Search

Yaping Yu,1,* Shun Ding,2,* Xiaoqing Xu,1,* Dongming Yan,3 Yonghao Fan,1 Banzhan Ruan,1 Xiaodian Zhang,1 Liping Zheng,1 Wei Jie,1 Shaojiang Zheng1,4 1Department of Oncology of the First Affiliated Hospital & Tumor Institute, Hainan Medical University, Haikou, 570102, People’s Republic of China; 2Department of Otolaryngology, Head and Neck Surgery, the First Affiliated Hospital, Hainan Medical University, Haikou, 570102, People’s Republic of China; 3Department of Neurosurgery, the First Affiliated Hospital of Hainan Medical University, Haikou, 570102, People’s Republic of China; 4Key Laboratory of Emergency and Trauma, Ministry of Education, Hainan Medical University, Haikou, 571199, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Jie; Shaojiang Zheng, Department of Oncology of the First Affiliated Hospital & Tumor Institute, Hainan Medical University, Haikou, 570102, People’s Republic of China, Tel +86-898-66968217 ; +86-898-66568158, Email wei_jie@hainmc.edu.cn; zhengsj2008@163.comPurpose: This study aimed to explore the pharmacological mechanism of Dangshen (Codonopsis pilosula) against hepatocellular carcinoma (HCC) based on network pharmacology and bioinformatics, and to verify the anticancer effect of luteolin, the active ingredient of Codonopsis pilosula, on HCC cells.Methods: The effective compounds and potential targets of Codonopsis pilosula were established using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. The genes related to HCC were obtained through the GeneCards database. The interactive genes were imported into the Visualization and Integrated Discovery database for Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal enrichment, and the hub genes were screened out. The Cancer Genome Atlas database was used to construct a prognosis model, and the prognosis and clinicopathological correlation were analyzed. In in vitro experiments, we verified the effects of luteolin, an active compound of Codonopsis pilosula, on the proliferation, cell cycle, apoptosis and migration of HCC cells.Results: A total of 21 effective compounds of Codonopsis pilosula and 98 potential downstream target genes were screened through the TCMSP database, and 1406 HCC target genes were obtained through the GeneCards database. Finally, 53 interacting genes between the two databases were obtained, among which, the 10 key node genes were CASP3, TP53, MDM2, AKT1, ESR1, BCL2L1, MCL1, HSP90AA1, CASP9, and CCND1, involving 77 typical GO terms and 72 KEGG signals. The Kaplan–Meier survival curve of the model group showed that the overall survival of the low-risk group was significantly higher than that of the high-risk group. Luteolin significantly inhibited the proliferation and migration of HCC cells, induced apoptosis, and increased the G2/M phase ratio. Mechanistically, luteolin significantly inhibited the phosphorylation of MAPK-JNK and Akt (Thr308) and subsequently led to upregulation of ESR1. Pharmacological inhibition of ESR1 with fulvestrant enhanced cell viability and migration and attenuated apoptosis.Conclusion: Codonopsis pilosula has potential for clinical development due to its anti-HCC properties. Luteolin, the effective component of Codonopsis pilosula, plays anti-HCC role through AKT- or MAPK-JNK signaling mediated ESR1.Keywords: Codonopsis pilosula, network pharmacology, bioinformatics, luteolin, hepatocellular carcinoma

Objective: The growing prevalence of obesity among college students is a major public health issue, as over one-third are overweight or obese. This study used gender-stratified multivariate analyses to examine psychological distress and social contextual factors as key determinants of obesity. Participants: Students of a large public university in Southern California (N = 2392). Methods: In-class survey administered across various departments and general education courses. Results: Among females, distress (OR = 1.02) and sophomores (OR = 1.87) were associated with increased odds of obesity; Greek life (OR = 0.53) was associated with decreased odds of obesity. Among males, distress was not associated with obesity (OR = 1.00); financial strain (OR = 1.16) was associated with increased odds of obesity. Conclusions: There are gendered patterns in obesity risk with social context having potentially protective effects among women. Enhancing psychological wellbeing as well as creating gender- and context-specific interventions may be an effective strategy to address the rising rates of obesity among the college population.

BackgroundPap tests remain an essential cervical cancer detection method in the United States, yet they are underutilized among Pacific Islanders (PI) who experience elevated cervical cancer incidence and mortality. This study describes the design, methods, participants, and outcomes of a multiyear (2010-2016), community-based randomized intervention trial in southern California. Based upon strong collectivistic norms, the trial tested the efficacy of a unique social support intervention targeting Chamorro, Samoan, and Tongan women and their male husbands/partners.MethodsA single-session educational intervention was designed and tailored for ethnic- and gender-specific groups to increase men's social support for their female wives/partners to receive a Pap test, and for women to receive a Pap test. The comparison group received preexisting brochures on Pap testing (for women) or general men's health (for men). Pretest and 6-month follow-up data were analyzed.ResultsIntervention and comparison groups were mostly equivalent on pretest demographics and outcome variables. Intervention women who were not compliant with Pap screening recommendations at pretest were significantly more likely to have scheduled and received a Pap test at 6-month follow-up. However, 6-month follow-up results indicated no intervention effect on changes in women's Pap testing knowledge, fatalistic attitudes, or perceived social support from their male partner.ConclusionsEthnic- and gender-tailored community interventions can successfully increase Pap test behaviors for PI women, although more research is needed on the specific pathways leading to behavior change.ImpactCollaborative community-based interventions lead to increases in women's cancer prevention and early detection for Pacific Islander and other collectivistic communities.

This study employed a Multi-Attribute Utility (MAU) model to examine the Pap test decision-making process among Pacific Islanders (PI) residing in Southern California. A total of 585 PI women were recruited through social networks from Samoan and Tongan churches, and Chamorro family clans. A questionnaire assessed Pap test knowledge, beliefs and past behaviour. The three MAU parameters of subjective value, subjective probability and momentary salience were measured for eight anticipated consequences of having a Pap test (e.g., feeling embarrassed, spending money). Logistic regression indicated that women who had a Pap test (Pap women) had higher total MAU utility scores compared to women who had not had a Pap test within the past three years (No Pap women) (adjusted Odds Ratio = 1.10). In particular, Pap women had higher utilities for the positive consequences 'Detecting cervical cancer early, Peace of mind, and Protecting my family', compared to No Pap women. It is concluded that the connection between utility and behaviour offers a promising pathway toward a better understanding of the decision to undergo Pap testing.

BackgroundPacific Islanders (PIs) experience high cervical cancer rates in the United States. Stage of diagnosis is also later for PIs than non-Hispanic Whites. The Pap test is severely underutilized among PIs: only 71% of Asian American and Pacific Islander women age 25 years or older received a Pap test within the last 3 years (U.S. average, 82%). Community-based participatory research (CBPR) is increasingly seen as an essential approach in designing and conducting culturally relevant and appropriate studies that reduce cancer incidence and other health disparities among minority and other medically underserved populations.PurposeThe purpose of this article is to describe the lessons learned thus far regarding the identification, recruitment, and retention of PI community organizations and members into a CBPR-informed, randomized, community trial promoting Pap testing.MethodsThis 5-year study used CBPR to develop and test the efficacy of a social support intervention for Chamorro, Samoan, and Tongan women to increase Pap testing in southern California. Eligible women were between the ages of 21 and 65, and married or in a long-term relationship with a man for at least 5 years. Women and their husbands or significant others received a 2-hour, culturally tailored workshop that include a group activity, information on Pap testing, a video, and corresponding materials. Comparison participants received a brochure about Pap testing. Three waves of data are collected from all participants: pretest (before workshop or brochure), posttest 1 (immediately after workshop or brochure), and posttest 2 (6 months follow-up).ResultsOf the 76 organizations approached to participate in the study, 67 (88.2%) eventually agreed to participate. Thus far, 473 women and 419 men completed the study pretest, post-test, education, and 6-month follow-up. Only 242 women and 204 men of the eligible participants have completed the follow-up survey (63.5% of women and 60.5% of men retained after 6 months).Lessons learnedThe main strategy to overcome initial recruitment challenges was study staff persistence, because they averaged five contacts with each church or clan leader before receiving confirmation that an educational session can be scheduled. Personal connections provided an introduction to the most appropriate church or clan leader. Other efforts for retention include creation of an online version of the survey, re-attending church services, and creating special events organized around clan activities.ConclusionsAlthough CBPR improves the cultural competence and relevance of study activities for ethnically diverse populations, selected past research shows that it does not ensure that such designs overcome all of the unique challenges in ethnically diverse communities. PI-specific organizational recruitment and individual retention is influenced by study issues and cultural factors in each community.

PurposeThis study examined differences in smoking prevalence and differences in associations between family functioning, self-image and adolescent smoking behavior among four Asian-American subgroups.MethodsStatistical analyses were conducted on responses about their smoking behaviors from 1139 students who self-identified as Chinese-Americans, Filipino-Americans, Korean-Americans, and Vietnamese-Americans.ResultsSignificant differences in the prevalence of ever-tried smoking and 30-day smoking were found across subgroups, but there were no overall gender differences. Korean-American adolescents reported the highest lifetime smoking and 30-day smoking rates, followed by Vietnamese- and Filipino-Americans. Chinese-Americans reported the lowest smoking rates. There were also differences in the associations between smoking and family functioning and self-image across the four subgroups. High family functioning was inversely associated with smoking for Chinese- and Korean-American adolescents, but not for Filipino- and Vietnamese-Americans. On the other hand, high self-image was associated with decreased risk of smoking for Filipino- and Vietnamese-Americans, but not for the other two subgroups.ConclusionFindings of this study demonstrate that family functioning and self-image varied across Asian-American subgroups. This suggests the need to understand etiological differences between the groups as well as potential implications for prevention cessation programs.

Introduction: The proportion of animal based foods in daily diet of consumers is constantly increasing, with chicken being highly favored due to its high protein and low fat characteristics. The consumption of chicken around the world is steadily increasing. Intramuscular fat (IMF) is a key indicator affecting meat quality. Object: High IMF content can contribute to improve the quality of chicken meat. The regulatory mechanism of IMF deposition in chicken is poorly understood, so its complete elucidation is essential to improve chicken meat quality. Method: Here, we performed whole genome resequencing on 516 yellow feather chickens and single-cell RNA sequencing on 3 63-day-old female JXY chickens. In addition, transcriptome sequencing techniques were also performed on breast muscle tissue of JXY chickens at different developmental stages. And 13C isotope tracing technique was applied. Results: In this study, a large-scale genetic analysis of an IMF-selected population and a control population identified fatty acid synthase (FASN) as a key gene for improving IMF content. Also, contrary to conventional view, de novo lipogenesis (DNL) was deemed to be an important contributor to IMF deposition. As expected, further analyses by isotope tracing and other techniques, confirmed that DNL mainly occurs in myocytes, contributing about 40% of the total fatty acids through the regulation of FASN, using the available FAs as substrates. Additionally, we also identified a relevant causal mutation in the FASN gene with effects on FA composition. Conclusion: These findings contribute to the understanding of fat metabolism in muscle tissue of poultry, and provide the feasible strategy for the production of high-quality chicken meat.

Abstract Background Laryngeal cancer (LCA) is one of the most common head and neck squamous cell carcinoma with poor outcome. LCA stem cells are the main reason for LCA therapy resistance and relapse. Understanding the molecular mechanisms of the self-renew of LCA stem cells is critical to develop now targets and strategies for LCA therapy. Methods Q-PCR and western blotting assays were used to determine NID1 level in LCA tissues and normal laryngeal tissues. MTT, colony formation assay, apoptosis assay and animal model were used to investigate the effect of NID1 on radiotherapy resistance. Side population assay and sphere formation assay were used to determine the role of LCA in the self-renew of LCA stem cells. Results NID1 was upregulated in LCA tissues, particularly in LCA tissues derived from relapsed patients, and associated with had poor outcome. NID1 knockdown suppressed radiotherapy resistance and the self-renew of LCA stem cells, while NID1 overexpression promoted radiotherapy resistance and the self-renew of LCA stem cells. Further analysis showed that NID1 promotes radiotherapy resistance and the self-renew of LCA stem cells via activating WNT pathway. Moreover, NID1 level was positively correlated with nuclear β-Catenin level in LCA tissues. Conclusion Our results show that NID1 promotes radiotherapy resistance and the self-renew of LCA stem cells via activating WNT pathway, providing a novel potential target for LCA treatment.

Abstract The preservation of the left colic artery (LCA) during rectal cancer resection remains a topic of controversy, and there is a notable absence of robust evidence regarding the outcomes associated with LCA preservation. And the advantages of robotic-assisted laparoscopy (RAL) surgery in rectal resection remain uncertain. The objective of this study was to assess the influence of LCA preservation surgery and RAL surgery on intraoperative and postoperative complications of rectal cancer resection. Patients who underwent laparoscopic (LSC) or RAL with or without LCA preservation resection for rectal cancer between April 2020 and May 2023 were retrospectively assessed. The patients were categorized into two groups: low ligation (LL) which with preservation of LCA and high ligation (HL) which without preservation of LCA. A one-to-one propensity score-matched analysis was performed to decrease confounding. The primary outcome was operative findings, operative morbidity, and postoperative genitourinary function. A total of 612 patients were eligible for this study, and propensity score matching yielded 139 patients in each group. The blood loss of the LL group was significantly less than that of the HL group (54.42 ± 12.99 mL vs. 65.71 ± 7.37 mL, p

Abstract Notch signaling activation drives an endothelial-to-mesenchymal transition (EndMT) critical for heart development, although evidence suggests that the reprogramming of endothelial cell metabolism can regulate endothelial function independent of canonical cell signaling. Herein, we investigated the crosstalk between Notch signaling and metabolic reprogramming in the EndMT process. Biochemically, we find that the NOTCH1 intracellular domain (NICD1) localizes to endothelial cell mitochondria, where it interacts with and activates the complex to enhance mitochondrial metabolism. Targeting NICD1 to mitochondria induces more EndMT compared with wild-type NICD1, and small molecule activation of PDH during pregnancy improves the phenotype in a mouse model of congenital heart defect. A NOTCH1 mutation observed in non-syndromic tetralogy of Fallot patients decreases NICD1 mitochondrial localization and subsequent PDH activity in heart tissues. Altogether, our findings demonstrate NICD1 enrichment in mitochondria of the developing mouse heart, which induces EndMT by activating PDH and subsequently improving mitochondrial metabolism.

Abstract Background Heat stress (HS) commonly occurring in summer has gradually become a factor threatening the reproductive performance of male dairy goats by reducing their fecundity. Despite the melatonin is applied to relieve HS, it is still unclear whether melatonin protects against reproductive damage induced by HS in dairy goats and how it works. The purpose of the present study is to evaluate the role of melatonin in alleviating HS-induced spermatogenesis dysfunction in male dairy goats and further explore its mechanism. Results HS impaired spermatogenesis, sperm formation in the testes, and sperm maturation in the epididymis of dairy goats, resulting in decreased sperm quality. Melatonin rescued the decrease of sperm quality induced by HS via decreasing inflammatory and oxidative stress levels in testicular tissue and enhancing intercellular barrier function within the testes. Amplicon-based microbiota analysis revealed that despite gut microbiota differences between melatonin-treated dairy goats and NC dairy goats to some extent, melatonin administration tends to return the gut microbiota of male dairy goats under HS to the levels of natural control dairy goats. To explore whether the protective role of melatonin in sperm quality is mediated by regulating gut microbiota, fecal microbiota of HS dairy goats with or without melatonin treatment were transferred to HS mice, respectively. We found HS mice that had received fecal bacteria of HS dairy goats experienced serious testicular injury and dyszoospermia, while this phenomenon was ameliorated in HS mice that had received fecal bacteria of dairy goats treated with melatonin, indicating melatonin alleviates HS-induced spermatogenic damage in a microbiota dependent manner. We further found that the testicular tissue of both HS dairy goats and mice transplanted with HS dairy goat feces produced large amounts of arachidonic acid (AA)-related metabolites, which were closely associated with semen quality. Consistently, supplementation with AA has been shown to elevate the levels of inflammation and oxidative stress in the testicular tissue of mice, disrupting intercellular connections and ultimately leading to spermatogenic disorders. Conclusion This study has revealed that melatonin can effectively alleviate spermatogenic disorders in dairy goats caused by HS. This beneficial effect was primarily achieved through the modulation of gut microbiota, which subsequently inhibited the excessive synthesis of AA in testicular tissue. These discoveries are of great significance for preventing or improving the decline in male livestock reproductive performance caused by HS, enhancing the reproductive efficiency of elite male breeds, and ultimately improving the production efficiency of animal husbandry. Video Abstract

Abstract Tropical cyclones have a big impact on flood risk, and understanding how their activity interacts with population exposure under climate change is critical. Here we investigate spatiotemporal changes in flood risk using numerical models together with historical observations and future projections of tropical cyclone tracks. We find that tropical cyclone-related flood risk shifts from the Mekong Delta to the eastern lower Mekong Basin, driven by the interaction between tropical cyclones and population exposure. Historically, extreme precipitation from tropical cyclones increased flood risk in about 14% and decreased in 7% of the basin. Future tropical cyclones may increase flood risk in about 7% and reduce in nearly 18% of the basin. Moreover, population exposure growth has historically increased flood risk in 3% of the basin and is projected to result in a 1% increase. These findings highlight the complex interactions of tropical cyclone hazards and socioeconomic factors influencing flood risk.

Abstract Background 3D brachial plexus MRI scanning is prone to examination failure due to the lengthy scan times, which can lead to patient discomfort and motion artifacts. Our purpose is to investigate the efficacy of artificial intelligence-assisted compressed sensing (ACS) in improving the acceleration efficiency and maintaining or enhancing the image quality of brachial plexus MR imaging. Methods A total of 30 volunteers underwent 3D sampling perfection with application-optimized contrast using different flip angle evolution short time inversion recovery using a 3.0T MR scanner. The imaging protocol included parallel imaging (PI) and ACS employing acceleration factors of 4.37, 6.22, and 9.03. Radiologists evaluated the neural detail display, fat suppression effectiveness, presence of image artifacts, and overall image quality. Signal intensity and standard deviation of specific anatomical sites within the brachial plexus and background tissues were measured, with signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) subsequently calculated. Cohen's weighted kappa (κ), One-way ANOVA, Kruskal–Wallis and pairwise comparisons with Bonferroni-adjusted significance level. P 0.05). For subjective scores, ACS 9.03 were lower than the other three sequences in neural details display, image artifacts and overall image quality. There was no significant difference in fat suppression. For objective quantitative evaluation, SNR of right C6 root in ACS 6.22 and ACS 9.03 was higher than that in PI; SNR of left C6 root in ACS 4.37, ACS 6.22 and ACS 9.03 was higher than that in PI; SNR of medial cord in ACS 6.22, ACS 9.03 was higher than that in PI. Conclusion Compared with PI, ACS can shorten scanning time while ensuring good image quality.

Abstract Introduction Major depressive disorder (MDD) is a common mental disease that significantly impact the daily lives of those affected. Acupuncture has shown promising therapeutic effects in the treatment of MDD, but its underlying mechanisms remain unclear. This study aims to evaluate the influence of acupuncture on the brain function of patients with MDD and it’s therapeutic effects on MDD. Methods This study plans to recruit 112 participants, who will be randomly allocated to either the acupuncture group or the sham acupuncture group in a 1:1 ratio. Both groups will undergo 8 weeks of treatment, consisting of three sessions per week, with each session lasting for 30 min. A follow-up period of 3 months will be conducted after the treatment. Assessments will be conducted at weeks 0, 8, 12, 16, and 20 in this study. The primary outcome measure will be functional near-infrared spectroscopy (fNIRS) brain imaging, while secondary outcome measures will include Beck Depression Inventory II (BDI-II), Self-Rating Anxiety Scale (SAS), 36-Item Short Form Survey Instrument (SF-36), Traditional Chinese Medicine (TCM) syndrome score scale, and symptom elimination rate. Discussion While acupuncture has been confirmed to have a certain degree of therapeutic efficacy in the treatment of MDD, research on the mechanisms underlying acupuncture’s treatment of MDD remains limited, particularly with regards to its impact on the brain function of individuals with MDD. This study aims to explore both the clinical effectiveness and treatment mechanisms of acupuncture for MDD, with a specific focus on its influence on brain function. This research endeavors to provide new insights into the potential of acupuncture as a therapeutic approach for the treatment of MDD in the future. Trial Registration www.chictr.org.cn , ID: ChiCTR2300076292. Registered on 28 September 2023.

Abstract Sepsis is a clinical syndrome caused by infection, leading to organ dysfunction due to a dysregulated host response. In recent years, its high mortality rate has made it a significant cause of death and disability worldwide. The pathophysiological process of sepsis is related to the body’s dysregulated response to infection, with microcirculatory changes serving as early warning signals that guide clinical treatment. The Peripheral Perfusion Index (PI), as an indicator of peripheral microcirculation, can effectively evaluate patient prognosis. This study aims to develop two new prediction models using PI and other common clinical indicators to assess the mortality risk of sepsis patients during hospitalization and within 28 days post-ICU admission. This retrospective study analyzed data from sepsis patients treated in the Intensive Care Unit of Peking Union Medical College Hospital between December 2019 and June 2023, ultimately including 645 patients. LASSO regression and logistic regression analyses were used to select predictive factors from 35 clinical indicators, and two clinical prediction models were constructed to predict in-hospital mortality and 28-day mortality. The models’ performance was then evaluated using ROC curve, calibration curve, and decision curve analyses. The two prediction models performed excellently in distinguishing patient mortality risk. The AUC for the in-hospital mortality prediction model was 0.82 in the training set and 0.73 in the validation set; for the 28-day mortality prediction model, the AUC was 0.79 in the training set and 0.73 in the validation set. The calibration curves closely aligned with the ideal line, indicating consistency between predicted and actual outcomes. Decision curve analysis also demonstrated high net benefits for the clinical utility of both models. The study shows that these two prediction models not only perform excellently statistically but also hold high practical value in clinical applications. The models can help physicians accurately assess the mortality risk of sepsis patients, providing a scientific basis for personalized treatment.

Abstract Due to the influence of construction quality, engineering geology and hydrological environment, defects such as dehollowing and insufficient compaction can occur in tunnels. Aiming at the problems of complex detection model, poor real-time performance and low accuracy of the current tunnel lining defect detection methods, the study proposes a lightweight defect detection algorithm of tunnel lining based on knowledge distillation. Firstly, a high-precision teacher model based on yolov5s was constructed by constructing a C3CSFM module that combines residual structure and attention mechanism, a MDFPN network structure with multi-scale feature fusion and a reweighted RWNMS re-screening mechanism. Secondly, in the distillation process, the feature and output dimension results are fused to improve the detection accuracy, and the mask feature relationship is learned in the space and channel dimension to improve the real-time detection. Tests on the tunnel lining radar defect image dataset showed that the number of parameters of the improved model was reduced from 16.03 MB to 3.20 MB, a reduction of 80%, and the average accuracy was improved from 83.4 to 86.5%, an increase of 3.1%. On the basis of maintaining the structure and detection performance of the model, the lightweight degree of the model is greatly improved, and the high-precision and real-time detection of tunnel lining defects is realized.

Abstract Due to the polycrystalline cubic boron nitride tool has the characteristics of high hardness, brittleness, etc., it is easy to break the tool or produce defects in the laser cutting process, which affects the cutting performance of the tool. Traditional defect detection methods can no longer meet the needs of modern manufacturing. Aiming at the problems of low accuracy and poor real-time detection of surface defects on laser-cutting polycrystalline cubic boron nitride tools, this study proposes the surface defect detection model of laser cutting polycrystalline cubic boron nitride tool based on asymptotic fusion strategy, which fills the gap in the field. In the backbone network, the C3SE module is constructed by modeling the correlation between feature channels to improve the model’s focus on key features in order to enhance the feature extraction and processing capability of the backbone network; In the neck network, adaptive spatial fusion operation and direct interaction of non-adjacent layers are utilized for multi-scale information fusion, and the asymptotic feature pyramid network for object detection (AFPN) is used instead of the FPN structure to improve the detection performance; In the head network, a soft suppression mechanism is introduced to reduce the overlapping frame score using a decay function, thus improving the detection accuracy. The experimental results based on the self-constructed laser-cutting polycrystalline cubic boron nitride tool surface defects dataset show that the average accuracy of the AFFS-YOLO model is improved by 5.6% compared with that of the YOLOv5 model, reaching 86.1%, and the detection effect is better than that of the original network and other classical target detection networks.

Abstract Neurons often grow highly branched and cell-type specific dendrite morphologies to receive and integrate information, which is the basis of precise neural circuit formation. Previous studies have identified numerous mechanisms that promote dendrite branching. In contrast, it is much less understood how this process is negatively regulated. Here we show that EAT-17/EVI5 acts together with the dynein adaptor protein BICD-1 and the motor protein dynein in C. elegans epidermal cells to restrict branching of PVD sensory dendrites. Loss-of-function mutants of these genes cause both ectopic branching and accumulation of the dendrite branching ligand SAX-7/L1CAM on epidermal plasma membranes. Mutants of genes regulating endo-lysosomal trafficking, including rab-5/RAB5 and dyn-1/DNM1, show similar defects. Biochemical characterization, genetic analysis, and imaging results support that EAT-17 and BICD-1 directly interact with each other and function in the endocytic degradation pathway to remove ectopically localized dendrite branching ligands to restrict abnormal branching.

Abstract The 2023/24 El Niño ranks as the second strongest event in the twenty-first century thus far. The event exhibited a two-step warming tendency and two warming centers, which could not be explained by the heat content buildup. Here, by conducting observational analysis and model experiments, we show that the record-breaking pantropical warming in 2023 mitigated this El Niño and confined the warming to the eastern basin, and that a series of westerly wind bursts induced another warming center in the central equatorial Pacific toward the end of 2023. Yet the effects of pantropical forcing and wind bursts coincidentally offset each other, leaving the heat content buildup appearing as the primary cause of the 2023/24 El Niño. Our results not only confirm the essential role of equatorial ocean heat recharge for El Niño development, but also demonstrate the necessity of accounting for multi-scale interactions from a global perspective to predict El Niño.

In this paper, the content of active ingredients and antioxidant capacity of different parts of Hoxylon and Red Willow Cistanche deserticola, from Hotan Cele County, Xinjiang, were evaluated. The results showed that the active substances, including total phenols, total flavonoids, total sugars, and verbascoside of Red Willow Cistanche deserticola, were the highest in the lower part of the plant, and decreased in the middle and upper parts. In terms of total phenols and total flavonoids, the contents of the lower part of Red Willow Cistanche deserticola (38.35 mg GAE/g DW, 35.61 mg RE/g DW) were 2.47 and 10.95 times compared to the lower part of Hoxylon Cistanche deserticola, respectively. The upper part of Hoxylon Cistanche deserticola showed the highest content of echinacoside with 92.93 mg/g DW. And the total triterpene content of the lower part-especially that of Hoxylon Cistanche deserticola was significantly higher than the upper and middle part (P

At the altitude of low-Earth-orbiting satellites, most details of lithospheric magnetic anomalies observed near surface are attenuated, and only slowly decaying long-wavelength magnetic anomalies can be detected. Long-wavelength magnetic anomalies are generated by large-scale magnetized rocks in the Earth's crust and uppermost mantle at depths shallower than the Curie depth. Interpretation of such lithospheric magnetic anomalies has been used in geological mapping, crustal composition and structure studies, plate tectonic reconstruction, and geodynamics. To introduce the origin of long-wavelength magnetic anomalies at a global scale, we first reviewed satellite magnetic anomaly maps in early periods and calculated anomaly maps using four main lithospheric magnetic field models, including the CHAOS-7, CM6, MF7, and CSES models. Then, based on the result of the CHAOS-7 model at 500 km altitude, 29 long-wavelength magnetic anomalies with amplitudes greater than 4 nT were identified and their geological origins were reviewed. Among these, there were twenty magnetic anomalies over continents and nine over the ocean. The long-wavelength magnetic anomalies over continental areas were mostly located in Precambrian basements related to the Archean nuclei, Proterozoic terrane, and iron-rich formations, with a few located in the orogenic background. The long-wavelength magnetic anomalies in the ocean region were all located in oceanic plateau, generally related to the breakup of Gondwana during the Cretaceous Period, and have the characteristics of thickened crust. Hence, the long-wavelength magnetic anomalies reveal a significant magnetization difference in the deep crust during crustal growth, a key issue that requires further study. Compared to satellite magnetic surveys in some other nations, detecting lithospheric magnetic anomalies by satellite started relatively late in China. The China Seismo-Electromagnetic Satellite (CSES) was launched in February 2018. It was China's first satellite designed to monitor earthquakes with multiple geophysical payloads, including magnetometers capable of measuring weak signals from the lithosphere. The Macau Science Satellite-1 (MSS-1) was launched in 2023 and is specially used for monitoring the geomagnetic field in low latitudes. Furthermore, a subsequent CSES-02 satellite is planned to be launched in 2024. With the vigorous development of satellite magnetic surveys in China, it is expected that progressively more Chinese researchers will pay attention to long-wavelength magnetic anomalies and promote the study of their origin.

Low Earth orbit (LEO) satellites have emerged as a primary tool for global geomagnetic field detection and model refinement, owing to their wide coverage, high resolution, and absence of geographical limitations. This paper provides a comprehensive review of the history, key characteristics, measurement accuracy, and future trends in LEO satellite magnetic field measurements. The first part of the paper outlines the evolution of LEO satellites, highlighting their unique advantages. The focus then shifts to the calibration methodology for in-orbit LEO satellite magnetic measurements, with a specific emphasis on vector magnetic field intrinsic calibration and alignment algorithms. Calibration results are presented to demonstrate the effectiveness of these methodologies. In the third section, the paper introduces the theory behind global geomagnetic field modeling. An overview of current global geomagnetic field models is provided, encompassing their sources, spatial resolutions, and other relevant attributes. The paper concludes by presenting the global morphology and features of the main field, lithospheric field, magnetospheric, and ionospheric field. Despite the significant progress enabled by LEO satellite technology, global geomagnetic field modeling faces challenges such as limited spatio-temporal resolution. To address this, incorporating near-surface observation data and continuously optimizing modeling technology are deemed essential solutions.

The development of piezoelectric ceramics characterized by both large piezoelectric response and high-temperature stability is imperative for the advancement of practical electromechanical devices. However, existing high-performance piezoelectric ceramics often encounter compromised temperature stability because ferroelectric phase transitions occur within low-temperature regions. In this work, we focused on Sm-doped Pb(Ni1/3Nb2/3)O3–PbZrO3–PbTiO3 (PNN–PZT:Sm) ceramics with a tetragonal (T)-phase structure to achieve the desired combination of high piezoelectricity and high temperature stability. The results indicate that 2 mol% Sm-doped samples exhibit a large piezoelectric constant (d33) of 575 pC/N, an effective piezoelectric strain coefficient (d33*) of 890 pm/V, and a high ferroelectric-to-paraelectric phase transition temperature (Tm) of 279 °C. Remarkably, d33 experiences only a 2.6% variation over the temperature range of 30–250 °C, while d33* changes by 8% within the temperature range of 30–180 °C. Microstructural and domain structure analyses suggest that Sm-doping effectively reduces the grain size, leading to a decreased domain size, thereby achieving excellent electromechanical properties. The superior temperature stability is attributed to the suppressive effect of Sm-doping on the R–T ferroelectric phase transition. These studies suggest that Sm-doping represents an effective strategy for achieving the collaborative optimization of piezoelectricity and temperature stability through grain and domain engineering techniques for perovskite ferroelectric materials.

Abstract Obesity-induced β cell dysfunction contributes to the onset of type 2 diabetes. Nevertheless, elucidating epigenetic mechanisms underlying islet dysfunction at single cell level remains challenging. Here we profile single-nuclei RNA along with enhancer marks H3K4me1 or H3K27ac in islets from lean or obese mice. Our study identifies distinct gene signatures and enhancer states correlating with β cell dysfunction trajectory. Intriguingly, while many metabolic stress-induced genes exhibit concordant changes in both H3K4me1 and H3K27ac at their enhancers, expression changes of specific subsets are solely attributable to either H3K4me1 or H3K27ac dynamics. Remarkably, a subset of H3K4me1+H3K27ac- primed enhancers prevalent in lean β cells and occupied by FoxA2 are largely absent after metabolic stress. Lastly, cell-cell communication analysis identified the nerve growth factor (NGF) as protective paracrine signaling for β cells through repressing ER stress. In summary, our findings define the heterogeneous enhancer responses to metabolic challenges in individual β cells.

Abstract Chronic pain dramatically affects life qualities of the sufferers. It has posed a heavy burden to both patients and the health care system. However, the current treatments for chronic pain are usually insufficient and cause many unwanted side effects. Chemokine C–X–C motif ligand 13 (CXCL13), formerly recognized as a B cell chemokine, binds with the cognate receptor CXCR5, a G-protein-coupled receptor (GPCR), to participate in immune cell recruitments and immune modulations. Recent studies further demonstrated that CXCL13–CXCR5 signaling is implicated in chronic pain via promoting neuroimmune interaction and neuroinflammation in the sensory system. In addition, some latest work also pointed out the involvement of CXCL13–CXCR5 in the pathogenesis of certain neurological diseases, including ischemic stroke and amyotrophic lateral sclerosis. Therefore, we aim to outline the recent findings in regard to the involvement of CXCL13–CXCR5 signaling in chronic pain as well as certain neurological diseases, with the focus on how this chemokine signaling contributes to the pathogenesis of these neurological diseases via regulating neuroimmune interaction and neuroinflammation. Strategies that can specifically target CXCL13–CXCR5 signaling in distinct locations may provide new therapeutic options for these neurological diseases.

Abstract Invasive fungal infections (IFIs) pose a significant threat to immunocompromised individuals, leading to considerable morbidity and mortality. Prompt and accurate diagnosis is essential for effective treatment. Here we develop a rapid molecular diagnostic method that involves three steps: fungal enrichment using affinity-magnetic separation (AMS), genomic DNA extraction with silicon hydroxyl magnetic beads, and detection through a one-pot system. This method, optimized to detect 30 CFU/mL of C. albicans in blood and bronchoalveolar lavage (BAL) samples within 2.5 h, is approximately 100 times more sensitive than microscopy-based staining. Initial validation using clinical samples showed 93.93% sensitivity, 100% specificity, and high predictive values, while simulated tests demonstrated 95% sensitivity and 100% specificity. This cost-effective, highly sensitive technique offers potential for use in resource-limited clinical settings and can be easily adapted to differentiate between fungal species and detect drug resistance.

Abstract Posttraumatic stress disorder (PTSD) is associated with glutamatergic neuron hyperactivation in the basolateral amygdala (BLA) brain area, while GABAergic interneurons in the BLA modulate glutamatergic neuron excitability. Studies have shown that propofol exerts its effects through potentiation of the inhibitory neurotransmitter γ-aminobutyric acid. The neuronal mechanism by which propofol anesthesia modulates fear memory is currently unknown. Here, we used optogenetics and chemogenetics to suppress glutamatergic neurons or activate GABAergic interneurons in the BLA to assess alterations in neuronal excitation-inhibition balance and investigate fear memory. The excitability of glutamatergic neurons in the BLA was significantly reduced by the suppression of glutamatergic neurons or activation of GABAergic interneurons, while propofol-mediated enhancement of fear memory was attenuated. We suggest that propofol anesthesia could reduce the excitability of GABAergic neurons through activation of GABAA receptors, subsequently increasing the excitability of glutamatergic neurons in the mice BLA; the effect of propofol on enhancing mice fear memory might be mediated by strengthening glutamatergic neuronal excitability and decreasing the excitability of GABAergic neurons in the BLA; neuronal excitation-inhibition imbalance in the BLA might be important in mediating the enhancement of fear memory induced by propofol.

Abstract Background Rapid on-site evaluation (ROSE) plays an important role during transbronchial sampling, providing an intraoperative cytopathologic evaluation. However, the shortage of cytopathologists limits its wide application. This study aims to develop a deep learning model to automatically analyze ROSE cytological images. Methods The hierarchical multi-label lung cancer subtyping (HMLCS) model that combines whole slide images of ROSE slides and serum biological markers was proposed to discriminate between benign and malignant lesions and recognize different subtypes of lung cancer. A dataset of 811 ROSE slides and paired serum biological markers was retrospectively collected between July 2019 and November 2020, and randomly divided to train, validate, and test the HMLCS model. The area under the curve (AUC) and accuracy were calculated to assess the performance of the model, and Cohen’s kappa (κ) was calculated to measure the agreement between the model and the annotation. The HMLCS model was also compared with professional staff. Results The HMLCS model achieved AUC values of 0.9540 (95% confidence interval [CI]: 0.9257–0.9823) in malignant/benign classification, 0.9126 (95% CI: 0.8756–0.9365) in malignancy subtyping (non-small cell lung cancer [NSCLC], small cell lung cancer [SCLC], or other malignancies), and 0.9297 (95% CI: 0.9026–0.9603) in NSCLC subtyping (lung adenocarcinoma [LUAD], lung squamous cell carcinoma [LUSC], or NSCLC not otherwise specified [NSCLC-NOS]), respectively. In total, the model achieved an AUC of 0.8721 (95% CI: 0.7714–0.9258) and an accuracy of 0.7184 in the six-class classification task (benign, LUAD, LUSC, NSCLC-NOS, SCLC, or other malignancies). In addition, the model demonstrated a κ value of 0.6183 with the annotation, which was comparable to cytopathologists and superior to trained bronchoscopists and technicians. Conclusion The HMLCS model showed promising performance in the multiclassification of lung lesions or intrathoracic lymphadenopathy, with potential application to provide real-time feedback regarding preliminary diagnoses of specimens during transbronchial sampling procedures. Clinical trial number Not applicable.

Abstract The Equilibrium Optimiser (EO) has been demonstrated to be one of the metaheuristic algorithms that can effectively solve global optimisation problems. Balancing the paradox between exploration and exploitation operations while enhancing the ability to jump out of the local optimum are two key points to be addressed in EO research. To alleviate these limitations, an EO variant named adaptive elite‐guided Equilibrium Optimiser (AEEO) is introduced. Specifically, the adaptive elite‐guided search mechanism enhances the balance between exploration and exploitation. The modified mutualism phase reinforces the information interaction among particles and local optima avoidance. The cooperation of these two mechanisms boosts the overall performance of the basic EO. The AEEO is subjected to competitive experiments with state‐of‐the‐art algorithms and modified algorithms on 23 classical benchmark functions and IEE CEC 2017 function test suite. Experimental results demonstrate that AEEO outperforms several well‐performing EO variants, DE variants, PSO variants, SSA variants, and GWO variants in terms of convergence speed and accuracy. In addition, the AEEO algorithm is used for the edge server (ES) placement problem in mobile edge computing (MEC) environments. The experimental results show that the author’s approach outperforms the representative approaches compared in terms of access latency and deployment cost.

Abstract Background Human Papillomavirus (HPV) DNA screening was a crucial element in the fight against cervical cancer and had been adopted in many countries, including China. However, the onset of the COVID-19 pandemic in March 2020 disrupted this program significantly. Methods The aim of this study is to investigate the prevalence and distribution of HPV genotypes among the population undergoing cervical cancer screening during the pandemic period. From January 2017 to December 2022, Peking Union Medical College Hospital gathered 45,496 cervical swabs from individuals undergoing cervical cancer screening. These samples were analyzed to detect fifteen high-risk HPV (HR-HPV) DNA types and a combination of two low-risk HPV (LR-HPV) types. Results The study revealed an overall infection rate of 11.24% (5,114/45,496), with 11.06% (5,032/45,496) of individuals infected with HR-HPV. The number of HPV screening patients and the infection rates of HPV, HR-HPV, LR-HPV, multiple genotype HPV (M-HPV), and single genotype HPV (S-HPV) during the pandemic were lower than those observed before the pandemic. Moreover, the age group with the highest percentage of infected individuals was under 45–49 years, with HPV52, HPV58, HPV16, and HPV51 being the most prevalent genotypes. Notably, HPV66 emerged as the fifth most commonly detected genotype during the pandemic. Additionally, among the eleven age groups examined, women under 25 exhibited the highest detection rate, with HPV52 and HPV16 infection rates exceeding those observed in the pre-pandemic period. Conclusions The findings of this study offer significant insights for shaping HPV prevention strategies and enhancing cervical cancer screening initiatives in China following the epidemic.

Abstract Background With the improvement of living standards, the quality of chicken has become a significant concern. Chinese Dagu Chicken (dual-purpose type) and Arbor Acres plus broiler (AA+ broiler) (meat-type) were selected as the research subjects in this study, the meat quality of the breast and leg muscles were measured. However, the molecular mechanism(s) underlying regulation of muscle development are not yet fully elucidated. Therefore, finding molecular markers or major genes that regulate muscle quality has become a crucial breakthrough in chicken breeding. Unraveling the molecular mechanism behind meat traits in chicken and other domestic fowl is facilitated by identifying the key genes associated with these developmental events. Here, a comparative transcriptomic analysis of chicken meat was conducted on breast muscles (BM) and leg muscles (LM) in AA+ broilers (AA) and Dagu chicken (DG) to explore the differences in their meat traits employing RNA-seq. Results Twelve cDNA libraries of BM and LM from AA and DG were constructed from four experimental groups, yielding 14,464 genes. Among them, Dagu chicken breast muscles (DGB) vs AA+ broilers breast muscles (AAB) showed 415 upregulated genes and 449 downregulated genes, Dagu chicken leg muscles (DGL) vs AA+ broilers leg muscles (AAL) exhibited 237 upregulated genes and 278 downregulated genes, DGL vs DGB demonstrated 391 upregulated genes and 594 downregulated genes, and AAL vs AAB displayed 122 upregulated genes and 154 downregulated genes. 13 genes, including nine upregulated genes (COX5A, COX7C, NDUFV1, UQCRFS1, UQCR11, BRT-1, FGF14, TMOD1, MYOZ2) and four downregulated genes (MYBPC3, MYO7B, MTMR7, and TNNC1), were found to be associated with the oxidative phosphorylation signaling pathway. Further analysis revealed that the differentially expressed genes (DEGs) from muscle were enriched in various pathways, such as metabolic pathways, oxidative phosphorylation, carbon metabolism, glycolysis, extracellular matrix-receptor interaction, biosynthesis of amino acids, focal adhesion, vascular smooth muscle contraction, and cardiac muscle contraction, all of which are involved in muscle development and metabolism. This study also measured the meat quality of the breast and leg muscles from the two breeds, which demonstrated superior overall meat quality in Chinese Dagu Chicken compared to the AA+ broiler. Conclusions Our findings show that the meat quality of dual-purpose breeds (Chinese Dagu chicken) is higher than meat-type (AA+ broiler), which may be related to the DEGs regulating muscle development and metabolism. Our findings also provide transcriptomic insights for a comparative analysis of molecular mechanisms underlying muscle development between the two breeds, and have practical implications for the improvement of chicken breeding practices.

Abstract Background To determine the optimal fluid resuscitation volume in septic patients with acutely decompensated heart failure (ADHF). Methods Septic patients with ADHF were identified from a tertiary urban medical center. The generalized additive models were used to explore the association between fluid resuscitation volume and endpoints, and the initial 3 h fluid resuscitation volume was divided into four groups according to this model: 15 to ≤ 20 mL/kg group, and > 20 mL/kg group. Logistic and Cox regression models were employed to explore the association between resuscitation volume and primary endpoint, in-hospital mortality, as well as secondary endpoints including 30-day mortality, 1-year mortality, invasive ventilation, and ICU admission. Results A total of 598 septic patients with a well-documented history of HF were enrolled in the study; 405 patients (68.8%) had sepsis-induced hypoperfusion. Patients with NYHA functional class III and IV were 494 (83.9%) and 22 (3.74%), respectively. Resuscitation volumes above 20 mL/kg (OR 3.19, 95% CI 1.31–8.15) or below 10 mL/kg (OR 2.33, 95% CI 1.14–5.20) significantly increased the risk of in-hospital mortality in septic patients, while resuscitation volumes between 15 and 20 mL/kg were not associated with the risk of in-hospital death in septic patients (OR 1.79, 95% CI 0.68–4.81). In the multivariable Cox models, the effect of resuscitation volume on 30-day and 1-year mortality in septic patients was similar to the effect on in-hospital mortality. Resuscitation volume exceeds 15 mL/kg significantly increased the risk of tracheal intubation, while fluid resuscitation volume was not associated with ICU admission in the septic patients. In septic patients with hypoperfusion, these fluid resuscitation volumes have similar effects on patient outcomes. This association was consistent across the three subgroups with worsened cardiac function, as well as in sensitivity analyses. Conclusions Our study observed that an initial fluid resuscitation volume of 10–15 mL/kg in the first 3 h was optimal for early resuscitation in septic patients with ADHF, particularly those with worsened cardiac function. These results need to be confirmed in randomized controlled trials with larger sample sizes.

Abstract Grassland is a widely distributed land use type that provides essential resources for livestock production and serves as a crucial ecosystem component. Over the past decades, grassland has significantly degraded and shrunk due to climate change and human activities, with ongoing changes in its area. This study utilized the Google Earth Engine (GEE) and the Res-UNet++ model to analyze the phenological and spectral characteristics of grasslands in Landsat images for long-term annual monitoring. Additionally, the LandTrendr algorithm was utilized to correct long-term time series data for grasslands, yielding a map of grassland distribution in Inner Mongolia from 1991 to 2020. The results indicate that the overall spatial accuracy from 1991 to 2020 exceeded 96%, with a Kappa coefficient over 0.92, demonstrating high monitoring accuracy. In particular, the 2019 grassland monitoring area showed high consistency with data from the Third National Land Survey (TNLS), with a coefficient of determination (R^2) reaching 0.97, reflecting the high accuracy and reliability.

Abstract This paper explores the mapping from specific digitalization practices to specific resilient performance against a great shock. Based on an adapted structure–conduct–performance framework, this paper hypothesizes by theoretically analyzing how the pre-shock establishment of digital retailing practices could trigger physical retailers’ bounce-back and bounce-forward performance against the COVID-19 crisis. Using a difference-in-differences strategy, the hypotheses are examined with a sample including 549 observations of 50 Chinese listed retailers from the first quarter of 2018 to the third quarter of 2020. The empirical results mainly indicate the following binary findings. First, regardless of the differences in triggering bounce-back performance, different digital retailing practices are found to be effective in triggering physical retailers’ bounce-forward performance against the COVID-19 crisis. This somewhat addresses the concern about the temporality of digitalization-enabled resilience by revealing the generality across digital retailing practices in the sense of triggering resilient performance. Second, it is shown that physical retailers’ bounce-back performance at a specific stage of the COVID-19 crisis could only be triggered by digital retailing practices that coincidentally apply to the shock-induced market structure changes at the stage. The results emphasize each digitalization practice’s individuality in triggering resilient performance. This justifies the non-negligibility of the direct mapping from specific digitalization practices to specific resilient performance in digitalization-enabled resilience evaluation.

Abstract Alkaline water electrolysis is a promising low-cost strategy for clean and sustainable hydrogen production but is largely limited by the sluggish anodic oxygen evolution reaction and the challenges in maintaining adequate separation between H2 and O2. Here, we reveal an anodic-cathodic sequential oxygen evolution process via electrochemical oxidation and subsequent reduction of Ni hydroxides, enabling much lower overpotentials than conventional anodic oxygen evolution. By using (isotope-labeled) differential electrochemical mass spectrometry and in situ Raman spectroscopy combined with density functional theory calculations, we evidence that the sequential oxygen evolution originates from the electrochemical oxidation of Ni hydroxides to NiOO– active species while undergoing a different, reductive step of NiOO– for the final release of O2 due to weakened Ni–O covalency. Based on this sequential process, we propose and demonstrate a hybrid water electrolysis and energy storage device, which enables time-decoupled hydrogen and oxygen evolution and electrochemical energy storage in the Ni hydroxides.

Abstract Dielectric ceramics possess a unique competitive advantage in electronic systems due to their high-power density and excellent reliability. Na1/2Bi1/2TiO3-based ceramics, one type of extensively studied energy storage dielectric, however, often experience A-site element volatilization and Ti4+ reduction during high-temperature sintering. These issues may result in increased energy loss, reduced polarization and low dielectric breakdown electric field, ultimately making it challenging to achieve both high energy storage density and efficiency. To address these issues, we introduce a synergistic optimization strategy that combine polarization engineering and grain alignment engineering. First principles calculations and experimental analyses show that the doping of Mn2+ can suppress the reduction of Ti4+ in Na1/2Bi1/2TiO3-based ceramics and enhance ion off-centering displacements, thereby reducing energy loss and improving polarization. In addition, we prepared multilayer ceramic capacitors with grains oriented along the direction using the template grain growth method. This approach effectively reduces electric-field-induced strain by 37% and markedly enhances breakdown electric field by 42% when compared with nontextured counterpart. As a result of this comprehensive strategy, -textured Na1/2Bi1/2TiO3-based multilayer ceramic capacitors achieve an ultra-high energy density of 15.7 J·cm−3 and an excellent efficiency beyond 95% at 850 kV·cm−1, exhibiting a superior overall energy storage performance.

Abstract Background Recent studies have established a correlation between ADAMTSL2 (ADAMTS-like 2) and the development of various cancers. This study aims to conduct a comprehensive pan-cancer analysis in 37 cancer types and investigate its potential role in colon and rectal adenocarcinoma (COADREAD). Method Pan-cancer and mutation data were sourced from The Cancer Genome Atlas (TCGA) database and analyzed using Sangerbox analysis platform. We explored the expression patterns and prognostic implications of ADAMTSL2, and investigated its relationships with tumor heterogeneity, stemness, immune checkpoint genes, immune cell infiltration, RNA modifications, and mutational profiles across different cancers. Additionally, with Ethics Committee approval, we conducted immunohistochemical (IHC) analysis on 120 COADEAD samples to evaluate ADAMTSL2 expression and its association with clinicopathological parameters. Results ADAMTSL2 expression was positively correlated with the hazard ratio of OS, DSS, DFI and PFI for ESCA and COADREAD. A negative correlation was observed between ADAMTSL2 expression and NEO levels in COAD. Gene alterations in ADAMTSL2 were observed, with a mutation frequency of 5.0% in COAD. There is a significant correlation between ADAMTSL2 expression and immune cell infiltration in a variety of cancers. The expression level of ADAMTSL2 protein was associated with T stage, N stage, M stage (p

Abstract Phenotypes play a fundamental role in medical genetics, serving as external manifestations of underlying genotypes. Deep phenotyping, a cornerstone of precision medicine, involves precise multi-system phenotype assessments, facilitating disease subtyping and genetic understanding. Despite their significance, the field lacks standardized protocols for accurate phenotype evaluation, hindering clinical comprehension and research comparability. We present a comprehensive workflow of deep phenotyping for rare bone diseases from the Genetics Clinic of Skeletal Deformity at Peking Union Medical College Hospital. Our workflow integrates referral, informed consent, and detailed phenotype evaluation through HPO standards, capturing nuanced phenotypic characteristics using clinical examinations, questionnaires, and multimedia documentation. Genetic testing and counseling follow, based on deep phenotyping results, ensuring personalized interventions. Multidisciplinary team consultations facilitate comprehensive patient care and clinical guideline development. Regular follow-up visits emphasize dynamic phenotype reassessment, ensuring treatment strategies remain responsive to evolving patient needs. In conclusion, this study highlights the importance of deep phenotyping in rare bone diseases, offering a standardized framework for phenotype evaluation, genetic analysis, and multidisciplinary intervention. By enhancing clinical care and research outcomes, this approach contributes to the advancement of precision medicine in the field of medical genetics.

Abstract This study investigates the microstructural characteristics and mechanical properties of a laser welded AZ80 magnesium alloy. The welding process led to the formation of coarse-grained fusion zone (FZ), where a secondary phase formed continuous network. Mg17Al12 precipitation and coarsening of grain boundaries occurred in the heat affected zone. The welded joint exhibited excellent mechanical properties with a yield strength of 202 MPa and a joint efficiency of 92%. The microstructure analysis via EPMA and EBSD in conjunction with synchrotron X-ray diffraction analysis reveals that precipitates and increased dislocation density in the fusion zone are primary strengthening mechanisms for the laser welded AZ80 Mg alloy.

Abstract In this study, XPS sputtering depth, SEM and electrochemical tests (CV, EIS, M-S, i-t, DPP) were used to study the structural composition and formation mechanism of surface passive film of Nb microalloyed rebar in SCPS with different pH. The results showed that after passivation for 10 d in SCPS with different pH, compared with CS rebar, the stability and compactness of surface passive film of 34Nb rebar gradually increased with the decreases of pH. Firstly, with the decreases of pH, the outer layer of surface passive film of 34Nb rebar was composed of Fe oxides and Fe hydroxides, and the inner layer was composed of Fe oxides and Nb oxides, thus increasing the mass ratio of Fe3+/Fe2+ and Nb2O5/(NbO2 + NbO). Secondly, with the decreases of pH, the addition of Nb promoted the formation of Fe oxides in 34Nb rebar, obtaining the excellent Rct, Ecorr and Ep. Finally, with the decreases of pH, the addition of Nb promoted the enrichment of Nb oxides in 34Nb rebar, inhibiting the degradation of Fe oxides, and the passive film exhibited the P-N type semiconductor, thus significantly decreasing the carrier density and enhancing the passivation rate of 34Nb rebar.

Abstract The COVID-19 pandemic has caused a global health crisis and significant social economic burden. While most individuals experience mild or non-specific symptoms, elderly individuals are at a higher risk of developing severe symptoms and life-threatening complications. Exploring the key factors associated with clinical severity highlights that key characteristics of aging, such as cellular senescence, immune dysregulation, metabolic alterations, and impaired regenerative potential, contribute to disruption of tissue homeostasis of the lung and worse clinical outcome. Senolytic and senomorphic drugs, which are anti-aging treatments designed to eliminate senescent cells or decrease the associated phenotypes, have shown promise in alleviating age-related dysfunctions and offer a novel approach to treating diseases that share certain aspects of underlying mechanisms with aging, including COVID-19. This review summarizes the current understanding of aging in COVID-19 progression, and highlights recent findings on anti-aging drugs that could be repurposed for COVID-19 treatment to complement existing therapies.

Abstract Eukaryotic Argonaute proteins (eAgos) utilize short nucleic acid guides to target complementary sequences for RNA silencing, while prokaryotic Agos (pAgos) provide immunity against invading plasmids or bacteriophages. The Sir2-domain associated short pAgo (SPARSA) immune system defends against invaders by depleting NAD+ and triggering cell death. However, the molecular mechanism underlying SPARSA activation remains unknown. Here, we present cryo-EM structures of inactive monomeric, active tetrameric and active NAD+-bound tetrameric SPARSA complexes, elucidating mechanisms underlying SPARSA assembly, guide RNA preference, target ssDNA-triggered SPARSA tetramerization, and tetrameric-dependent NADase activation. Short pAgos form heterodimers with Sir2-APAZ, favoring short guide RNA with a 5′-AU from ColE-like plasmids. RNA-guided recognition of the target ssDNA triggers SPARSA tetramerization via pAgo- and Sir2-mediated interactions. The resulting tetrameric Sir2 rearrangement aligns catalytic residue H186 for NAD+ hydrolysis. These insights advance our understanding of Sir2-domain associated pAgos immune systems and should facilitate the development of a short pAgo-associated biotechnological toolbox.

Abstract Immune evasion represents a crucial milestone in the progression of cancer and serves as the theoretical foundation for tumor immunotherapy. In this study, we reveal a negative association between Human Papillomavirus (HPV)-encoded circular RNA, circE7, and the infiltration of CD8+ T cells in head and neck squamous cell carcinoma (HNSCC). Both in vitro and in vivo experiments demonstrate that circE7 suppresses the function and activity of T cells by downregulating the transcription of LGALS9, which encodes the galectin-9 protein. The molecular mechanism involves circE7 binding to acetyl-CoA carboxylase 1 (ACC1), promoting its dephosphorylation and thereby activating ACC1. Activated ACC1 reduces H3K27 acetylation at the LGALS9 gene promoter, leading to decreased galectin-9 expression. Notably, galectin-9 interacts with immune checkpoint molecules TIM-3 and PD-1, inhibiting the secretion of cytotoxic cytokines by T cells and promoting T cell apoptosis. Here, we demonstrate a mechanism by which HPV promotes immune evasion in HNSCC through a circE7-driven epigenetic modification and propose a potential immunotherapy strategy for HNSCC that involves the combined use of anti-PD-1 and anti-TIM-3 inhibitors.

Abstract Magnetic skyrmions are potential candidates for high-density storage and logic devices because of their inherent topological stability and nanoscale size. Two-dimensional (2D) Janus transition metal chalcogenides (TMDs) are widely used to induce skyrmions due to the breaking of inversion symmetry. However, the experimental synthesis of Janus TMDs is rare, which indicates that the Janus configuration might not be the most stable MXY structure. Here, through machine-learning-assisted high-throughput first-principles calculations, we demonstrate that not all MXY compounds can be stabilized in Janus layered structure and a large proportion prefer to form other configurations with lower energy than the Janus configuration. Interestingly, these new configurations exhibit a strong Dzyaloshinskii–Moriya interaction (DMI), which can generate and stabilize skyrmions even under a strong magnetic field. This work provides not only an efficient method for obtaining ferromagnetic materials with strong DMI but also a theoretical guidance for the synthesis of TMDs via experiments.

Abstract Ferroptosis is a regulated cell death process dependent on iron, triggered by the accumulation of lipid peroxidation. The environmental context significantly impacts cellular sensitivities to ferroptosis. Serum, constituting the extracellular fluid composition in vivo, provides crucial environmental biomolecules. In this study, we investigated the influence of sera on ferroptosis induction, pinpointing the serum protein apolipoprotein H (APOH) as a pivotal inhibitor of ferroptosis. Moreover, we elucidated that APOH suppresses ferroptosis by activating the phosphoinositide 3-kinase (PI3K)-AKT-sterol regulatory element-binding proteins (SREBPs) pathway, thereby elevating stearoyl-CoA desaturase (SCD) levels and augmenting cellular monounsaturated fatty acid-containing phospholipids (MUFA-PLs). Furthermore, ApoHinfer, the peptide derivative of the active region of APOH, mimics its ferroptosis inhibitory activity. Our findings underscore the critical role of serum protein APOH in the inhibition of ferroptosis and indicates potential therapeutic applications in treating cancer and diseases associated with ferroptosis.

Abstract Well-functioning vascular access (VA) is essential for hemodialysis treatment in patients with end-stage renal disease (ESRD). However, continuous and accurate monitoring of blood flow to assess high-flux VA during hospitalization or at home is not feasible for either clinical instruments or wearable sensors. Here, we report the design and preclinical validation of a high-precision, long-term, epidermal blood flow sensor that self-adapts to unavoidable sensor-mounting deviations on the skin and is compatible with individual tissue differences. Specifically, the technology is based on thermal dissipation of the skin, and improves the signal-to-error ratio surpassing 4 times when measuring high-flux blood (100–600 mL/min). In preclinical validation, the sensor is compared with the Doppler ultrasound and demonstrate a blood flow resolution of 10–50 mL/min. Furthermore, it is highly-integrated and wearable, measuring 36 × 50 mm2. The sensor paves the way for accurate, convenient, high-flux blood monitoring, offering significant potential to extend the lives of patients with ESRD.

Abstract Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained‐release (SR) tablets. This study aimed to develop a population pharmacokinetic (PopPK) model for VPA in children with epilepsy and offer dose adjustment recommendation for switching dosage forms as needed. The study collected 1411 VPA steady‐state trough concentrations (Ctrough) from 617 children with epilepsy. Using NONMEM software, a PopPK model was developed, employing a stepwise approach to identify possible variables such as demographic information and concomitant medications. The final model underwent internal and external evaluation via graphical and statistical methods. Moreover, Monte Carlo simulations were used to generate a dose tailoring strategy for typical patients weighting 20–50 kg. As a result, the PK characteristics of VPA were described using a one‐compartment model with first‐order absorption. The absorption rate constant (ka) was set at 2.64 and 0.46 h−1 for syrup and SR tablets. Body weight and sex were identified as significant factors affecting VPA's pharmacokinetics. The final PopPK model demonstrated acceptable prediction performance and stability during internal and external evaluation. For children taking syrup, a daily dose of 25 mg/kg resulted in the highest probability of achieving the desired target Ctrough, while a dose of 20 mg/kg/day was appropriate for those taking SR tablets. In conclusion, we established a PopPK model for VPA in children with epilepsy to tailor VPA dosage when switching between syrup and SR tablets, aiming to improve plasma VPA concentrations fluctuations.

Abstract Background The initial randomized, double‐blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first‐line therapy in epidermal growth factor receptor (EGFR)‐mutated advanced non‐small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. Methods Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double‐blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow‐up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological‐BICR). The primary endpoint for this subgroup analysis was CNS progression‐free survival (PFS). Results Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological‐BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17‐0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11‐0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non‐CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. Conclusions These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR‐mutated advanced NSCLC with baseline CNS metastases. Trial registration ClinicalTrials.gov number, NCT03849768