Depression and risk of stroke and mortality after percutaneous coronary intervention: A nationwide population study.

BACKGROUND: Limited evidence exists on the role of depression in the risk of developing stroke and other cardiovascular outcomes in patients who have undergone percutaneous coronary interventions (PCI). We investigated this relationship with data from the Korean National Health Insurance Service database. METHODS: Our nationwide retrospective cohort study included 164,198 patients who had undergone PCI between 2010 and 2017. Depression was defined with the ICD-10 codes recorded prior to the PCI. The primary outcome was a new-onset stroke following the PCI. Secondary outcomes included PCI with myocardial infarction (MI), revascularization (PCI or coronary artery bypass grafting), and all-cause mortality. A multivariable Cox proportional hazards regression analysis was used to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI), adjusting for potential confounders, including sociodemographic and lifestyle factors, comorbidities, and MI at the index PCI. RESULTS: Over a median follow-up of 5.0 years, acute stroke occurred in 5.7% of patients with pre-existing depression (17.4% of the study population), compared to 3.5% of those without depression. Depression was associated with a 27% increased risk of acute stroke (aHR 1.27, 95% CI 1.20-1.35). Additionally, depression was linked with a 25% elevated risk of all-cause death (aHR 1.25, 95% CI, 1.21-1.29) and an 8% increased risk of revascularization (aHR 1.08, 95% CI 1.04-1.11). The associations with the risk of stroke and all-cause mortality were stronger in patients under 65 years. CONCLUSIONS: Our findings suggest that pre-existing depression may increase the risk of stroke and all-cause mortality following PCI, particularly in patients under 65 years. Additionally, depression was significantly associated with an increased need for revascularization. This underscores the potential benefits of managing depression to reduce stroke risk and overall cardiovascular outcomes following PCI.

Impact of non-traditional lipid profiles on 1-year vascular outcomes in ischemic stroke patients with prior statin therapy and LDL-C < 100 mg/dL.

This study aimed to investigate the association between non-traditional lipid profiles and the risk of 1-year vascular events in patients who were already using statins before stroke and had admission LDL-C < 100 mg/dL. This study was an analysis of a prospective, multicenter, nationwide registry of consecutive patients with acute ischemic stroke patients who treated with statin before index stroke and LDL-C < 100 mg/dL on admission. Non-traditional lipid profiles including non-HDL, TC/HDL ratio, LDL/HDL ratio, and TG/HDL ratio were analyzed as a continuous or categorical variable. The primary vascular outcome within one year was a composite of recurrent stroke (either hemorrhagic or ischemic), myocardial infarction (MI) and all-cause mortality. Hazard ratios (95% Cis) for 1-year vascular outcomes were analyzed using the Cox PH model for each non-traditional lipid profiles groups. A total of 7028 patients (age 70.3 ± 10.8years, male 59.8%) were finally analyzed for the study. In unadjusted analysis, no significant associations were observed in the quartiles of LDL/HDL ratio and 1-year primary outcome. However, after adjustment of relevant variables, compared with Q1 of the LDL/HDL ratio, Q4 was significantly associated with increasing the risk of 1-year primary outcome (HR 1.48 [1.19-1.83]). For the LDL/HDL ratio, a linear relationship was observed (P for linearity < 0.001). Higher quartiles of the LDL/HDL ratio were significantly and linearly associated with increasing the risk of 1-year primary vascular outcomes. These findings suggest that even during statin therapy with LDL-C < 100 mg/dl on admission, there should be consideration for residual risk based on the LDL/HDL ratio, following stroke.

Uncaria Rhynchophylla and hirsuteine as TRPV1 agonists inducing channel desensitization.

ETHNOPHARMACOLOGICAL RELEVANCE: Uncaria rhynchophylla (UR) is recognized for its therapeutic applications in treating hypertension and inflammation. However, the specific molecular mechanisms how UR and its bioactive constituents modulate inflammatory pathways remain unknown. This study investigates the effects of UR extract and its constituent, hirsuteine (HST), on TRPV1 channel modulation which is related to hypertension and inflammation. MATERIALS AND METHODS: Electrophysiological recordings and calcium imaging experiments were conducted to assess TRPV1 activation by UR extract and HST in HEK293T cells and sensory neurons. RESULTS: UR extract and HST activated TRPV1 in HEK293T cells, with repeated applications causing channel desensitization. HST application on TRPV1-positive sensory neurons significantly reduced electrical activity compared to capsaicin. CONCLUSION: This study demonstrated UR extract and HST are a novel TRPV1 agonists inducing channel desensitization and a potent agent for treatment of TRPV1 dependent pain relief.

Age- and ethnic-driven molecular and clinical disparity of East Asian breast cancers.

BACKGROUND: Breast cancer (BC) is a complex disease with profound genomic aberrations. However, the underlying molecular disparity influenced by age and ethnicity remains elusive. METHODS: In this study, we aimed to investigate the molecular properties of 843 primary and metastatic BC patients enrolled in the K-MASTER program. By categorizing patients into two distinct age subgroups, we explored their unique molecular properties. Additionally, we leveraged large-scale genomic data from the TCGA and MSK-IMPACT studies to examine the ethnic-driven molecular and clinical disparities. RESULTS: We observed a high prevalence of PI3KCA mutations in K-MASTER HER2 + tumors, particularly in older patients. Moreover, we identified increased mutation rates in DNA damage response molecules, including ARID1A, MSH6, and MLH1. The K-MASTER patients were mainly comprised of triple-negative breast cancer (TNBC) and HER2-positive tumors, while the TCGA and MSK-IMPACT cohorts exhibited a predominance of hormone receptor-positive (HR +) subtype tumors. Importantly, GATA3 mutations were less frequently observed in East Asian patients, which correlated with poor clinical outcomes. In addition to characterizing the molecular disparities, we developed a gradient-boosting multivariable model to identify a new molecular signature that could predict the therapeutic response to platinum-based chemotherapy. CONCLUSIONS: Our findings collectively provide unprecedented insights into the significance of age and ethnicity on the molecular and clinical characteristics of BC patients.

Novel Cosmetic Ingredient CS-AA Polyion Complex and Skin Moisturizing Effect.

PURPOSE: The study explored the enhanced skin moisturizing capabilities and moisture retention effects achieved by forming a polyion complex using sulfated glycosaminoglycan (GAG), specifically chondroitin sulfate (CS), and amino acids (AA) such as glutamine (Q) and arginine (R). The overall hydration effect of this CS-AA complex was examined. METHODS: After analyzing the CS-AA polyion complex structure using spectroscopic methods, the ex vivo moisture retention ability was assessed under dry conditions using porcine skin samples. Additionally, the efficacy of the CS-AA polyion complex in reducing transepidermal water loss (TEWL) and improving skin hydration was evaluated on human subjects using a digital evaporimeter and a corneometer, respectively. RESULTS: Validating a systematic reduction in particle size, the following order was observed: CS > CS/AA simple mixture > CS-AA complex based on dynamic light scattering (DLS) and transmission electron microscopy (TEM) analysis. Furthermore, observations revealed that the CS-AA complex exhibits negligible surface charge. Additionally, Fourier-transform infrared spectroscopy (FT-IR) analysis demonstrated a distinct peak shift in the complex, confirming the successful formation of the CS-AA complex. Subsequently, the water-holding effect through porcine skin was assessed, revealing a notable improvement in moisture retention (weight loss) for the CS-Q complex: 40.6% (1 h), 20.5% (2 h), and 18.7% (4 h) compared to glycerin. Similarly, the CS-R complex demonstrated enhancements of 50.2% (1 h), 37.5% (2 h), and 33% (4 h) compared to glycerin. Furthermore, TEWL improvement efficacy on human skin demonstrated approximately 25% improvement for both the CS-Q complex and CS-R complex, surpassing the modest 12.5% and 18% improvements witnessed with water and glycerin applications, respectively. Finally, employing a corneometer, hydration changes in the skin were monitored over 4 weeks. Although CS alone exhibited nominal alterations, the CS-Q complex and CS-R complex showed a significant increase in moisture levels after 4 weeks of application. CONCLUSION: In this study, polyion complexes were successfully formed between CS, a sulfated GAG, and AA. Comparisons with glycerin, a well-known moisturizing agent, confirmed that the CS-AA complex exhibits superior moisturizing effects in various aspects. These findings suggest that the CS-AA complex is a more effective ingredient than CS or AA alone in terms of efficacy.

Effects of white matter hyperintensity burden on functional outcome after mild versus moderate-to-severe ischemic stroke.

It is uncertain whether the prognostic power of white matter hyperintensity (WMH) on post-stroke outcomes is modulated as a function of initial neurological severity, a critical determinant of outcome after stroke. This multi-center MRI study tested if higher WMH quintiles were associated with 3-month poor functional outcome (modified Rankin Scale ≥ 3) for mild versus moderate-to-severe ischemic stroke. Mild and moderate-to-severe stroke were defined as admission National Institute of Health Stroke Scale scores of 1-4 and ≥ 5, respectively. Mean age of the enrolled patients (n = 8918) was 67.2 ± 12.6 years and 60.1% male. The association between WMH quintiles and poor functional outcome was modified by stroke severity (p-for-interaction = 0.008). In mild stroke (n = 4994), WMH quintiles associated with the 3-month outcome in a dose-dependent manner for the 2nd to 5th quintile versus the 1st quintile, with adjusted-odds-ratios (aOR [95% confidence interval]) being 1.29 [0.96-1.73], 1.37 [1.02-1.82], 1.60 [1.19-2.13], and 1.89 [1.41-2.53], respectively. In moderate-to-severe stroke (n = 3924), however, there seemed to be a threshold effect: only the highest versus the lowest WMH quintile was significantly associated with poor functional outcome (aOR 1.69 [1.29-2.21]). WMH burden aggravates 3-month functional outcome after mild stroke, but has a lesser modulatory effect for moderate-to-severe stroke, likely due to saturation effects.

Anatomical Study of the Superficial Musculoaponeurotic System in Relation to the Zygomaticus Major.

BACKGROUND: The superficial musculoaponeurotic system (SMAS) is crucial for the structural integrity and dynamics of facial expressions and is a particularly important consideration during facelift surgeries. This study investigated the anatomical structure and continuity of the SMAS at the site where the zygomaticus major (Zmj) originates, which is where the SMAS extends from the lateral to the anterior aspects of the face. Knowledge of these aspects is crucial for understanding the mechanics of facial movements and also the aging process. METHODS: Dissections of 66 specimens and histological analyses were used to explore the intricate relationships and attachments between the SMAS and facial muscles. RESULTS: The findings indicated that at the Zmj origin site, the SMAS-connected to the inferior margin of the orbicularis oculi-covered the superficial surface of the Zmj fibers. As it tracked downward, the SMAS was observed to split into two layers lateral to the Zmj fibers, enveloping them both superficially and deeply. Additionally, as the SMAS continued forward, it ceased to be distinctly visible in the buccal area. CONCLUSIONS: These results provide a deeper understanding of the complex layering and interconnectivity of the SMAS, which supports facial dynamics and structural integrity. This information could be particularly useful in surgical and aesthetic procedures in the midfacial area.

Target-Enhanced Whole-Genome Sequencing (TE-WGS) Shows Clinical Validity Equivalent to Commercially Available Targeted Oncology Panel.

Purpose: Cancer poses a significant global health challenge, demanding precise genomic testing for individualized treatment strategies. Targeted-panel sequencing (TPS) has improved personalized oncology but often lacks comprehensive coverage of crucial cancer alterations. Whole-genome sequencing (WGS) addresses this gap, offering extensive genomic testing. This study demonstrates the medical potential of WGS. Materials and Methods: This study evaluates target-enhanced WGS (TE-WGS), a clinical-grade WGS method sequencing both cancer and matched normal tissues. Forty-nine patients with various solid cancer types underwent both TE-WGS and TruSight Oncology 500 (TSO500), one of the mainstream TPS approaches. Results: TE-WGS detected all variants reported by TSO500 (100%, 498/498). A high correlation in variant allele fractions (VAF) was observed between TE-WGS and TSO500 (r=0.978). Notably, 223 variants (44.8%) within the common set were discerned exclusively by TE-WGS in peripheral blood, suggesting their germline origin. Conversely, the remaining subset of 275 variants (55.2%) were not detected in peripheral blood using the TE-WGS, signifying them as bona fide somatic variants. Further, TE-WGS provided accurate copy number profiles, fusion genes, microsatellite instability (MSI), and homologous-recombination deficiency (HRD) scores, which were essential for clinical decision-making. Conclusion: TE-WGS is a comprehensive approach in personalized oncology, matching TSO500's key biomarker detection capabilities. It uniquely identifies germline variants and genomic instability markers, offering additional clinical actions. Its adaptability and cost-effectiveness underscore its clinical utility, making TE-WGS a valuable tool in personalized cancer treatment.

Contemporary Statistics of Acute Ischemic Stroke and Transient Ischemic Attack in 2021: Insights From the CRCS-K-NIH Registry.

This report presents the latest statistics on the stroke population in South Korea, sourced from the Clinical Research Collaborations for Stroke in Korea-National Institute for Health (CRCS-K-NIH), a comprehensive, nationwide, multicenter stroke registry. The Korean cohort, unlike western populations, shows a male-to-female ratio of 1.5, attributed to lower risk factors in Korean women. The average ages for men and women are 67 and 73 years, respectively. Hypertension is the most common risk factor (67%), consistent with global trends, but there is a higher prevalence of diabetes (35%) and smoking (21%). The prevalence of atrial fibrillation (19%) is lower than in western populations, suggesting effective prevention strategies in the general population. A high incidence of large artery atherosclerosis (38%) is observed, likely due to prevalent intracranial arterial disease in East Asians and advanced imaging techniques. There has been a decrease in intravenous thrombolysis rates, from 12% in 2017-2019 to 10% in 2021, with no improvements in door-to-needle and door-to-puncture times, worsened by the coronavirus disease 2019 pandemic. While the use of aspirin plus clopidogrel for non-cardioembolic stroke and direct oral anticoagulants for atrial fibrillation is well-established, the application of direct oral anticoagulants for non-atrial fibrillation cardioembolic strokes in the acute phase requires further research. The incidence of early neurological deterioration (13%) and the cumulative incidence of recurrent stroke at 3 months (3%) align with global figures. Favorable outcomes at 3 months (63%) are comparable internationally, yet the lack of improvement in dependency at 3 months highlights the need for advancements in acute stroke care.

Efficacy on symptoms and mortality day vs. night administration of EGFR-TKIs for advanced non-small cell lung cancer.

PURPOSE: This study has a purpose to investigate the side effects of three EGFR-TKIs targeted therapeutic agents (gefitinib, erlotinib, and afatinib) and all-cause mortality in patients with metastatic lung cancer. METHODS: We performed a prospective cohort study. We selected all patients with newly diagnosed metastatic lung cancer between January and November 2019. Main exposure was daytime versus nighttime use of targeted EGFR TKIs. The study outcome was a symptom change using the mobile application, and all-cause mortality between January 2019 and March 2023. RESULTS: Among the 87 study participants, 35 (40%) took their medication at night. Among the 87 study participants, 35 (40%) took their medication at night. At 6 weeks of treatment, acne (1.36; 95% confidence interval [CI] 1.09, 1.64; p for interaction = 0.04) and dry skin (1.35; 95% CI 1.09, 1.61, p for interaction = 0.01) in the day group showed a much increase from baseline compared to the night group. In contrast, the night group reported greater reductions in lung cancer-related symptoms from baseline compared to the day. During follow-up (median 43 months), the night group had a lower risk of all-cause death than the day group, especially in younger patients (adjusted hazard ratio = 0.34; 95% CI 0.13, 0.87). CONCLUSIONS: The group taking EGFR-TKIs at night experienced fewer side effects and had longer overall survival compared to the day group. Clinicians should consider recommending that lung cancer patients take their once-daily oral anticancer drugs in the evening rather than the morning to improve treatment outcomes.

Stroke Measures Analysis of pRognostic Testing-Mortality nomogram predicts long-term mortality after ischemic stroke.

BACKGROUND: Predicting long-term mortality is essential for understanding prognosis and guiding treatment decisions in patients with ischemic stroke. Therefore, this study aimed to develop and validate the method for predicting 1- and 5-year mortality after ischemic stroke. METHODS: We used data from the linked dataset comprising the administrative claims database of the Health Insurance Review and Assessment Service and the Clinical Research Center for Stroke registry data for patients with acute stroke within 7 days of onset. The outcome was all-cause mortality following ischemic stroke. Clinical variables linked to long-term mortality following ischemic stroke were determined. A nomogram was constructed based on the Cox's regression analysis. The performance of the risk prediction model was evaluated using the Harrell's C-index. RESULTS: This study included 42,207 ischemic stroke patients, with a mean age of 66.6 years and 59.2% being male. The patients were randomly divided into training (n = 29,916) and validation (n = 12,291) groups. Variables correlated with long-term mortality in patients with ischemic stroke, including age, sex, body mass index, stroke severity, stroke mechanisms, onset-to-door time, pre-stroke dependency, history of stroke, diabetes mellitus, hypertension, coronary artery disease, chronic kidney disease, cancer, smoking, fasting glucose level, previous statin therapy, thrombolytic therapy, such as intravenous thrombolysis and endovascular recanalization therapy, medications, and discharge modified Rankin Scale were identified as predictors. We developed a predictive system named Stroke Measures Analysis of pRognostic Testing-Mortality (SMART-M) by constructing a nomogram using the identified features. The C-statistics of the nomogram in the developing and validation groups were 0.806 (95% confidence interval (CI), 0.802-0.812) and 0.803 (95% CI, 0.795-0.811), respectively. CONCLUSION: The SMART-M method demonstrated good performance in predicting long-term mortality in ischemic stroke patients. This method may help physicians and family members understand the long-term outcomes and guide the appropriate decision-making process.

Clinical application of whole-genome sequencing of solid tumors for precision oncology.

Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.

The extended fibers of the alar part of the nasalis connect to the levator labii superioris, zygomaticus minor, and skin adjacent to the nasal ala.

PURPOSE: This study aimed to elucidate the positions of the extended fibers of the alar part of the nasalis (Na), and their connections to the levator labii superioris (LLS), zygomaticus minor (Zmi), and adjacent skin near the nasal ala. METHODS: The extended fibers of the Na were investigated in 54 specimens obtained from 27 embalmed adult South Korean cadavers. RESULTS: In 51.9% of the specimens, some fibers of the Na extended over the alar facial crease, intermingling or blending with the LLS or Zmi, and attached to the skin lateral to the nasal ala. The quantity and distribution of these extended fibers varied: some fibers of the Na extended and intermingled or blended with the LLS in 25.9%, while another 25.9% exhibited the Na extending in a distinctive fan shape with longer fibers, and combining with both the LLS and Zmi. However, the Na had no extended fibers that reached the LLS, Zmi, or skin near the nasal ala in 48.1%. CONCLUSION: Contraction of the Na and its extended fibers can influence the nasal ala and also the laterally located skin and muscles, directing them inferomedially toward the incisive fossa of the maxilla, which is the origin of the nasalis. These insights offer a deeper understanding of the role and actions of facial muscles in facial expression. They will be instrumental in the comprehension and analysis of nose and mouth movements, and in conducting electromyographic analyses in this region.

Anatomical Trajectory of the Corrugator Supercilii Muscle in Koreans: Implications for Aesthetic and Clinical Practices.

BACKGROUND: Understanding the attachment patterns of the corrugator supercilii muscle (CS) is vital for treatments designed to improve facial symmetry and functionality. OBJECTIVES: The aim of this research was to elucidate the anatomical trajectory and intricate relationships of the CS within the upper face and midface, specifically focusing on its connections with the frontalis (FT) and orbicularis oculi (OOc) muscles. METHODS: The CS was examined in 41 specimens of embalmed adult Korean cadavers using microdissection, histological analyses, and microcomputed tomography, an in-depth exploration of its anatomical positioning and intricate interactions with adjacent muscles. RESULTS: Some lower fibers of the CS extended to the upper orbital part of the OOc in 59.5% of cases, while the CS interdigitated or blended exclusively with the FT in 40.5% of cases. The fibers of the CS demonstrated diverse extensions towards the upper face and midface, exhibiting varied trajectories and lengths. Additionally, lower fibers of the CS extended to significant anatomical landmarks such as the OOc, malaris muscle, and the superficial musculoaponeurotic system (SMAS). CONCLUSIONS: This study demonstrates that precise understanding of the CS and its relationship with the FT and OOc is crucial for optimizing invasive or non-invasive treatment like botulinum toxin injection, SMAS lifting and browplasty surgery. The extension of lower fibers of the CS to significant anatomical landmarks indicates complex interactions with adjacent facial structures, highlighting the necessity of detailed anatomical knowledge for clinical applications.

Cryo-EM structure of the human glucose transporter GLUT7.

GLUT7 is a Class II glucose transporter predominantly expressed at the apical membrane of enterocytes in the small intestine. Here, we report the cryo-EM structure of nanodisc-reconstituted human GLUT7 in the apo state at 3.3 Å resolution. Our atomic model reveals a typical major facilitator superfamily fold, with the substrate-binding site open to the extracellular side of the membrane. Despite the nearly identical conformation to its closest family member, rat GLUT5, our structure unveils distinct features of the substrate-binding cavity that may influence substrate specificity and binding mode. A homology model of the inward-open human GLUT7 indicates that similar to other members of the GLUT family, it may undergo a global rocker-switch-like reorientation of the transmembrane bundles to facilitate substrate translocation across the membrane. Our work enhances the current structural understanding of the GLUT family, and lays a foundation for rational design of regulators of GLUTs and other sugar transporters.

Arsenic exposure and measures of glucose tolerance in Bangladeshi adults: A cross-sectional study.

Background: Arsenic has been associated with diabetes and impaired glucose tolerance in many studies, although some reports have shown null findings. Methods: We conducted a cross-sectional study among 300 adults in Bangladesh. Participants were randomly selected from a roster of 1800 people who previously participated in studies of arsenic and skin lesions. We measured fasting glucose and insulin levels. We assessed drinking water arsenic concentration using graphite furnace atomic absorption spectrophotometry (GF-AAS) and toenail arsenic concentration using inductively coupled mass spectrometry (ICP-MS). We ran covariant-adjusted, linear regression and spline models to examine associations of arsenic concentrations with the homeostatic model assessment of insulin resistance (HOMA-IR), a marker of insulin resistance, and HOMA of beta-cell function (HOMA-ß), a marker of beta-cell function. Results: Among 285 participants with complete data, the median (IQR) arsenic concentration was 4.0 (6.9) µg/g in toenails and 39.0 (188.5) µg/L in drinking water. Arsenic concentrations were not associated with insulin resistance or beta-cell function. HOMA-IR was 0.67% lower and HOMA-ß was 0.28% lower per µg/g increment in toenail arsenic, but these effect estimates were small, and confidence intervals crossed the null value. Conclusions: Although arsenic exposure has been associated with diabetes, we found no evidence of an adverse effect on insulin resistance or beta-cell function.

Discovery of Triazolopyrimidine Derivatives as Selective P2X3 Receptor Antagonists Binding to an Unprecedented Allosteric Site as Evidenced by Cryo-Electron Microscopy.

The P2X3 receptor (P2X3R), an ATP-gated cation channel predominantly expressed in C- and Aδ-primary afferent neurons, has been proposed as a drug target for neurological inflammatory diseases, e.g., neuropathic pain, and chronic cough. Aiming to develop novel, selective P2X3R antagonists, tetrazolopyrimidine-based hit compound 9 was optimized through structure-activity relationship studies by modifying the tetrazole core as well as side chain substituents. The optimized antagonist 26a, featuring a cyclopropane-substituted triazolopyrimidine core, displayed potent P2X3R-antagonistic activity (IC50 = 54.9 nM), 20-fold selectivity versus the heteromeric P2X2/3R, and high selectivity versus other P2XR subtypes. Noncompetitive P2X3R blockade was experimentally confirmed by calcium influx assays. Cryo-electron microscopy revealed that 26a stabilizes the P2X3R in its desensitized state, acting as a molecular barrier to prevent ions from accessing the central pore. In vivo studies in a rat neuropathic pain model (spinal nerve ligation) showed dose-dependent antiallodynic effects of 26a, thus presenting a novel, promising lead structure.

Activation mechanism and novel binding sites of the BKCa channel activator CTIBD.

The large-conductance calcium-activated potassium (BKCa) channel, which is crucial for urinary bladder smooth muscle relaxation, is a potential target for overactive bladder treatment. Our prior work unveiled CTIBD as a promising BKCa channel activator, altering V 1/2 and G max This study investigates CTIBD's activation mechanism, revealing its independence from the Ca2+ and membrane voltage sensing of the BKCa channel. Cryo-electron microscopy disclosed that two CTIBD molecules bind to hydrophobic regions on the extracellular side of the lipid bilayer. Key residues (W22, W203, and F266) are important for CTIBD binding, and their replacement with alanine reduces CTIBD-mediated channel activation. The triple-mutant (W22A/W203A/F266A) channel showed the smallest V 1/2 shift with a minimal impact on activation and deactivation kinetics by CTIBD. At the single-channel level, CTIBD treatment was much less effective at increasing P o in the triple mutant, mainly because of a drastically increased dissociation rate compared with the WT. These findings highlight CTIBD's mechanism, offering crucial insights for developing small-molecule treatments for BKCa-related pathophysiological conditions.

ATAD5 functions as a regulatory platform for Ub-PCNA deubiquitination.

Ubiquitination status of proliferating cell nuclear antigen (PCNA) is crucial for regulating DNA lesion bypass. After the resolution of fork stalling, PCNA is subsequently deubiquitinated, but the underlying mechanism remains undefined. We found that the N-terminal domain of ATAD5 (ATAD5-N), the largest subunit of the PCNA-unloading complex, functions as a scaffold for Ub-PCNA deubiquitination. ATAD5 recognizes DNA-loaded Ub-PCNA through distinct DNA-binding and PCNA-binding motifs. Furthermore, ATAD5 forms a heterotrimeric complex with UAF1-USP1 deubiquitinase, facilitating the deubiquitination of DNA-loaded Ub-PCNA. ATAD5 also enhances the Ub-PCNA deubiquitination by USP7 and USP11 through specific interactions. ATAD5 promotes the distinct deubiquitination process of UAF1-USP1, USP7, and USP11 for poly-Ub-PCNA. Additionally, ATAD5 mutants deficient in UAF1-binding had increased sensitivity to DNA-damaging agents. Our results ultimately reveal that ATAD5 and USPs cooperate to efficiently deubiquitinate Ub-PCNA prior to its release from the DNA in order to safely deactivate the DNA repair process.

Visualization of the infratemporal fossa: enhancing anatomical learning through three-dimensional modeling.

The infratemporal fossa and pterygopalatine fossa are critical pathways for blood vessels and nerves leading to the orbit, nasal cavity, and oral cavity. Anatomical observation of these areas is challenging for learners due to their complex connections with surrounding structures and their deep location within the body. Since it is not easy to understand this area in three dimensions with only textbook images, there is a need to produce three-dimensional (3D) content. Most existing 3D data have reconstructed the digital imaging and communication in medicine files from computed tomography images with high accuracy; however, the surrounding structures often obstruct the view. For this reason, this project utilized Cinema4D (R18; Maxon) software to refine the modeled bones and to create 3D models of muscles, blood vessels, and nerves that accurately represent their anatomical shapes and pathways. To facilitate easier access for learners via PC, the content was converted into PDF format. This enables the educational materials to be more easily viewed and the main structures more clearly observed using a computer-based viewer.