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ABSTRACTAnimal models of COVID-19 facilitate the development of vaccines and antivirals against SARS-CoV-2. The efficacy of antivirals or vaccines may differ in different animal models with varied degrees of disease. Here, we introduce a mouse model expressing human angiotensin-converting enzyme 2 (ACE2). In this model, ACE2 with the human cytokeratin 18 promoter was knocked into the Hipp11 locus of C57BL/6J mouse by CRISPR – Cas9 (K18-hACE2 KI). Upon intranasal inoculation with high (3 × 105 PFU) or low (2.5 × 102 PFU) dose of SARS-CoV-2 wildtype (WT), Delta, Omicron BA.1, or Omicron BA.2 variants, all mice showed obvious infection symptoms, including weight loss, high viral loads in the lung, and interstitial pneumonia. 100% lethality was observed in K18-hACE2 KI mice infected by variants with a delay of endpoint for Delta and BA.1, and a significantly attenuated pathogenicity was observed for BA.2. The pneumonia of infected mice was accompanied by the infiltration of neutrophils and pulmonary fibrosis in the lung. Compared with K18-hACE2 Tg mice and HFH4-hACE2 Tg mice, K18-hACE2 KI mice are more susceptible to SARS-CoV-2. In the antivirals test, REGN10933 and Remdesivir had limited antiviral efficacies in K18-hACE2 KI mice upon the challenge of SARS-CoV-2 infections, while Nirmatrelvir, monoclonal antibody 4G4, and mRNA vaccines potently protected the mice from death. Our results suggest that the K18-hACE2 KI mouse model is lethal and stable for SARS-CoV-2 infection, and is practicable and stringent to antiviral development.

Abstract Previous studies through targeted mutagenesis of K-D-K-E motif have demonstrated that 2′-O-MTase activity is essential for efficient viral replication and immune evasion. However, the K-D-K-E catalytic motif of 2′-O-MTase is highly conserved across numerous viruses, including flaviviruses, vaccinia viruses, coronaviruses, and extends even to mammals. Here, we observed a stronger 2′-O-MTase activity in SARS-CoV-2 compared to SARS-CoV, despite the presence of a consistently active catalytic center. We further identified critical residues (Leu-36, Asn-138 and Ile-153) which served as determinants of discrepancy in 2′-O-MTase activity between SARS-CoV-2 and SARS-CoV. These residues significantly enhanced the RNA binding affinity of 2′-O-MTase and boosted its versatility toward RNA substrates. Of interest, a triple substitution (Leu36 → Ile36, Asn138 → His138, Ile153 → Leu153, from SARS-CoV-2 to SARS-CoV) within nsp16 resulted in a proportional reduction in viral 2′-O-methylation and impaired viral replication. Furthermore, it led to a significant upregulation of type I interferon (IFN-I) and proinflammatory cytokines both in vitro and vivo, relying on the cooperative sensing of melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2). In conclusion, our findings demonstrated that alterations in residues other than K-D-K-E of 2′-O-MTase may affect viral replication and subsequently influence pathogenesis. Monitoring changes in nsp16 residues is crucial as it may aid in identifying and assessing future alteration in viral pathogenicity resulting from natural mutations occurring in nsp16.

BackgroundMalnutrition has emerged as main side effects of inflammatory bowel disease (IBD) which might also affect the prognosis of IBD. However, whether these associations are causal remains unclear. We aimed to identify the causality of IBD on malnutrition and explore the causal relationship of malnutrition and nutrients intake on IBD by using Mendelian randomization (MR).MethodsSingle nucleotide polymorphisms associated with IBD, malnutrition and nutrients intake were obtained from previous researches of genome-wide association studies (GWAS) (p 0.05). Further analysis showed similar results that nutrients intake had no direct effect on IBD, neither CD or UC.ConclusionOur results indicated that IBD increases the risk of malnutrition, however, malnutrition and nutrients intake might not directly affect the progression of IBD.

Abstract Background Recent studies have demonstrated that APOC1 is associated with cancer progression, exerting cancer-promoting and immune infiltration-promoting effects. Nevertheless, there is currently no report on the presence of APOC1 in ovarian cancer (OV). Method In this study, we conducted data analysis using the GEO and TCGA databases. We conducted a thorough bioinformatics analysis to investigate the function of APOC1 in OV, utilizing various platforms including cBioPortal, STRING, GeneMANIA, LinkedOmics, GSCALite, TIMER, and CellMarker. Additionally, we performed immunohistochemical staining on tissue microarrays and conducted in vitro cellular assays to validate our findings. Result Our findings reveal that APOC1 expression is significantly upregulated in OV compared to normal tissues. Importantly, patients with high APOC1 levels show a significantly poorer prognosis. Furthermore, our study demonstrated that APOC1 exerted a crucial function in promoting the capacity of ovarian cancer cells to proliferate, migrate, and invade. Additionally, we have identified that genes co-expressed with APOC1 are primarily associated with adaptive immune responses. Notably, the levels of APOC1 in OV exhibit a correlation with the presence of M2 Tumor-associated Macrophages (TAMs). Conclusion APOC1 emerges as a promising prognostic biomarker for OV and exhibits a significant association with M2 TAMs in OV.

Streptococcus pneumoniae is an opportunistic pathogen that causes substantial illness and death among children worldwide. The genetic backgrounds of pneumococci that cause infection versus asymptomatic carriage vary substantially. To determine the evolutionary mechanisms of opportunistic pathogenicity, we conducted a genomic surveillance study in China. We collected 783 S. pneumoniae isolates from infected and asymptomatic children. By using a 2-stage genomewide association study process, we compared genomic differences between infection and carriage isolates to address genomic variation associated with pathogenicity. We identified 8 consensus k-mers associated with adherence, antimicrobial resistance, and immune modulation, which were unevenly distributed in the infection isolates. Classification accuracy of the best k-mer predictor for S. pneumoniae infection was good, giving a simple target for predicting pathogenic isolates. Our findings suggest that S. pneumoniae pathogenicity is complex and multifactorial, and we provide genetic evidence for precise targeted interventions.

To solve the problems of poor surface quality and low tool life in conventional machining (CM) of AerMet100 steel, an experimental study was conducted in laser-assisted machining (LAM) of AerMet100 steel. The effects of laser power, cutting speed, feed rate, and depth of cut on the surface roughness of AerMet100 steel were studied based on a single-factor experiment. The degree of influence of each factor on the surface roughness was evaluated by analyses of variance and range in the orthogonal experiment, and the combination of process parameters for the optimal surface roughness was obtained. The order of influence was as follows: laser power > cutting speed > depth of cut > feed rate; the optimal combination of process parameters was laser power 200 W, cutting speed 56.5 m/min, feed rate 0.018 mm/rev, and depth of cut 0.3 mm. Compared to CM, the surface morphology of the workpiece under the optimization of LAM was relatively smooth and flat, the surface roughness Ra was 0.402 μm, which was reduced by 62.11%, the flank wear was reduced from 208.69 μm to 52.17 μm, there were no tipping or notches, and the tool life was significantly improved. The study shows that the LAM of AerMet100 steel has obvious advantages in improving surface quality and reducing tool wear.

Potatoes are widely planted worldwide and are the third most important food crop. Mutation breeding involves the artificial use of various physical and chemical factors to induce plants to produce new genotypes. In this study, we established a potato radiation mutation system and analysed the features of a radiation mutant. The LD50 of the potato callus was 24.8 Gy after linear regression analysis. The radiation mutant 1 (RM1) showed significant dwarfism and strong growth; RM1 plants decreased in height by 31%. The root and leaf fresh weights of the RM1 increased 1.8-fold compared to the wild-type (WT, Chuanyu 10) cultivar. Leaf microstructure results showed that the thicknesses of the upper epidermis and lower epidermis of RM1 plants were greater than those of the WT cultivar. Transcriptome analysis of seeding revealed 1179 upregulated and 1641 downregulated differentially expressed genes (DEGs) in RM1 plants. Further analysis showed that the expression levels of WRKY and MYB transcription factors, CIPK and MAPK protein kinases, ABC transporters, hormones, and ROS pathway genes were altered. These results provide theoretical support for potato breeding research and enrich the functional network of vital breeding-related genes.

Abstract Ovarian cancer (OC) is one of the common malignant tumors that seriously threaten women's health, and there is a lack of clinical prognostic predictors, while m5c and lncRNA have been shown to be predictive of multiple cancers, including OC. Therefore, our goal was to construct a risk model for OC based on m5c-related lncRNA.340 m5c-related lncRNA were identified and a novel risk model of OC ground on nine m5C-related lncRNA was constructed using LASSO-COX regression analysis. Kaplan–Meier analysis showed there was a significant difference in prognosis between risk groups. We established a nomogram which was a good predictor of overall survival. In addition, GSEA was enriched in multiple pathways and immune function analysis suggested that immune infiltration varies depending on the risk group. In vitro experiments show that AC005562.1, a key lncRNA of the risk model, is highly expressed in OC cells and promotes OC cell proliferation. Finally, we further explored the potential biological markers of m5c-related lncRNA in OC with WGCNA analysis and established a ceRNA network. In conclusion,we have developed a reliable m5c-related prediction model and performed systematic validation and exploration of various aspects. These results can be used for the assessment of OC prognosis and the discovery of novel biomarkers.

The BTB/POZ (broad-complex, tramtrack, and bric-a-brac) family of proteins is widespread in plants and animals and plays important roles in growth, development, metabolism, and environmental responses. There are few reports on BTB family genes in potato. In this study, 34 sequences containing conserved BTB domains were obtained from the potato gene database, and the phylogenetic, physical, and chemical properties, gene structure, conserved motif, domain, and chromosomal localization of the potato BTB protein family were analyzed via bioinformatics methods. In addition, we used qRT-PCR to detect 12 selected StBTB genes. The results confirmed that these genes are involved in cold, ABA, salt, hydrogen peroxide (H2O2), drought, and low-nitrogen stress, which is highly important for elucidating BTB family members and studying stress response and tolerance mechanisms. This study provides a theoretical basis for the study of the function and expression of potato BTB and lays a solid foundation for further understanding the molecular mechanism of the potato BTB gene under various environmental stresses.

Chronic hepatitis B virus (HBV) infection is a major cause of liver cirrhosis and liver cancer, despite strong prevention and treatment efforts. The study of the epigenetic modification of HBV has become a research hotspot, including the N6-methyladenosine (m6A) modification of HBV RNA, which plays complex roles in the HBV life cycle. In addition to m6A modification, 5-methylcytosine (m5C) is another major modification of eukaryotic mRNA. In this study, we explored the roles of m5C methyltransferase and demethyltransferase in the HBV life cycle. The results showed that m5C methyltransferase NSUN2 deficiency could negatively regulate the expression of HBV while m5C demethyltransferase TET2 deficiency positively regulates the expression of HBV. Subsequently, we combined both in vitro bisulfite sequencing and high-throughput bisulfite sequencing methods to determine the distribution and stoichiometry of m5C modification in HBV RNA. Two sites: C2017 and C131 with the highest-ranking methylation rates were identified, and mutations at these two sites could lead to the decreased expression and replication of HBV, while the mutation of the "fake" m5C site had no effect. Mechanistically, NSUN2-mediated m5C modification promotes the stability of HBV RNA. In addition, compared with wild-type HepG2-NTCP cells and primary human hepatocytes, the replication level of HBV after NSUN2 knockdown decreased, and the ability of the mutant virus to infect and replicate in wild-type HepG2-NTCP cells and PHHs was substantially impaired. Similar results were found in the experiments using C57BL/6JGpt-Nsun2+/- mice. Interestingly, we also found that HBV expression and core protein promoted the endogenous expression of NSUN2, which implied a positive feedback loop. In summary, our study provides an accurate and high-resolution m5C profile of HBV RNA and reveals that NSUN2-mediated m5C modification of HBV RNA positively regulates HBV replication by maintaining RNA stability.

Single-cell RNA sequencing of cervical cancer reveals four different cancer subtypes and provides information on populations of cancer-associated fibroblasts as well as CD8+ T cell diversity.

Almost all of the wear debris generated during the operation of the machine is suspended in the circulating lubricating oil. The analysis of the wear debris in the lubricating oil can effectively monitor the wear state of the machine and provide early warning of failures. An overview on inductive sensors for measuring wear debris in lubrication is introduced. To begin with, the significance of analyzing the wear debris in lubricating oil is explained and the working principle of the inductive wear sensors is illustrated. Furthermore, the development of inductive wear sensors and the key limitations are summarized. Finally, some rest factors affecting the sensor and the processing method of the induction signal aliasing are discussed, and the future development trend is prospected. It is pointed out that developing high sensitivity wear debris inductive sensors, increasing sensor throughput, and solving the problem of aliasing of detection signals are the following issues that should be further studied in the future.

ABSTRACT Despite the widespread implementation of pneumococcal vaccines, hypervirulent Streptococcus pneumoniae serotype 19A is endemic worldwide. It is still unclear whether specific genetic elements contribute to complex pathogenicity of serotype 19A isolates. We performed a large-scale pan-genome-wide association study (pan-GWAS) of 1,292 serotype 19A isolates sampled from patients with invasive disease and asymptomatic carriers. To address the underlying disease-associated genotypes, a comprehensive analysis using three methods (Scoary, a linear mixed model, and random forest) was performed to compare disease and carriage isolates to identify genes consistently associated with disease phenotype. By using three pan-GWAS methods, we found consensus on statistically significant associations between genotypes and disease phenotypes (disease or carriage), with a subset of 30 consistently significant disease-associated genes. The results of functional annotation revealed that these disease-associated genes had diverse predicted functions, including those that participated in mobile genetic elements, antibiotic resistance, virulence, and cellular metabolism. Our findings suggest the multifactorial pathogenicity nature of this hypervirulent serotype and provide important evidence for the design of novel protein-based vaccines to prevent and control pneumococcal disease. IMPORTANCE It is important to understand the genetic and pathogenic characteristics of S. pneumoniae serotype 19A, which may provide important information for the prevention and treatment of pneumococcal disease. This global large-sample pan-GWAS study has identified a subset of 30 consistently significant disease-associated genes that are involved in mobile genetic elements, antibiotic resistance, virulence, and cellular metabolism. These findings suggest the multifactorial pathogenicity nature of hypervirulent S. pneumoniae serotype 19A isolates and provide implications for the design of novel protein-based vaccines.

Nitrogen is one of the most important elements for improving potato yield. However, excessive application of nitrogenous fertilizer not only produces river and other environmental pollution but also increases agricultural production costs. In recent years, to explain the molecular mechanisms of nitrogen metabolites, some vital genes involved have been reported; however, only limited success has been achieved in potato. Here, we report that the expression of cytosolic glyceraldehyde-3-phosphate dehydrogenase 1 (StGAPC1) is increased under low-nitrogen stress. StGAPC1-overexpressing potato seedlings had more biomass and a significant increase in total nitrogen content and root nitrate influx rate compared to the wild type. The overexpression of StGAPC1 also increased the expression of nitrate transporters and increased ROS system activity to reduce hydrogen peroxide content under low-nitrogen stress. Our results provide a foundation for further research on StGAPC1 function in nitrogen absorption and utilization mechanisms in potato.

Mixing method plays a critical role in the properties of concrete. Vibratory mixing as a novel mixing method has its advantages in improving the properties of concrete. But the specific property of concrete is sensitive to the operation parameters of the vibratory mixing. This paper is motivated to study the effect vibration amplitude and acceleration on the concrete properties and to compare with the conventional mixing at four groups of mix proportions. The macroscopic performance was measured by slump test, compressive strength test, and density test, and the microscopic characteristics was analyzed by scanning electron microscope (SEM). The test results indicates that the slump, compressive strength, and density of the different concrete were both improved using vibratory mixing. Analysis of variance (ANOVA) results showed that vibration amplitude significantly influenced the compressive strengths. At optimum vibration parameters, the slump of M1, M2, M3, M4 was increased by 36%,15% 25%, 26%, separately; the compressive strength increased by 13%, 15%, 35%, 44%; the density was improved by 1.3%, 2%, 1.4%, 1.3%. Concrete with a low w/c ratio (0.33) requires more vibration energy. Moreover, fewer defects and denser structure were observed by vibratory mixing, which benefited to a higher bond strength. Under the same mix proportions, the slump shows a positive relationship with compressive strength by vibratory mixing. The low w/c ratio concrete has the higher change rate of compressive strength with the density.

Abstract Background China was one of the few countries to achieve the Millennium Development Goals 5. China had taken many effective measures to reduce maternal mortality ratio (MMR) and has achieved encouraging progress. These measures were worth sharing for other countries to reduce the MMR, but the introduction of these measures from the national perspective was too grand, and the measures implemented in a city and the results achieved were more valuable. However, there were few studies on the prevalence and trends of prolonged maternal mortality in a city. In this study, we mainly introduced the prevalence of the MMR in Jinan,China from 1991 to 2020, analyzed the causes of trends and put forward some solutions to the difficulty existing in the process of reducing the MMR,hoping to serve as a model for some developing cities to reduce MMR. Methods We collected maternal mortality data from paper records, electronic files and network platforms. The time trend of MMR was tested by Cochran-Armitage Test (CAT). We divided the study period into three stages with 10 years as a stage and the Chi-square test or Fisher’s exact test was used to test the difference in MMR of different periods. Results From 1991 to 2020, We counted 1,804,162 live births and 323 maternal deaths, and the MMR was 17.93 per 100,000 live births. The MMR declined from 44.06 per 100,000 live births in 1991 to 5.94 per 100,000 live births in 2020, with a total decline of 86.52% and an annual decline of 2.89%. The MMR declined by 88.54% in rural areas, with an average annual decline 2.95%, faster than that in urban areas (82.06, 2.73%). From 1991 to 2020, the top five causes of maternal deaths were obstetric haemorrhage (4.55 per 100,000 live births), amniotic fluid embolism (3.27 per 100,000 live births), pregnancy-induced hypertension (2.61 per 100,000 live births), heart disease (2.33 per 100,000 live births) and other medical complications (2.05 per 100,000 live births). Postpartum hemorrhage, amniotic fluid embolism, pregnancy-induced hypertension showed a downward trend (P

Cervical cancer (CC) is one of the most frequent female malignancies worldwide. However, the molecular mechanism of lymph node metastasis in CC remains unclear. In this study, we investigated the transcriptome profile of 51,507 single cells from primary tumors, positive lymph nodes (P-LN), and negative lymph nodes (N-LN) using single-cell sequencing. Validation experiments were performed using bulk transcriptomic datasets and immunohistochemical assays. Our results indicated that epithelial cells in metastatic LN were associated with cell- cycle-related signaling pathways, such as E2F targets, and mitotic spindle, and immune response-related signaling pathways, such as allograft rejection, IL2_STAT5_signaling, and inflammatory response. However, epithelial cells in primary tumors exhibited high enrichment of epithelial-mesenchymal translation (EMT), oxidative phosphorylation, and interferon alpha response. Our analysis then indicated that metastasis LN exhibited an early activated tumor microenvironment (TME) characterized by the decrease of naive T cells and an increase of cytotoxicity CD8 T cells, NK cells, FOXP3+ Treg cells compared with normal LN. By comparing the differently expressed gene of macrophages between tumor and metastatic LN, we discovered that C1QA+ MRC1low macrophages were enriched in a tumor, whereas C1QA+ MRC1high macrophages were enriched in metastatic LN. Finally, we demonstrated that cancer-associated fibroblasts (CAFs) in P-LN were associated with immune regulation, while CAFs in tumor underwent EMT. Our findings offered novel insights into the mechanisms of research, diagnosis, and therapy of CC metastasis.

As of 10 May 2022, at least 450 cases of pediatric patients with acute hepatitis of unknown cause have been reported worldwide. Human adenoviruses (HAdVs) have been detected in at least 74 cases, including the F type HAdV41 in 18 cases, which indicates that adenoviruses may be associated with this mysterious childhood hepatitis, although other infectious agents or environmental factors cannot be excluded. In this review, we provide a brief introduction of the basic features of HAdVs and describe diseases caused by different HAdVs in humans, aiming to help understand the biology and potential risk of HAdVs and cope with the outbreak of acute child hepatitis.

BackgroundAccurately predicting the risk level of lymph node metastasis is essential for the treatment of patients with early cervical cancer. The purpose of this study is to construct a new nomogram based on 2-deoxy-2-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and clinical characteristics to assess early-stage cervical cancer patients’ risk of lymph node metastasis.Materials and MethodsFrom January 2019 to November 2020, the records of 234 patients with stage IA-IIA [International Federation of Gynecology and Obstetrics (FIGO) 2018] cervical cancer who had undergone PET/CT examination within 30 days before surgery were retrospectively reviewed. A nomogram to predict the risk of lymph node metastasis was constructed based on it. The nomogram was developed and validated by internal and external validation. The validation cohorts included 191 cervical cancer patients from December 2020 to October 2021.ResultsFour factors [squamous cell carcinoma associated antigen (SCCA), maximum standardized uptake value of lymph node (nSUVmax), uterine corpus invasion in PET/CT and tumor size in PET/CT] were finally determined as the predictors of the nomogram. At the area under the receiver operating characteristic curve cohort was 0.926 in the primary and was 0.897 in the validation cohort. The calibration curve shows good agreement between the predicted probability and the actual probability. The decision curve analysis showed the clinical utility of the nomogram.ConclusionWe had established and verified a simple and effective nomogram, which can be used to predict the lymph node metastasis of cervical cancer patients before surgery.

BackgroundAlthough congenital heart defect (CHD) was the dominating birth defect, the time trend analysis of CHD was largely unknown. In our study, the time trend analysis of CHD from 2005 to 2020 in Jinan was conducted, aimed to reveal the epidemiological characteristics in a city and provided the data basis for the government to make a policy intervention.MethodsA multi-institutional and retrospective review of CHD for all births from January 1, 2005 to December 31, 2020 was performed. Proportioner prevalence was used to describe the distribution of CHD. Comparisons of CHD characteristics among different groups were assessed with Chi-squares tests. Cochran-Armitage tests (CAT) were used to track changes in CHD prevalence.ResultsAbout 322,374 births and 5,180 CHD in Jinan were included from 2005 to 2020, and the total CHD prevalence was 3.92 per 1,000 births. The CHD prevalence showed an upward trend, with a total increase of 227.66% from 2005 to 2020. The CHD prevalence in urban areas was 34.17% higher than that in rural areas, but the gap was narrowing. Atrial septal defect (3.07 per 1,000 births), patent ductus arteriosus (1.62 per 1,000 births), ventricular septal defect (1.18 per 1,000 births), tetralogy of Fallot (0.62 per 1,000 births), and atrioventricular septal defect (0.47 per 1,000 births) were the 5 most common subtypes.ConclusionThe prevalence of CHD in Jinan was gradually on the rise, which needs to be highly focused on by the health management department. Older pregnant women and women in rural areas should be concerned, and targeted measures need to be introduced.

Abstract Background Genetic biomarkers of lung cancer (LC) susceptibility may provide a basis for treatment and prevention. This study analyzed an association between SNPs (single nucleotide polymorphisms) in the complementary region of the 3′-UTR (3′ untranslated region) of microRNAs of the gene RIPK1 (receptor-interacting serine/threonine-protein kinase 1) and LC among an adult Han Chinese population aged younger than 60 years. Also explored the effect of regulation of the RIPK1 gene via rs17548629 and microRNA-1197 on the occurrence of LC. Methods RIPK1 variants (rs17548629, rs77736895) were determined in a population of 571 adults (younger than 60 years) with LC, and 609 gender- and age-matched healthy individuals. Bioinformatics methods predicted the microRNAs bound to rs17548629. Dual luciferase reporter assay was performed to confirm the presence of both rs17548629 and the predicted microRNA. Results A mutation (T) of rs17548629 was associated with an increased risk for LC in this population under the codominant and recessive genetic models. The risk of lung adenocarcinoma in rs17548629 mutant carriers was 1.769-fold higher than that of the wildtype. In vitro, the luciferase activity of co-transfected mutant psiCHECK2-RIPK1 and microRNA-1197 mimics was less than that of the group transfected with microRNA-1197 mimics only. Factorial analysis indicated interactions between microRNA-1197 mimics and genotypes of rs17548629. Conclusion A mutation (T) of rs17548629 may increase the risk of LC/lung adenocarcinoma in adult Han populations younger than 60 years. When carrying the T allele, rs17548629 may be the target of hsa-miR-1197. This mutation may affect transcriptional level of the RIPK1, thereby promoting the occurrence of LC.

Objective: Radical hysterectomy (RH) is the surgical standard for the treatment of the early-stage cervical cancer (CC). However, this procedure is associated with a high rate of adverse impact on the quality of the life of the patient. Since the rate of parametrial involvement (PI) is low for the patients with the early-stage CC, some authors believe that the patients with the early-stage CC may benefit from the less radical surgery. This study aims to estimate the incidence of the PI in the patients with the early-stage CC and establish a simple nomogram to identify a cohort of the patients with low risk of the PI who may benefit from the less radical surgery.Methods: All the patients who underwent the RH and pelvic lymphadenectomy were included from 2013 to 2018. The significant independent predictors were identified through the Cox regression analysis and then incorporated into a nomogram to predicate the PI. The calibration plots and receiver operating characteristic (ROC) curves were used to assess the predictive accuracy of the nomogram.Results: A total of 4,533 patients met the inclusion criteria and 441 women (9.7%) had the PI. The positive PI rate in the ≤2 cm group (1.2%) was significantly lower compared to >2– ≤4 cm (6.2%) or >4 cm (22.4%) groups. The multivariate analyses revealed that tumor size (p = 0.002), lymphovascular space invasion (LVSI) (p = 0.001), vaginal involvement (VI) (p < 0.001), status of the pelvic lymph nodes (PLNs) (p = 0.001), and depth of stromal invasion (DSI) (p < 0.001) were the independent prognostic factors of the PI. Finally, the five variables were combined to construct the nomogram model. The concordance indexes (C-indexes) of the PI were 0.756 (95% CI 0.726–0.786) for the internal validation and 0.729 (95% CI 0.678–0.780) for the external validation. The calibration plots further showed good consistency between the nomogram prediction and the actual observation.Conclusion: This study confirmed that the patients with tumor size 2 cm or smaller were at very low risk for the PI. If other variables such as negative LVSI, DSI

Cultivated barley (Hordeum vulgare L.) has been proven to be an economically important model plant and having large genetic diversity among the species. The effective exploitation of qualitative characters in barley can be measured by its genetic diversity and interrelationship. This study aims to determine the assessment of genetic diversity in Chinese hulless barley accessions for qualitative traits. Presently, in this study, the genetic diversity of 208 Chinese hulless barley from different Provinces of China, 111 genotypes were from the Tibet plateau, 30 Sichuan, 2 USA, 1 Canada, 12 Gansu, 51 Qinghai, 1 Yunnan was investigated; collected. Almost all the qualitative traits including crude protein, fiber, starch, neutral detergent fiber, and acid detergent fiber exhibited significantly high variability (p≤0.0001) among the cultivars. The data were analyzed using Statistics 8.1. In this study, significantly high variation was observed between starch content and neutral detergent fiber (23.64% and 11.54%). However, the highest diversity is based on the magnitude of the coefficient of variation exhibited in crude protein (13.82%), starch (12.87%), and fiber (12.17%). There was a significantly positive correlation between fiber, acid detergent fiber, and neutral detergent fiber except for starch content with crude protein and fiber that exhibited a significant negative correlation (r= -0.38*** and r= -0.92***). A large genetic diversity was observed through cluster analysis among all the 208 barley accessions, distance coefficient ranging between 0.28 and 75.86. The histogram revealed that frequency distributions of 208 different genotypes of hulless barley crop with all five different characters, crude protein, fiber, starch, neutral detergent fiber, and acid detergent fiber, showed normal distribution. It is concluded that this hulless barley study showed genetic diversity among the accessions and confirmed genetic diversity in various traits used.

The neuropeptide oxytocin is a key modulator of social-emotional behavior and its intranasal administration can influence the functional connectivity of brain networks involved in the control of attention, emotion and reward reported in humans. However, no studies have systematically investigated the effects of oxytocin on dynamic or directional aspects of functional connectivity. The present study employed a novel computational framework to investigate these latter aspects in 15 oxytocin-sensitive regions using data from randomized placebo-controlled between-subject resting state functional MRI studies incorporating 200 healthy subjects. In order to characterize the temporal dynamics, the ‘temporal state’ was defined as a temporal segment of the whole functional MRI signal which exhibited a similar functional interaction pattern among brain regions of interest. Results showed that while no significant effects of oxytocin were found on brain temporal state related characteristics (including temporal state switching frequency, probability of transitions between neighboring states, and averaged dwell time on each state) oxytocin extensively (n = 54 links) modulated effective connectivity among the 15 regions. The effects of oxytocin were primarily characterized by increased effective connectivity both between and within emotion, reward, salience, attention and social cognition processing networks and their interactions with the default mode network. Top-down control over emotional processing regions such as the amygdala was particularly affected. Oxytocin also increased effective homotopic interhemispheric connectivity in almost all these regions. Additionally, the effects of oxytocin on effective connectivity were sex-dependent, being more extensive in males. Overall, these findings suggest that modulatory effects of oxytocin on both within- and between-network interactions may underlie its functional influence on social-emotional behaviors, although in a sex-dependent manner. These findings may be of particular relevance to potential therapeutic use of oxytocin in psychiatric disorders associated with social dysfunction, such as autism spectrum disorder and schizophrenia, where directionality of treatment effects on causal interactions between networks may be of key importance .

At present, conflicts between urban development and the climate environment are becoming increasingly apparent under rapid urbanization in China. Revealing the dynamic mechanism and controlling factors of the urban outdoor thermal environment is the necessary theoretical preparation for regulating and improving the urban climate environment. Taking Hangzhou as an example and based on the local climate zones classification system, we investigated the effects of land cover composition and structure on temperature variability at the local scale. The measurement campaign was conducted within four local climate zones (LCZ 2, 4, 5, and LCZ 9) during 7 days in the summer of 2018. The results showed that the temperature difference within the respective LCZ was always below 1.1 °C and the mean temperature difference between LCZs caused by different surface physical properties was as high as 1.6 °C at night. Among four LCZs, LCZ 2 was always the hottest, and LCZ 9 was the coolest at night. In particular, the percentage of pervious surface was the most important land cover feature in explaining the air temperature difference. For both daytime and nighttime, increasing the percentage of pervious surface as well as decreasing the percentage of impervious surface and the percentage of building surface could lower the local temperature, with the strongest influence radius range from 120 m to 150 m. Besides, the temperature increased with the SVF increased at day and opposite at night.

The human cerebral cortex is highly convoluted as convex gyri and concave sulci. In the past decades, extensive studies have consistently revealed substantial differences between gyri and sulci in terms of genetics, anatomy, morphology, axonal fiber connections, and function. Although interesting findings have been reported to date to elucidate the functional difference between gyri and sulci, the temporal variability of functional activity, which could explain individual differences in learning and higher-order cognitive functions, and as well as differences in gyri and sulci, remains to be explored. The present study explored the temporal variability of cortical gyral-sulcal resting state functional activity and its association with fluid intelligence measures on the Human Connectome Project dataset. We found that the temporal variance of resting state fMRI BOLD signal was significantly larger in gyri than in sulci. We also found that the temporal variability of certain regions including middle frontal cortex, inferior parietal lobe and visual cortex was positively associated with fluid intelligence. Moreover, those regions were predominately located in gyri rather than in sulci. This study reports initial evidence for temporal variability difference of functional activity between gyri and sulci, and its association with fluid intelligence measures, and thus provides novel insights to understand the mechanism and functional relevance of gyri and sulci.

Inflammatory bowel disease (IBD) is associated with dysregulation of both innate and adaptive immune response in the intestine. MicroRNA (miR)-155 is frequently expressed and functions in many immune cell types. Besides its function in adaptive immunity, miR-155 is a key regulator of the innate immune response in macrophages, dendritic cells, and even in epithelia cells. Although the roles of miR-155 within T and B lymphocytes in colitis have been reported, its function in innate immune cells has not been thoroughly examined. In this study, the dextran sulfate sodium (DSS)-induced colitis model was established in wild-type (WT) and miR-155−/− mice. Our results showed that miR-155 deficiency in macrophages recapitulated the alleviated colitis feature of miR-155−/− mice and appeared to skew toward the alterative M2 phenotype. Notably, the predominance of M2 in colon can result in dampened intestinal immune cell proliferation and inhibit CD4 T cell polarization toward Th1 and Th17. Moreover, C/EBPβ and SOCS1 were demonstrated as two key functional targets in this process. We also provided evidence for use of miR-155 inhibitor to treat colitis. Collectively, the findings highlight the central role of alternative M2 skewing for miR-155 function in colitis and reveal that macrophages might be a main target for therapeutics.

OBJECTIVE: To evaluate the prices and availability of paediatric essential medicines in Shaanxi Province, China. METHODS: Price and availability data for 28 paediatric essential medicines were collected from 60 public hospitals and 60 retail pharmacies in six areas of Shaanxi Province using a standardised methodology developed by the World Health Organization and Health Action International, during November to December 2012. Affordability was measured as the number of days' wages required for the lowest-paid unskilled government worker to purchase standard treatments for common conditions. Data on medicine price components were collected from hospitals, wholesalers and distributors to obtain price mark-ups. FINDINGS: The mean availabilities of originator brands (OBs) and lowest-priced generics (LPGs) were 10.8% and 27.3% in the public hospitals and 11.9% and 20.6% in the private pharmacies. The public procurement and retail prices were 2.25 and 2.59 times the international reference prices (IRPs) for three OBs, and 0.52 and 0.93 times for 20 LPGs. In the private sector, the final prices for OBs and LPGs were 3.89 and 1.25 times their IRPs. The final price in the private sector was 2.7% lower than in the public sector for OBs, and 14.1% higher for LPGs. Generally, standard treatments cost less than 1 day's wages in both sectors. Distribution mark-ups applied to brand salbutamol in Xi'an was 65.5%, and up to 185.3% for generic. Cumulative mark-ups for LPGs in Ankang were also high, from 33% to 50%. The manufacturer's selling price is the largest contributor to the final price in both areas. CONCLUSIONS: The government should approve a list of national paediatric essential medicines. The availability, price and affordability of these should be improved in both public hospitals and private pharmacies to enable children to obtain effective treatment. Measures should be taken to improve the efficiency of the centralised medicine purchasing system.

Background: Limited access to essential medicines is a global problem. Improving availability and affordability of essential medicines is a key objective of the National Essential Medicine Policy (NEMP) in China. In its initial implementation in 2009, the NEMP targeted primary hospitals with policies designed to increase availability of essential medicines and reduce patients' economic burden from purchasing medicines. We assessed medicine availability and price during the early years of the health reform in Shaanxi Province in underdeveloped western China. Methods: We undertook two public (hospitals) and private (pharmacy) sector surveys of prices and availability of medicines, in September, 2010 and April, 2012, by a standard methodology developed by WHO and Health Action International. We measured medicine availability in outlets at the time of the surveys and inflation-adjusted median unit prices (MUPs), taking 2010 as the base year. We used general estimating equations to calculate the significance of differences in availability from 2010 to 2012 and the Wilcoxon signed rank test to calculate the significance of differences in adjusted median prices. Findings: We collected data from 50 public sector hospitals and 36 private sector retail pharmacies in 2010 and 72 public hospitals and 72 retail pharmacies in 2012. Mean availability of surveyed medicines was low in both the public and private sectors; availability of many essential medicines decreased from 2010 to 2012, particularly in primary hospitals (from 27·4% to 22·3% for lowest priced generics; p

ObjectiveTo measure the prices and availability of selected medicines in Shaanxi Province after the implementation of new healthcare reform in 2009.MethodsData on the prices and availability of 47 medicines were collected from 50 public and 36 private sector medicine outlets in six regions of Shaanxi Province, Western China using a standardized methodology developed by the World Health Organization and Health Action International from September to October 2010. Medicine prices were compared with international reference prices to obtain a median price ratio. Affordability was measured as the number of days' wages required for the lowest-paid unskilled government worker to purchase standard treatments for common conditions.FindingsThe mean availabilities of originator brands and lowest-priced generics were 8.9% and 26.5% in the public sector, and 18.1% and 43.6% in the private sector, respectively. The public sector procured generics and originator brands at median price ratios of 0.75 and 8.49, respectively, while patients paid 0.97 and 10.16. Final patient prices for lowest-priced generics and originator brands in the private sector were about 1.53 and 8.36 times their international retail prices, respectively. Public sector vendors applied high markups of 30.4% to generics, and 19.6% to originator brands. In the private sector, originator brands cost 390.7% more, on average, than their generic equivalents. Generic medicines were priced 17.3% higher in the private sector than the public sector. The lowest-paid government worker would need 0.1 day's wages to purchase captopril for lowest-priced generics from private sector, while 6.6 days' wages for losartan. For originator brands, the costs rise to 1.2 days' wages for salbutamol inhaler and 15.6 days' wages for omeprazole.ConclusionsThe prices, availability and affordability of medicines in China should be improved to ensure equitable access to basic medical treatments, especially for the poor. This requires multi-faceted interventions, as well as the review and refocusing of policies, regulations and educational interventions.

A unique feature of coronaviruses is their utilization of self-encoded nonstructural protein 16 (nsp16), 2′-O-methyltransferase (2′-O-MTase), to cap their RNAs through ribose 2′-O-methylation modification. This process is crucial for maintaining viral genome stability, facilitating efficient translation, and enabling immune escape. Despite considerable advances in the ultrastructure of SARS-CoV-2 nsp16/nsp10, insights into its molecular mechanism have so far been limited. In this study, we systematically characterized the 2′-O-MTase activity of nsp16 in SARS-CoV-2, focusing on its dependence on nsp10 stimulation. We observed cross-reactivity between nsp16 and nsp10 in various coronaviruses due to a conserved interaction interface. However, a single residue substitution (K58T) in SARS-CoV-2 nsp10 restricted the functional activation of MERS-CoV nsp16. Furthermore, the cofactor nsp10 effectively enhanced the binding of nsp16 to the substrate RNA and the methyl donor S-adenosyl-l-methionine (SAM). Mechanistically, His-80, Lys-93, and Gly-94 of nsp10 interacted with Asp-102, Ser-105, and Asp-106 of nsp16, respectively, thereby effectively stabilizing the SAM binding pocket. Lys-43 of nsp10 interacted with Lys-38 and Gly-39 of nsp16 to dynamically regulate the RNA binding pocket and facilitate precise binding of RNA to the nsp16/nsp10 complex. By assessing the conformational epitopes of nsp16/nsp10 complex, we further determined the critical residues involved in 2′-O-MTase activity. Additionally, we utilized an in vitro biochemical platform to screen potential inhibitors targeting 2′-O-MTase activity. Overall, our results significantly enhance the understanding of viral 2′-O methylation process and mechanism, providing valuable targets for antiviral drug development. [ABSTRACT FROM AUTHOR]

Background: Radical hysterectomy (RH) is commonly used to treat early-stage cervical cancer in women of childbearing age and sexual dysfunction due to postoperative vaginal shortening is a major concern. The impact of intraoperative vaginoplasty on prognosis and quality of sexual life in patients with early-stage cervical cancer remains controversial and lacks high-level evidence. However, there are few reports on vaginoplasty after RH to lengthen vagina in patients. This prospective, multi-center, randomized controlled trial aims to explore the impact of peritoneal vaginoplasty with or without ovarian transposition after laparoscopic RH on sexual dysfunction in patients with early-stage cervical cancer. Methods: Eligible patients will be randomly assigned (1:1) to receive peritoneal vaginoplasty or not. The primary evaluation indicators are female sexual function index (FSFI) and male sexual satisfaction scale. The secondary evaluation indicators include EORTC QLQ-CX24, 2-year overall survival (OS), 5-year OS, 2-year progression-free survival (PFS), 5-year PFS and surgery-related complications. The trial will enroll 368 patients from 6 hospitals in China over a 3-year period and follow up for 5 years. [ABSTRACT FROM AUTHOR]