Unlocking the Potential of High-Quality Dopamine Transporter Pharmacological Data: Advancing Robust Machine Learning-Based QSAR Modeling.

The dopamine transporter (DAT) plays a critical role in the central nervous system and has been implicated in numerous psychiatric disorders. The ligand-based approaches are instrumental to decipher the structure-activity relationship (SAR) of DAT ligands, especially the quantitative SAR (QSAR) modeling. By gathering and analyzing data from literature and databases, we systematically assemble a diverse range of ligands binding to DAT, aiming to discern the general features of DAT ligands and uncover the chemical space for potential novel DAT ligand scaffolds. The aggregation of DAT pharmacological activity data, particularly from databases like ChEMBL, provides a foundation for constructing robust QSAR models. The compilation and meticulous filtering of these data, establishing high-quality training datasets with specific divisions of pharmacological assays and data types, along with the application of QSAR modeling, prove to be a promising strategy for navigating the pertinent chemical space. Through a systematic comparison of DAT QSAR models using training datasets from various ChEMBL releases, we underscore the positive impact of enhanced data set quality and increased data set size on the predictive power of DAT QSAR models.

HyGAnno: hybrid graph neural network-based cell type annotation for single-cell ATAC sequencing data.

Reliable cell type annotations are crucial for investigating cellular heterogeneity in single-cell omics data. Although various computational approaches have been proposed for single-cell RNA sequencing (scRNA-seq) annotation, high-quality cell labels are still lacking in single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) data, because of extreme sparsity and inconsistent chromatin accessibility between datasets. Here, we present a novel automated cell annotation method that transfers cell type information from a well-labeled scRNA-seq reference to an unlabeled scATAC-seq target, via a parallel graph neural network, in a semi-supervised manner. Unlike existing methods that utilize only gene expression or gene activity features, HyGAnno leverages genome-wide accessibility peak features to facilitate the training process. In addition, HyGAnno reconstructs a reference-target cell graph to detect cells with low prediction reliability, according to their specific graph connectivity patterns. HyGAnno was assessed across various datasets, showcasing its strengths in precise cell annotation, generating interpretable cell embeddings, robustness to noisy reference data and adaptability to tumor tissues.

Arthroscopic repair of large and massive rotator cuff tears-"sandwich augmentation" with the long head of the biceps tendon: a technical note.

For most shoulder surgeons, addressing massive rotator cuff tears that have retracted ends poses a significant challenge. This study introduces a technique, termed the "sandwich augmentation technique," which incorporates the long head of the biceps tendon (LHBT) into a single-row rotator cuff repair. The procedure, performed arthroscopically with the patient in the lateral decubitus position, involves attaching the LHBT and rotator cuff tissues together to the greater tuberosity. This effectively sandwiches them within the rotator cuff footprint. The goal of this technique is to enhance the thickness of the fully interposed cuff margin, thereby providing better support for the repair. The sandwich augmentation technique, which integrates the biceps into the rotator cuff repair, has demonstrated positive clinical outcomes and moderate anatomical results. It also prevents superior migration of the humeral head in cases of large or massive rotator cuff tears. Further research is required to assess the long-term effectiveness of this procedure.

Association between Atherosclerosis and High-Risk Colorectal Adenomas based on Cardio-Ankle Vascular Index and Ankle-Brachial Index.

Background/Aims: Colorectal adenomas are precancerous lesions that may lead to colorectal cancer. Recent studies have shown that colorectal adenomas are associated with atherosclerosis. The cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI) are noninvasive methods for evaluating atherosclerosis. This study examined the association between atherosclerosis and high-risk colorectal adenomas based on the CAVI and ABI. Methods: The data of patients aged ≥50 years who had a colonoscopy and CAVI and ABI measurements from August 2015 to December 2021 at the Kangwon National University Hospital were analyzed retrospectively. After the colonoscopy, subjects were divided into no, overall, and high-risk (size ≥1 cm, high-grade dysplasia or villous adenoma, three or more adenomas) adenoma groups based on the pathology findings. The data were subjected to univariate and multivariate logistic regression analyses. Results: Among the 1,164 subjects, adenomas and high-risk adenomas were found in 613 (52.6%) and 118 (10.1%) patients, respectively. The rate of positive ABI (<0.9) and positive CAVI (≥9.0) were significantly higher in the high-risk adenoma group (22.0% and 55.9%) than in the no adenoma (12.3% and 39.6%) and the overall adenoma group (15.7% and 44.0%) (p=0.008 and p=0.006, respectively). Multivariate analysis revealed a positive CAVI and smoking status to be significantly associated with high-risk adenoma with an odds ratio of 1.595 (95% confidence interval 1.055-2.410, p=0.027) and 1.579 (1.072-2.324, p=0.021), respectively. Conclusions: In this study, a significant correlation between positive CAVI and high-risk adenomas was observed. Therefore, CAVI may be a significant predictor for high-risk colorectal adenoma.

Two-in-one strategy for optimizing chemical and structural properties of carbon felt electrodes for vanadium redox flow batteries.

Vanadium redox flow batteries (VRFBs) have received significant attention for use in large-scale energy storage systems (ESSs) because of their long cycle life, flexible capacity, power design, and safety. However, the poor electrochemical activity of the conventionally used carbon felt electrode results in low energy efficiency of the VRFBs and consequently impedes their commercialization. In this study, a carbon felt (CF) electrode with numerous nanopores and robust oxygen-containing functional groups at its edge sites is designed to improve the electrochemical activity of a carbon felt electrode. To achieve this, Ni metal nanoparticles were initially precipitated on the surface of the CF electrode, followed by etching of the precipitated Ni nanoparticles on the CF electrode using sulfuric acid. The resulting CF electrode had a specific surface area eight times larger than that of the pristine CF electrode. In addition, the oxygen-containing functional groups anchored at the graphite edge sites of the nanopores can act as robust electrocatalysts for VO2+/VO2+ and V2+/V3+ redox reactions. Consequently, the VRFB cell with the resulting carbon felt electrode can deliver a high energy efficiency of 86.2% at the current density of 60 mA cm-2, which is 20% higher than that of the VRFB cell with the conventionally heat-treated CF electrode. Furthermore, the VRFB cell with the resultant carbon felt electrodes showed stable cycling performance with no considerable energy efficiency loss over 200 charge-discharge cycles. In addition, even at a high current density of 160 mA cm-2 , the developed carbon felt electrode can achieve an energy efficiency of 70.1%.

This work reveals the importance of the robust graphite edge-site oxygen functional group and the holey structure of the ET-CF electrode, emphasizing that high VRFB efficiency can be achieved by engineering both the structure and surface properties of the carbon felt electrode.

Association of secondhand smoke with fracture risk in community-dwelling nonsmoking adults in Korea.

Although the detrimental effects of active smoking on bone health have been widely recognized, the impact of secondhand smoke exposure on fracture risk in non-smokers remains less understood. A total of 4843 nonsmokers aged 40-69 yr, who participated in the Korean Genome and Epidemiology Study from 2001 to 2018, were analyzed. The participants were categorized into two groups based on their exposure status to secondhand smoke: currently exposed and unexposed. The exposure group was subsequently divided into two subgroups based on the median weekly exposure time (high vs low). The incidence of new fractures was determined using self-reported questionnaires. The identified fractures were categorized according to the fracture site: overall, vertebral, hip, non-vertebral, and non-vertebral non-hip fractures. The mean age of the participants was 52.4 yr (84.1% women). Exposure to secondhand smoke was associated with an increased risk of fracture (adjusted hazard ratio [aHR]: 1.27, P = 0.028) after adjusting for multiple covariates including age, sex, BMI, household income, bone density of mid-shaft tibia, C-reactive protein, alcohol consumption, and fracture history. Secondhand smoke remained as a significant risk factor for fracture, independent of the major osteoporotic fracture probabilities estimated using a fracture risk assessment tool (aHR: 1.24, P = 0.038). The high exposure group had higher risk of fracture than that of the unexposed group (aHR: 1.33, P = 0.025), whereas the fracture risk did not differ significantly between low exposure and unexposed groups (aHR: 1.18, P = 0.253), suggesting a potential dose-response relationship. Secondhand smoke showed robust association with increased risk of non-vertebral (aHR: 1.37, P = 0.008) or non-vertebral non-hip fractures (aHR: 1.36, P = 0.013), while its association with vertebral fracture was attenuated (aHR: 1.03, P = 0.908). Secondhand smoke was associated with an elevated risk of fracture in nonsmokers, independent of clinical risk factors.

Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia.

The stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING activation in layer V cortical motor neurons occurs in a mouse model of C9orf72 repeat-associated ALS and frontotemporal dementia (FTD). To establish that STING activation occurs in a neuron-autonomous manner, we demonstrate the integrity of the STING signaling pathway, including both upstream activators and downstream innate immune response effectors, in dissociated mouse cortical neurons and neurons derived from control human induced pluripotent stem cells (iPSCs). Human iPSC-derived neurons harboring different familial ALS-causing mutations exhibit increased STING signaling with DNA damage as a main driver. The elevated downstream inflammatory markers present in ALS iPSC-derived neurons can be suppressed with a STING inhibitor. Our results reveal an immunophenotype that consists of innate immune signaling driven by the STING pathway and occurs specifically within vulnerable neurons in ALS/FTD.

Transjugular approach in aspiration thrombectomy and angioplasty of a thrombosed straight arteriovenous graft compared to the direct hemodialysis access approach.

PURPOSE: To evaluate the efficacy and outcome of the transjugular approach in endovascular recanalization of a thrombosed straight arteriovenous graft (AVG) compared to those of the direct hemodialysis access approach (conventional approach). MATERIALS AND METHODS: We retrospectively assessed patients who underwent aspiration thrombectomy and percutaneous transluminal angioplasty for thrombosed straight AVG performed at a single institution between October 2006 and October 2021. A total of 138 thrombosed AVGs in 83 patients (39 male and 44 females) were divided into the transjugular approach group (Group A) and the conventional approach group (Group B). Technical and clinical success, postintervention primary patency, cumulative patency, and periprocedural complications were compared. RESULTS: There was no statistical difference in demographic data between groups A and B. The technical success rate of group A and B was 96.4% (80/83) and 98.2% 54/55, respectively (p > 0.05). The mean procedure time was 61.4 min (Group A) and 70.5 min (Group B) (p > 0.05). There was no statistically significant difference between the two groups in postintervention primary patency. The cumulative patency of Groups A and B was 911.9 days (range 122-6277) and 1062.3 days (range 72-2302 days), respectively (p > 0.05). One patient in Group B experienced a major graft rupture. Pseudoaneurysm formation at the sheath insertion site occurred in two patients in Group B. No cases of stenosis or thrombosis of the IJV or hematoma at the puncture site were observed in Group A. CONCLUSION: The transjugular approach is as safe and effective as the conventional approach for aspiration thrombectomy and percutaneous transluminal angioplasty of thrombosed straight AVGs.

Serum lipids as predictive markers for death by suicide.

Serum lipid levels have been associated with an increased risk of suicidal behaviors. This retrospective cohort study aimed to investigate the association between serum lipid levels and death by suicide among suicide attempters according to sex. Suicide attempters visiting emergency departments between 2007 and 2011 were followed up until the date of all-cause death or December 31, 2012. Sex-stratified Cox proportional hazards regression and competing risk models were constructed to obtain the hazard ratios (HR) of serum lipid measures and suicide. For each significant lipid variable in the final models, Kaplan-Meier survival analysis and cumulative incidence function (CIF) were employed to compare the time to suicide between the high- and low-lipid groups based on the best cutoff point from the receiver operating characteristic curve. In 408 female attempters (65.8 %), the HR in the Cox regression model and subdistribution HR in the competing risk model for increased total cholesterol (TC) were 0.968 and 0.970, respectively. In the Kaplan-Meier survival analysis and CIF, increased death by suicide was demonstrated in the low-TC group (< 165 mg/dL). Lower serum TC levels among female suicide attempters may predict suicide. More careful monitoring is warranted in women with lower TC levels who recently attempted suicide.

Clonogenic assay and computational modeling using real cell images to study physical enhancement and cellular sensitization induced by metal nanoparticles under MV and kV X-ray irradiation.

This study was initiated due to the physically unexplainable tumor controls resulting from metal nanoparticle (MNP) experiments even under MV X-ray irradiation. A more accurate explanation of the mechanism of radiosensitization induced by MNP is warranted, considering both its physical dose enhancement and biological sensitization, as related research is lacking. Thus, we aimed to examine the intricate dynamics involved in MNP-induced radiosensitization. We conducted specifically designed clonogenic assays for the A549 lung cancer cell line with MNP irradiated by 6 MV and 300 kVp X-rays. Two types of MNP were employed: one based on iron oxide, promoting ferroptosis, and the other on gold nanoparticles known for inducing a significant dose enhancement, particularly at low-energy X-rays. We introduced the lethality enhancement factor (LEF) as the fraction in the cell killing attributed to biological sensitization. Subsequently, Monte Carlo simulations were conducted to evaluate the radial dose profiles for each MNP, corresponding to the physical enhancement. Finally, the local effect model was applied to the clonogenic assay results on real cell images. The LEF and the dose enhancement in the cytoplasm were incorporated to increase the accuracy in the average lethal events and, consequently, in the survival fraction. The results reveal an increased cell killing for both of the MNP under MV and kV X-ray irradiation. In both types of MNP, the LEF reveals a biological sensitization evident. The sensitizer enhancement ratio, derived from the calculations, exhibited only 3% and 1% relative differences compared to the conventional linear-quadratic model for gold and ferroptosis inducer nanoparticles, respectively. These findings indicate that MNPs sensitize cells via radiation through mechanisms akin to ferroptosis inducers, not exclusively relying on a physical dose enhancement. Their own contributions to survival fractions were successfully integrated into computational modeling.

Genome-wide ATAC-see screening identifies TFDP1 as a modulator of global chromatin accessibility.

Chromatin accessibility is a hallmark of active regulatory regions and is functionally linked to transcriptional networks and cell identity. However, the molecular mechanisms and networks that govern chromatin accessibility have not been thoroughly studied. Here we conducted a genome-wide CRISPR screening combined with an optimized ATAC-see protocol to identify genes that modulate global chromatin accessibility. In addition to known chromatin regulators like CREBBP and EP400, we discovered a number of previously unrecognized proteins that modulate chromatin accessibility, including TFDP1, HNRNPU, EIF3D and THAP11 belonging to diverse biological pathways. ATAC-seq analysis upon their knockouts revealed their distinct and specific effects on chromatin accessibility. Remarkably, we found that TFDP1, a transcription factor, modulates global chromatin accessibility through transcriptional regulation of canonical histones. In addition, our findings highlight the manipulation of chromatin accessibility as an approach to enhance various cell engineering applications, including genome editing and induced pluripotent stem cell reprogramming.

Patient Navigator Intervention to Improve Palliative Care Outcomes for Hispanic Patients With Serious Noncancer Illness: A Randomized Clinical Trial.

Importance: Disparities persist across the trajectory of serious illness, including at the end of life. Patient navigation has been shown to reduce disparities and improve outcomes for underserved populations. Objective: To determine the effectiveness of a lay patient navigator intervention, Apoyo con Cariño, in improving palliative care outcomes among Hispanic patients. Design, Setting, and Participants: This was a multicenter randomized clinical trial that took place across academic, nonprofit, safety-net, and community health care systems in urban, rural, and mountain/frontier regions of Colorado from January 2017 to January 2021. Self-identifying Hispanic adults with serious noncancer medical illness and limited prognosis were recruited. Data were collected and analyzed from July 2022 to July 2023. Interventions: Participants randomized to the intervention group received 5 home visits from a bilingual, bicultural lay patient navigator; participants randomized to control received care as usual. Both groups received culturally tailored educational materials. Investigators/outcome accessors remained blinded to participant assignment. Main Outcomes and Measures: Change in score from baseline to 3 months on the Functional Assessment of Chronic Illness Therapy (FACIT) General quality of life (QOL) scale (primary outcome), Advance Care Planning (ACP) Engagement Survey, Brief Pain Inventory, Edmonton Symptom Assessment Scale, and FACIT Spiritual Well-Being subscale; at 6 months, advance directive (AD) documentation; and at 46 months or death, hospice utilization and length of stay, as well as aggressiveness of care at end of life. Results: Of 209 patients enrolled (mean [SD] age, 63.6 [14.3] years; 108 [51.7%] male), 105 patients were randomized to control and 104 patients to the intervention. There were no statistically significant differences in the change in mean (SD) QOL score between the intervention and control groups (5.0 [16.5] vs 4.3 [15.5]; P = .75). Participants in the intervention group, compared with the control group, had statistically significant greater increases in mean (SD) ACP engagement (0.8 [1.3] vs 0.1 [1.4]; P < .001) and were more likely to have a documented AD (62 of 104 [59.6%] vs 28 of 105 [26.9%]; P < .001). There were no statistically significant differences in mean (SD) change in pain intensity score (0-10) between patients in the intervention group compared with control (-0.4 [2.6] vs -0.5 [2.8]; P = .79), nor pain interference (-0.2 [3.7] vs -0.4 [3.7]; P = .71). Patients receiving the intervention were more likely to be referred to hospice compared with patients receiving control (19 of 43 patients [44.2%] vs 7 of 33 patients [21.2%]; P = .04) and less likely to receive aggressive care at end of life (27 of 42 patients [64.3%] vs 28 of 33 patients [84.8%]; P = .046). Conclusion and Relevance: In this randomized clinical trial, a culturally tailored patient navigator intervention did not improve QOL for patients. However, the intervention did increase ACP engagement, AD documentation, and hospice utilization in Hispanic persons with serious medical illness. Trial Registration: ClinicalTrials.gov Identifier: NCT03181750.

Series of (([1,1'-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity.

Currently, there are no FDA-approved medications for the treatment of psychostimulant use disorders (PSUD). We have previously discovered "atypical" dopamine transporter (DAT) inhibitors that do not display psychostimulant-like behaviors and may be useful as medications to treat PSUD. Lead candidates (e.g., JJC8-091, 1) have shown promising in vivo profiles in rodents; however, reducing hERG (human ether-à-go-go-related gene) activity, a predictor of cardiotoxicity, has remained a challenge. Herein, a series of 30 (([1,1'-biphenyl]-2-yl)methyl)sulfinylalkyl alicyclic amines was synthesized and evaluated for DAT and serotonin transporter (SERT) binding affinities. A subset of analogues was tested for hERG activity, and the IC50 values were compared to those predicted by our hERG QSAR models, which showed robust predictive power. Multiparameter optimization scores (MPO > 3) indicated central nervous system (CNS) penetrability. Finally, comparison of affinities in human DAT and its Y156F and Y335A mutants suggested that several compounds prefer an inward facing conformation indicating an atypical DAT inhibitor profile.

Genome-wide association study implicates the role of TBXAS1 in the pathogenesis of depressive symptoms among the Korean population.

Although depression is an emerging disorder affecting many people worldwide, most genetic studies have been performed in European descent populations. Herein, a genome-wide association study (GWAS) was conducted in Korean population to elucidate the genomic loci associated with depressive symptoms. Two independent cohorts were used as discovery datasets, which consisted of 6474 (1484 cases and 4990 controls) and 1654 (557 cases and 1097 controls) Korean participants, respectively. The participants were divided into case and control groups based on the Beck Depression Inventory (BDI). Meta-analysis using the two cohorts revealed that rs6945590 was significantly associated with the risk of depressive symptoms [P = 2.83 × 10-8; odds ratio (OR) = 1.23; 95% confidence interval (CI): 1.15-1.33]. This association was validated in other independent cohorts which were another Korean cohort (258 cases and 1757 controls) and the East Asian study of the Psychiatric Genomics Consortium (PGC) (12,455 cases and 85,548 controls). The predicted expression levels of thromboxane A synthase 1 gene (TBXAS1), which encodes the enzyme thromboxane A synthase 1 and participates in the arachidonic acid (AA) cascade, was significantly decreased in the whole blood tissues of the participants with depressive symptoms. Furthermore, Mendelian randomization (MR) analysis showed a causal association between TBXAS1 expression and the risk of depressive symptoms. In conclusion, as the number of risk alleles (A) of rs6945590 increased, TBXAS1 expression decreased, which subsequently caused an increase in the risk of depressive symptoms.

Nectar Characteristics and Honey Production Potential of Five Rapeseed Cultivars and Two Wildflower Species in South Korea.

The growing beekeeping industry in South Korea has led to the establishment of new honey plant complexes. However, studies on honey production from each species are limited. This study aimed to assess the honey production potential of various Brassica napus cultivars and two wildflower species. The nectar characteristics of B. napus varied significantly among the cultivars. Absolute sugar concentrations differed among the cultivars, but sugar composition ratios were similar. In contrast, the amino acid content remained relatively uniform regarding percentage values, irrespective of the absolute concentrations. Estimations of honey potential production per hectare (kg/ha) resulted in the following ranking among cultivars: 'JM7003' (107.1) > 'YS' (73.0) > 'JM7001' (63.7) > 'TL' (52.7) > 'TM' (42.4). The nectar volume of Pseudolysimachion rotundum var. subintegrum and Leonurus japonicus increased during the flowering stage. P. rotundum var. subintegrum was sucrose-rich and L. japonicus was sucrose-dominant. Both species predominantly contained phenylalanine, P. rotundum var. subintegrum had glutamine as the second most abundant amino acid, and L. japonicus had tyrosine. The honey production potential was 152.4 kg/ha for P. rotundum var. subintegrum and 151.3 kg/ha for L. japonicus. These findings provide a basis for identifying food resources for pollinators and selecting plant species to establish honey plant complexes.

Association between dementia diagnosis at dialysis initiation and mortality in older patients with end-stage kidney disease in South Korea.

Background: The prevalence of dementia is 2- to 7-fold higher among patients with end-stage kidney disease (ESKD) than among the general population; however, its clinical implications in this population remain unclear. Therefore, this study aimed to determine whether comorbid dementia increases mortality among older patients with ESKD undergoing newly initiated hemodialysis. Methods: We analyzed data from the Korean Society of Geriatric Nephrology retrospective cohort, which included 2,736 older ESKD patients (≥70 years old) who started hemodialysis between 2010 and 2017. Kaplan-Meier survival and Cox regression analyses were used to examine all-cause mortality between the patients with and without dementia in this cohort. Results: Of the 2,406 included patients, 8.3% had dementia at the initiation of dialysis; these patients were older (79.6 ± 6.0 years) than patients without dementia (77.7 ± 5.5 years) and included more women (male:female, 89:111). Pre-ESKD diagnosis of dementia was associated with an increased risk of overall mortality (hazard ratio, 1.503; p < 0.001), and this association remained consistent after multivariate adjustment (hazard ratio, 1.268; p = 0.009). In subgroup analysis, prevalent dementia was associated with mortality following dialysis initiation in female patients, those aged <85 years, those with no history of cerebrovascular accidents or severe behavioral disorders, those not residing in nursing facilities, and those with no or short-term hospitalization. Conclusion: A pre-ESKD diagnosis of dementia is associated with mortality following dialysis initiation in older Korean population. In older patients with ESKD, cognitive assessment at dialysis initiation is necessary.

Synergistic Effect of Ferroptosis-Inducing Nanoparticles and X-Ray Irradiation Combination Therapy.

Ferroptosis, characterized by the induction of cell death via lipid peroxidation, has been actively studied over the last few years and has shown the potential to improve the efficacy of cancer nanomedicine in an iron-dependent manner. Radiation therapy, a common treatment method, has limitations as a stand-alone treatment due to radiation resistance and safety as it affects even normal tissues. Although ferroptosis-inducing drugs help alleviate radiation resistance, there are no safe ferroptosis-inducing drugs that can be considered for clinical application and are still in the research stage. Here, the effectiveness of combined treatment with radiotherapy with Fe and hyaluronic acid-based nanoparticles (FHA-NPs) to directly induce ferroptosis, considering the clinical applications is reported. Through the induction of ferroptosis by FHA-NPs and apoptosis by X-ray irradiation, the therapeutic efficiency of cancer is greatly improved both in vitro and in vivo. In addition, Monte Carlo simulations are performed to assess the physical interactions of the X-rays with the iron-oxide nanoparticle. The study provides a deeper understanding of the synergistic effect of ferroptosis and X-ray irradiation combination therapy. Furthermore, the study can serve as a valuable reference for elucidating the role and mechanisms of ferroptosis in radiation therapy.

Calcium homeostasis modulator 2 (Calhm2) as slowly activating membrane current channel in mouse B cells.

In mouse B lymphocytes, an unidentified slow-activating voltage-dependent current resembling the characteristics of the Calhm family ion channel (ICalhm-L) was investigated. RT-PCR analysis revealed the presence of Calhm2 and 6 transcripts, with subsequent whole-cell patch-clamp studies indicating that the ICalhm-L is augmented by heat, alkaline pH, and low extracellular [Ca2+]. Overexpression of Calhm2, but not Calhm6, in N2A cells recapitulated ICalhm-L. Moreover, Calhm2 knockdown in Bal-17 cells abolished ICalhm-L. We firstly identify the voltage-dependent ion channel function of the Calhm2 in the mouse immune cells. ATP release assays in primary mouse B cells suggested a significant contribution of Calhm2 for purinergic signaling at physiological temperature.

Association of metformin with cardiovascular and graft outcomes in kidney transplant recipients with posttransplantation diabetes mellitus.

Background: Posttransplantation diabetes mellitus (PTDM) is a crucial problem after kidney transplantation. We aimed to determine whether metformin affects cardiovascular and graft outcomes in patients with PTDM. Methods: This retrospective cohort study included 1,663 kidney transplant recipients without preexisting diabetes mellitus. The patients were divided into metformin and non-metformin groups, with matched propensity scores. We also estimated metformin's effect on percutaneous coronary intervention (PCI), major adverse cardiovascular events (MACEs), acute rejection, and graft failure. Results: Of 634 recipients with PTDM, 406 recipients were treated with metformin. The incidence of PCI was 2.4% and 7.1% in the metformin and non-metformin groups, respectively (p = 0.04). The metformin group exhibited a lower risk of PCI in Cox regression analyses (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.10-0.77; p = 0.014), especially in subgroups with male sex, age over 49 years (median), long-term metformin use (mean of ≥1,729 days), and simultaneous tacrolimus administration. Long-term metformin use was also associated with lower incidence of MACEs (HR, 0.09; 95% CI, 0.01-0.67; p = 0.02). Incidence of graft failure was 9.9% and 17.0% in the metformin and non-metformin groups, respectively (p = 0.046). Both long-term use and higher dose of metformin, as well as tacrolimus administration with metformin, were associated with a lower risk of graft failure (HR, 0.29; 95% CI, 0.11-0.75; p = 0.01; HR, 0.39; 95% CI, 0.18-0.85; p = 0.02; and HR, 0.39; 95% CI, 0.19-0.79; p = 0.009, respectively). Conclusion: Metformin use is associated with a decreased risk of developing coronary artery disease and better graft outcomes in PTDM.