PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide-isomerase A3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein (CRP) level and disease activity score 28 (DAS28). Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor (TCR) signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing Th1 and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.

Intervention of asprosin attenuates oxidative stress and neointima formation in vascular injury.

AIMS: Asprosin, a newly discovered hormone, is linked to insulin resistance. This study shows the roles of asprosin in vascular smooth muscle cells (VSMCs) proliferation, migration, oxidative stress and neointima formation of vascular injury. METHODS: Mouse aortic VSMCs were cultured, and platelet-derived growth factor-BB (PDGF-BB) was used to induce oxidative stress, proliferation and migration in VSMCs. Vascular injury was induced by repeatedly moving a guidewire in the lumen of carotid artery in mice. RESULTS: Asprosin overexpression promoted VSMC oxidative stress, proliferation and migration, which were attenuated by toll-like receptor 4 (TLR4) knockdown, antioxidant NAC, NOX1 inhibitor ML171 or NOX2 inhibitor GSK2795039. Asprosin overexpression increased NOX1/2 expressions, while asprosin knockdown increased heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions. Asprosin inhibited Nrf2 nuclear translocation. Nrf2 activator sulforaphane increased HO-1 and NQO-1 expressions, and prevented asprosin-induced NOX1/2 upregulation, oxidative stress, proliferation and migration. Exogenous asprosin protein had similar roles to asprosin overexpression. PDGF-BB increased asprosin expressions. PDGF-BB-induced oxidative stress, proliferation and migration were enhanced by Nrf2 inhibitor ML385, but attenuated by asprosin knockdown. Vascular injury increased asprosin expression. Local asprosin knockdown in the injured carotid artery promoted HO-1 and NQO-1 expressions, but attenuated the NOX1 and NOX2 upregulation, oxidative stress, neointima formation and vascular remodeling in mice. INNOVATION AND CONCLUSION: Asprosin promotes oxidative stress, proliferation and migration of VSMCs via TLR4-Nrf2-mediated redox imbalance. Inhibition of asprosin expression attenuates VSMC proliferation and migration, oxidative stress and neointima formation in the injured artery. Asprosin might be a promising therapeutic target for vascular injury.

Global, regional, and national burdens of cancer in children aged zero to nine years from 1990 to 2019.

Background: The description of long-term trends in the cancer burden among children aged zero to nine years from 1990 to 2019 reveals significant changes in children's health. It helps in resource allocation and health policy planning. We analysed data on the incidence, mortality, and disability-adjusted life years (DALYs) by sex and age group in children aged zero to nine. Methods: Estimates of DALYs for children aged zero to nine years, appeared as part of the Global Burden of Diseases, Injuries, and Risk Factor Study 2019, by age, sex, and location for 1990-2019. We also provided estimations by the sociodemographic index (SDI) quintile, a systematic measure to indicate educational attainment, income per capita, and total fertility rate for those younger than 25 years. We used age-period-cohort models to investigate paediatric cancers prevalence, incidence, mortality, and DALYs rates and auto-regressive integrated moving average models to predict cancer in children of different age groups in males and females. Results: A total of 6 224 010 DALY numbers for cancer cases occurred globally in 2019 among children aged zero to nine years. Additionally, the incidence of paediatric cancers in 2019 in the middle SDI countries was the highest, including 60 662 cases, and the highest mortality and DALYs cases of paediatric cancers were in the low SDI countries (25 502 and 2 199 790). The joinpoint regression analysis revealed that the trend of total cancer burden in age-standardised mortality rates and age-standardised DALYs rates showed a significant decrease with an average annual percentage change of -2.10 and -2.03 from 1990 to 2019. Furthermore, the paediatric cancer spectrum was changing. Other malignant neoplasms and other leukaemia were the major components of cancer in all age groups of children. Conclusions: The disease burden in children aged zero to nine years decreased significantly globally from 1990 to 2019. However, the overall prediction of childhood cancer increased slightly from 2020 to 2040. Our findings may help guide investments and inform policies. This highlights the necessity to improve current treatment measures and establish effective prevention strategies to reduce the cancer burden among children aged zero to nine years.

Peri-device leakage and delayed endothelialization of the Watchman device: a computed tomography study.

OBJECTIVES: This study aimed to explore the endothelialization process and assess the potential association between endothelialization and peri-device leak (PDL) following Watchman implantation via a quantitative method. METHODS: This is a single-center retrospective study of consecutive patients undergoing LAAO between December 2015 and November 2021. Device endothelialization, compared between PDL and non-PDL group, were quantitatively analyzed based on hypoattenuated thickening in cardiac computed tomography angiography (CCTA). Advancement in endothelialization over time were explored using the Cochran-Armitage test and generalized estimating equation approach. Potential risk factors of delayed endothelialization were analyzed using the Cox proportional-hazards model. RESULTS: A total of 172 patients (mean age, 68 years ± 10 [standard deviation], 114 men) were finally included. The average endothelialization ratio of the study population was 89.8 ± 7.2 percent. In the follow-up period of postprocedural 3 months to more than 12 months, an incremental trend of endothelialization over time was observed with the ratio of 85.8 ± 8.0, 89.6 ± 7.6, 92.2 ± 4.5, 94.3 ± 2.9 percent, respectively (p < 0.0001). Notably, patients without PDL exhibited a swifter advancement in endothelialization compared to those with PDL, irrespective of device size. The multivariable Cox regression model showed that PDL (HR = 2.113, 95%CI: 1.300-3.435, p = 0.003), DSP (HR = 1.717, 95%CI: 1.113-2.647, p = 0.014) were independent risk factors of delayed endothelialization. CONCLUSION: CCTA holds promise as an effective means of quantitatively assessing device endothelialization. Endothelialization advanced gradually over time, with PDL potentially impeding device endothelialization. CLINICAL RELEVANCE STATEMENT: A comprehensive understanding of the correlation between endothelialization ratio, time, and residual shunt can establish a more dependable foundation for determining the appropriate anticoagulation treatment following left atrial appendage closure. KEY POINTS: Current recommendations for postleft atrial appendage occlusion anti-platelet and anticoagulation therapy are based on animal studies. Cardiac computed tomography angiography (CCTA) combined with the UNet neural network model enables the quantitative assessment of device endothelialization. This technique will allow for additional studies to better understand device endothelialization to optimize treatments in this population.

Unraveling the relationships between processing conditions and PhIP formation in chemical model system and roast pork patty via principal component analysis.

2-amino-1-methyl-6-phenylimidazole [4,5-b] pyridine (PhIP) is one of the higher levels of HAAs produced in protein foods during heating. The effects of heating temperature, time, and concentration of precursors on PhIP and related substances in the chemical model system and roast pork patty were studied using HPLC-Q-Orbitrap-HRMS and GC-MS. Results showed that the heating temperature, time, and concentration of four precursors significantly affected PhIP and its related substances (P < 0.05) in the chemical model system. Among them, PhIP production was greatest when heating at 200 min with 220 °C, and the concentrations of phenylalanine, creatinine, glucose, and creatine added were 10, 20, 20, and 20 mmol/L, respectively. Moreover, as the fat proportion of roast pork patties increased, PhIP and its intermediate-phenylacetaldehyde concentrations increased substantially (P < 0.05). PCA results showed that the samples of PhIP and related substances gradually dispersed as the temperature and time increased, and there were obvious effects among them.

Enlightenment of robotic gastrectomy from 527 patients with gastric cancer in the minimally invasive era: 5 years of optimizing surgical performance in a high-volume center - a retrospective cohort study.

BACKGROUND: Learning curves have been used in the field of RG. However, it should be noted that the previous study did not comprehensively investigate all changes related to the learning curve.This study aims to establish a learning curve for radical robotic gastrectomy (RG) and evaluate its effect on the short-term outcomes of patients with gastric cancer. METHODS: The clinicopathological data of 527 patients who underwent RG between August 2016 and June 2021 were retrospectively analyzed. Learning curves related to the operation time and postoperative hospital stay were determined separately using cumulative sum (CUSUM) analysis. Then, the impact of the learning curve on surgical efficacy was analyzed. RESULTS: Combining the CUSUM curve break points and technical optimization time points, the entire cohort was divided into three phases (patients 1-100, 101-250, and 251-527). The postoperative complication rate and postoperative recovery time tended to decrease significantly with phase advancement (P<0.05). More extraperigastric examined lymph nodes (LN) were retrieved in phase III than in phase I (I vs. III, 15.12±6.90 vs. 17.40±7.05, P=0.005). The rate of LN noncompliance decreased with phase advancement. Textbook outcome (TO) analysis showed that the learning phase was an independent factor in TO attainment (P<0.05). CONCLUSION: With learning phase advancement, the short-term outcomes were significantly improved. It is possible that our optimization of surgical procedures could have contributed to this improvement. The findings of this study facilitate the safe dissemination of RG in the minimally invasive era.

WASPSYN: A Challenge for Domain Adaptive Synapse Detection in Microwasp Brain Connectomes.

The size of image volumes in connectomics studies now reaches terabyte and often petabyte scales with a great diversity of appearance due to different sample preparation procedures. However, manual annotation of neuronal structures (e.g., synapses) in these huge image volumes is time-consuming, leading to limited labeled training data often smaller than 0.001% of the large-scale image volumes in application. Methods that can utilize in-domain labeled data and generalize to out-of-domain unlabeled data are in urgent need. Although many domain adaptation approaches are proposed to address such issues in the natural image domain, few of them have been evaluated on connectomics data due to a lack of domain adaptation benchmarks. Therefore, to enable developments of domain adaptive synapse detection methods for large-scale connectomics applications, we annotated 14 image volumes from a biologically diverse set of Megaphragma viggianii brain regions originating from three different whole-brain datasets and organized the WASPSYN challenge at ISBI 2023. The annotations include coordinates of pre-synapses and post-synapses in the 3D space, together with their one-to-many connectivity information. This paper describes the dataset, the tasks, the proposed baseline, the evaluation method, and the results of the challenge. Limitations of the challenge and the impact on neuroscience research are also discussed. The challenge is and will continue to be available at https://codalab.lisn.upsaclay.fr/competitions/9169. Successful algorithms that emerge from our challenge may potentially revolutionize real-world connectomics research and further the cause that aims to unravel the complexity of brain structure and function.

Rapid pulmonary 129Xe ventilation MRI of discharged COVID-19 patients with zigzag sampling.

PURPOSE: To demonstrate the feasibility of zigzag sampling for 3D rapid hyperpolarized 129Xe ventilation MRI in human. METHODS: Zigzag sampling in one direction was combined with gradient-recalled echo sequence (GRE-zigzag-Y) to acquire hyperpolarized 129Xe ventilation images. Image quality was compared with a balanced SSFP (bSSFP) sequence with the same spatial resolution for 12 healthy volunteers (HVs). For another 8 HVs and 9 discharged coronavirus disease 2019 subjects, isotropic resolution 129Xe ventilation images were acquired using zigzag sampling in two directions through GRE-zigzag-YZ. 129Xe ventilation defect percent (VDP) was quantified for GRE-zigzag-YZ and bSSFP acquisitions. Relationships and agreement between these VDP measurements were evaluated using Pearson correlation coefficient (r) and Bland-Altman analysis. RESULTS: For 12 HVs, GRE-zigzag-Y and bSSFP required 2.2 s and 10.5 s, respectively, to acquire 129Xe images with a spatial resolution of 3.96 × 3.96 × 10.5 mm3. Structural similarity index, mean absolute error, and Dice similarity coefficient between the two sets of images and ventilated lung regions were 0.85 ± 0.03, 0.0015 ± 0.0001, and 0.91 ± 0.02, respectively. For another 8 HVs and 9 coronavirus disease 2019 subjects, 129Xe images with a nominal spatial resolution of 2.5 × 2.5 × 2.5 mm3 were acquired within 5.5 s per subject using GRE-zigzag-YZ. VDP provided by GRE-zigzag-YZ was strongly correlated (R2 = 0.93, p < 0.0001) with that generated by bSSFP with minimal biases (bias = -0.005%, 95% limit-of-agreement = [-0.414%, 0.424%]). CONCLUSION: Zigzag sampling combined with GRE sequence provides a way for rapid 129Xe ventilation imaging.

Phage based magnetic capture method as an aid for real time RPA detection of Salmonella spp. in milk.

Salmonella is a major cause of foodborne diseases worldwide. Conventional rapid assays for detecting Salmonella in real samples often encounter severe matrix interference or detect the limited number of species of a genus, resulting the inaccuracy of detection. In this study, we developed a method that combined phage-based magnetic capture with real time recombinase polymerase amplification (RPA) for the rapid, highly sensitive, and specific detection of Salmonella in milk with an ultra-low detection limit. The Felix O-1 phage-conjugated magnetic beads (O-1 pMBs) synthesized in this method showed excellent capture ability for Salmonella spp. and ideal specificity for non-Salmonella strains. After O-1 pMBs-based magnetic separation, the limit of detection (LOD) of the real time RPA assay was 50 cfu/mL in milk samples, which was significantly increased by a magnitude of 3-4 orders. The method exhibited a high sensitivity (compatibility) of 100% (14/14) for all tested Salmonella serotype strains and an ideal specificity (exclusivity) of 100% (7/7) for the tested non-Salmonella strains. The entire detection process including Salmonella capture, DNA extraction, and real time RPA detection was completed within 1.5 h. Furthermore, milk samples spiked with 10 cfu/25 mL of Salmonella were detected positive after cultured in buffered peptone water for only 3 h. Therefore, the proposed method could be an alternative for the rapid and accurate detection of Salmonella.

Precede-Proceed Model-dominant Nursing Combined With Nutrition Support for Patients Discharged After Hepatobiliary Surgery With T Tube.

Context: Hepatobiliary disease requires surgical treatment and T-tube installment postoperatively, and discharged patients' usually still have a T tube. Little nursing care is available in China for patients after discharge, resulting in postdischarge complications. Also, the incidence of nutritional risk in patients with hepatobiliary surgery is high. Objective: The study aimed to investigate the benefits of a precede-proceed model-dominant nursing combined with nutritional support for patients discharged after hepatobiliary surgery with a T tube, so as to improve their prognoses and promote their rehabilitation. Design: The research team conducted a prospective, single-center, randomized controlled trial. Setting: The study took place at Wuhan No. 1 Hospital, Wuhan Hospital of Traditional Chinese and Western Medicine in Wuhan, Hubei, China. Participants: Participants were 120 patients discharged after hepatobiliary surgery at the hospital between June 2020 and June 2022. Interventions: The research team randomly divided participants into two groups using the random number table method, each with 60 participants: (1) an intervention group, which received precede-proceed model-dominant nursing combined with nutrition support and (2) a control group, which received routine care. Outcome Measures: At baseline and postintervention, the research team assessed: (1) nutritional status, (2) self-care agency, (3) compliance, (4) quality of life (QoL), (5) incidence of complications. Results: At baseline, no significant differences existed between the groups in nutritional status, self-care agency, QoL, or compliance (all P > .05). Postintervention compared to the control group, the intervention group's: (1) nutritional status, including albumin (P = .015), hemoglobin (P < .001), growth hormone (P < .001), BW (P = .047), BMI (P = .046), TST (P = .001), and MAMC (P = .016) were significantly higher and transferrin (P < .001) and NRS-2002 score (P < .001) were significantly lower; (2) self-care agency, including self-concept, self-responsibility, health knowledge, and self-nursing skills were significantly higher (all P < .001); (3) compliance scores, including observing the volume and color of bile correctly, clamping and opening the T tube properly, replacing the drainage bag correctly and in a timely manner, regularly disinfecting the skin around the drainage tube, keeping a balanced diet, adhering to medical regimens, exercising adequately were significantly higher (all P < .001); (4) QoL was significantly higher (P < .001); and (5) incidence of complications was significantly lower (P = .008). Conclusions: Precede-proceed model-dominant nursing combined with nutrition support can significantly improve nutritional status, self-care agency, and QoL and can significantly decrease the incidence of complications for patients discharged after hepatobiliary surgery with a T tube and is worthy of promotion in clinics.

Rare microbial taxa as the major drivers of nutrient acquisition under moss biocrusts in karst area.

Karst rocky desertification refers to the process of land degradation caused by various factors such as climate change and human activities including deforestation and agriculture on a fragile karst substrate. Nutrient limitation is common in karst areas. Moss crust grows widely in karst areas. The microorganisms associated with bryophytes are vital to maintaining ecological functions, including climate regulation and nutrient circulation. The synergistic effect of moss crusts and microorganisms may hold great potential for restoring degraded karst ecosystems. However, our understanding of the responses of microbial communities, especially abundant and rare taxa, to nutrient limitations and acquisition in the presence of moss crusts is limited. Different moss habitats exhibit varying patterns of nutrient availability, which also affect microbial diversity and composition. Therefore, in this study, we investigated three habitats of mosses: autochthonal bryophytes under forest, lithophytic bryophytes under forest and on cliff rock. We measured soil physicochemical properties and enzymatic activities. We conducted high-throughput sequencing and analysis of soil microorganisms. Our finding revealed that autochthonal moss crusts under forest had higher nutrient availability and a higher proportion of copiotrophic microbial communities compared to lithophytic moss crusts under forest or on cliff rock. However, enzyme activities were lower in autochthonal moss crusts under forest. Additionally, rare taxa exhibited distinct structures in all three habitats. Analysis of co-occurrence network showed that rare taxa had a relatively high proportion in the main modules. Furthermore, we found that both abundant and rare taxa were primarily assembled by stochastic processes. Soil properties significantly affected the community assembly of the rare taxa, indirectly affecting microbial diversity and complexity and finally nutrient acquisition. These findings highlight the importance of rare taxa under moss crusts for nutrient acquisition. Addressing this knowledge gap is essential for guiding ongoing ecological restoration projects in karst rocky desertification regions.

Development, Validation and Clinical Utility of a Risk Prediction Model for Maternal and Neonatal Adverse Outcomes in Pregnant Women with Hypothyroidism.

Purpose: This study aimed to create, verify and assess the clinical utility of a prediction model for maternal and neonatal adverse outcomes in pregnant women with hypothyroidism. Methods: A prediction model was developed, and its accuracy was tested using data from a retrospective cohort. The study focused exclusively on female patients diagnosed with hypothyroidism who were admitted to a tertiary hospital. The development and validation cohort comprised individuals who gave birth between 1 October 2020 and 31 December 2022. The primary outcome was a combination of crucial maternal and newborn problems (eg premature births, abortions and neonatal asphyxia). The prediction model was developed using logistic regression. Evaluation of the model's performance was conducted based on its ability to discriminate, calibrate and provide clinical value. Results: In total, nine variables were chosen to develop the predictive model for adverse maternal and neonatal outcomes during pregnancy with hypothyroidism. The area under the curve of the model for predicting maternal adverse outcomes was 0.845, and that for predicting neonatal adverse outcomes was 0.685. The calibration plots showed good agreement between the nomogram predictions and the actual observations in both the training and validation cohorts. Furthermore, decision curve analysis suggested that the nomograms were clinically useful and had good discriminative power to identify high-risk mother-infant cases. Conclusion: Two models to predict the risk probability of maternal and neonatal adverse outcomes in pregnant women with hypothyroidism were developed and verified to assist physicians in evaluating maternal and neonatal adverse outcomes throughout pregnancy with hypothyroidism and to facilitate decision-making regarding therapy.

Identification of S100A8/A9 involved in thromboangiitis obliterans development using tandem mass tags-labeled quantitative proteomics analysis.

Thromboangiitis obliterans (TAO) is characterized by inflammation and obstruction of small-and medium-sized distal arteries, with limited pharmacotherapies and surgical interventions. The precise pathogenesis of TAO remains elusive. By utilizing the technology of tandem mass tags (TMT) for quantitative proteomics and leveraging bioinformatics tools, a comparative analysis of protein profiles was conducted between normal and TAO rats to identify key proteins driving TAO development. The results unveiled 1385 differentially expressed proteins (DEPs) in the TAO compared with the normal group-comprising 365 proteins with upregulated expression and 1020 proteins with downregulated expression. Function annotation through gene ontology indicated these DEPs mainly involved in cell adhesion, positive regulation of cell migration, and cytosol. The principal signaling pathways involved regulation of the actin cytoskeleton, vascular smooth contraction, and focal adhesion. The roles of these DEPs and associated signaling pathways serve as a fundamental framework for comprehending the mechanisms underpinning the onset and progression of TAO. Furthermore, we conducted a comprehensive evaluation of the effects of S100A8/A9 and its inhibitor, paquinimod, on smooth muscle cells (SMCs) and in TAO rats. We observed that paquinimod reduces SMCs proliferation and migration, promotes phenotype switching and alleviates vascular stenosis in TAO rats. In conclusion, our study revealed that the early activation of S100A8/A9 in the femoral artery is implicated in TAO development, targeting S100A8/A9 signaling may provide a novel approach for TAO prevention and treatment.

Exploring the nexus between fatigue, body composition, and muscle strength in hemodialysis patients.

BACKGROUND: Fatigue is a relatively prevalent condition among hemodialysis patients, resulting in diminished health-related quality of life and decreased survival rates. The purpose of this study was to investigate the relationship between fatigue and body composition in hemodialysis patients. METHODS: This cross-sectional study included 92 patients in total. Fatigue was measured by Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) (cut-off ≤ 34). Body composition was measured based on quantitative computed tomography (QCT), parameters including skeletal muscle index (SMI), intermuscular adipose tissue (IMAT), and bone mineral density (BMD). Handgrip strength was also collected. To explore the relationship between fatigue and body composition parameters, we conducted correlation analyses and binary logistic regression. RESULTS: The prevalence of fatigue was 37% (n = 34), abnormal bone density was 43.4% (n = 40). There was a positive correlation between handgrip strength and FACIT-F score (r = 0.448, p < 0.001). Age (r = - 0.411, p < 0.001), IMAT % (r = - 0.424, p < 0.001), negatively associated with FACIT-F score. Multivariate logistic regression analysis shows that older age, lower serum phosphorus, higher IMAT% are associated with a high risk of fatigue. CONCLUSION: The significantly increased incidence and degree of fatigue in hemodialysis patients is associated with more intermuscular adipose tissue in paraspinal muscle.

Laparoscopic Spleen-Preserving Hilar Lymphadenectomy for Advanced Proximal Gastric Cancer Without Greater Curvature Invasion: Five-Year Outcomes From the Fuges-02 Randomized Clinical Trial.

Importance: Splenic hilar lymphadenectomy has been recommended for locally advanced proximal gastric cancer (APGC) involving the greater curvature. However, it is unclear whether laparoscopic spleen-preserving splenic hilar lymphadenectomy (LSPSHL) is associated with a long-term survival benefit for APGC without greater curvature invasion. Objective: To present the 5-year follow-up data from a randomized clinical trial that compared laparoscopic total gastrectomy (D2 group) with D2 plus LSPSHL (D2 + No. 10 group) among patients with resectable APGC. Design, Setting, and Participants: This is a post hoc secondary analysis of a randomized clinical trial that enrolled 536 patients with potentially resectable APGC (cT2-4a, N0 or N+, and M0) without greater curvature invasion from January 5, 2015, to October 10, 2018. All patients were tracked for at least 5 years. The final follow-up was on October 30, 2023. Interventions: Patients were randomly assigned in a 1:1 ratio to the D2 + No. 10 or D2 groups. Main Outcomes and Measures: The 5-year disease-free survival (DFS) and overall survival (OS) rates were measured. Recurrence patterns and causes of death were compared. Results: A total of 526 patients (392 men [74.5%]; mean [SD] age, 60.6 [9.6] years) were included in the modified intent-to-treat analysis, with 263 patients in each group. The 5-year DFS rate was 63.9% (95% CI, 58.1%-69.7%) for the D2 + No. 10 group and 55.1% (95% CI, 49.1%-61.1%) for the D2 group (log-rank P = .04). A statistically significant difference was observed in the 5-year OS between the D2 + No. 10 group and the D2 group (66.2% [95% CI, 60.4%-71.9%] vs 57.4% [95% CI, 51.4%-63.4%]; log-rank P = .03). The No. 10 lymph node exhibited a therapeutic value index (TVI) of 6.5, surpassing that of Nos. 8a (TVI, 3.0), 11 (TVI, 5.8), and 12a (TVI, 0.8). A total of 86 patients in the D2 + No. 10 group (cumulative incidence, 32.7%) and 111 patients in the D2 group (cumulative incidence, 42.2%) experienced recurrence (hazard ratio, 0.72; 95% CI, 0.54-0.95; P = .02). The multivariable competing risk regression model demonstrated that D2 + No. 10 remained an independent protective factor for a lower 5-year cumulative recurrence rate after surgery (hazard ratio, 0.75; 95% CI, 0.56-1.00; P = .05). There was a significant difference in the 5-year cumulative recurrence rate at the No. 10 lymph node area between the 2 groups (D2 + No. 10 group vs D2 group: 0% vs 2.3% [n = 6]; P = .01). Conclusions: This post hoc secondary analysis of a randomized clinical trial found that laparoscopic total gastrectomy with LSPSHL can improve the prognosis and reduce recurrence for APGC without greater curvature invasion. Future multicenter studies are warranted to validate these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT02333721.

[Research advances in nucleic acid drugs developed based on circular RNAs].

The development and clinical application of nucleic acid drugs has been a trendy field. One of the notable examples is mRNA vaccines, which have been used in the fighting against SARS-CoV-2. With short development cycles and mature preparation processes, mRNA vaccines demonstrate advantages in the global supply and in response to virus mutations. Circular RNAs (circRNAs) are a group of nucleic acid molecules with more stable structure, longer half-life, and weaker immunogenicity than mRNAs. Studies have proven that circRNAs can efficiently express protein products, indicating their potential in drug development. Despite extensive studies on the biogenesis and biological functions of circRNAs, there is limited research on developing nucleic acid drugs based on circRNAs. This article provides an overview of circRNAs, including their basic information, synthesis routes, and mechanisms, and discusses the future development directions of this field, hoping to provide inspiration for the research and development of drugs based on circRNAs.

Ring-opening polymerization of emulsion-templated deep eutectic system monomer for macroporous polyesters with controlled degradability.

Biodegradable polyesters with interconnected macroporosity, such as poly(l-lactide) (PLLA) and poly(ε-caprolactone) (PCL), have gained significant importance in the fields of tissue engineering and separation. This study introduces functional macroinitiators, specifically polycaprolactone triol (PCLT) and polyethylene glycol (PEG), both OH-terminated, in the solventless ring-opening polymerization (ROP) of a liquid deep eutectic system monomer (DESm) composed of LLA and CL at a 30 : 70 molar ratio, respectively. The macroinitiators selectively initiate the organocatalyzed ROP of LLA in the DESm during the first polymerization stage, thereby modifying the PLLA architecture. This results in the formation of either branched or linear PLLA copolymers depending on the macroinitiator, PCLT and PEG, respectively. In the second stage, the ROP of the CL, which is a counterpart of the DESm, produces PCL that blends with the previously formed PLLA. The insights gained into the PLLA architectures during the first stage of the DESm ROP, along with the overall molecular weight and hydrophobicity of the resulting PLLA/PCL blend in bulk, were advantageously used to design polymerizable high internal phase emulsions (HIPEs) oil-in-DESm. By incorporating a liquid mixture of DESm and macroinitiators (PCLT or PEG), stable HIPE formulations were achieved. These emulsions sustained the efficient organocatalyzed ROP of the continuous phase at 37 °C with high conversions. The resulting polymer replicas of the HIPEs, characterized by macroporous and interconnected structures, were subjected to a degradation assay in PBS at pH 7.4 and 37 °C and remained mechanically stable for at least 30 days. Notably, they exhibited the capability to sorb crude oil in a proof-of-concept test, with a rate of 2 g g-1. The macroporous and interconnected features of the polyHIPEs, combined with their inherent degradation properties, position them as promising degradable polymeric sorbents for efficient separation of hydrophobic fluids from water.

Ab initio determination of melting and sound velocity of neon up to the deep interior of the Earth.

The thermophysical properties and elemental abundances of the noble gases in terrestrial materials can provide unique insights into the Earth's evolution and mantle dynamics. Here, we perform extensive ab initio molecular dynamics simulations to determine the melting temperature and sound velocity of neon up to 370 GPa and 7500 K to constrain its physical state and storage capacity, together with to reveal its implications for the deep interior of the Earth. It is found that solid neon can exist stably under the lower mantle and inner core conditions, and the abnormal melting of neon is not observed under the entire temperature (T) and pressure (P) region inside the Earth owing to its peculiar electronic structure, which is substantially distinct from other heavier noble gases. An inspection of the reduction for sound velocity along the Earth's geotherm evidences that neon can be used as a light element to account for the low-velocity anomaly and density deficit in the deep Earth. A comparison of the pair distribution functions and mean square displacements of MgSiO3-Ne and Fe-Ne alloys further reveals that MgSiO3 has a larger neon storage capacity than the liquid iron under the deep Earth condition, indicating that the lower mantle may be a natural deep noble gas storage reservoir. Our results provide valuable information for studying the fundamental behavior and phase transition of neon in a higher T-P regime, and further enhance our understanding for the interior structure and evolution processes inside the Earth.

The Pathway-Selective Dependence of Nitric Oxide for Long-Term Potentiation in the Anterior Cingulate Cortex of Adult Mice.

Nitric oxide (NO) is a key diffusible messenger in the mammalian brain. It has been proposed that NO may diffuse in retrograde into presynaptic terminals, contributing to the induction of hippocampal long-term potentiation (LTP). Here, we present novel evidence that NO is selectively required for the synaptic potentiation of the interhemispheric projection in the anterior cingulate cortex (ACC). Unilateral low-frequency stimulation (LFS) induced a short-term synaptic potentiation on the contralateral ACC through the corpus callosum (CC). The use of the antagonists of the NMDA receptor (NMDAR), or the inhibitor of the L-type voltage-dependent Ca2+ channels (L-VDCCs), blocked the induction of this ACC-ACC potentiation. In addition, the inhibitor of NO synthase, or inhibitors for its downstream signaling pathway, also blocked this ACC-ACC potentiation. However, the application of the NOS inhibitor blocked neither the local electric stimulation-induced LTP nor the stimulation-induced recruitment of silent responses. Our results present strong evidence for the pathway-selective roles of NO in the LTP of the ACC.