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Abstract Background Calcium-dependent protein kinases (CDPKs) phosphorylate downstream target proteins in response to signals transmitted by free calcium ions (Ca2+, one of the second messengers) and thus play important regulatory roles in many biological processes, such as plant growth, development, and stress response. Results A bioinformatic analysis, as well as thorough evolutionary and expression investigations, were conducted to confirm previous reports of functional evidence for plant CDPKs. Using the Phytozome database’s BLAST search engine and the HMM search tool in TBtools software, we discovered that CDPKs are well conserved from green algae to flowering angiosperms in various gene family sizes. Additional investigations of the obtained CDPKs revealed high conservation of domain and motif numbers, gene architectures, and patterns. However, this conservation differed among plant species. Phylogenetic analysis demonstrated that the CDPK gene family diverged from a common ancient gene. Similarly, investigations into plant interspecies evolutionary relationships revealed common ancestral plant species, suggesting speciation of plants and evolution based on plant adaptation and diversification. A search for the driving force of CDPK gene family expansion revealed that dispersed duplication events, among other duplication events, contributed largely to CDPK gene family expansion. Gene localization analysis in P. trichocarpa demonstrated that most CDPK genes are localized within several cell organelles and bind other kinases and proteins to perform their biological functions efficiently. Using RNA-seq data and qPCR analyses, we postulated that PtCDPKs play functional roles in abiotic stress responses by regulating cold, heat, drought and salt stress to varying extents. Conclusion The CDPK genes are well conserved in plants and are critical entities in abiotic stress regulation, and further exploration and manipulation of these genes in the future may provide solutions to some of the challenges in agriculture, forestry and food security.

Abstract Latent Autoimmune Diabetes in Adults (LADA) is a type of diabetes mellitus often overlooked in clinical practice for its dual resemblance to Type 1 Diabetes Mellitus (T1DM) in pathogenesis and to Type 2 Diabetes Mellitus (T2DM) in clinical presentation. To better understand LADA’s distinctiveness from T1DM and T2DM, we conducted a comprehensive review encompassing etiology, pathology, clinical features, treatment modalities, and prognostic outcomes. With this comparative lens, we propose that LADA defies simple classification as either T1DM or T2DM. The specific treatments for the disease are limited and should be based on the therapies of T1DM or T2DM that address specific clinical issues at different stages of the disease. It is crucial to identify LADA cases potentially misdiagnosed as T2DM, warranting prompt screening for poor blood sugar control, short-term blood sugar deterioration, and other conditions. If the prognosis for LADA is similar to T2DM, it can be managed as T2DM. However, if the prognosis fundamentally differs, early LADA screening is crucial to optimize patient outcomes and enhance research on tailored treatments. The pathogenesis of LADA is clear, so the prognosis may be the key to determining whether it can be classified as T2DM, which is also the direction of future research. On the one hand, this paper aims to provide suggestions for the clinical screening and treatment of LADA based on the latest progress and provide worthy directions for future research on LADA.

Abstract Background Liriodendron chinense is susceptible to extinction due to the increasing severity of abiotic stresses resulting from global climate change, consequently impacting its growth, development, and geographic distribution. However, the L. chinense remains pivotal in both socio-economic and ecological realms. The LRR-RLK (leucine-rich repeat receptor-like protein kinase) genes, constituting a substantial cluster of receptor-like kinases in plants, are crucial for plant growth and stress regulation and are unexplored in the L. chinense. Result 233 LchiLRR-RLK genes were discovered, unevenly distributed across 17 chromosomes and 24 contigs. Among these, 67 pairs of paralogous genes demonstrated gene linkages, facilitating the expansion of the LchiLRR-RLK gene family through tandem (35.82%) and segmental (64.18%) duplications. The synonymous and nonsynonymous ratios showed that the LchiLRR-RLK genes underwent a purifying or stabilizing selection during evolution. Investigations in the conserved domain and protein structures revealed that the LchiLRR-RLKs are highly conserved, carrying conserved protein kinase and leucine-rich repeat-like domians that promote clustering in different groups implicating gene evolutionary conservation. A deeper analysis of LchiLRR-RLK full protein sequences phylogeny showed 13 groups with a common ancestor protein. Interspecies gene collinearity showed more orthologous gene pairs between L. chinense and P. trichocarpa, suggesting various similar biological functions between the two plant species. Analysis of the functional roles of the LchiLRR-RLK genes using the qPCR demonstrated that they are involved in cold, heat, and salt stress regulation, especially, members of subgroups VIII, III, and Xa. Conclusion Conclusively, the LRR-RLK genes are conserved in L. chinense and function to regulate the temperature and salt stresses, and this research provides new insights into understanding LchiLRR-RLK genes and their regulatory effects in abiotic stresses.

Abstract Previous research has primarily employed deep learning models such as Convolutional Neural Networks (CNNs), and Recurrent Neural Networks (RNNs) for decoding imagined character signals. These approaches have treated the temporal and spatial features of the signals in a sequential, parallel, or single-feature manner. However, there has been limited research on the cross-relationships between temporal and spatial features, despite the inherent association between channels and sampling points in Brain-Computer Interface (BCI) signal acquisition, which holds significant information about brain activity. To address the limited research on the relationships between temporal and spatial features, we proposed a Temporal-Spatial Cross-Attention Network model, named TSCA-Net. The TSCA-Net is comprised of four modules: the Temporal Feature (TF), the Spatial Feature (SF), the Temporal-Spatial Cross (TSCross), and the Classifier. The TF combines LSTM and Transformer to extract temporal features from BCI signals, while the SF captures spatial features. The TSCross is introduced to learn the correlations between the temporal and spatial features. The Classifier predicts the label of BCI data based on its characteristics. We validated the TSCA-Net model using publicly available datasets of handwritten characters, which recorded the spiking activity from two micro-electrode arrays (MEAs). The results showed that our proposed TSCA-Net outperformed other comparison models (EEG-Net, EEG-TCNet, S3T, GRU, LSTM, R-Transformer, and ViT) in terms of accuracy, precision, recall, and F1 score, achieving 92.66 $$\%$$ % , 92.77 $$\%$$ % , 92.70 $$\%$$ % , and 92.58 $$\%$$ % , respectively. The TSCA-Net model demonstrated a 3.65 $$\%$$ % to 7.49 $$\%$$ % improvement in accuracy over the comparison models.

Promotions of physical exercise for adolescents have become key elements of the country’s national sports and health campaigns in China. Specifically, these promotions have gone through four stages including Initial Institutionalization, Standardization and Legalization, Solidification and Publicization, and Comprehensiveness and Diversification, which are interpreted based on the Multiple Streams Framework with discussions of the role and dynamism of the problem streams, political streams, and policy streams included. The results reveal that the political streams, reified by the will of the governing party and the central government in particular, play a leading role in policy transformations. Consequently, identifications of existing problems and subsequent adoption of proper measures emerge as the key to generating policy developments in the promotion of physical exercise for adolescents in China.

Abstract Aims Accumulating evidence indicates that the use of antibiotics (ATBs) in cancer patients is potentially correlated with patient prognosis. Interestingly, the use of these agents is not uncommon in colorectal cancer (CRC) patients during surgery; however, their prognostic value in the clinic has never been addressed. Materials and methods Data on ATB use during surgery, including the cumulative defined daily dose (cDDD) and the number of categories, were collected. Differences in the clinical data between the low and high cDDD subgroups and between subgroups with ≤ 4 and >4 categories. Additionally, the disease-free survival (DFS) and overall survival (OS) among these subgroups and the specific categories were compared. Finally, a Cox proportional hazard model was used to validate the risk factors for the outcome. Results The number of categories, rather than the cDDD, was a significant predictor of both DFS (P = 0.043) and OS (P = 0.039). Patients with obstruction are more likely to have a high cDDD, whereas older patients are more likely to have multiple categories. There were no significant differences in the DFS (log rank = 1.36, P = 0.244) or OS (log rank = 0.40, P = 0.528) between patients in the low- and high-cDDD subgroups, whereas patients with ≤ 4 categories had superior DFS (log rank = 9.92, P = 0.002) and OS (log rank = 8.30, P = 0.004) compared with those with >4 categories. Specifically, the use of quinolones was harmful to survival (DFS: log rank = 3.67, P = 0.055; OS: log rank = 5.10, P = 0.024), whereas the use of macrolides was beneficial to survival (DFS: log rank = 12.26, P

This study presents two cases of type II mixed cryoglobulinemia. One case is essential, while the other is presumably associated with hepatitis B virus (HBV) infection. Both patients tested positive for monoclonal IgMκ, but negative for MyD88 mutation. They showed resistance to rituximab combined with a glucosteroid regimen, but responded positively to BTK inhibitors. These cases highlight the remarkable effectiveness of BTK inhibitors in treating refractory type II cryoglobulinemia without MyD88 mutation. The first patient achieved rapid complete remission of nephrotic syndrome within one month of starting ibrutinib, along with a significant reduction in cryoglobulin levels and abnormal clonal cells. The second patient had a rapid disappearance of rash within three days and accelerated wound healing within one week of initiating orelabrutinib, accompanied by a reduction in C-reactive protein. However, there was no reduction in cryoglobulin levels during the 12-month follow-up. These findings suggest varied mechanisms of action of BTK inhibitors in type II cryoglobulinemia through different mechanisms.

Abstract Background Brain microglia and macrophages (Mi/MΦ) can shift to a harmful or advantageous phenotype following an ischemic stroke. Identification of key molecules that regulate the transformation of resting Mi/MΦ could aid in the development of innovative therapies for ischemic stroke. The transcription factor signal transducer and activator of transduction 1 (STAT1) has been found to contribute to acute neuronal death (in the first 24 h) following ischemic stroke, but its effects on Mi/MΦ and influence on long-term stroke outcomes have yet to be determined. Methods We generated mice with tamoxifen-induced, Mi/MΦ-specific knockout (mKO) of STAT1 driven by Cx3cr1CreER. Expression of STAT1 was examined in the brain by flow cytometry and RNA sequencing after ischemic stroke induced by transient middle cerebral artery occlusion (MCAO). The impact of STAT1 mKO on neuronal cell death, Mi/MΦ phenotype, and brain inflammation profiles were examined 3–5 days after MCAO. Neurological deficits and the integrity of gray and white matter were assessed for 5 weeks after MCAO by various neurobehavioral tests and immunohistochemistry. Results STAT1 was activated in Mi/MΦ at the subacute stage (3 days) after MCAO. Selective deletion of STAT1 in Mi/MΦ did not alter neuronal cell death or infarct size at 24 h after MCAO, but attenuated Mi/MΦ release of high mobility group box 1 and increased arginase 1-producing Mi/MΦ 3d after MCAO, suggesting boosted inflammation-resolving responses of Mi/MΦ. As a result, STAT1 mKO mice had mitigated brain inflammation at the subacute stage after MCAO and less white matter injury in the long term. Importantly, STAT1 mKO was sufficient to improve functional recovery for at least 5 weeks after MCAO in both male and female mice. Conclusions Mi/MΦ-targeted STAT1 KO does not provide immediate neuroprotection but augments inflammation-resolving actions of Mi/MΦ, thereby facilitating long-term functional recovery after stroke. STAT1 is, therefore, a promising therapeutic target to harness beneficial Mi/MΦ responses and improve long-term outcomes after ischemic stroke.

Abstract The Tibetan Plateau (TP) is one of the most climate-sensitive regions around the world. Aerosols imported from adjacent regions reach their peak during the pre-monsoon season and play a vital role in the TP environment. However, the strong interannual variation in aerosols transported to the TP has not been fully understood. Here, we show that the interannual variability of pre-monsoon aerosols transported to the TP is influenced more by rainfall over the southern Himalayas than near-surface wind. Rainfall modulates fire events and biomass burning emissions and reduces aerosols over the TP by wet scavenging. Contrary to the role of wind in increasing aerosol transport, the positive correlation between wind and aerosols in the TP reported in previous studies is contributed by the negative interannual correlations between wind and rainfall and between rainfall and fire events over the southern Himalayas. This study highlights the co-variability of wind and rainfall and their confounding impacts on aerosols in the southern Himalayas and over the TP. With pre-monsoon rainfall projected to increase in adjacent regions of southern TP, aerosol transport to the TP may be mitigated in the future.

Abstract In this study, a global variable‐resolution modeling framework of atmospheric dust and its radiative feedback is established and evaluated. In this model, atmospheric dust is simulated simultaneously with meteorological fields, and dust‐radiation interactions are included. Five configurations of global mesh with refinement at different resolutions and over different regions are used to explore the impacts of regional refinement on modeling dust lifecycle at regional and global scales. The model reasonably produces the overall magnitudes and spatial variabilities of global dust metrics such as surface mass concentration, deposition, aerosol optical depth, and radiative forcing compared to observations and previous modeling results. Two global variable‐resolution simulations with mesh refinement over major deserts of North Africa (V16 km‐NA) and East Asia (V16 km‐EA) simulate less dust emissions and smaller dry deposition rates inside the refined regions due to the weakened near‐surface wind speed caused by better resolved topographic complexity at higher resolution. The dust mass loadings over North Africa are close to each other between V16 km‐NA and the quasi‐uniform resolution (∼120 km) (U120 km), while over East Asia, V16 km‐EA simulates higher dust mass loading. Over the non‐refined areas with the same resolution, the difference between global variable‐resolution and uniform‐resolution experiments also exists, which is partly related to their difference in dynamic time‐step and the coefficient for horizontal diffusion. Refinement at convection‐permitting resolution around the Tibetan Plateau (TP) simulates less dust due to its more efficient wet scavenging from resolved convective precipitation around the TP against coarse resolution.

Abstract Accumulating evidence indicates that the extracellular matrix (ECM) is not only a consequence of fibrosis, but also contributes to the progression of fibrosis, by creating a profibrotic microenvironment. Tenascin-C (TNC) is an ECM glycoprotein that contains multiple functional domains. We showed that following kidney injury, TNC was markedly induced in fibrotic areas in the kidney from both mouse models and humans with kidney diseases. Genetically deletion of TNC in mice significantly attenuated unilateral ureteral obstruction-induced kidney fibrosis. Further studies showed that TNC promoted the proliferation of kidney interstitial cells via STAT3 activation. TNC-expressing cells in fibrotic kidney were activated fibroblast 2 (Act.Fib2) subpopulation, according to a previously generated single nucleus RNA-seq dataset profiling kidney of mouse UUO model at day 14. To identify and characterize TNC-expressing cells, we generated a TNC-promoter-driven CreER2-IRES-eGFP knock-in mouse line and found that the TNC reporter eGFP was markedly induced in cells around injured tubules that had lost epithelial markers, suggesting TNC was induced in response to epithelium injury. Most of the eGFP-positive cells were both NG2 and PDGFRβ positive. These cells did not carry markers of progenitor cells or macrophages. In conclusion, this study provides strong evidence that matrix protein TNC contributes to kidney fibrosis. TNC pathway may serve as a potential therapeutic target for interstitial fibrosis and the progression of chronic kidney disease.

AbstractThe richness and diversity of bacterial community in the fermented pit mud from the new and old distilleries of Shedian Liquor were analysed via the Illumina Miseq PE300 high-throughput sequencing technology, so as to further understand the differences of bacterial community structure in fermented pit muds with different pit ages. The results show that the bacterial community is mainly distributed into five dominant phyla (> 1.0%): Firmicutes, Synergistes, Bacteroidetes, Proteobacteria and Verrucomicrobia. There are 13 dominant genera (> 1.0%), of which Lactobacillus is dominant in both samples with a higher content in the new pit (61.12%) and lower in the old pit (1.15%). Caproiciproducens accounting for 43.53% and Syntrophomonas accounting for 6.20%, norank_f__Family_XIV (17.68%), Aminobacterium (17.68%), Sedimentibacter (1.89%), Caldicoprobacter (1.52%) and Sporanaerobacter (1.29%) are the dominant bacteria in the old pit mud. Bacillus accounting for 6.02%, Bacteroides (6.27%), Akkermansia (1.51%), Hydrogenispora (2.15%) and norank_f__Bacteroidales_S24-7_group (1.15%) are the dominant bacteria in the new pit mud. The results showed that there is a great difference in the bacterial community structure of in the new and old pit mud. In addition, compared with the bacterial community composition in the pit mud of Luzhou flavour Baijiu in Sichuan, it was found that the microorganisms that formed caproic acid and butyric acid were different.

Eucommia ulmoides seed meal protein prepared by alkali extraction and acid precipitation was utilized as raw material. On the basis of single factor experiment, the total evaluation value of the hydrolysis degree and total antioxidant capacity (T-AOC) as response value was used to optimize the addition of enzyme, hydrolysis time and substrate concentration. And the Box-Behnken method was used for three factors and three levels response surface test design to determine the best enzymatic preparation process of hydrolyzed peptides from Eucommia ulmoides seed meal. The antioxidant activity of the obtained hydrolyzed peptides was determined in vitro. The results showed that neutral protease was the best protease, and the best enzymatic hydrolysis condition were enzyme was 10000 U/g, hydrolysis time 1.50 h and substrate concentration 20 g/L. Under these conditions, the degree of hydrolysis and T-AOC of hydrolyzed peptides were 47.45%±1.50% and 30.62±0.59 μmol/g, separately; the IC50 for DPPH free radical, superoxide anion radical and ABTS free radical scavenging rates were 0.731, 4.258 and 0.407 mg/mL, respectively. The Eucommia ulmoides seed meal peptides prepared under these conditions had great antioxidant capacity and provided a theoretical basis for the high-value utilization of Eucommia ulmoides seed meal and the development of antioxidant peptide functional products.

Introduction Isthmin-1 (Ism-1) is a novel adipokine. However, little is known regarding the association between Ism-1 and type 2 diabetes mellitus (T2DM). This study aimed to investigate the relationship between serum Ism-1 levels and glomerular filtration rate (GFR) in patients with T2DM.Research design and methods A total of 209 patients with T2DM were recruited into this retrospective study. Clinical data were collected. Fasting blood samples were collected for serum Ism-1 testing using ELISA kits. Based on the estimated glomerular filtration rate (eGFR), participants were divided into the normal eGFR group (n=167) and the decreased eGFR group (n=42). The relationship between Ism-1 and eGFR was assessed using linear and binary logistic regression analyses. Receiver operating characteristic (ROC) curve analysis was employed to examine the predictive efficacy of Ism-1 for distinguishing patients with eGFR 1.297 ng/mL) had predictive efficacy in patients with eGFR

Abstract Rapid expansion of the probiotics industry demands fast, sensitive, comprehensive, and low‐cost strategies for quality assessment. Here, we introduce a culture‐free, one‐cell‐resolution, phenome‐genome‐combined strategy called Single‐Cell Identification, Viability and Vitality tests, and Source‐tracking (SCIVVS). For each cell directly extracted from the product, the fingerprint region of D2O‐probed single‐cell Raman spectrum (SCRS) enables species‐level identification with 93% accuracy, based on a reference SCRS database from 21 statutory probiotic species, whereas the C–D band accurately quantifies viability, metabolic vitality plus their intercellular heterogeneity. For source‐tracking, single‐cell Raman‐activated Cell Sorting and Sequencing can proceed, producing indexed, precisely one‐cell‐based genome assemblies that can reach ~99.40% genome‐wide coverage. Finally, we validated an integrated SCIVVS workflow with automated SCRS acquisition where the whole process except sequencing takes just 5 h. As it is >20‐fold faster, >10‐time cheaper, vitality‐revealing, heterogeneity‐resolving, and automation‐prone, SCIVVS is a new technological and data framework for quality assessment of live‐cell products.

In 2020 early summer, a historically severe rainy season struck East Asia, causing extensive damage to life and property. Subseasonal forecast of this event challenges the limits of rainy season predictability. Employing the integrated atmospheric model across scales and the Sunway supercomputer, we conducted ensemble one-month forecasts at global 3 km, variable 4–60 km, and global 60 km resolutions. The global convection-permitting forecast accurately captures the rainband, while other forecasts exhibited northward and weaker shifts due to the northward shifts of the atmospheric rivers over Japan, attributed to intensified Western North Pacific Subtropical High (WNPSH). Further, the double-ITCZ-like tropical rainfall pattern in Western Pacific in global convection-permitting forecast contributes to a more accurate WNPSH and rainband. In contrast, other forecasts show a single-ITCZ-like pattern in Western Pacific, leading to a northward-shifted WNPSH and rainband, advocating the importance of accurately representing tropical convections, as they can significantly affect mid-/high-latitude weather and climate.

Abstract. Background:. Carbon monoxide (CO) poisoning remains a major cause of accidental injuries and multiple studies have indicated that CO is also associated with significantly severe or long-term toxicity to the central nervous system. Given that CO poisoning causes serious morbidity and mortality, a better understanding of epidemiological features and clinical characteristics of acute CO poisoning in China is crucial. Methods:. We collected the clinical data of acute CO poisoning in patients between November 2019 and April 2020 across Shandong province, China and analyzed its characteristics focusing on the weekly amount and the severity of the confirmed cases. Results:. A total number of 21,088 acute CO poisoning cases were diagnosed. The overall incidence of acute CO poisoning was approximately 0.021%. On severity rankings, 63% of confirmed cases (n = 13,378) were mild, 27% (n = 5635) were moderate, and 10% (n = 2075) were severe. Interestingly, the coastal cities had more confirmed cases than the inland/suburban areas in Shandong. Meanwhile, the number of confirmed cases was negatively correlated with the local mean daily temperature (P = 0.0167). Conclusions:. Mild acute CO poisoning cases accounted for the majority of all confirmed cases during the winter of 2019. In Shandong province, which is located in east China, residents of the coastal cities are more susceptible to CO poisoning than residents of inland cities.

Abstract Aims Adjuvant chemotherapy (ACT) plays an important role in improving the survival of stage II-III colorectal cancer (CRC) patients after curative surgery. However, the prognostic role of irregular delay of ACT (IDacT) for these patients has been less studied. Materials and methods A total of 117 stage II-III CRC patients who underwent radical resection and received at least 3 months ACT were enrolled retrospectively. The significance of IDacT, including total delay (TD) and delay per cycle (DpC), in predicting disease-free survival (DFS) was determined using receiver operating characteristic curve (ROC) analysis. The survival differences between the TD, DpC-short and DpC-long subgroups were tested using Kaplan–Meier analysis, and risk factors for prognosis were determined using a Cox proportional hazards model. Results Using 35.50 and 3.27 days as the optimal cut-off points for TD and DpC, respectively, ROC analysis revealed that TD and DpC had sensitivities of 43.60% and 59.00% and specificities of 83.30% and 62.80%, respectively, in predicting DFS (both P

To investigate the influence of S. cerevisiae and L. plantarum co-fermentation on the storage characteristics of noodles. Texture analyzer (TA), low field pulsed nuclear magnetic resonance (LF-NMR) and X-ray diffraction (XRD) were used to analyze the quality changes of noodles during storage at 4 ℃. The main research results were as follows: The breakage rate and pH of fermented noodles were lower than these of blank group, there was no significant difference in water absorption rate among different samples(P>0.05), titratable acid (TTA) value increased with fermentation time prolonging. At the same storage time, the hardness and chewiness of the fermented noodles was lower than that of blank group. The cohesiveness decreased with time and was lower than that of blank group after 10~15 days storage. The elasticity first increased and then decreased during the storage duration. Compared with the blank group, the relaxation time of strongly bound water showed a descending trend. After stored at low temperature, the proportion of strongly bound water decreased. The X-ray diffraction pattern illustrated that the relative crystallinity (RC) of the blank group noodles was 16.77% after low temperature storage for 15 days, and the RC value of noodles fermented for 60 min was 12.10%, which was significantly lower than the blank group (P

Abstract Background The prognostic value of intratumor T regulatory cells (Tregs) in colorectal cancer (CRC) was previously reported, but the role of these cells in tumor draining lymph nodes (TDLNs) was less addressed. Methods A total of 150 CRC stages I-IV were retrospectively enrolled. Intratumor and TDLN Tregs were examined by immunohistochemical assay. The association of these cells was estimated by Pearson correlation. Survival analyses of subgroups were conducted by Kaplan–Meier curves, and the log-rank test and risk factors for survival were tested by the Cox proportional hazard model. Results High accumulation of Tregs in tumors was significant in patients with younger age and good histological grade, where enrichment of these cells in TDLNs was more apparent in those with node-negative disease and early TNM stage disease, both of which were more common in early T stage cases. A significant correlation of intratumoral and TDLN Tregs was detected. Patients with higher intratumoral Tregs displayed significantly better PFS and OS than those with lower Tregs. However, no such differences were found, but a similar prognostic prediction trend was found for these cells in TDLNs. Finally, intratumoral Tregs were an independent prognostic factor for both PFS (HR = 0.97, 95% CI 0.95–0.99, P

Abstract Tetrandrine (TET) has been used to treat silicosis in China for decades. The aim of this study was to facilitate rational repurposing of TET against SARS‐CoV‐2 infection. In this study, we confirmed that TET exhibited antiviral potency against SARS‐CoV‐2 in the African green monkey kidney (Vero E6), human hepatocarcinoma (Huh7), and human lung adenocarcinoma epithelial (Calu‐3) cell lines. TET functioned during the early‐entry stage of SARS‐CoV‐2 and impeded intracellular trafficking of the virus from early endosomes to endolysosomes. An in vivo study that used adenovirus (AdV) 5‐human angiotensin‐converting enzyme 2 (hACE2)‐transduced mice showed that although TET did not reduce pulmonary viral load, it significantly alleviated pathological damage in SARS‐CoV‐2‐infected murine lungs. The systemic preclinical pharmacokinetics were investigated based on in vivo and in vitro models, and the route‐dependent biodistribution of TET was explored. TET had a large volume of distribution, which contributed to its high tissue accumulation. Inhaled administration helped TET target the lung and reduced its exposure to other tissues, which mitigated its off‐target toxicity. Based on the available human pharmacokinetic data, it appeared feasible to achieve an unbound TET 90% maximal effective concentration (EC90) in human lungs. This study provides insights into the route‐dependent pulmonary biodistribution of TET associated with its efficacy.

Abstract SHORT syndrome (short stature, hyperextensibility, ocular depression [deeply set eyes], Rieger anomaly and teething delay) is very rare, with a few cases reported in the literature. We report a case of SHORT syndrome with a novel PIK3R1 mutation (c.2008delT) and complicated with severe insulin resistance. Although no treatment guidelines are available to relieve insulin resistance in SHORT syndrome, our treatment plans, including lifestyle intervention combined with metformin and pioglitazone, were carried out for this patient. After the intervention, insulin resistance and hyperinsulinemia in this patient were significantly decreased during a 6‐month follow up, which showed the effect of our therapeutic strategies.

Summary: Diabetic kidney disease (DKD) is the leading cause of end-stage renal diseases. DKD does not have efficacious treatment. The cGAS-STING pathway is activated in podocytes at the early stage of kidney dysfunction, which is associated with the activation of STING downstream effectors TBK1 and NF-κB but not IRF3. Lipotoxicity induces mitochondrial damage and mtDNA leakage to the cytosol through Bcl-2 associated X protein (BAX) in podocytes. BAX-mediated mtDNA cytosolic leakage can activate the cGAS-STING pathway in the absence of lipotoxicity and is sufficient to cause podocyte injury. Depletion of cytosolic mtDNA, genetic STING knockdown, or pharmacological inhibition of STING or TBK1 alleviates podocyte injury and improves renal functions in cultured podocytes or mouse models of diabetes and obesity. These results suggest that the mtDNA-cGAS-STING pathway promotes podocyte injury and is a potential therapeutic target for DKD or other obesity-related kidney diseases.

Introduction Isthmin-1 (Ism-1), as a novel adipokine, plays a role in glucose homeostasis and lipid metabolism. However, the relationship between Ism-1 and type 2 diabetes mellitus (T2DM) remains unclear. This study aims to investigate the association of serum Ism-1 levels with albuminuria and insulin resistance in patients with T2DM and preserved renal function.Research design and methods A total of 150 patients with T2DM were recruited. The presence of albuminuria was evaluated by urinary albumin:creatinine ratio (UACR) in first morning urine sample. Serum Ism-1 levels were tested by ELISA. Homeostasis model assessments were used to evaluate insulin resistance. Binary logistic regression and multivariable linear regression analyses were used to assess the association of serum Ism-1 levels with albuminuria. Multivariable linear regression analyses were performed to explore the correlation of serum Ism-1 levels with insulin resistance.Results Compared with the normal-albuminuria and microalbuminuria groups, serum Ism-1 levels were significantly higher in the macroalbuminuria group (p

Severe fever with thrombocytopenia syndrome (SFTS) caused by a novel bunyavirus (SFTSV) is an emerging infectious disease with up to 30% case fatality. Currently, there are no specific antiviral drugs or vaccines for SFTS. Here, we constructed a reporter SFTSV in which the virulent factor nonstructural protein (NSs) was replaced by eGFP for drug screening. First, we developed a reverse genetics system based on the SFTSV HBMC5 strain. Then, the reporter virus SFTSV-delNSs-eGFP was constructed, rescued, and characterized in vitro. SFTSV-delNSs-eGFP showed similar growth kinetics with the wild-type virus in Vero cells. We further detected the antiviral efficacy of favipiravir and chloroquine against wild-type and recombinant SFTSV by the quantification of viral RNA, and compared the results with that of fluorescent assay using high-content screening. The results showed that SFTSV-delNSs-eGFP could be used as a reporter virus for antiviral drug screening in vitro. In addition, we analyzed the pathogenesis of SFTSV-delNSs-eGFP in interferon receptor-deficient (IFNAR−/−) C57BL/6J mice and found that unlike the fatal infection of the wild-type virus, no obvious pathological change or viral replication were observed in SFTSV-delNSs-eGFP-infected mice. Taken together, the green fluorescence and attenuated pathogenicity make SFTSV-delNSs-eGFP a potent tool for the future high-throughput screening of antiviral drugs.

Myricaria elegans, an endemic species to the Himalayas, is a distinctive deciduous shrubbery plant-primarily distributed in the Qinghai-Tibet Plateau and adjacent regions in China. It is a kind of fuelwood, medicinal, and ecology-protecting woody plant species. In this study, the whole chloroplast (cp) genome sequence of M. elegans was assembled and characterized by high-throughput sequencing data. The complete cp genome of M. elegans was 155,245 bp in length with a GC content of 37.4%. It contained a large single-copy region (LSC) of 84,846 bp, and a small single-copy region (SSC) of 18,290 bp, which were separated by a pair of 26,053 bp inverted repeat regions (IRs). The cp genome of M. elegans was composed of 130 genes, including 85 protein-coding genes, 37 transfer RNA (tRNA) genes, and eight ribosomal RNA (rRNA) genes. Phylogenetic analysis revealed that M. elegans formed a clade with Myricaria, and it showed a close relationship with Myricaria prostrata.

AimTransanal endoscopic microsurgery (TEM) is widely performed in early rectal cancer. This technique offers greater organ preservation and decreases the risk of subsequent surgery. However, postoperative local recurrence and distant metastasis remain challenges for patients with high-risk pathological factors. This single-center study reports the prognosis of early rectal cancer patients over 60 years old after TEM.MethodsThe data of the patients over 60 years old who underwent local anal resection were collected retrospectively. Moreover, the 5-year follow-up data were analyzed to determine the 5-year DFS and OS.Results47 early rectal cancer patients over 60 years old underwent TEM. There were 27 patients with high-risk factors and 20 patients without high-risk factors. Two patients underwent radical surgery after TEM and ten patients received adjuvant treatment. Local recurrence occurred in 7 patients, of which 4 underwent salvage surgery. The 5-year progression-free survival rate was 75.6%, which was lower in the high-risk patients group (69.6%) than in the non-high-risk patients group (83.3%) (P>0.05). The 5-year OS was 90.2%, but there was no statistically significant difference between the two groups (high-risk patients 87.0%, non-high-risk patients 94.4%). Furthermore, there was no significant difference in DFS and OS between people over and under 70 years old.ConclusionSome high-risk factor patients over 60 years old do not have inferior 5-year DFS and OS to the non-high-risk patients. TEM is an option for old patients with high surgical risks. Even if postoperative pathology revealed high-risk factors, timely surgical treatment after local recurrence would be beneficial to improve the 5-year DFS and OS.

BackgroundEarly diagnosis and effective intervention are the keys to delaying the progression of Alzheimer’s Disease (AD). Therefore, we aimed to identify new biomarkers for the early diagnosis of AD through bioinformatic analysis and elucidate the possible underlying mechanisms.Methods and ResultsGSE1297, GSE63063, and GSE110226 datasets from the GEO database were used to screen the highly differentially expressed genes. We identified a potential biomarker, Platelet activating factor receptor (PTAFR), significantly upregulated in the brain tissue, peripheral blood, and cerebrospinal fluid of AD patients. Furthermore, PTAFR levels in the plasma and brain tissues of APP/PS1 mice were significantly elevated. Simultaneously, PTAFR could mediate the inflammatory responses to exaggerate the microenvironment, particularly mediated by the microglia through the IL10-STAT3 pathway. In addition, PTAFR was a putative target of anti-AD compounds, including EGCG, donepezil, curcumin, memantine, and Huperzine A.ConclusionPTAFR was a potential biomarker for early AD diagnosis and treatment which correlated with the microglia-mediated microenvironment. It is an important putative target for the development of a novel strategy for clinical treatment and drug discovery for AD.

Objective(s): Endometritis is the inflammation of the uterine lining that is associated with infertility. It affects milk production and reproductive performance and leads to huge economic losses in dairy cows. Dimethyl itaconate (DI), a promising chemical agent, has recently been proved to have multiple health-promoting effects. However, the effects of DI on endometritis remain to be unknown. Materials and Methods: In this study, we assessed the anti-inflammatory effects of DI on Lipopolysaccharide (LPS)-induced endometritis in mice. The endometritis was induced by LPS treatment for 24 hr, and DI was given 24 hr before induction of LPS.Results: As a result, DI administered mice significantly suffered less impairment of uterine tissue and less recruitment of inflammatory cells than LPS administered mice. In addition, DI markedly inhibited uterine myeloperoxidase (MPO) activity and pro-inflammatory cytokines of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) induced by LPS. Moreover, LPS-induced toll-like receptor 4/ nuclear factor-kappa B (TLR4/NF-κB) activation was suppressed by DI. In addition, the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase (HO-1) were upregulated by DI.Conclusion: These findings suggest that DI has anti-inflammatory functions in the LPS-induced mice and may be a therapeutic agent against endometritis.

Background: Preoperative serum albumin (ALB) and carcinoembryonic antigen (CEA) were useful prognostic factors in colorectal cancer (CRC); however, the ALB to CEA ratio (ACR) and their individual prognostic efficacies have been less studied. Methods: A retrospective study with 156 CRC patients staged I to IV was performed. The prognostic efficacy of ACR was estimated and subsequently compared with ALB, CEA, and other systemic inflammation markers, including the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR). Differences in progression-free survival (PFS) and overall survival (OS) were determined by Kaplan–Meier (K-M) analysis, and the risk factors for survival were calculated by the Cox proportional hazards model. Results: A total of 31.41% (49 of 156) of patients presented with ACR-low disease, and these patients had tumors with advanced T stages, larger tumor diameters and distant metastases, and a lower LMR. When 5.98 was used as the cut-off point, it had a sensitivity of 58.50% and 61.50% and a specificity of 83.50% and 80.50% for PFS and OS, respectively. ACR displayed a superior prognostic efficacy than individual ALB, CEA and NLR, LMR, and PLR for both PFS and OS (except LMR). Patients in the ACR-low group displayed significantly worse PFS and OS than those in the ACR-high group. Finally, ACR was an independent prognostic factor for both PFS (HR = 0.31, 95% CI: 0.17−0.56, P

An unprecedented heavy rainfall event occurred in Henan Province of central China during 19–20 July 2021 with the maximum hourly rainfall rate of 201.9 mm, which broke the historical record in mainland China. To investigate the impacts of predicted atmospheric circulation on the regional convection-permitting prediction of this event, two sets of nested experiments with different convective parameterizations (GF and MSKF) in the outer domain and at convection-permitting resolution in the inner domain are performed with the Weather Research and Forecasting (WRF) model. The analysis found the prediction of ‘21.7’ rainstorm at convection-permitting resolution in the inner domain is largely affected by convective scheme in the outer domain. The atmospheric circulation forcing from the outer domain with different convective schemes is significantly different, which ultimately affects the regional synoptic pattern and precipitation in the refined region through lateral boundary forcing. The difference in regional prediction at convection-permitting resolution can be mitigated by adjusting convective latent heat parameterization in the outer domain. This work highlights that appropriately parameterizing convective latent heat is the key to provide reasonable large-scale forcing for regionally predicting this catastrophic heavy rainfall event at convection-permitting resolution, which may also be applicable to other events and other regions.

White matter injury is a crucial component of human stroke, but it has often been neglected in preclinical studies. Most human stroke is associated with one or more comorbidities, including aging, hypertension, diabetes and metabolic syndrome including hyperlipidemia. The purpose of this review is to examine how age and hypertension impact stroke-induced white matter injury as well as white matter repair in both human stroke and preclinical models. It is essential that comorbidities be examined in preclinical trials as they may impact translatability to the clinic. In addition, understanding how comorbidities impact white matter injury and repair may provide new therapeutic opportunities for patients with those conditions.

In this experiment, a Sn35Bi0.3Ag–xIn (x = 0, 0.5, 1.0, 1.5) alloy solder was prepared by electromagnetic induction heating furnace. The effects of In on the thermodynamic properties, wettability, interface microstructure, and soldering performance of Sn35Bi0.3Ag–xIn/Cu solder joints were studied by a synchrotron thermal analyzer (DSC), contact-angle measuring instrument, scanning electron microscope (SEM), energy dispersive spectrometer (EDS), and universal tensile testing machine. The research showed that adding a small amount of In reduced the solid–liquid temperature and improved the wettability of the alloy solder. At the interface of SnBiAg–xIn/Cu joint, it was found that In atoms replaced part of Sn atoms, forming the Cu6 (Sn, In)5 phase and scallop-like Cu3 (Sn, In) phase. When adding 0.5% and 1.0% In elements, it was found that the Bi phase appeared on the solder side of the interface layer, which hindered the growth of the intermetallic compound (IMC) and reduced the thickness of the IMC layer. Among them, the thickness of the IMC layer of the SnBiAg–1.0In/Cu joint was the smallest, and the shear strength was the highest, which was 55.1 MPa. In addition, the fracture morphology of the solder joint was observed, and it was found that the fracture mode was brittle fracture, and the SnBiAg–xIn/Cu solder joint fractured from the IMC and solder side.

Aim To develop an autophagy-gene-based signature that could help to anticipate the therapeutic effects of Colorectal Cancer (CRC). Methods We downloaded the gene expression profiles of CRC samples from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets. Genes with significant prognostic value in CRC were screened through univariate Cox regression analysis, while the LASSO Cox regression method was applied to screen optimal genes to construct the autophagy‐related prognostic signature. Results 11 autophagy genes were identified and selected for the establishment of prognosis prediction model for CRC patients. The CRC patients were classified into the low- and high-risk groups according to the optimal cutoff value. The time-dependent ROC curves indicated the good performance of this model in prognosis prediction, with AUC values of 0.66, 0.66, and 0.67 at 1, 3 and 5 years for TCGA samples, as well as AUC values of 0.63, 0.65 and 0.64 for GEO samples, respectively. The multivariate Cox regression analysis results confirmed risk score as the independent marker for prognosis prediction in CRC. Besides, the constructed nomogram also had high predictive value. The results analysis on the tumor infiltrating immune cells (TIICs) relative ratios and mRNA levels of key immune checkpoint receptors indicated the signature was closely related to immune microenvironment of CRC in the context of TIICs and immune checkpoint receptors’ mRNA level. The proportion of MSI-L + MSI-H in the high-risk group was higher than that in the low-risk group. Moreover, the tumor purity was evaluated by estimate function package suggested that lower tumor purity in CRC might lead to a poorer prognosis. Conclusion The autophagy-related features obtained in this study were able to divide the CRC patients into low- and high-risk groups, which should be contribute to the decision-making of CRC treatment.

The models of time-varying network have a profound impact on the study of virus spreading on the networks. On the basis of an activity-driven memory evolution model, a time-varying spatial memory model (TSM) is proposed. In the TSM model, the cumulative number of connections between nodes is recorded, and the spatiality of nodes is considered at the same time. Therefore, the active nodes tend to connect the nodes with high intimacy and close proximity. Then, the TSM model is applied to epidemic spreading, and the epidemic spreading on different models is compared. To verify the universality of the TSM model, this model is also applied to rumor spreading, and it is proved that it can also play a good inhibiting effect. We find that, in the TSM network, the introduction of spatiality and memory can slow down the propagation speed and narrow the propagation scope of disease or rumor, and memory is more important. We then explore the impact of different prevention and control methods on pandemic spreading to provide reference for COVID-19 management control and find when the activity of node is restricted, the spreading will be controlled. As floating population has been acknowledged as a key parameter that affects the situation of COVID-19 after work resumption, the factor of population mobility is introduced to calculate the interregional population interaction rate, and the time-varying interregional epidemic model is established. Finally, our results of infectious disease parameters based on daily cases are in good agreement with the real data, and the effectiveness of different control measures is evaluated.

Summary: Although adult neurogenesis recapitulates processes that occur during embryonic development, it exhibits distinct characteristics from the embryonic counterpart. However, the intrinsic mechanism underlying the differential regulation of neurogenesis between these two stages remains unclear. Herein, we show that the ablation of RNA-binding protein HuR in NSCs impairs adult but not embryonic neurogenesis. HuR is predominantly expressed in the cytoplasm of embryonic NSCs but translocates into the nucleus of adult NSCs. Transcriptomic analysis of HuR-deficient adult NSCs revealed that HuR primarily regulates alternative splicing of numerous premRNA transcripts, including focal adhesion kinase (FAK). HuR-deficient adult NSCs generate increased FAK mRNA isoforms with shorter 5′-UTRs, leading to enhanced FAK mRNA translation and hyperactivated FAK signaling, and inhibition of FAK ameliorates defective adult neurogenesis and impaired hippocampus-dependent learning in HuR-deficient mice. These findings provide mechanistic insights into the differential regulation of embryonic and adult neurogenesis through developmental cytoplasmic-to-nuclear translocation of HuR. : Wang et al. demonstrate that developmental cytoplasmic-to-nuclear translocation of RNA-binding protein HuR is essential for adult neurogenesis. Nuclear HuR regulates adult neurogenesis through modulating the FAK premRNA splicing switch.

Plant host defense peptides (HDPs), also known as antimicrobial peptides (AMPs), are regarded as one of the most prevalent barriers elaborated by plants to combat various infective agents. Among the multiple classes of HDPs, the Snakin class attracts special concern, as they carry 12 cysteine residues, being the foremost cysteine-rich peptides of the plant HDPs. Also, their cysteines are present at very highly conserved positions and arranged in an extremely similar way among different members. Like other plant HDPs, Snakins have been shown to exhibit strong antifungal and antibacterial activity against a wide range of plant pathogens. Moreover, they display diversified biological activities in many aspects of plant growth and the development process. This review is devoted to present the general characters of the Snakin class of plant HDPs, as well as the individual features of different Snakin family members. Specifically, the sequence properties, spatial structures, distributions, expression patterns and biological activities of Snakins are described. In addition, further detailed classification of the Snakin family members, along with their possible mode of action and potential applications in the field of agronomy and pathology are discussed.

To establish the most convenient and effective method to dry tangerine peels, different methods (sun drying, hot-air drying, freeze drying, vacuum drying, and medium- and short-wave infrared drying) were exploited. Our results indicated that medium- and short-wave infrared drying was the best method to preserve nutraceutical components; for example, vitamin C was raised to 6.77 mg/g (D.W.) from 3.39 mg/g (sun drying). Moreover, the drying time can be shortened above 96% compared with sun drying. Importantly, the efficiency of DPPH radical scavenging was enhanced from 26.66% to 55.92%. These findings would provide a reliable and time-saving methodology to produce high-quality dried tangerine peels.

Xiaoyao Powder (XYP), a common Chinese medicine, comprises eight traditional Chinese herbs and has been widely used clinically to treat liver damage and mental disorders. An ultra-performance liquid chromatography–tandem mass spectrometry method was developed to investigate the pharmacokinetics of 14 compounds (albiflorin, paeoniflorin, ferulic acid, senkyunolide I, quercetin, isoliquiritigenin, atractylenolide III, ligustilide, atractylenolide II, liquiritin, liquiritigenin, saikosaponin c, glycyrrhizic acid, and saikosaponin a) in XYP. Naringenin was used as the internal standard. The compounds were separated using an ACQUITY UPLCTM BEH C18 column (1.7 μm, 50 × 2.1 mm) with a mobile phase consisting of acetonitrile and 0.1% formic acid in water at a flow rate of 0.3 mL/min. Detection was performed on a triple-quadrupole tandem mass spectrometer using multiple reaction monitoring and an electrospray ionization source in both positive and negative ionization modes. All calibration curves exhibited good linearity (r2 > 0.9974) over the measured ranges. The intra- and inter-day precisions were within 12%, and the accuracy ranged from 89.93% to 106.64%. Extraction recovery and matrix effect results were satisfactory. The method was successfully applied in a pharmacokinetic study of the 14 compounds in rat plasma after the oral administration of XYP.

Waterlogging tolerance is typically evaluated at a specific development stage, with an implicit assumption that differences in waterlogging tolerance expressed in these systems will result in improved yield performance in fields. It is necessary to examine these criteria in fields. In the present study, three experiments were conducted to screen waterlogging tolerance in 25 rapeseed (Brassica napus L.) varieties at different developmental stages, such as seedling establishment stage and seedling stage at controlled environment, and maturity stage in the fields. The assessments for physiological parameters at three growth stages suggest that there were difference of waterlogging tolerance at all the development stages, providing an important basis for further development of breeding more tolerant materials. The results indicated that flash waterlogging restricts plant growth and growth is still restored after removal of the stress. Correlation analysis between waterlogging tolerance coefficient (WTC) of yield and other traits revealed that there was consistency in waterlogging tolerance of the genotypes until maturity, and good tolerance at seedling establishment stage and seedling stage can guarantee tolerance in later stages. The waterlogging-tolerant plants could be selected using some specific traits at any stage, and selections would be more effective at the seedling establishment stage. Thus, our study provides a method for screening waterlogging tolerance, which would enable the suitable basis for initial selection of a large number of germplasm or breeding populations for waterlogging tolerance and help for verifying their potential utility in crop-improvement.

In the digital era, with the development and reform of artificial intelligence and judicial systems, AI technology has gradually become involved in and assisting judicial trials. AI-assisted judicial trials is a new trial methodology based on digital technologies such as big data, the Internet of Things, and cloud computing. This methodology can fully leverage AI's ability to ensure judicial fairness and improve judicial efficiency in the field of judicial trials. In China, artificial intelligence, as an emerging technology, has become widespread in assisting judicial trials in the current digital era. The state provides policy guidance, while local judicial authorities innovate many convenient and efficient trial systems using artificial intelligence technology. However, the application of artificial intelligence technology still faces challenges, such as its own limitations, the lack of intelligent judicial talent, and insufficient depth and breadth of application scenarios. In the digital era, legal education should be deeply integrated with AI-assisted adjudication, and in the process of integration, measures such as improving data governance, broadening the scope of application, and strengthening the talent development for intelligent legal governance can be taken. [ABSTRACT FROM AUTHOR]