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Synergistic effects of herbicidal rice husks and pyrolysis liquid from waste wood-based panels were studied relative to the germination of three common weed species in a tea plantation. The pyrolysis liquid consisted of various organic acids, phenols, alcohols, ketones, and nitrogen compounds, with organic acids accounting for up to 46.8% of the content. Three seeds of smooth crabgrass (Digitaria ischaemum), annual fleabane (Erigeron annuus), and hedge-parsley (Torilis scabra (Thunb.) DC) were treated with 2000 and 4000 L/ha of pyrolysis liquid, as well as 50, 100, and 200 m3/ha of pyrolysis liquid as a cover material. The pre-emergence herbicide tests demonstrated that the combination of rice husks and pyrolysis liquid effectively inhibited seed germination and aboveground biomass of the weeds. The weed control effect increased with the increase in the amount applied. The combination of rice husks (200 m3/ha) and pyrolysis liquid (4000 L/ha) exhibited the highest weed control efficacy, reducing seed germination and aboveground biomass by 69.1%, 79.5%, and 97.6% for smooth crabgrass, annual fleabane, and hedge-parsley, respectively. Discarded furniture materials and rice husks can both be used as sustainable materials for weed control, offering a fresh approach to the efficient utilization of waste materials.

Abstract Background Even with advances in primary health care, depressive disorders remain a major global public health problem. We conducted an in-depth analysis of global, regional and national trends in depressive disorders incidence over the past 30 years. Methods Data on the incidence of depressive disorders were obtained by sex (female, male, and both), location (204 countries), age (5–84 years), year (1990–2019) from the Global Burden of Disease Study (GBD) 2019. Further, age-period-cohort modeling was used to estimate the net drift, local drift, age, period and cohort effects between 1990 and 2019. Results In 2019, although the incidence of depressive disorders has increased by 59.3% to 290 million (95% UI: 256, 328), the age-standardized incidence rate has decreased by 2.35% to 3588.25 per 100,000 people (3152.71, 4060.42) compared to 1990. There was an emerging transition of incidences from the young and middle-aged population to the old population. From 1990 to 2019, the net drift of incidence rate ranged from −0.54% (−0.61%, −0.47%) in low-middle Socio-demographic Index (SDI) regions to 0.52% (0.25%, 0.79%) in high SDI regions. Globally, the incidence rate of depressive disorders increases with age, period effects showing a decreasing risk and cohort effects beginning to decline after the 1960s. Conclusions Our current findings reflect substantial health disparities and potential priority-setting of depressive disorders incidence in the three dimensions of age, period and cohort across SDI regions, countries. The scope of healthcare to improve the progression of depressive disorders events can be expanded to include males, females of all ages.

The fibroblast growth factor receptor (FGFR) is a crucial receptor tyrosine kinase involved in essential biological processes, including growth, development, and tissue repair. However, FGFR gene mutations, including amplification, fusion, and mutation, can disrupt epigenetics, transcriptional regulation, and tumor microenvironment interactions, leading to cancer development. Targeting these kinase mutations with small molecule drugs or antibodies has shown clinical benefits. For example, erdafitinib is approved for treating locally advanced or metastatic urothelial cancer patients with FGFR2/FGFR3 mutations, and pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusion/rearrangement. Effective screening of FGFR variant patients is crucial for the clinical application of FGFR inhibitors. Various detection methods, such as polymerase chain reaction, next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry, are available, and their selection should be based on diagnostic and treatment decision-making needs. Our developed expert consensus aims to standardize the diagnosis and treatment process for FGFR gene mutations and facilitate the practical application of FGFR inhibitors in clinical practice.

Abstract In this paper, Voronoi cell finite element method (VCFEM) based on assumed flux hybrid formulation has been presented for heat conduction problem of particle reinforced composites material. The heat fluxes satisfying a priori internal thermal balance are directly approximated independently in the matrix and the inclusion respectively. The temperatures on element boundary and matrix-inclusion interface are interpolated by nodal temperature. The thermal balance on the interelement boundary and matrix-inclusion interface is relaxed and introduced into the functional by taking the temperature as Lagrange multiplier. In this way, a functional containing two variables of heat flux and temperature is proposed. Full field heat flux and effective thermal conductivity are obtained. Feasibility and effectiveness of the proposed approach are verified through several numerical examples.

Abstract Lakes are hotspots for the biogeochemical processing of carbon, including dissolved organic matter (DOM). A less degradable fraction of DOM, preserved for a long time, can be categorized as recalcitrant DOM (RDOM). Lake RDOM is an important but neglected carbon sink, and its characteristics and transformation processes remain largely unknown.

Cell-free fetal DNA (cffDNA) screening is a valuable tool in clinical practice for detecting chromosomal abnormalities and autosomal dominant (AD) conditions. This study introduces a novel proof-of-concept assay designed for autosomal recessive (AR) cffDNA screening, focusing on cases involving the NPC1 gene. We aim to illustrate the significant benefits of AR cffDNA screening in managing high-risk pregnancies, specifically where biallelic pathogenic variants in NPC1 cause Niemann–Pick disease, type C1 (NPC), a disorder marked by progressive neurodegeneration. Three participants for this study were recruited and gave consent to a hospital in Saudi Arabia. These participants were either carriers of NPC or had a first- or second-degree relative affected by the disorder. No specific criteria were set for the age of the participants. All were between 15 and 18 weeks of gestation. Using amplicon-based next-generation sequencing (NGS), we analyzed the zygosity and variants in cffDNA extracted from maternal peripheral blood. After amplicon NGS, analysis was completed by a custom data analysis pipeline that included in-house-built data processing scripts and commonly used software packages. Importantly, the results were not disclosed to the patients. Our findings showed that in all three cases, AR cffDNA screening results were consistent with standard invasive diagnostic testing. This screening method offers several advantages: it provides critical information to families earlier in the pregnancy compared to invasive diagnostic tests, and it helps to alleviate parental anxiety. Moreover, this non-invasive method can determine pregnancy status in the first trimester for known familial variants. Future research may extend this approach to screen for known disease-causing variants in common AR conditions.

Vascular smooth muscle cells (VSMCs) envelop vertebrate brain arteries and play a crucial role in regulating cerebral blood flow and neurovascular coupling. The dedifferentiation of VSMCs is implicated in cerebrovascular disease and neurodegeneration. Despite its importance, the process of VSMC differentiation on brain arteries during development remains inadequately characterized. Understanding this process could aid in reprogramming and regenerating dedifferentiated VSMCs in cerebrovascular diseases. In this study, we investigated VSMC differentiation on zebrafish circle of Willis (CoW), comprising major arteries that supply blood to the vertebrate brain. We observed that arterial specification of CoW endothelial cells (ECs) occurs after their migration from cranial venous plexus to form CoW arteries. Subsequently, acta2+ VSMCs differentiate from pdgfrb+ mural cell progenitors after they were recruited to CoW arteries. The progression of VSMC differentiation exhibits a spatiotemporal pattern, advancing from anterior to posterior CoW arteries. Analysis of blood flow suggests that earlier VSMC differentiation in anterior CoW arteries correlates with higher red blood cell velocity and wall shear stress. Furthermore, pulsatile flow induces differentiation of human brain PDGFRB+ mural cells into VSMCs, and blood flow is required for VSMC differentiation on zebrafish CoW arteries. Consistently, flow-responsive transcription factor klf2a is activated in ECs of CoW arteries prior to VSMC differentiation, and klf2a knockdown delays VSMC differentiation on anterior CoW arteries. In summary, our findings highlight blood flow activation of endothelial klf2a as a mechanism regulating initial VSMC differentiation on vertebrate brain arteries.

Cancer, a complex and heterogeneous disease, arises from genomic instability. Currently, DNA damage-based cancer treatments, including radiotherapy and chemotherapy, are employed in clinical practice. However, the efficacy and safety of these therapies are constrained by various factors, limiting their ability to meet current clinical demands. Metal nanoparticles present promising avenues for enhancing each critical aspect of DNA damage-based cancer therapy. Their customizable physicochemical properties enable the development of targeted and personalized treatment platforms. In this review, we delve into the design principles and optimization strategies of metal nanoparticles. We shed light on the limitations of DNA damage-based therapy while highlighting the diverse strategies made possible by metal nanoparticles. These encompass targeted drug delivery, inhibition of DNA repair mechanisms, induction of cell death, and the cascading immune response. Moreover, we explore the pivotal role of physicochemical factors such as nanoparticle size, stimuli-responsiveness, and surface modification in shaping metal nanoparticle platforms. Finally, we present insights into the challenges and future directions of metal nanoparticles in advancing DNA damage-based cancer therapy, paving the way for novel treatment paradigms.

Abstract The overall picture of degloving skin and soft tissue injuries (DSTI) remains a blank space in China. Therefore, a retrospective study was designed to summarize the current situation of this injury. Patients diagnosed with DSTI hospitalized between 2013 and 2018 were identified from the Hospital Quality Monitoring System (HQMS) database, of whom demographics, injury characteristics, hospitalization and cost information were analyzed. A total of 62,709 patients were enrolled in this study. Male sex predominated, with a mean age of 43.01 ± 19.70 years. Peasants seemed to be the most vulnerable. East China and Hubei province had the most patients. The most and least frequently injured anatomic site were lower extremity and torso, respectively. Traffic-related accidents and summer accounted for the highest proportion in terms of injury mechanism and season. The operation rate of DSTI roughly showed a growing trend, and the average length of stay was 22.02 ± 29.73 days. At discharge, 0.93% of DSTI patients ended up in death. Medicine accounted mostly for hospitalization cost, while the proportion decreased year by year. More than half DSTI patients paid at their own charge. This study made a relatively detailed description of DSTI patients nationwide, and might provide enlightenments for better prevention and treatment.

The fusion genes NRG1 and NRG2, members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1-positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2. Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Abstract Background Endoplasmic reticulum (ER) stress, promoting lipid metabolism disorders and steatohepatitis, contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Hugan Qingzhi tablets (HQT) has a definite effect in the clinical treatment of NAFLD patients, but its mechanism is still unclear. This study aims to investigate the effects of HQT on ER stress in the liver tissues of NAFLD rats and explore the underlying mechanism. Methods The NAFLD rat model was managed with high-fat diet (HFD) for 12weeks. HQT was administrated in a daily basis to the HFD groups. Biochemical markers, pro-inflammatory cytokines, liver histology were assayed to evaluate HQT effects in HFD-induced NAFLD rats. Furthermore, the expression of ER stress-related signal molecules including glucose regulating protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), p-PERK, eukaryotic translation initiation factor 2α (EIF2α), p-EIF2α, activating transcription factor 4 (ATF4), acetyl-coenzyme A-carboxylase (ACC), activating transcription factor (ATF6), and nuclear factor-kappa B-p65 (NF-κB-p65) were detected by western blot and/or qRT-PCR. Results The histopathological characteristics and biochemical data indicated that HQT exhibited protective effects on HFD-induced NAFLD rats. Furthermore, it caused significant reduction in the expression of ERS markers, such as GRP78, PERK, p-PERK, and ATF6, and subsequently downregulated the expression of EIF2α, p-EIF2α ATF4, ACC, and NF-κB-p65. Conclusions The results suggested that HQT has protective effect against hepatic steatosis and inflammation in NAFLD rats by attenuating ER stress, and the potential mechanism is through inhibition of PERK and ATF6 pathways.

Abstract Background Undetermined lung nodules are common in locally advanced rectal cancer (LARC) and lack precise risk stratification. This study aimed to develop a radiomic‐based score (Rad‐score) to distinguish metastasis and predict overall survival (OS) in patients with LARC and lung nodules. Methods Retrospective data from two institutions (July 10, 2006—September 24, 2015) was used to develop and validate the Rad‐score for distinguishing lung nodule malignancy. The prognostic value of the Rad‐score was investigated in LARC cohorts, leading to the construction and validation of a clinical and radiomic score (Cli‐Rad‐score) that incorporates both clinical and radiomic information for the purpose of improving personalized clinical prognosis prediction. Descriptive statistics, survival analysis, and model comparison were performed to assess the results. Results The Rad‐score demonstrated great performance in distinguishing malignancy, with C‐index values of 0.793 [95% CI: 0.729–0.856] in the training set and 0.730 [95% CI: 0.666–0.874] in the validation set. In independent LARC cohorts, Rad‐score validation achieved C‐index values of 0.794 [95% CI: 0.737–0.851] and 0.747 [95% CI: 0.615–0.879]. Regarding prognostic prediction, Rad‐score effectively stratified patients. Cli‐Rad‐score outperformed the clinicopathological information alone in risk stratification, as evidenced by significantly higher C‐index values (0.735 vs. 0.695 in the internal set and 0.618 vs. 0.595 in the external set). Conclusions CT‐based radiomics could serve as a reliable and powerful tool for lung nodule malignancy distinction and prognostic prediction in LARC patients. Rad‐score predicts prognosis independently. Incorporation of Cli‐Rad‐score significantly enhances the persionalized clinical prognostic capacity in LARC patients with lung nodules.

Abstract Precise agriculture based on intelligent agriculture plays a significant role in sustainable development. The agricultural Internet of Things (IoTs) is a crucial foundation for intelligent agriculture. However, the development of agricultural IoTs has led to exponential growth in various sensors, posing a major challenge in achieving long‐term stable power supply for these distributed sensors. Introducing a self‐powered active biochemical sensor can help, but current sensors have poor sensitivity and specificity making this application challenging. To overcome this limitation, a triboelectric nanogenerator (TENG)‐based self‐powered active urea sensor which demonstrates high sensitivity and specificity is developed. This device achieves signal enhancement by introducing a volume effect to enhance the utilization of charges through a novel dual‐electrode structure, and improves the specificity of urea detection by utilizing an enzyme‐catalyzed reaction. The device is successfully used to monitor the variation of urea concentration during crop growth with concentrations as low as 4 µm, without being significantly affected by common fertilizers such as potassium chloride or ammonium dihydrogen phosphate. This is the first self‐powered active biochemical sensor capable of highly specific and highly sensitive fertilizer detection, pointing toward a new direction for developing self‐powered active biochemical sensor systems within sustainable development‐oriented agricultural IoTs.

Corona Virus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has presented unprecedented challenges to the world. Changes after acute COVID-19 have had a significant impact on patients with neurodegenerative diseases. This study aims to explore the mechanism of neurodegenerative diseases by examining the main pathways of central nervous system infection of SARS-CoV-2. Research has indicated that chronic inflammation and abnormal immune response are the primary factors leading to neuronal damage and long-term consequences of COVID-19. In some COVID-19 patients, the concurrent inflammatory response leads to increased release of pro-inflammatory cytokines, which may significantly impact the prognosis. Molecular imaging can accurately assess the severity of neurodegenerative diseases in patients with COVID-19 after the acute phase. Furthermore, the use of FDG-PET is advocated to quantify the relationship between neuroinflammation and psychiatric and cognitive symptoms in patients who have recovered from COVID-19. Future development should focus on aggressive post-infection control of inflammation and the development of targeted therapies that target ACE2 receptors, ERK1/2, and Ca2+.

Abstract Background Circular RNAs (circRNAs) play a significant role in the tumorigenesis and progression of diverse human cancers, including lung adenocarcinoma. A previous study suggested that circ_0004140 expression was increased in lung adenocarcinoma cells. However, the molecular mechanism of circRNA circ_0004140 involved in lung adenocarcinoma is poorly defined. Methods Circ_0004140, microRNA‐330‐5p (miR‐330‐5p), and NOVA alternative splicing regulator 2 (NOVA2) expression were determined by real‐time quantitative polymerase chain reaction (RT‐qPCR). Cell proliferation, apoptosis, migration, invasion, and angiogenesis ability were assessed using 5‐ethynyl‐2’‐deoxyuridine (EdU), flow cytometry, wound healing, transwell, and capillary‐like network formation assays. Proliferating cell nuclear antigen (PCNA), cyclin D1, and NOVA2 protein levels were detected using Western blot assay. The interaction between miR‐330‐5p and circ_0004140 or NOVA2 was verified by dual‐luciferase reporter assay. Xenograft tumor model was utilized to assess the role of circ_0004140 in tumor growth in vivo. Results Circ_0004140 was upregulated in lung adenocarcinoma tissues and cell lines. Circ_0004140 silencing suppressed cell proliferation, migration, invasion and tube formation ability, and triggered the apoptosis of lung adenocarcinoma cells. Circ_0004140 acted as a molecular sponge for miR‐330‐5p, and miR‐330‐5p silencing largely reversed circ_0004140 knockdown‐induced effects in lung adenocarcinoma cells. NOVA2 was a target of miR‐330‐5p, and NOVA2 overexpression might largely overturn miR‐330‐5p overexpression‐induced influences in lung adenocarcinoma cells. Circ_0004140 upregulated NOVA2 expression via sponging miR‐330‐5p in lung adenocarcinoma cells. Circ_0004140 silencing restrained xenograft tumor growth in vivo. Conclusion Circ_0004140 knockdown might suppress the malignant biological behaviors of lung adenocarcinoma cells via miR‐330‐5p‐dependent regulation of NOVA2.

Abstract G protein-coupled receptors (GPCRs) are versatile and vital proteins involved in a wide array of physiological processes and responses, such as sensory perception (e.g., vision, taste, and smell), immune response, hormone regulation, and neurotransmission. Their diverse and essential roles in the body make them a significant focus for pharmaceutical research and drug development. Currently, approximately 35% of marketed drugs directly target GPCRs, underscoring their prominence as therapeutic targets. Recent advances in structural biology have substantially deepened our understanding of GPCR activation mechanisms and interactions with G-protein and arrestin signaling pathways. This review offers an in-depth exploration of both traditional and recent methods in GPCR structure analysis. It presents structure-based insights into ligand recognition and receptor activation mechanisms and delves deeper into the mechanisms of canonical and noncanonical signaling pathways downstream of GPCRs. Furthermore, it highlights recent advancements in GPCR-related drug discovery and development. Particular emphasis is placed on GPCR selective drugs, allosteric and biased signaling, polyphamarcology, and antibody drugs. Our goal is to provide researchers with a thorough and updated understanding of GPCR structure determination, signaling pathway investigation, and drug development. This foundation aims to propel forward-thinking therapeutic approaches that target GPCRs, drawing upon the latest insights into GPCR ligand selectivity, activation, and biased signaling mechanisms.

Ni-rich Li(NixCoyMnz)O2 (x ≥ 0.8)-layered oxide materials are highly promising as cathode materials for high-energy-density lithium-ion batteries in electric and hybrid vehicles. However, their tendency to undergo side reactions with electrolytes and their structural instability during cyclic lithiation/delithiation impairs their electrochemical cycling performance, posing challenges for large-scale applications. This paper explores the application of an Al2O3 coating using an atomic layer deposition (ALD) system on Ni-enriched Li(Ni0.8Co0.1Mn0.1)O2 (NCM811) cathode material. Characterization techniques, including X-ray diffraction, scanning electron microscopy, and transmission electron microscopy, were used to assess the impact of alumina coating on the morphology and crystal structure of NCM811. The results confirmed that an ultrathin Al2O3 coating was achieved without altering the microstructure and lattice structure of NCM811. The alumina-coated NCM811 exhibited improved cycling stability and capacity retention in the voltage range of 2.8–4.5 V at a 1 C rate. Specifically, the capacity retention of the modified NCM811 was 5%, 9.11%, and 11.28% higher than the pristine material at operating voltages of 4.3, 4.4, and 4.5 V, respectively. This enhanced performance is attributed to reduced electrode–electrolyte interaction, leading to fewer side reactions and improved structural stability. Thus, NCM811@Al2O3 with this coating process emerges as a highly attractive candidate for high-capacity lithium-ion battery cathode materials.

The in vitro maturation efficiency of porcine oocytes is relatively low, and this limits the production of in vitro porcine embryos. Since melatonin is involved in mammalian reproductive physiology, in this study, we have explored whether endogenously produced melatonin can help in porcine oocyte in vitro maturation. We have found, for the first time in the literature, that mitochondria are the major sites for melatonin biosynthesis in porcine oocytes. This mitochondrially originated melatonin reduces ROS production and increases the activity of the mitochondrial respiratory electron transport chain, mitochondrial biogenesis, mitochondrial membrane potential, and ATP production. Therefore, melatonin improves the quality of oocytes and their in vitro maturation. In contrast, the reduced melatonin level caused by siRNA to knockdown AANAT (siAANAT) is associated with the abnormal distribution of mitochondria, decreasing the ATP level of porcine oocytes and inhibiting their in vitro maturation. These abnormalities can be rescued by melatonin supplementation. In addition, we found that siAANAT switches the mitochondrial oxidative phosphorylation to glycolysis, a Warburg effect. This metabolic alteration can also be corrected by melatonin supplementation. All these activities of melatonin appear to be mediated by its membrane receptors since the non-selective melatonin receptor antagonist Luzindole can blunt the effects of melatonin. Taken together, the mitochondria of porcine oocytes can synthesize melatonin and improve the quality of oocyte maturation. These results provide an insight from a novel aspect to study oocyte maturation under in vitro conditions.

Objective: Brown adipose tissue (BAT) development and function are essential for maintaining energy balance. However, the key factors that specifically regulate brown adipogenesis require further identification. Here, we demonstrated that the nuclear receptor subfamily 2 group F member 6 (NR2F6) played a pivotal role in brown adipogenesis and energy homeostasis. Methods: We examined the differentiation of immortalized brown adipocytes and primary brown adipocytes when NR2F6 were deleted, and explored the mechanism through which NR2F6 regulated adipogenesis using ChIP-qPCR in vitro. Male wild type (WT) and Pdgfra-Cre-mediated deletion of Nr2f6 in preadipocytes (NR2F6-PKO) mice were fed with high fat diet (HFD) for 12 weeks, and adiposity, glucose intolerance, insulin resistance and inflammation were assessed. Results: NR2F6 exhibited abundant expression in BAT, while its expression was minimal in white adipose tissue (WAT). Within BAT, NR2F6 was highly expressed in preadipocytes, experienced a transient increase in the early stage of brown adipocyte differentiation, and significantly decreased in the mature adipocytes. Depletion of NR2F6 in preadipocytes inhibited brown adipogenesis, caused hypertrophy of brown adipocytes, and impaired thermogenic function of BAT, but without affecting WAT development. NR2F6 transcriptionally regulated PPARγ expression to promote adipogenic process in brown adipocytes. Loss of NR2F6 in preadipocytes led to increased susceptibility to diet-induced metabolic disorders. Conclusions: Our findings unveiled NR2F6 as a novel key regulator of brown adipogenesis, potentially opening up new avenues for maintaining metabolic homeostasis by targeting NR2F6.

Introduction The preliminary result of the TORCH trial has shown a promising complete response (CR) for managing locally advanced rectal cancer with neoadjuvant short-course radiotherapy (SCRT) combined with chemotherapy and PD-1 inhibitor. For locally advanced colon cancer (LACC) with bulky nodal disease and/or clinically T4, neoadjuvant chemotherapy followed by colectomy with en bloc removal of regional lymph nodes is the suggested treatment. However, the CR rate is less than 5%. TORCH-C will aim to investigate neoadjuvant SCRT combined with chemotherapy and PD-1 inhibitor in LACC.Methods and analysis TORCH-C is a randomised, prospective, multicentre, double-arm, open, phase II trial of SCRT combined with chemotherapy and immunotherapy in LACC with microsatellite stable (MSS) patients and cT4 or bulky nodes. Eligible patients will be identified by the multidisciplinary team. 120 patients will be randomised 1:1 to the intervention or control arm. The patients in the control arm will receive four cycles of capecitabine plus oxaliplatin (CAPOX). The patients in the intervention arm will receive SCRT, followed by four cycles of CAPOX and PD-1 inhibitor (serplulimab). Both arms will receive curative surgery, followed by four cycles of CAPOX. The primary endpoint is pathological complete regression.TORCH-C (TORCH-colon) trial aims to investigate whether the combination of immunotherapy and chemoradiotherapy improves the treatment effect in LACC with MSS. TORCH-C will establish the TORCH platform, a key part of our long-term strategy to develop neoadjuvant treatment for colorectal cancer.Ethics and dissemination This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (approval number: 2211265-12).Trial registration number NCT05732493

Abstract In addressing the demand for hierarchically mesoporous metal‐organic frameworks (HMMOFs) with adjustable large mesopores, a method based on the synergistic effects of low‐temperature microemulsions and Hofmeister ions is developed. Low temperature dramatically enhanced the solubility of hydrophobic solvent in the microemulsion core, enlarging the mesopores in HMMOFs replica. Meanwhile, Hofmeister salt‐in ions continuously controlled mesopore expansion by modulating the permeability of swelling agent into the microemulsion core. The large mesopores up to 33 nm provided sufficient space for the alkaline phosphatase (ALP) enrichment, and retained the remaining channel to facilitate the free mass diffusion. Leveraging these advantages, a colorimetric sensor is successfully developed using large‐mesopore HMMOFs for femtomolar ALP detection based on the enrichment and cycling amplification principles. The sensor exhibited a linear detection range of 100 to 7500 fm and a limit of detection of 42 fm, presenting over 4000 times higher sensitivity than classic para‐nitrophenyl phosphate colorimetric methods. Such high sensitivity highlights the importance of adjustable mesoporous structures of HMMOFs in advanced sensing applications, and prefigures their potential for detecting large biomolecules in diagnostics and biomedical research.

Background: The skeletal muscle index (SMI) can serve as a surrogate for a patient’s nutritional status, which is associated with treatment toxicity. This study aims to investigate the potential of baseline skeletal muscle radiomics features to predict gastrointestinal toxicity of neoadjuvant chemoradiotherapy for rectal cancer. Methods: A total of 214 rectal cancer patients (115, 49 and 50 in the training, internal and external validation set, respectively) who underwent neoadjuvant pelvic radiotherapy with capecitabine and irinotecan were retrospectively identified. The skeletal muscle at the level of the third lumber vertebra was contoured, and the radiomics features were extracted from computed tomography scans. In the training set, the least absolute shrinkage and selection operator (LASSO) regression algorithm was applied to select features that were most significantly associated with grade 3–4 gastrointestinal toxicity (diarrhea, nausea, vomiting and proctitis). The predictive performance and clinical utility were estimated using the area under the receiver operator characteristic curve (AUC), F1-score and decision curve analysis (DCA). Results: Nine features, including the SMI and eight radiomics features, were associated with grade 3–4 gastrointestinal toxicity and included in the logistic regression. This combined predictive model, which incorporated the SMI and radiomics features, showed better discrimination than the SMI alone, with an AUC of 0.856 (95 % CI: 0.782–0.929) in the training cohort, 0.812 (95 % CI: 0.667–0.956) in the internal validation cohort and 0.745 (95 % CI: 0.600–0.890) in the external validation cohort. DCA further verified the clinical utility of the combined predictive model. Conclusion: Radiomics features of skeletal muscle were significantly associated with gastrointestinal toxicity. The predictive model incorporating the SMI and radiomics features exhibits favorable discrimination and may be highly informative for clinical decision-makings.

Abstract Enhancements of edge zonal flows, radial electric fields, and turbulence are observed in electron cyclotron resonance heating-heated plasmas (Zhao et al 2013 Nucl. Fusion 53 083011). In this paper, the effects of sawtooth heat pulses on flows and turbulence are presented. These experiments are performed using multiple Langmuir probe arrays in the edge plasmas of the HL-2A tokamak. The edge zonal flows, radial electric fields, and turbulence are all enhanced by sawteeth. Propagation of the zonal flow and turbulence intensities is also observed. The delay time of the maximal intensity of the electric fields, zonal flows, and turbulence with respect to the sawtooth crashes is estimated as ∼1 ms and comparable to that of the sawtooth-triggered intermediate phases. Not only the zonal flows but also the radial electric fields lag behind the turbulence. Furthermore, the intensities of both the zonal flows and electric fields nearly linearly increase/decrease with the increase/decrease of the turbulence intensity. A double-source predator–prey model analysis suggests that a relatively strong turbulence source may contribute to the dominant zonal flow formation during sawtooth cycles.

Abstract The PI3K/AKT pathway plays an essential role in tumour development. NOD-like receptors (NLRs) regulate innate immunity and are implicated in cancer, but whether they are involved in PI3K/AKT pathway regulation is poorly understood. Here, we report that NLRP6 potentiates the PI3K/AKT pathway by binding and destabilizing p85α, the regulatory subunit of PI3K. Mechanistically, NLRP6 recruits the E3 ligase RBX1 to p85α and ubiquitinates lysine 256 on p85α, which is recognized by the autophagy cargo receptor OPTN, causing selective autophagic degradation of p85α and subsequent activation of the PI3K/AKT pathway by reducing PTEN stability. We further show that loss of NLRP6 suppresses cell proliferation, colony formation, cell migration, and tumour growth in glioblastoma cells in vitro and in vivo. Disruption of the NLRP6/p85α interaction using the Pep9 peptide inhibits the PI3K/AKT pathway and generates potent antitumour effects. Collectively, our results suggest that NLRP6 promotes p85α degradation via selective autophagy to drive tumorigenesis, and the interaction between NLRP6 and p85α can be a promising therapeutic target for tumour treatment.

Abstract Background The majority of epidemiological studies on migraine have been conducted in a specific country or region, and there is a lack of globally comparable data. We aim to report the latest information on global migraine incidence overview trends from 1990 to 2019. Methods In this study, the available data were obtained from the Global Burden of Disease 2019. We present temporal trends in migraine for the world and its 204 countries and territories over the past 30 years. Meanwhile, an age-period-cohort model be used to estimate net drifts (overall annual percentage change), local drifts (annual percentage change in each age group), longitudinal age curves (expected longitudinal age-specific rate), and period (cohort) relative risks. Results In 2019, the global incidence of migraine increased to 87.6 million (95% UI: 76.6, 98.7), with an increase of 40.1% compared to 1990. India, China, United States of America, and Indonesia had the highest number of incidences, accounting for 43.6% of incidences globally. Females experienced a higher incidence than males, the highest incidence rate was observed in the 10–14 age group. However, there was a gradual transition in the age distribution of incidence from teenagers to middle-aged populations. The net drift of incidence rate ranged from 3.45% (95% CI: 2.38, 4.54) in high-middle Socio-demographic Index (SDI) regions to -4.02% (95% CI: -4.79, -3.18) in low SDI regions, 9 of 204 countries showed increasing trends (net drifts and its 95% CI were > 0) in incidence rate. The age-period-cohort analysis results showed that the relative risk of incidence rate generally showed unfavorable trends over time and in successively birth cohorts among high-, high-middle-, and middle SDI regions, but low-middle- and low-SDI regions keep stable. Conclusions Migraine is still an important contributor to the global burden of neurological disorders worldwide. Temporal trends in migraine incidence are not commensurate with socioeconomic development and vary widely across countries. Both sexes and all age groups should get healthcare to address the growing migraine population, especially adolescents and females.

Non-alcoholic fatty liver disease (NAFLD) is a type of metabolic stress liver injury closely related to insulin resistance (IR) and genetic susceptibility without alcohol consumption, which encompasses a spectrum of liver disorders ranging from simple hepatic lipid accumulation, known as steatosis, to the more severe form of steatohepatitis (NASH). NASH can progress to cirrhosis and hepatocellular carcinoma (HCC), posing significant health risks. As a multisystem disease, NAFLD is closely associated with systemic insulin resistance, central obesity, and metabolic disorders, which contribute to its pathogenesis and the development of extrahepatic complications, such as cardiovascular disease (CVD), type 2 diabetes mellitus, chronic kidney disease, and certain extrahepatic cancers. Recent evidence highlights the indispensable roles of intestinal barrier dysfunction and gut microbiota in the onset and progression of NAFLD/NASH. This review provides a comprehensive insight into the role of intestinal barrier dysfunction and gut microbiota in NAFLD, including intestinal barrier function and assessment, inflammatory factors, TLR4 signaling, and the gut–liver axis. Finally, we conclude with a discussion on the potential therapeutic strategies targeting gut permeability and gut microbiota in individuals with NAFLD/NASH, such as interventions with medications/probiotics, fecal transplantation (FMT), and modifications in lifestyle, including exercise and diet.

Abstract Background Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking. Methods We adopted cross-species, single-cell RNA sequencing (scRNA-seq) analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis. Flow cytometry, laser scanning confocal microscopy (LSCM) imaging and Western blotting were applied to identify the presence of S100A9+ monocytes at protein level. To interrogate the immunosuppressive function of this subset, splenic monocytes isolated from septic wild-type or S100a9 −/− mice were co-cultured with naïve CD4+ T cells, followed by proliferative assay. Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage. Results ScRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis, for which distinct monocyte subsets were enriched in disparate subclusters of septic patients. We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR (HLA-DR), which were prominently enriched in septic patients and might exert immunosuppressive function. By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments, we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice, corresponding to HLA-DR low S100A high monocytes in human sepsis. Moreover, we found that S100A9+ monocytes exhibited profound immunosuppressive function on CD4+ T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression. Conclusions This study identifies HLA-DR low S100A high monocytes correlated with immunosuppressive state upon septic challenge, inhibition of which can markedly mitigate sepsis-induced immune depression, thereby providing a novel therapeutic strategy for the management of sepsis.