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

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors have changed the therapeutic landscape for diabetic kidney disease (DKD) patients, but their underlying mechanisms are complicated and not fully understood. Mitochondria-associated endoplasmic reticulum membranes (MAMs), the dynamic contact sites between mitochondria and the endoplasmic reticulum (ER), serve as intracellular platforms important for regulating cellular fate and function. This study explored the roles and mechanisms of SGLT2 inhibitors in regulating MAMs formation in diabetic podocytes. Methods We assessed MAMs formation in podocytes from DKD patients’ renal biopsy samples and induced an increase in MAMs formation in cultured human podocytes by transfecting OMM-ER linker plasmid to investigate the effects of MAMs imbalance on podocyte injury. Empagliflozin-treated diabetic mice and podocyte-specific SGLT2 knockout diabetic mice (diabetic states were induced by streptozotocin and a high-fat diet), empagliflozin-treated podocytes, SGLT2-downregulated podocytes, and SGLT2-overexpressing podocytes were used to investigate the effects and mechanisms of SGLT2 inhibitors on MAMs formation in diabetic podocytes. Results MAMs were increased in podocytes and were associated with renal dysfunction in DKD patients. Increased MAMs aggravated HG-induced podocyte injury. The expression of SGLT2 was increased in diabetic podocytes. In addition, empagliflozin-treatment and podocyte-specific SGLT2 knockout attenuated MAMs formation and podocyte injury in diabetic mice. Empagliflozin treatment and SGLT2 knockdown decreased podocyte MAMs formation by activating the AMP-activated protein kinase (AMPK) pathway, while SGLT2 overexpression had the opposite effect. Conclusions Inhibition of SGLT2 attenuates MAMs imbalance in diabetic podocytes by activating the AMPK pathway. This study expands our knowledge of the roles of SGLT2 inhibitors in improving DKD podocyte injury and provides new insights into DKD treatment.

Abstract Background Blocking the RhoA/ROCK II/MLC 2 (Ras homolog gene family member A/Rho kinase II/myosin light chain 2) signaling pathway can initiate neuroprotective mechanisms against neurological diseases such as stroke, cerebral ischemia, and subarachnoid hemorrhage. Nevertheless, it is not clear whether and how disrupting the RhoA/ROCK II/MLC 2 signaling pathway changes the pathogenic processes of the blood–brain barrier (BBB) after intracerebral hemorrhage (ICH). The present investigation included the injection of rat caudal vein blood into the basal ganglia area to replicate the pathophysiological conditions caused by ICH. Methods Scalp acupuncture (SA) therapy was performed on rats with ICH at the acupuncture point “Baihui”‐penetrating “Qubin,” and the ROCK selective inhibitor fasudil was used as a positive control to evaluate the inhibitory effect of acupuncture on the RhoA/ROCK II/MLC 2 signaling pathway. Post‐assessments included neurological deficits, brain edema, Evans blue extravasation, Western blot, quantitative polymerase chain reaction, and transmission electron microscope imaging. Results We found that ROCK II acts as a promoter of the RhoA/ROCK II/MLC 2 signaling pathway, and its expression increased at 6 h after ICH, peaked at 3 days, and then decreased at 7 days after ICH, but was still higher than the pre‐intervention level. According to some experimental results, although 3 days is the peak, 7 days is the best time point for acupuncture treatment. Starting from 6 h after ICH, the neurovascular structure and endothelial cell morphology around the hematoma began to change. Based on the changes in the promoter ROCK II, a 7‐day time point was selected as the breakthrough point for treating ICH model rats in the main experiment. The results of this experiment showed that both SA at “Baihui”‐penetrating “Qubin” and treatment with fasudil could improve the expression of endothelial‐related proteins by inhibiting the RhoA/ROCK II/MLC 2 signaling pathway and reduce neurological dysfunction, brain edema, and BBB permeability in rats. Conclusion This study found that these experimental data indicated that SA at “Baihui”‐penetrating “Qubin” could preserve BBB integrity and neurological function recovery after ICH by inhibiting RhoA/ROCK II/MLC 2 signaling pathway activation and by regulating endothelial cell–related proteins.

Abstract This study aimed to develop and validate prediction models to estimate the risk of death and intensive care unit admission in COVID-19 inpatients. All RT-PCR-confirmed adult COVID-19 inpatients admitted to Fujian Provincial Hospital from October 2022 to April 2023 were considered. Elastic Net Regression was used to derive the risk prediction models. Potential risk factors were considered, which included demographic characteristics, clinical symptoms, comorbidities, laboratory results, treatment process, prognosis. A total of 1906 inpatients were included finally by inclusion/exclusion criteria and were divided into derivation and test cohorts in a ratio of 8:2, where 1526 (80%) samples were used to develop prediction models under a repeated cross-validation framework and the remaining 380 (20%) samples were used for performance evaluation. Overall performance, discrimination and calibration were evaluated in the validation set and test cohort and quantified by accuracy, scaled Brier score (SbrS), the area under the ROC curve (AUROC), and Spiegelhalter-Z statistics. The models performed well, with high levels of discrimination (AUROCICU [95%CI]: 0.858 [0.803,0.899]; AUROCdeath [95%CI]: 0.906 [0.850,0.948]); and good calibrations (Spiegelhalter-Z ICU : − 0.821 (p-value: 0.412); Spiegelhalter-Z death : 0.173) in the test set. We developed and validated prediction models to help clinicians identify high risk patients for death and ICU admission after COVID-19 infection.

Manure utilization in China is below optimum due to the inconsistency between farmers’ behavior and their intention to apply manure to their crops. With increasing constraints on the availability of chemical fertilizer and their impact on the environment, understanding how farmers’ perceptions affect their intention and behavior toward manure application is an issue for the implementation of sustainable agricultural development. This study uses primary survey data from 653 farmers. A probit model was used to assess the influence of cognition on farmers’ intentions, behavior, and the inconsistency between them in the use of manure application. Heterogeneity analysis was conducted to identify differences between farmers with different education levels and operation scales. The results showed that enhancing subjective norms, perceived behavioral control, and behavioral attitudes could increase their intention and behavior. Furthermore, improving the perceived behavioral control and behavioral attitudes of farmers would reduce the inconsistency between behavior and intention. In addition, some differences were identified in the role of farmers’ cognition with different education levels and operation scales. In general, it is necessary to enhance farmers’ comprehensive cognition of the value of manure through publicity and popularization of technology, reduce farmers’ perceptions about difficulties in applying manure through new policies and subsidies, and stimulate farmers’ enthusiasm to participate in the practice.

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system CNS characterized by demyelination, inflammation, and neurodegenerative changes, making it the most common nontraumatic disabling neurological disease in young adults. While current pharmacological treatments primarily target immunomodulation or immunosuppression, exercise is gaining increasing attention from the scientific community as an adjunctive therapy. This review explores the potential biological mechanisms of exercise in animal models of MS, focusing on its effects on neuroprotection and inflammation. The review examines how exercise inhibits pro-inflammatory microglial reactivity, stabilizes the blood–brain barrier, and enhances neurotrophic factor expression in animal studies. Future research directions are proposed by summarizing the evidence and limitations of existing animal models of MS, emphasizing the need to further validate these mechanisms in humans to better integrate exercise into the comprehensive management of MS. Additionally, investigating exercise-induced biomarkers for MS symptom reduction may provide a scientific basis for new therapeutic strategies.

Intracerebral hemorrhage (ICH) is the second most common subtype of stroke, characterized by high mortality and a poor prognosis. Despite various treatment methods, there has been limited improvement in the prognosis of ICH over the past decades. Therefore, it is imperative to identify a feasible treatment strategy for ICH. Mitochondria are organelles present in most eukaryotic cells and serve as the primary sites for aerobic respiration and energy production. Under unfavorable cellular conditions, mitochondria can induce changes in permeability through the opening of the mitochondrial permeability transition pore (mPTP), ultimately leading to mitochondrial dysfunction and contributing to various diseases. Recent studies have demonstrated that mPTP plays a role in the pathological processes associated with several neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, ischemic stroke and ischemia-reperfusion injury, among others. However, there is limited research on mPTP involvement specifically in ICH. Therefore, this study comprehensively examines the pathological processes associated with mPTP in terms of oxidative stress, apoptosis, necrosis, autophagy, ferroptosis, and other related mechanisms to elucidate the potential mechanism underlying mPTP involvement in ICH. This research aims to provide novel insights for the treatment of secondary injury after ICH.

ObjectiveThere is currently a lack of evidence in evidence-based medicine regarding acupuncture treatment for experimental intracerebral hemorrhage (ICH). The aim of this study was to systematically evaluate the efficacy of acupuncture treatment for experimental ICH based on neurological function scores and brain water content (BWC).MethodsEight mainstream Chinese and English databases were searched. Outcome measures included neurological function scores and BWC, and subgroup analysis was conducted based on study characteristics.ResultsA total of 32 studies were included. Meta-analysis results indicated that compared to the control group, the acupuncture group showed significant reductions in mNSS (MD = −3.16, p

Abstract Butyric acid is a volatile saturated monocarboxylic acid, which is widely used in the chemical, food, pharmaceutical, energy, and animal feed industries. This study focuses on producing butyric acid from pre-treated rape straw using simultaneous enzymatic hydrolysis semi-solid fermentation (SEHSF). Clostridium beijerinckii BRM001 screened from pit mud of Chinese nongxiangxing baijiu was used. The genome of C. beijerinckii BRM001 was sequenced and annotated. Using rape straw as the sole carbon source, fermentation optimization was carried out based on the genomic analysis of BRM001. The optimized butyric acid yield was as high as 13.86 ± 0.77 g/L, which was 2.1 times higher than that of the initial screening. Furthermore, under optimal conditions, non-sterile SEHSF was carried out, and the yield of butyric acid was 13.42 ± 0.83 g/L in a 2.5-L fermentor. This study provides a new approach for butyric acid production which eliminates the need for detoxification of straw hydrolysate and makes full use of the value of fermentation waste residue without secondary pollution, making the whole process greener and more economical, which has a certain industrial potential. Graphical Abstract

Abstract Background Secondary immunodeficiency can arise from various clinical conditions that include HIV infection, chronic diseases, malignancy and long-term use of immunosuppressives, which makes the suffering patients susceptible to all types of pathogenic infections. Other than HIV infection, the possible pathogen profiles in other aetiology-induced secondary immunodeficiency are largely unknown. Methods Medical records of the patients with secondary immunodeficiency caused by various aetiologies were collected from the First Affiliated Hospital of Nanchang University, China. Based on these records, models were developed with the machine learning method to predict the potential infectious pathogens that may inflict the patients with secondary immunodeficiency caused by various disease conditions other than HIV infection. Results Several metrics were used to evaluate the models’ performance. A consistent conclusion can be drawn from all the metrics that Gradient Boosting Machine had the best performance with the highest accuracy at 91.01%, exceeding other models by 13.48, 7.14, and 4.49% respectively. Conclusions The models developed in our study enable the prediction of potential infectious pathogens that may affect the patients with secondary immunodeficiency caused by various aetiologies except for HIV infection, which will help clinicians make a timely decision on antibiotic use before microorganism culture results return.

Abstract Background (Pro)renin receptor (PRR) is highly expressed in renal tubules, which is involved in physiological and pathological processes. However, the role of PRR, expressed in renal tubular epithelial cells, in diabetic kidney disease (DKD) remain largely unknown. Methods In this study, kidney biopsies, urine samples, and public RNA-seq data from DKD patients were used to assess PRR expression and cell pyroptosis in tubular epithelial cells. The regulation of tubular epithelial cell pyroptosis by PRR was investigated by in situ renal injection of adeno-associated virus9 (AAV9)-shRNA into db/db mice, and knockdown or overexpression of PRR in HK-2 cells. To reveal the underlined mechanism, the interaction of PRR with potential binding proteins was explored by using BioGrid database. Furthermore, the direct binding of PRR to dipeptidyl peptidase 4 (DPP4), a pleiotropic serine peptidase which increases blood glucose by degrading incretins under diabetic conditions, was confirmed by co-immunoprecipitation assay and immunostaining. Results Higher expression of PRR was found in renal tubules and positively correlated with kidney injuries of DKD patients, in parallel with tubular epithelial cells pyroptosis. Knockdown of PRR in kidneys significantly blunted db/db mice to kidney injury by alleviating renal tubular epithelial cells pyroptosis and the resultant interstitial inflammation. Moreover, silencing of PRR blocked high glucose-induced HK-2 pyroptosis, whereas overexpression of PRR enhanced pyroptotic cell death of HK-2 cells. Mechanistically, PRR selectively bound to cysteine-enrich region of C-terminal of DPP4 and augmented the protein abundance of DPP4, leading to the downstream activation of JNK signaling and suppression of SIRT3 signaling and FGFR1 signaling, and then subsequently mediated pyroptotic cell death. Conclusions This study identified the significant role of PRR in the pathogenesis of DKD; specifically, PRR promoted tubular epithelial cell pyroptosis via DPP4 mediated signaling, highlighting that PRR could be a promising therapeutic target in DKD.

Abstract Background With the arrival of the era of large-scale production, sharing and application of data, digital use has gradually changed people’s daily entertainment, consumption, social interaction, learning and other behaviors in its efficient form. This paper mainly discusses whether this fast and convenient behavior leads Chinese older adults to adopt healthier lifestyles. Methods Using the most recent information from the Chinese Family Panel Studies (CFPS) in 2020, this paper conducted a descriptive statistical analysis on the basic situation of digital use and lifestyles among Chinese older adults and used a structural equation model to analyse the influence of frequency and types of digital use in a variety of different aspects of the real life of Chinese older adults. Results Research revealed that the quality of life of Chinese older adults improved significantly as a result of their use of digital technology. The frequency of digital use (FDU) significantly improved Chinese older adults’ diet, sleep, exercise, smoking and drinking, and relieved their depression. The types of digital use (TDU) had a significant positive correlation with the lifestyle of Chinese older adults, especially in the influence of digital entertainment (DE), digital consumption (DC) and digital social interaction (DI) on the lifestyle of Chinese older adults. Conclusions Digital use can improve the health of Chinese older adults by promoting a healthy lifestyle through various means. The findings of this study have a substantial positive impact on bridging the digital divide that Chinese older adults face, as well as fostering the integration of digital use into their healthy lifestyles.

Abstract A mathematical morphological filter-based de-noising method is developed in this study for bridge cable force monitoring data. Structure elements, one of the most important parameters in the mathematical morphology, dominate de-noising effects. The de-noising effects subject to single structure element and multi-structure element filters are discussed based on the simulation signals. The results indicate that the de-noising effects by using the spherical structure element are better than using the straight line or rhombic structure element. Moreover, the multi-structure element filter outperforms the single one. Through simulation analysis, the de-noising performance of the low-pass filter, wavelet filter and morphological filter is compared. The results show that the performance of the wavelet and morphological filters is better than that of the low-pass filter. For low signal-to-noise signals, the performance of the wavelet filter is superior. With the increase of signal-to-noise ratio, the morphological filters show more advantages. Taking the cable force monitoring data of the 3rd Nanjing Yangtze River Bridge as an example, the de-noising performance of the wavelet and morphological filters is discussed. The results show that both the wavelet filters and morphological filters have satisfactory de-noising effects. The mathematical morphology method can provide an optional and effective de-nosing choice, which enriches the means of de-noising for bridge monitoring data.

In the dynamic operation of a boom sprayer, the boom oscillation will cause the detection value of the boom height to fluctuate greatly, resulting in failures of the control system. Based on the previously developed static boom height detection model for the entire wheat growth cycle, this study aimed to optimize the model to reduce the impact of boom oscillation on the accuracy of boom height detection. Three ultrasonic sensors were installed on each section boom of a three-section boom sprayer, and dynamic boom height detection tests were conducted at vehicle speeds of 4 to 8 km/h across six growth stages of winter wheat in Beijing, a total detection area within a single fixed operational row of approximately 14 ha. The test results showed that as vehicle speed increased, boom oscillations intensified across all sections. By setting the boom oscillation correction parameters, the detecting value of each section of boom height is corrected. The results show that the fluctuation and deviation degree of the boom height-detecting value are obviously reduced, and the correction effect is obvious. Further analysis of the detecting value of the boom height after the correction shows that the previously established detection model still maintains high detection accuracy under dynamic conditions; that is, the detection position of the ultrasonic sensor does not downward shift. This paper provides a low-cost technical method that can be directly applied to the dynamic detection of boom height.

Establishing robust correspondences between two images is important for computer version tasks. However, in the real scene incorrect correspondences are inevitable no matter what kind of correspondence matching algorithms are adopted due to some complex factors, such as illumination, occlusion, and so on. To reduce the number of incorrect correspondences, an algorithm with the same object and same position constraints (SOSPC), is proposed to remove wrong correspondences from the given putative correspondences in this paper. The algorithm is based on the fact that in the given image pairs correct correspondences locate at the same position on the same objects. To select the correspondences on the same objects, an object matching method based on the correspondences selected by GMS is proposed. To select the correspondences on the correct positions, an iterative fundamental matrix estimation method based on clustering is presented. The experimental results have validated the effectiveness of the same object and the same position constraints, and the method achieves the state-of-art performance on five datasets.

With the aging of the population, the health of the elderly has become increasingly important. Postoperative cognitive dysfunction (POCD) is a common neurological complication in elderly patients following general anesthesia or surgery. It is characterized by cognitive decline that may persist for weeks, months, or even longer. Electroacupuncture (EA), a novel therapy that combines physical nerve stimulation with acupuncture treatment from traditional Chinese medicine, holds potential as a therapeutic intervention for preventing and treating POCD, particularly in elderly patients. Although the beneficial effects of EA on POCD have been explored in preclinical and clinical studies, the reliability of EA is limited by methodological shortcomings, and the underlying mechanisms remain largely unexplored. Therefore, we have synthesized existing evidence and proposed potential biological mechanisms underlying the effects of EA on neuroinflammation, oxidative stress, autophagy, the microbiota-gut-brain axis, and epigenetic modification. This review summarizes recent advances in EA and POCD, provides a theoretical foundation, explores potential molecular mechanisms for the prevention and treatment of POCD, and offers a basis for conducting relevant clinical trials.

In this paper, a two-dimensional (2D) composite fuzzy iterative learning control (ILC) scheme for nonlinear batch processes is proposed. By employing the local-sector nonlinearity method, the nonlinear batch process is represented by a 2D uncertain T-S fuzzy model with non-repetitive disturbances. Then, the feedback control is integrated with the ILC scheme to be investigated under the constructed model. Sufficient conditions for robust asymptotic stability and 2D $ H_\infty $ performance requirements of the resulting closed-loop fuzzy system are established based on Lyapunov functions and some matrix transformation techniques. Furthermore, the corresponding controller gains can be derived from a set of linear matrix inequalities (LMIs). Finally, simulations on the three-tank system and the highly nonlinear continuous stirred tank reactor (CSTR) are carried out to prove the feasibility and efficiency of the proposed approach.

Abstract Treatment of osteoporosis commonly diminishes osteoclast number which suppresses bone formation thus compromising fracture prevention. Bone formation is not suppressed, however, when bone degradation is reduced by retarding osteoclast functional resorptive capacity, rather than differentiation. We find deletion of deubiquitinase, BRCA1-associated protein 1 (Bap1), in myeloid cells (Bap1 ∆LysM ), arrests osteoclast function but not formation. Bap1 ∆LysM osteoclasts fail to organize their cytoskeleton which is essential for bone degradation consequently increasing bone mass in both male and female mice. The deubiquitinase activity of BAP1 modifies osteoclast function by metabolic reprogramming. Bap1 deficient osteoclast upregulate the cystine transporter, Slc7a11, by enhanced H2Aub occupancy of its promoter. SLC7A11 controls cellular reactive oxygen species levels and redirects the mitochondrial metabolites away from the tricarboxylic acid cycle, both being necessary for osteoclast function. Thus, in osteoclasts BAP1 appears to regulate the epigenetic-metabolic axis and is a potential target to reduce bone degradation while maintaining osteogenesis in osteoporotic patients.

Abstract Aim This study aimed to explore a novel subtype classification method based on the stemness characteristics of patients with non-small cell lung cancer (NSCLC). Methods Based on the Cancer Genome Atlas database to calculate the stemness index (mRNAsi) of NSCLC patients, an unsupervised consensus clustering method was used to classify patients into two subtypes and analyze the survival differences, somatic mutational load, copy number variation, and immune characteristics differences between them. Subsequently, four machine learning methods were used to construct and validate a stemness subtype classification model, and cell function experiments were performed to verify the effect of the signature gene ARTN on NSCLC. Results Patients with Stemness Subtype I had better PFS and a higher somatic mutational burden and copy number alteration than patients with Stemness Subtype II. In addition, the two stemness subtypes have different patterns of tumor immune microenvironment. The immune score and stromal score and overall score of Stemness Subtype II were higher than those of Stemness Subtype I, suggesting a relatively small benefit to immune checkpoints. Four machine learning methods constructed and validated classification model for stemness subtypes and obtained multiple logistic regression equations for 22 characteristic genes. The results of cell function experiments showed that ARTN can promote the proliferation, invasion, and migration of NSCLC and is closely related to cancer stem cell properties. Conclusion This new classification method based on stemness characteristics can effectively distinguish patients' characteristics and thus provide possible directions for the selection and optimization of clinical treatment plans.

Based on the unique insulator-metal phase transition property of vanadium dioxide (VO2), we propose an integrated metasurface with a switchable mechanism between ultra-broadband absorption and polarization conversion, operating in the terahertz (THz) frequency range. The designed metasurface device is constructed using a stacked structure composed of VO2 quadruple rings, a dielectric layer, copper stripes, VO2 film, a dielectric layer, and a copper reflection layer. Our numerical simulations demonstrate that our proposed design, at high temperatures (above 358 K), exhibits an ultra-broadband absorption ranging from 4.95 to 18.39 THz, maintaining an absorptivity greater than 90%, and achieves a relative absorption bandwidth of up to 115%, significantly exceeding previous research records. At room temperature (298 K), leveraging VO2’s insulating state, our proposed structure transitions into an effective polarization converter, without any alteration to its geometry. It enables efficient conversion between orthogonal linear polarizations across 3.51 to 10.26 THz, with cross-polarized reflection exceeding 90% and a polarization conversion ratio over 97%. More importantly, its relative bandwidth reaches up to 98%. These features highlight its wide-angle, extensive bandwidth, and high-efficiency advantages for both switching functionalities. Such an ultra-broadband convertible design offers potential applications in optical switching, temperature dependent optical sensors, and other tunable THz devices in various fields.

ObjectiveTo examine incidence and mortality trends of ischemic stroke (IS) among Chinese residents from 1990 to 2019 and to provide a reference for the prevention and control of IS in China. MethodsThe data on IS incidence and mortality among Chinese residents from 1990 to 2019 were collected from the Global Burden of Disease Study 2019 (GBD 2019). Joinpoint regression model was used to analyze changing trend of IS incidence and mortality. The age-period-cohort (APC) model was used to assess the effects of age, period, and birth cohort on the risk of IS incidence and mortality. ResultsThe crude incidence rate (per 100 000 population) of IS increased from 74.26 in 1990 to 201.74 in 2019 for all Chinese residents; and the rate increased from 64.58 to 183.60 for the male residents and from 84.55 to 220.59 for the female residents. The standardized incidence rate (per 100 000 population) of IS also increased from 107.49 in 1990 to 144.78 in 2019 for all Chinese residents; for male and female residents, the standardized incidence rate increased from 101.14 and 113.72 to 141.10 and 149.44, respectively. During 30-year period, the average annual percentage change (AAPC) in standardized IS incidence rate for all, male and female Chinese residents were 1.04%, 1.16% and 0.94% (all P < 0.001). The crude IS mortality rate (per 100 000 population) for all, male and female Chinese residents increased from 32.08, 32.09 and 32.06 in 1990 to 72.37, 79.89 and 64.55 in 2019; the standardized IS mortality rate (per 100 000 population) for all and female Chinese residents decreased from 64.32 and 56.13 in 1990 to 62.18 and 48.26 in 2019; but the standardized IS mortality rate for male Chinese residents increased from 77.34 in1990 to 83.55 in 2019. During 30-year period, the AAPC in standardized IS mortality rate for all, male and female Chinese residents were – 0.12% (P = 0.463), 0.29% and – 0.50% (both P < 0.05). The results of the APC model analysis showed that the local drift values of IS incidence rate for male residents aged 35 – 89 years and female residents aged 45 – 89 years were greater than 0, and the local drift values of IS mortality rate for male residents aged 75 – 94 years were greater than 0. The longitudinal curve for age-specific IS incidence and mortality for both male and female residents in the same birth cohort showed an increasing trend. The IS risk of male residents remained stable in each period group from 1990 to 2004, then increased slowly from 2005 to 2009, and rapidly increased in each period group from 2010 to 2019. The IS risk of the female residents decreased in each period group from 1990 to 2004, and increased slowly from 2005 to 2009; from 2010 to 2014, the risk increased rapidly, and from 2015 to 2019, the increasing trend was very smooth and almost remained stable. From 1990 to 2019, the IS mortality risk of male and female Chinese residents showed a downward trend over the time period and the mortality risk reached the minimum from 2015 to 2019. From 1990 to 2019, the IS risk of male and female Chinese residents increased first and then decreased with the birth cohort. The peak of the birth cohort effect on IS in male residents occurred from 1973 to 1977, and that in female residents occurred from 1958 to 1962. The IS mortality risk in male and female Chinese residents from 1990 to 2019 showed an overall downward trend along with the birth cohort. ConclusionThe incidence of ischemic stroke in Chinese residents showed an increasing trend from 1990 to 2019. Age, period, and birth cohort effect have a certain influence on the risk of ischemic stroke with gender disparity. Although the period and cohort effect on IS mortality risk showed a decline trend, the continuous increasing age effect made the actual burden of IS mortality much heavier among Chinese residents, especially among elderly male residents.

Abstract The study aimed to assess the biocompatibility and efficacy of a prostatic urethral lift (PUL) for benign prostatic hyperplasia (BPH). Human BPH-1 cells were co-cultured with implant anchors and sutures, and cytotoxicity was measured. Scanning electron microscopy (SEM) was used to observe adhesion and growth of cells and to evaluate implant biocompatibility. Fifteen male beagle dogs were randomly assigned to the surgical (n = 9) or sham-operated (n = 6) groups. The surgical group underwent cystotomy, and PUL was used to insert two implants in each lobe of the prostate to compress the enlarged prostate and dilate the urethra; the sham group underwent cystotomy without implant insertion. Compared with the control group, no significant difference in cell viability among the groups with different co-culture times of implant anchors and sutures (P > 0.05) was observed. SEM revealed good adhesion and growth of prostate cells on the implants. Improvements in urine flow rates remained stable at 7, 28, and 180 days after surgery, and the urethral diameter in the prostate region was significantly increased compared with that before surgery. PUL is a biocompatible and effective treatment for BPH, improving the urine flow rate without causing inflammation, tissue damage, or cytotoxic effects. Here, the basis for further PUL application was provided.

Abstract Investigating gene function relies on the efficient manipulation of endogenous gene expression. Currently, a limited number of tools are available to robustly manipulate endogenous gene expression between “on” and “off” states. In this study, we insert a 63 bp coding sequence of T3H38 ribozyme into the 3’ untranslated region (UTR) of C. elegans endogenous genes using the CRISPR/Cas9 technology, which reduces the endogenous gene expression to a nearly undetectable level and generated loss-of-function phenotypes similar to that of the genetic null animals. To achieve conditional knockout, a cassette of loxP-flanked transcriptional termination signal and ribozyme is inserted into the 3’ UTR of endogenous genes, which eliminates gene expression spatially or temporally via the controllable expression of the Cre recombinase. Conditional endogenous gene turn-on can be achieved by either injecting morpholino, which blocks the ribozyme self-cleavage activity or using the Cre recombinase to remove the loxP-flanked ribozyme. Together, our results demonstrate that these ribozyme-based tools can efficiently manipulate endogenous gene expression both in space and time and expand the toolkit for studying the functions of endogenous genes.

Abstract Mutation-based greybox fuzzing has been one of the most prevalent techniques for security vulnerability discovery and a great deal of research work has been proposed to improve both its efficiency and effectiveness. Mutation-based greybox fuzzing generates input cases by mutating the input seed, i.e., applying a sequence of mutation operators to randomly selected mutation positions of the seed. However, existing fruitful research work focuses on scheduling mutation operators, leaving the schedule of mutation positions as an overlooked aspect of fuzzing efficiency. This paper proposes a novel greybox fuzzing method, PosFuzz, that statistically schedules mutation positions based on their historical performance. PosFuzz makes use of a concept of effective position distribution to represent the semantics of the input and to guide the mutations. PosFuzz first utilizes Good-Turing frequency estimation to calculate an effective position distribution for each mutation operator. It then leverages two sampling methods in different mutating stages to select the positions from the distribution. We have implemented PosFuzz on top of AFL, AFLFast and MOPT, called Pos-AFL, -AFLFast and -MOPT respectively, and evaluated them on the UNIFUZZ benchmark (20 widely used open source programs) and LAVA-M dataset. The result shows that, under the same testing time budget, the Pos-AFL, -AFLFast and -MOPT outperform their counterparts in code coverage and vulnerability discovery ability. Compared with AFL, AFLFast, and MOPT, PosFuzz gets 21% more edge coverage and finds 133% more paths on average. It also triggers 275% more unique bugs on average.

Intracerebral hemorrhagic stroke, characterized by acute hemorrhage in the brain, has a significant clinical prevalence and poses a substantial threat to individuals’ well-being and productivity. Recent research has elucidated the role of gut microorganisms and their metabolites in influencing brain function through the microbiota-gut-brain axis (MGBA). This article provides a comprehensive review of the current literature on the common metabolites, short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO), produced by gut microbiota. These metabolites have demonstrated the potential to traverse the blood–brain barrier (BBB) and directly impact brain tissue. Additionally, these compounds have the potential to modulate the parasympathetic nervous system, thereby facilitating the release of pertinent substances, impeding the buildup of inflammatory agents within the brain, and manifesting anti-inflammatory properties. Furthermore, this scholarly analysis delves into the existing dearth of investigations concerning the influence of gut microorganisms and their metabolites on cerebral functions, while also highlighting prospective avenues for future research.

Intracerebral hemorrhage (ICH) manifests precipitously and profoundly impairs the neurological function in patients who are affected. The etiology of subsequent injury post-ICH is multifaceted, characterized by the intricate interplay of various factors, rendering therapeutic interventions challenging. Astrocytes, a distinct class of glial cells, interact with neurons and microglia, and are implicated in a series of pathophysiological alterations following ICH. A comprehensive examination of the functions and mechanisms associated with astrocytic proteins may shed light on the role of astrocytes in ICH pathology and proffer innovative therapeutic avenues for ICH management.

BackgroundPost-stroke depression is a common complication of stroke, with a high incidence rate and low recognition rate. Many patients do not receive effective intervention at the onset, which affects subsequent treatment outcomes. Post-stroke depression not only impacts the patient's mental well-being but also increases the risk of stroke recurrence and poor prognosis. Therefore, it has become a significant public health concern. Acupuncture has gained significant popularity in the treatment of post-stroke depression. However, there are inconsistent clinical research results regarding its efficacy and safety. This systematic review aims to gather and critically assess all available evidence regarding the effectiveness and safety of acupuncture in the treatment of post-stroke depression in patients.MethodsWe will conduct thorough searches for relevant studies in multiple electronic databases (PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, VIP Database, Wan-fang Data and China Biomedical Database). Our search scope will encompass studies published from the inception of each database until September 2023. To evaluate the potential bias in all the included studies, we will adhere to the guidelines offered in the Cochrane Handbook. The total effective rate will be the primary outcome. To conduct a systematic review, we will employ RevMan 5.4 software.ResultsThis study will obtain efficacy and safety of acupuncture for the treatment of post-stroke depression.ConclusionsThe conclusions of this study will provide evidence-based perspectives that can guide clinical decision-making regarding the practicality and recommended timing of using acupuncture to treat post-stroke depression. Furthermore, this study will help advance the clinical application of acupuncture treatment for post-stroke depression and enhance its efficacy while ensuring patient safety.

ObjectiveInflammation participates in the pathology and progression of secondary brain injury after intracerebral hemorrhage (ICH). This meta-analysis intended to explore the prognostic role of inflammatory indexes, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), white blood cell (WBC), and C-reactive protein (CRP) in ICH patients.MethodsEmbase, PubMed, Web of Science, and Cochrane Library were searched until June 2023. Two outcomes, including poor outcome and mortality were extracted and measured. Odds ratio (OR) and 95% confidence interval (CI) were presented for outcome assessment.ResultsForty-six studies with 25,928 patients were included in this meta-analysis. The high level of NLR [OR (95% CI): 1.20 (1.13–1.27), p

The bone is one of the most commonly affected organs in sickle cell disease (SCD). Repeated ischemia, oxidative stress and inflammation within the bone is largely responsible for promoting bone pain. As more individuals with SCD survive into adulthood, they are likely to experience a synergistic impact of both aging and SCD on their bone health. As bone health deteriorates, bone pain will likely exacerbate. Recent mechanistic and observational studies emphasize an intricate relationship between bone remodeling and the peripheral nervous system. Under pathological conditions, abnormal bone remodeling plays a key role in the propagation of bone pain. In this review, we first summarize mechanisms and burden of select bone complications in SCD. We then discuss processes that contribute to pathological bone pain that have been described in both SCD as well as non-sickle cell animal models. We emphasize the role of bone-nervous system interactions and pitfalls when designing new therapies especially for the sickle cell population. Lastly, we also discuss future basic and translational research in addressing questions about the complex role of stress erythropoiesis and inflammation in the development of SCD bone complications, which may lead to promising therapies and reduce morbidity in this vulnerable population.

Introduction To examine the burden of rheumatoid arthritis (RA) at the global, regional, and national levels in terms of sex, age, geographic distribution, and the Socio-demographic Index (SDI). Material and methods Using Global Burden of Disease study data, the global incidence, disability-adjusted life years (DALYs), and estimated annual percentage change (EAPC) of RA from 1990 to 2019 were analysed. Results From 1990 to 2019, the global RA incidence and DALYs increased by 6.47% and 1.15%, respectively. Moreover, both the global age-standardized incidence rate (EAPC = 0.30; 95% confidence interval (CI): 0.25–0.34) and DALYs (EAPC = 0.12; 95% CI: 0.08–0.17) increased. The age-standardized RA incidence was substantially higher in the high-SDI regions than in the other regions. By geographical region, the largest increases in the age-standardized RA incidence and DALYs were observed in Andean Latin America. By country, the largest increase in RA incidence was observed in Equatorial Guinea (EAPC = 1.78), followed by Bhutan (EAPC = 1.54) and Peru (EAPC = 1.53). The age-standardized RA incidence was lower in men than in women. Positive correlations were found between the EAPC of the age-standardized RA incidence and the SDI. Conclusions Increasing trends in the age-standardized RA incidence and DALYs worldwide were shown. Future strategies for RA prevention should focus on women and older adults, as well as individuals from Andean Latin America, southern Latin America, central Asia, western sub-Saharan Africa, and other high-risk regions.

Abstract The difficulties of injured and degenerated neurons to regenerate neurites and regain functions are more significant than in other body tissues, making neurodegenerative and related diseases hard to cure. Uncovering the secrets of neural regeneration and how this process may be inhibited after injury will provide insights into novel management and potential treatments for these diseases. Caenorhabditis elegans and Drosophila melanogaster are two of the most widely used and well-established model organisms endowed with advantages in genetic manipulation and live imaging to explore this fundamental question about neural regeneration. Here, we review the classical models and techniques, and the involvement and cooperation of subcellular structures during neurite regeneration using these two organisms. Finally, we list several important open questions that we look forward to inspiring future research.

In this paper, experimental and numerical studies were conducted to differentiate solvent exsolution and liberation processes from different heavy oil–solvent systems in bulk phases and porous media. Experimentally, two series of constant-composition-expansion (CCE) tests in a PVT cell and differential fluid production (DFP) tests in a sandpacked model were performed and compared in the heavy oil–CO2, heavy oil–CH4, and heavy oil–C3H8 systems. The experimental results showed that the solvent exsolution from each heavy oil–solvent system in the porous media occurred at a higher pressure. The measured bubble-nucleation pressures (Pn) of the heavy oil–CO2 system, heavy oil–CH4 system, and heavy oil–C3H8 system in the porous media were 0.24 MPa, 0.90 MPa, and 0.02 MPa higher than those in the bulk phases, respectively. In addition, the nucleation of CH4 bubbles was found to be more instantaneous than that of CO2 or C3H8 bubbles. Numerically, a robust kinetic reaction model in the commercial CMG-STARS module was utilized to simulate the gas exsolution and liberation processes of the CCE and DFP tests. The respective reaction frequency factors for gas exsolution (rffe) and liberation (rffl) were obtained in the numerical simulations. Higher values of rffe were found for the tests in the porous media in comparison with those in the bulk phases, suggesting that the presence of the porous media facilitated the gas exsolution. The magnitudes of rffe for the three different heavy oil–solvent systems followed the order of CO2 > CH4 > C3H8 in the bulk phases and CH4 > CO2 > C3H8 in the porous media. Hence, CO2 was exsolved from the heavy oil most readily in the bulk phases, whereas CH4 was exsolved from the heavy oil most easily in the porous media. Among the three solvents, CH4 was also found most difficult to be liberated from the heavy oil in the DFP test with the lowest rffl of 0.00019 min−1. This study indicates that foamy-oil evolution processes in the heavy oil reservoirs are rather different from those observed from the bulk-phase tests, such as the PVT tests.

In this study, we conducted an extensive investigation into broadband near-infrared luminescence of Cr3+-doped Ca3Y2Ge3O12 garnet, employing first-principles calculations within the density functional theory framework. Our initial focus involved determining the site occupancy of Cr3+ activator ions, which revealed a pronounced preference for the Y3+ sites over the Ca2+ and Ge4+ sites, as evidenced by the formation energy calculations. Subsequently, the geometric structures of the excited states 2E and 4T2, along with their optical transition energies relative to the ground state 4A2 in Ca3Y2Ge3O12:Cr3+, were successfully modeled using the ΔSCF method. Calculation convergence challenges were effectively addressed through the proposed fractional particle occupancy schemes. The constructed host-referred binding energy diagram provided a clear description of the luminescence kinetics process in the garnet, which explained the high quantum efficiency of emission. Furthermore, the accurate prediction of thermal excitation energy yielded insights into the thermal stability of the compound, as illustrated in the calculated configuration coordinate diagram. More importantly, all calculated data were consistently aligned with the experimental results. This research not only advances our understanding of the intricate interplay between geometric and electronic structures, optical properties, and thermal behavior in Cr3+-doped garnets but also lays the groundwork for future breakthroughs in the high-throughput design and optimization of luminescent performance and thermal stability in Cr3+-doped phosphors.

The pulse-width modulation (PWM) variable spray system is the most widely used variable spray system in the world at present, which has the characteristics of a fast response, large flow adjustment range, and good atomization. Recently, the pressure fluctuation and droplet deposition uniformity of the PWM variable spray system caused by the intermittent spray mode of the nozzle have attracted more and more attention. In this study, a method for eliminating the inhomogeneity of ground deposition in low-frequency PWM variable sprays based on a staggered-phase drive mode was proposed, and a PWM variable spray system was built. The experimental results indicated that the pressure fluctuation amplitude upstream of the nozzle of the PWM variable spray system with the staggered-phase drive was reduced by 40.91%, and the dispersion rate of the pressure fluctuation was reduced by 62.78% (the initial pressure was 0.3 MPa, solenoid valve frequency was 5 Hz, and duty cycle was 50%). The PWM control parameters had a significant effect on the upstream pressure fluctuation (initial pressure > duty cycle > frequency). The droplet spectrum relative span of the staggered phased PWM variable spray system decreased by 24.83%, the coefficient of variation of the droplet particle size decreased by 4.40%, the particle size was more uniform, and the atomization effect was improved. The average deposition of droplets in the forward direction driven by the staggered phase was 4.87% greater than that in the same phase, and the variation rate decreased by 20.87%. The average deposition amount increased, and the deposition became more uniform. Staggered-phase spray control could effectively reduce the inhomogeneity of deposition in low-frequency PWM intermittent spraying. This research provides strong technical support for a precision variable spraying effect and droplet drift prevention.

Background Tumor samples from the phase III IMpower010 study were used to compare two programmed death-ligand 1 (PD-L1) immunohistochemistry assays (VENTANA SP263 and Dako 22C3) for identification of PD-L1 patient subgroups (negative, positive, low, and high expression) and their predictive value for adjuvant atezolizumab compared with best supportive care (BSC) in resectable early-stage non-small cell lung cancer (NSCLC).Methods PD-L1 expression was assessed by the SP263 assay, which measured the percentage of tumor cells with any membranous PD-L1 staining, and the 22C3 assay, which scored the percentage of viable tumor cells showing partial or complete membranous PD-L1 staining.Results When examining the concordance at the PD-L1-positive threshold (SP263: tumor cell (TC)≥1%; 22C3: tumor proportion score (TPS)≥1%), the results were concordant between assays for 83% of the samples. Similarly, at the PD-L1–high cut-off (SP263: TC≥50%; 22C3: TPS≥50%), the results were concordant between assays for 92% of samples. The disease-free survival benefit of atezolizumab over BSC was comparable between assays for PD-L1-positive (TC≥1% by SP263: HR, 0.58 (95% CI: 0.40 to 0.85) vs TPS≥1% by 22C3: HR, 0.65 (95% CI: 0.45 to 0.95)) and PD-L1-high (TC≥50% by SP263: HR, 0.27 (95% CI: 0.14 to 0.53) vs TPS≥50% by 22C3: HR, 0.31 (95% CI: 0.16 to 0.60)) subgroups.Conclusions The SP263 and 22C3 assays showed high concordance and a comparable clinical predictive value of atezolizumab at validated PD-L1 thresholds, suggesting that both assays can identify patients with early-stage NSCLC most likely to experience benefit from adjuvant atezolizumab.Trial registration number NCT02486718.

Measurements of rice physical traits, such as length, width, and percentage of filled/unfilled grains, are essential steps of rice breeding. A new approach for measuring the physical traits of rice grains for breeding purposes was presented in this study, utilizing image processing techniques. Backlight photography was used to capture a grayscale image of a group of rice grains, which was then analyzed using a clustering algorithm to differentiate between filled and unfilled grains based on their grayscale values. The impact of backlight intensity on the accuracy of the method was also investigated. The results show that the proposed method has excellent accuracy and high efficiency. The mean absolute percentage error of the method was 0.24% and 1.36% in calculating the total number of grain particles and distinguishing the number of filled grains, respectively. The grain size was also measured with a little margin of error. The mean absolute percentage error of grain length measurement was 1.11%, while the measurement error of grain width was 4.03%. The method was found to be highly accurate, non-destructive, and cost-effective when compared to conventional methods, making it a promising approach for characterizing physical traits for crop breeding.

Transcription factors (TFs) play critical roles in specifying many aspects of neuronal cell fate including dendritic morphology. How TFs are accurately regulated during neuronal morphogenesis is not fully understood. Here, we show that LIM homeodomain protein MEC-3, the key TF for C. elegans PVD dendrite morphogenesis, is regulated by both alternative splicing and an E3 ubiquitin ligase. The mec-3 gene generates several transcripts by alternative splicing. We find that mbl-1, the orthologue of the muscular dystrophy disease gene muscleblind-like (MBNL), is required for PVD dendrite arbor formation. Our data suggest mbl-1 regulates the alternative splicing of mec-3 to produce its long isoform. Deleting the long isoform of mec-3(deExon2) causes reduction of dendrite complexity. Through a genetic modifier screen, we find that mutation in the E3 ubiquitin ligase EEL-1 suppresses mbl-1 phenotype. eel-1 mutants also suppress mec-3(deExon2) mutant but not the mec-3 null phenotype. Loss of EEL-1 alone leads to excessive dendrite branches. Together, these results indicate that MEC-3 is fine-tuned by alternative splicing and the ubiquitin system to produce the optimal level of dendrite branches.

Abstract Background The tobacco leaf–derived cembratriene-ol exhibits anti-insect effects, but its content in plants is scarce. Cembratriene-ol is difficult and inefficiently chemically synthesised due to its complex structure. Moreover, the titer of reported recombinant hosts producing cembratriene-ol was low and cannot be applied to industrial production. Results In this study, Pantoea ananatis geranylgeranyl diphosphate synthase (CrtE) and Nicotiana tabacum cembratriene-ol synthase (CBTS) were heterologously expressed to synthsize the cembratriene-ol in Escherichia coli. Overexpression of cbts*, the 1-deoxy-d-xylulose 5-phosphate synthase gene dxs, and isopentenyl diphosphate isomerase gene idi promoted the production of cembratriene-ol. The cembratriene-ol titer was 1.53-folds higher than that of E. coli Z17 due to the systematic regulation of ggpps, cbts*, dxs, and idi expression. The production of cembratriene-ol was boosted via the overexpression of genes ispA, ispD, and ispF. The production level of cembratriene-ol in the optimal medium at 72 h was 8.55-folds higher than that before fermentation optimisation. The cembratriene-ol titer in the 15-L fermenter reached 371.2 mg L− 1, which was the highest titer reported. Conclusion In this study, the production of cembratriene-ol in E. coli was significantly enhanced via systematic optimization. It was suggested that the recombinant E. coli producing cembratriene-ol constructed in this study has potential for industrial production and applications.

In this paper, the bubble-point pressures and pseudo bubble-point pressures of various heavy crude oil−solvent systems were measured and studied by conducting the constant-composition-expansion (CCE) tests, during which the test pressure was depleted in a stepwise manner. A total of fourteen CCE tests were performed for five heavy crude oil−CO2 systems, four heavy crude oil−CH4 systems, and five heavy crude oil−C3H8 systems, respectively. All the CCE tests were conducted by using a pressure−volume−temperature (PVT) system. It was found that for most heavy crude oil−solvent systems with relatively low solvent concentrations, the measured PVT cell pressure vs. molar volume (Pcell−νmix) data in the CCE tests had three distinct regions, which were one-liquid phase region (Regions I), foamy-oil region (Region II) and two-phase region (Region III). Accordingly, the PVT cell pressure at the intersection point of Regions I and II was referred to as the measured bubble-point pressure, whereas the PVT cell pressure at the intersection point of Regions II and III was termed as the measured pseudo bubble-point pressure. For some heavy crude oil−solvent systems with high solvent concentrations, however, the measured Pcell−νmix data may have two regions only. In this special case, the PVT cell pressure at the intersection point of the two regions was considered as the measured bubble-point pressure and no pseudo bubble-point pressure could be obtained. It was also found that the heavy crude oil−CH4 system had not only the highest bubble-point pressure and pseudo bubble-point pressure but also the largest difference between the bubble-point pressure and pseudo bubble-point pressure, in comparison with the heavy crude oil−CO2 system and the heavy crude oil−C3H8 system at the same solvent concentration. These facts indicate that CH4 not only is the most volatile solvent but also can remain as dispersed gas bubbles to induce the most stable foamy oil in the largest pressure range after it is nucleated from a live heavy oil.

Abstract Background Penyanqing (PYQ), a traditional Chinese medicine (TCM), has a good clinical efficacy for the treatment of pelvic inflammatory disease (PID). Previously, researches on its anti-inflammatory effect and mechanism in vitro, in silico, and in vivo have been reported by our team. However, the interrelationship between the anti-inflammatory activity and the active compounds in PYQ are not clear. Here, the pharmacokinetics-pharmacodynamics (PK-PD) study was carried out for more proper clinical use. Methods The plasma concentrations of salvianolic acid B (SAB), protocatechualdehyde (PRO), paeoniflorin (PE), astilbin (AST), ferulic acid (FE), and chlorogenic acid (CH) in SD rats after PYQ administration were determined by a selective and rapid HPLC–MS/MS method. In addition, the PK-PD on cell model was used to explore the relationship between the plasma concentration and inflammatory biomarkers (TNF-α, IL-1β). Results The results of this study showed that the six components could reach the peak blood concentration within 0.29 h, indicating the rapid absorption of it. The eliminations of AST, CH, FE, PE, and PRO were relatively fast due to their mean residence times (MRTs) within 3 h, while the elimination of SAB was slower (MRT 5.67 ± 0.66 h). Combined with a THP-1 cell model, there was a significant correlation between inflammatory factors and component plasma concentrations with correlation coefficients in the range of -0.9—-0.746. Correspondingly, the drug-containing plasma obtained at 0.25 h point exhibited the best inhibition effect on production of IL-1β and TNF-α in LPS-induced THP-1 cells. Conclusion The six main components in PYQ could be quickly absorbed, and there was a potential good correlation between their pharmacokinetics and the pharmacodynamics of PYQ.

Gene activation methods are valuable for studying gene functions and may have potential applications in bioengineering and medicine. Here the authors developed Narta technology to achieve gene activation by recruiting artificial transcription factors to transcription sites through nascent RNAs of the target gene.

Abstract Background In view of the fact that there is no effective treatment for dementia, the number of years that dementia patients have to live with dementia will gradually increase for the rest of their lives, and the disability loss caused by dementia will increase. It is urgent to study the influence of risk factors on dementia by making use of the potential of prevention. The purpose of this study is to quantify the burden of dementia disability attributable to risk factors by assessing the population attributable fractions (PAFs) in Jiangxi Province, which is one of the regions of moderate aging process of China. Methods The prevalence data of nine risk factors were obtained through the Sixth National Health Service Survey in 2018, which covered 2713 older people. Levin’s formula was used to calculate the PAF for each risk factor for dementia. We adjusted the PAF for communality between risk factors, and used these values to calculate overall weighted PAFs and the years lived with disability (YLDs), which were attributable to nine risk factors. Results The number of dementia cases and their proportions that can theoretically be prevented by nine identified risk factors were 111636 (99595-120877) and 66.8% (59.6-72.3), respectively. The total YLDs of dementia were estimated to be 61136 (46463-78369) (males: 36434 [24100-49330], females: 23956 [14716-34589]). Physical inactivity (11639 [8845-14920]), low social contact (9324 [7086-11952]), and hearing loss (5668 [4307-7265] were the top three contributors to dementia. Conclusions The moderate aging areas represented by Jiangxi Province have great potential in the prevention of dementia. Targeted interventions and management of risk factors can effectively reduce the disability burden of dementia.

Abstract Background Tumor deposits (TDs) have been identified as an independent prognostic factor in gastric cancer (GC). However, the associated clinicopathological factors and how to simply and reasonably incorporate TD into the TNM staging system remain undetermined. The aim of the current study was therefore to assess the significance of TD among radically resected GC patients. Methods We retrospectively reviewed 1915 patients undergoing radical resection between 2007 and 2012. The patients were classified into two groups according to TD status (absent vs. present), and the clinicopathologic characteristics, DFS, and OS were compared. Associations of TD presence with other clinicopathologic factors were evaluated by logistic regression analysis. Univariate and multivariate Cox regression analyses were performed to determine the prognostic factors for DFS and OS in the primary cohort. Propensity score matching (PSM) was performed to reduce the possibility of selection bias according to the presence of TD. External validation of previously proposed modified staging systems incorporating TD was conducted. Results The detection rate of TD was 10.5% (201/1915). The presence of TD was significantly related to unfavorable clinicopathologic variables, including advanced T and N categories. According to the multivariate Cox regression analysis, the presence of TD was identified as an independent prognostic factor for DFS and OS in the primary cohort (both P < 0.001). In the after-PSM cohort, TD presence also significantly shortened DFS and OS. In the external validation, one system that incorporated TD into the pTNM stage had the best performance. Conclusions The presence of TD was significantly associated with poor survival in radically resected GC patients. The incorporation of TD into the TNM staging system can further improve the predictive capability. A multicenter cohort with a large sample size is needed to determine the appropriate method of incorporation.

In order to guarantee the accuracy of turntable angle measurement, a real-time compensation method for turntable positioning precision based on harmonic analysis is proposed in this paper. Firstly, the principle and feasibility of the real-time compensation method are analysed, and a detailed description of harmonic compensation is provided herein. Secondly, we analyse the relationships between the surface number of the polygon with the compensation order of the harmonic function and its corresponding compensation accuracy. The effects of the iterations number and the data width on calculation accuracy in the coordinate rotation digital computer (CORDIC) algorithm are analysed and the quantization models of the approximation error and rounding error of the CORDIC algorithm are established. Then, the calculation of the harmonic error function and real-time compensation processes are implemented on a field programmable gate array (FPGA) chip. The resource occupation and time delay of the phase angle calculation and the harmonic component calculation are discussed separately. Finally, the validity of the harmonic compensation method is proven through comparing the compensation effect with that of linear interpolation and the polynomial compensation method. The influences of the compensation order, the iterations number and the data width on the compensation results are demonstrated by simulation. A test platform with a laboratory-made FPGA circuit is built to evaluate the effect of real-time compensation with the harmonic function and the positioning error compensation can be performed within 760 ns. The results confirmed the effectiveness of the harmonic compensation method, revealing an improvement of the positioning precision from 54.21″ to 1.63″, equivalent to 96.99% reduction in positioning error.

Abstract Grey-box fuzzing techniques have been widely used in software bug finding. In general, there are many decisions to make in the fuzzing process, including which code block in the target program should be explored first, which bytes of an input seed should be mutated to reach the target code block, and how to mutate the chosen input bytes. However, existing solutions usually rely on random exploration or certain heuristics to choose where and how to fuzz, which limits the efficiency of fuzzing. In this paper, we propose a novel solution CAMFuzz to guide the fuzzing process with explainable decisions in explainable artificial intelligence (XAI). First, we propose a dynamic weight adjustment algorithm, which considers both the difficulty of reaching a block and the number of unvisited blocks nearby, to find code blocks worthy to explore first. Second, we utilize a widely used local interpretation technique, i.e., class activation mapping (CAM), to recognize which part of an input seed should be mutated to reach a given target code block. Therefore, CAMFuzz can distinguish which part of code in the program is more important and which positions in the input file should be mutated first, in order to achieve a better code coverage and bug finding efficiency. Third, to further help the fuzzer increase fuzzing efficiency, we leverage a lightweight static program analysis to help the fuzzer identify magic values. We implement a prototype of CAMFuzz and evaluate it on 13 real-world programs (including 11 open source targets, 2 closed-source commercial products including a Microsoft component and Hancom Office) Results show that CAMFuzz outperforms state-of-the-art fuzzers in both code coverage and bug finding. To detail, CAMFuzz on average achieves 2.07 $$\times$$ × more bugs and 1.17 $$\times$$ × coverage improvements. In total, it found 19 previously unknown vulnerabilities, of which 6 have been assigned by CVE so far.

Abstract Background Interleukin‐33 (IL‐33) exacerbates asthma probably through type 2 innate lymphoid cells (ILC2s). Nevertheless, the association between eosinophilic asthma (EA) and ILC2s remains obscure, and the mechanisms by which IL‐33 affects ILC2s are yet to be clarified. Methods ILC2s were evaluated in peripheral blood mononuclear cells, induced sputum, and bronchoalveolar lavage fluid obtained from patients with EA. Confocal microscopy was performed to locate ILC2s in lung tissue and the mRNA expression of ILC2‐related genes was also evaluated in the EA model. The proliferation of ILC2s isolated from humans and mice was assessed following IL‐33 or anti‐IL‐33 stimulation. Results The counts, activation, and mRNA expression of relevant genes in ILC2s were higher in PBMCs and airways of patients with EA. In addition, ILC2 cell counts correlated with Asthma control test, blood eosinophil count, Fractional exhaled nitric oxide level, and predicted eosinophilic airway inflammation. IL‐33 induced stronger proliferation of ILC2s and increased their density around blood vessels in the lungs of mice with EA. Moreover, IL‐33 treatment increased the counts and activation of ILC2s and lung inflammatory scores, whereas anti‐IL‐33 antibody significantly reversed these effects in EA mice. Finally, IL‐33 enhanced PI3K and AKT protein expression in ILC2s, whereas inhibition of the PI3K/AKT pathway decreased IL‐5 and IL‐13 production by ILC2s in EA. Conclusions ILC2s, especially activated ILC2s, might be critical markers of EA. IL‐33 can induce and activate ILC2s in the lungs via the PI3K/AKT pathway in EA. Thus, using anti‐IL‐33 antibody could be a part of an effective treatment strategy for EA.

Diabetes nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide, and podocyte injury is the central contributor to the progression of DN. Despite the emerging evidence that has established the importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of DN, abnormal protein O-GlcNAcylation is also augmented. Currently, the mechanism associating these two hyperglycemia-induced disorders remains poorly understood. This study intended to elucidate whether ER stress drives hyper-protein O-GlcNAcylation to cause podocyte injury in DN. We used both type 1 and type 2 DN models to confirm the occurrence of ER stress and excessive protein O-GlcNAcylation, and then podocyte purification was also conducted for further investigation. Nephroseq V5 data were mined and in vitro studies were applied to reveal the involvement of ER stress and hyper-O-GlcNAcylation in podocyte injury. Our results indicated that ER stress was induced in both type 1 and type 2 DN, and the human RNA-seq data from Nephroseq V5 showed that O-GlcNAcylation-related genes were significantly upregulated in the DN patients. We further demonstrated that ER stress occurred prior to hyper-O-GlcNAc modification and that pharmacologically inhibited protein O-GlcNAcylation can help decrease the podocyte apoptosis induced by hyperglycemia. Together, these discoveries will aid in uncovering the activation of the ER stress–O-GlcNAcylation axis in podocyte injury under DN, which will help open up new therapeutic approaches for preventing DN progression.

Fiscal and land policies are important tools in developing agriculture in China. Understanding how agricultural subsidies and land fragmentation jointly affect agricultural Total Factor Productivity (TFP) is crucial for building a strong agricultural nation. This paper utilizes microdata from fixed observation points in rural China from 2003 to 2017 and employs panel bidirectional fixed-effect models and moderation-effect models to empirically analyze the impact of agricultural subsidies and land fragmentation on agricultural TFP. The research finds: (1) Agricultural subsidies positively affect agricultural TFP, while land fragmentation leads to decreased agricultural TFP. (2) Land fragmentation hinders the positive effects of agricultural subsidies on agricultural TFP. A 1% increase in land fragmentation could lead to approximately a 3% decrease in the enhancement effect of agricultural subsidies, with significant impacts on households in major grain-producing areas and those primarily engaged in agriculture. (3) There is no evidence that reforms in the “three agricultural subsidies” would alter the combined effect of agricultural subsidies and land fragmentation on agricultural TFP. The obstructive role of land fragmentation cannot be mitigated through the “three agricultural subsidies” reform. The study indicates that the incentivizing role of agricultural subsidies has not been fully realized, and land fragmentation remains a key bottleneck in agricultural development. Fiscal support for agriculture should be coupled with effective land reform policies for synergistic efforts.

Abstract Background Perioperative chemotherapy (ChT) and preoperative chemoradiation (CRT) are both the standard treatments for locally advanced gastric cancer (LAGC). CRT can achieve a higher pathological complete regression (pCR) rate, but whether this higher pCR rate can be transformed into a long-term survival benefit remains inconclusive. Therefore, relevant studies are in progress. On the other hand, immunotherapy has been established for the first-line treatment of advanced gastric cancer (AGC) and has been widely explored in the perioperative setting. The combination of chemotherapy/radiotherapy and immunotherapy may have a synergistic effect, which will lead to a better antitumor effect. The preliminary reports of ongoing studies show promising results, including a further improved pCR rate. However, the preferred treatment combination for LAGC is still not established. To solve this problem, we are carrying out this randomized phase II trial, which aims to evaluate the efficacy and safety of perioperative chemotherapy plus the use of PD-1 antibody with or without preoperative chemoradiation for LAGC. Methods Eligible patients with LAGC or gastroesophageal junction (GEJ) adenocarcinoma were randomized to receive perioperative ChT, PD-1 antibody, surgery with (Arm A) or without preoperative CRT (Arm B), and PD-1 antibody maintenance until one year after surgery. The primary endpoint of this study is that the pCR rate of Arm A will be significantly higher than that of Arm B. The secondary endpoints include the pathological partial regression (pPR) rate, R0 resection rate, objective response rate (ORR), event-free survival (EFS), overall survival (OS), safety and surgical complications. Moreover, several explorative endpoints will be evaluated to find and validate the predictive biomarkers of immunotherapy. Discussion The results of the NeoRacing study will provide important information concerning the application of PD-1 antibody in LAGC patients during the perioperative setting. Meanwhile, the two treatment protocols will be compared in terms of efficacy and safety. Trial registration ClinicalTrials.gov , NCT05161572 . Registered 17 December 2021 - Retrospectively registered.

The rapid development of nanotechnology has aroused considerable attentions toward understanding the effects of engineered nanomaterials (ENMs) on the propagation of antibiotic resistance. Molybdenum disulfide (MoS2) is an extensively used ENM and poses potential risks associated with environmental exposure; nevertheless, the role of MoS2 toward antibiotic resistance genes (ARGs) transfer remains largely unknown. Herein, it was discovered that MoS2 nanosheets accelerated the horizontal transfer of RP4 plasmid across Escherichia coli in a dose-dependent manner (0.5–10 mg/L), with the maximum transfer frequency 2.07-fold higher than that of the control. Integration of physiological, transcriptomics, and metabolomics analyses demonstrated that SOS response in bacteria was activated by MoS2 due to the elevation of oxidative damage, accompanied by cell membrane permeabilization. MoS2 promoted bacterial adhesion and intercellular contact via stimulating the secretion of extracellular polysaccharides. The ATP levels were maximally increased by 305.7 % upon exposure to MoS2, and the expression of plasmid transfer genes was up-regulated, contributing to the accelerated plasmid conjugation and increased ARG abundance in soil. Our findings highlight the roles of emerging ENMs (e.g., MoS2) in ARGs dissemination, which is significant for the safe applications and risk management of ENMs under the development scenarios of nanotechnology.