The Combination of Zhuli Decoction and N-butylphthalide Inhibits Cell Apoptosis Induced by CO Poisoning through the PI3K/AKT/GSK-3ß Signaling Pathway.

Carbon monoxide poisoning (COP) represents a significant global health burden, characterized by its morbidity and high mortality rates. The pathogenesis of COP-induced brain injury is complex, and effective treatment modalities are currently lacking. In this study, we employed network pharmacology to identify therapeutic targets and associated signaling pathways of Zhuli Decoction (ZLD) for COP. Subsequently, we conducted both in vitro and in vivo experiments to validate the therapeutic efficacy of ZLD in combination with N-butylphthalide (NBP) for acute COP-induced injury. Our network pharmacology analysis revealed that the primary components of ZLD exerted therapeutic effects through the modulation of multiple targets and pathways. The in vitro and in vivo experiments demonstrated that the combination of NBP and ZLD effectively inhibited apoptosis and up-regulated the activities of P-PI3K (Tyr458), P-AKT (Ser473), P-GSK-3ß (Ser9), and Bcl-2, thus leading to the protection of neuronal cells and improvement in cognitive function in rats following COP, which was better than the effects observed with NBP or ZLD alone. The rescue experiment further showed that LY294002, a PI3K inhibitor, significantly attenuated the therapeutic efficacy of NBP + ZLD. The neuroprotection effects of NBP and ZLD against COP-induced brain injury are closely linked to the activation of the PI3K/AKT/GSK-3ß signaling pathway.

Associations of tau, Aß, and brain volume of the Papez circuit with cognition in Alzheimer's disease.

This study aimed to investigate the cross-sectional associations between regional Alzheimer's disease (AD) biomarkers, including tau, ß-amyloid (Aß), and brain volume, within the Papez circuit, and neuropsychological functioning across the preclinical and clinical spectrum of AD. We utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 251 Aß-positive participants. Participants were categorized into three groups based on the Clinical Dementia Rating (CDR): 73 individuals with preclinical AD (CDR = 0), 114 with prodromal AD (CDR = 0.5), and 64 with clinical AD dementia (CDR ≥ 1). Linear regression analyses, adjusted for age, gender, and education years, were employed to evaluate the associations between five regions of interest (the hippocampus, para-hippocampus, entorhinal cortex, posterior cingulate cortex, and thalamus) and five neuropsychological tests across the three imaging modalities. In the preclinical stage of AD, flortaucipir PET was associated with impaired global cognition and episodic memory (range standardized ß = 0.255-0.498, p < 0.05 corrected for multiple comparisons), while florbetapir PET and brain volume were marginally related to global cognition (range standardized ß = 0.221-0.231, p < 0.05). In the clinical stages of AD (prodromal and dementia), both increased flortaucipir uptake and decreased brain volume were significantly associated with poorer global neuropsychological and episodic memory performance (range standardized ß = 0.222-0.621, p < 0.05, most regions of interest survived correction for multiple comparisions). However, a slight relationship was observed between florbetapir uptake and poorer global cognitive function. The regions most affected by flortaucipir PET were the hippocampus, para-hippocampus, and posterior cingulate cortex. During the clinical stages, the hippocampus and entorhinal cortex exhibited the most significant volumetric changes. Tau PET and brain volume measurements within the Papez circuit are more sensitive indicators of early cognitive deficits in AD than Aß PET. Furthermore, during the clinical stages of AD, both flortaucipir PET and brain volume of the Papez circuit are closely correlated with cognitive decline. These findings underscore the importance of integrating multiple biomarkers for the comprehensive evaluation of AD pathology and its impact on cognition.

Edge-oriented growth of cadmium sulfide nanoparticles on nickel metal-organic framework nanosheets for photocatalytic hydrogen evolution.

In this study, a directional loading of cadmium sulfide (CdS) nanoparticles (NPs) was achieved on the opposite edges of nickel metal-organic framework (Ni-MOF) nanosheets (NSs) by adjusting the weight ratio of CdS NPs in the reaction process to produce effective visible light photocatalysts. The close contact between the zero-dimensional (0D) and two-dimensional (2D) regions and the matching positions of the bands promoted charge separation and heterojunction formation. The optimal CdS NPs loading of composite material was 40 wt%. At this ratio, CdS NPs grew primarily at the opposite edges of the Ni-MOF NSs rather than on their surfaces. When lactic acid was used as the sacrificial agent, the hydrogen production rate of the 40 %-CdS/Ni-MOF heterojunction under visible light irradiation was 19.6 mmol h-1 g-1, making a 20-fold enhancement compared to the original CdS NPs sample (1.0 mmol h-1 g-1). The charge carriers generated in CdS NPs were transferred to Ni-MOF NSs through heterojunctions, where Ni-MOF NSs also served as cocatalysts to improve hydrogen production. The combination of the two materials improved the light absorption ability. In particular, the 40 %-CdS/Ni-MOF heterojunction exhibited good photostability, effectively preventing the photocorrosion of CdS NPs. This study introduces an approach for constructing efficient and stable photocatalysts for visible light-driven photocatalytic hydrogen production.

Validation and Evaluation of 5 Scoring Systems for Predicting Metastatic Risk in Pheochromocytoma and Paraganglioma.

Currently, 5 scoring systems have been proposed in the literature for predicting metastatic risk in pheochromocytoma and paraganglioma (PPGL): Pheochromocytoma of the Adrenal Gland Scaled Score (PASS), Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP), Composite Pheochromocytoma/paraganglioma Prognostic Score (COPPS), Age, Size, Extra-adrenal location, Secretion type (ASES) score, and Size, Genetic, Age, and PASS (SGAP) model. To validate and evaluate these 5 scoring systems, we conducted a retrospective review of cases diagnosed as PPGL at the Department of Pathology, West China Hospital of Sichuan University, between January 2012 and December 2019. A total of 185 PPGL cases were included, comprising 35 cases with metastasis and 150 cases remained metastasis-free for over 8 years after surgery. The criteria of the 5 scoring systems were used for scoring and risk classification. The predictive performance of the 5 scoring systems was validated, compared, and evaluated using concordance index (C-index) and decision curve analysis (DCA). The C-indices for PASS, GAPP, and SGAP were 0.600, 0.547, and 0.547, respectively, indicating low discriminative ability. In contrast, COPPS and ASES had C-indices of 0.740 and 0.706, respectively, indicating better discriminative performance. DCA also showed that the predictive capability of COPPS was superior to that of ASES, with both outperformed PASS, while PASS had better predictive ability than GAPP and SGAP. Our analysis indicated that pathology-based scoring systems cannot accurately predict metastatic risk of PPGL. Establishing a precise prediction system requires integrating clinical, pathologic, and molecular information, using a scientific methodology for predictive factor selection and weight assessment.

The deubiquitinating enzyme USP4 regulates BRCA1 stability and function.

BRCA1 plays a suppressive role in breast tumorigenesis. Ubiquitin-dependent degradation is a common mechanism that regulates BRCA1 protein stability, and several ubiquitin ligases involved have been identified. However, the deubiquitinating enzyme for BRCA1 remains less defined. Here, we report that the deubiquitinase USP4 interacts with, deubiquitinates and stabilizes BRCA1, maintaining the protein level of BRCA1. USP4 knockdown results in a decreased BRCA1 protein level, impairment in homologous recombination mediated double-stranded break repair, and increased genome instability, and confers resistance to DNA damage-inducing agents and PARP inhibitors. Ectopic expression of USP4 stabilizes BRCA1 and reverse the effects caused by USP4 knockdown. Moreover, USP4 is low expressed in human breast cancer tissues and its low expression correlates with poorer survival of patients. Furthermore, we identified several loss-of-function mutations of USP4 in human gynecological cancers, the catalytic activity of which or their interaction with BRCA1 is disrupted. Together, we reveal that USP4 is a deubiquitinase for BRCA1. USP4 positively regulates the stability and function of BRCA1 through de-ubiquitination, and plays important role in the suppression of breast cancer.

Is Chinese Medicine Facing a Potential Workforce Crisis in Australia? Demographic Changes in the Profession over the Last Decade.

Background: As a prominent part of complementary and alternative medicine, Chinese Medicine (CM) has proved its strengths in treating a diverse range of acute and chronic medical conditions and is at present recognized in 196 countries and territories worldwide. In 2012, Australia regulated the CM profession under the National Regulation and Accreditation Scheme (NRAS) by legislation and reports quarterly demographic information about individual CM practitioners so to ensure public interest, although research examining the change of CM workforce in Australia has been scarce. Objective: This study aims to investigate the construction of the CM workforce in Australia and more importantly, evaluated its development in the last decade to capture the trajectory and trend in the present period and future potential changes. Methods: Data were sourced from the Australian Health Practitioner Regulation Agency (AHPRA) annual reports and the Chinese Medicine Board of Australia (CMBA) registration statistics from 2012 to 2023. A descriptive analysis was conducted with demographic variables, including profession, age, and gender, and chi-square tests and linear regression modeling were carried out to assess the variations between regions and across years. Results: The population of CM practitioners in 2022/2023 stagnated with slight decrease to 4,823, in contrast to the increase rate of 2.9% in the whole health care community. The number of young CM registrants (<35 y) shrank by 37.5% from 691 in 2012 to 432 in 2023. In comparison with other health care professions, CM comprises the smallest proportion of the population aged younger than 25 (0.2%) and the largest proportion aged older than 65 years (16.2%), advancing into an aging era. Conclusions: This study indicates a worrying potential decline in CM workforce in Australia, which is likely to be further exacerbated by the lack of new graduates and rise of median age among practitioners. Meanwhile, continued advancement in Western medicine technology and standards requires substantial efforts to increase both a better understanding of CM and demonstration of its efficacy. Furthermore, greater effort is needed to recruit and educate new young CM practitioners in Australia and to broaden the international training pipeline for a sustainable development of CM practice.

Alkali and alkaline earth elements in follicular fluid and the likelihood of diminished ovarian reserve in reproductive-aged women: a case‒control study.

BACKGROUND: Imbalances in alkali elements (AEs) and alkaline earth elements (AEEs) cause reproductive disorders. However, it remains unclear whether AEs/AEEs in follicular fluid have a relationship with the serious reproductive disorder known as diminished ovarian reserve (DOR). METHODS: A nested case‒control study was carried out in China. Follicular fluid samples from 154 DOR patients and 154 controls were collected and assessed for nine AEs/AEE levels. Both the mixed and single effects of the elements on DOR were estimated with a Bayesian kernel machine (BKMR) and logistic regressions. RESULTS: The DOR group had higher median concentrations of Li, Na, and K in follicular fluid (all P values < 0.05). The logistic regression showed that compared with their lowest tertile, the high tertiles of K [OR:2.45 (1.67-4.43)], Li [OR: 1.89 (1.06-3.42)], and Cs [OR: 1.97 (1.10-3.54)] were significantly associated with the odds of DOR. The BKMR model reported that the DOR likelihood increased linearly across the 25th through 75th percentiles of the nine-AE/AEE mixture, while the AE group contributed more to the overall effect. CONCLUSION: This study revealed an association in which the likelihood of DOR increased with higher overall concentrations of AE/AEEs in follicular fluid. Among the nine detected elements, K, Li, and Cs exhibited significant individual associations with DOR. We provide new clues for the environmental factors on female fertility decline. TRIAL REGISTRATION: Retrospectively registered.

Comparison of clinical characteristics between patients with axial spondyloarthritis with and without acute anterior uveitis: a multicentre study of the Chinese Spondyloarthritis Registry.

OBJECTIVES: This study explores the clinical characteristics associated with the occurrence of acute anterior uveitis (AAU) in patients with axial spondyloarthritis (axSpA) within a large, multicentre database. METHODS: This observational, cross-sectional study of patients with axSpA used data from the Chinese Spondyloarthritis Registry between August 1, 2018, and March 31, 2020. The demographic and clinical features of patients with and without AAU were compared. Univariate and multivariate analyses were performed to determine the association between variables and uveitis. RESULTS: A total of 4304 patients were included in this study. The prevalence of AAU in patients with axSpA was 10.59%. Multivariate logistic regression analysis revealed a positive correlation between AAU and age at diagnosis (odds ratio [OR], 1.026; p<0.001), disease duration (OR, 2.117; p<0.001), current or past Achilles tendinitis (OR, 1.692; p<0.001), current or past dactylitis (OR, 1.687; p=0.002), current or past psoriasis (OR, 3.932; p<0.001), presence of human leukocyte antigen-B27 (HLA-B27) (OR, 2.787; p<0.001), and a good response to non-steroidal anti-inflammatory drugs (NSAIDs) (OR, 1.343; p=0.027). CONCLUSIONS: AAU was the most common extra-articular manifestation in the Chinese Spondyloarthritis Registry. In Chinese patients with axSpA, older age at diagnosis, longer disease duration, presence of HLA-B27, current or past Achilles tendinitis, current or past dactylitis, current or past psoriasis, and a good response to NSAIDs were positively associated with AAU.

Zein/fucoidan-coated phytol nanoliposome: preparation, characterization, physicochemical stability, in vitro release, and antioxidant activity.

BACKGROUND: To improve phytol bioavailability, a novel method of magnetic stirring and high-pressure homogenization (HPH) combination was used to prepare zein/fucoidan-coated phytol nanoliposomes (P-NL-ZF). The characterization, the simulated in vitro digestion, and the antioxidant activity of these phytol nanoliposomes from the different processes have been studied. RESULTS: Based on the results of dynamic light scattering (DLS) and gas chromatography-mass spectrometer (GC-MS) analysis, P-NL-ZF prepared through the combination of magnetic stirring and HPH exhibited superior encapsulation efficiency at 76.19% and demonstrated exceptional physicochemical stability under a series of conditions, including storage, pH, and ionic in comparison to single method. It was further confirmed that P-NL-ZF by magnetic stirring and HPH displayed a uniform distribution and regular shape through transmission electron microscopy (TEM). Fourier-transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) analysis showed that electrostatic interactions and hydrogen bonding were the primary driving forces for the formation of composite nanoliposomes. Additionally, an in vitro digestion study revealed that multilayer composite nanoliposomes displayed significant and favorable slow-release properties (58.21%) under gastrointestinal conditions compared with traditional nanoliposomes (82.36%) and free phytol (89.73%). The assessments of chemical and cell-based antioxidant activities demonstrated that the coating of zein/fucoidan on phytol nanoliposomes resulted in enhanced effectiveness in scavenging activity of ABTS free radical and hydroxyl radical and mitigating oxidative damage to HepG2 cells. CONCLUSION: Based on our studies, the promising delivery carrier of zein/fucoidan-coated nanoliposomes is contributed to the encapsulation of hydrophobic natural products and enhancement of their biological activity. © 2024 Society of Chemical Industry.

Multi-tissue transcriptome profiling linked the association between tissue-specific circRNAs and the heterosis for feed intake and efficiency in chicken.

Heterosis has been widely utilized in chickens. The nonadditive inheritance of genes contributes to this biological phenomenon. However, the role of circRNAs played in the heterosis is poorly determined. In this study, we observed divergent heterosis for residual feed intake (RFI) between 2 crossbreds derived from a reciprocal cross between White Leghorns and Beijing You chickens. Then, circRNA landscape for 120 samples covering the hypothalamus, liver, duodenum mucosa and ovary were profiled to elucidate the regulatory mechanisms of heterosis. We detected that a small proportion of circRNAs (7.83-20.35%) were additively and non-additively expressed, in which non-additivity was a major inheritance of circRNAs in the crossbreds. Tissue-specific expression of circRNAs was prevalent across 4 tissues. Weighted gene co-expression network analysis revealed circRNA-mRNA co-expression modules associated with feed intake and RFI in the hypothalamus and liver, and the co-expressed genes were enriched in oxidative phosphorylation pathway. We further identified 8 nonadditive circRNAs highly correlated with 16 nonadditive genes regulating negative heterosis for RFI in the 2 tissues. Circ-ITSN2 was validated in the liver tissue for its significantly positive correlation with PGPEP1L. Moreover, the bioinformatic analysis indicated that candidate circRNAs might be functioned by binding the microRNAs and interacting with the RNA binding proteins. The integration of multi-tissue transcriptome firstly linked the association between tissue-specific circRNAs and the heterosis for feed intake and efficiency in chicken, which provide novel insights into the molecular mechanism underlying heterosis for feed efficiency. The validated circRNAs can act as potential biomarkers for predicting RFI and its heterosis.

Obstetrical and neonatal outcomes after vitrified-warmed blastocyst transfer in day 1 rescue intracytoplasmic sperm injection cycles: a retrospective cohort study.

BACKGROUND: Fertilization failure often occurs in conventional IVF cycles, and day 1 rescue ICSI is frequently recommended. In this study, the effect of rescue ICSI on obstetrical and neonatal outcomes after a single blastocyst transfer in vitrified-warmed cycles is evaluated. METHODS: This cohort study was a retrospective analysis of 703 vitrified-warmed single blastocyst transfers and 219 singletons in the r-ICSI group compared with 11,611 vitrified-warmed single blastocyst transfers in the IVF/ICSI and 4472 singletons in the IVF/ICSI group, respectively, and patients just undergoing their first IVF treatments were included in this study. Pregnancy rate (PR), live birth rate (LBR), and singleton birthweight were the primary outcome measures. Multiple linear regression analysis and logistic regression analysis were performed to evaluate the possible relationship between obstetrical and neonatal outcomes and fertilization method (including IVF, ICSI, and r-ICSI) after adjusting for other potential confounding factors. RESULTS: PR and the LBR were lower in the r-ICSI group compared with the IVF/ ICSI group. Singletons from the r-ICSI group had a higher Z-score and the proportion of large for gestational age (LGA) newborns was greater compared with singletons from the IVF/ICSI group. CONCLUSION: The results of the study indicated that a 31% LBR after r-ICSI is acceptable for vitrified-warmed blastocyst transfer, but the safety of transfer is a concern because of the lower PR and LBR compared with IVF/ICSI. The safety of r-ICSI newborns is also a concern because of the significantly higher birthweight and the proportion of LGA in r-ICSI group newborns compared with the IVF/ICSI group.

Contrasting nidification behaviors facilitate diversification and colonization of the Music frogs under a changing paleoclimate.

In order to cope with the complexity and variability of the terrestrial environment, amphibians have developed a wide range of reproductive and parental behaviors. Nest building occurs in some anuran species as parental care. Species of the Music frog genus Nidirana are known for their unique courtship behavior and mud nesting in several congeners. However, the evolution of these frogs and their nidification behavior has yet to be studied. With phylogenomic and phylogeographic analyses based on a wide sampling of the genus, we find that Nidirana originated from central-southwestern China and the nidification behavior initially evolved at ca 19.3 Ma but subsequently lost in several descendants. Further population genomic analyses suggest that the nidification species have an older diversification and colonization history, while N. adenopleura complex congeners that do not exhibit nidification behavior have experienced a recent rapid radiation. The presence and loss of the nidification behavior in the Music frogs may be associated with paleoclimatic factors such as temperature and precipitation. This study highlights the nidification behavior as a key evolutionary innovation that has contributed to the diversification of an amphibian group under past climate changes.

Body Composition in Advanced Non-Small Cell Lung Cancer Treated With Immunotherapy.

Importance: The association between body composition (BC) and cancer outcomes is complex and incompletely understood. Previous research in non-small-cell lung cancer (NSCLC) has been limited to small, single-institution studies and yielded promising, albeit heterogeneous, results. Objectives: To evaluate the association of BC with oncologic outcomes in patients receiving immunotherapy for advanced or metastatic NSCLC. Design, Setting, and Participants: This comprehensive multicohort analysis included clinical data from cohorts receiving treatment at the Dana-Farber Brigham Cancer Center (DFBCC) who received immunotherapy given alone or in combination with chemotherapy and prospectively collected data from the phase 1/2 Study 1108 and the chemotherapy arm of the phase 3 MYSTIC trial. Baseline and follow-up computed tomography (CT) scans were collected and analyzed using deep neural networks for automatic L3 slice selection and body compartment segmentation (skeletal muscle [SM], subcutaneous adipose tissue [SAT], and visceral adipose tissue). Outcomes were compared based on baseline BC measures or their change at the first follow-up scan. The data were analyzed between July 2022 and April 2023. Main Outcomes and Measures: Hazard ratios (HRs) for the association of BC measurements with overall survival (OS) and progression-free survival (PFS). Results: A total of 1791 patients (878 women [49%]) with NSCLC were analyzed, of whom 487 (27.2%) received chemoimmunotherapy at DFBCC (DFBCC-CIO), 825 (46.1%) received ICI monotherapy at DFBCC (DFBCC-IO), 222 (12.4%) were treated with durvalumab monotherapy on Study 1108, and 257 (14.3%) were treated with chemotherapy on MYSTIC; median (IQR) ages were 65 (58-74), 66 (57-71), 65 (26-87), and 63 (30-84) years, respectively. A loss in SM mass, as indicated by a change in the L3 SM area, was associated with worse oncologic outcome across patient groups (HR, 0.59 [95% CI, 0.43-0.81] and 0.61 [95% CI, 0.47-0.79] for OS and PFS, respectively, in DFBCC-CIO; HR, 0.74 [95% CI, 0.60-0.91] for OS in DFBCC-IO; HR, 0.46 [95% CI, 0.33-0.64] and 0.47 [95% CI, 0.34-0.64] for OS and PFS, respectively, in Study 1108; HR, 0.76 [95% CI, 0.61-0.96] for PFS in the MYSTIC trial). This association was most prominent among male patients, with a nonsignificant association among female patients in the MYSTIC trial and DFBCC-CIO cohorts on Kaplan-Meier analysis. An increase of more than 5% in SAT density, as quantified by the average CT attenuation in Hounsfield units of the SAT compartment, was associated with poorer OS in 3 patient cohorts (HR, 0.61 [95% CI, 0.43-0.86] for DFBCC-CIO; HR, 0.62 [95% CI, 0.49-0.79] for DFBCC-IO; and HR, 0.56 [95% CI, 0.40-0.77] for Study 1108). The change in SAT density was also associated with PFS for DFBCC-CIO (HR, 0.73; 95% CI, 0.54-0.97). This was primarily observed in female patients on Kaplan-Meier analysis. Conclusions and Relevance: The results of this multicohort study suggest that loss in SM mass during systemic therapy for NSCLC is a marker of poor outcomes, especially in male patients. SAT density changes are also associated with prognosis, particularly in female patients. Automated CT-derived BC measurements should be considered in determining NSCLC prognosis.

One-Step Molten-Salt-Assisted Approach for Direct Preparation and Regeneration of LiNi0.6Co0.2Mn0.2O2 Cathode.

Single-crystal lithium-nickel-manganese-cobalt-oxide (SC-NMC) is attracting increasing attention due to its excellent structural stability. However, its practical production faces challenges associated with complex precursor preparation processes and severe lithium-nickel cation mixing at high temperatures, which restricts its widespread application. Here, a molten-salt-assisted method is proposed using low-melting-point carbonates. This method obviates the necessity for precursor processes and simplified the synthetic procedure for SC-NMC down to a single isothermal sintering step. Multiple characterizations indicate that the acquired SC-LiNi0.6Mn0.2Co0.2O2 (SC-622) exhibits favorable structural capability against intra-granular fracture and suppressive Li+/Ni2+ cation mixing. Consequently, the SC-622 exhibits superior electrochemical performance with a high initial specific capacity (174 mAh g-1 at 0.1 C, 3.0-4.3 V) and excellent capacity retention (87.5% after 300 cycles at 1C). Moreover, this molten-salt-assisted method exhibits its effectiveness in directly regenerating SC-622 from spent NMC materials. The recovered material delivered a capacity of 125.4 mAh g-1 and retained 99.4% of the initial capacity after 250 cycles at 1 C. This work highlights the importance of understanding the process-structure-property relationships and can broadly guide the synthesis of other SC Ni-rich cathode materials.

DDX39B protects against sorafenib-induced ferroptosis by facilitating the splicing and cytoplasmic export of GPX4 pre-mRNA in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the main histological subtype of primary liver cancer and remains one of the most common solid malignancies globally. Ferroptosis was recently defined as an iron-catalyzed form of regulated necrosis. Because cancer cells exhibit higher iron requirements than noncancer cells, treatment with ferroptosis-inducing compounds may be a feasible strategy for cancer therapy. However, cancer cells develop acquired resistance to evade ferroptosis, and the mechanisms responsible for ferroptosis resistance are not fully clarified. In the current study, we reported that DDX39B was downregulated during sorafenib-induced ferroptosis in a dose- and time-dependent manner. Exogenous introduction of DDX39B ensured the survival of HCC cells upon exposure to sorafenib, while the opposite phenomenon was observed in DDX39B-silenced HCC cells. Mechanistically, we demonstrated that DDX39B increased GPX4 levels by promoting the splicing and cytoplasmic translocation of GPX4 pre-mRNA, which was sufficient to detoxify sorafenib-triggered excess lipid ROS production, lipid peroxidation accumulation, ferrous iron levels, and mitochondrial damage. Inhibition of DDX39B ATPase activity by CCT018159 repressed the splicing and cytoplasmic export of GPX4 pre-mRNA and synergistically assisted sorafenib-induced ferroptotic cell death in HCC cells. Taken together, our data uncover a novel role for DDX39B in ferroptosis resistance by modulating the maturation of GPX4 mRNA via a posttranscriptional approach and suggest that DDX39B inhibition may be a promising therapeutic strategy to enhance the sensitivity and vulnerability of HCC cells to sorafenib.

Artificial intelligence-based classification of breast lesion from contrast enhanced mammography: a multicenter study.

PURPOSE: The authors aimed to establish an artificial intelligence (AI)-based method for preoperative diagnosis of breast lesions from contrast enhanced mammography (CEM) and to explore its biological mechanism. MATERIALS AND METHODS: This retrospective study includes 1430 eligible patients who underwent CEM examination from June 2017 to July 2022 and were divided into a construction set (n=1101), an internal test set (n=196), and a pooled external test set (n=133). The AI model adopted RefineNet as a backbone network, and an attention sub-network, named convolutional block attention module (CBAM), was built upon the backbone for adaptive feature refinement. An XGBoost classifier was used to integrate the refined deep learning features with clinical characteristics to differentiate benign and malignant breast lesions. The authors further retrained the AI model to distinguish in situ and invasive carcinoma among breast cancer candidates. RNA-sequencing data from 12 patients were used to explore the underlying biological basis of the AI prediction. RESULTS: The AI model achieved an area under the curve of 0.932 in diagnosing benign and malignant breast lesions in the pooled external test set, better than the best-performing deep learning model, radiomics model, and radiologists. Moreover, the AI model has also achieved satisfactory results (an area under the curve from 0.788 to 0.824) for the diagnosis of in situ and invasive carcinoma in the test sets. Further, the biological basis exploration revealed that the high-risk group was associated with the pathways such as extracellular matrix organization. CONCLUSIONS: The AI model based on CEM and clinical characteristics had good predictive performance in the diagnosis of breast lesions.

Soluble dietary fiber from Dendrocalamus brandisii (Munro) Kurz shoot improves liver injury by regulating gut microbial disorder in mice.

Bamboo shoot has long been regarded as a nutritious and healthy food. It is low in calorie and rich in high-quality dietary fiber (DF), making them a potential DF resource. However, the protective mechanism of soluble dietary fibers from Dendrocalamus brandisii (Munro) Kurz shoot (DS-SDF) on methionine and choline deficient (MCD) diet-induced non-alcoholic fatty liver disease (NAFLD) is still unclear. This study was aimed to investigate the regulation of DS-SDF on gut microbiota in MCD diet-induced mice and its potential protective effect on liver injury. The NAFLD model was induced by the MCD diet for 8 weeks. Through observation of changes in liver function and gut microorganisms, it was found that DS-SDF supplementation could inhibit liver inflammation, improve liver injury, regulate the diversity of gut microorganisms, increase the abundance of beneficial bacteria and short-chain fatty acid-producing bacteria, and reverse the gut disorders induced by the MCD diet in mice. This study showed that DS-SDF supplementation could treat NAFLD by regulating gut microbiota composition, improving liver function, and inhibiting the inflammatory response. It might broaden the idea of high-value utilization of DS-SDF.

Upregulation of rate-limiting enzymes in cholesterol metabolism by PKCδ mediates endothelial apoptosis in diabetic wound healing.

Diabetic foot ulcer (DFU) is a prevalent complication of diabetes that poses significant challenges in terms of treatment and management. It is characterized by heightened endothelial apoptosis and impaired angiogenesis. In this study, we aimed to investigate the role of protein kinase Cδ (PKCδ) in regulating endothelial apoptosis in diabetic wounds by promoting cholesterol biosynthesis. The expression of PKCδ was increased in human umbilical vascular endothelial cells (HUVECs) cultivated in high glucose medium and skin tissue isolated from diabetic mice. High glucose-induced HUVECs apoptosis was reduced by PKCδ inhibition with siRNA or rottlerin. RNA-seq identified two enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), as the downstream of PKCδ. PKCδ knockdown or inhibition suppressed the expression of HMGCS1 and HMGCR and lowered free cholesterol (FC) levels. Cholesterol restored high glucose-induced apoptosis in siRNA- or rottlerin-treated HUVECs. In vivo use of rosuvastatin calcium, an inhibitor of HMGCR, downregulated free cholesterol levels and accelerated the wound healing process. In conclusion, PKCδ expression in endothelial cells was activated by high glucose, which subsequently upregulates the expression of two enzymes catalyzing cholesterol biosynthesis, HMGCS1 and HMGCR. Enhanced cholesterol biosynthesis raises free cholesterol levels, promotes endothelial apoptosis, and finally delays wound healing.

Global One Health index for zoonoses: A performance assessment in 160 countries and territories.

The One Health (OH) approach is used to control/prevent zoonotic events. However, there is a lack of tools for systematically assessing OH practices. Here, we applied the Global OH Index (GOHI) to evaluate the global OH performance for zoonoses (GOHI-Zoonoses). The fuzzy analytic hierarchy process algorithm and fuzzy comparison matrix were used to calculate the weights and scores of five key indicators, 16 subindicators, and 31 datasets for 160 countries and territories worldwide. The distribution of GOHI-Zoonoses scores varies significantly across countries and regions, reflecting the strengths and weaknesses in controlling or responding to zoonotic threats. Correlation analyses revealed that the GOHI-Zoonoses score was associated with economic, sociodemographic, environmental, climatic, and zoological factors. Additionally, the Human Development Index had a positive effect on the score. This study provides an evidence-based reference and guidance for global, regional, and country-level efforts to optimize the health of people, animals, and the environment.