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Background and Objectives: Hypoglycemia is a known risk of intensive postoperative glucose control in neurosurgical patients. However, the impact of postoperative hypoglycemia after craniotomy remains unexplored. This study aimed to determine the association between postoperative hypoglycemia and mortality in patients undergoing elective craniotomy., Methods: This study involved adult patients who underwent elective craniotomy at the West China Hospital, Sichuan University, between January 2011 and March 2021. We defined moderate hypoglycemia as blood glucose levels below 3.9 mmol/L (70 mg/dL) and severe hypoglycemia as blood glucose levels below 2.2 mmol/L (40 mg/dL). The primary outcome was postoperative 90-day mortality., Results: This study involved 15 040 patients undergoing an elective craniotomy. Overall, 504 (3.4%) patients experienced moderate hypoglycemia, whereas 125 (0.8%) patients experienced severe hypoglycemia. Multivariable analysis revealed that both moderate hypoglycemia (adjusted odds ratio [aOR] 1.86, 95% CI 1.24-2.78) and severe (aOR 2.94, 95% CI 1.46-5.92) hypoglycemia were associated with increased 90-day mortality compared with patients without hypoglycemia. Moreover, patients with moderate (aOR 2.78, 95% CI 2.28-3.39) or severe (aOR 16.70, 95% CI 10.63-26.23) hypoglycemia demonstrated a significantly higher OR for major morbidity after adjustment, compared with those without hypoglycemia. Patients experiencing moderate (aOR 3.20, 95% CI 2.65-3.88) or severe (aOR 14.03, 95% CI 8.78-22.43) hypoglycemia had significantly longer hospital stays than those without hypoglycemia. The risk of mortality and morbidity showed a tendency to increase with the number of hypoglycemia episodes in patients undergoing elective craniotomy (P for trend = .01, <.001)., Conclusion: Among patients undergoing an elective craniotomy, moderate hypoglycemia and severe hypoglycemia are associated with increased mortality, major morbidity, and prolonged hospital stays. In addition, the risk of mortality and major morbidity increases with the number of hypoglycemia episodes., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC 50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Kiwifruit ripening is a complex and highly coordinated process that occurs in conjunction with the formation of fruit edible quality. The significance of epigenetic changes, particularly the impact of N6-methyladenosine (m6A) RNA modification on fruit ripening and quality formation, has been largely overlooked. We monitored m6A levels and gene expression changes in kiwifruit at four different stages using LC-MS/MS, MeRIP, RNA-seq, and validated the function of AcALKBH10 through heterologous transgenic expression in tomato. Notable m6A modifications occurred predominantly at the stop codons and the 3' UTRs and exhibited a gradual reduction in m6A levels during the fruit ripening process. Moreover, these m6A modifications in the aforementioned sites demonstrated a discernible inverse relationship with the levels of mRNA abundance throughout the ripening process, suggesting a repression effect of m6A modification in the modulation of kiwifruit ripening. We further demonstrated that AcALKBH10 rather than AcECT9 predominantly regulates m6A levels in ripening-related genes, thereby exerting the regulatory control over the ripening process and the accumulation of soluble sugars and organic acids, ultimately influencing fruit ripening and quality formation. In conclusion, our findings illuminate the epi-regulatory mechanism involving m6A in kiwifruit ripening, offering a fresh perspective for cultivating high-quality kiwifruit with enhanced nutritional attributes., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Abnormal gene alternative splicing (AS) events are strongly associated with cancer progression. Here, we summarize AS events that contribute to the development of drug resistance and classify them into three categories: alternative cis-splicing (ACS), alternative trans-splicing (ATS), and alternative back-splicing (ABS). The regulatory mechanisms underlying AS processes through cis-acting regulatory elements and trans-acting factors are comprehensively described, and the distinct functions of spliced variants, including linear spliced variants derived from ACS, chimeric spliced variants arising from ATS, and circRNAs generated through ABS, are discussed. The identification of dysregulated spliced variants, which contribute to drug resistance and hinder effective cancer treatment, suggests that abnormal AS processes may together serve as a precise regulatory mechanism enabling drug-resistant cancer cell survival or, alternatively, represent an evolutionary pathway for cancer cells to adapt to changes in the external environment. Moreover, this review summarizes recent advancements in treatment approaches targeting AS-associated drug resistance, focusing on cis-acting regulatory elements, trans-acting factors, and specific spliced variants. Collectively, gaining an in-depth understanding of the mechanisms underlying aberrant alternative splicing events and developing strategies to target this process hold great promise for overcoming cancer drug resistance., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ovarian cancer, the deadliest gynecological malignancy, primarily treated with chemotherapy. However, systemic chemotherapy often leads to severe toxic side effects and chemoresistance. Drug-loaded aerogels have emerged as a promising method for drug delivery, as they can improve drug solubility and bioavailability, control drug release, and reduce drug distribution in non-targeted tissues, thereby minimizing side effects. In this research, chitosan oligosaccharide (COS)-loaded nanofibers composite chitosan (CS) aerogels (COS-NFs/CS) with a porous network structure were created using nanofiber recombination and freeze-drying techniques. The core layer of the aerogel has a COS loading rate of 60 %, enabling the COS-NFs/CS aerogel to significantly inhibit the migration and proliferation of ovarian cancer cells (resulting in a decrease in the survival rate of ovarian cancer cells to 33.70 % after 48 h). The coaxial fiber's unique shell-core structure and the aerogel's porous network structure enable the COS-NFs/CS aerogels to release COS steadily and slowly over 30 days, effectively reducing the initial burst release of COS. Additionally, the COS-NFs/CS aerogels exhibit good biocompatibility, degradability (only retaining 18.52 % of their weight after 6 weeks of implantation), and promote angiogenesis, thus promoting wound healing post-oophorectomy. In conclusion, COS-NFs/CS aerogels show great potential for application in the treatment of ovarian cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hua Liu reports financial support was provided by Natural Science Foundation of Hubei Province. Yan-Xiang Cheng reports financial support was provided by Cross-innovation talent project in Renmin Hospital of Wuhan University. Yan-Xiang Cheng reports financial support was provided by Undergraduate education quality construction comprehensive reform project. Yan-Xiang Cheng reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Drought, especially terminal drought, severely limits wheat growth and yield. Understanding the complex mechanisms behind the drought response in wheat is essential for developing drought-resistant varieties. This study aimed to dissect the genetic architecture and high-yielding wheat ideotypes under terminal drought. An automated high-throughput phenotyping platform was used to examine 28 392 image-based digital traits (i-traits) under different drought conditions during the flowering stage of a natural wheat population. Of the i-traits examined, 17 073 were identified as drought-related. A genome-wide association study (GWAS) identified 5320 drought-related significant single-nucleotide polymorphisms (SNPs) and 27 SNP clusters. A notable hotspot region controlling wheat drought tolerance was discovered, in which TaPP2C6 was shown to be an important negative regulator of the drought response. The tapp2c6 knockout lines exhibited enhanced drought resistance without a yield penalty. A haplotype analysis revealed a favored allele of TaPP2C6 that was significantly correlated with drought resistance, affirming its potential value in wheat breeding programs. We developed an advanced prediction model for wheat yield and drought resistance using 24 i-traits analyzed by machine learning. In summary, this study provides comprehensive insights into the high-yielding ideotype and an approach for the rapid breeding of drought-resistant wheat., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Various biological effects of ionizing radiation, especially continuous exposure to low-dose radiation (LDR), have attracted considerable attention. Impaired bone structure caused by LDR has been reported, but little is known about the mechanism involved in the disruption of bone metabolism. In this study, given that LDR was found to (at a cumulative dose of 0.10 Gy) disturb the serum Mg 2+ level and Notch1 signal in the mouse femur tissues, the effects of LDR on osteogenesis and the underlying molecular mechanisms were investigated based on an in vitro culture system for bone marrow stromal cells (BMSCs). Our data showed that cumulative LDR suppressed the osteogenic potential in BMSCs as a result of upregulation of Notch1 signaling. Further analyses indicated that the upregulation of NICD1 (Notch1 intracellular domain), the key intracellular domain for Notch1 signaling, under LDR was a consequence of enhanced protein stabilization caused by SUMOylation (small ubiquitin-like modification). Specifically, the downregulation of SENP1 (sentrin/SUMO-specific protease 1) expression induced by LDR enhanced the SUMOylation of NICD1, causing the accumulation of Notch1 signaling, which eventually inhibited the osteogenic potential of BMSCs. In conclusion, this work expounded on the mechanisms underlying the impacts of LDR on bone metabolism and shed light on the research on bone regeneration under radiation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Borneol, a highly lipid-soluble bicyclic terpene mainly extracted from plants, is representative of monoterpenoids. Modern medicine has established that borneol exhibits a range of pharmacological activities and used in the treatment of many diseases, particularly Cardio-cerebrovascular diseases (CVDs). The crucial role in enhancing drug delivery and improving bioavailability has attracted much attention. In addition, borneol is also widely utilized in food, daily chemicals, fragrances, and flavors industries., Purpose: This review systematically summarized the sources, pharmacological activities and mechanisms, clinical trial, pharmacokinetics, toxicity, and application of borneol. In addition, this review describes the pharmacological effects of borneol ester and the combination of borneol with nanomaterial. This review will provide a valuable resource for those pursuing researches on borneol inspiring the pharmacological applications in the medicine, food and daily chemical products, and developing of new drugs containing borneol or its derivatives., Methods: This review searched the keywords ("borneol" or "bornyl esters") and ("pharmacology" or "Traditional Chinese medicine" or "Cardio-cerebrovascular diseases" or "blood-brain barrier" or "ischemic stroke" or "nanomaterials" or "neurodegenerative diseases" or "diabetes" or "toxicity") in Web of Science, PubMed, Google Scholar and China National Knowledge Infrastructure (CNKI) from January 1990 to May 2024. The search was limited to articles published in English and Chinese., Results: Borneol exhibits extensive pharmacological activities including anti-inflammatory effects, analgesia, antioxidation, and has the property of crossing biological barriers and treating CVDs. The intrinsic molecular mechanisms are involved in multiple components, such as regulation of various key factors (including Tumor necrosis factor-α, Nuclear factor kappa-B, Interleukin-1β, Malondialdehyde), inhibiting transporter protein function, regulating biochemical levels, and altering physical structural changes. In addition, this review describes the pharmacological effects of borneol ester and the combination of borneol with nanomaterial., Conclusion: The pharmacological properties and applications of borneol are promising, including anti-inflammatory, analgesic, antimicrobial, and antioxidant properties, as well as enhancing drug delivery and treating CVDs. However, its clinical application is hindered by the limited research on safety, efficacy, and pharmacokinetics. Therefore, this review systemically summarized the advances on pharmacological activities and mechanisms of the borneol. Standardized clinical trials and exploration of synergistic effects with other drugs were also are outlined., Competing Interests: Declaration of competing interest The authors report no potential conflict of interest., (Copyright © 2024. Published by Elsevier GmbH.)

Purpose: To investigate the clinical features of hand, foot, and mouth disease (HFMD) caused by coxsackievirus A6 (CVA6) and this work may help early diagnose of atypical HFMD., Methods: From January 2013 to December 2019, a total of 7,208 patients with a clinical diagnosis of HFMD in Xi'an Children's Hospital, Xi'an Central Hospital, and Xi'an Jiaotong University Second Affiliated Hospital, were included in this observational study. The clinical data, specimens and follow-up results were collected. Real-time RT‒PCR was performed for the detection and typing of enterovirus nucleic acids., Results: Of the 7,208 clinically diagnosed HFMD patients, 5,622 were positive for enterovirus nucleic acids, and the positive proportions of CVA6, enterovirus 71 (EV-A71), coxsackievirus A16 (CVA16), and other enteroviruses were 31.0% (1,742/5,622), 27.0% (1,518/5,622), 35.0% (1,968/5,622), and 7.0% (394/5,622), respectively. Based on the etiology, patients were divided into CVA6 group, EV-A71group, and CVA16 group. The mean age at onset was significantly higher in the CVA6 group (4.62±2.13 years) than in the EV-A71 group and CVA16 group (3.45±2.25 years and 3.35±2.13 years, respectively; both P < 0.05). The male/female ratio was 1.45 (1,031/711) in the CVA6 group and was not significantly different from the other two groups. The incidence of fever was significantly higher in the CVA6 group [82.5% (1,437/1,742)] than in the EV-A71 group [51.3% (779/1,518)] and the CVA16 group [45.9% (903/1,968)] (P < 0.05). In the CVA6 group, the rashes were more frequently on the trunk and elbows/knees and were significantly different from the other two groups (P < 0.05). The number of patients with two or more rash morphologies was significantly higher in the CVA6 group than in the other two groups (P < 0.05). The incidence of bullous rash in the CVA6 group [20.2%; n = 352] was higher than in the EV-A71 group [0.33%; n = 5] and CVA16 group [0.66%; n = 13] (P < 0.05). The incidence of neurological complications was significantly higher in the EV-A71 group [52.1% (791/1,518)] than in the CVA16 group [5.1% (100/1,968)] and the CVA6 group [0.8% (14/1,742)] (P < 0.05). In the follow-up period, 160 patients (9.2%) with CVA6 HFMD experienced onychomadesis, but no onychomadesis was observed in the EV-A71 and CVA16 groups. The average WBC count was significantly higher in the CVA6 group than in the CVA16 group (P < 0.05). The number of patients with increased CRP was significantly larger in the CVA6 group than in the CVA16 group but was significantly smaller than that in the EV-A71 group (P < 0.05)., Conclusions: CVA6 has become one of the main pathogens of HFMD in the Xi'an area during 2013-2019. The main clinical manifestations were slightly different from those of HFMD caused by EV-A71 or CVA16, with a higher frequency of fever, diverse morphologies and diffuse distribution of rashes, fewer neurological complications and some onychomadesis., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Krüppel-like factor 12 (KLF12) has been characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and natural killer (NK) cell proliferation. However, the contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma (ESCC). Mechanistically, KLF12 binds to the promoters of L1 Cell Adhesion Molecule (L1CAM) and represses its expression. Depletion of L1CAM abrogates cisplatin resistance and cancer metastasis caused by KLF12 loss. Moreover, the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC. Targeting these genes could be a promising approach for ESCC treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: This study attempts to examine long-term pain medication usage after burn injury and its association with functional and psychosocial outcomes., Design: This is a multicenter retrospective cohort study utilizing the Burn Model System National Longitudinal Database. Participants injured from 2015 to 2021 were divided into two groups, those taking and not taking prescription pain medication at 12 mos after injury. Regression analyses examined associations between pain medication use and outcomes at 12 mos, adjusting for demographics, burn size, length of hospital stay, and preinjury pain medication use and employment status. Outcomes included VR-12 Physical and Mental Component Summary scores Patient-Reported Outcomes Measurement Information System Anxiety and Depression scores, Satisfaction with Life Scale, and employment status., Results: Of 358 participants analyzed, prescription pain medication use was associated with worse outcomes at 12 mos: Physical Component Summary (β = -7.11, P < 0.001), Mental Component Summary (β = -6.01, P < 0.001), and Patient-Reported Outcomes Measurement Information System Depression (β = 4.88, P < 0.001) and Anxiety (β = 6.16, P < 0.001). Satisfaction with Life Scale was not significantly associated with pain medication use ( P = 0.069) and those taking pain medication were 52% less likely to be employed at 12 mos ( P = 0.035)., Conclusions: There is a significant association between prescription pain medication use and worse physical, mental, and employment outcomes at 12 mos after burn injury., Competing Interests: All authors have met criteria for authorship and have substantially contributed to contributing to the conception and design or analyzing and interpreting data and/or drafting the article or revising it critically for important intellectual content. No authors have any competing interests, financial benefits, or conflicts of interest to disclose. This work was supported by the National Institute on Disability, Independent Living, and Rehabilitation Research (grant number: #90DPBU0001, #90DPBU0003, #90DPBU0004, #90DPBU0008), with author Jeffrey Schneider, MD, as a recipient. All other authors did not directly receive funding for the conduction of this study. Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Study Objective: To estimate the incidence of postoperative oxygenation impairment after lung resection in the era of lung-protective management, and to identify perioperative factors associated with that impairment., Design: Registry-based retrospective cohort study., Setting: Two large academic hospitals in the United States., Patients: 3081 ASA I-IV patients undergoing lung resection., Measurements: 79 pre- and intraoperative variables, selected for inclusion based on a causal inference framework. The primary outcome of impaired oxygenation, an early marker of lung injury, was defined as at least one of the following within seven postoperative days: (1) SpO 2  < 92%; (2) imputed PaO 2 /FiO 2  < 300 mmHg [(1) or (2) occurring at least twice within 24 h]; (3) intensive oxygen therapy (mechanical ventilation or > 50% oxygen or high-flow oxygen)., Main Results: Oxygenation was impaired within seven postoperative days in 70.8% of patients (26.6% with PaO 2 /FiO 2  < 200 mmHg or intensive oxygen therapy). In multivariable analysis, each additional cmH 2 O of intraoperative median driving pressure was associated with a 7% higher risk of impaired oxygenation (OR 1.07; 95%CI 1.04 to 1.10). Higher median intraoperative FiO 2 (OR 1.23; 95%CI 1.14 to 1.31 per 0.1) and PEEP (OR 1.12; 95%CI 1.04 to 1.21 per 1 cm H 2 O) were also associated with increased risk. History of COPD (OR 2.55; 95%CI 1.95 to 3.35) and intraoperative albuterol administration (OR 2.07; 95%CI 1.17 to 3.67) also showed reliable effects., Conclusions: Impaired postoperative oxygenation is common after lung resection and is associated with potentially modifiable pre- and intraoperative respiratory factors., Competing Interests: Declaration of competing interest No relevant conflicts of interest to report for any authors., (Copyright © 2023. Published by Elsevier Inc.)

The liver is the most common organ for the formation of colorectal cancer metastasis. Non-invasive prognostication of colorectal cancer liver metastasis (CRLM) may better inform clinicians for decision-making. Contrast-enhanced computed tomography images of 180 CRLM cases were included in the final analyses. Radiomics features, including shape, first-order, wavelet, and texture, were extracted with Pyradiomics, followed by feature engineering by penalized Cox regression. Radiomics signatures were constructed for disease-free survival (DFS) by both elastic net (EN) and random survival forest (RSF) algorithms. The prognostic potential of the radiomics signatures was demonstrated by Kaplan-Meier curves and multivariate Cox regression. 11 radiomics features were selected for prognostic modelling for the EN algorithm, with 835 features for the RSF algorithm. Survival heatmap indicates a negative correlation between EN or RSF risk scores and DFS. Radiomics signature by EN algorithm successfully separates DFS of high-risk and low-risk cases in the training dataset (log-rank test: p < 0.01, hazard ratio: 1.45 (1.07-1.96), p < 0.01) and test dataset (hazard ratio: 1.89 (1.17-3.04), p < 0.05). RSF algorithm shows a better prognostic implication potential for DFS in the training dataset (log-rank test: p < 0.001, hazard ratio: 2.54 (1.80-3.61), p < 0.0001) and test dataset (log-rank test: p < 0.05, hazard ratio: 1.84 (1.15-2.96), p < 0.05). Radiomics features have the potential for the prediction of DFS in CRLM cases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: In agricultural pest management, especially in combatting the invasive red imported fire ant (RIFA, Solenopsis invicta), significant challenges emerge as a consequence of the constraints of solely depending on chemical insecticides or entomopathogenic nematodes (EPNs). The utilization of chemical insecticides carries environmental and ecological hazards, whereas EPNs, when applied independently, might not offer the immediate effectiveness necessary for adequate RIFA suppression. Acknowledging these hurdles, our study investigates a synergistic method that integrates EPNs with chemical insecticides, aiming to fulfill the urgent demand for more efficient and environmentally friendly pest control solutions., Results: Our evaluation focused on the interaction between the highly pathogenic Steinernema riobrave 7-12 EPN strain and prevalent insecticides, specifically beta-cypermethrin and a mixture of bifenthrin and clothianidin, applied at highly diluted recommended concentrations. The findings revealed a notable increase in RIFA mortality rates when EPNs and these insecticides were used together, outperforming the results achieved with each method individually. Remarkably, this enhanced efficacy was especially evident at lower concentrations of the bifenthrin-clothianidin mixture, indicating a valuable approach to minimizing reliance on chemical insecticides in agriculture. Furthermore, the high survival rates of EPNs alongside the tested insecticides indicate their compatibility and potential for sustained use in integrated pest management programs., Conclusion: Our research underscores the effectiveness of merging EPNs with chemical insecticides as a powerful and sustainable strategy for RIFA management. This combined approach not only meets the immediate challenges of pest control in agricultural settings, but also supports wider environmental objectives by reducing the dependency on chemical insecticides. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Background: Cardiovascular-kidney-metabolic (CKM) health is affected by social determinants of health, especially education. CKM syndrome has not been evaluated in Chinese population, and the association of education with CKM syndrome in different sexes and its intertwined relation with lifestyles have not been explored., Objective: We aimed to explore the association between educational attainment and the prevalence of CKM syndrome stages in middle-aged and older Chinese men and women as well as the potential role of health behavior based on Life's Essential 8 construct., Methods: This study used data from the nationwide, community-based REACTION (Risk Evaluation of Cancers in Chinese diabetic individuals: a longitudinal study). A total of 132,085 participants with complete information to determine CKM syndrome stage and education level were included. Educational attainment was assessed by the self-reported highest educational level achieved by the participants and recategorized as low (elementary school or no formal education) or high (middle school, high school, technical school/college, or above). CKM syndrome was ascertained and classified into 5 stages according to the American Heart Association presidential advisory released in 2023., Results: Among 132,085 participants (mean age 56.95, SD 9.19 years; n=86,675, 65.62% women) included, most had moderate-risk CKM syndrome (stages 1 and 2), and a lower proportion were at higher risk of CKM (stages 3 and 4). Along the CKM continuum, low education was associated with 34% increased odds of moderate-risk CKM syndrome for women (odds ratio 1.36, 95% CI 1.23-1.49) with a significant sex disparity, but was positively correlated with high-risk CKM for both sexes. The association between low education and high-risk CKM was more evident in women with poor health behavior but not in men, which was also interactive with and partly mediated by behavior., Conclusions: Low education was associated with adverse CKM health for both sexes but was especially detrimental to women. Such sex-specific educational disparity was closely correlated with health behavior but could not be completely attenuated by behavior modification. These findings highlight the disadvantage faced by women in CKM health ascribed to low education, underscoring the need for public health support to address this inequality., (© Yi Ding, Xianglin Wu, Qiuyu Cao, Jiaojiao Huang, Xiaoli Xu, Youjin Jiang, Yanan Huo, Qin Wan, Yingfen Qin, Ruying Hu, Lixin Shi, Qing Su, Xuefeng Yu, Li Yan, Guijun Qin, Xulei Tang, Gang Chen, Min Xu, Tiange Wang, Zhiyun Zhao, Zhengnan Gao, Guixia Wang, Feixia Shen, Zuojie Luo, Li Chen, Qiang Li, Zhen Ye, Yinfei Zhang, Chao Liu, Youmin Wang, Tao Yang, Huacong Deng, Lulu Chen, Tianshu Zeng, Jiajun Zhao, Yiming Mu, Shengli Wu, Yuhong Chen, Jieli Lu, Weiqing Wang, Guang Ning, Yu Xu, Yufang Bi, Mian Li. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org).)

Background: Leukemia inhibitory factor (LIF) is a multifunctional member of the IL-6 cytokine family that activates downstream signaling pathways by binding to the heterodimer consisting of LIFR and gp130 on the cell surface. Previous research has shown that LIF is highly expressed in various tumor tissues (e.g. pancreatic cancer, breast cancer, prostate cancer, and colorectal cancer) and promotes cancer cell proliferation, migration, invasion, and differentiation. Moreover, the overexpression of LIF correlates with poor clinicopathological characteristics. Therefore, we hypothesized that LIF could be a promising target for the treatment of cancer. In this work, we developed the antagonist antibody 1G11 against LIF and investigated its anti-tumor mechanism and its therapeutic efficacy in mouse models., Results: A series of single-chain variable fragments (scFvs) targeting LIF were screened from a naive human scFv phage library. These scFvs were reconstructed in complete IgG form and produced by the mammalian transient expression system. Among the antibodies, 1G11 exhibited the excellent binding activity to human, cynomolgus monkey and mouse LIF. Functional analysis demonstrated 1G11 could block LIF binding to LIFR and inhibit the intracellular STAT3 phosphorylation signal. Interestingly, 1G11 did not block LIF binding to gp130, another LIF receptor that is involved in forming the receptor complex together with LIFR. In vivo, intraperitoneal administration of 1G11 inhibited tumor growth in CT26 and MC38 models of colorectal cancer. IHC analysis demonstrated that p-STAT3 and Ki67 were decreased in tumor tissue, while c-caspase 3 was increased. Furthermore, 1G11 treatment improves CD3+, CD4 + and CD8 + T cell infiltration in tumor tissue., Conclusions: We developed antagonist antibodies targeting LIF/LIFR signaling pathway from a naive human scFv phage library. Antagonist anti-LIF antibody exerts antitumor effects by specifically reducing p-STAT3. Further studies revealed that anti-LIF antibody 1G11 increased immune cell infiltration in tumor tissues., (© 2024. The Author(s).)

Regulatory T cells (Treg) play key roles in inhibiting effective antitumor immunity. However, therapeutic Treg depletion fails to consistently enhance immune responses due to the emergence of a wave of peripherally converted Treg cells postdepletion, along with undesired off-target side effects. Here, we report a nanoextinguisher decorated with functional peptides via tumor microenvironment responsive linkers to selectively block Treg function and maintain Treg levels rather than deplete them. The nanoextinguisher specifically neutralizes TGF-β to inhibit the recruitment of Treg cells and the conversion of naive T cells into Treg cells, thus promoting antitumor immunity. Moreover, the nanoextinguisher can alleviate tumor resistance to immunogenic photodynamic therapy, vaccination therapy, and checkpoint inhibition. The nanoextinguisher showed 30-fold potentiation in antitumor effect compared to standalone photodynamic therapy or vaccination therapy. Overall, utilizing a nanoextinguisher to inhibit Treg function without triggering reconversion represents a generalizable method to reverse immune evasion, yielding antitumor efficacy.

Bladder cancer (BC), the predominant urological malignancy in men, exhibits complex molecular underpinnings contributing to its progression. This investigation aims to elucidate the expression dynamics of calcium-binding protein 39 (CAB39) in both healthy and cancerous tissues and to explore its functional role in the epithelial-mesenchymal transition (EMT) within human bladder cancer contexts. Utilizing immunohistochemistry and quantitative reverse transcription analyses, we assessed CAB39 expression across BC specimens and cell lines. Further, we implemented wound healing, cell invasion, and CCK-8 proliferation assays in CAB39-knockdown cell lines, alongside a nude mouse xenograft model, to gauge the impact of diminished CAB39 expression on the invasive, migratory, and proliferative capacities of BC cells. Our gene set enrichment analysis probed into the repertoire of genes augmented by increased CAB39 expression in BC cells, with subsequent validation via western blotting. Our findings reveal a pronounced overexpression of CAB39 in both BC tissues and cellular models, inversely correlated with disease prognosis. Remarkably, the oncogenic trajectory of bladder cancer was mitigated upon the establishment of shRNA-mediated CAB39 knockdown in vitro and in vivo, effectively reversing the cancer's invasive and metastatic behaviors and curbing tumorigenesis in xenograft models. Hence, CAB39 emerges as a critical biomarker for bladder cancer progression, significantly implicated in facilitating EMT via the upregulation of neural cadherin (N-cadherin) and the suppression of epithelial cadherin through NF-κB signaling pathways. CU-T12-9 effectively overturned the downregulation of p65-NF-kB and N-cadherin, key elements involved in EMT and cell motility, induced by CAB39 knockdown. This study underscores CAB39's pivotal role in bladder cancer pathophysiology and its potential as a therapeutic target., (© 2024 Wiley Periodicals LLC.)

Mcl-1 is a main antiapoptotic protein in acute myeloid leukemia (AML) and is used as a target to develop inhibitors. Currently, potent Mcl-1 inhibitors primarily interact with the P2-P4 pockets of Mcl-1, but pharmacological modulation by targeting the P1 pocket is less explored. We designed a series of 1 H -indole-2-carboxylic acid compounds as novel Mcl-1 inhibitors occupying the P1-P3 pockets and evaluated their Mcl-1 inhibition and apoptosis induction in AML cells. Two-dimensional 15 N-HSQC spectroscopy indicated that 47 ( K i = 24 nM) bound to the BH3 binding groove, occupied the P1 pocket in Mcl-1, and formed interactions with Lys234 and Val249. 47 exhibited good microsomal stability and pharmacokinetic profiles, with low potential risk of cardiotoxicity. 47 inhibited tumor growth in HL-60 and THP-1 xenograft models with growth inhibition rate of 63.7% and 57.4%, respectively. Collectively, 47 represents a novel Mcl-1 inhibitor targeting the P1-P3 pockets with excellent antileukemia effects.

Biomineralization is a natural process in which organisms regulate the growth of inorganic minerals to form biominerals with unique layered structures, such as bones and teeth, primarily composed of calcium and phosphorus. Tooth decay significantly impacts our daily lives, and the key to tooth regeneration lies in restoring teeth through biomimetic approaches, utilizing mineralization strategies or materials that mimic natural processes. This review delves into the types, properties, and transformations of calcium and phosphorus minerals, followed by an exploration of the mechanisms behind physiological and pathological mineralization in living organisms. It summarizes the mechanisms and commonalities of biomineralization and discusses the advancements in dental biomineralization research, guided by insights into calcium and phosphorus mineral biomineralization. This review concludes by addressing the current challenges and future directions in the field of dental biomimetic mineralization.

Background: Treatment of gliomas, the most prevalent primary malignant neoplasm of the central nervous system, is challenging. Arachidonate 5-lipoxygenase activating protein (ALOX5AP) is crucial for converting arachidonic acid into leukotrienes and is associated with poor prognosis in multiple cancers. Nevertheless, its relationship with the prognosis and the immune microenvironment of gliomas remains incompletely understood., Methods: The differential expression of ALOX5AP was evaluated based on public Databases. Kaplan-Meier, multivariate Cox proportional hazards regression analysis, time-dependent receiver operating characteristic, and nomogram were used to estimate the prognostic value of ALOX5AP. The relationship between ALOX5AP and immune infiltration was calculated using ESTIMATE and CIBERSORT algorithms. Relationships between ALOX5AP and human leukocyte antigen molecules, immune checkpoints, tumor mutation burden, TIDE score, and immunophenoscore were calculated to evaluate glioma immunotherapy response. Single gene GSEA and co-expression network-based GO and KEGG enrichment analysis were performed to explore the potential function of ALOX5AP. ALOX5AP expression was verified using multiplex immunofluorescence staining and its prognostic effects were confirmed using a glioma tissue microarray., Result: ALOX5AP was highly expressed in gliomas, and the expression level was related to World Health Organization (WHO) grade, age, sex, IDH mutation status, 1p19q co-deletion status, MGMTp methylation status, and poor prognosis. Single-cell RNA sequencing showed that ALOX5AP was expressed in macrophages, monocytes, and T cells but not in tumor cells. ALOX5AP expression positively correlated with M2 macrophage infiltration and poor immunotherapy response. Immunofluorescence staining demonstrated that ALOX5AP was upregulated in WHO higher-grade gliomas, localizing to M2 macrophages. Glioma tissue microarray confirmed the adverse effect of ALOX5AP in the prognosis of glioma., Conclusion: ALOX5AP is highly expressed in M2 macrophages and may act as a potential biomarker for predicting prognosis and immunotherapy response in patients with glioma., (© 2024. The Author(s).)

The global rise of antibiotic resistance has renewed interest in phage therapy, as an alternative to antibiotics to eliminate multidrug-resistant (MDR) bacterial pathogens. However, optimizing the broad-spectrum efficacy of phage therapy remains a challenge. In this study, we addressed this issue by employing strategies to improve antimicrobial efficacy of phage therapy against MDR Klebsiella pneumoniae strains, which are notorious for their resistance to conventional antibiotics. This includes the selection of broad host range phages, optimization of phage formulation, and combinations with last-resort antibiotics. Our findings unveil that having a broad host range was a dominant trait of isolated phages, and increasing phage numbers in combination with antibiotics significantly enhanced the suppression of bacterial growth. The decreased incidence of bacterial infection was explained by a reduction in pathogen density and emergence of bacterial resistance. Furthermore, phage-antibiotic synergy (PAS) demonstrated considerable broad-spectrum antibacterial potential against different clades of clinical MDR K. pneumoniae pathogens. The improved treatment outcomes of optimized PAS were also evident in a murine model, where mice receiving optimized PAS therapy demonstrated a reduced bacterial burden in mouse tissues. Taken together, these findings offer an important development in optimizing PAS therapy and its efficacy in the elimination of MDR K. pneumoniae pathogens., Importance: The worldwide spread of antimicrobial resistance (AMR) has posed a great challenge to global public health. Phage therapy has become a promising alternative against difficult-to-treat pathogens. One important goal of this study was to optimize the therapeutic efficiency of phage-antibiotic combinations, known as phage-antibiotic synergy (PAS). Through comprehensive analysis of the phenotypic and genotypic characteristics of a large number of CRKp-specific phages, we developed a systematic model for phage cocktail combinations. Crucially, our finding demonstrated that PAS treatments not only enhance the bactericidal effects of colistin and tigecycline against multidrug-resistant (MDR) K. pneumoniae strains in in vitro and in vivo context but also provide a robust response when antibiotics fail. Overall, the optimized PAS therapy demonstrates considerable potential in combating diverse K. pneumoniae pathogens, highlighting its relevance as a strategy to mitigate antibiotic resistance threats effectively.

Premise: The impact of inbreeding on biological processes is well documented in individuals with severe inbreeding depression. However, the biological processes influencing the adaptive growth of normal selfed individuals are unknown. Here, we aimed to investigate how inbreeding affects gene expression for adaptive growth of normal selfed seedlings from a self-fertilizing parent in Chinese fir (Cunninghamia lanceolata)., Methods: Using RNA-seq data from above- and underground tissues of abnormal and normal selfed seedlings, we analyzed GO biological processes network. We also sequenced small RNAs in the aboveground tissues and measured the copy number variations (CNV) of the hub genes., Results: Phenotypic fitness analysis revealed that the normal seedlings were better adapted than their abnormal counterparts. Upregulated differentially expressed genes (DEGs) were associated with development processes, and downregulated DEGs were mainly enriched in fundamental metabolism and stress response. Results of mRNA-miRNA parallel sequencing revealed that upregulated target genes were predominantly associated with development, highlighting their crucial role in phosphorylation in signal transduction networks. We also discovered a moderate correlation (0.1328 < R 2  < 0.6257) between CNV and gene expression levels for three hub genes (TMKL1, GT2, and RHY1A)., Conclusions: We uncovered the key biological processes underpinning the growth of normal selfed seedlings and established the relationship between CNV and the expression levels of hub genes in selfed seedlings. Understanding the candidate genes involved in the growth of selfed seedlings will help us comprehend the genetic mechanisms behind inbreeding depression in the evolutionary biology of plants., (© 2024 Botanical Society of America.)

Tumor suppressor genes play critical roles in normal tissue homeostasis, and their dysregulation underlies human diseases including cancer. Besides human genetics, model organisms such as Drosophila have been instrumental in discovering tumor suppressor pathways that were subsequently shown to be highly relevant in human cancer. Here we show that hyperplastic disc (Hyd), one of the first tumor suppressors isolated genetically in Drosophila and encoding an E3 ubiquitin ligase with hitherto unknown substrates, and Lines (Lin), best known for its role in embryonic segmentation, define an obligatory tumor suppressor protein complex (Hyd-Lin) that targets the zinc finger-containing oncoprotein Bowl for ubiquitin-mediated degradation, with Lin functioning as a substrate adaptor to recruit Bowl to Hyd for ubiquitination. Interestingly, the activity of the Hyd-Lin complex is directly inhibited by a micropeptide encoded by another zinc finger gene, drumstick ( drm ), which functions as a pseudosubstrate by displacing Bowl from the Hyd-Lin complex, thus stabilizing Bowl. We further identify the epigenetic regulator Polycomb repressive complex1 (PRC1) as a critical upstream regulator of the Hyd-Lin-Bowl pathway by directly repressing the transcription of the micropeptide drm Consistent with these molecular studies, we show that genetic inactivation of Hyd, Lin, or PRC1 resulted in Bowl-dependent hyperplastic tissue overgrowth in vivo. We also provide evidence that the mammalian homologs of Hyd (UBR5, known to be recurrently dysregulated in various human cancers), Lin (LINS1), and Bowl (OSR1/2) constitute an analogous protein degradation pathway in human cells, and that OSR2 promotes prostate cancer tumorigenesis. Altogether, these findings define a previously unrecognized tumor suppressor pathway that links epigenetic program to regulated protein degradation in tissue growth control and tumorigenesis., (© 2024 Wen et al.; Published by Cold Spring Harbor Laboratory Press.)

Nationwide estimates of the impact of common modifiable risk factors on mortality remain crucial. We aim to assess the influence of social determinants, lifestyle, and metabolic factors on mortality in 174,004 adults aged ≥40 years from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. We reveal that 17 modifiable factors are independently associated with mortality, accounting for 64.8% of all-cause mortality, 77.4% of cardiovascular mortality, and 44.8% of cancer mortality. Low education emerges as the leading factor for both all-cause and cancer mortality, while hypertension is predominant for cardiovascular mortality. Moreover, low gross domestic product per capita and high ambient particulate matter with a diameter of <2.5 μm (PM 2 .5 ) air pollution account for 7.8% and 4.3% for all-cause mortality, respectively, using a different method. Gender-specific analyses reveal distinct patterns, with women's mortality primarily associated with social determinants and men exhibiting stronger associations with lifestyle factors. Targeted health interventions are essential to mitigate mortality risks effectively in China., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Danggui-Jianzhong decoction (DGJZ) is a famous classical traditional Chinese medicine formula, which ingredients are complex and the quality is difficult to control. Our study aimed to identify the overall chemical profile of DGJZ qualitatively by ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and UPLC. A total of 77 components, including terpenoids, flavonoids, phenolic acids, gingerols and other components, were firstly detected and characterized by UPLC-Q-TOF-MS and 18 peaks marked after analyzing the UPLC fingerprint. Finally, paeoniflorin, liquiritin, ferulic acid, cinnamic acid, glycyrrhizic acid and 6-gingerol were quantified, which was validated in terms of linearity, precision, accuracy, repeatability and recovery. Taken together, the chemical constitutes of DGJZ were systematically identified and a reliable quantitative method coupled with fingerprint analysis was successfully employed for evaluating the holistic quality, which will provide a robust foundation for the quality control of DGJZ., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Backgroup: The pathogenesis of shoulder impingement syndrome (SIS) is still unclear, and its questionable causal relationship with rotator cuff (RC) injury has led to confusion in treatment. The purpose of this study was to explore the bidirectional causal relationship between SIS and RC injury., Methods: SIS and RC injury datasets downloaded from the IEU Open GWAS project and GWAS catalog databases. Inverse variance weighted (IVW), MR Egger, Weighted median, and Weighted mode were used in this Mendelian randomization (MR) analysis. Cochran's Q test, leave-one-out, and funnel plot method were used to evaluate heterogeneity between single nucleotide polymorphisms (SNPs). MR-Egger regression was used to test the horizontal pleiotropy of this study., Results: The IVW method (OR = 1.189, P = 0.0059) suggest the putative causal effect of RC injury on SIS. The results of MR Egger method (OR = 1.236, P = 0.2013), weighted median method (OR = 1.097, P = 0.2428) and weighted mode method (OR = 1.013, P = 0.930) showed no statistically significant (OR = 1.069071, P = 0.6173). Heterogeneity test and horizontal pleiotropy analysis suggested that there was no significant heterogeneity and horizontal pleiotropy in the results of this MR analysis. The reverse MR analysis showed heterogeneity, and the conclusion needs to be further explored., Conclusions: The results of MR analysis support that RC injury may be causally associated with SIS., (© 2024. The Author(s).)

The regeneration of tendon-bone interface tissue has become a topic of great interest in recent years. However, the complex nature of this interface has posed challenges in finding suitable solutions. Tissue engineering, with its potential to improve clinical outcomes and play a crucial role in musculoskeletal function, has been increasingly explored for tendon-bone interface regeneration. This review focuses on the research advancements of electrospinning technology in interface tissue engineering. By utilizing electrospinning, researchers have been able to fabricate scaffolds with tailored properties to promote the regeneration and integration of tendon and bone tissues. The review discusses the unique structure and function of the tendon-bone interface, the mechanisms involved in its healing, and the limitations currently faced in achieving successful regeneration. Additionally, it highlights the potential of electrospinning technology in scaffold fabrication and its role in facilitating the development of functional and integrated tendon-bone interface tissues. Overall, this review provides valuable insights into the application of electrospinning technology for tendon-bone interface tissue engineering, emphasizing its significance in addressing the challenges associated with regeneration in this complex interface., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

Background: The clinical benefits of immune checkpoint inhibitor (ICI)-based treatments in treating individuals with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who have progressed on EGFR tyrosine-kinase inhibitors (TKIs) remain controversial. We aimed to review the literature to comprehensively investigate the individual and comparative clinical outcomes of various ICI-based treatment strategies in this population., Methods: In this systematic review and meta-analysis, we used single-arm, pairwise, and network meta-analytical approaches. We searched PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and relevant international conference proceedings from database inception to Jan 31, 2024, without language restrictions, to identify eligible clinical trials that assessed ICI-based treatments for individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs. Studies considered eligible were published and unpublished phase 1, 2, or 3 clinical trials enrolling participants with histologically or cytologically confirmed advanced EGFR-mutated NSCLC who had progressed after at least one EGFR-TKI treatment, and that evaluated ICI-based treatment strategies on at least one of the clinical outcomes of interest. The primary outcome analysed was progression-free survival. The protocol is registered with PROSPERO, CRD42021292626., Findings: 17 single-arm trials and 15 randomised controlled trials, involving 2886 participants and seven ICI-based treatment strategies (ICI monotherapy, ICI plus chemotherapy [ICI-chemo], ICI plus antiangiogenesis [ICI-antiangio], ICI plus antiangiogenesis plus chemotherapy [ICI-antiangio-chemo], dual ICIs [ICI-ICI], dual ICIs plus chemotherapy [ICI-ICI-chemo], and ICI plus EGFR-TKI [ICI-TKI]), were included. Three of these strategies-ICI monotherapy, ICI-antiangio-chemo, and ICI-chemo-had sufficient data across the included studies to perform a pairwise meta-analysis. The pairwise meta-analysis showed that, compared with chemotherapy, ICI monotherapy led to shorter progression-free survival (hazard ratio [HR] 1·73 [95% CI 1·30-2·29], I 2 =0%), whereas ICI-antiangio-chemo (HR 0·54 [0·44-0·67], I 2 =0%) and ICI-chemo (HR 0·77 [0·67-0·88], I 2 =0%) prolonged progression-free survival. The network meta-analysis showed that ICI-antiangio-chemo yielded the best progression-free survival results, with substantial benefits over ICI-chemo (HR 0·71 [95% credible interval 0·59-0·85]), ICI monotherapy (HR 0·30 [0·22-0·41]), and non-ICI treatment strategies including antiangio-chemo (HR 0·76 [0·58-1·00]) and chemotherapy alone (HR 0·54 [0·45-0·64]). ICI-antiangio-chemo was associated with higher risks of both any-grade and grade 3 or worse adverse events over ICI-chemo and chemotherapy in the network meta-analysis., Interpretation: For individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs, ICI-antiangio-chemo was identified as the optimal treatment option. The toxicity of this treatment was acceptable but needs careful attention. ICI-chemo showed appreciably greater efficacy than the standard-of-care chemotherapy. These findings clarified the roles of ICI-based treatment strategies in this difficult-to-treat refractory population, potentially complementing recent guidelines., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Insomnia is the second most prevalent psychiatric disorder worldwide, but the understanding of the pathophysiology of insomnia remains fragmented. In this study, we calculated the connectome gradient in 50 chronic insomnia disorder (CID) patients and 38 healthy controls (HC) to assess changes due to insomnia and utilized these gradients in a connectome-based predictive modeling (CPM) to predict clinical symptoms associated with insomnia. The results suggested that insomnia led to significant alterations in the functional gradients of some brain areas. Specifically, the gradient scores in the middle frontal gyrus, superior anterior cingulate gyrus, and right nucleus accumbens were significantly higher in the CID patients than in the HC group, whereas the scores in the middle occipital gyrus, right fusiform gyrus, and right postcentral gyrus were significantly lower than in the HC group. Further correlation analysis revealed that the right middle frontal gyrus is positively correlated with the self-rating anxiety scale (r=0.3702). Additionally, the prediction model built with functional gradients could well predict the sleep quality (r=0.5858), anxiety (r=0.6150), and depression (r=0.4022) levels of insomnia patients. This offers an objective depiction of the clinical diagnosis of insomnia, yielding a beneficial impact on the identification of effective biomarkers and the comprehension of insomnia., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Directly regressing the non-rigid shape and camera pose from the individual 2D frame is ill-suited to the Non-Rigid Structure-from-Motion (NRSfM) problem. This frame-by-frame 3D reconstruction pipeline overlooks the inherent spatial-temporal nature of NRSfM, i.e., reconstructing the 3D sequence from the input 2D sequence. In this paper, we propose to solve deep sparse NRSfM from a sequence-to-sequence translation perspective, where the input 2D keypoints sequence is taken as a whole to reconstruct the corresponding 3D keypoints sequence in a self-supervised manner. First, we apply a shape-motion predictor on the input sequence to obtain an initial sequence of shapes and corresponding motions. Then, we propose the Context Layer, which enables the deep learning framework to effectively impose overall constraints on sequences based on the structural characteristics of non-rigid sequences. The Context Layer constructs modules for imposing the self-expressiveness regularity on non-rigid sequences with multi-head attention (MHA) as the core, together with the use of temporal encoding, both of which act simultaneously to constitute constraints on non-rigid sequences in the deep framework. Experimental results across different datasets such as Human3.6M, CMU Mocap, and InterHand prove the superiority of our framework. The code will be made publicly available.

Background: Colorectal polyps, which are characterized by a high recurrence rate, represent preneoplastic conditions of the intestine. Due to unclear mechanisms of pathogenesis, first-line therapies for non-hereditary recurrent colorectal polyps are limited to endoscopic resection. Although recent studies suggest a mechanistic link between intestinal dysbiosis and polyps, the exact compositions and roles of bacteria in the mucosa around the lesions, rather than feces, remain unsettled., Aim: To clarify the composition and diversity of bacteria in the mucosa surrounding or 10 cm distal to recurrent intestinal polyps., Methods: Mucosal samples were collected from four patients consistently with adenomatous polyps (Ade), seven consistently with non-Ade (Pol), ten with current Pol but previous Ade, and six healthy individuals, and bacterial patterns were evaluated by 16S rDNA sequencing. Linear discriminant analysis and Student's t -tests were used to identify the genus-level bacteria differences between groups with different colorectal polyp phenotypes. Pearson's correlation coefficients were used to evaluate the correlation between intestinal bacteria at the genus level and clinical indicators., Results: The results confirmed a decreased level of probiotics and an enrichment of pathogenic bacteria in patients with all types of polyps compared to healthy individuals. These changes were not restricted to the mucosa within 0.5 cm adjacent to the polyps, but also existed in histologically normal tissue 10 cm distal from the lesions. Significant differences in bacterial diversity were observed in the mucosa from individuals with normal conditions, Pol, and Ade. Increased abundance of Gram-negative bacteria, including Klebsiella , Plesiomonas , and Cronobacter , was observed in Pol group and Ade group, suggesting that resistance to antibiotics may be one risk factor for bacterium-related harmful environment. Meanwhile, age and gender were linked to bacteria changes, indicating the potential involvement of sex hormones., Conclusion: These preliminary results support intestinal dysbiosis as an important risk factor for recurrent polyps, especially adenoma. Targeting specific pathogenic bacteria may attenuate the recurrence of polyps., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Microplastics (MPs) and nanoplastics (NPs) are ubiquitous in the aquatic environment and have caused widespread concerns globally due to their potential hazards to humans. Especially, NPs have smaller sizes and higher penetrability, and therefore can penetrate the human barrier more easily and may pose potentially higher risks than MPs. Currently, most reviews have overlooked the differences between MPs and NPs and conflated them in the discussions. This review compared the differences in physicochemical properties and environmental behaviors of MPs and NPs. Commonly used techniques for removing MPs and NPs currently employed by wastewater treatment plants and drinking water treatment plants were summarized, and their weaknesses were analyzed. We further comprehensively reviewed the latest technological advances (e.g., emerging coagulants, new filters, novel membrane materials, photocatalysis, Fenton, ozone, and persulfate oxidation) for the separation and degradation of MPs and NPs. Microplastics are more easily removed than NPs through separation processes, while NPs are more easily degraded than MPs through advanced oxidation processes. The operational parameters, efficiency, and potential governing mechanisms of various technologies as well as their advantages and disadvantages were also analyzed in detail. Appropriate technology should be selected based on environmental conditions and plastic size and type. Finally, current challenges and prospects in the detection, toxicity assessment, and removal of MPs and NPs were proposed. This review intends to clarify the differences between MPs and NPs and provide guidance for removing MPs and NPs from urban water systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The label probe plays a crucial role in enhancing the sensitivity of lateral flow immunoassays. However, conventional fluorescent microspheres (FMs) have limitations due to their short fluorescence lifetime, susceptibility to background fluorescence interference, and inability to facilitate multi-component detection. In this study, carboxylate-modified Eu(III)-chelate-doped polystyrene nanobeads were employed as label probes to construct a multiple time-resolved fluorescent microsphere-based immunochromatographic test strip (TRFM-ICTS). This novel TRFM-ICTS facilitated rapid on-site quantitative detection of three mycotoxins in grains: Aflatoxin B1 (AFB1), Zearalenone (ZEN), and Deoxynivalenol (DON). The limit of detection (LOD) for AFB1, ZEN, and DON were found to be 0.03 ng/g, 0.11 ng/g, and 0.81 ng/g, respectively. Furthermore, the TRFM-ICTS demonstrated a wide detection range for AFB1 (0.05-8.1 ng/g), ZEN (0.125-25 ng/g), and DON (1.0-234 ng/g), while maintaining excellent selectivity. Notably, the test strip exhibited remarkable stability, retaining its detection capability even after storage at 4 °C for over one year. Importantly, the detection of these mycotoxins relied solely on simple manual operations, and with a portable reader, on-site detection could be accomplished within 20 min. This TRFM-ICTS presents a promising solution for sensitive on-site mycotoxin detection, suitable for practical application in various settings due to its sensitivity, accuracy, simplicity, and portability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Liquid biopsies utilizing tumor exosomes offer a noninvasive approach for cancer diagnosis. However, validation studies consistently report that in the early stages of cancer, the secretion of exosomes by cancer cells is relatively low, while bodily fluids exhibit a high abundance of other interfering biomolecules. Additionally, target mutations or differences in biomarker expression among various lung cancer subtypes may contribute to detection failures. In this study, we propose a targeted nanoarray-based early cancer diagnostic approach for multiple subtypes of lung cancer. The targeted nanoarray was constructed by modifying five targeting aptamers onto mesoporous silica nanoparticles through the conjugation between amino and carboxyl groups. The flow cytometry experiments demonstrated the specific recognition ability of the targeted nanoarray to tumor exosomes in PBS, even at biomarker expression levels as low as 1.5 %. Moreover, the TEM results indicated that the targeted nanoarray could isolate tumor exosomes in the blood of tumor-bearing mice. Furthermore, the targeted nanoarray could detect tumor exosomes in the blood of various lung cancer bearing mice, including at the early stages of cancer, which has just been established for 7 days. Overall, the targeted nanoarray represents a promising tool for the early detection of various subtypes of lung cancer., Competing Interests: Declaration of competing interest Xie Xiaodong is applying for a patent related to this work. The rest of the authors have no financial or non-financial competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, starch (S) was gelatinized and carbonized to prepare carbonized/gelatinized S (CGS) as the research material. Then, peat extract (Pe) and surfactants with different ratios were single- and multi-modified on CGS, respectively, to prepare Pe-modified CGS (Pe-CGS) and multi-modified CGS, respectively. The microscopic morphology of multi-modified CGS was studied using various testing methods. The de-risking effect on Cd(II) and hymexazol in wastewater was investigated, and the effects of temperature, pH, and ionic strength were compared. The spheroidal structure of S was destroyed after carbonization, and Pe and surfactants were modified on the surface and changed the surface properties of CGS. The adsorption processes of Cd(II) and hymexazol were suitable to be described by the Langmuir and Freundlich models, respectively. The maximum adsorption capacities (q m ) of Cd(II) and adsorption capacity parameter (k) of hymexazol on different modified CGSs presented the peak value at BS/Pe-CGS. With the increase in the modification ratio of Pe, BS, and SDS, q m and k increased, which showed a high value at 100 % modification. Increases in temperature and pH were beneficial to Cd(II) adsorption but were not conducive to hymexazol adsorption. The adsorption amount decreased for Cd(II) and increased first and then reduced for hymexazol with the rise in ionic strength. The adsorption process exhibited spontaneity, endothermic behavior for Cd(II), exothermic behavior for hymexazol, and an entropy-increasing reaction. The adsorption amount of Cd(II) and hymexazol by multi-modified CGS maintained approximately 81 % of the original sample after three rounds of regeneration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Immune dysfunction in early pregnancy including overactivation of cytotoxic CD16 + NK cells and proinflammatory M1 macrophages at the maternal-fetal interface interferes with trophoblast invasion, spiral artery remodeling, and decidualization, potentially leading to miscarriage. Immunosuppressants like glucocorticoids (GCs) are used to regulate the immune microenvironment in clinical treatment, but the lack of safe and efficient tissue-specific drug delivery systems, especially immune cell-specific vectors, limits their widespread clinical application. Here, a previously uncharacterized delivery system is reported, termed GC-Exo-CD16Ab, in which GCs are loaded into purified exosomes derived from human umbilical cord mesenchymal stem cells, and subsequently decorated with antibody CD16Ab. GC-Exo-CD16Ab is biocompatible and has remarkable delivery efficiency toward CD16 + decidual natural killer (NK) cells and CD16 + macrophages in mice. This innovative approach effectively suppresses the cytotoxicity of decidual NK cells, inhibits M1 macrophage polarization, and regulates the decidual microenvironment, thereby enhancing placental and fetal morphology, and ultimately mitigating miscarriage risk in the abortion-prone mice. The developed GC-Exo-CD16Ab provides a feasible platform for precise and tissue-specific therapeutic strategies for miscarriage and pregnancy-related diseases., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Machine learning techniques have significantly transformed the way materials scientists conduct research. However, the widespread deployment of machine learning software in daily experimental and simulation research for materials and chemical design has been limited. This is partly due to the substantial time investment and learning curve associated with mastering the necessary codes and computational environments. In this paper, we introduce a user-friendly, data-driven machine learning interface featuring multiple "button-clicking" functionalities to streamline the design of materials and chemicals. This interface automates the processes of transforming materials and molecules, performing feature selection, constructing machine learning models, making virtual predictions, and visualizing results. Such automation accelerates materials prediction and analysis in the inverse design process, aligning with the time criteria outlined by the Materials Genome Initiative. With simple button clicks, researchers can build machine learning models and predict new materials once they have gathered experimental or simulation data. Beyond the ease of use, NJmat offers three additional features for data-driven materials design: (1) automatic feature generation for both inorganic materials (from chemical formulas) and organic molecules (from SMILES), (2) automatic generation of Shapley plots, and (3) automatic construction of "white-box" genetic models and decision trees to provide scientific insights. We present case studies on surface design for halide perovskite materials encompassing both inorganic and organic species. These case studies illustrate general machine learning models for virtual predictions as well as the automatic featurization and Shapley/genetic model construction capabilities. We anticipate that this software tool will expedite materials and molecular design within the scope of the Materials Genome Initiative, particularly benefiting experimentalists.

Mycotoxins have strong immunotoxicity and can induce oxidative stress and mitochondrial dynamics imbalance. Mitochondrial antiviral signaling protein (MAVS) in the RIG-I like receptor (RLR) pathway of innate immunity is located on mitochondria, and whether it is affected by mycotoxins has not been reported yet. This experiment used porcine alveolar macrophages (PAM) to evaluate the antagonism of three isomers of chlorogenic acid (chlorogenic acid, isochlorogenic acid A, and neochlorogenic acid) against combined mycotoxins (Aflatoxin B1, Deoxynivalenol, and Ochratoxin A) induced mitochondrial damage and their effects on the RLR pathway, providing assistance for further elucidating the mechanism of mycotoxin immunotoxicity. Western blotting, enzyme linked immunosorbent assay (ELISA), and flow cytometry were used to detect relevant indicators. All three types of chlorogenic acid treatment can antagonize the cytotoxicity induced by combined mycotoxins, especially isochlorogenic acid A, which can protect cells from mycotoxins damage by maintaining mitochondrial dynamic homeostasis and improving innate immune function related to the RLR pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ferrous ion accumulation and lethal oxidative stress mediate irreversible retinal pigment epithelial (RPE) cell ferroptosis and subsequent photoreceptor degeneration, a potential key pathogenic factor in the onset of dry age-related macular degeneration (dAMD), causing irreversible vision loss in the global elderly population. However, currently, no effective interventional treatment strategy exists in clinical practice. Herein, lesion site-targeted melanin-like nanoparticles, named ConA-MelNPs, are designed as a novel ferroptosis inhibitor for retinal degenerative diseases. ConA-MelNPs possessed chelating iron ion characteristics, alleviating severe mitochondrial damage caused by oxidative stress and protecting RPE cells from ferroptosis induced by sodium iodate (NaIO 3 ). In a preclinical dAMD mouse model, a single intravitreal injection of ConA-MelNPs yielded significant responses in electroretinograms and visually-driven optomotor responses in visually impaired mice, resisting the challenge posed by secondary NaIO 3 -induced injuries, with the long-term sustainability of its therapeutic effect. Mechanistically, ConA-MelNPs achieve a therapeutic effect by interrupting the detrimental cascade involving "RPE cell ferroptosis, lethal oxidative stress, and microglial proinflammatory activation," affording the restoration of retinal homeostasis. The synthesized ConA-MelNPs demonstrated good biosafety, with no detected ophthalmic or systemic side effects. Collectively, ConA-MelNPs are proposed as a promising therapeutic option for atrophic retinal diseases such as dAMD., (© 2024 Wiley‐VCH GmbH.)

Bone tissue engineering scaffolds are an important means of repairing bone defects, but current solutions do not adequately simulate complex extracellular microenvironment fibrous structures and adjustable mechanical properties. We use template-assisted fiber freeze-shaping technology to construct silk fibroin nanofiber aerogels (SNFAs) with nanofibrous textures and adjustable mechanical properties. The parallel arranged channels, the pores, electrospun nanofibers, and silk protein conformation together constitute the hierarchical structure of SNFAs. Especially, the introduced electrospun nanofibers formed a biomimetic nanofibrous texture similar to the extracellular matrix, providing favorable conditions for cell migration and tissue regeneration. In addition, Young's modulus of SNFAs can be adjusted freely between 7 and 88 kPa. The rationally designed 3D architecture makes SNFAs perfectly mimic the fiber structure of the extracellular matrix and can adjust its mechanical properties to match the bone tissue perfectly. Finally, fiber-containing SNFAs observably promoted cell adhesion, proliferation, and differentiation, accelerating the bone repair process. The bone density in the defect area reached 0.53 g/cm 3 and the bone volume/total volume (BV/TV) ratio reached 57 % at 12 weeks, respectively. It can be expected that this kind of tissue engineering scaffold with highly simulating extracellular matrix microenvironment and adjustable mechanical properties will possess broad prospects in the field of bone repair., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Despite recent studies implicating liquid-like biomolecular condensates in diverse cellular processes, many biomolecular condensates exist in a solid-like state, and their function and regulation are less understood. We show that the tumor suppressor Merlin, an upstream regulator of the Hippo pathway, localizes to both cell junctions and medial apical cortex in Drosophila epithelia, with the latter forming solid-like condensates that activate Hippo signaling. Merlin condensation required phosphatidylinositol-4-phosphate (PI4P)-mediated plasma membrane targeting and was antagonistically controlled by Pez and cytoskeletal tension through plasma membrane PI4P regulation. The solid-like material properties of Merlin condensates are essential for physiological function and protect the condensates against external perturbations. Collectively, these findings uncover an essential role for solid-like condensates in normal physiology and reveal regulatory mechanisms for their formation and disassembly.