes and psychiatric disorders. METHODS: We performed two-sample Mendelian randomization (MR) using summary data from existing expression quantitative trait loci (eQTL) and protein QTL in the brain, along with public genome-wide association studies of disease. We also explored gut microbiota's mediating effect. The statistics encompassed six psychiatric disorders involving 9,725-500,199 individuals. Colocalization analysis enhanced the MR evidence. RESULTS: We uncovered a causal link between TPMT (a target of olsalazine) expression in the amygdala and bipolar disorder (BD) risk (odds ratio [OR] = 1.08; P = 4.29 × 10-4). This association was observed even when the sigmoid colon and whole blood eQTL were considered as exposures. Colocalization analysis revealed a shared genetic variant (rs11751561) between TPMT expression and BD, with a posterior probability of 61.6 %. Interestingly, this causal effect was influenced by a decrease in the gut microbiota abundance of the genus Roseburia (effect proportion = 10.05 %). Moreover, elevated ACAT1 expression was associated with higher obsessive-compulsive disorder risk (OR = 1.62; P = 3.64 × 10-4; posterior probability = 3.1 %). CONCLUSION: These findings provide novel targets for the treatment of psychiatric disorders, underscore the potential of repurposing olsalazine, and emphasize the importance of TPMT and ACAT1 in future drug development.

Ligand Dissociation of Metal-Complex Photocatalysts toward pH-Photomanipulation in Dynamic Covalent Hydrogels for Printing Reprocessable and Recyclable Devices.

Dynamic covalent hydrogels are gaining attention for their potential in smart materials, soft devices, electronics, and more thanks to their impressive mechanical properties, biomimetic structures, and dynamic behavior. However, a significant challenge lies in designing precise and efficient dynamic photochemistry for their preparation, allowing for complex structures and control over the dynamic process. Herein, we propose a general and straightforward orthogonal dynamic covalent photochemistry strategy for preparing high-performance printable dynamic covalent hydrogels, thereby broadening their advanced applications. This photochemical strategy uses a bifunctional photocatalyst to initiate radical polymerization and release ligands through a rapid light-mediated dissociation mechanism. This process leads to a controlled increase in system pH from mildly acidic to alkaline conditions within one hundred seconds, which in turn triggers the pH-sensitive model reactions of boronic acid/diol complexation and Knoevenagel condensation. The orthogonal photochemistry enables the formation of interpenetrated and conjoined networks, significantly enhancing the mechanical properties of the hydrogels. The reversible bonds formed during the process, i.e., boronic ester and unsaturated ketone bonds, confer excellent self-healing, reprocessable, and recyclable properties on the hydrogels through photochemical pH variations. Furthermore, this rapid, controlled fabrication process and dynamic behavior are highly compatible with printing techniques, enabling the design of adaptive and recyclable sensors with different structures. These advancements are promising for various material science, medicine, and engineering applications.

Distribution and trophodynamics of substituted diphenylamine antioxidants and benzotriazole UV stabilizers in a freshwater ecosystem and the adjacent riparian environment.

Substituted diphenylamine antioxidants (SDPAs) and benzotriazole UV stabilizers (BZT-UVs) are industrial additives of emerging environmental concern. However, little is known about their environmental fate and bioaccumulation. This study investigated the concentrations of SDPAs and BZT-UVs in the water, sediment and biota samples in the freshwater ecosystem and adjacent riparian environment using Hamilton Harbour in the Great Lakes of North America as a study site. The bioaccumulation factors and trophodynamics of these contaminants were studied using field-collected samples. Eight target SDPAs and two BZT-UVs (2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol (UV234) and 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV328)) were frequently detected in the sediment, water and biota samples. UV328 showed significantly greater concentrations in water (0.28-2.8 ng L-1) and sediment (8.3-48 ng g-1, dry weight) than other target contaminants, implying greater contamination of UV328 in Hamilton Harbour. SDPAs exhibited trophic dilution in species living in the water, whereas UV234 was biomagnified in the same samples. No clear trophodynamic trend was found for UV328 for water-respiring species. Air-breathing invertebrates had higher concentrations of both SDPAs and BZT-UVs than water-respiring invertebrates, and biomagnification was observed particularly for adult dragonflies. These results suggest that the trophodynamics of SDPAs and BZT-UVs vary depending on whether the food web is terrestrial or aquatic. Future research should investigate the occurrence and partitioning of SDPAs and BZT-UVs in the air-water interface and evaluate the toxicities of these contaminants in air-breathing species.

Spartina alterniflora invasion benefits blue carbon sequestration in China.

Spartina alterniflora has rapidly and extensively encroached on China's coastline over the past decades. Among the coastal areas invaded by S. alterniflora, at most 93% are mudflats. However, the effect of S. alterniflora invasion on soil organic carbon (SOC) stocks of coastal mudflats has not been systematically studied on a national scale. Here, we quantified the nationwide changes in SOC stocks in coastal mudflats associated with S. alterniflora invasion between 1990 and 2020. We found that S. alterniflora invasion significantly enhanced SOC stocks in coastal China. Nonetheless, the benefit of S. alterniflora invasion of coastal SOC stock may be weakened by continuing human intervention. We found that S. alterniflora invading mudflats added 2.3 Tg SOC stocks to China's coastal blue carbon, while 1.78 Tg SOC stocks were lost mainly due to human activities, resulted in a net SOC stock gain of 0.52 Tg C. These findings overturned the traditionally thought that S. alterniflora invasion would reduce ecosystem services by highlighting that the historical invasion of S. alterniflora has broadly and consistently enhanced blue carbon stock in coastal China.

Gas-Phase-Induced Engineering for Fabrication of 3D Hierarchical Porous Nickel and Its Application toward High-Performance Supercapacitors.

Commercial nickel foam (NF), which is composed of numerous interconnected ligaments and hundred-micron pores, is widely acknowledged as a current collector/electrode material for catalysis, sensing, and energy storage applications. However, the commonly used NF often does not work satisfactorily due to its smooth surface and hollow structure of the ligaments. Herein, a gas-phase-induced engineering, two-step gaseous oxidation-reduction (GOR) is presented to directly transform the thin-walled hollow ligament of NF into a three-dimensional (3D) nanoporous prism structure, resulting in the fabrication of a unique hierarchical porous nickel foam (HPNF). This 3D nanoporous architecture is achieved by utilizing the spontaneous reconstruction of nickel atoms during volume expansion and contraction in the GOR process. The process avoids the involution of acid-base corrosion and sacrificial components, which are facile, environmentally friendly, and suitable for large-scale fabrication. Furthermore, MnO2 is electrochemically deposited on the HPNF to form a supercapacitor electrode (HPNF/MnO2). Because of the fully open structure for ion transport, superhydrophilic properties, and the increased contact area between MnO2 and the current collector, the HPNF/MnO2 electrode exhibits a high specific capacitance of 997.5 F g-1 at 3 A g-1 and remarkable cycling stability with 99.6% capacitance retention after 20000 cycles in 0.1 M Na2SO4 electrolyte, outperforming most MnO2-based supercapacitor electrodes.

Enhanced Cathode Performance in Pr0.5Sr0.5FeO3-δ of Perovskite Catalytic Materials via Doping with VB Subgroup Elements (V, Nb, and Ta).

Perovskite-style materials are cathode systems known for their stability in solid oxide fuel cells (SOFCs). Pr0.5Sr0.5FeO3-δ (PSF) exhibits excellent electrode performance in perovskite cathode systems at high temperatures. Via VB subgroup metals (V, Nb, and Ta) modifying the B-site, the oxidation and spin states of iron elements can be adjusted, thereby ultimately adjusting the cathode's physicochemical properties. Theoretical predictions indicate that PSF has poor stability, but the relative arrangement of the three elements on the B-site can significantly improve this material's properties. The modification of Nb has a large effect on the stability of PSF cathode materials, reaching a level of -2.746 eV. The surface structure of PSF becomes slightly more stable with an increase in the percentage of oxygen vacancy structures, but the structural instability persists. Furthermore, the differential charge density distribution and adsorption state density of the three modified cathode materials validate our adsorption energy prediction results. The initial and final states of the VB subgroup metal-doped PSF indicate that PSFN is more likely to complete the cathode surface adsorption reaction. Interestingly, XRD and EDX characterization are performed on the synthesized pure and Nb-doped PSF material, which show the orthorhombic crystal system of the composite theoretical model structure and subsequent experimental components. Although PSF exhibits strong catalytic activity, it is highly prone to decomposition and instability at high temperatures. Furthermore, PSFN, with the introduction of Nb, shows greater stability and can maintain its activity for the ORR. EIS testing clearly indicates that Nb most significantly improves the cathode. The consistency between the theoretical predictions and experimental validations indicates that Nb-doped PSF is a stable and highly active cathode electrode material with excellent catalytic activity.

Development and validation of a clinical prediction model for ischemic stroke recurrence after successful stent implantation in symptomatic intracranial atherosclerotic stenosis.

OBJECTIVE: This study aimed to analyze the risk factors for recurrent ischemic stroke in patients with symptomatic intracranial atherosclerotic stenosis (ICAS) who underwent successful stent placement and to establish a nomogram prediction model. METHODS: We utilized data from a prospective collection of 430 consecutive patients at Jining NO.1 People's Hospital from November 2021 to November 2022, conducting further analysis on the subset of 400 patients who met the inclusion criteria. They were further divided into training (n=321) and validation (n=79) groups. In the training group, we used univariate and multivariate COX regression to find independent risk factors for recurrent stroke and then created a nomogram. The assessment of the nomogram's discrimination and calibration was performed through the examination of various measures including the Consistency index (C-index), the area under the receiver operating characteristic (ROC) curves (AUC), and the calibration plots. Decision curve analysis (DCA) was used to evaluate the clinical utility of the nomogram by quantifying the net benefit to the patient under different threshold probabilities. RESULTS: The nomogram for predicting recurrent ischemic stroke in symptomatic ICAS patients after stent placement utilizes six variables: coronary heart disease (CHD), smoking, multiple ICAS, systolic blood pressure (SBP), in-stent restenosis (ISR), and fasting plasma glucose. The C-index (0.884 for the training cohort and 0.87 for the validation cohort) and the time-dependent AUC (>0.7) indicated satisfactory discriminative ability of the nomogram. Furthermore, DCA indicated a clinical net benefit from the nomogram. CONCLUSIONS: The predictive model constructed includes six predictive factors: CHD, smoking, multiple ICAS, SBP, ISR and fasting blood glucose. The model demonstrates good predictive ability and can be utilized to predict ischemic stroke recurrence in patients with symptomatic ICAS after successful stent placement.

The Association of Redox Regulatory Drug Target Genes with Psychiatric Disorders: A Mendelian Randomization Study.

Redox regulatory drug (RRD) targets may be considered potential novel drug targets of psychosis due to the fact that the brain is highly susceptible to oxidative stress imbalance. The aim of the present study is to identify potential associations between RRD targets' perturbation and the risk of psychoses; to achieve this, Mendelian randomization analyses were conducted. The expression quantitative trait loci (eQTL) and protein QTL data were used to derive the genetic instrumental variables. We obtained the latest summary data of genome-wide association studies on seven psychoses as outcomes, including schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD), attention-deficit/hyperactivity disorder, autism, obsessive-compulsive disorder and anorexia nervosa. In total, 95 unique targets were included in the eQTL panel, and 48 targets in the pQTL one. Genetic variations in the vitamin C target (OGFOD2, OR = 0.784, p = 2.14 × 10-7) and melatonin target (RORB, OR = 1.263, p = 8.80 × 10-9) were significantly related to the risk of SCZ. Genetic variation in the vitamin E (PRKCB, OR = 0.248, p = 1.24 × 10-5) target was related to an increased risk of BD. Genetic variation in the vitamin C target (P4HTM: cerebellum, OR = 1.071, p = 4.64 × 10-7; cerebellar hemisphere, OR = 1.092, p = 1.98 × 10-6) was related to an increased risk of MDD. Cognitive function mediated the effects on causal associations. In conclusion, this study provides supportive evidence for a causal association between RRD targets and risk of SCZ, BD or MDD, which were partially mediated by cognition.

Projection Stereolithography 3D Printing High-Conductive Hydrogel for Flexible Passive Wireless Sensing.

Hydrogel-based electronics have inherent similarities to biological tissues and hold potential for wearable applications. However, low conductivity, poor stretchability, nonpersonalizability, and uncontrollable dehydration during use limit their further development. In this study, projection stereolithography 3D printing high-conductive hydrogel for flexible passive wireless sensing is reported. The prepared photocurable silver-based hydrogel is rapidly planarized into antenna shapes on substrates using surface projection stereolithography. After partial dehydration, silver flakes within the circuits form sufficient conductive pathways to achieve high conductivity (387 S cm-1). By sealing the circuits to prevent further dehydration, the resistance remains stable when tensile strain is less than 100% for at least 30 days. Besides, the sealing materials provide versatile functionalities, such as stretchability and shape memory property. Customized flexible radio frequency identification tags are fabricated by integrating with commercial chips to complete the accurate recognition of eye movement, realizing passive wireless sensing.

Theoretical Study on Ion Diffusion Mechanism in W-Doped K3SbS4 as Solid-State Electrolyte for K-Ion Batteries.

The development of a solid-state electrolyte (SSE) is crucial for overcoming the side reactions of metal potassium anodes and advancing the progress of K-ion batteries (KIBs). Exploring the diffusion mechanism of the K ion in SSE is important for deepening our understanding and promoting its development. In this study, we conducted static calculations and utilized deep potential molecular dynamics (DeepMD) to investigate the behavior of cubic K3SbS4. The original K3SbS4 exhibited poor ionic conductivity, but we discovered that introducing heterovalent tungsten doping created vacancies, which significantly reduced the activation energy to 0.12 eV and enhanced the ionic conductivity to 1.80 × 10-2 S/cm. The diffusion of K-ions in K3SbS4 primarily occurs through the exchange of positions with K vacancies. This research provides insights into the design of SSE with high ionic conductivity. Furthermore, it highlights the effectiveness of DeepMD as a powerful tool for studying the SSE.

TRIM27 elicits protective immunity against tuberculosis by activating TFEB-mediated autophagy flux.

Infectious diseases, such as Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), remain a global threat exacerbated by increasing drug resistance. Host-directed therapy (HDT) is a promising strategy for infection treatment through targeting host immunity. However, the limited understanding of the function and regulatory mechanism of host factors involved in immune defense against infections has impeded HDT development. Here, we identify the ubiquitin ligase (E3) TRIM27 (tripartite motif-containing 27) as a host protective factor against Mtb by enhancing host macroautophagy/autophagy flux in an E3 ligase activity-independent manner. Mechanistically, upon Mtb infection, nuclear-localized TRIM27 increases and functions as a transcription activator of TFEB (transcription factor EB). Specifically, TRIM27 binds to the TFEB promoter and the TFEB transcription factor CREB1 (cAMP responsive element binding protein 1), thus enhancing CREB1-TFEB promoter binding affinity and promoting CREB1 transcription activity toward TFEB, eventually inducing autophagy-related gene expression as well as autophagy flux activation to clear the pathogen. Furthermore, TFEB activator 1 can rescue TRIM27 deficiency-caused decreased autophagy-related gene transcription and attenuated autophagy flux, and accordingly suppressed the intracellular survival of Mtb in cell and mouse models. Taken together, our data reveal that TRIM27 is a host defense factor against Mtb, and the TRIM27-CREB1-TFEB axis is a potential HDT-based TB target that can enhance host autophagy flux.Abbreviations: ATG5: autophagy related 5; BMDMs: bone marrow-derived macrophages; CFU: colony-forming unit; ChIP-seq: chromatin immunoprecipitation followed by sequencing; CREB1: cAMP responsive element binding protein 1; CTSB: cathepsin B; E3: ubiquitin ligase; EMSA: electrophoretic mobility shift assay; HC: healthy control; HDT: host-directed therapy; LAMP: lysosomal associated membrane protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCOLN1: mucolipin TPR cation channel 1; Mtb: Mycobacterium tuberculosis; NLS: nuclear localization signal; PBMCs: peripheral blood mononuclear cells; PRKA/PKA: protein kinase cAMP-activated; qRT-PCR: quantitative real-time PCR; RFP: RET finger protein; TB: tuberculosis; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; TRIM: tripartite motif; TSS: transcription start site; ULK1: unc-51 like autophagy activating kinase 1.

The effect of screw orientation on internal fixation of Letenneur type II Hoffa fractures: a biomechanics study.

BACKGROUND: To investigate the biomechanical effects of screw orientation and fracture block size on the internal fixation system for Letenneur type II Hoffa fractures. METHODS: The fracture models were randomly divided into six groups according to the fracture subtypes and the direction of nail placement, and a plumb line of the posterior condylar tangent was made across the base of the posterior femoral condyle. The fracture blocks of the three types of fracture were calculated and recorded in the sagittal position, and the biomechanical performance of the six groups was evaluated by biomechanical tests. The axial load on the fracture block at a displacement of 2 mm was set as the failure load, a gradually increasing axial load was applied to each fracture model using a customized indenter at a load of 250-750 N, and the displacements and failure loads of the six groups were recorded at different axial loads. RESULTS: Biomechanical test results showed that the larger the fracture block, the greater was the stability when nailing from front to back, and the smaller the fracture block, the greater was the strength when nailing from back to front (p < 0.001). As the fracture block became larger, the biomechanical advantage of nailing from posterior to anterior decreased.The displacement under 250 N load were 1.351 ± 0.113 mm, 1.465 ± 0.073 mm for Group IIa AP and Group IIa PA. The displacement under 500 N load were 2.596 ± 0.125 mm, 2.344 ± 0.099 mm for Group IIa AP and Group IIa PA. The displacement under 750 N load were 3.997 ± 0.164, 3.386 ± 0.125 mm for Group IIa AP and Group IIa PA. The failure loads were 384 ± 14 N, 415 ± 19 N for Group IIa AP and Group IIa PA. In the type IIa fracture group, the difference was no longer significant (p > 0.001). Therefore, there is a mechanical threshold that ranges from 38.36 to 52.33% between type IIa and type IIb fractures. CONCLUSIONS: The effect of the nailing direction on the strength of fixation has a fracture-block critical point, which is consistent overall with the trend that the larger the fracture block is, the greater the stability when nailing from anterior to posterior, and the smaller the fracture block is, the greater the strength when nailing from posterior to anterior.

Genome-wide association study implicates lipid pathway dysfunction in antipsychotic-induced weight gain: multi-ancestry validation.

Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic medication and may contribute to diabetes and coronary heart disease. To expand the unclear genetic mechanism underlying AIWG, we conducted a two-stage genome-wide association study in Han Chinese patients with schizophrenia. The study included a discovery cohort of 1936 patients and a validation cohort of 534 patients, with an additional 630 multi-ancestry patients from the CATIE study for external validation. We applied Mendelian randomization (MR) analysis to investigate the relationship between AIWG and antipsychotic-induced lipid changes. Our results identified two novel genome-wide significant loci associated with AIWG: rs10422861 in PEPD (P = 1.373 × 10-9) and rs3824417 in PTPRD (P = 3.348 × 10-9) in Chinese Han samples. The association of rs10422861 was validated in the European samples. Fine-mapping and functional annotation revealed that PEPD and PTPRD are potentially causal genes for AIWG, with their proteins being prospective therapeutic targets. Colocalization analysis suggested that AIWG and type 2 diabetes (T2D) shared a causal variant in PEPD. Polygenic risk scores (PRSs) for AIWG and T2D significantly predicted AIWG in multi-ancestry samples. Furthermore, MR revealed a risky causal effect of genetically predicted changes in low-density lipoprotein cholesterol (P = 7.58 × 10-4) and triglycerides (P = 2.06 × 10-3) caused by acute-phase of antipsychotic treatment on AIWG, which had not been previously reported. Our model, incorporating antipsychotic-induced lipid changes, PRSs, and clinical predictors, significantly predicted BMI percentage change after 6-month antipsychotic treatment (AUC = 0.79, R2 = 0.332). Our results highlight that the mechanism of AIWG involves lipid pathway dysfunction and may share a genetic basis with T2D through PEPD. Overall, this study provides new insights into the pathogenesis of AIWG and contributes to personalized treatment of schizophrenia.