Notes

[Effect of self-consciousness regarding Porphyromonas endodontalis on osteoblast differentiation].
ss provinces in China from 1990 to 2019.

The disease burden of stroke is still severe in China, although the age-standardised incidence and mortality rates have decreased since 1990. The stroke burden in China might be reduced through blood pressure management, lifestyle interventions, and air pollution control. Moreover, because substantial heterogeneity of stroke burden existed in different provinces, improved health care is needed in provinces with heavy stroke burden.

National Key Research and Development Program of China and Taikang Yicai Public Health and Epidemic Control Fund.
National Key Research and Development Program of China and Taikang Yicai Public Health and Epidemic Control Fund.
Helicobacter pylori infection is a major cause of non-cardia gastric cancer (NCGC), but its causal role in cardia gastric cancer (CGC) is unclear. Moreover, the reported magnitude of association with NCGC varies considerably, leading to uncertainty about population-based H pylori screening and eradication strategies in high-risk settings, particularly in China, where approximately half of all global gastric cancer cases occur. Our aim was to assess the associations of H pylori infection, both overall and for individual infection biomarkers, with the risks of NCGC and CGC in Chinese adults.

A case-cohort study was done in adults from the prospective China Kadoorie Biobank study, aged 30-79 years from ten areas in China (Qingdao, Haikou, Harbin, Suzhou, Liuzhou, Henan, Sichuan, Hunan, Gansu, and Zhejiang), and included 500 incident NCGC cases, 437 incident CGC cases, and 500 subcohort participants who were cancer-free and alive within the first two years since enrolment in 2004-08. H pylori biomarkers were n this population, 78·5% of NCGC and 62·1% of CGC cases could be attributable to H pylori infection. H pylori infection accounted for an estimated 339 955 cases of gastric cancer in China in 2018.

Among Chinese adults, H pylori infection is common and is the cause of large numbers of gastric cancer cases. Population-based mass screening and the eradication of H pylori should be considered to reduce the burden of gastric cancer in high-risk settings.

Cancer Research UK, Wellcome Trust, UK Medical Research Council, British Heart Foundation, Kadoorie Charitable Foundation, National Key Research and Development Program of China, and National Natural Science Foundation of China.
Cancer Research UK, Wellcome Trust, UK Medical Research Council, British Heart Foundation, Kadoorie Charitable Foundation, National Key Research and Development Program of China, and National Natural Science Foundation of China.
Stage information is crucial for cancer care and essential to improve polices for cancer control. However, the distribution of stage at diagnosis for common cancers in China is not well known. We aimed to identify the distribution and factors associated with stage at diagnosis for five major cancers in China.

In this multicentre, hospital-based, observational study, we included 23 hospitals in 12 provinces from China. We focused on cancers of the lung, stomach, oesophagus, colorectum, and female breast, and using electronic medical records at the individual level from the local hospitals, and cancer registration records from population-based cancer registries, identified diagnoses made between Jan 1, 2016, and Dec 31, 2017. We collected information on sociodemographic characteristics, lifestyle factors, insurance types, and stage at diagnosis. We analysed the prevalence of late-stage (stages III-IV) cancer cases overall, by sex, and by geographical region. We used logistic regression to identify the factor (72·4% in China vs 48·8% in the USA), lung cancer (82·7% in China vs 74·7% in the USA), and colorectal cancer (84·8% in China vs 75·9% in the USA).

The disparities of cancer diagnosis within China, and between China and the USA, indicate an urgent need for early detection of cancer in China.

National Key R&D Programme of China, Major State Basic Innovation Programme of the Chinese Academy of Medical Sciences, and National Natural Science Fund.
National Key R&D Programme of China, Major State Basic Innovation Programme of the Chinese Academy of Medical Sciences, and National Natural Science Fund.DNA ligases act in the final step of many DNA repair pathways and are commonly regulated by the DNA sliding clamp proliferating cell nuclear antigen (PCNA), but there are limited insights into the physical basis for this regulation. Here, we use single-particle cryoelectron microscopy (cryo-EM) to analyze an archaeal DNA ligase and heterotrimeric PCNA in complex with a single-strand DNA break. The cryo-EM structures highlight a continuous DNA-binding surface formed between DNA ligase and PCNA that supports the distorted conformation of the DNA break undergoing repair and contributes to PCNA stimulation of DNA ligation. DNA ligase is conformationally flexible within the complex, with its domains fully ordered only when encircling the repaired DNA to form a stacked ring structure with PCNA. The structures highlight DNA ligase structural transitions while docked on PCNA, changes in DNA conformation during ligation, and the potential for DNA ligase domains to regulate PCNA accessibility to other repair factors.Structure-based antibody design and accurate predictions of antibody-antigen interactions remain major challenges in computational biology. By using molecular dynamics simulations, we show that a single static X-ray structure is not sufficient to identify determinants of antibody-antigen recognition. Here, we investigate antibodies that undergo substantial conformational changes upon antigen binding and have been classified as difficult cases in an extensive benchmark for antibody-antigen docking. CHIR-99021 We present thermodynamics and transition kinetics of these conformational rearrangements and show that paratope states can be used to improve antibody-antigen docking. By using the unbound antibody X-ray structure as starting structure for molecular dynamics simulations, we retain a binding competent conformation substantially different to the unbound antibody X-ray structure. We also observe that the kinetically dominant antibody paratope conformations are chosen by the bound antigen conformation with the highest probability. Thus, we show that paratope states in solution can improve antibody-antigen docking and structure prediction.Anti-COVID-19 immunity dynamics were assessed in patients with cancer in a prospective clinical trial. Waning of immunity was detected 4-6 months post-vaccination with significant increases in anti-spike IgG titers after booster dosing, and 56% of seronegative patients seroconverted post-booster vaccination. Prior anti-CD20/BTK inhibitor therapy was associated with reduced vaccine efficacy.
SARS-CoV-2 variants of concern (VOCs) have threatened COVID-19 vaccine effectiveness. We aimed to assess the effectiveness of the ChAdOx1 nCoV-19 vaccine, predominantly against the delta (B.1.617.2) variant, in addition to the cellular immune response to vaccination.

We did a test-negative, case-control study at two medical research centres in Faridabad, India. All individuals who had a positive RT-PCR test for SARS-CoV-2 infection between April 1, 2021, and May 31, 2021, were included as cases and individuals who had a negative RT-PCR test were included as controls after matching with cases on calendar week of RT-PCR test. The primary outcome was effectiveness of complete vaccination with the ChAdOx1 nCoV-19 vaccine against laboratory-confirmed SARS-CoV-2 infection. The secondary outcomes were effectiveness of a single dose against SARS-CoV-2 infection and effectiveness of a single dose and complete vaccination against moderate-to-severe disease among infected individuals. link2 Additionally, we tested in-vitrhumoral immunity.

Department of Biotechnology India, Council of Scientific and Industrial Research India, and Fondation Botnar.
Department of Biotechnology India, Council of Scientific and Industrial Research India, and Fondation Botnar.A proportion of people infected with SARS-CoV-2 develop moderate or severe COVID-19, with an increased risk of thromboembolic complications. The inflammatory response to SARS-CoV-2 infection can cause an acute-phase response and endothelial dysfunction, which contribute to COVID-19-associated coagulopathy, the clinical and laboratory features of which differ in some respects from those of classic disseminated intravascular coagulation. Understanding of the pathophysiology of thrombosis in COVID-19 is needed to develop approaches to management and prevention, with implications for short-term and long-term health outcomes. Evidence is emerging to support treatment decisions in patients with COVID-19, but many questions remain about the optimum approach to management. In this Viewpoint, we provide a summary of the pathophysiology of thrombosis and associated laboratory and clinical findings, and highlight key considerations in the management of coagulopathy in hospitalised patients with severe COVID-19, including coagulation assessment, identification of thromboembolic complications, and use of antithrombotic prophylaxis and therapeutic anticoagulation. We await the results of trials that are underway to establish the safety and benefits of prolonged thromboprophylaxis after hospital discharge.Genetically encoded fluorescent biosensors are powerful tools for monitoring biochemical activities in live cells, but their multiplexing capacity is limited by the available spectral space. We overcome this problem by developing a set of barcoding proteins that can generate over 100 barcodes and are spectrally separable from commonly used biosensors. Mixtures of barcoded cells expressing different biosensors are simultaneously imaged and analyzed by deep learning models to achieve massively multiplexed tracking of signaling events. link3 Importantly, different biosensors in cell mixtures show highly coordinated activities, thus facilitating the delineation of their temporal relationship. Simultaneous tracking of multiple biosensors in the receptor tyrosine kinase signaling network reveals distinct mechanisms of effector adaptation, cell autonomous and non-autonomous effects of KRAS mutations, as well as complex interactions in the network. Biosensor barcoding presents a scalable method to expand multiplexing capabilities for deciphering the complexity of signaling networks and their interactions between cells.Viral-deletion mutants that conditionally replicate and inhibit the wild-type virus (i.e., defective interfering particles, DIPs) have long been proposed as single-administration interventions with high genetic barriers to resistance. However, theories predict that robust, therapeutic DIPs (i.e., therapeutic interfering particles, TIPs) must conditionally spread between cells with R0 >1. Here, we report engineering of TIPs that conditionally replicate with SARS-CoV-2, exhibit R0 >1, and inhibit viral replication 10- to 100-fold. Inhibition occurs via competition for viral replication machinery, and a single administration of TIP RNA inhibits SARS-CoV-2 sustainably in continuous cultures. Strikingly, TIPs maintain efficacy against neutralization-resistant variants (e.g., B.1.351). In hamsters, both prophylactic and therapeutic intranasal administration of lipid-nanoparticle TIPs durably suppressed SARS-CoV-2 by 100-fold in the lungs, reduced pro-inflammatory cytokine expression, and prevented severe pulmonary edema.
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