A large number of SARS-related coronaviruses (SARSr-CoV) have been detected in horseshoe bats since 2005 in different areas of China. However, these bat SARSr-CoVs show sequence differences from SARS ...coronavirus (SARS-CoV) in different genes (S, ORF8, ORF3, etc) and are considered unlikely to represent the direct progenitor of SARS-CoV. Herein, we report the findings of our 5-year surveillance of SARSr-CoVs in a cave inhabited by multiple species of horseshoe bats in Yunnan Province, China. The full-length genomes of 11 newly discovered SARSr-CoV strains, together with our previous findings, reveals that the SARSr-CoVs circulating in this single location are highly diverse in the S gene, ORF3 and ORF8. Importantly, strains with high genetic similarity to SARS-CoV in the hypervariable N-terminal domain (NTD) and receptor-binding domain (RBD) of the S1 gene, the ORF3 and ORF8 region, respectively, were all discovered in this cave. In addition, we report the first discovery of bat SARSr-CoVs highly similar to human SARS-CoV in ORF3b and in the split ORF8a and 8b. Moreover, SARSr-CoV strains from this cave were more closely related to SARS-CoV in the non-structural protein genes ORF1a and 1b compared with those detected elsewhere. Recombination analysis shows evidence of frequent recombination events within the S gene and around the ORF8 between these SARSr-CoVs. We hypothesize that the direct progenitor of SARS-CoV may have originated after sequential recombination events between the precursors of these SARSr-CoVs. Cell entry studies demonstrated that three newly identified SARSr-CoVs with different S protein sequences are all able to use human ACE2 as the receptor, further exhibiting the close relationship between strains in this cave and SARS-CoV. This work provides new insights into the origin and evolution of SARS-CoV and highlights the necessity of preparedness for future emergence of SARS-like diseases.
The prognosis of biliary tract cancer (BTC) remains unsatisfactory. This single-arm, phase II clinical trial (ChiCTR2000036652) investigated the efficacy, safety, and predictive biomarkers of ...sintilimab plus gemcitabine and cisplatin as the first-line treatment for patients with advanced BTCs. The primary endpoint was overall survival (OS). Secondary endpoints included toxicities, progression-free survival (PFS), and objective response rate (ORR); multi-omics biomarkers were assessed as exploratory objective. Thirty patients were enrolled and received treatment, the median OS and PFS were 15.9 months and 5.1 months, the ORR was 36.7%. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Predefined biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations or loss-of-function mutations in chromatin remodeling genes presented better tumor response and survival outcomes. Furthermore, transcriptome analysis revealed a markedly longer PFS and tumor response were associated with higher expression of a 3-gene effector T cell signature or an 18-gene inflamed T cell signature. Sintilimab plus gemcitabine and cisplatin meets pre-specified endpoints and displays acceptable safety profile, multiomics potential predictive biomarkers are identified and warrant further verification.
Aims
Propranolol may have shown excellent results as a first line therapy in infantile haemangiomas (IHs) at all sites in the body, but this conclusion remains controversial. In an attempt to resolve ...this issue, we performed a meta‐analysis.
Methods
A search of the literature using PubMed, MEDLINE, Cochrane Library databases and China National Knowledge Infrastructure (CNKI) was performed to identify studies which estimated the efficacy of propranolol therapy in infants with haemangiomas all sites of the body. The pooled odds ratio (OR) along with the corresponding 95% confidence intervals (CI) were assessed using a fixed effects model.
Results
Thirty‐five studies involving 324 infantile haemangioma(IH) patients and 248 controls were retrieved and analyzed. The efficacy of propranolol was greater than other therapies in treating IHs (OR = 9.67, 95% CI 6.62, 14.12, P < 0.001). In a stratified analysis by sites of tumour, propranolol was a more effective therapy when compared with steroids (OR = 9.67, 95% CI 6.61, 14.15, P < 0.001), vincristine (OR = 9.00, 95% CI 2.15, 37.66, P = 0.003) and laser treatment (OR = 9.00, 95% CI 1.42, 57.12, P = 0.020) in treating cutaneous IHs (OR = 24.95, 95% CI 9.48, 65.64, P < 0.001), peri‐ocular IHs (OR = 9.39, 95% CI 3.88, 22.71, P < 0.001), infantile airway haemangiomas (OR = 20.91, 95% CI 7.81, 55.96, P < 0.001) and infantile hepatic haemangiomas (OR = 9.89, 95% CI 1.20, 81.54, P = 0.033).
Conclusion
The current meta‐analysis provided strong evidence for propranolol as a first line therapy for IHs.
Since 2015, stroke has become the leading cause of death and disability in China, posing a significant threat to the health of its citizens as a major chronic non-communicable disease. According to ...the China Stroke High-risk Population Screening and Intervention Program, an estimated 17.8 million 95% confidence interval (CI) 17.6-18.0 million adults in China had experienced a stroke in 2020, with 3.4 million (95% CI 3.3-3.5 million) experiencing their first-ever stroke and another 2.3 million (95% CI 2.2-2.4 million) dying as a result. Additionally, approximately 12.5% (95% CI 12.4-12.5%) of stroke survivors were left disabled, as defined by a modified Rankin Scale score greater than 1, equating to 2.2 million (95% CI 2.1-2.2 million) stroke-related disabilities in 2020. As the population ages and the prevalence of risk factors like diabetes, hypertension, and hyperlipidemia continues to rise and remains poorly controlled, the burden of stroke in China is also increasing. A large national epidemiological survey initiated by the China Hypertension League in 2017 showed that the prevalence of hypertension was 24.7%; the awareness, treatment, and control rates in hypertensive patients were: 60.1%, 42.5%, and 25.4%, respectively. A nationally representative sample of the Chinese mainland population showed that the weighted prevalence of total diabetes diagnosed by the American Diabetes Association criteria was 12.8%, suggesting there are 120 million adults with diabetes in China, and the awareness, treatment, and control rates in diabetic patients were: 43.3%, 49.0%, and 49.4%, respectively. The "Sixth National Health Service Statistical Survey Report in 2018" showed that the proportion of the obese population in China was 37.4%, an increase of 7.2 points from 2013. Data from 1599 hospitals in the Hospital Quality Monitoring System and Bigdata Observatory Platform for Stroke of China (BOSC) showed that a total of 3,418,432 stroke cases mean age ± standard error (SE) was (65.700 ± 0.006) years, and 59.1% were male were admitted during 2020. Of those, over 80% (81.9%) were ischemic stroke (IS), 14.9% were intracerebral hemorrhage (ICH) strokes, and 3.1% were subarachnoid hemorrhage (SAH) strokes. The mean ± SE of hospitalization expenditures was Chinese Yuan (CNY) (16,975.6 ± 16.3), ranging from (13,310.1 ± 12.8) in IS to (81,369.8 ± 260.7) in SAH, and out-of-pocket expenses were (5788.9 ± 8.6), ranging from (4449.0 ± 6.6) in IS to (30,778.2 ± 156.8) in SAH. It was estimated that the medical cost of hospitalization for stroke in 2020 was CNY 58.0 billion, of which the patient pays approximately CNY 19.8 billion. In-hospital death/discharge against medical advice rate was 9.2% (95% CI 9.2-9.2%), ranging from 6.4% (95% CI 6.4-6.5%) for IS to 21.8% for ICH (95% CI 21.8-21.9%). From 2019 to 2020, the information about 188,648 patients with acute IS receiving intravenous thrombolytic therapy (IVT), 49,845 patients receiving mechanical thrombectomy (MT), and 14,087 patients receiving bridging (IVT + MT) were collected through BOSC. The incidence of intracranial hemorrhage during treatment was 3.2% (95% CI 3.2-3.3%), 7.7% (95% CI 7.5-8.0%), and 12.9% (95% CI 12.3-13.4%), respectively. And in-hospital death/discharge against medical advice rate was 8.9% (95% CI 8.8-9.0%), 16.5% (95% CI 16.2-16.9%), and 16.8% (95% CI 16.2-17.4%), respectively. A prospective nationwide hospital-based study was conducted at 231 stroke base hospitals (Level III) from 31 provinces in China through BOSC from January 2019 to December 2020 and 136,282 stroke patients were included and finished 12-month follow-up. Of those, over 86.9% were IS, 10.8% were ICH strokes, and 2.3% were SAH strokes. The disability rate % (95% CI) in survivors of stroke at 3-month and 12-month was 14.8% (95% CI 14.6-15.0%) and 14.0% (95% CI 13.8-14.2%), respectively. The mortality rate % (95% CI) of stroke at 3-month and 12-month was 4.2% (95% CI 4.1-4.3%) and 8.5% (95% CI 8.4-8.6%), respectively. The recurrence rate % (95% CI) of stroke at 3-month and 12-month was 3.6% (95% CI 3.5-3.7%) and 5.6% (95% CI 5.4-5.7%), respectively. The Healthy China 2030 Stroke Action Plan was launched as part of this review, and the above data provide valuable guidelines for future stroke prevention and treatment efforts in China.
M2C eutectic carbide favours the mechanical properties of high-speed steels, but is often largely replaced by coarse M6C eutectic carbide in as-cast M42 steel. To deeply understand the formation ...behavior of M2C and M6C carbides, M2C and M6C eutectic alloys were prepared according to the composition of M2C and M6C eutectic mixtures in M42 steel, and their solidification behavior was investigated. Only one type of eutectic carbide is formed in water-quenched M2C and M6C eutectic alloys, i.e., M2C and M6C, respectively. Both M2C and M6C carbides appear in the alloys cooled at 3°C/min. However, the M2C eutectic alloy was more significantly affected in terms of carbide type by the low cooling rate. According to thermodynamic calculation, M6C carbide in the M2C eutectic alloy is only slightly more stable in thermodynamics above 1210.1°C, below which M2C carbide becomes stable. For the M6C eutectic alloy, however, only M6C eutectic carbide is thermodynamically stable. Furthermore, thermodynamic results reveal that besides raising the content of C and V, reducing the content of Mo can also greatly promote the formation of M2C carbide in M42 steel, which updates the traditional opinion on the influence of Mo element. The results in this work provide the underlying insights needed to promote the formation of M2C carbide in M42 steel by fine-tuning the composition.
Mammalian orthoreovirus (MRV) infections are ubiquitous in mammals. Increasing evidence suggests that some MRVs can cause severe respiratory disease and encephalitis in humans and other animals. ...Previously, we isolated six bat MRV strains. However, the pathogenicity of these bat viruses remains unclear. In this study, we investigated the host range and pathogenicity of 3 bat MRV strains (WIV2, 3 and 7) which represent three serotypes. Our results showed that all of them can infect cell lines from different mammalian species and displayed different replication efficiency. The BALB/c mice infected by bat MRVs showed clinical symptoms with systematic infection especially in lung and intestines. Obvious tissue damage were found in all infected lungs. One of the strains, WIV7, showed higher replication efficiency in vitro and vivo and more severe pathogenesis in mice. Our results provide new evidence showing potential pathogenicity of bat MRVs in animals and probable risk in humans.
•Bat MRVs show wide cell tropism in vivo and in vitro and have a high replication efficiency in lung and intestines.•Mice infected by bat MRVs showed clinical illness, but without death.•The higher replication in brain, lung damage and weak innate immune response may be responsible for severe diseases for WIV7.•The results indicate the potential pathogenicity of bat MRV to human and animals.
Objective
To investigate if co-transfection of human bone morphogenetic protein 2 (BMP-2, BMP2) and human fibroblast growth factor 2 (FGF2, FGF2) via chitosan nanoparticles promotes osteogenesis in ...human adipose tissue-derived stem cells (ADSCs) in vitro.
Materials and Methods
Recombinant BMP2 and/or FGF2 expression vectors were constructed and packaged into chitosan nanoparticles. The chitosan nanoparticles were characterized by atomic force microscopy. Gene and protein expression levels of BMP-2 and FGF2 in ADSCs in vitro were evaluated by real-time polymerase chain reaction (PCR), western blot, and enzyme-linked immunosorbent assay. Osteocalcin (OCN) and bone sialoprotein (BSP) gene expression were also evaluated by real-time PCR to assess osteogenesis.
Results
The prepared chitosan nanoparticles were spherical with a relatively homogenous size distribution. The BMP2 and FGF2 vectors were successfully transfected into ADSCs. BMP-2 and FGF2 mRNA and protein levels were significantly up-regulated in the co-transfection group compared with the control group. OCN and BSP mRNA levels were also significantly increased in the co-transfection group compared with cells transfected with BMP2 or FGF2 alone, suggesting that co-transfection significantly enhanced osteogenesis.
Conclusions
Co-transfection of human ADSCs with BMP2/FGF2 via chitosan nanoparticles efficiently promotes the osteogenic properties of ADSCs in vitro.
Severe acute respiratory syndrome coronavirus (SARS-CoV-1) and SARS-CoV-2 are highly pathogenic to humans and have caused pandemics in 2003 and 2019, respectively. Genetically diverse SARS-related ...coronaviruses (SARSr-CoVs) have been detected or isolated from bats, and some of these viruses have been demonstrated to utilize human angiotensin-converting enzyme 2 (ACE2) as a receptor and to have the potential to spill over to humans. A pan-sarbecovirus vaccine that provides protection against SARSr-CoV infection is urgently needed. In this study, we evaluated the protective efficacy of an inactivated SARS-CoV-2 vaccine against recombinant SARSr-CoVs carrying two different spike proteins (named rWIV1 and rRsSHC014S, respectively). Although serum neutralizing assays showed limited cross-reactivity between the three viruses, the inactivated SARS-CoV-2 vaccine provided full protection against SARS-CoV-2 and rWIV1 and partial protection against rRsSHC014S infection in human ACE2 transgenic mice. Passive transfer of SARS-CoV-2-vaccinated mouse sera provided low protection for rWIV1 but not for rRsSHC014S infection in human ACE2 mice. A specific cellular immune response induced by WIV1 membrane protein peptides was detected in the vaccinated animals, which may explain the cross-protection of the inactivated vaccine. This study shows the possibility of developing a pan-sarbecovirus vaccine against SARSr-CoVs for future preparedness.
The genetic diversity of SARSr-CoVs in wildlife and their potential risk of cross-species infection highlight the necessity of developing wide-spectrum vaccines against infection of various SARSr-CoVs. In this study, we tested the protective efficacy of the SARS-CoV-2 inactivated vaccine (IAV) against two SARSr-CoVs with different spike proteins in human ACE2 transgenic mice. We demonstrate that the SARS-CoV-2 IAV provides full protection against rWIV1 and partial protection against rRsSHC014S. The T-cell response stimulated by the M protein may account for the cross protection against heterogeneous SARSr-CoVs. Our findings suggest the feasibility of the development of pan-sarbecovirus vaccines, which can be a strategy of preparedness for future outbreaks caused by novel SARSr-CoVs from wildlife.
DNA repair gene X-ray repair cross complementing group 1 (XRCC1) plays an important role in the maintenance of the genomic integrity and protection of cells from DNA damage. Sequence variation in ...XRCC1 gene may alter head and neck cancer (HNC) susceptibility. However, these results are inconclusive. To derive a more precise estimation of the relationship between XRCC1 polymorphism and HNC risk, we undertook a meta-analysis involving 16,344 subjects.
A search of the literature by PubMed, Embase, Web of Science and China National Knowledge Infrastructure was performed to identify studies based on the predetermined inclusion criteria. The odds ratio (OR) with 95% confidence interval (CI) was combined using a random-effects model or a fixed-effects model.
Twenty-nine studies consisting of 6,719 cases and 9,627 controls were identified and analyzed. Overall, no evidence of significant association was observed between XRCC1 Arg194Trp, XRCC1 Arg280His, XRCC1 Arg399Gln genotypes and the risk of HNC in any genetic models. Subgroup analyses according to ethnicity, tumor site, publication year, genotyping method also detected no significant association in any subgroup, except that oral cancer was associated with Arg194Trp variant in recessive model. Furthermore, no significant effect of these polymorphisms interacted with smoking on HNC risk was detected but Arg194Trp homozygous variant.
In conclusion, this meta-analysis suggests that the XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphism may not involve in HNC susceptibility. Further studies about gene-gene and gene-environment interactions in different populations are required.
Water project and watershed management is currently being reengineered under digital twin schemes in China through pilot projects. An evaluation on pilot reengineering is important for its further ...implementation and improvement. This paper investigates national legislation and pilot projects’ implementations of a digital twin watershed and digital twin water project from the perspectives of design, policy, technology, investment, personnel, cyberspace security, co-construction, and sharing through interviews and expert review, and it uses a Bayesian network to study their reliability. First, the design of the digital twin watershed and digital twin water project is reasonable with regard to system architecture and business management. Second, although there are some national legislations on cyberspace security and geospatial data, they are incomplete for policy making and are probably infeasible for some technology. Third, there are insufficient mechanisms to sustainably support investment, personnel, and cyberspace security. Forth, co-construction and sharing are required for both inside and outside water departments. Fifth, the Bayesian network is useful for investigating the reliability of weak nodes, and it is helpful for the design and further implementation of the digital twin watershed and digital twin water project, as will be demonstrated with an anonymous example. This study could provide useful insights into the further reengineering of water projects and watershed management under a digital twin scheme in the world.
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