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Abstract Receptor-interacting protein kinase 1 (RIPK1) is a therapeutic target in treating neurodegenerative diseases and cancers. RIPK1 has three distinct functional domains, with the center domain containing a receptor-interacting protein homotypic interaction motif (RHIM), which mediates amyloid formation. The functional amyloid formed by RIPK1 and/or RIPK3 is a crucial intermediate in regulating cell necroptosis. In this study, the amyloid structure of mouse RIPK1, formed by an 82-residue sequence centered at RHIM, is presented. It reveals the “N”-shaped folding of the protein subunit in the fibril with four β-strands. The folding pattern is shared by several amyloid structures formed by proteins with RHIM, with the central β-strand formed by the most conserved tetrad sequence I/VQI/VG. However, the solid-state NMR results indicate a structural difference between mouse RIPK1 and mouse RIPK3. A change in the structural rigidity is also suggested by the observation of weakened signals for mouse RIPK3 upon mixing with RIPK1 to form the RIPK1/RIPK3 complex fibrils. Our results provide vital information to understand the interactions between different proteins with RHIM, which will help us further comprehend the regulation mechanism in cell necroptosis.

Abstract Background The hyperinflammatory condition and lymphoproliferation due to Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) affect the detection of lymphomas by 18F-FDG PET/CT. We aimed to improve the diagnostic capabilities of 18F-FDG PET/CT by combining laboratory parameters. Methods This retrospective study involved 46 patients diagnosed with EBV-positive HLH, who underwent 18F-FDG PET/CT before beginning chemotherapy within a 4-year timeframe. These patients were categorized into two groups: EBV-associated HLH (EBV-HLH) (n = 31) and EBV-positive lymphoma-associated HLH (EBV + LA-HLH) (n = 15). We employed multivariable logistic regression and regression tree analysis to develop diagnostic models and assessed their efficacy in diagnosis and prognosis. Results A nomogram combining the SUVmax ratio, copies of plasma EBV-DNA, and IFN-γ reached 100% sensitivity and 81.8% specificity, with an AUC of 0.926 (95%CI, 0.779–0.988). Importantly, this nomogram also demonstrated predictive power for mortality in EBV-HLH patients, with a hazard ratio of 4.2 (95%CI, 1.1–16.5). The high-risk EBV-HLH patients identified by the nomogram had a similarly unfavorable prognosis as patients with lymphoma. Conclusions The study found that while 18F-FDG PET/CT alone has limitations in differentiating between lymphoma and EBV-HLH in patients with active EBV infection, the integration of a nomogram significantly improves the diagnostic accuracy and also exhibits a strong association with prognostic outcomes.

Water resource shortage has become an important factor limiting agricultural sustainability in China. In addition, the development and utilization of unconventional water resources are greatly important for alleviating agricultural water resource deficit. The Pakchoi was cultivated by using the surface soil (0–20 cm) from the field in this pot experiment. The experiment lasted for approximately 1 month to study microbial community structure variation under brackish water and reclaimed water irrigation. The 16S rDNA high-throughput assays revealed that soil bacteria mainly consisted of Proteobacteria and Actinobacteria at the Phylum level, along with Arenimonas and Nocardioides at the Genus level under mixed irrigation with brackish water and reclaimed water. In summary, irrigation with pure reclaimed water promoted part of microbial communities and irrigation with pure brackish water inhibited the growth and activities of certain microbial communities. We found that mixed irrigation improved the microbial community structure diversity compared with that in response to pure brackish water irrigation, while decreased the community structure diversity compared with that in response to fresh water irrigation and pure reclaimed water irrigation.

Selenium (Se) is a beneficial element for plant growth and development. In this study, three-year-old potted 'Qingcui' plums were treated with Na2SeO4 (Se6+) or selenomethionine (SeMet Se2-) to explore the effect of Se on the plant growth, fruit quality, and 5-hydroxytryptophan (5-HTP) metabolism. Flower and fruit numbers, fruit quality and yield, Se content, and 5-HTP metabolites and enzymes were detected. The results showed that the flower and fruit numbers, and yield were significantly increased by the Se application. There were no significant differences in the fruit diameters, fruit mass, edible part ratio, titratable acids, water content, and solid acid ratio among the treatments. The total soluble solids, soluble protein, and malondialdehyde contents under the Se6+ treatment showed no significant difference compared to the Se2- treatment, but they were significantly higher than these under control by 16.71%, 39.13%, and 36.27%, respectively. The Se application markedly increased plant the Se content, and Se contents in the roots and leaves, or the fruits were significantly larger by the Se6+ treatments than the Se2- treatment. The leaves' pigment contents under the Se2- treatments were significantly larger than those under the control or Se6+ treatment. Tryptophan was not significantly influenced, the 5-HTP and 5-methoxytryptophan contents were reduced in the roots, and increased in the leaves, and the serotonin content was only significantly increased in the roots by the Se treatments. The tryptophan hydroxylase and hydroxyindole-O-methyltransferase levels were slightly influenced, and the tryptophan decarboxylase level in the roots or fruits was significantly increased by the Se treatments. The Se application had beneficial effects on the plant growth, fruit quality, and Se content, especially in the Se6+ treatment, and influenced the 5-HTP metabolism.

Abstract Purpose The purpose of the study was to evaluate the expression and function of basic leucine zipper ATF-like transcription factor (BATF) in colorectal cancer (CRC), and its correlation with 2-deoxy-2[18F]fluoro-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) parameters. Methods The TIMER database, GEPIA database, TCGA, and GEO database were used to analyze the expression profile of BATF in human cancers. The reverse transcription‑quantitative PCR and western blot analyses were used to evaluate the mRNA level and protein expression in different CRC cell lines. The expression of BATF in SW620 and HCT116 cells was silenced and cell counting kit-8 assays and clonogenic assay were utilized to evaluate the role of BATF in CRC proliferation. The expression of tumor BATF and glucose transporter 1 (GLUT-1) were examined using immunohistochemical tools in 37 CRC patients undergoing preoperative 18F-FDG PET/CT imaging. The correlation between the PET/CT parameters and immunohistochemical result was evaluated. Results In database, BATF was highly expressed in pan-cancer analyses, including CRC, and was associated with poor prognosis in CRC. In vitro, the results showed that knocking down of BATF expression could inhibit the proliferation of SW620 and HCT116 cells. In CRC patients, BATF expression was upregulated in tumor tissues compared with matched para-tumoral tissues, and was related with gender and Ki-67 levels. BATF expression was positively related to GLUT-1 expression and PET/CT parameters, including tumor size, maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis. The multiple logistic analyses showed that SUVmax was an independent predictor of BATF expression. With 15.96 g/cm3 as the cutoff, sensitivity was 85.71%, specificity 82.61%, and area-under-the-curve 0.854. Conclusion BATF may be an oncogene associated with 18F-FDG PET/CT parameters in CRC. SUVmax may be an independent predictor of BATF expression.

For statistical inference on regression models with a diverging number of covariates, the existing literature typically makes sparsity assumptions on the inverse of the Fisher information matrix. Such assumptions, however, are often violated under Cox proportion hazards models, leading to biased estimates with under-coverage confidence intervals. We propose a modified debiased lasso method, which solves a series of quadratic programming problems to approximate the inverse information matrix without posing sparse matrix assumptions. We establish asymptotic results for the estimated regression coefficients when the dimension of covariates diverges with the sample size. As demonstrated by extensive simulations, our proposed method provides consistent estimates and confidence intervals with nominal coverage probabilities. The utility of the method is further demonstrated by assessing the effects of genetic markers on patients' overall survival with the Boston Lung Cancer Survival Cohort, a large-scale epidemiology study investigating mechanisms underlying the lung cancer.

We report a case of endovascular treatment of bone cement embolism after percutaneous vertebroplasty. The patient underwent percutaneous vertebroplasty for acute L1 compression fracture. Two weeks later, the patient developed symptoms of pulmonary embolism. Computed tomography pulmonary angiogram confirmed the presence of a bone cement foreign body in the pulmonary artery. Endovascular treatment was performed, and the cement embolism was caught, pulled to the level of the iliac vein, and fixed with stents. At the 1-year follow-up, the patient did not have any complaints, postoperative computed tomography pulmonary angiogram showed no obvious manifestations of pulmonary embolism, and angiography showed that the bone cement was fixed in place and that the iliac veins were normal.

Modeling and drawing inference on the joint associations between single-nucleotide polymorphisms and a disease has sparked interest in genome-wide associations studies. In the motivating Boston Lung Cancer Survival Cohort (BLCSC) data, the presence of a large number of single nucleotide polymorphisms of interest, though smaller than the sample size, challenges inference on their joint associations with the disease outcome. In similar settings, we find that neither the debiased lasso approach (van de Geer et al., 2014), which assumes sparsity on the inverse information matrix, nor the standard maximum likelihood method can yield confidence intervals with satisfactory coverage probabilities for generalized linear models. Under this large n, diverging p scenario, we propose an alternative debiased lasso approach by directly inverting the Hessian matrix without imposing the matrix sparsity assumption, which further reduces bias compared to the original debiased lasso and ensures valid confidence intervals with nominal coverage probabilities. We establish the asymptotic distributions of any linear combinations of the parameter estimates, which lays the theoretical ground for drawing inference. Simulations show that the proposed refined debiased estimating method performs well in removing bias and yields honest confidence interval coverage. We use the proposed method to analyze the aforementioned BLCSC data, a large-scale hospital-based epidemiology cohort study investigating the joint effects of genetic variants on lung cancer risks.

Food protein is one of the most important nutrients for human beings. The existing ways of obtaining protein are difficult to satisfy the huge demand for protein supply owing to the continuous growth of population and the continuous improvement in living standards. Microbial protein manufacturing is the efficient production of protein raw materials by using cheap biomass raw materials in the way of workshop production, which is expected to become one of the most effective and feasible alternative protein sources in the future. This research introduces industrial application status of several microprotein such as yeast protein, microalgae protein, and filamentous fungi protein, and functional proteins such as lactoprotein, ovalbumin, and hemoglobin. The research also sorts out key manufacturing technical systems involved in substrate selection and utilization, strain breeding, fermentation process control, and protein extraction. It is concluded that in the context that microbial protein has multiple production advantages and few application cases in the food industry, to promote food application and industrialization of microbial protein, it is urgent to solve two problems: food processing as well as evaluation of nutrition and safety. The research can provide a basic reference for national alternative protein strategies and the development layout of the microprotein industry.

Abstract Diquat (DQ) is among the most widely used herbicides, and its intake can cause severe systemic toxicity that manifests rapidly. The resultant symptoms can cause the dysfunction of a range of tissues and organs,. As there is no specific antidote for diquat poisoning and the efficacy of extant treatments is suboptimal, physicians must acquire a more comprehensive understanding of the most effective approaches to managing affected patients. Relative few studies have been published to date focused on diquat poisoning in pediatric patients. In this report, we compare two similar cases of juvenile diquat poisoning with dynamic changes in clinical manifestations, laboratory values, and imaging results. For the first time, the difference in whether to perform blood flow perfusion and the time difference of initiation of hemoperfusion had a clear clinical difference in the subsequent effects of diquat poisoning in children with diquat poisoning. Limited evidence is available regarding the efficacy of early hemoperfusion for diquat poisoning; however, the differences in clinical outcomes articulated here highlight the benefits of early and timely hemoperfusion therapy in the treatment of DQ toxicity in children, in conjunction with primary supportive care in the management of DQ poisoning in children.

Abstract The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor progression. However, the precise molecular mechanisms governing the nuclear import of YAP are not fully understood. In this study, we have uncovered a crucial role of SOX9 in the activation of YAP. SOX9 promotes the nuclear translocation of YAP by direct interaction. Importantly, we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of YAP. Additionally, we have discovered a novel asymmetrical dimethylation of YAP at Arg-124 (YAP-R124me2a) catalyzed by PRMT1. YAP-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple cancers. Furthermore, we disrupted the interaction between SOX9 and YAP using a competitive peptide, S-A1, which mimics an α-helix of SOX9 containing Asp-125. S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor growth. This study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.

Abstract Background Root caries are prevalent issues that affect dental health, particularly among elderly individuals with exposed root surfaces. Fluoride therapy has shown effectiveness in preventing root caries, but limited studies have addressed its cost-effectiveness in elderly persons population. This study aimed to evaluate the cost-effectiveness of a fluoride treatment program for preventing root caries in elderly persons within the context of Chinese public healthcare. Methods A Markov simulation model was adopted for the cost-effectiveness analysis in a hypothetical scenario from a healthcare system perspective. A 60-year-old subject with 23 teeth was simulated for 20 years. A 5% sodium fluoride varnish treatment was compared with no preventive intervention in terms of effectiveness and cost. Tooth years free of root caries were set as the effect. Transition probabilities were estimated from the data of a community-based cohort and published studies, and costs were based on documents published by the government. The incremental cost-effectiveness ratio (ICER) was calculated to evaluate cost-effectiveness. Univariate and probabilistic sensitivity analyses were performed to evaluate the influence of data uncertainty. Results Fluoride treatment was more effective (with a difference of 10.20 root caries-free tooth years) but also more costly (with a difference of ¥1636.22). The ICER was ¥160.35 per root caries-free tooth year gained. One-way sensitivity analysis showed that the risk ratio of root caries in the fluoride treatment group influenced the result most. In the probabilistic sensitivity analysis, fluoride treatment was cost-effective in 70.5% of the simulated cases. Conclusions Regular 5% sodium fluoride varnish application was cost-effective for preventing root caries in the elderly persons in most scenarios with the consideration of data uncertainty, but to a limited extent. Improved public dental health awareness may reduce the incremental cost and make the intervention more cost-effective. Overall, the study shed light on the economic viability and impact of such preventive interventions, providing a scientific basis for dental care policies and healthcare resource allocation.

Abstract Background Long-distance transportation, a frequent practice in the cattle industry, stresses calves and results in morbidity, mortality, and growth suppression, leading to welfare concerns and economic losses. Alkaline mineral water (AMW) is an electrolyte additive containing multiple mineral elements and shows stress-mitigating effects on humans and bovines. Results Here, we monitored the respiratory health status and growth performance of 60 Simmental calves subjected to 30 hours of road transportation using a clinical scoring system. Within the three days of commingling before the transportation and 30 days after the transportation, calves in the AMW group (n = 30) were supplied with AMW, while calves in the Control group (n = 29) were not. On three specific days, namely the day before transportation (day -3), the 30th day (day 30), and the 60th day (day 60) after transportation, sets of venous blood, serum, and nasopharyngeal swab samples were collected from 20 calves (10 from each group) for routine blood testing, whole blood transcriptomic sequencing, serology detection, serum untargeted metabolic sequencing, and 16S rRNA gene sequencing. The field data showed that calves in the AMW group displayed lower rectal temperatures (38.967 ℃ vs. 39.022 ℃; p = 0.004), respiratory scores (0.079 vs. 0.144; p < 0.001), appetite scores (0.024 vs. 0.055; p < 0.001), ocular and ear scores (0.185 vs. 0.338; p < 0.001), nasal discharge scores (0.143 vs. 0.241; p < 0.001), and higher body weight gains (30.870 kg vs. 7.552 kg; p < 0.001). The outcomes of laboratory and high throughput sequencing data revealed that the calves in the AMW group demonstrated higher cellular and humoral immunities, antioxidant capacities, lower inflammatory levels, and intestinal absorption and lipogenesis on days -3 and 60. The nasopharynx 16S rRNA gene microbiome analysis revealed the different composition and structure of the nasopharyngeal microflora in the two groups of calves on day 30. Joint analysis of multi-omics revealed that on days -3 and 30, bile secretion was a shared pathway enriched by differentially expressed genes and metabolites, and there were strong correlations between the differentially expressed metabolites and the main genera in the nasopharynx. Conclusions These results suggest that AMW supplementation enhances peripheral immunity, nutrition absorption, and metabolic processes, subsequently affecting the nasopharyngeal microbiota and improving the respiratory health and growth performance of transported calves. This investigation provided a practical approach to mitigate transportation stress and explored its underlying mechanisms, which are beneficial for the development of the livestock industry. Video Abstract

Abstract Exploiting thin Li metal anode is essential for high-energy-density battery, but is severely plagued by the poor processability of Li, as well as the uncontrollable Li plating/stripping behaviors and Li/electrolyte interface. Herein, a thickness/capacity-adjustable thin alloy-type Li/LiZn@Cu anode is fabricated for high-energy-density Li metal batteries. The as-formed lithophilic LiZn alloy in Li/LiZn@Cu anode can effectively regulate Li plating/stripping and stabilize the Li/electrolyte interface to deliver the hierarchical Li electrochemistry. Upon charging, the Li/LiZn@Cu anode firstly acts as Li source for homogeneous Li extraction. At the end of charging, the de-alloy of LiZn nanostructures further supplements the Li extraction, actually playing the Li compensation role in battery cycling. While upon discharging, the LiZn alloy forms just at the beginning, thereby regulating the following Li homogeneous deposition. The reversibility of such an interesting process is undoubtedly verified from the electrochemistry and in-situ XRD characterization. This work sheds light on the facile fabrication of practical Li metal anodes and useful Li compensation materials for high-energy-density Li metal batteries.

ABSTRACTThe China-Pakistan Transportation Corridor (CPTC) has long faced great challenges in natural disasters and sustainable development. This study develops a localised indicator evaluation system for the CPTC sustainable development. It contains 27 Tier I and 8 Tier II indicators, covering 11 sustainable development goals. Based on this evaluation system, a single-goal, multidimensional, and comprehensive evaluation of the CPTC sustainable development level is conducted for 2015, 2017 and 2020. The results show that, in terms of single goals, Xinjiang has the highest sustainable development level. Khyber Pakhtunkhwa has the poorest level of sustainable development. The Islamabad Capital Territory is better developed for all goals, especially in SDG5, SDG8 and SDG9. Besides these three goals, SDG6, and SDG11 are more prominent in Punjab, whereas SDG2 and SDG3 performed worst. From a multidimensional evaluation, the CPTC sustainable development level has been steadily increasing. However, the social and environmental dimensions of Khyber Pakhtunkhwa have experienced a ‘regression’. The comprehensive evaluation results show that the level of sustainable development in all provinces of the CPTC increase, except for Khyber Pakhtunkhwa. This study identifies CPTC sustainability issues and proposes targeted recommendations for sustainable development.

ObjectivePneumonia is a common and serious infectious disease that affects the older adult population. Severe pneumonia can lead to high mortality and morbidity in this group. Therefore, it is important to identify the risk factors and develop a prediction model for severe pneumonia in older adult patients.MethodIn this study, we collected data from 1,000 older adult patients who were diagnosed with pneumonia and admitted to the intensive care unit (ICU) in a tertiary hospital. We used logistic regression and machine learning methods to analyze the risk factors and construct a prediction model for severe pneumonia in older adult patients. We evaluated the performance of the model using accuracy, sensitivity, specificity, area under the receiver operating characteristic curve (AUC), and calibration plot.ResultWe found that age, comorbidities, vital signs, laboratory tests, and radiological findings were associated with severe pneumonia in older adult patients. The prediction model had an accuracy of 0.85, a sensitivity of 0.80, a specificity of 0.88, and an AUC of 0.90. The calibration plot showed good agreement between the predicted and observed probabilities of severe pneumonia.ConclusionThe prediction model can help clinicians to stratify the risk of severe pneumonia in older adult patients and provide timely and appropriate interventions.

Abstract The percent global glomerulosclerosis is a key factor in determining the outcome of renal transfer surgery. At present, the rate is typically computed by pathologists, which is labour intensive and nonstandardized. With the development of Deep Learning (DL), DL-based segmentation models can be used to better identify and segment normal and sclerosed glomeruli. Based on this, we can better quantify percent global glomerulosclerosis to reduce the discard rate of donor kidneys. We used 51 whole slide images (WSIs) from different institutions that are publicly available on the internet. However, the number of sclerosed glomeruli is much smaller than that of normal glomeruli in different WSIs, which can reduce the effectiveness of Deep Learning. For better sclerosed glomerular identification and segmentation performance, we modified and trained a GAN (generative adversarial network)-based image inpainting model to obtain more synthetic sclerosed glomeruli. Our proposed inpainting method achieved an average SSIM (Structural Similarity) of 0.8086 and an average PSNR (Peak Signal-to-Noise Ratio) of 22.8943 dB in the area of generated sclerosed glomeruli. We obtained sclerosed glomerular segmentation performance improvement by adding synthetic sclerosed glomerular images and achieved the best Dice of glomerular segmentation in different test sets based on the modified Unet model.

Abstract Background Declined skeletal muscle mass and function are inevitable consequences of long‐term diabetes and bring about many adverse events. Muscle fibre atrophy and interstitial fibrosis are major pathological manifestations of diabetic sarcopenia. Stimulator of interferon genes (STING) participates in various metabolic diseases. We aimed to explore whether and how STING regulates the above pathological manifestations of diabetic sarcopenia. Methods Wild‐type and STINGgt/gt C57BL/6J mice and C2C12 myotubes were used to study the role of STING in the regulation of diabetic sarcopenia and the underlying mechanisms. Results STING was abnormally activated in diabetic muscles and in PA‐treated myotubes (P

Powdery mildew (PM) is a fungus that causes disease in both the field and the greenhouse. Utilizing resistant cultivars is the most effective approach of disease management. To develop insertion-deletion (InDel) markers associated to this trait, the whole genomes of the PM resistant line M17050 (P1) and the PM-susceptible line 28-1-1 (P2) were sequenced. A total of 1 200 InDels, with an average of 100 markers per chromosome, were arbitrarily chosen from the sequencing data for experimental validation. One hundred InDel markers were ultimately selected due to their informative genetic bands. Further, an F2 segregating population of melons generated from these two parents was inoculated by the PM pathogen. Based on bulk segregant analysis (BSA) using these 100 InDel markers, the powdery mildew resistance was associated with the genomic region LVpm12.1 on the melon chromosome 12. This region overlapped the previously described quantitative trait locus (QTL)-hotspot area carrying multiple PM-resistance QTLs. Moreover, conventional QTL mapping analysis was done, which located LVpm12.1 in the region between 22.72 and 23.34 Mb, where three highly polymorphic InDel markers MInDel89, MInDel92, and MInDel93 were detected. Therefore, these markers could be used to track this resistance locus in melon while the lines carrying this locus could be employed in PM melon resistance breeding programs after validation tests.