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Cancer early detection and treatment response prediction continue to pose significant challenges. Cancer liquid biopsies focusing on detecting circulating tumor cells (CTCs) and DNA (ctDNA) have shown enormous potential due to their non-invasive nature and the implications in precision cancer management. Recently, liquid biopsy has been further expanded to profile glycoproteins, which are the products of post-translational modifications of proteins and play key roles in both normal and pathological processes, including cancers. The advancements in chemical and mass spectrometry-based technologies and artificial intelligence-based platforms have enabled extensive studies of cancer and organ-specific changes in glycans and glycoproteins through glycomics and glycoproteomics. Glycoproteomic analysis has emerged as a promising tool for biomarker discovery and development in early detection of cancers and prediction of treatment efficacy including response to immunotherapies. These biomarkers could play a crucial role in aiding in early intervention and personalized therapy decisions. In this review, we summarize the significant advance in cancer glycoproteomic biomarker studies and the promise and challenges in integration into clinical practice to improve cancer patient care.

UNLABELLED: PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.

ABSTRACT Aims Diabetes mellitus (DM) is closely associated with Alzheimer's disease (AD), and is considered an accelerator of AD. Our previous study has confirmed that the Calpain inhibitor Calpeptin may alleviate AD‐like complications of diabetes mellitus. This work further investigated its underlying mechanism. Materials and Methods Diabetes mellitus rat model was constructed by a high‐fat and high‐sugar diet combined with streptozotocin, followed by the administration of Calpeptin. Moreover, rats were micro‐injected with LV‐TXNIP‐OE/vector into the CA1 region of the hippocampus one day before streptozotocin injection. The Morris water maze test assessed the spatial learning and memory ability of rats. Immunohistochemistry and western blotting detected the expression of the pericyte marker PDGFRβ, tight junction proteins occludin and ZO‐1, calpain‐1, calpain‐2, APP, Aβ, Aβ‐related, and TXNIP/NLRP3 inflammasome‐related proteins. Immunofluorescence staining examined the blood vessel density and neurons in the hippocampus. Evans blue extravasation and fluorescence detected the permeability of the blood–brain barrier (BBB) in rats. Additionally, the oxidative stress markers and inflammatory‐related factors were assessed by enzyme‐linked immunosorbent assay. Results Calpeptin effectively reduced the expression of Calpain‐2 and TXNIP/NLRP3 inflammasome‐related proteins, improved the decreased pericyte marker (PDGFR‐β) and cognitive impairment in hippocampus of DM rats. The neuronal loss, microvessel density, permeability of BBB, Aβ accumulation, inflammation, and oxidative stress injury in the hippocampus of DM rats were also partly rescued by calpeptin treatment. The influence conferred by calpeptin treatment was reversed by TXNIP overexpression. Conclusions These data demonstrated that calpeptin treatment alleviated AD‐like symptoms in DM rats through regulating TXNIP/NLRP3 inflammasome. Thus, calpeptin may be a potential drug to treat AD‐like complications of diabetes mellitus.

Abstract Aim We aimed to examine the relationships among nurses’ career compromise, job satisfaction, and turnover intention and the mediating role of job satisfaction in the relationship between career compromise and turnover intention. Background Nurses are prone to career compromise when there is a discrepancy between the reality of their job and their personal career expectations due to personal or family factors. High levels of career compromise may have a significant impact on turnover intentions through low job satisfaction, thereby affecting the stability of the nursing workforce. There is a paucity of research on the impact of nurses’ career compromise on turnover intentions. Method This was a cross-sectional research design of nurses in hospitals in Guangdong Province using a convenience sampling method. The Career Compromise Scale (CCS), Job Satisfaction Scale (JSS), and Turnover Intention Scale (TIS) were used. The obtained data were analyzed through descriptive statistics, Spearman’s correlation coefficient, and the mediating effect of perceived organizational support was tested through the PROCESS macro mediation model in SPSS. Results Data from 821 nurses who met the inclusion criteria were analyzed. The total score of nurses’ turnover intention was 14.68 ± 4.32. Spearman’s correlation analysis showed that career compromise was negatively correlated with job satisfaction (r = -0.594, p

Abstract Background The increasing incidence of diabetes mellitus has established diabetic cataracts (DC) as a significant worldwide public health issue. The mechanisms underlying DC remain unknown, and effective prevention and treatment strategies are lacking. Accordingly, we aimed to explore the role and mechanism behind N6-methyladenosine (m6A) in DC progression. Methods Methyltransferase-like 3 (METTL3), p21, Beclin1, LC3, and p62 expression levels were measured in human tissues. This study assessed total m6A levels and common m6A-regulated biomarkers in both in vitro and in vivo DC models. Autophagy flux was detected in vitro through Ad-mCherry-GFP-LC3B and Monodansylcadaverine (MDC) staining. Cellular senescence was assessed utilizing the senescence-associated β-galactosidase (SA-β-Gal) assay. Furthermore, the effect of METTL3 on SIRT1 mRNA modification was demonstrated, and its mechanism was elucidated using RT-qPCR, western blot, RNA stability assays, and RIP analysis. Results METTL3, p21, and p62 expression levels were elevated in lens epithelial cells (LECs) from DC patients, while Beclin1 and LC3 levels were reduced. Silencing METTL3-mediated m6A modifications restored high-glucose-induced autophagy inhibition and prevented premature senescence in LECs. Notably, SIRT1720 and Metformin significantly enhanced autophagosome generation and delayed cellular senescence. The m6A-reading protein YTHDF2 bound to m6A modifications, and YTHDF2 silencing significantly reduced METTL3-mediated SIRT1 inactivation. Conclusions METTL3 induces senescence in DC by destabilizing SIRT1 mRNA in an m6A-YTHDF2-dependent manner. The METTL3-YTHDF2-SIRT1 axis is a key target and potential pathogenic mechanism in DC.

Abstract Selenium, a crucial antioxidant in the body, has been linked to all-cause and cause-specific mortality. However, the relationship between selenium and mortality in the general population remains unclear. A total of 5449 participants in the National Health and Nutrition Examination Survey (NHANES) (2003–2004, 2011–2016) were analyzed to track participant mortality until December 31, 2019. The COX proportional hazard model, Kaplan‒Meier survival analysis and restricted cubic spline regression analysis were used to investigate the associations. Subgroup analysis was conducted on the basis of age (≤ 60, > 60), sex (male, female), and smoking status (nonsmoker, former smoker, and current smoker). The second quartile was associated with lower all-cause mortality and noncardiovascular mortality (HR and 95% CI 0.61,0.45–0.83;0.59,0.42–0.83, respectively). The third quartile was associated with lower cardiovascular-related mortality (HR and 95% CI 0.49, 0.32–0.76). Elevated serum selenium concentrations were associated with lower all-cause mortality, noncardiovascular mortality (range ≤ 129.82 μg/L), and cardiovascular mortality (range ≤ 129.08 μg/L). Subgroup analysis revealed a positive correlation between the serum selenium concentration (range ≥ 129.82 μg/L) and all-cause mortality among the subgroup of current smokers (p

Abstract Single-cell transcriptomics has emerged as a powerful tool for understanding how different cells contribute to disease progression by identifying cell types that change across diseases or conditions. However, detecting changing cell types is challenging due to individual-to-individual and cohort-to-cohort variability and naive approaches based on current computational tools lead to false positive findings. To address this, we propose a computational tool, scDist, based on a mixed-effects model that provides a statistically rigorous and computationally efficient approach for detecting transcriptomic differences. By accurately recapitulating known immune cell relationships and mitigating false positives induced by individual and cohort variation, we demonstrate that scDist outperforms current methods in both simulated and real datasets, even with limited sample sizes. Through the analysis of COVID-19 and immunotherapy datasets, scDist uncovers transcriptomic perturbations in dendritic cells, plasmacytoid dendritic cells, and FCER1G+NK cells, that provide new insights into disease mechanisms and treatment responses. As single-cell datasets continue to expand, our faster and statistically rigorous method offers a robust and versatile tool for a wide range of research and clinical applications, enabling the investigation of cellular perturbations with implications for human health and disease.

Energy decarbonization is essential for achieving carbon neutrality. To facilitate the low-carbon transition of the energy system, extensive utilization of low-carbon energy technologies is crucial across various sectors, including primary energy supply, energy processing and conversion, and end-use consumption. This study provides a comprehensive overview of the current status and future trends of key energy utilization technologies from the perspective of low-carbon energy system analysis and optimization. We analyze the application prospects and layout challenges of energy utilization technologies in China’s path toward carbon neutrality from multiple dimensions. Our study highlights the following points: Wind and solar energy, as the fastest-growing renewable energy sources, will continue to play a crucial role in energy supply. The utilization of biomass resources requires systematic evaluation of different conversion technologies, optimizing the allocation of biomass resources across industries. Utilization technologies of secondary energies such as hydrogen and energy storage face challenges related to materials, performance, and lifespan. Overcoming these technical bottlenecks is necessary to achieve low-cost and scalable system applications. Future end-use energy utilization technologies will focus on electrification, which depends on the secure and stable transformation and expansion of electricity distribution systems. Achieving low-carbon transformation in the energy system requires balancing the coordinated development of different energy technologies while addressing non-technical factors such as market dynamics, institutional frameworks, and societal acceptance, ultimately accelerating the decarbonization process.

Abstract Global warming has led to the enhancement of diurnal (daytime-nighttime) compound heat waves, which can severely affect the population’s physical health and productive life; this is particularly the case for vulnerable populations that are more susceptible to psychological and physiological harm with the future normalization of heatwave scenarios. In this study, we attributed the changes in population exposure under diurnal compound high temperatures (HTs) and extremely high temperatures (EHTs) to the influence of climatic (exposure duration) and population factors and their combined influence to determine the relationship between exposure duration and the changes in exposure of vulnerable populations. Diurnal compound HT and EHT covered a land area of 4,016,800 and 1,984,200 km2, respectively. The heat-exposed area spread step-like in all directions, centering on the 24-h high-exposure area with a strong gradient effect. The area of prolonged exposure shifted from the Yellow-Huai-Huai Plain across the geographical boundary between the south and the north to the middle and lower reaches of the Yangtze River Plain. Meanwhile, the average maximum value of vulnerable population exposure reached 186,800 and 93,100 person-h, with high values in Zhengzhou, Chongqing, Wuhan, Chengdu, Beijing, and other cities. Changes in vulnerable population exposure were dominated first by demographic factors and then by climatic factors, with the dominance of climatic factors evident in areas of prolonged exposure. Under prolonged exposure to daytime-nighttime compound EHT, changes in the exposure of child and older populations were dominated by climatic factors with a contribution rate of 87.16% and 87.43%, respectively. Therefore, suitable cooling measures should be proposed for vulnerable populations under prolonged exposure, focusing more on the physical and mental health of children and older adults exposed to compound EHT.

Abstract Introduction The aim of this work was to compare the prognosis and characteristics of patients with Cytomegalovirus (CMV) infection (CMV+) with those of patients without virus infection (Virus–) undergoing repeat keratoplasty. Methods This prospective propensity score-matched cohort study enrolled patients who underwent repeat keratoplasty for graft failure at the Peking University Third Hospital between January 2016 and May 2022. Patients with prior viral keratitis before the first keratoplasty were excluded. The primary outcome measure was the graft failure rate. The secondary outcome measures included the anterior segment characteristics, intraocular pressure (IOP), and endothelial cell density. Results Ninety-four matched patient pairs were included. The graft failure rate in the CMV+ group (71%) was higher than that in the Virus– group (29%) (P

Abstract Introduction Lung cancer (LC) is the most common solid tumor and is currently considered the primary cause of cancer-related deaths worldwide. In clinical efficacy studies, it was not difficult to find that the combination of SFI and chemotherapy could improve the general condition of patients, reduce the side effects of chemotherapy drugs, and have a cooperative antitumor effect in NSCLC patients. However, whether SFI can be used as a novel antitumor drug is still unknown. Methods First, meta-analysis aimed to explore the efficacy of SFI in NSCLC patients, and SFI was identified by ultra-performance liquid chromatography‒mass spectrometry (UPLC‒MS). Cell proliferation, migration, and invasion were explored by Cell Counting Kit-8 (CCK-8), scratch healing, and Transwell assays, respectively. Cell cycle and apoptosis assays were performed by flow cytometry. Transcriptome sequencing analysis was performed in four NSCLC cell lines. Differential expression analysis was used to identify potential targets. Apoptosis-related protein levels were detected by Western blotting assays. The effects of SFI in NSCLC were further investigated by mouse xenografts. Results SFI could markedly improve the chemotherapy efficacy of NSCLC patients. The main active ingredients include flavonoids and terpenoids, which can effectively exert antitumor effects. SFI could not only inhibit tumor cell proliferation and cell migration/invasion but also regulate the cell cycle and promote tumor cell apoptosis. In NSCLC, SFI could enhance the transcription level of the CHOP gene, thereby upregulating the expression of the proapoptotic proteins Bax and caspase 3, and inhibiting the expression of the antiapoptotic protein Bcl-2. SFI hindered the growth of mouse NSCLC xenografts in vivo. Conclusions SFI hindered tumor progression and might promote apoptosis by increasing the expression of Bax, caspase 3 and decreasing the level of Bcl-2 in NSCLC.

Abstract Objectives Motoric cognitive risk syndrome (MCR) is a pre-dementia condition characterized by subjective complaints in cognition and slow gait. Pain interference has previously been linked with cognitive deterioration; however, its specific relationship with MCR remains unclear. We aimed to examine how pain interference is associated with concurrent and incident MCR. Methods This study included older adults aged ≥ 65 years without dementia from the Health and Retirement Study. We combined participants with MCR information in 2006 and 2008 as baseline, and the participants were followed up 4 and 8 years later. The states of pain interference were divided into 3 categories: interfering pain, non-interfering pain, and no pain. Logistic regression analysis was done at baseline to examine the associations between pain interference and concurrent MCR. During the 8-year follow-up, Cox regression analysis was done to investigate the associations between pain interference and incident MCR. Results The study included 7120 older adults (74.6 ± 6.7 years; 56.8% females) at baseline. The baseline prevalence of MCR was 5.7%. Individuals with interfering pain had a significantly increased risk of MCR (OR = 1.51, 95% CI = 1.17–1.95; p = 0.001). The longitudinal analysis included 4605 participants, and there were 284 (6.2%) MCR cases on follow-up. Participants with interfering pain at baseline had a higher risk for MCR at 8 years of follow-up (HR = 2.02, 95% CI = 1.52–2.69; p

Abstract Purpose To summarize the outcomes of corneal sight rehabilitating surgery in Stevens-Johnson syndrome (SJS). Methods This is a retrospective analysis of a consecutive case series. Twenty-four eyes of 18 SJS patients were included in this study. The ocular parameters, surgical procedures, postoperative complications, and additional treatments of the cases were reviewed. Results A total of 29 corneal sight rehabilitating surgeries, which consists of 9 keratoplasties, 8 Keratolimbal allograft (KLAL) and 12 combined surgeries (keratoplasty and KLAL simultaneously) were performed on the 24 eyes. All patients were treated with glucocorticoid eyedrops and tacrolimus eyedrops for anti-rejection treatment without combining systemic immunosuppression, except two patients who were prescribed prednisone tablets for the management of systemic conditions. The mean follow-up period was 50.6 ± 28.1 months. The optimal visual acuity (VA) (0.74 ± 0.60 logarithm of the minimum angle of resolution [logMAR]) and endpoint VA (1.06 ± 0.82 logMAR) were both significantly better than the preoperative VA (1.96 ± 0.43 logMAR) (95% CI, p = 0.000). 57.1% patients (8/14) were no longer in the low vision spectrum, and 88.9% patients (8/9) were no longer blind. The mean epithelialization time was 7.1 ± 7.6 weeks. The success rate was 86.7%. Additional treatments for improving epithelialization included administration of serum eyedrops (n = 10), contact lens (n = 15), amniotic membrane transplantation (n = 6), and tarsorrhaphy (n = 8). Complications included delayed epithelialization (n = 4, over 12 weeks), glaucoma (n = 11), and severe allograft opacity (n = 4). Only one graft rejection was observed. Conclusions Keratoplasty and KLAL can remarkably enhance VA and improve low vision or even eliminate blindness for ocular complications of SJS. The outcome of the surgeries was correlated with the preoperative ocular situation and choice of operative methods.

The COVID-19 pandemic has forced many college students in developing countries to engage in online learning for the first time, and the sudden transit has raised concerns regarding students' competencies for, perception of, and attitude towards online learning. To address those concerns, this study measured three essential constructs of online learning (self-regulated learning, perceived presences, and learning motivation) based on a national survey in China (N = 12,826) and employed structural equation modeling to investigate their intertwined relationship. The study results reveal that (1) college students' academic achievement cannot effectively predict their self-regulated learning in an online learning context; (2) self-regulation can be further differentiated into general and task-specific strategies with a varying impact on three types of presences; (3) online learning motivation is best predicted by cognitive presence, followed by social presence and teaching presence; and (4) the path of task-specific self-regulated learning [right arrow] cognitive presence [right arrow] online learning motivation generates the largest positive compound effect. Implications for online teaching and learning practice are also discussed through the stakeholder perspectives of students, teachers, and platform developers.

Crop resistance to herbicides is crucial for agricultural productivity and sustainability amidst escalating challenges of weed resistance. Uncovering herbicide resistant genes is particularly important for rice production. In this study, we tested the resistance to three commonly used herbicides: glufosinate, glyphosate and mesotrione of 421 diverse rice cultivars and employed genome-wide association studies (GWAS) to unravel the genetic underpinnings of resistance to these three herbicides in rice. We discovered that cultivated rice exhibited rich variation in resistance to the three herbicides, and the differences among subpopulations were significant. Six identified associations harboring candidate genes for resistance to these herbicides were significant. Among them, RGlu6 and RGly8 were the major QTL for resistance to glufosinate and glyphosate, respectively. The favorable alleles of RGlu6 and RGly8 were primarily present in japonica cultivars that originated from Europe, highlighting the geographic and genetic diversity of herbicide resistance and emphasizing the localized selection pressures in European rice varieties. Moreover, our findings might suggest that traditional target genes may not contain tolerant alleles in nature, and alternative mechanisms with novel loci associated with resistance may work. By mapping the genes for herbicide resistance, our results may help develop new strategies to combat the dual challenges on effective weed management and herbicide sustainability.

BackgroundThis study aims to analyze the relationship between psychological resilience, perceived organizational support, and intention to stay among nurses. Additionally, it explores the mediating role of perceived organizational support in the relationship between psychological resilience and nurses’ intention to stay.MethodsA cross-sectional survey was conducted between August and September 2023, involving 1,402 nurses from five Grade 3A hospitals in Guangdong. The survey utilized several instruments, including the General Information Questionnaire (GIQ), the Chinese version of the Connor-Davidson Resilience Scale (CD-RISC), the Chinese version of the Perceived Organizational Support Scale (POSS), and the Chinese version of the Intention to Stay Scale (ITSS). The obtained data were analyzed using descriptive statistics and Pearson’s correlation coefficient, while the mediating effect of perceived organizational support was assessed using the PROCESS macro mediation model in SPSS.ResultsThe overall mean score for psychological resilience among nurses in the five Grade 3A hospitals in Guangdong was 60.54 ± 19.17, the overall mean score for perceived organizational support was 45.77 ± 11.49, and the mean score for intention to stay was 20.82 ± 4.65. The results of the statistical analysis revealed positive correlations between psychological resilience and intention to stay (r = 0.388, p

BackgroundHypertension (HT) is a common chronic disease in older adults. It not only leads to dizziness and other symptoms affecting balance in older adults with HT but also affects the hemodynamics of the cerebral cortex. At present, potential neural mechanisms of balance control in older adults with HT are still unclear. Therefore, this study aimed to explore the differences in the center of pressure (COP) and cerebral cortex activation between older adults with HT and normotension (NT) during standing balance tasks. This study May provide guidance for the early detection of the risk of falls among older adults with HT and the development of clinical rehabilitation strategies.MethodsIn this cross-sectional study, 30 older adults with NT (NT group) and 27 older adults with HT (HT group) were subjected to three conditions: task 1, standing with eyes open on a stable surface; task 2, standing with eyes closed on a stable surface; and task 3, standing with eyes open on the surface of the foam pad. Cortical hemodynamic reactions were measured using functional near-infrared spectroscopy, and COP parameters were measured using a force plate.ResultsThe mean velocity of the COP in the medial–lateral direction in the NT group was significantly higher than that in the HT group (F = 5.955, p = 0.018) during task 3. When proprioception was disturbed, the activation of the left premotor cortex and supplementary motor cortex in the HT group was significantly lower than that in the NT group (F = 14.381, p

ObjectiveTo understand the current situation of nursing manpower allocation, explore the factors affecting nurse staffing, improve nurse staffing level, and provide reference for better formulation of nursing human resources staffing standards.MethodsA descriptive research method was used to conduct semi-structured interviews with 14 nursing managers. The data were analyzed and refined by content analysis. The sample size was subject to content saturation.ResultsNine themes and twenty sub-themes of influencing factors for nursing staffing were identified across four levels: hospital level, department level, patient level, and nurse level.ConclusionHospital and department managers need to comprehensively consider the factors of affecting nurse staffing. Adopting multidimensional optimization measures, improving relevant systems, optimizing nurse structure, and establishing flexible and mobile nurse database to cope with public emergencies, so as to effectively improve nurse staffing and nursing service quality.

Background: This study was conducted to investigate whether baseline creatinine–cystatin C ratio is associated with all-cause mortality in adult Chinese patients hospitalized with coronavirus disease 2019. Methods: This study included 933 patients with coronavirus disease 2019 who were admitted to The Affiliated Hospital of Guangdong Medical University between December 2022 and March 2023. All-cause mortality was determined by telephone follow-up after 28 days. Multivariate Cox proportional risk models were used to investigate the relationship between baseline creatinine–cystatin C ratio and all-cause mortality. Restricted cubic spline and two-piecewise Cox proportional hazards risk models were used to identify non-linear correlations. Results: Of the 933 patients, 128 died during the 28 days follow-up. The restricted cubic spline analysis of hospitalized patients with coronavirus disease 2019 revealed an L-shaped association between baseline creatinine–cystatin C ratio and all-cause mortality, with a threshold creatinine–cystatin C ratio of ≤0.93 predicting all-cause mortality. Specifically, a baseline creatinine–cystatin C ratio below this threshold value was negatively correlated with mortality (hazard ratio 0.12, 95 % confidence interval 0.03–0.48), but a creatinine–cystatin C ratio >0.93 was not correlated with mortality (hazard ratio 1.29, 95 % confidence interval 0.65–2.55). Conclusions: In Chinese adult patients hospitalized with coronavirus disease 2019, an L-shaped relationship was observed between the baseline creatinine–cystatin C ratio and all-cause mortality.