Comparison of visual acuity outcome and choroidal thickness variation of intravitreal ranibizumab injection for myopic choroidal neovascularization with or without dome-shaped macula.

BACKGROUND: To investigate the visual acuity outcome and choroid thickness (CT) change after intravitreal ranibizumab in highly myopic eyes with or without dome-shaped macula (DSM) in Chinese patients. METHODS: This retrospective, observative study included 80 treatment-naive eyes (80 patients), which received ranibizumab according to the 1+PRN protocol. The best corrective visual acuity (BCVA) and CT change were compared between eyes with or without DSM. RESULTS: There was no significant difference between eyes with or without DSM in BCVA and central macular thickness (CMT). The recurrent rate was not different between the two groups during the first year of treatment. The CT was significantly thinner in eyes with DSM than in eyes without DSM before treatment (median 40.00um versus 71.00um), at 1 month after treatment (median 31.00um versus 65.50um), and in the last follow up (median, 32.00um versus 65.00um) (p=0.0101). Axial length (AL) was longer in eyes with DSM than those without DSM (median, 29.17mm versus 28.10mm) before treatment, and in the last follow up (median, 29.44mm versus 28.20mm) (p=0.0055). The CT was significantly correlated with AL (p<0.0001). CONCLUSIONS: No difference was found in visual outcome between eyes with or without DSM. The visual acuity significantly improved at 1 month after ranibizumab injection and it was recovery sooner in extrafoveal choroidal neovascularization (CNV) group than in subfoveal CNV group. The CT was thinner in eyes with DSM, which was significantly correlated with AL.

Decreasing the rate of incontinence-associated dermatitis in intensive care units: A quality improvement project.

PURPOSE: Patients in the intensive care unit (ICU) are at a high risk of developing incontinence-associated dermatitis (IAD), the incidence and severity of which are positively related to pressure injuries, thus affecting nursing quality indicators. This quality improvement project aimed to decrease the severity and incidence of IAD, with a focus on enhancing awareness among nursing staff. DESIGN: This 36-month project was implemented via the Plan-Do-Study-Act (PDSA) model. SUBJECTS: and setting: Included staff members worked in the ICUs (central and emergency ICUs) at a Grade A tertiary hospital in Suzhou (South of Jiangsu), China. METHODS: The quality improvement project included three main procedures: (1) formulating and implementing a modified prevention and treatment nursing protocol for early structured skin care with perineum ventilation, formulating a guidance sheet for incontinence nursing care; (2) organizing training and assessments of theories and skills, including three special sections on incontinence care training (theoretical knowledge, project process, video watching), skills training for nursing staff, and an incontinence nursing workshop to engage and evaluate all staff; (3) annual analysis and discussion of nursing quality control. RESULTS: Following project completion, there was a decrease in the overall incidence of IAD. Moreover, ICU nurses may attach more importance/awareness to IAD. CONCLUSIONS: This project successfully reduced the incidence of IAD among ICU patients.

Physical activity and risk of Parkinson's disease: an updated systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Although recent meta-analyses have shown that the association between physical activity (PA) and the risk of developing Parkinson's disease (PD) is influenced by gender differences, a growing number of studies are revealing the general applicability of this association across genders. This study aimed to reassess the association and dose-response relationship between PA and PD risk in populations. METHODS: A systematic search of PubMed, Embase, Cochrane Library, and Web of Science databases was conducted in this study from inception to February 1, 2024, without language restrictions. Stratified analyses were conducted to explore the association between PA and PD risk, combining multivariate-adjusted effect estimates via random-effects models, and to validate the dose-response relationship between the two. RESULTS: This study included 21 observational studies, comprising 13 cohort studies and 8 case-control studies. The pooled analysis revealed that PA significantly reduced the risk of developing PD [relative risk (RR) = 0.77, 95% CI 0.70-0.85]. In addition, the dose-response analysis revealed both linear and nonlinear associations, with linear results indicating a 9% reduction in PD risk for every 10 MET-h/wk increase in PA. The study also demonstrated that the protective effect of PA against PD was significant for both sexes. Moreover, no statistically significant effects of PA on preventing PD were observed in individuals with a BMI > 26 (RR = 0.35, 95% CI 0.12-1.02) or in Asian populations (RR = 0.78, 95% CI 0.60-1.01); however, the trends suggest potential protective effects, warranting further investigation. Sensitivity analyses confirmed the robustness of these findings. CONCLUSION: This meta-analysis produced substantial evidence to reaffirm the protective effect of high PA on PD across various population groups and the inverse dose-response relationship with PD risk, and to validate the protective effect of PA among different demographic groups.

Structural Insight into Melatonin's Influence on the Conformation of Aß42 Dimer Studied by Molecular Dynamics Simulation.

The accumulation of amyloid-beta (Aß) oligomers is recognized as a potential culprit in Alzheimer's disease (AD). Experimental studies show that melatonin, a hormone that mainly regulates circadian rhythm and sleep, can interact with Aß peptides and disrupt the formation of oligomers. However, how melatonin inhibits the oligomerization of soluble Aß is unclear. Here, by computational simulations, we investigate the effect of different levels of melatonin on the conformation of the Aß42 dimer. We find that the conformation of the Aß42 dimer is dependent on melatonin levels. When melatonin is absent, the dimer mainly forms a parallel ß-sheet in the CHC region. When one melatonin molecule is present, the overall conformation of the dimer does not change much, but the N-terminal of the dimer tends to adopt antiparallel ß-sheets. When two melatoinin molecules are present, the Aß42 dimer exhibits significant structural change, especially in its central region, resulting in a more compact conformation, and forms parallel ß-sheets in the C-terminal. This conformational difference induced by different levels of melatoinin can shed light on the protective role of melatonin.

Efficacy and Safety of Roxadustat for Anemia in Patients Receiving Chemotherapy for Nonmyeloid Malignancies: A Randomized, Open-Label, Active-Controlled Phase III Study.

PURPOSE: We evaluated the efficacy and safety of roxadustat, a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor, for chemotherapy-induced anemia (CIA) in patients with nonmyeloid malignancies receiving multicycle treatments of chemotherapy. PATIENTS AND METHODS: In this open-label, noninferiority phase III study conducted at 44 sites in China, 159 participants age ≥18 years with CIA nonmyeloid malignancy and CIA were randomly assigned (1:1) to oral roxadustat or subcutaneous recombinant human erythropoietin-α (rHuEPO-α) three times a week for 12 weeks. Roxadustat starting dosages were 100, 120, and 150 mg three times a week for participants weighing 40-<50, 50-60, and >60 kg, respectively. rHuEPO-α starting dosage for all participants was 150 IU/kg three times a week. Both roxadustat and rHuEPO-α dosages could be modified. The primary end point was least-squares mean (LSM) change in hemoglobin (Hb) concentration from baseline to the concentration averaged over weeks 9-13. RESULTS: Of the 159 participants randomly assigned, 140 were included in the per-protocol set (roxadustat, n = 78; rHuEPO-α, n = 62). The LSM (95% two-sided CI) change from baseline to weeks 9-13 in Hb concentration was 17.1 (13.58 to 20.71) g/L with roxadustat and 15.4 (11.34 to 19.50) g/L with rHuEPO-α (mean difference [95% CI], 1.7 [-3.39 to 6.84]). The lower bound of the one-sided 97.5% CI for the treatment difference (‒3.4 g/L) was greater than the predefined noninferiority margin of ‒6.6 g/L, establishing noninferiority. Noninferiority was supported by five of six key secondary end points. Rates of adverse events were generally comparable between treatments and consistent with previous findings. CONCLUSION: Roxadustat was noninferior to rHuEPO-α in treating CIA in participants with nonmyeloid malignancies receiving multicycle treatments of myelosuppressive chemotherapy. The oral formulation of roxadustat may potentially increase compliance.

Early B lymphocyte subsets in blood predict prognosis in sepsis.

Background: B lymphocytes play a key role in immunosuppression. This study investigated the prognostic value of B cell subsets in sepsis. Methods: Flow cytometry was used to assess peripheral B cell subsets from patients with sepsis on the first and seventh days following admission, as well as 111 healthy controls. The patients were divided into survivors and non-survivors, based on 28-day prognosis. Results: The analysis showed abnormal distribution and selective depletion of B cells and its subsets in the early stages of sepsis. On day 1, compared with survivors, non-survivors showed significant decreases in the proportion and absolute count of transitional (Tr) B cells, reductions in the proportion of CD5+ B cells, and increases in the proportion of double-negative (DN) B cells. On day 7, the proportions and absolute counts of Tr and CD5+ B cells significantly decreased whereas the proportion of DN B cells significantly increased in non-survivors. Ninety-four survivors and 15 non-survivors were included in our paired-sample rank-sum test. Compared to day 1, only the survivors showed significant increases in absolute B, Tr B, and CD5+ B cell counts by day 7. Multivariate Cox regression analysis showed that the proportion of DN B cells on day 1 (hazard ratio = 1.092 [95% confidence interval: 1.035-1.152], P = 0.001) was a risk factor for mortality, and Kaplan-Meier survival curve analysis showed that patients with proportions of DN B cells > 11.81% on day 1 had poorer prognoses. Receiver operating characteristic curve analysis showed that B cell subset parameters could predict mortality (area under the receiver operating characteristic curve [AUC], 0.741) and enhanced the prognostic value of the Acute Physiology and Chronic Health Evaluation II score (AUC, 0.840). Conclusion: Our study revealed that deficiencies of B, Tr B, and CD5+ B cells, as well as a persistent increase in the proportion of DN B cells, were associated with poor prognosis-and that B cell subsets showed predictive value to mortality. These results provide new insights into the roles of B cell subsets in sepsis, as well as ways to better manage its progression and predict its course.

Large Orbital Moment and Dynamical Jahn-Teller Effect of AlCl-Phthalocyanine on Cu(100).

Submonolayer amounts of chloroaluminum-phthalocyanine on Cu(100) were studied with scanning tunneling spectroscopy. The molecule can be prepared in a fourfold symmetric state whose conductance spectrum exhibits a zero-bias feature similar to a Kondo resonance. In magnetic fields, however, this resonance splits far more than expected from the spin of a single electron. Density functional theory calculations reveal a charge transfer of 1.3 electrons to the degenerate lowest unoccupied molecular orbitals. These orbitals are mixed by the orbital momentum operator L[over ^]_{z} with a large matrix element corresponding to m_{L}≈2.7. Dehydrogenation of a ligand lifts the degerenracy of the lowest unoccupied molecular orbital, reduces the splitting in magnetic fields, and induces a polarity dependence of the spectra. Using model calculations of the spin, orbital, and vibrational degrees of freedom we show that a dynamical Jahn-Teller effect reproduces the main experimental observations.

Whole-genome sequencing of the invasive golden apple snail Pomacea canaliculata from Asia reveals rapid expansion and adaptive evolution.

Pomacea canaliculata, an invasive species native to South America, is recognized for its broad geographic distribution and adaptability to a variety of ecological conditions. The details concerning the evolution and adaptation of P. canaliculate remain unclear due to a lack of whole-genome resequencing data. We examined 173 P. canaliculata genomes representing 17 geographic populations in East and Southeast Asia. Interestingly, P. canaliculata showed a higher level of genetic diversity than other mollusks, and our analysis suggested that the dispersal of P. canaliculata could have been driven by climate changes and human activities. Notably, we identified a set of genes associated with low temperature adaptation, including Csde1, a cold shock protein coding gene. Further RNA sequencing analysis and reverse transcription quantitative polymerase chain reaction experiments demonstrated the gene's dynamic pattern and biological functions during cold exposure. Moreover, both positive selection and balancing selection are likely to have contributed to the rapid environmental adaptation of P. canaliculata populations. In particular, genes associated with energy metabolism and stress response were undergoing positive selection, while a large number of immune-related genes showed strong signatures of balancing selection. Our study has advanced our understanding of the evolution of P. canaliculata and has provided a valuable resource concerning an invasive species.

Detecting anomalous anatomic regions in spatial transcriptomics with STANDS.

Detection and Dissection of Anomalous Tissue Domains (DDATD) from multi-sample spatial transcriptomics (ST) data provides unprecedented opportunities to characterize anomalous tissue domains (ATDs), revealing both population-level and individual-specific pathogenic factors for understanding pathogenic heterogeneities behind diseases. However, no current methods can perform de novo DDATD from ST data, especially in the multi-sample context. Here, we introduce STANDS, an innovative framework based on Generative Adversarial Networks which integrates three core tasks in multi-sample DDATD: detecting, aligning, and subtyping ATDs. STANDS incorporates multimodal-learning, transfer-learning, and style-transfer techniques to effectively address major challenges in multi-sample DDATD, including complications caused by unalignable ATDs, under-utilization of multimodal information, and scarcity of normal ST datasets necessary for comparative analysis. Extensive benchmarks from diverse datasets demonstrate STAND's superiority in identifying both common and individual-specific ATDs and further dissecting them into biologically distinct subdomains. STANDS also provides clues to developing ATDs visually indistinguishable from surrounding normal tissues.

Role of naringin in the treatment of atherosclerosis.

Atherosclerosis (AS) is a major pathological basis of coronary heart disease. However, the currently available medications are unable to effectively reduce the incidence of cardiovascular events in the majority of patients with AS. Therefore, naringin has been attracting considerable attention owing to its anti-AS effects. Naringin can inhibit the growth, proliferation, invasion, and migration of vascular smooth muscle cells, ameliorate endothelial cell inflammation and apoptosis, lower blood pressure, halt the cell cycle at the G1 phase, and impede growth via its antioxidant and free radical scavenging effects. These activities suggest the potential anti-AS effects of naringin. In this review article, we comprehensively summarized the latest findings on the anti-AS effects of naringin and their underlying mechanisms, providing a crucial reference for future research on the anti-AS potential of this agent.

Ultrahigh Extinction Ratio Leaky-Guided Hollow Core Fiber Mach-Zehnder Interferometer Assisted by a Large Core Hollow Fiber Beam Splitter.

We proposed a novel fiber Mach-Zehnder interferometer (FMZI) that can perform an ultrahigh extinction ratio (ER), ultracompact, and ultra-broadband interference characteristics. The FMZI structure is based on an extremely tiny hollow core fiber (HCF) with a small diameter of 10 µm (named HCF10) connected with a beam splitter of a large core of 50 µm HCF (named HCF50). The refractive index (RI) of the air core is lower than that of the HCF cladding; a leaky-guided fiber waveguide (LGFW) occurs in such a short-section HCF10 waveguide to simultaneously have the core and cladding modes. To achieve better fringe visibility of the interference, the section of HCF50 assists in splitting the optical light into core and cladding beams launched into the HCF10 with appropriate intensities. Experimental and simulation results show that the optical characteristics of the proposed LGFW-FMZI are very similar. Based on the results of the study, the length of the HCF10 primarily influences the free spectral range (FSR) of the interference spectra, and the HCF50 splitter significantly controls the optimal extinction ratio (ER) of the interference fringes. By exactly adjusting the lengths of HCF10 and HCF50, the proposed fiber interferometers can perform the capability of an ultrahigh ER over 50 dB with the arbitrary FSR in the transmitted interference spectra over an ultra-broad wavelength range of 1250 nm to 1650 nm.

Review of pharmacogenetics of antiseizure medications: focusing on genetic variants of mechanistic targets.

Antiseizure medications (ASMs) play a central role in seizure management, however, unpredictability in the response to treatment persists, even among patients with similar seizure manifestations and clinical backgrounds. An objective biomarker capable of reliably predicting the response to ASMs would profoundly impact epilepsy treatment. Presently, clinicians rely on a trial-and-error approach when selecting ASMs, a time-consuming process that can result in delays in receiving alternative non-pharmacological therapies such as a ketogenetic diet, epilepsy surgery, and neuromodulation therapies. Pharmacogenetic studies investigating the correlation between ASMs and genetic variants regarding their mechanistic targets offer promise in predicting the response to treatment. Sodium channel subunit genes have been extensively studied along with other ion channels and receptors as targets, however, the results have been conflicting, possibly due to methodological disparities including inconsistent definitions of drug response, variations in ASM combinations, and diversity of genetic variants/genes studied. Nonetheless, these studies underscore the potential effect of genetic variants on the mechanism of ASMs and consequently the prediction of treatment response. Recent advances in sequencing technology have led to the generation of large genetic datasets, which may be able to enhance the predictive accuracy of the response to ASMs.

Structural characterization and Bacteroides proliferation promotion activity of a novel homogeneous arabinoglucuronoxylan from Commelina communis L.

Commelina communis L., a functional food and herbal plant in Asia, has been used against obesity, diabetes, and infections for centuries. A growing body of studies has demonstrated that indigestible polysaccharides are significant in obesity management. However, the structures and bioactivities of homogeneous polysaccharides from C. communis remain unclear. This study presented the structural characterization, simulated digestion, and human gut Bacteroides proliferation promotion activity of a novel homogeneous polysaccharide (CCB-3) from C. communis. The results showed that CCB-3 was an arabinoglucuronoxylan, primarily composed of arabinose, galactose, xylose, glucuronic acid (GlcA), and 4-O-methyl GlcA with a molecular weight (Mw) of 58.8 kDa. Following a 6-hour exposure to simulated gastrointestinal fluid, the Mw of CCB-3 remained unchanged, revealing that CCB-3 was an indigestible polysaccharide. Notably, CCB-3 could promote the proliferation of B. thetaiotaomicron, B. ovatus, and B. cellulosilyticus and produce short-chain fatty acids (SCFAs) and 1,2-propanediol. These findings might shed light on the discovery of polysaccharide-based leading compounds from C. communis against obesity.

Perirenal Fat Thickness Is Associated With Contrast-Induced Nephropathy in Type 2 Diabetic Patients Undergoing Coronary Catheterization.

Background: Deposition of adipose tissue may have a promoting role in the development of diabetic complications. This study is aimed at investigating the relationship between adipose tissue thickness and risk of contrast-induced nephropathy (CIN) in patients with Type 2 diabetes mellitus (T2DM). Methods: A total of 603 T2DM patients undergoing percutaneous coronary angiography or angioplasty with suspicious or confirmed stable coronary artery disease were enrolled in this study. The thicknesses of perirenal fat (PRF), subcutaneous fat (SCF), intraperitoneal fat (IPF), and epicardial fat (ECF) were measured by color Doppler ultrasound, respectively. The association of various adipose tissues with CIN was analyzed. Results: Seventy-seven patients (12.8%) developed CIN in this cohort. Patients who developed CIN had significantly thicker PRF (13.7 ± 4.0 mm vs. 8.9 ± 3.6 mm, p < 0.001), slightly thicker IPF (p = 0.046), and similar thicknesses of SCF (p = 0.782) and ECF (p = 0.749) compared to those who did not develop CIN. Correlation analysis showed that only PRF was positively associated with postoperation maximal serum creatinine (sCr) (r = 0.18, p = 0.012), maximal absolute change in sCr (r = 0.33, p < 0.001), and maximal percentage of change in sCr (r = 0.36, p < 0.001). In receiver operating characteristic (ROC) analysis, the area under the curve (AUC) of PRF (0.809) for CIN was significantly higher than those of SCF (0.490), IPF (0.594), and ECF (0.512). Multivariate logistic regression analysis further confirmed that thickness of PRF, rather than other adipose tissues, was independently associated with the development of CIN after adjusted for confounding factors (odds ratio (OR) = 1.53, 95% CI: 1.38-1.71, p < 0.001). Conclusions: PRF is independently associated with the development of CIN in T2DM patients undergoing coronary catheterization.

Efficacy and Safety of General Anesthesia Induction with Ciprofol in Hip Fracture Surgery of Elderly Patients: A Randomized Controlled Trial.

Background: Ciprofol is a new intravenous sedative / anesthetic drug. In recent years, many clinical studies have also confirmed the sedative effect of ciprofol. However, more clinical research is still needed on its clinical application characteristics in special populations. Objective: The aim of this study was to compare the clinical effects of ciprofol and propofol in general anesthesia induction of elderly patients. Methods: 60 elderly (aged ≥ 75 years) patients underwent hip fracture surgery were randomly into two groups of a 1:1 ratio. Group C (ciprofol group): 0.3mg/kg ciprofol was infused. Group P (propofol group): 1.5mg/kg propofol was infused. The observation period was from the infusion of test drug to 5 min after endotracheal intubation. The primary outcomes included the incidence of severe hypotension and hypotension during the observation period. The secondary outcomes were as follows: the success rate of general anesthesia induction, the number of additional sedation, the time of loss of consciousness (LOC), Δ MAP, Δ HR, adverse events and the frequency of vasoactive drugs used. Results: Finally, 60 subjects completed the study. Compared with Group P, the incidence of severe hypotension in Group C was lower (26.7% vs 53.3%, P = 0.035), the incidence of hypotension was also lower (36.7% vs 63.3%, P = 0.037), Δ MAP in Group C was significantly lower (31.4 ± 11.4 vs 39.6 ± 15.7, P = 0.025), the frequency of ephedrine used and the incidence of injection pain in Group C were also significantly lower. Conclusion: Ciprofol showed similar efficacy to propofol when used for general anesthesia induction in elderly patients underwent hip fracture surgery and could maintain more stable blood pressure.

Electrically tunable planar liquid-crystal singlets for simultaneous spectrometry and imaging.

Conventional hyperspectral cameras cascade lenses and spectrometers to acquire the spectral datacube, which forms the fundamental framework for hyperspectral imaging. However, this cascading framework involves tradeoffs among spectral and imaging performances when the system is driven toward miniaturization. Here, we propose a spectral singlet lens that unifies optical imaging and computational spectrometry functions, enabling the creation of minimalist, miniaturized and high-performance hyperspectral cameras. As a paradigm, we capitalize on planar liquid crystal optics to implement the proposed framework, with each liquid-crystal unit cell acting as both phase modulator and electrically tunable spectral filter. Experiments with various targets show that the resulting millimeter-scale hyperspectral camera exhibits both high spectral fidelity ( > 95%) and high spatial resolutions ( ~1.7 times the diffraction limit). The proposed "two-in-one" framework can resolve the conflicts between spectral and imaging resolutions, which paves a practical pathway for advancing hyperspectral imaging systems toward miniaturization and portable applications.

Elevated Serum IL-17A in Kawasaki Disease Patients Predicts Responsiveness to Intravenous Immunoglobulin Therapy.

INTRODUCTION: This study aimed to investigate the correlation between serum interleukin (IL)-17A levels and responsiveness to intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD) patients. METHODS: A retrospective analysis on data from 192 KD patients admitted to the Anqing Municipal Hospital between January 2021 and January 2024 was conducted. Patients were categorized into IVIG-nonresponsive and IVIG-sensitive groups as per the treatment outcomes. Outcome measures included serum IL-17A levels, left coronary artery (LCA) Z scores, and relevant laboratory parameters. Logistic regression analysis was performed to identify predictive factors for IVIG responsiveness, and diagnostic performance was assessed using receiver operating characteristic (ROC) curves and calculation of the area under the curve (AUC). RESULTS: A total of 40 IVIG-nonresponsive cases and 152 IVIG-sensitive cases were included. Prior to intervention, IVIG-nonresponsive patients had significantly higher serum IL-17A levels compared to IVIG-sensitive patients, with a statistically significant difference. After intervention, serum IL-17A levels significantly decreased in IVIG-sensitive patients while remaining elevated in IVIG-nonresponsive patients. IVIG-nonresponsive patients exhibited significantly higher levels of C-reactive protein (CRP), white blood cell count (WBC), NE, and ALT compared to IVIG-sensitive patients, whereas no significant differences in LCA Z scores between the two groups existed. Multivariable logistic regression analysis identified pre-IL-17A, CRP, WBC, and ALT as independent predictors of IVIG-nonresponsiveness in KD. When pre-IL-17A was ≥39.96 pg/mL, the specificity and sensitivity for predicting IVIG-nonresponsive KD were 63.9% and 71.9%, respectively, with an AUC of 0.637. The combined diagnosis of IL-17A, CRP, WBC, and ALT yielded an AUC of 0.780. CONCLUSION: Serum IL-17A levels were remarkably elevated in IVIG-nonresponsive KD patients both before and after intervention. A serum IL-17A level (≥39.96 pg/mL) demonstrated good predictive profile for IVIG-nonresponsive KD, and combining IL-17A with CRP, WBC, and ALT improved diagnostic performance.

Fracture risk prediction in diabetes patients based on Lasso feature selection and Machine Learning.

Fracture risk among individuals with diabetes poses significant clinical challenges due to the multifaceted relationship between diabetes and bone health. Diabetes not only affects bone density but also alters bone quality and structure, thereby increases the susceptibility to fractures. Given the rising prevalence of diabetes worldwide and its associated complications, accurate prediction of fracture risk in diabetic individuals has emerged as a pressing clinical need. This study aims to investigate the factors influencing fracture risk among diabetic patients. We propose a framework that combines Lasso feature selection with eight classification algorithms. Initially, Lasso regression is employed to select 24 significant features. Subsequently, we utilize grid search and 5-fold cross-validation to train and tune the selected classification algorithms, including KNN, Naive Bayes, Decision Tree, Random Forest, AdaBoost, XGBoost, Multi-layer Perceptron (MLP), and Support Vector Machine (SVM). Among models trained using these important features, Random Forest exhibits the highest performance with a predictive accuracy of 93.87%. Comparative analysis across all features, important features, and remaining features demonstrate the crucial role of features selected by Lasso regression in predicting fracture risk among diabetic patients. Besides, by using a feature importance ranking algorithm, we find several features that hold significant reference values for predicting early bone fracture risk in diabetic individuals.

TMEM100 acts as a TAK1 receptor that prevents pathological cardiac hypertrophy progression.

Pathological cardiac hypertrophy is the primary cause of heart failure, yet its underlying mechanisms remain incompletely understood. Transmembrane protein 100 (TMEM100) plays a role in various disorders, such as nervous system disease, pain and tumorigenesis, but its function in pathological cardiac hypertrophy is still unknown. In this study, we observed that TMEM100 is upregulated in cardiac hypertrophy. Functional investigations have shown that adeno-associated virus 9 (AAV9) mediated-TMEM100 overexpression mice attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis, and impaired heart structure and function. We subsequently demonstrated that adenoviral TMEM100 (AdTMEM100) mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy and downregulates the expression of cardiac hypertrophic markers in vitro, whereas TMEM100 knockdown exacerbates cardiomyocyte hypertrophy. The RNA sequences of the AdTMEM100 group and control group revealed that TMEM100 was involved in oxidative stress and the MAPK signaling pathway after PE stimulation. Mechanistically, we revealed that the transmembrane domain of TMEM100 (amino acids 53-75 and 85-107) directly interacts with the C-terminal region of TAK1 (amino acids 1-300) and inhibits the phosphorylation of TAK1 and its downstream molecules JNK and p38. TAK1-binding-defective TMEM100 failed to inhibit the activation of the TAK1-JNK/p38 pathway. Finally, the application of a TAK1 inhibitor (iTAK1) revealed that TAK1 is necessary for TMEM100-mediated cardiac hypertrophy. In summary, TMEM100 protects against pathological cardiac hypertrophy through the TAK1-JNK/p38 pathway and may serve as a promising target for the treatment of cardiac hypertrophy.

Cryo-EM structures of Candida albicans Cdr1 reveal azole-substrate recognition and inhibitor blocking mechanisms.

In Candida albicans, Cdr1 pumps azole drugs out of the cells to reduce intracellular accumulation at detrimental concentrations, leading to azole-drug resistance. Milbemycin oxime, a veterinary anti-parasitic drug, strongly and specifically inhibits Cdr1. However, how Cdr1 recognizes and exports azole drugs, and how milbemycin oxime inhibits Cdr1 remain unclear. Here, we report three cryo-EM structures of Cdr1 in distinct states: the apo state (Cdr1Apo), fluconazole-bound state (Cdr1Flu), and milbemycin oxime-inhibited state (Cdr1Mil). Both the fluconazole substrate and the milbemycin oxime inhibitor are primarily recognized within the central cavity of Cdr1 through hydrophobic interactions. The fluconazole is suggested to be exported from the binding site into the environment through a lateral pathway driven by TM2, TM5, TM8 and TM11. Our findings uncover the inhibitory mechanism of milbemycin oxime, which inhibits Cdr1 through competition, hindering export, and obstructing substrate entry. These discoveries advance our understanding of Cdr1-mediated azole resistance in C. albicans and provide the foundation for the development of innovative antifungal drugs targeting Cdr1 to combat azole-drug resistance.