DNp73 enhances tumor progression and immune evasion in multiple myeloma by targeting the MYC and MYCN pathways.

Introduction: Multiple myeloma (MM) is an incurable hematological malignancy with high chromosome instability and heavy dependence on the immunosuppressive bone marrow microenvironment. P53 mutations are adverse prognostic factors in MM; however, clinically, some patients without P53 mutations also exhibit aggressive disease progression. DNp73, an inhibitor of TP53 tumor suppressor family members, drives drug resistance and cancer progression in several solid malignancies. Nevertheless, the biological functions of DNp73 and the molecular mechanisms in myelomagenesis remain unclear. Methods: The effects of DNp73 on proliferation and drug sensitivity were assessed using flow cytometry and xenograft models. To investigate the mechanisms of drug resistance, RNA-seq and ChIP-seq analyses were performed in MM cell lines, with validation by Western blot and RT-qPCR. Immunofluorescence and transwell assays were used to assess DNA damage and cell invasion in MM cells. Additionally, in vitro phagocytosis assays were conducted to confirm the role of DNp73 in immune evasion. Results: Our study found that activation of NF-κB-p65 in multiple myeloma cells with different p53 mutation statuses upregulates DNp73 expression at the transcriptional level. Forced expression of DNp73 promoted aggressive proliferation and multidrug resistance in MM cells. Bulk RNA-seq analysis was conducted to assess the levels of MYCN, MYC, and CDK7. A ChIP-qPCR assay was used to reveal that DNp73 acts as a transcription factor regulating MYCN gene expression. Bulk RNA-seq analysis demonstrated increased levels of MYCN, MYC, and CDK7 with forced DNp73 expression in MM cells. A ChIP-qPCR assay revealed that DNp73 upregulates MYCN gene expression as a transcription factor. Additionally, DNp73 promoted immune evasion of MM cells by upregulating MYC target genes CD47 and PD-L1. Blockade of the CD47/SIRPα and PD-1/PD-L1 signaling pathways by the SIRPα-Fc fusion protein IMM01 and monoclonal antibody atezolizumab significantly restored the anti-MM activity of macrophages and T cells in the microenvironment, respectively. Discussion: In summary, our study demonstrated for the first time that the p53 family member DNp73 remarkably induces proliferation, drug resistance, and immune escape of myeloma cells by directly targeting MYCN and regulating the MYC pathway. The oncogenic function of DNp73 is independent of p53 status in MM cells. These data contribute to a better understanding of the function of TP53 and its family members in tumorigenesis. Moreover, our study clarified that DNp73 overexpression not only promotes aggressive growth of tumor cells but, more importantly, promotes immune escape of MM cells through upregulation of immune checkpoints. DNp73 could serve as a biomarker for immunotherapy targeting PD-L1 and CD47 blockade in MM patients.

Hyperthermophilic composting coupled with vermicomposting stimulates transformation of organic matter by altering bacterial community.

Hyperthermophilic composting (HTC) has been proven to be an effective strategy to recycle organic wastes, while vermicomposting (VC) has been widely applied to produce humic fertilizer. The combination of HTC with VC (HVC) is expected to integrate the advantages of both. This study showed that HTC pre-fermentation provided plentiful substances such as dissolved organic matter (DOM) for the subsequent VC enriching humic acid (HA). Compared to thermophilic composting (TC), HVC significantly stimulated the degradation of organic matter (OM) and the production of N-rich HA, and incubated higher diversity of bacterial community. SHapley Additive exPlanations (SHAP), correlation network, Mantel test and PLS-LM model were constructed to identify the potential roles of the key bacterial groups contributing to OM transformation. Firmicutes (e.g., Bacillus and Tuberibacillus) dominant in HTC may mineralize and mobilize OM, providing affluent bioavailable nutrients as part of DOM for microbial metabolism and abundant precursors for HA formation in the further VC. Actinobacteriota (e.g., Microbacterium) and Bacteroidota (e.g., Flavobacterium and Parapedobacter) prominent in VC metabolized DOM, mineralized OM and produced HA probably by enhancing the metabolic activity involved in OM degradation and amino acid generation. However, when DOM was exhausted, some members especially Proteobacteria (e.g., Ochrobactrum, Devosia and Cellvibrio) would change their roles from promoter to inhibitor of mineralization and humification. Altering the nutrient bioavailability and the composition of bacterial community can regulate the mineralization, mobilization and humification of OM. Overall, this study provides new insights into the roles of bacteria participating in transforming organic wastes into HA-rich composts.

Arsenic-contaminated soil remediation with hyperthermophilic compost: Effects on arsenic bioavailability, soil fertility and bacterial community.

Soil arsenic (As) contamination has posed a significant global environmental challenge seriously threatening human health. Compost has attracted broad interests as a kind of eco-friendly and versatile amendment. However, hyperthermophilic compost (HTC), which is newly-developed and more advantageous to environment, has not yet been widely utilized to remediate As-contaminated soil, and its effectiveness remains unclear. Herein, the effects of HTC amendment on soil fertility, As bioavailability, plant growth and soil bacterial community were investigated. After amended with HTC, soil nutrient content and enzyme activity were improved. Concurrently, the content of both total As and available As in soil was reduced, partially due to the formation of organo-As complex with the presence of humic acid and fulvic acid in HTC. Notably, Chinese white cabbage (Brassica campestris L. ssp. chinensis Makino) cultivated in HTC-treated soil exhibited better growth and less As uptake, but showed enhanced translocation of As from the below-ground part to the above-ground part. In particular, the lowest HTC addition ratio (HTC:Soil = 1:10, v:v) proved to be the most optimal, increasing the height, width and biomass of Chinese white cabbage from 9.92 ± 0.72 cm, 6.76 ± 0.31 cm and 4.43 ± 0.49 g, to 21.29 ± 0.48 cm, 19.3 ± 1.44 cm and 23.27 ± 2.45 g, respectively. The results of soil bacterial community analysis revealed that HTC amendment stimulated the growth and metabolism of soil microbes, augmenting the richness and diversity of bacteria related to the methylation and volatilization of As and plant growth. This work suggests that HTC can serve as an effective amendment for As-contaminated soil remediation, and a superior alternative to compound fertilizer for plant cultivation, displaying promising potential for agricultural applications.

Chiral Co-assembly Based on a Stimuli-Responsive Polymer towards Amplified Full-Color Circularly Polarized Luminescence.

Stimuli-responsive circularly polarized luminescence (CPL) materials have been attaching wide attention in the field of optical information storage and encryption, while still facing the challenge of the realization of high luminescence dissymmetry factors (glum). This work presents a pair of stimuli-responsive chiral co-assemblies P7R3 and P7S3 by combining polymer PFIQ containing iso-quinoline units with chiral inducers. The obtained chiral co-assemblies can reversibly undergo significant modification in CPL behavior under trifluoroacetic acid (TFA) fumigation and annealing treatment, with the |glum| values exhibiting a reversible shift between 0.2 and 0.3. Moreover, the chiral co-assemblies before TFA fumigating can effectively induce achiral emitters to generate intense full-color CPL signals through CPL energy transfer (CPL-ET), with the corresponding |glum| values larger than 0.2. Moreover, information encryption and decryption as well as a multi-level logic gates application are achieved by leveraging the reversible stimuli-responsive CPL activity of the chiral co-assembly. This work provides a new perspective for the construction of stimuli-responsive chiral luminescent materials with large |glum| values and the activation of CPL behavior in achiral emitters.

Scalable, High-Yield Monolayer MXene Preparation from Multilayer MXene for Many Applications.

MXene (Ti3C2Tx) is renowned for its exceptional conductivity and hydrophilicity; however, the low yield of monolayers hinders its industrial scalability. Herein, we present a strategy to substantially enhance the monolayer yield by disrupting the hydrogen-bonding cage confinement of multilayer MXene using high-temperature ultrasound, challenging the conventional belief that monolayer MXene can only be prepared at lower temperatures. At approximately 70 °C, the weakened hydrogen bonding between the oxygen-containing terminal groups of multilayer MXene and surrounding water molecules weakens the hydrogen-bond cage confinement. This enables ultrasonic cavitation to generate more microbubbles that penetrate the interlayers of multilayer MXene, resulting in gentle and thorough delamination into larger monolayer nanosheets. Achieving up to a 95% yield in just tens of minutes, these nanosheets exhibit properties comparable to those produced by traditional ice-bath methods. Furthermore, the high-concentration MXene ink produced on a large scale using this high-yield approach exhibits excellent printing and processing capabilities, and the corresponding products showcase superior infrared stealth and Joule heating characteristics. This work addresses a key technical bottleneck in MXene production, paving the way for its extensive technological and industrial applications.

Ultraviolet (UV) radiation: a double-edged sword in cancer development and therapy.

It has long been widely acknowledged that ultraviolet (UV) light is an environment risk factor that can lead to cancer, particularly skin cancer. However, it is worth noting that UV radiation holds potential for cancer treatment as a relatively high-energy electromagnetic wave. With the help of nanomaterials, the role of UV radiation has caught increasing attention in cancer treatment. In this review, we briefly summarized types of UV-induced cancers, including malignant melanoma, squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma. Importantly, we discussed the primary mechanisms underlying UV carcinogenesis, including mutations by DNA damage, immunosuppression, inflammation and epigenetic alterations. Historically limited by its shallow penetration depth, the introduction of nanomaterials has dramatically transformed the utilization of UV light in cancer treatment. The direct effect of UV light itself generally leads to the suppression of cancer cell growth and the initiation of apoptosis and ferroptosis. It can also be utilized to activate photosensitizers for reactive oxygen species (ROS) production, sensitize radiotherapy and achieve controlled drug release. Finally, we comprehensively weigh the significant risks and limitations associated with the therapeutic use of UV radiation. And the contradictory effect of UV exposure in promoting and inhibiting tumor has been discussed. This review provides clues for potential clinical therapy as well as future study directions in the UV radiation field. The precise delivery and control of UV light or nanomaterials and the wavelength as well as dose effects of UV light are needed for a thorough understanding of UV radiation.

Growth differentiation factor 11 alleviates oxidative stress-induced senescence of endothelial progenitor cells via activating autophagy.

BACKGROUND: Stem cell transplantation has been regarded as a promising therapeutic strategy for myocardial regeneration after myocardial infarction (MI). However, the survival and differentiation of the transplanted stem cells in the hostile ischaemic and inflammatory microenvironment are poor. Recent studies have focused on enhancing the survival and differentiation of the stem cells, while strategies to suppress the senescence of the transplanted stem cells is unknown. Therefore, we investigated the effect of growth differentiation factor 11 (GDF11) on attenuating oxidative stress-induced senescence in the engrafted endothelial progenitor cells (EPCs). METHODS: Rat models of oxidative stress were established by hydrogen peroxide conditioning. Oxidative stress-induced senescence was assessed through senescence-associated ß-galactosidase expression and lipofuscin accumulation. The effects of GDF11 treatment on senescence and autophagy of EPCs were evaluated 345, while improvement of myocardial regeneration, neovascularization and cardiac function were examined following transplantation of the self-assembling peptide (SAP) loaded EPCs and GDF11 in the rat MI models. RESULTS: Following hydrogen peroxide conditioning, the level of ROS in EPCs decreased significantly upon treatment with GDF11. This resulted in reduction in the senescent cells and lipofuscin particles, as well as the damaged mitochondria and rough endoplasmic reticula. Concurrently, there was a significant increase in LC3-II expression, LC3-positive puncta and the presence of autophagic ultrastructures were increased significantly. The formulated SAP effectively adhered to EPCs and sustained the release of GDF11. Transplantation of SAP-loaded EPCs and GDF11 into the ischaemic abdominal pouch or myocardium resulted in a decreased number of the senescent EPCs. At four weeks after transplantation into the myocardium, neovascularization and myocardial regeneration were enhanced, reverse myocardial remodeling was attenuated, and cardiac function was improved effectively. CONCLUSIONS: This study provides novel evidence suggesting that oxidative stress could induce senescence of the transplanted EPCs in the ischemic myocardium. GDF11 demonstrates the ability to mitigate oxidative stress-induced senescence in the transplanted EPCs within the myocardium by activating autophagy.

Brain single-cell transcriptomics highlights comorbidity-related cell type-specific changes of Parkinson's disease with major depressive disorder after paraquat exposure.

Paraquat (PQ), a commonly used herbicide, is a potent environmental neurotoxin associated with Parkinson's disease (PD) and major depressive disorder (MDD). While the involvement of various brain cell types in the etiology of each disorder is well recognized, the specific cell subtypes implicated in the comorbidity of PD and MDD, especially under PQ neurotoxicity, remain poorly understood. In this study, we used single-cell RNA sequencing (scRNA-seq) to analyze brain tissues from mice with PQ-induced PD with MDD. By integrating genomic data with scRNA-seq profiles, we identified differences in cellular heterogeneity related to the pathogenesis of PD and MDD under PQ exposure. Our analysis of risk enrichment in genes with cell type-specific expression patterns revealed that astrocytes are predominantly linked to the comorbidity of PQ-induced PD and MDD. Furthermore, we identified a specific astrocyte subtype that plays a major role in the comorbidity-related changes observed in PQ-induced PD and MDD. This subtype appears to interact with and potentially transform into MDD-specific and PD-specific subtypes. Additionally, pathways related to chemical synaptic function and neuro-projection development were involved in all key stages of PD and MDD co-occurrence. We also identified RNF7 and MTCH2 as shared diagnostic hub genes for PD and MDD, which changed significantly in astrocytes following PQ exposure. These genes may serve as potential markers for astrocyte-specific prognostic diagnosis of PQ-induced PD with MDD. In summary, this study provides the first scRNA-seq profile of comorbidity in a PQ-exposed model. It highlights the heterogeneity of astrocytes in comorbidity and elucidates potential mechanisms underlying the co-occurrence of PD and MDD. These findings emphasize the need for further research into the pathogenesis of PD comorbid with MDD and offer novel insights into PQ neurotoxicity.

Determination of MYD88 and CXCR4 mutation for clinical detection and their significance in Waldenström macroglobulinemia.

PURPOSE: This study aims to explore the incidence and clinical features of MYD88 and CXCR4 mutations in patients with Waldenström macroglobulinemia (WM) and determine the optimal method for routine clinical practice. Additionally, we seek to evaluate the prognostic significance of these features across various therapeutic backgrounds [cytotoxic group, the Rituximab/Bortezomib-based group, and the Bruton's tyrosine kinase inhibitor (BTKi) group]. EXPERIMENTAL DESIGN: 385 symptomatic WM patients were analyzed for MYD88 and CXCR4 mutations using Sanger sequencing, next-generation sequencing (NGS), allele-specific quantitative polymerase chain reaction (AS-PCR), and/or droplet digital PCR (ddPCR). RESULTS: The overall MYD88 mutation rate was 87.8%, relatively lower than that in Western cohort. Both AS-PCR and ddPCR demonstrated high sensitivity in unsorted samples, detecting 98.5% and 97.7% of mutations, respectively, including those with low tumor burdens. The total CXCR4 mutation rate was 30.9%, with NGS exhibiting the highest sensitivity of 78.0%. CXCR4 mutation was significantly linked to shorter OS only within the BTKi treatment group. The multivariate analysis indicated that MYD88 and CXCR4 mutations were not independent prognostic factors in the non-BTKi group when considering IPSSWM clinical staging. However, in the BTKi treatment group, these mutations emerged as independent adverse prognostic factors, overshadowing the prognostic significance of IPSSWM classification (MYD88: HR=0.229, P=0.030; CXCR4: HR=3.349, P=0.012). CONCLUSIONS: Testing for MYD88 mutations using AS-PCR or ddPCR in unsorted samples is viable for routine clinical practice. Under BTKi treatment, MYD88 and CXCR4 mutations hold greater prognostic importance than IPSSWM staging in WM.

Vitamin D deficiency may increase the risk of acute kidney injury in patients with diabetes and predict a poorer outcome in patients with acute kidney injury.

BACKGOUND: People with diabetes are much more likely to develop acute kidney injury (AKI) than people without diabetes. Low 25-hydroxy-vitamin D [25(OH)D] concentrations increased the risk of AKI in specific populations. Few studies have explored the relationship between the 25(OH)D level and AKI in patients with diabetes. We conducted this study to investigate the relationship between the plasma level of 25(OH)D and the risk of AKI in patients with diabetes, and to evaluate whether the 25(OH)D level could be a good prognostic marker for AKI progression. METHODS: A total of 347 patients with diabetes were retrospectively reviewed. The primary endpoint was the first event of AKI. The secondary endpoint is need-of-dialysis. AKI patients were further followed up for 6 months with the composite endpoint of end-stage renal disease (ESRD) or all-cause death. Kaplan-Meier survival analysis and Cox proportional hazards models were used. RESULTS: During a median follow-up of 12 weeks (12.3 ± 6.7), 105 incident AKI were identified. The middle and high tertiles of baseline 25(OH)D levels were associated with a significantly decreased risk of AKI and dialysis compared to the low tertile group (HR = 0.25, 95% CI 0.14-0.46; HR = 0.24, 95% CI 0.13-0.44, respectively, for AKI; HR = 0.15; 95% CI 0.05-0.46; HR = 0.12; 95% CI 0.03-0.42, respectively, for dialysis). Sensitivity analysis revealed similar trends after excluding participants without history of CKD. Furthermore, AKI patients with 25(OH)D deficiency were associated with a higher risk for ESRD or all-cause death (HR, 4.24; 95% CI, 1.80 to 9.97, P < 0.001). CONCLUSION: A low 25 (OH) vitamin D is associated with a higher risk of AKI and dialysis in patients with diabetes. AKI patients with 25(OH)D deficiency were associated with a higher risk for ESRD or all-cause death.

Perioperative systemic and prophylactic intraperitoneal chemotherapy for type 4/large type 3 gastric cancer: DRAGON-10.

Large type 3 and type 4 gastric cancers (GC) have a significantly poor prognosis, primarily due to their high predisposition for peritoneal dissemination. The application of intraperitoneal chemotherapy has emerged as a viable therapeutic strategy for managing GC patients with peritoneal metastasis. This study is planned to enroll 37 resectable large type 3 or type 4 GC patients. These patients are scheduled to undergo a treatment comprising preoperative chemotherapy with paclitaxel, oxaliplatin and S-1, followed by D2 gastrectomy, and concluding with postoperative treatments that include prophylactic intraperitoneal chemotherapy. The study's primary objective is to evaluate the 3-year peritoneal recurrence rate. Secondary objectives are to assess the 3-year disease-free survival, 3-year overall survival and to monitor the adverse events.Clinical trial registration number: ChiCTR2400083253 (https://www.chictr.org.cn).

Gastric cancer (GC), specifically the large type 3 and type 4 kinds, is a serious health condition that often leads to a very poor chance of survival. This is mainly because these types of cancer easily spread to the lining of the abdomen, a process known as peritoneal dissemination. One way to tackle this issue is through a treatment known as intraperitoneal chemotherapy, which directly targets the abdominal lining to kill cancer cells. In our study, 37 resectable large type 3 and type 4 GC patients will receive a combination of chemotherapy drugs before undergoing surgery to remove the cancer. After surgery, they will receive additional treatment that combines chemotherapy into the abdomen with standard chemotherapy. The main goal of our study is to see if this treatment approach can reduce the chance of cancer returning to the abdominal lining within 3 years. We are also looking at how long patients remain free from cancer, their overall survival after 3 years, and any side effects they may experience from the treatment. This study aims to provide a clearer understanding of how effective this combined treatment is for patients with these aggressive types of GC, with the hope of improving their chances of survival and quality of life.

Evaluation of gridded cropland phosphorus budget and use efficiency in China.

Changes in soil phosphorus (P) distribution and budget critically impact the sustainability of agricultural systems. Yet, few studies have examined the long-term evolution of cropland (and crop-specific) P budget and use efficiency (PUE) at a grid level. Here, we conducted a comprehensive evaluation of the cropland P budget and PUE and their human-environmental drivers in China during 1992-2018 at a spatial resolution of 0.1°. The results reveal a significant shift in China's cropland P budget from a deficit of -3.70 Tg P yr-1 in 1992 to a surplus of 0.31 Tg P yr-1 in 2018, mainly driven by increased fertilizer application and decreased soil erosion by water. The concurrent national average cropland PUE initially decreased from 0.51 in 1992 to 0.34 in 2003, but afterwards increased to 0.39 in 2015. An environmental-Kuznets-curve-like (EKC) relationship was identified between the national average P budget (inverted U-shaped) or PUE (U-shaped) and per capita GDP in China, with the turning point occurring in 2013 for the previous and at per capita GDP of US$8.85 k (constant 2017 US$) for the latter. But PUE had been well below a threshold of 0.40 at the national level after crossing the turning point and showed a considerable trend divergence among crops, particularly for cash ones. Spatially, northern and northwestern China exhibited high positive P budget but achieved relatively low PUE in the 2010s. Crop leaf area, irrigation, fertilizer input, and precipitation were identified as the most important factors determining the multi-year spatial pattern of P budget, while fertilizer input, temperature, and residue return played a dominant role in regulating PUE. Our findings highlight the need for a long-term commitment to regionalized and crop-specific synthetic management practices for controlling P inputs and minimizing P loss in the context of global change in China.

Effects of arabinoxylan extracted from vinegar residue on physicochemical and structural properties of gluten proteins obtained from freeze-thaw wheat dough.

BACKGROUND: Arabinoxylan is commonly used as a hydrocolloid in frozen dough to improve the texture and the sensory qualities of the products. The effects of vinegar residue arabinoxylan (VRAX) on the secondary structures and microstructures of gluten proteins during freeze-thaw storage were studied, and the underlying mechanism governing these effects was clarified. RESULTS: The results revealed that VRAX improved the textural properties of gluten proteins, but had a negative impact on their viscoelasticity. Additionally, the addition of VRAX increased the number of disulfide bonds and also improved the freezing tolerance of the gluten proteins. It was found that the enthalpy of the gluten proteins decreased by 19.78% following VRAX addition. As a result of the use of VRAX, the freezing procedure resulted in reduced formation of ice crystals, protecting the gluten network structure and preserving the dough's elasticity. The network structure of gluten proteins after VRAX treatment was more ordered and integrated relative to that of frozen blank control gluten proteins. CONCLUSION: Overall, the freeze-thaw stability of the gluten proteins was enhanced by VRAX. These results suggest that VRAX has potential as an effective cryoprotectant in frozen dough. © 2024 Society of Chemical Industry.

The efficacy and safety of per-nasal "GTS partner" assisted traction technique for gastric endoscopic submucosal dissection: a prospective single-center randomized clinical trial.

BACKGROUND: Since the snare traction-assisted ESD has been proven effective in treating flat lesions of the digestive tract, we modified and innovated the process and path of the traditional snare entering the digestive tract, aiming to investigate the efficacy and safety of using the per-nasal "GTS partner" assisted traction technology in gastric ESD. METHODS: Patients with superficial gastric neoplasms were prospectively enrolled between November 2022 and May 2024 and randomly assigned to a conventional ESD (C-ESD) group or per-nasal "GTS partner" traction-assisted ESD (GTS-ESD) group. The primary outcomes were procedure time and dissection speed. RESULTS: The GTS-ESD and C-ESD groups included 40 patients each, and all the enrolled patients underwent the assigned treatment. The median procedure time in the GTS-ESD group was shorter than that in the C-ESD group (38 min vs. 48 min; P < 0.001), and the mean resection speed of the GTS-ESD group was faster than that of the C-ESD group (17.95 mm2/min vs. 11.86 mm2/min; P = 0.033). The median resection speed of lesions ≥ 20 mm was faster by GTS-ESD than by C-ESD (21.21 mm2/min vs. 12.83 mm2/min, P = 0.002). The en bloc resection rate (100% vs 100%) and R0 resection rate (100% vs. 97.5%) were similar between the two groups. There were no adverse events related to the per-nasal "GTS partner" assisted traction technology, and the traction technology had little interference with the endoscopist. CONCLUSIONS: The per-nasal "GTS partner" assisted traction technique can significantly shorten the gastric ESD procedure time and has the advantages of no damage to normal mucosa and adjustable traction direction, especially in the lower 1/3 of the stomach or lesions with a diameter of ≥ 20 mm.

Positive association between constipation and mild cognitive impairment in elders: A cross-sectional study.

This study aimed to examine the association between constipation and mild cognitive impairment (MCI); and further elucidate the possible mechanisms involved. A cross-sectional study was conducted among community-dwelling elders (N = 789) in Nanning, China. Trained research staffs collected detailed information through questionnaires and physical examinations. A Bayesian network model was used to explore the hypothesized causal path. Synergistic effects of constipation with infrequent fruit consumption, inactive physical exercise, or history of stroke were observed in the risks of MCI occurrence. The Bayesian network model analyses showed 3 hypothesized causal-association paths leading to MCI occurrence. Among these, constipation, history of stroke, and years of schooling were directly related to the occurrence of MCI. Years of schooling indirectly affected MCI through infrequent fruit consumption and constipation; or through inactive physical exercises and history of stroke. This study demonstrates a direct association between constipation and increased risks of MCI.

Determinants of Visual Impairment Among Chinese Middle-Aged and Older Adults: Risk Prediction Model Using Machine Learning Algorithms.

Background: Visual impairment (VI) is a prevalent global health issue, affecting over 2.2 billion people worldwide, with nearly half of the Chinese population aged 60 years and older being affected. Early detection of high-risk VI is essential for preventing irreversible vision loss among Chinese middle-aged and older adults. While machine learning (ML) algorithms exhibit significant predictive advantages, their application in predicting VI risk among the general middle-aged and older adult population in China remains limited. Objective: This study aimed to predict VI and identify its determinants using ML algorithms. Methods: We used 19,047 participants from 4 waves of the China Health and Retirement Longitudinal Study (CHARLS) that were conducted between 2011 and 2018. To envisage the prevalence of VI, we generated a geographical distribution map. Additionally, we constructed a model using indicators of a self-reported questionnaire, a physical examination, and blood biomarkers as predictors. Multiple ML algorithms, including gradient boosting machine, distributed random forest, the generalized linear model, deep learning, and stacked ensemble, were used for prediction. We plotted receiver operating characteristic and calibration curves to assess the predictive performance. Variable importance analysis was used to identify key predictors. Results: Among all participants, 33.9% (6449/19,047) had VI. Qinghai, Chongqing, Anhui, and Sichuan showed the highest VI rates, while Beijing and Xinjiang had the lowest. The generalized linear model, gradient boosting machine, and stacked ensemble achieved acceptable area under curve values of 0.706, 0.710, and 0.715, respectively, with the stacked ensemble performing best. Key predictors included hearing impairment, self-expectation of health status, pain, age, hand grip strength, depression, night sleep duration, high-density lipoprotein cholesterol, and arthritis or rheumatism. Conclusions: Nearly one-third of middle-aged and older adults in China had VI. The prevalence of VI shows regional variations, but there are no distinct east-west or north-south distribution differences. ML algorithms demonstrate accurate predictive capabilities for VI. The combination of prediction models and variable importance analysis provides valuable insights for the early identification and intervention of VI among Chinese middle-aged and older adults.

Mechanistic insights into multimetal synergistic and electronic effects in a hexanuclear iron catalyst with a [Fe3(µ3-O)(µ2-OH)]2 core for enhanced water oxidation.

Multinuclear molecular catalysts mimicking natural photosynthesis have been shown to facilitate water oxidation; however, such catalysts typically operate in organic solutions, require high overpotentials and have unclear catalytic mechanisms. Herein, a bio-inspired hexanuclear iron(III) complex I, Fe6(µ3-O)2(µ2-OH)2(bipyalk)2(OAc)8 (H2bipyalk = 2,2'-([2,2'-bipyridine]-6,6'-diyl)bis(propan-2-ol); OAc = acetate) with desirable water solubility and stability was designed and used for water oxidation. Our results showed that I has high efficiency for water oxidation via the water nucleophilic attack (WNA) pathway with an overpotential of only ca. 290 mV in a phosphate buffer of pH 2. Importantly, key high-oxidation-state metal-oxo intermediates formed during water oxidation were identified by in situ spectroelectrochemistry and oxygen atom transfer reactions. Theoretical calculations further supported the above identification. Reversible proton transfer and charge redistribution during water oxidation enhanced the electron and proton transfer ability and improved the reactivity of I. Here, we have shown the multimetal synergistic and electronic effects of catalysts in water oxidation reactions, which may contribute to the understanding and design of more advanced molecular catalysts.

Cognitive impairment induced by sevoflurane anesthesia is mediated by the cholinergic system after gastrointestinal surgery in older patients: A randomized, controlled trial.

Delayed neurocognitive recovery after surgery is associated with increased morbidity and mortality. However, its mechanism of action remains controversial and complex. A prospective, double-blind, randomized controlled trial was performed at the Affiliated Hospital of Zunyi Medical University. Older patients (aged 65 years and older) who underwent gastrointestinal surgery were randomly divided into sevoflurane-based or propofol-based anesthesia groups. The Mini-Mental State Examination was performed to evaluate cognitive function. Peripheral venous blood was collected to test the levels of choline acetyltransferase and acetylcholinesterase. A total of 75 patients were enrolled and 30 patients in each group completed the study. On Day 1 postoperation, patients in the sevoflurane group showed worse performance on the Mini-Mental State Examination than patients in the propofol group. Lower blood choline acetyltransferase concentrations and higher acetylcholinesterase concentrations were observed in patients who had sevoflurane anesthesia than in patients who had propofol anesthesia 1 day postoperative. At 3 days postoperation, patients with sevoflurane- or propofol-based general anesthesia did not differ regardless of Mini-Mental State Examination score or choline acetyltransferase and acetylcholinesterase levels. Sevoflurane-based anesthesia has short-term delayed neurocognitive recovery in older surgical patients, which may be related to central cholinergic system degeneration.

Ovatodiolide inhibits endometrial cancer stemness via reactive oxygen species-mediated DNA damage and cell cycle arrest.

Endometrial cancer (EC) is a common gynecological cancer worldwide, often associated with a poor prognosis after recurrence or metastasis. Ovatodiolide (OVA) is a macrocyclic diterpenoid derived from Anisomeles indica that shows anticancer effects in various malignancies. This study aimed to evaluate the cytotoxic effects of OVA on EC cell proliferation and cancer stem cell (CSC) activity and explore its underlying molecular mechanisms. OVA treatment dose-dependently reduced the viability and colony formation of three EC cell lines (AN3CA, HEC-1A, and EMC6). It induced G2/M phase cell cycle arrest, associated with decreased cell division cycle 25C (CDC25C) expression and reduced activation of cyclin-dependent kinases 1 (CDK1) and 2 (CDK2). OVA also increased reactive oxygen species (ROS) production and DNA damage, activating the DNA damage-sensitive cell cycle checkpoint kinases 1 (CHK1) and 2 (CHK2) and upregulating the DNA damage marker γ-H2A.X variant histone (H2AX). It also suppressed the activation of mechanistic target of rapamycin kinase (mTOR) and nuclear factor kappa B (NF-κB) and downregulated glutathione peroxidase 1 (GPX1), an antioxidant enzyme counteracting oxidative stress. Moreover, OVA reduced the self-renewal capacity of CSCs, reducing the expression of key stemness proteins Nanog homeobox (NANOG) and octamer-binding transcription factor 4 (OCT4). The ROS inhibitor N-acetylcysteine attenuated the anti-proliferative and anti-CSC effects of OVA. Our findings suggest that OVA acts via ROS generation, leading to oxidative stress and DNA damage, culminating in cell cycle arrest and the suppression of CSC activity in EC. Therefore, OVA is a promising therapeutic agent for EC, either as a standalone treatment or an adjunct to existing therapies.

Using AI to Differentiate Mpox From Common Skin Lesions in a Sexual Health Clinic: Algorithm Development and Validation Study.

BACKGROUND: The 2022 global outbreak of mpox has significantly impacted health facilities, and necessitated additional infection prevention and control measures and alterations to clinic processes. Early identification of suspected mpox cases will assist in mitigating these impacts. OBJECTIVE: We aimed to develop and evaluate an artificial intelligence (AI)-based tool to differentiate mpox lesion images from other skin lesions seen in a sexual health clinic. METHODS: We used a data set with 2200 images, that included mpox and non-mpox lesions images, collected from Melbourne Sexual Health Centre and web resources. We adopted deep learning approaches which involved 6 different deep learning architectures to train our AI models. We subsequently evaluated the performance of each model using a hold-out data set and an external validation data set to determine the optimal model for differentiating between mpox and non-mpox lesions. RESULTS: The DenseNet-121 model outperformed other models with an overall area under the receiver operating characteristic curve (AUC) of 0.928, an accuracy of 0.848, a precision of 0.942, a recall of 0.742, and an F1-score of 0.834. Implementation of a region of interest approach significantly improved the performance of all models, with the AUC for the DenseNet-121 model increasing to 0.982. This approach resulted in an increase in the correct classification of mpox images from 79% (55/70) to 94% (66/70). The effectiveness of this approach was further validated by a visual analysis with gradient-weighted class activation mapping, demonstrating a reduction in false detection within the background of lesion images. On the external validation data set, ResNet-18 and DenseNet-121 achieved the highest performance. ResNet-18 achieved an AUC of 0.990 and an accuracy of 0.947, and DenseNet-121 achieved an AUC of 0.982 and an accuracy of 0.926. CONCLUSIONS: Our study demonstrated it was possible to use an AI-based image recognition algorithm to accurately differentiate between mpox and common skin lesions. Our findings provide a foundation for future investigations aimed at refining the algorithm and establishing the place of such technology in a sexual health clinic.