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MicroRNAs (miRNAs) have been demonstrated to control chicken skeletal muscle growth, however, the potential function of the miR-181-5p family in chicken myogenesis remains largely unknown. Here, our study identified the two chicken (Gallus gallus; Gga) miR-181-5p family members widely expressed in various tissues, specifically miR-181a-5p and miR-181b-5p. Besides, the breast muscles of fast-growing broilers expressed higher levels of miR-181a-5p and miR-181b-5p than those of slow-growing layers. Functionally, miR-181a-5p and miR-181b-5p both promote the expression level of myogenic factors including myogenin (MyoG), myogenic differentiation 1 (MyoD1), and myosin heavy chain (MyHC), meanwhile accelerating the myotube formation of skeletal muscle satellite cells (SMSCs). Mechanistically, miR-181a-5p and miR-181b-5p directly bind to the 3´ untranslated region (UTR) of the transforming growth factor beta receptor 1 (TGFBR1) mRNA, further reducing the expression of TGFBR1. TGFBR1 is a key Transforming growth factor beta (TGF-β) signaling transduction receptor and had a negative function in muscle cell differentiation. Furthermore, knockdown of TGFBR1 facilitated the expression of chicken myogenic factors, boosted myotube formation, and decreased the SMAD family member 2/3 (SMAD2/3) phosphorylation in chicken SMSCs. SMAD2/3 are downstream of TGF-β signaling, and miR-181a-5p and miR-181b-5p could reduce the expression of TGFBR1 to further diminish the SMAD2/3 phosphorylation. Our findings revealed that the miR-181-5p family targets TGFBR1 to break the TGF-β signaling transduction, which resulted in promoting chicken skeletal muscle development.

Abstract Background This study reviews the research status of Diagnosis-related groups (DRGs) payment system in China and globally by analyzing topical issues in this field and exploring the evolutionary trends of DRGs in different developmental stages. Methods Abstracts of relevant literature in the field of DRGs were extracted from the China National Knowledge Infrastructure (CNKI) database and the Web of Science (WoS) core database and used as text data. A probabilistic distribution-based Latent Dirichlet Allocation (LDA) topic model was applied to mine the text topics. Topical issues were determined by topic intensity, and the cosine similarity of the topics in adjacent stages was calculated to analyze the topic evolution trend. Results A total of 6,758 English articles and 3,321 Chinese articles were included. Foreign research on DRGs focuses on grouping optimization, implementation effects, and influencing factors, whereas research topics in China focus on grouping and payment mechanism establishment, medical cost change evaluation, medical quality control, and performance management reform exploration. Conclusions Currently, the field of DRGs in China is developing rapidly and attracting deepening research. However, the implementation depth of research in China remains insufficient compared with the in-depth research conducted abroad.

Abstract Thermal comfort studies are usually employed to find subjective thermal responses [indicated by neutral temperature (NT), i.e. the temperature with no thermal stress] of residents from a region towards thermal environments. According to the recently published works in the literature, NTs are affected by many factors, such as geographical location and microenvironments. To elucidate the origins of these effects, the impact of microenvironment elements around a water surface on pedestrians’ thermal perceptions was systematically investigated in this work. The Fujiang River (FJR) in Mianyang City was taken as the sample site. The municipal meteorology station is located next to the site by around 2.5 km. By performing meteorology measurements combining questionnaires, it was found that the riverside NT (indicated by physiologically equivalent temperature, PET) of Mianyang in the summer of 2023 was 21.4 °C. The relationship between the distance from the water (DFW) and NT was quadratic linear. The same phenomenon took place by using either PET or Universal Thermal Climate Index (UTCI) indexes. Meanwhile, the meteorological contexts also affected NTs, including relative humidity (RH) and air velocity (Va). Regarding RH, the NPET increased from 15.2 °C (RH = 50%) to 26.9 °C (RH = 90%). In contrast, the NPET dropped from 23.0 to − 50.6 °C when the Va increased from 0.2 to 2.5 m/s, respectively. From our analysis, it was demonstrated that human thermal responses are significantly affected by both the microenvironmental and meteorological backgrounds around the water surface. Our work provides valuable insights for the proper use of water surfaces in urban design for adjusting thermal comfort.

Abstract Research background and purpose Osteoporosis (OP) is one of the most common bone diseases worldwide, characterized by low bone mineral density and susceptibility to pathological fractures, especially in postmenopausal women and elderly men. Ferroptosis is one of the newly discovered forms of cell death regulated by genes in recent years. Many studies have shown that ferroptosis is closely related to many diseases. However, there are few studies on ferroptosis in osteoporosis, and the mechanism of ferroptosis in osteoporosis is still unclear. This study aims to identify biomarkers related to osteoporosis ferroptosis from the GEO (Gene Expression Omnibus) database through bioinformatics technology, and to mine potential therapeutic small molecule compounds through molecular docking technology, trying to provide a basis for the diagnosis and treatment of osteoporosis in the future. Materials and methods We downloaded the ferroptosis-related gene set from the FerrDb database ( http://www.zhounan.org/ferrdb/index.html ), downloaded the data sets GSE56815 and GSE7429 from the GEO database, and used the R software “limma” package to screen differentially expressed genes (DEGs) from GSE56815, and intersected with the ferroptosis gene set to obtain ferroptosis-related DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by the R software “clusterProfiler” package. The random forest model was further screened to obtain essential ferroptosis genes. R software “corrplot” package was used for correlation analysis of essential ferroptosis genes, and the Wilcox test was used for significance analysis. The lncRNA-miRNA-mRNA-TF regulatory network was constructed using Cytoscape software. The least absolute shrinkage and selection operator (LASSO) was used to construct a disease diagnosis model, and a Receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic performance, and then GSE7429 was used to verify the reliability of the diagnosis model. Molecular docking technology was used to screen potential small molecule compounds from the Drugbank database. Finally, a rat osteoporosis model was constructed, and peripheral blood mononuclear cells were extracted for qRT-PCR detection to verify the mRNA expression levels of crucial ferroptosis genes. Result Six DEGs related to ferroptosis were initially screened out. GO function and KEGG pathway enrichment analysis showed that ferroptosis-related DEGs were mainly enriched in signaling pathways such as maintenance of iron ion homeostasis, copper ion binding function, and ferroptosis. The random forest model identified five key ferroptosis genes, including CP, FLT3, HAMP, HMOX1, and SLC2A3. Gene correlation analysis found a relatively low correlation between these five key ferroptosis genes. The lncRNA-miRNA-mRNA-TF regulatory network shows that BAZ1B and STAT3 may also be potential molecules. The ROC curve of the disease diagnosis model shows that the model has a good diagnostic performance. Molecular docking technology screened out three small molecule compounds, including NADH, Midostaurin, and Nintedanib small molecule compounds. qRT-PCR detection confirmed the differential expression of CP, FLT3, HAMP, HMOX1 and SLC2A3 between OP and normal control group. Conclusion This study identified five key ferroptosis genes (CP, FLT3, HAMP, HMOX1, and SLC2A3), they were most likely related to OP ferroptosis. In addition, we found that the small molecule compounds of NADH, Midostaurin, and Nintedanib had good docking scores with these five key ferroptosis genes. These findings may provide new clues for the early diagnosis and treatment of osteoporosis in the future.

Abstract Background Colleges and universities face an increased risk of public health emergencies. Among them, medical colleges and universities deserve more attention as they serve as the play a fundamental role in providing public health emergency services and in cultivating medical professionals. Effectively managing infectious disease prevention and control, as well as responding to public health emergencies in medical colleges and universities, is of great importance for enhancing the capacity of social emergency governance and improving the completeness of the public health system. This study aims to understand the management of public health emergencies in medical colleges in a city in southwest China, explore the factors associated with medical college students’ evaluations, and provide recommendations for emergency management mechanisms in colleges and universities. Methods In total, 781 medical college students were selected through stratified random sampling and surveyed using a questionnaire. The main factors affecting students’ evaluation of emergency management were analyzed using multiple linear regression and structural equation modeling. Results The overall emergency management situation in medical colleges was relatively complete, with satisfactory results. Medical college students’ satisfaction with the timeliness of prevention measures was the highest, while the publicity and education were the lowest. Multiple linear regression analysis showed that grades, emergency education, -simulation training, -information reporting, and dynamic adjustment measures were associated with the evaluation of emergency management by medical students. Conclusions Although the evaluation of emergency management in medical colleges was generally positive, certain limitations still existed. To improve the development of the public health system, colleges and universities should constantly reform and innovate emergency management mechanisms according to the important links in the prevention and control processes.

Abstract Background Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC. Methods This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints. Discussion This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC. Trial registration ChiCTR1800017646.

Summary: A wide variety of electrophilic derivatives of itaconate, the Kreb’s cycle-derived metabolite, are immunomodulatory, yet these derivatives have overlapping and sometimes contradictory activities. Therefore, we generated a genetic system to interrogate the immunomodulatory functions of endogenously produced itaconate in human macrophages. Endogenous itaconate is driven by multiple innate signals restraining inflammatory cytokine production. Endogenous itaconate directly targets cysteine 13 in IRAK4 (disrupting IRAK4 autophosphorylation and activation), drives the degradation of nuclear factor κB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1β in response to these innate activators. In contrast, the production of interferon (IFN)β, downstream of LPS, requires the production of itaconate. These data demonstrate that itaconate is a critical arbiter of inflammatory cytokine production downstream of multiple innate signaling pathways, laying the groundwork for the development of itaconate mimetics for the treatment of autoimmunity.

Leaf functional traits (LFTs) are highly plastic and essential to plant resource acquisition and utilization. However, the collinearity of environmental factors and differences in the response of distinct functional types generate challenges in clarifying the contributions of environment variables to LFTs. This study selected 28 species from four forests in northern China with similar mean annual precipitation (MAP) to explore how other dissimilar environmental factors influence LFTs after controlling for the most influential factor. Specifically, we examined the effect of geographical (latitude, longitude, and altitude) and non-precipitation environmental factors (mean annual temperature (MAT), aridity index (AI), and soil pH) on leaf dry matter content (LDMC), and leaf carbon (LCC), nitrogen (LNC), and phosphorus (LPC) concentration, and pH. The collinearity of environmental factors on LFTs can be attributed to the regulation of moisture and temperature by geographical factors. Therefore, the remaining geo-environmental factors still played a significant role in LFT variation after excluding the most influential factor, which assist LFTs to maintain the original pattern of change across the environmental gradient. As latitude, longitude, and AI decreased, MAT increased, LCC and LPC decreased, LNC first increased, then decreased, and LDMC and leaf pH did not change significantly. The trends and intensity of LFTs variation varied between functional types. Significant differences in correlation were observed in LPC-to-LDMC and LPC-to-LNC across all regions for each species. Trait-trait relationships were inconsistent between life forms (herbs and woody plants) for leaf pH-to-nutrient concentration (C, N, P), LCC-to-LPC, and LCC-to-LDMC. Environmental variables were larger contributors to LFTs (especially LNC, LPC, and LDMC) variation than plant functional types (PFTs), while LCC and leaf pH were largely dependent of PFTs. These patterns result from plant adaptations to multiple variables, and a single environmental factor (even the core element that generated the collinearity of environmental factors such as MAP) in northern China cannot dominant geographic patterns among LFTs. This study sheds light on plant adaptation strategies to environmental change, deepening our understanding of ecosystem function and functional coordination.

Abstract Background Brucellosis poses a significant public health concern. This study explores the spatial and temporal dynamic evolution of human brucellosis in China and analyses the spatial heterogeneity of the influencing factors related to the incidence of human brucellosis at the provincial level. Methods The Join-point model, centre of gravity migration model and spatial autocorrelation analysis were employed to evaluate potential changes in the spatial and temporal distribution of human brucellosis in mainland China from 2005 to 2021. Ordinary Least Squares (OLS), Geographically Weighted Regression (GWR), and Multi-scale Geographically Weighted Regression (MGWR) models were constructed to analyze the spatial and temporal correlation between the incidence rate of human brucellosis and meteorological and social factors. Results From 2005 to 2021, human brucellosis in China showed a consistent upward trend. The incidence rate rose more rapidly in South, Central, and Southwest China, leading to a shift in the center of gravity from the North to the Southwest, as illustrated in the migration trajectory diagram. Strong spatial aggregation was observed. The MGWR model outperformed others. Spatio-temporal plots indicated that lower mean annual temperatures and increased beef, mutton, and milk production significantly correlated with higher brucellosis incidence. Cities like Guangxi and Guangdong were more affected by low temperatures, while Xinjiang and Tibet were influenced more by beef and milk production. Inner Mongolia and Heilongjiang were more affected by mutton production. Importantly, an increase in regional GDP and health expenditure exerted a notable protective effect against human brucellosis incidence. Conclusions Human brucellosis remains a pervasive challenge. Meteorological and social factors significantly influence its incidence in a spatiotemporally specific manner. Tailored prevention strategies should be region-specific, providing valuable insights for effective brucellosis control measures.

Abstract To test the effectiveness of N2 and CO2 in preventing coal from spontaneously combusting, researchers used an adiabatic oxidation apparatus to conduct an experiment with different temperature starting points. Non-adsorbed helium (He) was used as a reference gas, and coal and oxygen concentration temperature variations were analyzed after inerting. The results showed that He had the best cooling effect, N2 was second, and CO2 was the worst. At 70℃ and 110℃, the impact of different gases on reducing oxygen concentration and the cooling effect was the same. However, at the starting temperature of 150℃, CO2 was less effective in lowering oxygen concentration at the later stage than He and N2. N2 and CO2 can prolong the flame retardation time of inert gas and reduce oxygen displacement with an initial temperature increase. When the starting temperature is the same, N2 injection cools coal samples and replaces oxygen more effectively than CO2 injection. The flame retardancy of inert gas is the combined result of the cooling effect of inert gas and the replacement of oxygen. These findings are essential for using inert flame retardant technology in the goaf.

The liver is a vital organ in chickens that performs a number of crucial physiological functions, including the storage of hepatic glycogen, protein synthesis, detoxification, and deoxidation. The growth and metabolism of the liver are complex processes influenced by factors such as environment, diet, and genetics. MicroRNAs (miRNAs), as post-transcriptional regulatory molecules, play a role in various biological processes. There is growing evidence that miR-27b-5p plays a key role in the regulation of liver development and metabolism in various species. However, its role in chicken livers has yet to be determined. In our experiment, we found that chickens with fatty livers had significantly higher levels of serum triglyceride (TG) and total cholesterol (TC) compared to the normal chickens, while the control group had significantly higher levels of very low-density lipoprotein (VLDL) and serum hormones. Further research showed that the mRNA of miR-27b-5p was highly expressed in fatty livers. By exploring the function of miR-27b-5p in chicken livers, we discovered that it promotes lipogenesis, oxidative stress, and inflammatory responses, leading to hepatocyte apoptosis. Our study also established the mechanism by which miR-27b-5p interacts with its target gene, and found that miR-27b-5p targets insulin receptor substrate 2 (IRS2) and modulates the PI3K/AKT signaling pathway. Additionally, our investigation of IRS2 in chicken hepatocytes revealed that knocking down IRS2 has the same effects as overexpressing miR-27b-5p. In conclusion, our study revealed that miR-27b-5p directly binds to IRS2, inhibiting the PI3K/AKT signaling pathway and causing steatosis, oxidative stress, inflammation, and apoptosis in chicken liver.

Human capability to perform routine tasks declines with age and age-related problems. Remote human activity recognition (HAR) is beneficial for regular monitoring of the elderly population. This paper addresses the problem of the continuous detection of daily human activities using a mm-wave Doppler radar. In this study, two strategies have been employed: the first method uses un-equalized series of activities, whereas the second method utilizes a gradient-based strategy for equalization of the series of activities. The dynamic time warping (DTW) algorithm and Long Short-term Memory (LSTM) techniques have been implemented for the classification of un-equalized and equalized series of activities, respectively. The input for DTW was provided using three strategies. The first approach uses the pixel-level data of frames (UnSup-PLevel). In the other two strategies, a convolutional variational autoencoder (CVAE) is used to extract Un-Supervised Encoded features (UnSup-EnLevel) and Supervised Encoded features (Sup-EnLevel) from the series of Doppler frames. The second approach for equalized data series involves the application of four distinct feature extraction methods: i.e., convolutional neural networks (CNN), supervised and unsupervised CVAE, and principal component Analysis (PCA). The extracted features were considered as an input to the LSTM. This paper presents a comparative analysis of a novel supervised feature extraction pipeline, employing Sup-ENLevel-DTW and Sup-EnLevel-LSTM, against several state-of-the-art unsupervised methods, including UnSUp-EnLevel-DTW, UnSup-EnLevel-LSTM, CNN-LSTM, and PCA-LSTM. The results demonstrate the superiority of the Sup-EnLevel-LSTM strategy. However, the UnSup-PLevel strategy worked surprisingly well without using annotations and frame equalization.

Abstract Atmospheric pressure fluctuation is one of the most important factors affecting the climate environment and gas emission in the fire area. To obtain the influence rule of the surface atmospheric pressure change on the gas sampling and abnormal emission in the mine closed goaf, the No. 1 coal mine in Dananhu was taken as the research object. Using Fourier transform and Fisher harmonic analysis and other statistical methods, the influence of the periodic variation of atmospheric pressure on the gas leakage and outflow in the closed goaf was studied. The results showed that there were three atmospheric pressure periods of 15.2 d, 1 d and 182.2 d, and the probability was greater than 95%. The time period with the highest number of atmospheric pressure peaks was 7:00–8:00, which accounted for 20.2% of total occurrence number in a day. And the time periods with the highest number of atmospheric pressure trough were 2:00, 15:00 and 16:00, accounting for 27.4%. The peak-to-trough transition time was mainly concentrated around 6 h, and the diurnal variation curve of atmospheric pressure was mainly bimodal. The atmospheric pressure change rate was mostly concentrated in 10–50 Pa/h. It was determined that the distance that the gas sampling pipe was pre-laid into the inner side of the closed wall should be greater than 44.4 m, and the CO concentration and atmospheric pressure in the closed goaf were both periodic and negative with atmospheric pressure. The research results have important guiding significance for the monitoring, early warning and environmental protection of the goaf.

Abstract Background Soil fauna is an important driver of carbon (C) and nitrogen (N) release from decomposing litter in forest ecosystems. However, its role in C and N cycling concerning climate and litter traits remains less known. In a 4-year field experiment, we evaluated the effects of soil fauna on litter C and N release across an elevation gradient (453, 945, 3023, and 3582 m) and litter traits (coniferous vs. broadleaf) in southwestern China. Results Our results showed that N was retained by –0.4% to 31.5%, but C was immediately released during the early stage (156–516 days) of decomposition for most litter species. Soil fauna significantly increased the peak N content and N retention across litter species, but reduced the C/N ratio for certain species (i.e., Juniperus saltuaria, Betula albosinensis, Quercus acutissima, and Pinus massoniana litter), leading to more C and N being released from decomposing litter across the elevation gradient. Contributions of soil fauna to C and N release were 3.87–9.90% and 1.10–8.71%, respectively, across litter species after 4 years of decomposition. Soil environment and initial litter quality factors caused by elevation directly affected litter C and N release. Changes in soil fauna resulting from elevation and fauna exclusion factors had a direct or indirect impact on C and N release during litter decomposition. Conclusions Our findings suggest that soil fauna promote C and N release from decomposing litter in different magnitudes, mainly controlled by environmental conditions (i.e., temperature and moisture), litter quality (i.e., lignin and cellulose content, and lignin/cellulose), and its diversity across the elevation gradient.

To study the variation laws and effects of asphalt mastic under the cooperative interaction of different temperatures and humidities, cyclic conditions for different temperature ranges were set to conduct indoor experimental simulations of thermal–humidity coupling cycles. Firstly, the macroscopic performance changes in styrene butadiene styrene polymer (SBS)-modified asphalt mastic were evaluated by the penetration test, softening point test, ductility test, Brookfield rotational viscosity test, and double-edge notched tensile (DENT) test; then, the mechanism of performance changes was explored from the perspective of chemical composition by combining this with Fourier transform infrared spectroscopy (FTIR). The research results show that with the increase in thermal–humidity coupling cycles, SBS-modified asphalt mastic exhibited aging phenomena such as hardening and embrittlement, and its macroscopic performance deteriorated; under the same test conditions, the interval with a higher temperature difference had a greater impact on the performance of the mastic; the sulfoxide index (IS=O) of SBS-modified asphalt mastic increases after thermal–humidity coupling cycles, while the isoprene index (IB) decreases.

Background: Similar to the high-fat diet (HFD), the high-glycemic diet (HGD) contributes to the development and progression of type 2 diabetes mellitus (T2DM). However, the effect of HGD on gastrointestinal motility in T2DM and its u nderlying mechanisms remain unclear. Methods: Thirty C57BL/6J mice were randomly designated into the normal-feeding diet (NFD) group, HFD group, and HGD group. The plasma glucose, plasma insulin, and gastrointestinal motility were examined. Meanwhile, the tension of isolated colonic smooth muscle rings was calculated, and the gut microbiota was analyzed by 16s rDNA high-throughput sequencing. Result: After 16 weeks of HGD feeding, obesity, hyperglycemia, insulin resistance, and constipation were observed in HGD mice. Autonomic contraction frequency of the colonic neuromuscular system and electrical field stimulation-induced contractions were reduced in HGD mice. On the contrary, neuronal nitric oxide synthase activity and neuromuscular relaxation were found to be enhanced. Finally, gut microbiota analysis revealed that Rhodospirillaceae abundance significantly increased at the family level in HGD mice. At the genus level, the abundance of Insolitispirillum increased remarkably, whereas Turicibacter abundance decreased significantly in HGD mice. Conclusion: HGD induced constipation in obese diabetic mice, which we speculated that it may be related to neuromuscular dysmotility and intestinal microbiota dysbiosis.

In order to study the impact initiation process and mechanism of hypervelocity PTFE/Al composite structure reactive fragments on a shielded charge, first, an existing PTFE/Al reactive fragment hypervelocity collision experiment was numerically simulated using the SPH algorithm in ANSYS/AUTODYN 17.0 software. Then, the Lee–Tarver model was verified to describe the detonation reaction behavior and explosion damage effect of reactive materials. A numerical simulation analysis of the impact of two kinds of ultra-high-speed PTFE/Al composite-structure reactive fragments on a shielded charge was carried out using the SPH algorithm. These were steel-coated PTFE/Al and steel-semi-coated PTFE/Al fragments, and they were compared with the impact of steel fragments. The results indicate that the threshold velocities of the impact initiation of the two composite-structure reactive fragments on the shielded charge were both 2.6 km/s, while the threshold velocity of the steel fragment was 2.7 km/s. Under the threshold velocity condition, the two composite-structure reactive fragments increase the time and intensity of the compressed shock wave pulse in the explosive due to the impact energy release effect of the reactive materials, causing the shielded charge to detonate under the continuous long-term pulse loads. However, the mechanism of the steel fragment on the shielded charge belongs to the shock–detonation transition. The research results can provide scientific references for the design of hypervelocity reactive fragments and the study of their damage mechanism.

Abstract Background Renal tubulointerstitial fibrosis is the hallmark of various chronic kidney diseases. Symmetric dimethylarginine (SDMA) is an independent cardiovascular risk factor in patients with chronic kidney diseases, which is mostly excreted through renal tubules. However, the effect of SDMA on kidneys in a pathological condition is currently unknown. In this study, we investigated the role of SDMA in renal tubulointerstitial fibrosis and explored its underlying mechanisms. Methods Mouse unilateral ureteral obstruction (UUO) and unilateral ischemia–reperfusion injury (UIRI) models were established to study renal tubulointerstitial fibrosis. SDMA was injected into kidneys through ureter retrogradely. TGF-β stimulated human renal epithelial (HK2) cells were used as an in vitro model and treated with SDMA. Signal transducer and activator of transcription-4 (STAT4) was inhibited by berbamine dihydrochloride or siRNA or overexpressed by plasmids in vitro. Masson staining and Western blotting were performed to evaluate renal fibrosis. Quantitative PCR was performed to validate findings derived from RNA sequencing analysis. Results We observed that SDMA (from 0.01 to 10 µM) dose-dependently inhibited the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells. Intrarenal administration of SDMA (2.5 µmol/kg or 25 µmol/kg) dose-dependently attenuated renal fibrosis in UUO kidneys. A significant increase in SDMA concentration (from 19.5 to 117.7 nmol/g, p

BackgroundSHANK2 encodes a postsynaptic scaffolding protein involved in synapse formation, stabilization and homeostasis. Variations or microdeletions in the SHANK2 gene have been linked to a variety of neurodevelopmental disorders, including autism spectrum disorders (ASD) and mild to moderate intellectual disability (ID) in human. However, the number of reported cases with SHANK2 defects remains limited, with only 14 unrelated patients documented worldwide.MethodsIn this study, we investigated four patients from three families with ID. Whole-exome sequencing (WES) was performed to explore the genetic causes, while Sanger sequencing was used to confirm the identified variants. Furthermore, RNA sequencing and functional enrichment analysis were performed on patients with likely pathogenic variants to gain further insights into the molecular landscape associated with these variants.ResultsTwo novel variants in the SHANK2 gene: a heterozygous splicing substitution (NM_012309.5:c.2198-1G>A p.Pro734Glyfs*22) in Family 1, and a heterozygous nonsense variant [NM_012309.5:c.2310dupT p.(Lys771*)] in Family 2 were identified by WES and confirmed by Sanger sequencing. RNA sequencing and cohort analysis identified a total of 1,196 genes exhibiting aberrant expression in three patients. Functional enrichment analysis revealed the involvement of these genes in protein binding and synaptic functions.ConclusionWe identified two novel loss of function variants that broadens the spectrum of SHANK2 variants. Furthermore, this study enhances our understanding of the molecular mechanisms underlying SHANK2-related disorders.

As agroecology deteriorates, agricultural production is threatened by the combined stressors of exposure to environmental pollutants and pathogenic microbes. Proper agronomic practices for crop growth management and fertilization require understanding plant tolerance strategies. Both rice blast and heavy metals substantially impair rice crops, while silicon (Si) is an effective amendment to alleviate the combined stressors. Herein, this study was conducted to investigate the rice physiology and pathology perspective on the mechanism of Si alleviation against both lead (Pb) toxicity and Magnaporthe oryzae infection, utilizing pot experiments with inoculation of the virulent Magnaporthe oryzae strain. Exogenous Si reduced the phyto-availability and plant absorption of Pb, resulting in a 73.5% reduction in exchangeable Pb concentration in soil and a 40.23% reduction in rice plants. Furthermore, Si addition boosted the plant antioxidant system by increasing the activities of related enzymes, as the activities of catalase, superoxide dismutase, and polyphenol oxidase were significantly improved while the activity of peroxidase in rice panicles decreased. As a result, an improvement in dry matter quantity by 19.19% was observed compared to treatments without Si application, and the panicle blast severity (PBS) was reduced by 0.4–37.52%. Notwithstanding the interaction between the combined stressors, this study revealed that the speciation of Pb formation in the rhizosphere was the primary contributor to the alleviation of abiotic stresses, whereas the regulation of oxidative stress by enzymatic antioxidants played a dominant role in alleviating Magnaporthe oryzae colonization and impairments. The regulation process may reveal the mechanism of siliceous fertilizer functioning in the paddy system. Thereby the role of exogenous Si in anti-fungal, heavy metal toxicology, and plant physiology needs further study to fully elucidate the role of Si amendment, which is proposed to be considered from the perspective of soil chemistry and plant physiology.

To address the problems of long run times, long path length and low efficiencies of traditional intelligent algorithms to optimise free-form surface inspection path algorithms, this paper proposes a method based on an improved cuckoo search algorithm. Since the basic cuckoo search algorithm suffers from problems such as low search efficiency and the tendency to fall into local optimum solutions, the basic cuckoo search algorithm is improved by using a parameter adaptive adjustment strategy and dynamic neighbourhood search strategy, so that the improved cuckoo search algorithm can obtain the optimised inspection path stably and quickly. The local composition of the free-form surface inspection path and the corresponding mathematical model are first analysed, and then traditional intelligent algorithms and the improved cuckoo search algorithm are applied to optimise the mathematical model. The results of inspection experiments conducted with an engine impeller showed that the improved cuckoo search algorithm reduced the length of the optimised inspection path by at least 8.6%, reduced the algorithm run time by at least 35%, and improved the inspection efficiency by at least 1.2% compared to those of the genetic algorithm, simulated annealing algorithm, and ant colony Optimisation algorithm. The improved cuckoo search algorithm allows for effective free-form surface inspection path Optimisation and an improved inspection efficiency.

As an important part of terrestrial ecosystems, the forest soil nutrient content is easily affected by thinning. However, the effects of thinning on soil phosphorus (P) stocks and dynamics have not yet been systematically analyzed. In this study, we aimed to investigate the effects of thinning on the soil P stock and rate of soil P stock change in the 0–30, 30–60, and 0–60 cm soil layers by integrating 237 data points on a global scale. In addition, we aimed to determine whether these factors are regulated by forest type, recovery time, and thinning intensity. The results indicated that thinning increased the soil P stock in the 0–30, 30–60, and 0–60 cm soil layers by 9.0, 13.2, and 10.2%, respectively, and the soil P stock change rates were 0.017, 0.013, and 0.025 Mg ha−1 yr−1, respectively. Furthermore, the promoting effect of thinning on soil P stocks was greater in coniferous forests than in broadleaf and mixed forests. In addition, the stocks and change rates of soil P increased with recovery time and decreased with thinning intensity and mean annual precipitation. This study highlights the effects of thinning on forest soil P accumulation on a global scale. The results are of great significance for understanding soil nutrient cycling and sustainable forest management.

CCCTC-Binding Factor (CTCF) is a protein-coding gene involved in transcriptional regulation, insulator activity, and regulation of chromatin structure, and is closely associated with intellectual developmental disorders. In this study, we report two unrelated Chinese patients with intellectual disability (ID). According to variant interpretation results from exome sequencing data and RNA-seq data, we present two novel heterozygous CTCF variants, NM_006565.3:c.1519_2184del (p. Glu507_Arg727delins47) and NM_006565.3:c.1838_1852del (p.Glu613_Pro617del), found in two distinct unrelated patients, respectively. Moreover, RNA-seq data of patient 1 indicated the absence of the mutant transcript, while in patient 2, the RNA-seq data revealed a CTCF mRNA transcript with a deletion of 15 nucleotides. Notably, the RNA sequencing data revealed 507 differentially expressed genes shared between these two patients. Specifically, among them, 194 were down-regulated, and 313 were up-regulated, primarily involved in gene regulation and cellular response. Our study expands the genetic and clinical spectrum of CTCF and advances our understanding of the pathogenesis of CTCF in vivo.

Summary: The present study examines whether there is a mechanism beyond the current concept of post-translational modifications to regulate the function of a protein. A small gas molecule, hydrogen sulfide (H2S), was found to bind at active-site copper of Cu/Zn-SOD using a series of methods including radiolabeled binding assay, X-ray absorption near-edge structure (XANES), and crystallography. Such an H2S binding enhanced the electrostatic forces to guide the negatively charged substrate superoxide radicals to the catalytic copper ion, changed the geometry and energy of the frontier molecular orbitals of the active site, and subsequently facilitated the transfer of an electron from the superoxide radical to the catalytic copper ion and the breakage of the copper-His61 bridge. The physiological relevance of such an H2S effect was also examined in both in vitro and in vivo models where the cardioprotective effects of H2S were dependent on Cu/Zn-SOD.

This study presents a simple technique for strengthening the adhesive-bond strength between aluminium (Al) substrate and carbon fibre reinforced polymer (CFRP) utilising resin pre-coating (RPC) with carbon nanotubes (CNTs). The CNT-containing RPC solution with 90 ​wt% acetone and 10 ​wt% resin (without hardener) was applied onto Al substrates, where micro-/nano-vertical channels had been created by chemical or mechanical surface treatments to accommodate CNTs. RPC was able to fill all micro-/nano-cavities over the Al substrate surface, then CNTs were pulled into those vertical micro-channels by the capillary action generated from acetone evaporation. Normal epoxy adhesive (resin ​+ ​hardener) was applied after the CNT-containing RPC treatment. CNTs bridging across the interface between the adhesive joint and Al substrate and sealing of micro-/nano-cavities by RPC effectively enhanced the interfacial shear bond strength between the Al substrate and CFRP by 30–100% depending on the Al substrate surface profiles. Al substrates with two different chemical treatments were compared in this study for the effectiveness of CNT interfacial reinforcement. Results from a steel substrate after sandblasting were also included for comparison.

Abstract Objective We presented a non-consanguineous healthy Chinese couple with five pregnancies, three early miscarriages, the fetus II-2 and II-5 with similar abnormal phenotypes of fetal hydrops, scoliosis, fetal akinesia and polyhydramnios. This study aimed to uncover the molecular etiology of this family with a history of multiple adverse pregnancies. Materials and methods DNA extracted from the fifth fetal umbilical cord and parents’ peripheral blood were subjected to SNP-array and whole exome sequencing. The result was verified by Sanger sequencing. Functional characterization of the c.2682G > C (p.Ile860_Pro894del) variant was completed by minigene splicing assay. Results Trio whole-exome sequencing has identified compound heterozygous variants in RYR1 (c.2682G > C; p.Ile860_Pro894del and c.12572G > A; p.Arg4191His) in fetus II-5. The variant c.2682G > C (p.Ile860_Pro894del) comes from the father and the c.12572G > A (p.Arg4191His) comes from the mother. The c.2682G > C (p.Ile860_Pro894del) affects the splice site resulting in exon 21 skipping, therefore is classified as likely pathogenic. The c.12572G > A (p.Arg4191His) locates in the C-terminal hot spots region of the RYR1, classified as of uncertain significance. Conclusions We report the first prenatal case of RYR1-related disorders in Chinese population, expanding the variant spectrum of RYR1 in fetuses.

NK cells can be affected by tumour cells and this difference could be utilised as a cancer diagnostic. Here the authors use a nickel based plasmonic spectroscopy system to measure metabolic differences in NK cells that have been exposed to cancer cells as a method of cancer detection.

The study of the suitability of prehistoric human settlements (SPHE) can help us reproduce the process and characteristics of prehistoric human settlements, and is an important entry point for exploring the relationship between prehistoric humans and land. In this study, we discuss the definition, compositional structure, evolutionary mechanism, and spatiotemporal representation of the suitability of prehistoric human settlements, and propose its main research lines and possible research contents. We believe that the suitability of prehistoric human settlement environments refers to the ability and process of natural and social environmental conditions to meet the needs of human survival within a certain spatial range centered on the settlement of prehistoric humans. Additionally, with the temporal and spatial evolution of humans, society, and nature, it shows local consistency and global gradual and continuous change characteristics, and the human settlement environment has a suitability hierarchy of natural original, livelihood, and living spaces nested step by step. We believe that we can adopt the main research line of prehistoric human settlement suitability system construction to conduct extensive experiments and demonstrations on the theoretical construction, the evolution of the environment and living process, the relationship and evaluation of prehistoric human needs, the transformation of the living environment, living adaptation theories and models, and value and limitation verification. Thus, a complete research system can be formed to explore the evolution of the prehistoric human–land relationship.

To examine the effect mechanism of rubber and diatomite on asphalt as well as the performance of asphalt mixtures for road applications, various composite-modified asphalts are prepared using rubber and diatomite. The performance of modified asphalts with various proportions is analyzed, and the optimal dosage ratio of modifiers is determined via the response surface approach. The microstructure of rubber–diatomite composite-modified asphalt is methodically examined using Fourier transform infrared spectroscopy and scanning electron microscopy. The road performance, aging resistance, and long-term stability of asphalt mixtures are evaluated through Marshall tests, wheel tracking tests, aging wheel tracking tests, freeze–thaw splitting tests, and cyclic freeze–thaw drying aging splitting tests. The obtained results reveal that asphalt with 22% rubber and 4% diatomite exhibits the best overall performance. The composite-modified asphalt essentially demonstrates the physical blending between rubber powder, diatomite, and base asphalt. The asphalt built from them formed a uniform and stable overall structure. Compared with rubber asphalt and rubber–SBS composite-modified asphalt, rubber–diatomite composite-modified asphalt exhibits superior road performance, including better aging resistance and long-term water stability in asphalt mixtures. This study can promote the further extensive application of rubber–diatomite-modified asphalt in road engineering, while providing new ideas for cost-saving and environmentally friendly asphalt modification.

Gaining a deep understanding of how climate change affects the carbon cycle in dryland vegetation is of utmost importance, as it plays a pivotal role in shaping the overall carbon cycle in global ecosystems. It is currently not clear how plant communities at varying elevations in arid mountainous regions will respond to climate change in terms of their productivity. The aim of this study was to investigate the effect of climate change on vegetation productivity in different altitudinal vegetation belts of the Tianshan Mountains between 2000 and 2021, utilizing satellite-derived vegetation productivity and climate data. The findings suggest a notable increase in vegetation productivity across diverse altitudinal vegetation belts. The productivity of vegetation in the coniferous forest and alpine meadow belts displayed a notably higher interannual trend compared to other vegetation belts. Notably, an increase in vegetation productivity was accompanied by warming and drying. The productivity of altitudinal vegetation belts, however, appears to be resilient to current climate trends and was not significantly impacted by the severity of atmospheric drought. The trend of increased vegetation productivity was primarily driven by CO2 fertilization. Our results highlight that the extent of climate change may need to reach a threshold to noticeably affect variations in vegetation productivity in arid mountainous.

Measurement(s) spatial distribution data of cultural sites Technology Type(s) Geographic Information System • digital curation Independent variable(s) geographic location • age • geographical landscape type Sample Characteristic - Environment prehistoric human sites Sample Characteristic - Location China

Abstract When studying the human settlement process, it is of great significance to understand the prehistoric environment, economy and society by exploring the human–land relationship and the evolution of civilization reflected by the settlement environment. This paper explores the natural and social environmental preferences of early human settlements in Xinjiang, China, from the Palaeolithic to the Bronze Age (45 ka BP–2250 a BP). Through the characteristics of settlement preferences, the distribution of settlements is accurately predicted, and the relationship between settlement preferences and the evolution of the environment and civilization is verified and discussed. We summarize the needs and conditions of early human settlement from the perspectives of the social environment and natural environment and explain the stages, consistency and differentiation of the spatial and temporal evolution of settlement preferences with the interaction of adaptation and transformation. On this basis, we discuss the logical focuses and content of early human settlement preference research. This research provides a reference for the process, representation, driving mode, and research ideas of early human settlement preferences.

ABSTRACT: Follicular atresia is a natural physiological phenomenon in poultry reproduction. It is well known that follicular atresia is caused by both autophagy and apoptosis of granulosa cells. In current experiment, we evaluated the function of miR-34a-5p on autophagy and apoptosis in chicken follicular atresia. First, the follicular atresia model of chicken was successfully constructed by subcutaneous injection of tamoxifen (TMX), and found the expression of miR-34a-5p in the atresia follicles obviously increased. Then, we confirmed that miR-34a-5p accelerates autophagy and apoptosis of chicken granulose cells in vitro, and miR-34a-5p could induce apoptosis by mediating autophagy. Mechanistically, lymphoid enhancer binding factor 1 (LEF1) was deemed as a target gene for miR-34a-5p. On the contrary, LEF1 overexpression attenuated the autophagy and apoptosis of chicken granular cells. In addition, it was confirmed that the miR-34a-5p/LEF1 axis plays a regulatory role in chicken granulosa cells by mediating the Hippo-YAP signaling pathway. Taken together, this study demonstrated that miR-34a-5p contributes to autophagy and apoptosis of chicken follicular granulosa cells by targeting LEF1 to mediate the Hippo-YAP signaling pathway.

The biological functions of N6-methyladenosine (m6A) modification of mRNA have recently received a great deal of attention. In previous studies, m6A methylation modification has been shown to regulate mRNA fate and to be crucial for the progression and development of tumors. BTG2 (B-cell translocation gene 2) is a member of BTG/TOB anti-proliferative protein family. BTG2 could inhibit cell proliferation and migration and regulate the cell cycle progression. In this study, we confirm that BTG2 is frequently down-regulated in renal cell carcinoma (RCC) tissues and its low expression is associated with unfavorable prognosis and decreased m6A level. Moreover, we found that m6A methylation modifies the 5’UTR of BTG2 to promote its mRNA stability by binding to IGF2BP2. It has been shown that CRISPR/dCas13b-METLL3 can specifically increase BTG2 m6A modification to significantly increase its m6A and expression levels. Then m6A hypermethylation in BTG2 mRNA could dramatically inhibit RCC cells proliferation and migration, and induce cells apoptosis. Taken together, our data show that BTG2 functions as a tumor suppressor and is frequently silenced via m6A modification in RCC.

Accumulating evidence suggests that gut microbiota as a critical mediator of gut-brain axis plays an important role in human health. Altered gut microbial profiles have been implicated in increasing the vulnerability of psychiatric disorders, such as autism, depression, and schizophrenia. However, the cellular and molecular mechanisms underlying the association remain unknown. Here, we modified the gut microbiome with antibiotics in newborn mice, and found that gut microbial alteration induced behavioral impairment by decreasing adult neurogenesis and long-term potentiation of synaptic transmission, and altering the gene expression profile in hippocampus. Reconstitution with normal gut flora produced therapeutic effects against both adult neurogenesis and behavioral deficits in the dysbiosis mice. Furthermore, our results show that circulating metabolites changes mediate the effect of gut dysbiosis on hippocampal plasticity and behavior outcomes. Elevating the serum 4-methylphenol, a small aromatic metabolite produced by gut bacteria, was found to induce autism spectrum disorder (ASD)-like behavior impairment and hippocampal dysfunction. Together our finding demonstrates that early-life gut dysbiosis and its correlated metabolites change contribute to hippocampal dysfunction and behavior impairment, hence highlight the potential microbiome-mediated therapies for treating psychiatric disorders.

Hydrogen sulfide (H2S), produced by cystathionine γ lyase (CSE), is an important endogenous gasotransmitter to maintain heart function. However, the molecular mechanism for how H2S influences the mitochondrial morphology during heart failure remains poorly understood. Here, we found that CSE/H2S pathway mediated cardiac function and mitochondrial morphology through regulating dynamin related protein 1 (Drp1) activity and translocation. Mechanistically, elevation of H2S levels by CSE overexpression declined protein level, phosphorylation (Ser 616), oligomerization and GTPase activity of Drp1 by S-sulfhydration in mouse hearts. Interestingly, Drp1 S-sulfhydration directly competed with S-nitrosylation by nitric oxide at the specific cysteine 607. The non-S-sulfhydration of Drp1 mutation (C607A) attenuated the regulatory effect of H2S on Drp1 activation, mitochondrial fission and heart function. Moreover, the non-canonical role of Drp1 mediated isoprenaline-induced mitochondrial dysfunction and cardiomyocyte death through interaction with voltage-dependent anion channel 1. These results uncover that a novel mechanism that H2S S-sulfhydrated Drp1 at cysteine 607 to prevent heart failure through modulating its activity and mitochondrial translocation. Our findings also provide initial evidence demonstrating that Drp1 may be a critical regulator as well as an effective strategy for heart dysfunction.

Human mesenchymal stem cells (hMSCs) were labeled with Dotarem or (Gd-DOTA)2- EM7 (EM7Gd2) via electroporation (EP). Cellular transmission electron microscopy (TEM) reveals free distribution of Gd agents and formation of EM7Gd2 clusters in the cytosol. Cellular magnetic resonance imaging (MRI) reveals that the free Gd agents induce MRI signal enhancement effect due to its fast exocytosis and subsequent interaction with intercellular water molecules. The EM7Gd2 clusters exhibits a longer intracellular retention time and induce a persistent MRI signal reduction effect. The cellular MRI results are interpreted by taking into account both T1 and T2 relaxation rates and their correlation with cellular binding structures of Dotarem and EM7Gd2.

Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions), and few studies have assessed the whole-brain functional connectivity architecture of OCD with electroencephalogram (EEG) during different resting states. Graph theory and network-based statistics (NBS) were employed to examine the neural synchronization and the whole-brain functional connectivity (FC) based on the phase-locking value (PLV) of OCD patients and healthy controls (HCs) during eyes-closed (EC) and eyes-open (EO) states. Compared with HCs, OCD patients exhibited not only decreased global synchronization in terms of phase synchrony but also aberrant global topological properties (decreased average shortest path lengths and normalized shortest path lengths together with increased global efficiencies and normalized clustering coefficients) together with inhibited intra-hemispheric and interhemispheric FCs during rest, which suggested an imbalance between functional integration and segregation of brain networks for OCD patients. Meanwhile, OCD patients had increased global efficiencies and normalized clustering coefficients, but decreased average clustering coefficients and normalized shortest path lengths together with significantly decreased FCs in the alpha band from EC to EO states, which suggested a dynamic switch between highly integrated (EC state) and highly specialized (EO state) modes of information processing. Moreover, the decreased FCs of OCD patients showed obvious hemispheric asymmetry within or between groups during EC and EO states, which might serve as a potential biomarker to classify OCD patients from HCs.

Driven by the extended applications and scarce spectrum resources, integrating the radio sensing functions into the future mobile system has been a consensus between the stakeholders. This paper demonstrates the feasibility of joint localization and imaging functions by exploiting the reference signal in the radio frame defined in the mobile system. Essentially, the subspace-based algorithms are adopted to jointly estimate the angle and distance and to enable the localization function for uplink and downlink signals and the derivation of theoretical performance boundaries. The vector antenna and virtual array concepts are introduced in the downlink scenario to enhance the angle estimation resolution. The uplink sounding reference signal is exploited to enable the imaging function as analog to synthetic-aperture radar (SAR). The joint localization and imaging performances are verified with a realistic ray-tracing channel based on the 3D ground and buildings model of Muret airport in France. The simulation results show that the reference signal can provide acceptable localization accuracy and target-distinguishing capability by adopting a virtual array and joint time-spatial smoothing in downlink and uplink, respectively. The joint localization and imaging results prove that the future mobile network is potentially a viable infrastructure to provide economic surveillance solutions for airports, particularly for secondary airports that are not well equipped with dedicated surveillance systems.

Background and Purpose: Irritable bowel syndrome (IBS) is usually associated with chronic gastrointestinal disorders. Its most common subtype is accompanied with diarrhea (IBS-D). The enteric nervous system (ENS) modulates major gastrointestinal motility and functions whose aberration may induce IBS-D. The enteric neurons are susceptible to long-term neurotransmitter level alterations. The patchouli alcohol (PA), extracted from Pogostemonis Herba, has been reported to regulate neurotransmitter release in the ENS, while its effectiveness against IBS-D and the underlying mechanism remain unknown.Experimental Approach: In this study, we established an IBS-D model in rats through chronic restraint stress. We administered the rats with 5, 10, and 20 mg/kg of PA for intestinal and visceral examinations. The longitudinal muscle myenteric plexus (LMMP) neurons were further immunohistochemically stained for quantitative, morphological, and neurotransmitters analyses.Key Results: We found that PA decreased visceral sensitivity, diarrhea symptoms and intestinal transit in the IBS-D rats. Meanwhile, 10 and 20 mg/kg of PA significantly reduced the proportion of excitatory LMMP neurons in the distal colon, decreased the number of acetylcholine (Ach)- and substance P (SP)-positive neurons in the distal colon and restored the levels of Ach and SP in the IBS-D rats.Conclusion and Implications: These findings indicated that PA modulated LMMP excitatory neuron activities, improved intestinal motility and alleviated IBS-induced diarrheal symptoms, suggesting the potential therapeutic efficacy of PA against IBS-D.

Lung cancer is the leading cause of cancer-related death worldwide. The development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) has brought favorable survival benefits to patients with non–small-cell lung cancer (NSCLC); unfortunately, acquired drug resistance remains a major barrier to the treatment of NSCLC. Recent studies have demonstrated that the transcriptional co-activator with a PDZ-binding motif (TAZ, also called WWTR1) induces tumor immune evasion by directly modulating the expression of programmed death ligand 1 (PD-L1), a key therapeutic target for checkpoint immunotherapy. Moreover, aberrant activation of TAZ is also a major mechanism of acquired resistance to EGFR-TKIs in NSCLC. Therefore, TAZ signaling blockade might be an effective strategy to overcome resistance to ICIs and EGFR-TKIs in NSCLC. In this study, we showed for the first time that artesunate effectively reduced TAZ and PD-L1 expression in NSCLC. We further demonstrated that artesunate suppressed TAZ/PD-L1–induced T-cell growth inhibition in vitro and enhanced anti-tumor immunity by recruiting infiltrating CD8 + T-cells in syngeneic mouse models. Artesunate also inhibited the stem cell–like properties of NSCLC cells and suppressed tumor growth in xenografts bearing gefitinib-resistant tumors. In addition, our results of molecular docking and cellular thermal shift assay analysis suggested that artesunate might directly target the TAZ–TEAD complex and induce proteasome-dependent TAZ degradation in NSCLC cells. These results suggest that artesunate enhanced anti-tumor immunity and overcame EGFR-TKI resistance in NSCLC at least in part by suppressing TAZ/PD-L1 signaling.

Trichoderma spp., a genus of fast-growing and highly adaptable fungi that form symbiotic relationships with plant roots, rendering them ideal for practical use in controlled environment agriculture. Herein, this paper aims to understand how the Nicotiana benthamiana with inoculation of Trichoderma harzianum strain TRA1-16 responds to light intensity variation. Pot experiments were conducted under low and high light intensities (50 and 150 μmol·m-2·s-1, respectively) and microbial treatments. Plant growth, physio-biochemical attributes, activities of antioxidant enzymes, and phytohormones regulation were investigated. The results showed that for non-inoculated plants, the reduction in light intensity inhibited plant growth, nitrogen (N) and phosphorus (P) uptake, chlorophyll a/b, and carotenoid content. Trichoderma inoculation resulted in 1.17 to 1.51 times higher concentrations of available N and P in the soil than the non-inoculated group, with higher concentrations at high light intensity. Plant height, dry weight, nutrient uptake, and antioxidant activity were significantly increased after inoculation (p

ObjectivesThis study aimed to describe the HIV/AIDS knowledge, sexual attitudes, and sexual behaviors of young students (14–25 years) in Chongqing, China, and to examine their use of preventive services and related factors.MethodA cross-sectional study was conducted with students from 67 schools from December 2019 to June 2021. The chi-square test, non-parametric test to assess the differences between respondents with different characteristics in the above aspects. Additionally, univariate and multivariate logistic regression analyses were conducted to examine factors associated with the awareness of HIV/AIDS knowledge. Confidence intervals without crossover or P < 0.05 was considered significant.ResultsA total of 31,782 participants were included in the study. A total of 62.62% of the respondents were considered to be aware of basic HIV/AIDS knowledge, including 78.44%, 62.15%, and 52.08% in undergraduate colleges, junior colleges and secondary vocational schools, respectively. In total, 60.96% of males and 29.42% of females accepted premarital sex, 15.49% of males and 6.18% of females reported being sexually experienced, and only 57.18% of the students used condoms every time they had sex. The percentage of condom use among students who were aware of HIV/AIDS knowledge was higher than that among students who were not aware. A total of 85.60% of the students thought they needed HIV/AIDS prevention and control knowledge, and 94.60% thought more health education activities on HIV/AIDS prevention needed to be conducted in schools. Entrance education, lectures or consultation hotlines, WeChat official accounts and other media platforms were rated as the most acceptable HIV/AIDS prevention education methods.ConclusionThese respondents lacked knowledge about HIV/AIDS, and an increasing number of students show an open attitude toward premarital sex and engage in risky sexual behaviors. It is urgent to enhance and widely disseminate comprehensive HIV/AIDS and sexual health education in multiple formats.

Mammalian protein arginine methyltransferase 3 (PRMT3) catalyzes the monomethylation and dimethylation of the arginine residues of proteins. The role of PRMT3 in renal fibrosis is currently unknown. We aimed to study the role of PRMT3 in renal fibrosis and explored its underlying mechanisms. Quantitative PCR analysis and Western blotting analysis showed that the expression of PRMT3 was up-regulated in unilateral ureteral obstruction (UUO) mouse kidneys. Knockout of Prmt3 gene enhanced interstitial fibrosis in UUO kidneys as shown by Masson staining and Western blotting analysis the expression of pro-fibrotic markers. The production of asymmetric dimethylarginine (ADMA) was increased in wide type UUO kidneys but not further increased in Prmt3 knockout UUO kidneys. Administration of exogeneous ADMA in UUO kidneys blocked the enhanced renal interstitial fibrosis in Prmt3 mutant mice. Moreover, genetic deletion of Prmt3 gene increased blood urea nitrogen levels and renal deposition of collagen in folic acid injected mice. We conclude that PRMT3 inhibits renal tubulointerstitial fibrosis through elevating renal ADMA levels.

G protein–coupled receptors can signal through both G proteins and ß-arrestin2. For the µ-opioid receptor (MOR), early experimental evidence from a single study suggested that G protein signaling mediates analgesia and sedation, whereas ß-arrestin signaling mediates respiratory depression and constipation. Then, receptor mutations were used to clarify which residues interact with ligands to selectively regulate signals in a ligand-specific manner. However, there is no systematic study on how to determine these residues and clarify the molecular mechanism of their influence on signal pathways. We have therefore used molecular docking to predict the amino acid sites that affect the binding of ligands and MOR. Then, the corresponding sites were mutated to determine the effect of the structural determinant of MOR on Gi/o protein and ß-arrestin pathways. The pharmacological and animal behavioral experiments in combination with molecular dynamics simulations were used to elucidate the molecular mechanism of key residues governing the signaling. Without affecting ligand binding to MOR, MORY7.43A attenuated the activation of both Gi/o protein and ß-arrestin signaling pathways stimulated by fentanyl, whereas it did not change these two pathways stimulated by morphine. Likewise, the activation peak time of extracellular regulated protein kinases was significantly prolonged at MORY7.43A compared with that at MORwildtype stimulated by fentanyl, but there was no difference stimulated by morphine. In addition, MORY7.43A significantly enhanced analgesia by fentanyl but not by morphine in the mice behavioral experiment. Furthermore, the molecular dynamics simulations showed that H6 moves toward the cellular membrane. H6 of the fentanyl–Y7.43A system moved outward more than that in the morphine–Y7.43A system. Y7.43 mutation disrupted hydrophobic interactions between W6.48 and Y7.43 in the fentanyl–Y7.43A system but not in the morphine–Y7.43A system. Our results have disclosed novel mechanisms of Y7.43 mutation affecting MOR signaling pathways. Y7.43 mutation reduced the activation of the Gi/o protein pathway and blocked the ß-arrestin2 recruitment, increased the H6 outward movement of MOR, and disrupted hydrophobic interactions. This may be responsible for the enhanced fentanyl analgesia. These findings are conducive to designing new drugs from the perspective of ligand and receptor binding, and Y7.43 is also expected to be a key site to structure optimization of synthesized compounds.

Background Regulatory T cells (Treg) are an integral part of the tumor immune tolerance. Carcinoma-associated fibroblasts (CAFs) is a pivotal driver for accumulation of Treg cells in the tumor microenvironment (TME). The molecular nature underpinning Treg cells and CAFs coupling needs to be further defined.Methods The Il1r2flox/floxFoxp3Cre mice were generated to establish the conditional knock-out of Il1r2 in Foxp3+ Tregs in vivo. Using the MC38 tumor model, we evaluated the antitumor efficacy of immune checkpoint inhibitors (ICIs) and further analyzed the immune profiling of the TME by multicolor flow cytometry. Single-cell RNA sequencing of the whole tumor tissues, TCR repertoire analysis of sorted CD3+ TILs were also performed.Results We showed that IL1 receptor 2 (IL1R2), a decoy receptor that neutralizes IL1, was highly expressed in Treg cells in the TME. In addition, we found that Il1r1 was largely expressed in the CAFs, suggesting IL1R2 plays a role in modulating crosstalk between Tregs and CAFs. We further demonstrated that Il1r2 deficiency in Treg cells led to greater antitumor efficacy of ICI, decreased Tregs and increased CD8+ T cells in the TME, as well as reduced levels of T cell dysfunction. Mechanistically, we showed that IL1 inhibited major histocompatibility complex class II (MHC-II) expression on fibroblasts and Treg-specific Il1r2 deletion led to a decrease in genes associated with MHC-II antigen presentation in CAFs.Conclusions Our study established a critical role of IL1 signaling in inhibiting Treg-mediated tumor immune suppression through downregulating MHC-II antigen presentation in CAFs.

SET binding protein 1 (SETBP1) is essential for human development, and pathogenic germline variants in SETBP1 lead to a recognizable developmental syndrome and variable clinical features. In this study, we assessed a patient with facial dysmorphism, intellectual disability and delayed motor development. Whole genome sequencing identified a novel de novo variation of the SETBP1 (c.2631C > A; p. S877R) gene, which is located in the SKI domain, as a likely pathogenic variant for the proband’s phenotype. RNA sequencing was performed to investigate the potential molecular mechanism of the novel variation in SETBP1. In total, 77 and 38 genes were identified with aberrant expression and splicing, respectively. Moreover, the biological functions of these genes were involved in DNA/protein binding, expression regulation, and the cell cycle, which may advance our understanding of the pathogenesis of SETBP1 in vivo.