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Alzheimer's disease (AD) has recently been associated with diverse cell states 1-11 , yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain's cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations-one drives amyloid-β proteinopathy while the other mediates the effect of amyloid-β on tau proteinopathy-as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Structure, stability, electronic structure, spectroscopy and chemical bonding properties of a fluorine atom doped gas-phase small to medium-sized magnesium clusters, FMg n (n = 2-20), systematically investigated by CALYPSO software together with density functional theory (DFT). Structural calculations showed that FMg n has a structural diversity which is rarely reported in other magnesium-based clusters before. F atoms were always located in the outer layer of the Mg n host clusters and only two or three Mg atoms surround it. FMg 18 was revealed to be supposed to have robust relative stability. Charge transfer and density of states were calculated for analyzing the electronic structure characteristics. Theoretical calculations of IR, Raman and UV-Vis spectra were computed to provide data guidelines for future experimental observations. Finally, the F-Mg and Mg-Mg chemical bonds of the FMg n clusters were analyzed, including the critical bonding points (BCPs) of Laplacian of electron density (Δρ), electron localization function (ELF) and interaction region indicator (IRI). The kind and strength of chemical bonds reveal the mechanism by which the F atom was rapidly stabilized by Mg n (n = 2-20) host clusters., (© 2024. The Author(s).)

Protein-encoding circular RNAs (circRNAs) are newly identified RNA molecules characterized by intense interaction with translating ribosome. Emerging evidence has implicated physiological and pathological significance of these non-canonical RNAs, yet a large body of them remains unidentified. Due to limited tools at hand, we developed CircProPlus, an automated computational pipeline for de novo detection of translated circRNAs. In comparison to previously established CircPro, CircProPlus adjusts the overall workflow and integrates more robust implements for achieving easier accessibility, higher flexibility and productivity. In present study, we tested the performance of CircProPlus when using different circRNA-detecting implements (i.e., CIRI2, CirComPara2) in the evaluation of coding ability of circRNAs. Results showed that CirComPara2, a state-of-the-art algorithm, consistently outperformed CIRI2 when coupled with CircProPlus in testing real data collected from different RNA libraries and species, which highlighted its potency in data mining of circRNAs with protein-coding potential., (© 2024. The Author(s).)

Smartphone distraction (SD) is closely related to depression, and the prevalence of SD among nursing students is gradually increasing. However, the potential mechanism of the effect of SD on nursing students' depression is unclear. A total of 574 nursing students were assessed using Smartphone Distraction Scale, Ruminative Response Scale, Hikikomori Questionnaire, and Patient Health Questionnaire-9. The results indicated that SD among nursing students had an impact on depression through four pathways: (1) SD was positively associated with depression (β = 0.353, P < 0.001); (2) Rumination (β = 0.199, 95% CI: 0.081 to 0.162) and social withdrawal (β = 0.061, 95% CI: 0.034 to 0.091) mediated the effects of SD on depression, respectively; and (3) Rumination and social withdrawal played a chain mediating role in the effect of SD on nursing students' depression (β = 0.027, 95% CI: 0.015 to 0.042). The negative impact of SD on nursing students' mental health should not be taken lightly. Schools and hospitals should guide nursing students to use smartphones correctly, including providing mental health education and professional psychological counselling; families could play a supervisory role and communicate regularly to understand the psychological state and learning of nursing students. These measures can help nursing students cope with stress and reduce the risk of depression., (© 2024. The Author(s).)

Branch retinal vein occlusion (BRVO) is the most prevalent retinal vascular disease that constitutes a threat to vision due to increased venous pressure caused by venous effluent in the space, leading to impaired visual function. Optical Coherence Tomography Angiography (OCTA) is an innovative non-invasive technique that offers high-resolution three-dimensional structures of retinal blood vessels. Most publicly available datasets are collected from single visits with different patients, encompassing various eye diseases for distinct tasks and areas. Moreover, due to the intricate nature of eye structure, professional labeling not only relies on the expertise of doctors but also demands considerable time and effort. Therefore, we have developed a BRVO-focused dataset named Soul (Source of ocular vascular) and propose a human machine collaborative annotation framework (HMCAF) using scrambled retinal blood vessels data. Soul is categorized into 6 subsets based on injection frequency and follow-up duration. The dataset comprises original images, corresponding blood vessel labels, and clinical text information sheets which can be effectively utilized when combined with machine learning., (© 2024. The Author(s).)

Perineural invasion (PNI) is an adverse prognostic feature of pancreatic ductal adenocarcinoma (PDAC). However, the understanding of the interactions between tumors and neural signaling within the tumor microenvironment is limited. In the present study, we found that MUC21 servers as an independent risk factor for poor prognosis in PDAC. Furthermore, we demonstrated that MUC21 promoted the metastasis and PNI of PDAC cells by activating JNK and inducing epithelial-mesenchymal transition (EMT). Mechanistically, glial cell-derived neurotrophic factor, secreted by Schwann cells, phosphorylates the intracellular domain S543 of MUC21 via CDK1 in PDAC cells, facilitating the interaction between MUC21 and RAC2. This interaction leads to membrane anchoring and activation of RAC2, which in turn activates the JNK/ZEB1/EMT axis, ultimately enhancing the metastasis and PNI of PDAC cells. Our results present a novel mechanism of PNI, suggesting that MUC21 is a potential prognostic marker and therapeutic target for PDAC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Heart failure (HF) is a significant global public health concern with a high readmission rate, posing a serious threat to the health of the elderly population. While several studies have used machine learning (ML) to develop all-cause readmission risk prediction models for elderly patients with HF, few have integrated ML-selected features with those chosen by human experts to assess HF patients readmission. A retrospective analysis of 8396 elderly HF patients hospitalized at the Affiliated Hospital of North Sichuan Medical College from January 1, 2018 to December 31, 2021 was conducted. Variables selected by XGBoost, LASSO regression, and random forest constituted the machine group, while the human expert group comprised variables chosen by two experienced cardiovascular professors. The variables selected by both groups were combined to form a human-machine collaboration group. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC). The SHapley Additive exPlanations (SHAP) method was used to elucidate the importance of each predictive feature, explain the impact of individual features on the model, and provide visual representation. A total of 73 features were included for model development. The human-machine collaboration model, utilizing CatBoost, achieved an AUC of 0.83617, an F1-score of 0.73521, and a Brier score of 0.16536 on the validation set. This model demonstrated superior predictive performance compared to those created solely by human experts or machine. The SHAP plot was then used to visually display the feature analysis of the human-machine collaboration model, revealing HGB, NT-proBNP, smoking history, NYHA classification, and LVEF as the 5 most important features. This study indicate that the human-machine collaboration model outperforms those relying solely on human expert selection or machine algorithm at predicting all-cause readmission in elderly HF patients. The application of the SHAP method enhanced the interpretability of the model outcomes, aiding clinicians in accurately pinpointing risk factors associated with HF readmission. This advancement enables the formulation of tailored treatment strategies, offering a more personalized approach to patient care., (© 2024. The Author(s).)

Background: Extremely preterm infants (EPIs) are at high-risk of white matter injury (WMI), leading to long-term neurodevelopmental impairments. We aimed to develop nomograms for WMI., Methods: The study included patients from 31 provinces, spanning ten years. 6074 patients before 2018 were randomly divided into a training and internal validation group (7:3). The external validation group comprised 1492 patients from 2019. Predictors were identified using the least absolute shrinkage and selection operator (LASSO) and multivariable logistic regression and nomograms were constructed. Models' performance was evaluated using receiver operating characteristic (ROC), decision curve analysis (DCA) and calibration curves., Results: The prenatal nomogram included multiple gestation, premature rupture of membranes (PROM), chorioamnionitis, prenatal glucocorticoids, hypertensive disorder complicating pregnancy (HDCP) and Apgar 1 min, with area under the curve (AUC) of 0.805, 0.816 and 0.799 in the training, internal validation and external validation group, respectively. Days of mechanical ventilation (MV), shock, patent ductus arteriosus (PDA) ligation, intraventricular hemorrhage (IVH) grade III-IV, septicemia, hypothermia and necrotizing enterocolitis (NEC) stage II-III were identified as postpartum predictors. The AUCs were 0.791, 0.813 and 0.823 in the three groups, respectively. DCA and calibration curves showed good clinical utility and consistency., Conclusion: The two nomograms provide clinicians with precise and efficient tools for prediction of WMI., Impact: This study is a large-sample multicenter study, spanning 10 years. The two nomograms are convenient for identifying high-risk infants early, allowing for reducing poor prognosis., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Oxyberberine (OBB) is a significant natural compound, with excellent hepatoprotective properties. However, the poor water solubility of OBB hinders its release and absorption thus resulting in low bioavailability. To overcome these drawbacks of OBB, amorphous spray-dried powders (ASDs) of OBB were formulated. The dissolution, characterizations, and pharmacokinetics of OBB-ASDs formulation were investigated, and its hepatoprotective action was disquisitive in the D-GalN/LPS-induced acute liver injury (ALI) mouse model. The characterizations of OBB-ASDs indicated that the crystalline form of OBB active pharmaceutical ingredients (API) was changed into an amorphous form in OBB-ASDs. More importantly, OBB-ASDs showed a higher bioavailability than OBB API. In addition, OBB-ASDs treatment restored abnormal histopathological changes, improved liver functions, and relieved hepatic inflammatory mediators and oxidative stress in ALI mice. The spray drying techniques produced an amorphous form of OBB, which could significantly enhance the bioavailability and exhibit excellent hepatoprotective effects, indicating that the OBB-ASDs can exhibit further potential in hepatoprotective drug delivery systems. Our results provide guidance for improving the bioavailability and pharmacological activities of other compounds, especially insoluble natural compounds. Meanwhile, the successful development of OBB-ASDs could shed new light on the research process of poorly soluble medicine., (© 2024. The Author(s).)

To elucidate the currently unknown relationship between hyperthyroidism and osteoarthritis (OA). During 2007-2012, 7,433 participants (hyperthyroidism patients = 125; OA patients = 675) were included in the National Health and Nutrition Examination Survey database. We used a weighted multivariable-adjusted logistic regression analysis to assess the association between hyperthyroidism and OA. We also assessed the causality of that relationship using publicly available genome-wide association study data and three Mendelian randomization (MR) analysis methods. The heterogeneity test, pleiotropy test, and leave-one-out tests were used for sensitivity analysis. In this cross-sectional study, after adjusting for potential confounding factors, we found that hyperthyroidism significantly (P = 0.018) increased the risk of OA (odds ratio [OR] = 2.23, 95% confidence interval [CI] = 1.2-4.17). Age-stratified analysis revealed that hyperthyroidism was associated with a greater risk of OA in the 60-80-year-old age group (OR = 2.86, 95% CI = 1.46-5.59, P = 0.002), with no significant association in the 18-59-year-old age group (all P > 0.05). The results of the inverse-variance weighting (IVW) analysis showed that hyperthyroidism increased the risk of OA (OR = 1.23, 95% CI = 1.04-1.46; P = 0.017). The weighted median estimator (WME) and MR-Egger method also confirmed this causal association (OR = 1.27 and OR = 1.32, respectively). The sensitivity analysis results confirmed the reliability of this conclusion. In addition, IVW-based reverse-MR analysis revealed that OA did not increase the risk of hyperthyroidism (OR = 1.02, 95% CI = 0.97-1.08; P = 0.449). Hyperthyroidism is associated with an increased risk of OA, but the underlying pathological mechanism still needs to be clarified in future research., (© 2024. The Author(s).)

To investigate the factors that influence readmissions in patients with acute non-ST elevation myocardial infarction (NSTEMI) after percutaneous coronary intervention (PCI) by using multiple machine learning (ML) methods to establish a predictive model. In this study, 1576 NSTEMI patients who were hospitalized at the Affiliated Hospital of North Sichuan Medical College were selected as the research subjects. They were divided into two groups: the readmitted group and the non-readmitted group. The division was based on whether the patients experienced complications or another incident of myocardial infarction within one year after undergoing PCI. Common variables selected by univariate and multivariate logistic regression, LASSO regression, and random forest were used as independent influencing factors for NSTEMI patients' readmissions after PCI. Six different ML models were constructed using these common variables. The area under the ROC curve, accuracy, sensitivity, and specificity were used to evaluate the performance of the six ML models. Finally, the optimal model was selected, and a nomogram was created to visually represent its clinical effectiveness. Three different methods were used to select seven representative common variables. These variables were then utilized to construct six different ML models, which were subsequently compared. The findings indicated that the LR model exhibited the most optimal performance in terms of AUC, accuracy, sensitivity, and specificity. The outcome, admission mode (walking and non-walking), communication ability, CRP, TC, HDL, and LDL were identified as independent predicators of readmissions in NSTEMI patients after PCI. The prediction model constructed by the LR algorithm was the best. The established column graph model established proved to be effective in identifying high-risk groups with high accuracy and differentiation. It holds a specific predictive value for the occurrence of readmissions after direct PCI in NSTEMI patients., (© 2024. The Author(s).)

The increasing demands for more efficient and brighter thin-film light-emitting diodes (LEDs) in flat-panel display and solid-state lighting applications have promoted research into three-dimensional (3D) perovskites. These materials exhibit high charge mobilities and low quantum efficiency droop 1-6 , making them promising candidates for achieving efficient LEDs with enhanced brightness. To improve the efficiency of LEDs, it is crucial to minimize nonradiative recombination while promoting radiative recombination. Various passivation strategies have been used to reduce defect densities in 3D perovskite films, approaching levels close to those of single crystals 3 . However, the slow radiative (bimolecular) recombination has limited the photoluminescence quantum efficiencies (PLQEs) of 3D perovskites to less than 80% (refs.  1,3 ), resulting in external quantum efficiencies (EQEs) of LED devices of less than 25%. Here we present a dual-additive crystallization method that enables the formation of highly efficient 3D perovskites, achieving an exceptional PLQE of 96%. This approach promotes the formation of tetragonal FAPbI 3 perovskite, known for its high exciton binding energy, which effectively accelerates the radiative recombination. As a result, we achieve perovskite LEDs with a record peak EQE of 32.0%, with the efficiency remaining greater than 30.0% even at a high current density of 100 mA cm -2 . These findings provide valuable insights for advancing the development of high-efficiency and high-brightness perovskite LEDs., (© 2024. The Author(s).)

A significant number of intensive care unit (ICU) survivors experience new-onset functional impairments that impede their activities of daily living (ADL). Currently, no effective assessment tools are available to identify these high-risk patients. This study aims to develop an interpretable machine learning (ML) model for predicting the onset of functional impairment in critically ill patients. Data for this study were sourced from a comprehensive hospital in China, focusing on adult patients admitted to the ICU from August 2022 to August 2023 without prior functional impairments. A least absolute shrinkage and selection operator (LASSO) model was utilized to select predictors for inclusion in the model. Four models, logistic regression, support vector machine (SVM), random forest (RF), and extreme gradient boosting (XGBoost), were constructed and validated. Model performance was assessed using the area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Additionally, the DALEX package was employed to enhance the interpretability of the final models. The study ultimately included 1,380 patients, with 684 (49.6%) exhibiting new-onset functional impairment on the seventh day after leaving the ICU. Among the four models evaluated, the SVM model demonstrated the best performance, with an AUC of 0.909, accuracy of 0.838, sensitivity of 0.902, specificity of 0.772, PPV of 0.802, and NPV of 0.886. ML models are reliable tools for predicting new-onset functional impairments in critically ill patients. Notably, the SVM model emerged as the most effective, enabling early identification of patients at high risk and facilitating the implementation of timely interventions to improve ADL., (© 2024. The Author(s).)

Corrosion-resistant steel plays a vital role in marine steel structures. This study developed an SS304/HRB400 stainless-steel-clad rebar for application in a cross-sea bridge in Zhejiang Province. CO 2 gas shielded welding was employed in the prefabricated steel structure, with SS304 steel as the welding wire. This study investigated the welding on the corrosion resistance of clad rebars and explored corrosion protection measures for welded joints.The results indicated that refined grains appeared in both stainless steel and carbon steel due to distinct dynamic recrystallization (DRX) during welding. The corrosion resistance, as determined by potentiodynamic polarization curve analysis of the material's interaction with the solution ranked as follows: clad rebar (polished) > clad rebar welding (CRW) > painting the clad rebar after welding (PCRW) > clad rebar (unpolished) > carbon-steel welding (CSW) > carbon-steel bar > cold spraying zinc after clad rebar welding (ZCRW). However, an accelerated corrosion test with four samples for 600 s with a corrosion current of 0.8 A revealed minimal corrosion damage on zinc-coated surfaces. Hence, welding joints for clad steel structures are considered feasible and must be subject to cold zinc spraying after polishing to enhance their corrosion resistance., (© 2024. The Author(s).)

According to the latest cancer research data, there are a significant number of new cancer cases and a substantial mortality rate each year. Although a substantial number of clinical patients are treated with existing cancer drugs each year, the efficacy is unsatisfactory. The incidence is still high and the effectiveness of most cancer drugs remains unsatisfactory. Therefore, we evaluated the human proteins for their causal relationship to for cancer risk and therefore also their potential as drug targets. We used summary tumors data from the FinnGen and cis protein quantitative trait loci (cis-pQTL) data from a genome-wide association study, and employed Mendelian randomization (MR) to explore the association between potential drug targets and nine tumors, including breast, colorectal, lung, liver, bladder, prostate, kidney, head and neck, pancreatic caners. Furthermore, we conducted MR analysis on external cohort. Moreover, Bidirectional MR, Steiger filtering, and colocalization were employed to validate the main results. The DrugBank database was used to discover potential drugs of tumors. Under the threshold of False discovery rate (FDR) < 0.05, results showed that S100A16 was protective protein and S100A14 was risk protein for human epidermal growth factor receptor 2-positive (HER-positive) breast cancer, phosphodiesterase 5A (PDE5A) was risk protein for colorectal cancer, and melanoma inhibitory activity (MIA) was protective protein for non-small cell lung carcinoma (NSCLC). And there was no reverse causal association between them. Colocalization analysis showed that S100A14 (PP.H4.abf = 0.920) and S100A16 (PP.H4.abf = 0.932) shared causal variation with HER-positive breast cancer, and PDE5A (PP.H4.abf = 0.857) shared causal variation with colorectal cancer (CRC). The MR results of all pQTL of PDE5A and MIA were consistent with main results. In addition, the MR results of MIA and external outcome cohort were consistent with main results. In this study, genetic predictions indicate that circulating S100 calcium binding protein A14 (S100A14) and S100 calcium binding protein A16 (S100A16) are associated with increase and decrease in the risk of HER-positive breast cancer, respectively. Circulating PDE5A is associated with increased risk of CRC, while circulating MIA is associated with decreased risk of NSCLC. These findings suggest that four proteins may serve as biomarkers for cancer prevention and as potential drug targets that could be expected for approval., (© 2024. The Author(s).)

Cigarette smoke (CS) exposure is known to cause injury to respiratory tract epithelial cells and is a contributing factor in the development of chronic obstructive pulmonary disease and lung cancer. Electronic cigarettes (e-cigarettes) are gaining popularity as a potential substitute for conventional cigarettes due to their potential for aiding smoking cessation. However, the safety of e-cigarettes remains uncertain, and scientific evidence on this topic is still limited. In this study, we aimed to investigate the effects of CS and e-cigarette smoke (ECS) of different flavors on human lung bronchial epithelial cells. Real-time smoke exposure was carried out using an air-liquid interface system, and cell viability was assessed. RNA-Seq transcriptome analysis was performed to compare the differences between CS and ECS. The transcriptome analysis revealed a significantly higher number of differentially expressed genes in CS than in ECS. Moreover, the impact of mint-flavored e-cigarettes on cells was found to be greater than that of tobacco-flavored e-cigarettes, as evidenced by the greater number of differentially expressed genes. These findings provide a reference for future safety research on traditional cigarettes and e-cigarettes, particularly those of different flavors. The use of omics-scale methodologies has improved our ability to understand the biological effects of CS and ECS on human respiratory tract epithelial cells, which can aid in the development of novel approaches for smoking cessation and lung disease prevention., (© 2024. The Author(s).)

Cardiac fibroblasts (CFs) are the primary cells tasked with depositing and remodeling collagen and significantly associated with heart failure (HF). TEAD1 has been shown to be essential for heart development and homeostasis. However, fibroblast endogenous TEAD1 in cardiac remodeling remains incompletely understood. Transcriptomic analyses revealed consistently upregulated cardiac TEAD1 expression in mice 4 weeks after transverse aortic constriction (TAC) and Ang-II infusion. Further investigation revealed that CFs were the primary cell type expressing elevated TEAD1 levels in response to pressure overload. Conditional TEAD1 knockout was achieved by crossing TEAD1-floxed mice with CFs- and myofibroblasts-specific Cre mice. Echocardiographic and histological analyses demonstrated that CFs- and myofibroblasts-specific TEAD1 deficiency and treatment with TEAD1 inhibitor, VT103, ameliorated TAC-induced cardiac remodeling. Mechanistically, RNA-seq and ChIP-seq analysis identified Wnt4 as a novel TEAD1 target. TEAD1 has been shown to promote the fibroblast-to-myofibroblast transition through the Wnt signalling pathway, and genetic Wnt4 knockdown inhibited the pro-transformation phenotype in CFs with TEAD1 overexpression. Furthermore, co-immunoprecipitation combined with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated interaction between TEAD1 and BET protein BRD4, leading to the binding and activation of the Wnt4 promoter. In conclusion, TEAD1 is an essential regulator of the pro-fibrotic CFs phenotype associated with pathological cardiac remodeling via the BRD4/Wnt4 signalling pathway., (© 2024. The Author(s).)

To explore the molecular network mechanism of Celastrol in the treatment of rheumatoid arthritis (RA) based on a novel strategy (integrated systems pharmacology, proteomics, transcriptomics and single-cell transcriptomics). Firstly, the potential targets of Celastrol and RA genes were predicted through the database, and the Celastrol-RA targets were obtained by taking the intersection. Then, transcriptomic data and proteomic data of Celastrol treatment of RA were collected. Subsequently, Celastrol-RA targets, differentially expressed genes, and differentially expressed proteins were imported into Metascape for enrichment analysis, and related networks were constructed. Finally, the core targets of Celastrol-RA targets, differentially expressed genes, and differentially expressed proteins were mapped to synoviocytes of RA mice to find potential cell populations for Celastrol therapy. A total of 195 Celastrol-RA targets, 2068 differential genes, 294 differential proteins were obtained. The results of enrichment analysis showed that these targets, genes and proteins were mainly related to extracellular matrix organization, TGF-β signaling pathway, etc. The results of single cell sequencing showed that the main clusters of these targets, genes, and proteins could be mapped to RA synovial cells. For example, Mmp9 was mainly distributed in Hematopoietic cells, especially in Ptprn+fibroblast. The results of molecular docking also suggested that Celastrol could stably combine with molecules predicted by network pharmacology. In conclusion, this study used systems pharmacology, transcriptomics, proteomics, single-cell transcriptomics to reveal that Celastrol may regulate the PI3K/AKT signaling pathway by regulating key targets such as TNF and IL6, and then play an immune regulatory role., (© 2024. The Author(s).)

The outlet temperature of the heat recovery reservoir is an important parameter in the design of refrigeration with heat recovery systems. In this paper the second law of thermodynamics has been applied to an irreversible Carnot refrigerator with heat recovery (CRHR) coupled to variable-temperature heat reservoirs. The refrigerating rate, input power, refrigeration coefficient, heat recovery coefficient, comprehensive coefficient of performance and exergy efficiency are chosen as the objective functions. The design rule chosen for this study is that the heat transfer area should be constrained. The mathematical expressions for assessing performance parameters with respect to area ratio, were derived for this study. These expressions are transcendental equations. The numerical solution method was employed to calculate the approximate solutions of the optimum performance parameters in a numerical example. The results indicate that the increase in the outlet temperature of heat recovery reservoir could lead to a rise in the maximum value of refrigerating rate and minimum value of input power; also it will lead to the decline in the maximum value of refrigeration coefficient, heat recovery coefficient, comprehensive coefficient and the exergy efficiency. When the ratio of heat recovery heat exchanger area to the summation of high temperature heat exchanger area and the heat recovery heat exchanger area is 1.0, the performance coefficients would attain their limit values and all of the condensing heat could be recycled. Our findings are helpful to the design and optimization to inform preparation of standard relating to the development of refrigerator with heat recovery., (© 2023. The Author(s).)

Adenotonsillectomy is the most common daytime surgery performed on children. Anesthesiologists must select the optimal combination of drugs to ensure effective anesthesia effect and prompt recovery in children. The optimal induction dose of ciprofol in children is unclear. In this study, we aim to investigate the effect of different doses of ciprofol on anesthesia induction in children undergoing daytime adenotonsillectomy and provide a reference for clinical use. 144 children aged 3-12 years, ASA I-II, undergoing daytime adenotonsillectomy, were included in this clinical trial. The children were randomly divided into three groups and given 0.4 mg/kg (C4), 0.6 mg/kg (C6), or 0.8 mg/kg (C8) of ciprofol for anesthesia induction. The primary outcome was intubation conditions. Vital signs and injection pain were also recorded. The rates of unacceptable intubation conditions were 30.6%, 8.7%, and 8.2% in the C4, C6, and C8 groups (P value < 0.0167). The overall incidence of reported injection pain was 3.5%. The heart rate and mean arterial pressure did not differ between the groups at the same time points. We found that combining 0.6 mg/kg of ciprofol with low-dose rocuronium could provide optimal intubation conditions in pediatric daytime adenotonsillectomy patients. This combination resulted in stable circulation and BIS values. This study is registered at the Chinese Clinical Trial Registry (Registration number: ChiCTR2200063144, Date of Registration: 31/08/2022)., (© 2023. The Author(s).)

Accumulated evidence showed that thyroid diseases induced cognitive decline. However, the relationship between thyroid hormones (THs) and cognition in older euthyroid people is still unclear. Our study aimed to estimate the association between THs within the euthyroid range and cognition in community-dwelling older adults in China. Data were extracted from a cohort study on the health status of rural older adults from the Guizhou province in China (HSRO). Serum thyroid-stimulating hormone (TSH), free thyroxine (FT 4 ), and free triiodothyronine (FT 3 ) were measured using the electrochemiluminescence immunoassay. Cognitive function was evaluated by the Mini-Mental State Examination (MMSE). Linear regression and a binary logistic regression model were used to explore the relationship between THs and cognition in euthyroidism (TSH level of 0.27 ~ 4.20mIU/L). A total of 957 euthyroidism individuals were included in this study, with a mean (SD) age of 71.34 (6.35) years. In individuals with euthyroidism, serum TSH and FT 3 levels were positively associated with cognition (TSH:β = 0.06, 95% CI  0.01 ~ 0.11, P = 0.03; FT 3 :β = 0.07, 95% CI  0.01 ~ 0.12, P = 0.01); and serum FT 3 and TSH levels were significantly associated with cognitive domains (P < 0.05). Further, euthyroid individuals in the lowest serum FT 3 (OR = 1.96; 95% CI 1.27 ~ 3.03) quartile had a twofold increased risk of cognitive impairment compared to those in the highest quartile after adjusting for potential confounding factors. These findings suggested that low levels of FT 3 could be an independent risk factor for cognitive impairment in older euthyroid adults. Additionally, a positive linear association exists between serum FT 3 levels and cognitive domains (such as immediate memory, language, and attention). Further studies are needed to determine the underlying mechanisms and the community significance of these findings., (© 2023. The Author(s).)

The association between the systemic immune-inflammation index (SII) and the risk of sarcopenia has not yet been revealed. The purpose of this study was to investigate the relationship between the SII and sarcopenia in individuals aged 18-59 years. All data for this study are from the National Health and Nutrition Examination Survey (NHANES) database, including 7258 participants (age range: 18-59 years). We divided SII values by quartiles (quartiles 1-4: 0.3-3.1, 3.2-4.4, 4.4-6.2, and 6.2-58.5). We constructed a multivariate logistic regression model to assess the association between the SII and the risk of sarcopenia, and an interaction test was run to test the stability of the model and identify high-risk individuals with sarcopenia. Compared to nonsarcopenia participants, sarcopenia patients had a significantly higher SII value (weighted average: 6.65 vs. 5.16) (P = 0.002). Multivariate logistic regression results showed a positive linear relationship between the SII and sarcopenia (OR [odds ratio] = 1.12, 95% CI [confidence interval] 1.03-1.21). Compared to the quartile 1 group, the quartile 4 group was associated with a higher risk of sarcopenia (OR = 3.94, 95% CI 1.42-10.94). Compared with the quartile 1 group, the OR value of the quartile 2 to quartile 4 groups showed an upwards trend (P trend  < 0.001) as the level of SII increased. Subgroup analysis also indicate that the correlation between higher SII values and the risk of sarcopenia was stable. There was a significant positive linear relationship between SII and sarcopenia, indicating that higher SII values can increase the risk of sarcopenia in individuals aged 18-59 in the United States. The findings of this study will be beneficial in promoting the use of SII alone or in combination with other tools for the risk screening of sarcopenia in communities or large populations., (© 2023. The Author(s).)

Quasi-continuous wave (QCW) laser has a very broad application in the industrial field, especially in additive manufacturing, surface treatment, laser cutting, laser cleaning, and laser drilling. Compared with the unidirectional fiber laser, the bidirectional output can be achieved two ports high power output with only one resonator, which can greatly reduce the industrial cost. However, there are few researches on QCW fiber lasers with bidirectional output. Here, we optimized and demonstrated a bidirectional output QCW laser with output power of 2 × 4.5 kW based on a double-clad ytterbium-doped fiber with a core/cladding diameter of 25/400 μm. The peak power at both ends reached 4515 W and 4694 W, respectively. The Raman suppression ratio at both ends of A and B is about 12 dB, and the beam quality factor M 2 is about 1.37 and 1.42, respectively. The corresponding optical-to-optical efficiency is 79%. To the best of our knowledge, this is the highest peak power of QCW laser with near-single-mode beam quality in a bidirectional structure laser., (© 2023. The Author(s).)

Acute appendicitis is one of the common acute abdominal diseases in pediatrics. However, the implementation of radiological examination guided endoscopic retrograde appendicitis therapy (ERAT) in adults is limited in children. Our previous research explored the non-invasive guidance of high-frequency ultrasound (HFUS) for ERAT and achieved good therapeutic effects. This study mainly focuses on exploring the application value of HFUS in the feasibility assessment of ERAT in children with appendicitis. 163 children with appendicitis received ERAT guided by HFUS were analyzed retrospectively. According to the parameters evaluated by HFUS before and during ERAT, the results indicated that the distance between the appendix orifice and the ileocecal valve significantly affected the time required for the guidewire to enter the appendix cavity (P < 0.05). The diameter and the texture of the fecalith, the thickness of the intestinal wall of the appendiceal orifice all had significant effects on the successful removal of the fecalith (P < 0.05). The success rate, treatment time and final flushing effect of the guidewire to reach the blind end of the appendix were significantly affected by the tortuosity of the appendix and whether there was adhesion with surrounding tissues (P < 0.05). HFUS can accurately assess the feasibility of ERAT in children with appendicitis., (© 2023. The Author(s).)

Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening condition in children with sepsis. We herein aimed to identify clinical and laboratory predictors of HLH in children with sepsis. We conducted a retrospective study of 568 children with sepsis admitted to Guangdong Women and Children Hospital from January 2019 to June 2022. HLH, while rare (6.34%), proved to be a highly fatal complication (37.14%) in children with sepsis. Children with HLH had higher levels of aspartate aminotransferase, lactate dehydrogenase, triglycerides, and ferritin than children without HLH; conversely, they displayed decreased levels of neutrophils, hemoglobin, platelets, fibrinogen, and albumin. Additionally, the HLH group showed higher rates of prolonged fever (> 10 days), hepatomegaly, and splenomegaly than the non-HLH group. Our retrospective analysis identified hypofibrinogenemia (OR = 0.440, P = 0.024) as an independent predictor for the development of HLH in patients with sepsis. The optimal cutoff value for fibrinogen was found to be < 2.43 g/L. The area under the curve for diagnosing HLH was 0.80 (95% confidence interval: 0.73-0.87, P < 0.0001), with a sensitivity of 72.41% and specificity of 76.27%. Thus, hypofibrinogenemia emerges as a potentially valuable predictor for HLH in children with sepsis., (© 2023. Springer Nature Limited.)

C-Myc overexpression contributes to multiple hallmarks of human cancer but directly targeting c-Myc is challenging. Identification of key factors involved in c-Myc dysregulation is of great significance to develop potential indirect targets for c-Myc. Herein, a collection of long non-coding RNAs (lncRNAs) interacted with c-Myc is detected in pancreatic ductal adenocarcinoma (PDAC) cells. Among them, lncRNA BCAN-AS1 is identified as the one with highest c-Myc binding enrichment. BCAN-AS1 was abnormally elevated in PDAC tumors and high BCAN-AS1 level was significantly associated with poor prognosis. Mechanistically, Smad nuclear-interacting protein 1 (SNIP1) was characterized as a new N 6 -methyladenosine (m 6 A) mediator binding to BCAN-AS1 via recognizing its m 6 A modification. m 6 A-modified BCAN-AS1 acts as a scaffold to facilitate the formation of a ternary complex together with c-Myc and SNIP1, thereby blocking S phase kinase-associated protein 2 (SKP2)-mediated c-Myc ubiquitination and degradation. Biologically, BCAN-AS1 promotes malignant phenotypes of PDAC in vitro and in vivo. Treatment of metastasis xenograft and patient-derived xenograft mouse models with in vivo-optimized antisense oligonucleotide of BCAN-AS1 effectively represses tumor growth and metastasis. These findings shed light on the pro-tumorigenic role of BCAN-AS1 and provide an innovant insight into c-Myc-interacted lncRNA in PDAC., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Neptune-sized planets exhibit a wide range of compositions and densities, depending on factors related to their formation and evolution history, such as the distance from their host stars and atmospheric escape processes. They can vary from relatively low-density planets with thick hydrogen-helium atmospheres 1,2 to higher-density planets with a substantial amount of water or a rocky interior with a thinner atmosphere, such as HD 95338 b (ref.  3 ), TOI-849 b (ref.  4 ) and TOI-2196 b (ref.  5 ). The discovery of exoplanets in the hot-Neptune desert 6 , a region close to the host stars with a deficit of Neptune-sized planets, provides insights into the formation and evolution of planetary systems, including the existence of this region itself. Here we show observations of the transiting planet TOI-1853 b, which has a radius of 3.46 ± 0.08 Earth radii and orbits a dwarf star every 1.24 days. This planet has a mass of 73.2 ± 2.7 Earth masses, almost twice that of any other Neptune-sized planet known so far, and a density of 9.7 ± 0.8 grams per cubic centimetre. These values place TOI-1853 b in the middle of the Neptunian desert and imply that heavy elements dominate its mass. The properties of TOI-1853 b present a puzzle for conventional theories of planetary formation and evolution, and could be the result of several proto-planet collisions or the final state of an initially high-eccentricity planet that migrated closer to its parent star., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

A drug-loaded diaphragm is an easy-to-use and effective drug delivery system that is often used to treat mouth ulcers. In this study, an ultrafine fiber film loaded with capsaicin was successfully prepared using the electrospinning technology. poly-L-lactic acid and gelatin were selected as the matrix materials to form the composite fiber, and trifluoroethanol was used as a co-solvent for poly-L-lactic acid, gelatin and capsaicin to prepare the spinning solution, which was simple to fabricate. The prepared fiber films were characterized based on their microscopic morphology and tested to derive their mechanical properties. Thereafter, the capsaicin release behavior of the film was investigated. In vitro experiments revealed certain anti-inflammatory and antibacterial abilities while animal experiments revealed that the capsaicin-loaded ultrafine fiber film could promote the healing of oral ulcers in rats. Healing of the tongue tissue in rats administered 10% capsaicin-loaded fiber film was found to be better than that in rats administered the commercial dexamethasone patch. Overall, this development strategy may prove to be promising for the development of oral ulcer patch formulations., (© 2023. Springer Nature Limited.)

Analytically solvable models are benchmarks in studies of phase transitions and pattern-forming bifurcations. Such models are known for phase transitions of the second kind in uniform media, but not for localized states (solitons), as integrable equations which produce solitons do not admit intrinsic transitions in them. We introduce a solvable model for symmetry-breaking phase transitions of both the first and second kinds (alias sub- and supercritical bifurcations) for solitons pinned to a combined linear-nonlinear double-well potential, represented by a symmetric pair of delta-functions. Both self-focusing and defocusing signs of the nonlinearity are considered. In the former case, exact solutions are produced for symmetric and asymmetric solitons. The solutions explicitly demonstrate a switch between the symmetry-breaking transitions of the first and second kinds (i.e., sub- and supercritical bifurcations, respectively). In the self-defocusing model, the solution demonstrates the transition of the second kind which breaks antisymmetry of the first excited state., (© 2023. Springer Nature Limited.)

Stroke is a major healthcare problem worldwide, particularly in the elderly population. Despite limited research on the development of prediction models for mortality in elderly individuals with ischemic stroke, our study aimed to address this knowledge gap. By leveraging data from the Medical Information Mart for Intensive Care IV database, we collected comprehensive raw data pertaining to elderly patients diagnosed with ischemic stroke. Through meticulous screening of clinical variables associated with 28-day mortality, we successfully established a robust nomogram. To assess the performance and clinical utility of our nomogram, various statistical analyses were conducted, including the concordance index, integrated discrimination improvement (IDI), net reclassification index (NRI), calibration curves and decision curve analysis (DCA). Our study comprised a total of 1259 individuals, who were further divided into training (n = 894) and validation (n = 365) cohorts. By identifying several common clinical features, we developed a nomogram that exhibited a concordance index of 0.809 in the training dataset. Notably, our findings demonstrated positive improvements in predictive performance through the IDI and NRI analyses in both cohorts. Furthermore, calibration curves indicated favorable agreement between the predicted and actual incidence of mortality (P > 0.05). DCA curves highlighted the substantial net clinical benefit of our nomogram compared to existing scoring systems used in routine clinical practice. In conclusion, our study successfully constructed and validated a prognostic nomogram, which enables accurate short-term mortality prediction in elderly individuals with ischemic stroke., (© 2023. Springer Nature Limited.)

Sepsis is the uncontrolled reaction of the body to infection-induced inflammation, which results in life-threatening multiple-organ dysfunction (MODS). Although the research on sepsis has advanced significantly in recent years, its pathophysiology remains entirely unknown. Ferroptosis is a new-fashioned type of programmed cell death that may have an impact on sepsis development. However, the precise mechanism still needs to be explored. In this paper, Four pediatric sepsis datasets [training datasets (GSE26378 and GSE26440) and validation datasets (GSE11755 and GSE11281)] were chosen through the GEO (Gene Expression Omnibus) database, and 63 differentially expressions of ferroptosis-relation-genes (DE-FRGs) were eventually discovered using bioinformatics investigation. Functional annotation was performed using GO and KEGG pathway enrichment analysis. Then, four Core-FRGs (FTH1, GPX4, ACSL1, and ACSL6) were extracted after the construction of the protein-protein interaction (PPI) network and the research of the MCODE module. Consequently, Hub-FRG (GPX4) was found using the validation datasets, and correlation exploration of immunity populations (neutrophils, r =  - 0.52; CD8 T-cells, r = 0.43) and immunity checkpoints (CD274, r =  - 0.42) was implemented. The usefulness of GPX4 as a marker in sepsis was assessed in a mouse model of sepsis. The findings demonstrate that GPX4 is a crucial biomarker and a new latent immunotherapy target for the prediction and therapy of pediatric sepsis., (© 2023. The Author(s).)

The tunable bandgaps and facile fabrication of perovskites make them attractive for multi-junction photovoltaics 1,2 . However, light-induced phase segregation limits their efficiency and stability 3-5 : this occurs in wide-bandgap (>1.65 electron volts) iodide/bromide mixed perovskite absorbers, and becomes even more acute in the top cells of triple-junction solar photovoltaics that require a fully 2.0-electron-volt bandgap absorber 2,6 . Here we report that lattice distortion in iodide/bromide mixed perovskites is correlated with the suppression of phase segregation, generating an increased ion-migration energy barrier arising from the decreased average interatomic distance between the A-site cation and iodide. Using an approximately 2.0-electron-volt rubidium/caesium mixed-cation inorganic perovskite with large lattice distortion in the top subcell, we fabricated all-perovskite triple-junction solar cells and achieved an efficiency of 24.3 per cent (23.3 per cent certified quasi-steady-state efficiency) with an open-circuit voltage of 3.21 volts. This is, to our knowledge, the first reported certified efficiency for perovskite-based triple-junction solar cells. The triple-junction devices retain 80 per cent of their initial efficiency following 420 hours of operation at the maximum power point., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Despite the advent of precision medicine and immunotherapy, mortality due to lung cancer remains high. The sonic hedgehog (SHH) cascade and its key terminal factor, glioma-associated oncogene homolog 1 (GLI1), play a pivotal role in the stemness and drug resistance of lung cancer. Here, we investigated the molecular mechanism of non-canonical aberrant GLI1 upregulation. The SHH cascade was upregulated in stem spheres and chemo-resistant lung cancer cells and was accountable for drug resistance against multiple chemotherapy regimens. GLI1 and the long non-coding RNA SOX2OT were positively regulated, and the GLI1-SOX2OT loop mediated the proliferation of parental and stem-like lung cancer cells. Further mechanistic investigation revealed that SOX2OT facilitated METTL3/14/IGF2BP2-mediated m6A modification and stabilization of the GLI1 mRNA. Additionally, SOX2OT upregulated METTL3/14/IGF2BP2 by sponging miR-186-5p. Functional analysis corroborated that GLI1 acted as a downstream target of METTL3/14/IGF2BP2, and GLI1 silencing could block the oncogenicity of lung cancer stem-like cells. Pharmacological inhibition of the loop remarkably inhibited the oncogenesis of lung cancer cells in vivo. Compared with paired adjacent normal tissues, lung cancer specimens exhibited consistently upregulated GLI1/SOX2OT/METTL3/14/IGF2BP2. The m6A-modified GLI1-SOX2OT loop may serve as a potential therapeutic target and prognostic predictor for lung cancer therapy and diagnosis in the clinic., (© 2023. The Author(s).)

In order to realize the application of the nasal spray vaccination in the prevention and protection of respiratory infectious diseases, a nasal spray vaccination device is designed in this paper. The device uses a Laval nozzle structure to generate a high-speed airflow that impinges on the vaccine reagent and forms nebulized particles. Through optimizing of the Laval nozzle structure and testing experiments on spray particle size, spray velocity, spray angle and spray rate, a set of parameters which is applicable to actual nasal spray vaccination is obtained. The experimental results show that when the air source pressure is 2 bar, the spray angle is about 15°, the diameter of the spray particles Dv50 is about 17 μm, the volume fraction of particles with diameter smaller than 10um is about 24%, the spray rate is close to 300 μl/s. The vaccine activity tests demonstrate that under these conditions, not only the biological activity of vaccines is guaranteed, but also the delivery efficiency is well assured., (© 2023. The Author(s).)

Though triazole antifungals are the first choice for preventing and treating invasive fungal infections, periostitis caused by voriconazole has been described in emerging case reports; however, no studies exist on this association in real-world clinical settings. Our study aimed to identify the association between periostitis and triazole antifungals by analyzing data from the FDA Adverse Event Reporting System (FAERS). We extracted and analyzed reports on the association between periostitis and triazole antifungals in FAERS from the first quarter of 2004 to the second quarter of 2022 using OpenVigil 2.1. Disproportionality analysis was performed to evaluate the association between periostitis and triazole antifungals, and chi-squared (χ 2 ), relative reporting ratio (RRR), reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural networks (BCPNN) of information components (IC) were reported. In total, 143 patients experienced periostitis while using voriconazole. Disproportionality analysis identified an association between periostitis and voriconazole (χ 2  = 82,689.0, RRR = 583.6, 95%CI [472.4, 721.1], PRR = 1808.9, 95%CI [1356.0, 2412.9], ROR = 1831.7, 95%CI [1371.6, 2446.3], IC = 9.2, 95%CI [8.6, 9.8]). However, no safety signals were observed between periostitis and other triazole antifungals. When stratified by sex and age, disproportionality analysis identified positive signals between periostitis and voriconazole. The possible association between periostitis and voriconazole should attract sufficient attention in clinical practice. Alternative treatment with other triazole antifungals can be considered, and causality needs to be verified in further prospective studies., (© 2023. The Author(s).)

The noise and redundant information are the main reasons for the performance bottleneck of medical image segmentation algorithms based on the deep learning. To this end, we propose a deep network embedded with rough fuzzy discretization (RFDDN) for OCT fundus image segmentation. Firstly, we establish the information decision table of OCT fundus image segmentation, and regard each category of segmentation region as a fuzzy set. Then, we use the fuzzy c-means clustering to get the membership degrees of pixels to each segmentation region. According to membership functions and the equivalence relation generated by the brightness attribute, we design the individual fitness function based on the rough fuzzy set, and use a genetic algorithm to search for the best breakpoints to discretize the features of OCT fundus images. Finally, we take the feature discretization based on the rough fuzzy set as the pre-module of the deep neural network, and introduce the deep supervised attention mechanism to obtain the important multi-scale information. We compare RFDDN with U-Net, ReLayNet, CE-Net, MultiResUNet, and ISCLNet on the two groups of 3D retinal OCT data. RFDDN is superior to the other five methods on all evaluation indicators. The results obtained by ISCLNet are the second only inferior to those obtained by RFDDN. DSC, sensitivity, and specificity of RFDDN are evenly 3.3%, 2.6%, and 7.1% higher than those of ISCLNet, respectively. HD95 and ASD of RFDDN are evenly 6.6% and 19.7% lower than those of ISCLNet, respectively. The experimental results show that our method can effectively eliminate the noise and redundant information in Oct fundus images, and greatly improve the accuracy of OCT fundus image segmentation while taking into account the interpretability and computational efficiency., (© 2023. The Author(s).)

The open-circuit voltage (V OC ) deficit in perovskite solar cells is greater in wide-bandgap (over 1.7 eV) cells than in perovskites of roughly 1.5 eV (refs.  1,2 ). Quasi-Fermi-level-splitting measurements show V OC -limiting recombination at the electron-transport-layer contact 3-5 . This, we find, stems from inhomogeneous surface potential and poor perovskite-electron transport layer energetic alignment. Common monoammonium surface treatments fail to address this; as an alternative, we introduce diammonium molecules to modify perovskite surface states and achieve a more uniform spatial distribution of surface potential. Using 1,3-propane diammonium, quasi-Fermi-level splitting increases by 90 meV, enabling 1.79 eV perovskite solar cells with a certified 1.33 V V OC and over 19% power conversion efficiency (PCE). Incorporating this layer into a monolithic all-perovskite tandem, we report a record V OC of 2.19 V (89% of the detailed balance V OC limit) and over 27% PCE (26.3% certified quasi-steady state). These tandems retained more than 86% of their initial PCE after 500 h of operation., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Cyclic dinucleotides (CDNs) are ubiquitous signalling molecules in all domains of life 1,2 . Mammalian cells produce one CDN, 2'3'-cGAMP, through cyclic GMP-AMP synthase after detecting cytosolic DNA signals 3-7 . 2'3'-cGAMP, as well as bacterial and synthetic CDN analogues, can act as second messengers to activate stimulator of interferon genes (STING) and elicit broad downstream responses 8-21 . Extracellular CDNs must traverse the cell membrane to activate STING, a process that is dependent on the solute carrier SLC19A1 22,23 . Moreover, SLC19A1 represents the major transporter for folate nutrients and antifolate therapeutics 24,25 , thereby placing SLC19A1 as a key factor in multiple physiological and pathological processes. How SLC19A1 recognizes and transports CDNs, folate and antifolate is unclear. Here we report cryo-electron microscopy structures of human SLC19A1 (hSLC19A1) in a substrate-free state and in complexes with multiple CDNs from different sources, a predominant natural folate and a new-generation antifolate drug. The structural and mutagenesis results demonstrate that hSLC19A1 uses unique yet divergent mechanisms to recognize CDN- and folate-type substrates. Two CDN molecules bind within the hSLC19A1 cavity as a compact dual-molecule unit, whereas folate and antifolate bind as a monomer and occupy a distinct pocket of the cavity. Moreover, the structures enable accurate mapping and potential mechanistic interpretation of hSLC19A1 with loss-of-activity and disease-related mutations. Our research provides a framework for understanding the mechanism of SLC19-family transporters and is a foundation for the development of potential therapeutics., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments., (© 2022. The Author(s).)

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries., (© 2022. The Author(s).)