Prognostic factors in children and adolescents with differentiated thyroid cancer treated with total thyroidectomy and radioiodine therapy: a retrospective two-center study from China.

Purpose: This two-center study aimed to explore the main prognostic factors affecting the final disease status in children and adolescents with differentiated thyroid cancer (caDTC) following total thyroidectomy and radioiodine therapy (RAIT). Materials and methods: All caDTC patients from two centers in the period from 2004-2022 were retrospectively included. At the last follow-up, the patients' disease status was assessed and classified as an incomplete response (IR) or as an excellent or indeterminate response (EIDR). Then, the difference in preablation stimulated thyroglobulin (ps-Tg) levels between the two groups was compared, and the threshold for predicting IR was determined using receiver operating characteristic (ROC) analysis. Moreover, univariate and multivariate analyses were conducted to identify the factors influencing the patients' ultimate disease outcomes. Results: A total of 143 patients (98 females, 45 males; median age 16 years) were recruited. After a median follow-up of 42.9 months, 80 patients (55.9%) exhibited an EIDR, whereas 63 patients (44.1%) exhibited an IR. Patients with an IR had significantly greater ps-Tg levels than did those with an EIDR (median ps-Tg 79.2 ng/mL vs. 9.3 ng/mL, p<0.001). The ROC curve showed that ps-Tg ≥20 ng/mL was the most accurate for predicting IR at the last follow-up. According to multivariate analysis, only ps-Tg, T stage and the therapeutic response to initial RAIT were significantly associated with IR. Conclusion: In caDTC patients, the ps-Tg level, T stage, and response to initial RAIT are critical final outcome indicators.

A genetic basis for sex differences in Xp11 translocation renal cell carcinoma.

Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences.

Helicobacter pylori Outer Membrane Vesicles: Biogenesis, Composition, and Biological Functions.

Helicobacter pylori has been recognized not only as a causative agent of a spectrum of gastroduodenal diseases including chronic gastritis, peptic ulcer, mucosa-associated lymphoid tissue lymphoma, and gastric cancer, but also as the culprit in several extra-gastric diseases. However, the association of H. pylori infection with extra-gastric diseases remains elusive, prompting a reevaluation of the role of H. pylori-derived outer membrane vesicles (OMVs). Like other gram-negative bacteria, H. pylori constitutively sheds biologically active OMVs for long-distance delivery of bacterial virulence factors in a concentrated and protected form, averting the need of direct bacterial contact with distant host cells to induce extra-gastric diseases associated with this gastric pathogen. Additionally, H. pylori-derived OMVs contribute to bacterial survival and chronic gastric pathogenesis. Moreover, the immunogenic activity, non-replicable nature, and anti-bacterial adhesion effect of H. pylori OMVs make them a desirable vaccine candidate against infection. The immunogenic potency and safety concerns of the OMV contents are challenges in the development of H. pylori OMV-based vaccines. In this review, we discuss recent advances regarding H. pylori OMVs, focusing on new insights into their biogenesis mechanisms and biological functions.

Conversion chemoradiotherapy combined with nab-paclitaxel plus cisplatin in patients with locally advanced borderline-resectable or unresectable esophageal squamous cell carcinoma: a phase i/ii prospective cohort study.

BACKGROUND: To evaluate the efficacy and safety of nab-paclitaxel plus cisplatin as the regimen of conversional chemoradiotherapy (cCRT) in locally advanced borderline resectable or unresectable esophageal squamous cell carcinoma (ESCC). METHODS: Patients with locally advanced ESCC (cT3­4, Nany, M0­1, M1 was limited to lymph node metastasis in the supraclavicular area) were enrolled. All the patients received the cCRT of nab-paclitaxel plus cisplatin. After the cCRT, those resectable patients received esophagectomy; those unresectable patients continued to receive the definitive chemoradiotherapy (dCRT). The locoregional control (LRC), overall survival (OS), event-free survival (EFS), distant metastasis free survival (DMFS), pathological complete response (pCR), R0 resection rate, adverse events (AEs) and postoperative complications were calculated. RESULTS: 45 patients with ESCC treated from October 2019 to May 2021 were finally included. The median follow-up time was 30.3 months. The LRC, OS, EFS, DMFS at 1 and 2 years were 81.5%, 86.6%, 64.3%, 73.2 and 72.4%, 68.8%, 44.8%, 52.7% respectively. 21 patients (46.7%) received conversional chemoradiotherapy plus surgery (cCRT+S). The pCR rate and R0 resection rate were 47.6 and 84.0%. The LRC rate at 1 and 2 years were 95.0%, 87.1% in cCRT+S patitents and 69.3%, 58.7% in dCRT patients respectively (HR, 5.14; 95%CI, 1.10-23.94; P = 0.021). The toxicities during chemoradiotherapy were tolerated, and the most common grade 3-4 toxicitiy was radiation esophagitis (15.6%). The most common postoperative complication was pleural effusion (38.1%) and no grade ≥ IIIb complications were observed. CONCLUSION: nab-paclitaxel plus cisplatin are safe as the regimen of conversional chemoradiotherapy of ESCC.

Inflammatory stimulus-responsive polymersomes reprogramming glucose metabolism mitigates rheumatoid arthritis.

Inflammation-resident cells within arthritic sites undergo a metabolic shift towards glycolysis, which greatly aggravates rheumatoid arthritis (RA). Reprogramming glucose metabolism can suppress abnormal proliferation and activation of inflammation-related cells without affecting normal cells, holding potential for RA therapy. Single 2-deoxy-d-glucose (2-DG, glycolysis inhibitor) treatment often cause elevated ROS, which is detrimental to RA remission. The rational combination of glycolysis inhibition with anti-inflammatory intervention might cooperatively achieve favorable RA therapy. To improve drug bioavailability and exert synergetic effect, stable co-encapsulation of drugs in long circulation and timely drug release in inflamed milieu is highly desirable. Herein, we designed a stimulus-responsive hyaluronic acid-triglycerol monostearate polymersomes (HTDD) co-delivering 2-DG and dexamethasone (Dex) to arthritic sites. After intravenous injection, HTDD polymersomes facilitated prolonged circulation and preferential distribution in inflamed sites, where overexpressed matrix metalloproteinases and acidic pH triggered drug release. Results indicated 2-DG can inhibit the excessive cell proliferation and activation, and improve Dex bioavailability by reducing Dex efflux. Dex can suppress inflammatory signaling and prevent 2-DG-induced oxidative stress. Thus, the combinational strategy ultimately mitigated RA by inhibiting glycolysis and hindering inflammatory signaling. Our study demonstrated the great potential in RA therapy by reprogramming glucose metabolism in arthritic sites.

Label Consistency-Based Ground Truth Inference for Crowdsourcing.

In crowdsourcing scenarios, we can obtain each instance's multiple noisy labels from different crowd workers and then infer its unknown ground truth via a ground truth inference method. However, to the best of our knowledge, the existing ground truth inference methods always attempt to aggregate multiple noisy labels into a single consensus label as the ground truth. In this article, we aim to explore a new strategy, i.e., label selection, which directly selects the label of the highest quality worker as the ground truth. To this end, we propose a label consistency-based ground truth inference (LCGTI) method. In LCGTI, we argue that high-quality workers should have a low bias with other workers in labeling the same instances and a low variance with themselves in labeling similar instances. To estimate the bias, we calculate the label consistency of different workers on the same instances. To estimate the variance, we calculate the label consistency of the same worker on similar instances. Finally, we combine these two components to calculate the labeling quality of each worker on the inferred instance and perform label selection instead of label aggregation to achieve inference. The experimental results on 34 simulated and two real-world datasets show that LCGTI significantly outperforms all the other state-of-the-art label aggregation-based ground truth inference methods.

To nap or not? Evidence from a meta-analysis of cohort studies of habitual daytime napping and health outcomes.

Habitual daytime napping is a common behavioral and lifestyle practice in particular countries and is often considered part of a normal daily routine. However, recent evidence suggests that the health effects of habitual daytime napping are controversial. We systematically searched PubMed, Web of Science, Embase, and Cochrane Library databases from inception to March 9, 2024, to synthesize cohort studies of napping and health outcome risk. A total of 44 cohort studies with 1,864,274 subjects aged 20-86 years (mean age 56.4 years) were included. Overall, habitual napping increased the risk of several adverse health outcomes, including all-cause mortality, cardiovascular disease, metabolic disease, and cancer, and decreased the risk of cognitive impairment and sarcopenia. Individuals with a napping duration of 30 min or longer exhibited a higher risk of all-cause mortality, cardiovascular disease, and metabolic disease, whereas those with napping durations less than 30 min had no significant risks. No significant differences in napping and health risks were observed for napping frequency, percentage of nappers, sample size, sex, age, body mass index, follow-up years, or comorbidity status. These findings indicate that individuals with a long napping duration should consider shortening their daily nap duration to 30 min or less.

The phosphatase inhibitor BVT-948 can be used to efficiently screen functional sexual development proteins in the malaria parasite Plasmodium berghei.

BACKGROUND: Studying and discovering the molecular mechanism of Plasmodium sexual development is crucial for the development of transmission blocking drugs and malaria eradication. The aim of this study was to investigate the feasibility of using phosphatase inhibitors as a tool for screening proteins essential for Plasmodium sexual development and to discover proteins affecting the sexual development of malaria parasites. METHODS: Differences in protein phosphorylation among Plasmodium gametocytes incubated with BVT-948 under in vitro ookinete culture conditions were evaluated using phosphoproteomic methods. Gene Ontology (GO) analysis was performed to predict the mechanism by which BVT-948 affected gametocyte-ookinete conversion. The functions of 8 putative proteins involved in Plasmodium berghei sexual development were evaluated. Bioinformatic analysis was used to evaluate the possible mechanism of PBANKA_0100800 in gametogenesis and subsequent sexual development. RESULTS: The phosphorylation levels of 265 proteins decreased while those of 67 increased after treatment with BVT-948. Seven of the 8 genes selected for phenotype screening play roles in P. berghei sexual development, and 4 of these were associated with gametocytogenesis. PBANKA_0100800 plays essential roles in gametocyte-ookinete conversion and transmission to mosquitoes. CONCLUSIONS: Seven proteins identified by screening affect P. berghei sexual development, suggesting that phosphatase inhibitors can be used for functional protein screening.

Fluorescent Sensors Based on Lanthanide-Based Metal-Organic Frameworks via Devices and pH Response.

In light of the escalating industrial and environmental pollution, there is a pressing need for the development of novel materials capable of swiftly detecting pollutants. Here, we report the synthesis of five lanthanide metal-organic frameworks sharing a common structure, prepared via a hydrothermal method and denoted as [Ln2(H2DHBDC)2(phen)(H2O)6]n (where CUST-888 corresponds to Tb, CUST-889 corresponds to Eu, CUST-890 corresponds to Gd, CUST-891 corresponds to Dy, and CUST-892 corresponds to Nd). Notably, CUST-888 and CUST-889 exhibit discernible visual alterations in response to acidic and alkaline conditions. To assess their practical utility, luminescent test strips and light-emitting diode lights based on CUST-888 and CUST-889 were devised, enabling the visual detection of luminescence color changes induced by Hg2+, Cr2O72-, tetracycline, and 2,4,6-trinitrophenol. Furthermore, highlighters derived from CUST-888 and CUST-889 were designed, showcasing robust stability, adjustable color, and substantial potential for application in the realm of anticounterfeiting.

Novel humanized monoclonal antibodies against ROR1 for cancer therapy.

BACKGROUND: Overexpression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) contributes to cancer cell proliferation, survival and migration, playing crucial roles in tumor development. ROR1 has been proposed as a potential therapeutic target for cancer treatment. This study aimed to develop novel humanized ROR1 monoclonal antibodies and investigate their anti-tumor effects. METHODS: ROR1 expression in tumor tissues and cell lines was analyzed by immunohistochemistry and flow cytometry. Antibodies from mouse hybridomas were humanized by the complementarity-determining region (CDR) grafting technique. Surface plasmon resonance spectroscopy, ELISA assay and flow cytometry were employed to characterize humanized antibodies. In vitro cellular assay and in vivo mouse experiment were conducted to comprehensively evaluate anti-tumor activity of these antibodies. RESULTS: ROR1 exhibited dramatically higher expression in lung adenocarcinoma, liver cancer and breast cancer, and targeting ROR1 by short-hairpin RNAs significantly inhibited proliferation and migration of cancer cells. Two humanized ROR1 monoclonal antibodies were successfully developed, named h1B8 and h6D4, with high specificity and affinity to ROR1 protein. Moreover, these two antibodies effectively suppressed tumor growth in the lung cancer xenograft mouse model, c-Myc/Alb-cre liver cancer transgenic mouse model and MMTV-PyMT breast cancer mouse model. CONCLUSIONS: Two humanized monoclonal antibodies targeting ROR1, h1B8 and h6D4, were successfully developed and exhibited remarkable anti-tumor activity in vivo.

An explainable predictive model of direct pulp capping in carious mature permanent teeth.

OBJECTIVE: To introduce a novel approach for predicting the personalized probability of success of DPC treatment in carious mature permanent teeth using explainable machine learning (ML) models. METHODS: Clinical data were obtained from our previous single-center retrospective study, comprising 393 carious mature permanent teeth from 372 patients who underwent DPC and attended 1-year follow-up between January 2015 and February 2021. Six ML models were derived based on 80 % cases of the cohort, with the remaining 20 % cases used for validation. Shapley additive explanation (SHAP) values were utilized to assess feature importance and the clinical relevance of prediction models. RESULTS: Within the cohort, 9.67 % (38 out of 393) of teeth experienced failure at the 1-year follow-up after DPC treatment. Among the six evaluated ML models, the XGBoost model exhibited the highest discriminative ability. By prioritizing features based on their importance, streamlined and interpretable XGBoost model with 11 features were developed for 1-year prognostication post-DPC. The model demonstrated predictive accuracy with area under the curve (AUC) scores of 0.86 for the 1-year prediction. The final model has been translated into a web application to facilitate clinical decision-making. CONCLUSION: By incorporating demographic and clinical examination data, the XGBoost model offered a user-friendly tool for dentists to predict personalized probability of success, thereby improving personalized dental care and patient counseling. The utilization of SHAP for model interpretation provided transparent insights into the decision-making process.

Extracellular vesicle-bound VEGF in oral squamous cell carcinoma and its role in resistance to Bevacizumab Therapy.

BACKGROUND: Vascular endothelial growth factor (VEGF) is an important proangiogenic factor and has been considered as a key target of antiangiogenetic therapy in oral squamous cell carcinoma (OSCC). However, clinical application of bevacizumab, a specific VEGF antibody, didn't improve the survival rate of OSCC patients. One possible explanation is that VEGF gene expresses diverse isoforms, which associate with extracellular vesicles (EVs), and EVs potentially contribute to VEGF resistance to bevacizumab. However, clear solution is lacking in addressing this issue. METHODS: Expression of VEGF isoforms in OSCC cells was confirmed by reverse transcription and polymerase chain reaction (RT-PCR) and western blot. EVs isolated from OSCC cell's conditioned medium (CM) were characterized by western blot, transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Flow cytometry, immunogold labeling and western blot were applied to study the VEGF on EVs. Tube formation assay and Matrigel plug angiogenesis assay were used for analyzing the angiogenesis capacity of EV-VEGF. RESULTS: The most popular isoforms expressed by VEGF gene are VEGF121, VEGF165 and VEGF189. In this study, we demonstrated that all three isoforms of mRNA could be detected at varying levels in OSCC cells, while only VEGF165 and VEGF189 proteins were found. CM derived from OSCC cells, both soluble and non-soluble forms of VEGF could be detected. We further confirmed the presence of VGEF189 bound to EVs as a non-soluble form. EV-bound VEGF189 presented angiogenic activity, which could not be neutralized by bevacizumab. It was found that VEGF189 bound to EVs by heparan sulfate proteoglycans (HSPG). In addition, the angiogenic effect of EV-VEGF could be reversed by surfen, a kind of HSPG antagonist both in vitro and in vivo. CONCLUSION: Antagonists targeting HSPG might potentially overcome the resistance of EV-VEGF to bevacizumab and serve as an alternative for anti-VEGF therapy in OSCC.

Interplay of kernel shape and surface structure for NIR luminescence in atomically precise gold nanorods.

It is challenging to attain strong near-infrared (NIR) emissive gold nanoclusters. Here we show a rod-shaped cluster with the composition of [Au28(p-MBT)14(Hdppa)3](SO3CF3)2 (1 for short, Hdppa is N,N-bis(diphenylphosphino)amine, p-MBT is 4-methylbenzenethiolate) has been synthesized. Single crystal X-ray structural analysis reveals that it has a rod-like face-centered cubic (fcc) Au22 kernel built from two interpenetrating bicapped cuboctahedral Au15 units. 1 features NIR luminescence with an emission maximum at 920 nm, and the photoluminescence quantum yield (PLQY) is 12%, which is 30-fold of [Au21(m-MBT)12(Hdppa)2]SO3CF3 (2, m-MBT is 3-methylbenzenethiolate) with a similar composition and 60-fold of Au30S(S­t­Bu)18 with a similar structure. time-dependent DFT(TDDFT)calculations reveal that the luminescence of 1 is associated with the Au22 kernel. The small Stokes shift of 1 indicates that it has a very small excited state structural distortion, leading to high radiative decay rate (kr) probability. The emission of cluster 1 is a mixture of phosphorescence and thermally activated delayed fluorescence(TADF), and the enhancement of the NIR emission is mainly due to the promotion of kr rather than the inhibition of knr. This work demonstrates that the metal kernel and the surface structure are both very important for cluster-based NIR luminescence materials.

TFE3 fusions direct an oncogenic transcriptional program that drives OXPHOS and unveils vulnerabilities in translocation renal cell carcinoma.

Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic metabolism of most other renal cancers. This TFE3 fusion-driven OXPHOS program, together with heightened glutathione levels found in renal cancers, renders tRCCs sensitive to reductive stress - a metabolic stress state induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1a and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability to OXPHOS-dependent tRCC cells. Our study defines a distinctive tRCC-essential metabolic program driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy to counteract fusion-induced metabolic rewiring.

[Establishment of an Engineered Bacterial Membrane Biomimetic Nanodrug Delivery System and Its Role in the Treatment of Glioma]. / å·¥ç¨‹åŒ–ç»†èŒè†œä»¿ç”Ÿçº³ç±³è¯ç‰©é€’é€ç³»ç»Ÿçš„å»ºç«‹åŠåœ¨è„‘èƒ¶è´¨ç˜¤æ²»ç–—ä¸­çš„ä½œç”¨ç ”ç©¶.

Objective: To develop engineered bacterial membrane biomimetic nanoparticles, Angiopep-2 E. coli membrane (ANG-2 EM)@PDA-PEI-CpG (ANG-2 EM@PPC), for efficient targeted drug delivery in the treatment of glioma, and to provide theoretical and technical support for targeted glioma therapy. Methods: The expression of inaX-N-angiopep-2 engineered bacteria was constructed in the laboratory, and ANG-2 EM was obtained through lysozyme treatment and ultrafiltration centrifugation. ANG-2 EM@PPC was prepared by ultrasonication of bacterial membranes. Western blotting, agarose gel electrophoresis, and transmission electron microscopy (TEM) were used to verify the preparation. Particle size and Zeta potential were measured to investigate the stability of ANG-2 EM@PPC. Regarding cell experiments, CCK-8 assay was performed to determine the effect of ANG-2 EM@PPC on the survival rate of neutrophils. A flow chamber model was designed and constructed, and the uptake efficiency of neutrophils was measured by flow cytometry to investigate the hitchhiking efficiency of ANG 2 EM@PPC on neutrophils in inflammatory environment. Neutrophil death patterns were characterized by fluorescence microscopy, and flow cytometry and Western blotting were performed to examine neutrophil apoptotic bodies and the proportion of apoptotic bodies produced. Regarding animal experiments, a mouse model of in situ glioma was established and the inflammatory environment of tumor tissue was verified. The tumor model mice were divided into three groups, including DiR group, EM@PPC group, and ANG-2 EM@PPC group (all n=3), which were injected with DiR, ANG-2 EM@PDA-PEI-CpG, and EM@PDA-PEI-CpG via the tail vein, respectively (all at 10 mg/kg). Fluorescence images of organs and the brain were used to examine the distribution of the three formulations in vivo and in the brain. The tumor model mice were further divided into PBS group, PDA group, PC group, PPC group, EM@PPC group, and ANG-2 EM@PPC group (all n=4), which were injected with PBS, PDA, PC, PPC, EM@PPC, and ANG-2 EM@PPC injected via the tail vein, respectively (all at 10 mg/kg). Imaging was performed in vivo to observe tumor regression, and the survival rate and body mass of mice were measured to evaluate in vivo pharmacodynamics. TUNEL staining (brain tissue) and HE staining (brain, heart, liver, spleen, lung and kidney tissues) were performed to evaluate the therapeutic effect. Results: The results of TEM showed successful preparation of engineered bacterial membrane biomimetic nanoparticles, with PPC exhibiting a distinct shell-core structure and a shell thickness of about 8.2 nm. Due to the coating of ANG-2 EM, the shell thickness of ANG-2 EM@PPC increased to about 9.6 nm, with a clear bacterial membrane layer on the surface. Stability was maintained for at least one week. ANG-2 EM@PPC had no significant effect on the activity of neutrophils according to the findings from the CCK-8 assay. Flow cytometry showed that ANG-2 EM@PPC uptake is enhanced in activated neutrophils and hitchhiking on neutrophils was more efficient in the stationary state than that in the flowing condition. Compared with the EM@PPC group, the neutrophil hitchhiking ability of the ANG-2 EM@PPC group was enhanced (uptake efficiency 24.9% vs. 31.1%). Fluorescence microscopy showed that ANG-2 EM@PPC changed the death pathway of neutrophils from neutrophil extracellular traps-osis (NETosis) to apoptosis. Western blot confirmed the production of neutrophil apoptotic bodies, and flow cytometry showed that the production rate was as high as 77.7%. Animal experiments showed that there was no significant difference in the distribution of engineered bacterial membrane biomimetic nanoparticles in the organs (heart, liver, spleen, lungs, and kidney) in the DiR group, the EM@PPC gropu, and the ANG-2 EM@PPC group (P>0.05), but there was higher distribution in the brain tissue in EM@PPC and ANG-2 EM@PPC groups compared to the DiR group (P<0.05). Engineered bacterial membrane biomimetic nanoparticles crossed the blood-brain barrier (BBB), and exhibited high affinity to and internalization by neutrophils located in brain tumors. Compared with PBS, PDA, PC, and PPC groups, the survival rate and body mass of mice in the EM@PPC group were improved, tumor fluorescence intensity was weakened, and apoptotic cells were increased. These trends were even more prominent in the ANG-2 EM@PPC group. No abnormality was found in the HE staining of any group. Conclusion: An ANG-2 EM@PPC nanodelivery system with inflammation response characteristics was successfully prepared, capable of crossing BBB and targeting the tumor inflammatory microenvironment to improve the anti-glioma efficacy. This study provides a new drug delivery strategy for glioma treatment and offers a new idea for targeted drug delivery in the non-invasive inflammatory microenvironments in other central nervous system diseases.

Treatment of vedolizumab with exclusive enteral nutrition in adult patients with moderate to severe Crohn's Disease (CEEN Study).

BACKGROUND: Despite increasing studies confirming the efficacy of vedolizumab in Crohn's disease (CD), improving the responses to this biologic agent remains challenging in clinical practice. Here, we investigated the efficacy of combined treatment of vedolizumab and 16-week exclusive enteral nutrition (EEN) in moderately to severely active CD. METHODS: From October 2020 to October 2023, 81 patients with moderately to severely active CD treated with vedolizumab from three IBD centers were retrospectively selected. Forty-one patients received treatment of vedolizumab with concomitant 16-week EEN (vedolizumab, VDZ+EEN cohort) and 40 patients received vedolizumab treatment alone (VDZ cohort). Clinical and biological outcomes were evaluated. Endoscopic response and mucosal healing were assessed by colonoscopy at week 16 and 52. RESULTS: There was no statistically significant difference between two groups at baseline for demographic and clinical characteristics. Compared to patients treated with vedolizumab alone, patients in the VDZ+EEN cohort achieved higher rates of clinical response (84.2% vs. 40.0%), clinical remission (81.6% vs. 30.0%), endoscopic response (91.4 % vs. 34.6%) including mucosal healing (85.7% vs. 26.9%) at week 16. The superiority of VDZ+EEN treatment sustained in maintenance, with 76.7% (vs. 33.3%) clinical response, 70.0% (vs. 26.7%) clinical remission, 76.9% (vs. 33.3%) endoscopic response, and 61.5% (vs. 26.7%) mucosal healing at week 52. None of patients experienced severe adverse events. CONCLUSION: Vedolizumab with concomitant 16-week EEN might be an effective and optimized approach with solid efficacy in the induction and maintenance treatment of active CD.

Chemoarchitectural signatures of subcortical shape alterations in generalized epilepsy.

Genetic generalized epilepsies (GGE) exhibit widespread morphometric alterations in the subcortical structures. Subcortical structures are essential for understanding GGE pathophysiology, but their fine-grained morphological diversity has yet to be comprehensively investigated. Furthermore, the relationships between macroscale morphological disturbances and microscale molecular chemoarchitectures are unclear. High-resolution structural images were acquired from patients with GGE (n = 97) and sex- and age-matched healthy controls (HCs, n = 184). Individual measurements of surface shape features (thickness and surface area) of seven bilateral subcortical structures were quantified. The patients and HCs were then compared vertex-wise, and shape anomalies were co-located with brain neurotransmitter profiles. We found widespread morphological alterations in GGE and prominent disruptions in the thalamus, putamen, and hippocampus. Shape area dilations were observed in the bilateral ventral, medial, and right dorsal thalamus, as well as the bilateral lateral putamen. We found that the shape area deviation pattern was spatially correlated with the norepinephrine transporter and nicotinic acetylcholine (Ach) receptor (α4ß2) profiles, but a distinct association was seen in the muscarinic Ach receptor (M1). The findings provided a comprehensive picture of subcortical morphological disruptions in GGE, and further characterized the associated molecular mechanisms. This information may increase our understanding of the pathophysiology of GGE.

The new region demarcation framework for implementing the joint prevention and control of groundwater pollution: A case study in western of Bohai Bay, China.

The joint groundwater pollution prevention and control (GPPC) strategy has been extensively implemented to address the coastal region groundwater pollution challenges in China. However, regional groundwater pollution control and treatment efficiency cannot achieve the expected results due to the lack of regional priority control orders and accurate restoration levels. Thus, this study developed a new region demarcation framework method for delineating GPPC zones, in tandem with a comprehensive pollution index method, the DRASTIC model, source apportionment. To validate the new methodological framework, a case study of groundwater pollution in Qinhuangdao, the western of Bohai Bay, China, was implemented to calculate pollution prevention and control zoning. In total, 340 groundwater samples from shallow aquifers with 9 target pollutants (NO3-, NO2-, NH4+, As, Cd, Cr, Cu, Pb, and Ni) were selected as the dataset for GPPC regionalization. The results showed that GPPC zoning further clarified the direction of groundwater pollution protection and management in Qinhuangdao. Compared to the traditional method, the new GPPC zoning better reflects groundwater mobility characteristics and pollution transport and enrichment patterns in terms of groundwater functional integrity and delineation. This new regional demarcation framework method contributes to providing support for the fine division of groundwater pollution zoning and precise pollution control for groundwater resource management in China.

Divergent responses of woody plant leaf and root non-structural carbohydrates to nitrogen addition in China: Seasonal variations and ecological implications.

Plant non-structural carbohydrates (NSCs), which largely comprise starch and soluble sugars, are essential energy reserves to support plant growth and physiological functions. While it is known that increasing global deposition of nitrogen (N) affects plant concentration of NSCs, quantification of seasonal responses and drivers of woody species leaf and root NSCs to N addition at larger spatial scales remains lacking. Here, we systematically analyzed data from 53 field experiments distributed across China, comprising 1202 observations, to test for effects of N addition on woody plant leaf and root NSCs across and within growing and non-growing seasons. We found (1) no overall effects of N addition on the concentrations of leaf and root NSCs, soluble sugars or starch during the growing season or the non-growing season for leaves. However, N addition decreased root NSC and starch concentrations by 13.8 % and 39.0 %, respectively, and increased soluble sugars concentration by 15.0 % during the non-growing season. (2) Shifts in leaf NSC concentration under N addition were driven by responses by soluble sugars in both seasons, while shifts in root NSC were driven by soluble sugars in the non-growing season and starch and soluble sugars in the growing season. (3) Relationships between N, carbon, and phosphorus stoichiometry with leaf and root NSCs indicated effects of N addition on woody plant NSCs allocation through impacts on plant photosynthesis, respiration, and growth. (4) Effects of N addition on leaf and root NSCs varied with plant functional types, where effects were more pronounced in roots than in leaves during the non-growing season. Overall, our results reveal divergent responses of woody plant leaf and root NSCs to N addition within non-growing season and highlight the role of ecological stoichiometry and plant functional types in woody plant allocation patterns of NSCs in response to ongoing N deposition under global change.

Molecular dynamics analysis of subsurface brittleness mechanism of nanocrystalline 3C-SiC rough friction surface.

To study the effect of polycrystalline 3C-SiC rough friction surface on the mechanism of subsurface brittleness during nanocrystalline grinding. Initial grinding models of polycrystalline 3C-SiC and diamond abrasive grains on rough friction surfaces are developed using molecular dynamics methods and the Voronoi method for constructing polycrystalline abrasive grains. The processing mechanism of 3C-SiC is analyzed by post-processing methods such as dislocation defect analysis, atomic arrangement analysis and stress analysis. At 2.6 nm, "stress concentration" occurs between the abrasive particles and the workpiece, forming irregular force shapes. The larger the grain size, the smaller the crystal hardness, the greater the possibility of crystal fracture, and it is obvious in the crystal of larger grains. At 8 nm, the crystal breaks and creates vacancies. The roughness of the polycrystalline 3C-SiC friction surface and the cross-cutting mechanism between grains with grain boundaries are found to be effective in ameliorating the damage in the subsurface layer.