Publications by authors named "Wei Zheng"

3,909 Publications

  • Page 1 of 1

White matter damage as a consequence of vascular dysfunction in a spontaneous mouse model of chronic mild chronic hypoperfusion with eNOS deficiency.

Mol Psychiatry 2022 Aug 10. Epub 2022 Aug 10.

Department of Pharmacology, Addiction Science, Toxicology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, 38163, USA.

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer's disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID remain elusive. White matter change represents an invariant feature. Compelling clinical neuroimaging and pathological evidence suggest a link between white matter changes and neurodegeneration. Our prior study detected hypoperfused lesions in mice with partial deficiency of endothelial nitric oxide (eNOS) at very young age, precisely matching to those hypoperfused areas identified in preclinical AD patients. White matter tracts are particularly susceptible to the vascular damage induced by chronic hypoperfusion. Using immunohistochemistry, we detected severe demyelination in the middle-aged eNOS-deficient mice. The demyelinated areas were confined to cortical and subcortical areas including the corpus callosum and hippocampus. The intensity of demyelination correlated with behavioral deficits of gait and associative recognition memory performances. By Evans blue angiography, we detected blood-brain barrier (BBB) leakage as another early pathological change affecting frontal and parietal cortex in eNOS-deficient mice. Sodium nitrate fortified drinking water provided to young and middle-aged eNOS-deficient mice completely prevented non-perfusion, BBB leakage, and white matter pathology, indicating that impaired endothelium-derived NO signaling may have caused these pathological events. Furthermore, genome-wide transcriptomic analysis revealed altered gene clusters most related to mitochondrial respiratory pathways selectively in the white matter of young eNOS-deficient mice. Using eNOS-deficient mice, we identified BBB breakdown and hypoperfusion as the two earliest pathological events, resulting from insufficient vascular NO signaling. We speculate that the compromised BBB and mild chronic hypoperfusion trigger vascular damage, along with oxidative stress and astrogliosis, accounting for the white matter pathological changes in the eNOS-deficient mouse model. We conclude that eNOS-deficient mice represent an ideal spontaneous evolving model for studying the earliest events leading to white matter changes, which will be instrumental to future therapeutic testing of drug candidates and for targeting novel/specific vascular mechanisms contributing to VCID and AD.
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http://dx.doi.org/10.1038/s41380-022-01701-9DOI Listing
August 2022

Spatial and temporal variation of heat islands in the main urban area of Zhengzhou under the two-way influence of urbanization and urban forestry.

PLoS One 2022 10;17(8):e0272626. Epub 2022 Aug 10.

School of Horticulture and Landscape Architecture, Henan Institute of Science and Technology, Xinxiang, China.

Urban heat islands are major factors hindering the quality of present-day urban habitats. The ongoing acceleration of the worldwide urbanization process is leading to an exacerbation of the urban heat island effect; however, urban forestry can mitigate it. For a sustainable urban development, it is particularly important to evaluate the dual effect of both factors on the urban heat island phenomenon. In this study, we focused on Zhengzhou City (China), at the center of the Central Plains Forest City Cluster. The spatial and temporal evolutions of the local urban heat island and vegetation coverage were measured from Landsat 5 and Landsat 8 remote sensing images taken between 2006-2020 and the effects of urban construction and urban forestry on the urban heat island effect were evaluated. The results showed that, in the past 15 years, the high-temperature zone in the urban area of Zhengzhou City has gradually spread from its center to surrounding areas. Within the same period, the whole urban heat island has deteriorated and gradually improved: its area increased by 138.72 km2 between 2006-2014 and decreased by 135.66 km2 between 2014-2020. Notably, the development of vegetation coverage occurred consistently with the improvement of the heat island. A quantitative analysis of the relationship between urban construction, the urban forest, and the urban heat island has shown that factors like population density (representing urban construction), urban planning, and vegetation cover (representing the urban forest) all have an impact on the urban heat island. Based on the dynamic changes of the urban heat island in the urban area of Zhengzhou City between 2006-2020, we conclude that urban forest construction strategies are beginning to bear fruit. Overall, the findings of this study provide a theoretical basis for future urban construction and urban forest construction plans; moreover, they can support landscape pattern optimization and urban heat island mitigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0272626PLOS
August 2022

A humanized nanobody phage display library yields potent binders of SARS CoV-2 spike.

PLoS One 2022 10;17(8):e0272364. Epub 2022 Aug 10.

National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States of America.

Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two distinct binding modes. The most potent nanobody, RBD-1-2G(NCATS-BL8125), tolerates the N501Y RBD mutation and remains capable of neutralizing the B.1.1.7 (Alpha) variant. Molecular dynamics simulations provide a structural basis for understanding the neutralization process of nanobodies exclusively focused on the spike-ACE2 interface with and without the N501Y mutation on RBD. A primary human airway air-lung interface (ALI) ex vivo model showed that RBD-1-2G-Fc antibody treatment was effective at reducing viral burden following WA1 and B.1.1.7 SARS-CoV-2 infections. Therefore, this presented strategy will serve as a tool to mitigate the threat of emerging SARS-CoV-2 variants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0272364PLOS
August 2022

Dual-channel lanthanide-doped nanoprobe for reliable multi-signal ratiometric detection of HS in whole blood.

Chem Commun (Camb) 2022 Aug 9. Epub 2022 Aug 9.

Beijing Key Laboratory for Optical Materials and Photonic Devices & Department of Chemistry, Capital Normal University, 100048 Beijing, China.

Wavelength-dependent absorbance of blood has impeded the development of fluorescence biodetection in whole blood. Here, by replacing the fluorescence working signal with a temperature signal, reliable HS detection was performed in samples of whole blood. The developed system was based on a dual-channel lanthanide-doped nanoprobe, which further allowed precise serodiagnosis of acute pancreatitis.
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http://dx.doi.org/10.1039/d2cc03360gDOI Listing
August 2022

RNA mA demethylase ALKBH5 regulates the development of γδ T cells.

Proc Natl Acad Sci U S A 2022 Aug 8;119(33):e2203318119. Epub 2022 Aug 8.

Department of Geriatrics, Center for Immune-Related Diseases, Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

γδ T cells are an abundant T cell population at the mucosa and are important in providing immune surveillance as well as maintaining tissue homeostasis. However, despite γδ T cells' origin in the thymus, detailed mechanisms regulating γδ T cell development remain poorly understood. -methyladenosine (mA) represents one of the most common posttranscriptional modifications of messenger RNA (mRNA) in mammalian cells, but whether it plays a role in γδ T cell biology is still unclear. Here, we show that depletion of the mA demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells, which confers enhanced protection against gastrointestinal infection. Mechanistically, loss of ALKBH5 favors the development of γδ T cell precursors by increasing the abundance of mA RNA modification in thymocytes, which further reduces the expression of several target genes including Notch signaling components and . As a result, impairment of Jagged1/Notch2 signaling contributes to enhanced proliferation and differentiation of γδ T cell precursors, leading to an expanded mature γδ T cell repertoire. Taken together, our results indicate a checkpoint role of ALKBH5 and mA modification in the regulation of γδ T cell early development.
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http://dx.doi.org/10.1073/pnas.2203318119DOI Listing
August 2022

I-TASSER-MTD: a deep-learning-based platform for multi-domain protein structure and function prediction.

Nat Protoc 2022 Aug 5. Epub 2022 Aug 5.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.

Most proteins in cells are composed of multiple folding units (or domains) to perform complex functions in a cooperative manner. Relative to the rapid progress in single-domain structure prediction, there are few effective tools available for multi-domain protein structure assembly, mainly due to the complexity of modeling multi-domain proteins, which involves higher degrees of freedom in domain-orientation space and various levels of continuous and discontinuous domain assembly and linker refinement. To meet the challenge and the high demand of the community, we developed I-TASSER-MTD to model the structures and functions of multi-domain proteins through a progressive protocol that combines sequence-based domain parsing, single-domain structure folding, inter-domain structure assembly and structure-based function annotation in a fully automated pipeline. Advanced deep-learning models have been incorporated into each of the steps to enhance both the domain modeling and inter-domain assembly accuracy. The protocol allows for the incorporation of experimental cross-linking data and cryo-electron microscopy density maps to guide the multi-domain structure assembly simulations. I-TASSER-MTD is built on I-TASSER but substantially extends its ability and accuracy in modeling large multi-domain protein structures and provides meaningful functional insights for the targets at both the domain- and full-chain levels from the amino acid sequence alone.
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http://dx.doi.org/10.1038/s41596-022-00728-0DOI Listing
August 2022

Cardioprotection of Klotho against myocardial infarction-induced heart failure through inducing autophagy.

Mech Ageing Dev 2022 Aug 3;207:111714. Epub 2022 Aug 3.

Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, Jiangsu 210029, China. Electronic address:

Myocardial infarction (MI) is the most common cause of heart failure (HF) worldwide. The aim of this study was to investigate the role of Klotho in cardiac function and remodeling as well as its underlying mechanism in mice with MI-induced HF. For in vivo analyses, MI or sham MI were established in C57BL/6 mice. For in vitro analyses, the H9C2 cells were used to establish a model of oxygen glucose deprivation (OGD). The In vivo and in vitro models were treated with or without Klotho. 3-methyladenine (3-MA) was used to inhibit autophagy in MI mice and H9C2 cells. Cardiac function, cardiac fibrosis, cardiomyocyte autophagy, inflammatory cytokines and myocardial apoptosis were measured. Our results revealed that Klotho significantly improved cardiac function and remodeling, reduced cardiac fibrosis, and suppressed the levels of myocardial inflammatory factors and apoptosis in MI-induced HF model. Klotho enhanced autophagy in cardiomyocytes and inhibited PI3K/AKT/mTOR signaling pathway in the mouse model of MI. Similar observations were made in the OGD model after treatment with Klotho. However, the cardioprotective effects of Klotho was significantly suppressed by 3-MA. Our data indicate that Klotho exerts its cardioprotective effects against MI-induced HF by inducing autophagy through the inhibition of PI3k/AKT/mTOR signaling pathway.
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http://dx.doi.org/10.1016/j.mad.2022.111714DOI Listing
August 2022

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.

Am J Hum Genet 2022 08;109(8):1366-1387

Division of Genome Science, Department of Precision Medicine, National Institute of Health, Chungbuk, South Korea.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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http://dx.doi.org/10.1016/j.ajhg.2022.06.012DOI Listing
August 2022

HSP90AB1 Promotes the Proliferation, Migration, and Glycolysis of Head and Neck Squamous Cell Carcinoma.

Technol Cancer Res Treat 2022 Jan-Dec;21:15330338221118202

Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, 144984Medical School of Nanjing University, Nanjing, China.

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide. Heat shock protein 90 alpha family class B member 1 (HSP90AB1) is highly expressed in a variety of cancers and is associated with poor prognosis, however, its role in HNSCC is still poorly understood. This study aimed to explore the function HSP90AB1 played in HNSCC progression. The expression level of HSP90AB1 in HNSCC was analyzed by bioinformatics analysis and western blotting, and its relationship with clinicopathological parameters was analyzed by bioinformatics analysis and immunohistochemistry. Three stable HSP90AB1 knockdown HNSCC cell lines were constructed by lentiviral transfection. The effect of HSP90AB1 knockdown on the proliferation and migration of HNSCC cells was tested by CCK-8 assay, EdU incorporation assay, colony formation assay, nude mouse xenograft models, transwell migration assay, wound healing assay, and western blotting. The effect of HSP90AB1 knockdown on glycolysis in HNSCC cells was assessed by quantitative real-time PCR and related assay kits. Finally, the levels of Akt and phospho-Akt (Ser473) proteins after HSP90AB1 knockdown were detected by western blotting. HSP90AB1 was highly expressed in HNSCC and associated with T grade, lymph node metastasis, and prognosis. Knockdown of HSP90AB1 inhibited the proliferation, migration, and glycolysis of HNSCC, and reduced the level of phospho-Akt. HSP90AB1 functions as an oncogene in HNSCC, and has the potential to become a prognostic factor and therapeutic target.
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http://dx.doi.org/10.1177/15330338221118202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9358565PMC
August 2022

Surgical outcomes and sexual function after laparoscopic colon cancer surgery with transvaginal versus conventional specimen extraction: A retrospective propensity score matched cohort study.

Int J Surg 2022 Jul 31;104:106787. Epub 2022 Jul 31.

Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, NO.17 Panjiayuannanli, Chaoyang District, Beijing, 100021, China. Electronic address:

Background: Natural orifice specimen extraction has been shown to reduce postoperative pain and wound complications, and provide better cosmetic outcome. However, whether transvaginal specimen extraction affects sexual function remains controversial. The purpose of this study was to investigate the short-term outcomes, sexual function, cosmetic outcomes and prognosis after colon cancer surgery with transvaginal specimen extraction.

Method: This study was a propensity score-matched comparative retrospective study, based on prospectively collected data in a single center. This study included 70 pairs of propensity score-matched female patients who underwent laparoscopic curative resection for stage I-III colon cancer with transvaginal specimen extraction and conventional specimen extraction between November 2015 and November 2020. Covariates used in the propensity score included age, tumor diameter, tumor differentiation, T stage and American Joint Committee on Cancer stage. Outcome measures included postoperative complication, postoperative sexual function, cosmetic result, disease-free survival and overall survival.

Results: Patients in transvaginal group were administered with less additional analgesics (P = 0.008), and had fewer wound complications (P = 0.028). None of patient in the two groups underwent anastomotic leakage, incisional disruption or vaginal fistula. The baseline pre-operative Female Sexual Function Index scores in two groups were the same, and no difference was found in postoperative score between the two groups (P = 0.790). The cosmetic score was significantly better in transvaginal group than that of conventional laparoscopy group (P = 0.000). During the follow-up period, there were no differences in OS or DFS between the two groups (P = 0.658, P = 0.663).

Conclusions: Compared with laparoscopic colon cancer radical resection with specimen extraction, transvaginal specimen extraction is oncologically safe, brings better short-term outcomes, improved cosmetic results and has limited adverse effect on female's sexual function. This procedure can be further carried out in more appropriate patients.
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http://dx.doi.org/10.1016/j.ijsu.2022.106787DOI Listing
July 2022

Prevalence and heart rate variability characteristics of premature ventricular contractions detected by 24-hour Holter among outpatients with palpitations in China: a cross-sectional study.

BMJ Open 2022 08 2;12(8):e059337. Epub 2022 Aug 2.

Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

Objective: To analyse the prevalence and heart rate variability (HRV) characteristics of premature ventricular contraction (PVC) detected by 24-hour Holter among Chinese outpatients with palpitations.

Design: A cross-sectional study.

Setting: This study was conducted in a tertiary hospital.

Participants: A total of 4754 outpatients who received 24-hour Holter for palpitations.

Main Outcome Measures: Prevalence, HRV time-domain and frequency-domain analyses of 24-hour Holter, and echocardiographic parameters were assessed. Propensity score matching (PSM) was applied to balance baseline variables (age, gender) to decrease the bias between comparison groups.

Results: The prevalence of PVC was 67.7% (3220/4754), and was higher in men than women (69.9% vs 66.0%, p=0.004); the prevalence of frequent PVCs (PVC burden≥5%) was 7.7% (368/4754). Older patients had the highest frequency of PVC among all patients. However, among 3220 patients with PVC, younger patients' PVC burden was much higher. Matched 1:1 by age and gender, the HRV time-domain parameters in patients with PVC were all lower than those in patients without PVC (all p<0.05); for the HRV frequency-domain parameters, the patients with frequent PVCs had a higher low frequency/high frequency (LF/HF) ratio (5.4 vs 2.8, p<0.001) than those with PVC burden less than 5%.

Conclusions: The prevalence of PVC and frequent PVCs were 67.7% and 7.7%, respectively, detected by 24-hour Holter among Chinese outpatients with palpitations. Decreased HRV time-domain parameters suggested the occurrence of PVC, and increased LF/HF ratio represented the imbalance of autonomic nervous system in patients with frequent PVCs. Further studies are needed to understand the HRV indexes in PVC patients.
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http://dx.doi.org/10.1136/bmjopen-2021-059337DOI Listing
August 2022

The association of serum hsCRP with the risk of site-specific cancer mortality: the Health Examinee Study (HEXA) cohort.

Am J Epidemiol 2022 Aug 2. Epub 2022 Aug 2.

Department of Preventive Medicine, College of Medicine, Seoul National University, 103 Daehakro, Jongno-gu, Seoul 03080, Korea.

Few studies have investigated the association of high sensitivity C-reactive protein(hsCRP) levels with site-specific cancer-mortality. This study is aimed to examine the association of hsCRP with overall and site-specific cancer-mortality among Korean using the Health Examinees Study(HEXA) cohort (41,070 men and 81,011 women aged 40 years and over). Mortality information was obtained from the National Statistical Office of Korea, which provided the date and cause of death occurring until 12/31/2015 by linking the participant's unique national identifier. Cox-proportional hazard and restricted-cubic spline models were used to assess the association between hsCRP and cancer-mortality with adjustment for covariates. An analysis of site-specific cancer-mortality was focused on five major cancers (lung, liver, gastric, colorectal, and breast/prostate). The median of hsCRP were 0.77 and 0.59 mg/L for men and women, respectively. A dose-response association of hsCRP with overall cancer-mortality was observed in men but was disappeared in women after excluding death before 1 or 2 years from recruitment. The risk of lung, liver, and gastric cancer-mortality was significantly increased in subjects with elevated hsCRP levels but that colorectal and breast/prostate cancer-mortality were not, predominantly in men. The dose-response association of hsCRP with cancer-mortality was observed differently depending on the site-specific cancer-mortality as sex.
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http://dx.doi.org/10.1093/aje/kwac141DOI Listing
August 2022

Isoflavone and soy food intake and risk of lung cancer in never smokers: report from prospective studies in Japan and China.

Eur J Nutr 2022 Aug 1. Epub 2022 Aug 1.

Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Purpose: Evidence from several cohorts has suggested that a higher intake of isoflavone is associated with lower risk of lung cancer in never smokers, but the association has not been investigated by histologic type of lung cancer. Adenocarcinoma is a common histologic type found in never smokers. We hypothesized that a higher intake of isoflavone is associated with a lower risk of lung adenocarcinoma among never smokers. Here, we examined the associations of isoflavone and soy food intake with lung cancer and its histologic types in never smokers.

Methods: We performed a pooled analysis using data from the Japan Public Health Center-based Prospective Study, Shanghai Women's Health Study and Shanghai Men's Study with 147,296 never smokers aged 40-74 years with no history of cancer. During 1,990,040 person-years of follow-up, 1247 lung cancer cases were documented. Dietary isoflavone and soy food intake were assessed using a food-frequency questionnaire. Multivariable Cox proportional hazards models assessed the associations between isoflavone and soy intake with incidence of lung cancer by histologic type.

Results: A higher intake of dietary isoflavone and soy food were associated with reduced risk of lung adenocarcinoma. The multivariable hazard ratios (HRs) (95% CI) of risk of lung adenocarcinoma for the highest versus lowest intakes of isoflavone and soy food were 0.74 (0.60-0.92) and 0.78 (0.63-0.96), respectively. The multivariable HRs of risk of lung adenocarcinoma associated with each 10 mg/day increase in isoflavone and each 50 g/day increase in soy food intake were 0.81 (0.70-0.94) and 0.84 (0.73-0.96), respectively.

Conclusion: Higher intake of isoflavone and soy food was associated with lower risk of lung adenocarcinoma in never smokers.
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http://dx.doi.org/10.1007/s00394-022-02968-yDOI Listing
August 2022

Characterization of Treponema denticola Major Surface Protein (Msp) by Deletion Analysis and Advanced Molecular Modeling.

J Bacteriol 2022 Aug 1:e0022822. Epub 2022 Aug 1.

Department of Biologic and Materials Sciences and Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.

Treponema denticola, a keystone pathogen in periodontitis, is a model organism for studying Treponema physiology and host-microbe interactions. Its major surface protein Msp forms an oligomeric outer membrane complex that binds fibronectin, has cytotoxic pore-forming activity, and disrupts several intracellular processes in host cells. T. denticola is an ortholog of the Treponema pallidum to - gene family that includes , whose remarkable hypervariability is proposed to contribute to T. pallidum immune evasion. We recently identified the primary Msp surface-exposed epitope and proposed a model of the Msp protein as a β-barrel protein similar to Gram-negative bacterial porins. Here, we report fine-scale Msp mutagenesis demonstrating that both the N and C termini as well as the centrally located Msp surface epitope are required for native Msp oligomer expression. Removal of as few as three C-terminal amino acids abrogated Msp detection on the T. denticola cell surface, and deletion of four residues resulted in complete loss of detectable Msp. Substitution of a FLAG tag for either residues 6 to 13 of mature Msp or an 8-residue portion of the central Msp surface epitope resulted in expression of full-length Msp but absence of the oligomer, suggesting roles for both domains in oligomer formation. Consistent with previously reported Msp N-glycosylation, proteinase K treatment of intact cells released a 25 kDa polypeptide containing the Msp surface epitope into culture supernatants. Molecular modeling of Msp using novel metagenome-derived multiple sequence alignment (MSA) algorithms supports the hypothesis that Msp is a large-diameter, trimeric outer membrane porin-like protein whose potential transport substrate remains to be identified. The Treponema denticola gene encoding its major surface protein (Msp) is an ortholog of the T. pallidum to - gene family that includes , whose remarkable hypervariability is proposed to contribute to T. pallidum immune evasion. Using a combined strategy of fine-scale mutagenesis and advanced predictive molecular modeling, we characterized the Msp protein and present a high-confidence model of its structure as an oligomer embedded in the outer membrane. This work adds to knowledge of Msp-like proteins in oral treponemes and may contribute to understanding the evolutionary and potential functional relationships between T. denticola Msp and the orthologous T. pallidum Tpr proteins.
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http://dx.doi.org/10.1128/jb.00228-22DOI Listing
August 2022

Quality analysis of hawthorn leaves (the leaves of Crataegus pinnatifida Bge. var major N.E.Br) in different harvest time.

Phytochem Anal 2022 Jul 31. Epub 2022 Jul 31.

Beijing Institute of Radiation Medicine, Beijing, China.

Introduction: Harvest time plays an important role on the quality of medicinal plants. The leaves of Crataegus pinnatifida Bge. var major N.E.Br (hawthorn leaves) could be harvested in summer and autumn according to the Pharmacopoeia of the People's Republic of China (Pharmacopoeia). However, little is known about the difference of the chemical constituents in hawthorn leaves with the harvest seasonal variations.

Objective: The chemical constituents of hawthorn leaves in different months were comprehensively analysed to determine the best harvest time.

Methods: Initially, the chemical information of the hawthorn leaves were obtained by ultra-high-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS). Subsequently, principal component analysis (PCA) was applied to compare the chemical compositions of hawthorn leaves harvested in different months. Then, an absolute quantitation method was established using high-performance liquid chromatography-charged aerosol detector (HPLC-CAD) to determine the contents of five compounds and clarify the changes of these components with the harvest seasonal variations. Meanwhile, a semi-quantitative method by integrating HPLC-CAD with inverse gradient compensation was also established and verified.

Results: Fifty-eight compounds were identified through UHPLC-Q-TOF-MS. PCA revealed that the harvest season of hawthorn leaves had a significant effect on the chemical compositions. The contents of five components were relatively high in autumn. Other four main components without reference standards were further analysed through the semi-quantitative method, which also showed a high content in autumn.

Conclusions: This work emphasised the effect of harvest time on the chemical constituents of hawthorn leaves and autumn is recommended to ensure the quality.
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http://dx.doi.org/10.1002/pca.3166DOI Listing
July 2022

A novel form of precise segmentectomy-Triumphal arch-like anatomical segmentectomy.

Thorac Cancer 2022 Jul 28. Epub 2022 Jul 28.

Thoracic Department, Fujian Medical University Union Hospital, Fuzhou, China.

The increasingly accurate sublobar anatomical resection is constantly being explored and practiced. Surgeons try to preserve as much viable lung tissue as possible. Sublobar resection of the target tissue is similar with a cone-shaped structure which penetrates deeply into the pulmonary parenchyma and runs through the lobe at both ends. This has not previously been described. The remaining lung tissue resembles the Triumphal Arch in Paris, France. Here, we describe triumphal arch-like sublobectomy in detail, aiming to provide clinicians with an idea to explore this novel sublobectomy under similar conditions.
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http://dx.doi.org/10.1111/1759-7714.14584DOI Listing
July 2022

Human Grasp Mechanism Understanding, Human-Inspired Grasp Control and Robotic Grasping Planning for Agricultural Robots.

Sensors (Basel) 2022 Jul 13;22(14). Epub 2022 Jul 13.

College of Artificial Intelligence, Nanjing Agricultural University, Nanjing 210031, China.

As the end execution tool of agricultural robots, the manipulator directly determines whether the grasping task can be successfully completed. The human hand can adapt to various objects and achieve stable grasping, which is the highest goal for manipulator design and development. Thus, this study combines a multi-sensor fusion tactile glove to simulate manual grasping, explores the mechanism and characteristics of the human hand, and formulates rational grasping plans. According to the shape and size of fruits and vegetables, the grasping gesture library is summarized to facilitate the matching of optimal grasping gestures. By analyzing inter-finger curvature correlations and inter-joint pressure correlations, we investigated the synergistic motion characteristics of the human hand. In addition, the force data were processed by the wavelet transform algorithms and then the thresholds for sliding detection were set to ensure robust grasping. The acceleration law under the interaction with the external environment during grasping was also discussed, including stable movement, accidental collision, and placement of the target position. Finally, according to the analysis and summary of the manual gripping mechanism, the corresponding pre-gripping planning was designed to provide theoretical guidance and ideas for the gripping of robots.
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http://dx.doi.org/10.3390/s22145240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324230PMC
July 2022

Electrochemical Immunoassay for Tumor Marker CA19-9 Detection Based on Self-Assembled Monolayer.

Molecules 2022 Jul 18;27(14). Epub 2022 Jul 18.

Cancer Research Institute, Henan Academy Institute of Chinese Medicine, Zhengzhou 450000, China.

A CA19-9 electrochemical immunosensor was constructed using a hybrid self-assembled membrane modified with a gold electrode and applied to detect real samples. Hybrid self-assembled membranes were selected for electrode modification and used to detect antigens. First, the pretreated working electrodes were placed in a 3-mercaptopropionic acid (MPA)/β-mercaptoethanol (ME) mixture for 24 h for self-assembly. The electrodes were then placed in an EDC/NHS mixture for 1 h. Layer modification was performed by stepwise dropwise addition of CA19-9 antibody, BSA, and antigen. Differential pulse voltammetry was used to characterize this immunosensor preparation process. The assembled electrochemical immunosensor enables linear detection in the concentration range of 0.05-500 U/mL of CA19-9, and the detection limit was calculated as 0.01 U/mL. The results of the specificity measurement test showed that the signal change of the interfering substance was much lower than the response value of the detected antigen, indicating that the sensor has good specificity and strong anti-interference ability. The repeatability test results showed that the relative standard deviations were less than 5%, showing good accuracy and precision. The CA19-9 electrochemical immunosensor was used for the actual sample detection, and the experimental results of the standard serum addition method showed that the RSD values of the test concentrations were all less than 10%. The recoveries were 102.4-115.0%, indicating that the assay has high precision, good accuracy, and high potential application value.
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http://dx.doi.org/10.3390/molecules27144578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324264PMC
July 2022

ATP13A2 Declines Zinc-Induced Accumulation of α-Synuclein in a Parkinson's Disease Model.

Int J Mol Sci 2022 Jul 21;23(14). Epub 2022 Jul 21.

College of Life and Health Sciences, Northeastern University, Shenyang 110169, China.

Parkinson's disease (PD) is characterized by the presence of Lewy bodies caused by α-synuclein. The imbalance of zinc homeostasis is a major cause of PD, promoting α-synuclein accumulation. ATP13A2, a transporter found in acidic vesicles, plays an important role in Zn homeostasis and is highly expressed in Lewy bodies in PD-surviving neurons. ATP13A2 is involved in the transport of zinc ions in lysosomes and exosomes and inhibits the aggregation of α-synuclein. However, the potential mechanism underlying the regulation of zinc homeostasis and α-synuclein accumulation by ATP13A2 remains unexplored. We used α-synuclein-GFP transgenic mice and HEK293 α-synuclein-DsRed cell line as models. The spatial exploration behavior of mice was significantly reduced, and phosphorylation levels of α-synuclein increased upon high Zn treatment. High Zn also inhibited the autophagy pathway by reducing LAMP2a levels and changing the expression of LC3 and P62, by reducing mitochondrial membrane potential and increasing the expression of cytochrom C, and by activating the ERK/P38 apoptosis signaling pathway, ultimately leading to increased caspase 3 levels. These protein changes were reversed after ATP13A2 overexpression, whereas ATP13A2 knockout exacerbated α-synuclein phosphorylation levels. These results suggest that ATP13A2 may have a protective effect on Zn-induced abnormal aggregation of α-synuclein, lysosomal dysfunction, and apoptosis.
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http://dx.doi.org/10.3390/ijms23148035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9318580PMC
July 2022

Racial/Ethnic Disparities in Mortality Related to Access to Care for Major Cancers in the United States.

Cancers (Basel) 2022 Jul 12;14(14). Epub 2022 Jul 12.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37203, USA.

The reasons underlying racial/ethnic mortality disparities for cancer patients remain poorly understood, especially regarding the role of access to care. Over five million patients with a primary diagnosis of lung, breast, prostate, colon/rectum, pancreas, ovary, or liver cancer during 2004-2014, were identified from the National Cancer Database. Cox proportional hazards models were applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for total mortality associated with race/ethnicity, and access to care related factors (i.e., socioeconomic status [SES], insurance, treating facility, and residential type) for each cancer. Racial/ethnic disparities in total mortality were observed across seven cancers. Compared with non-Hispanic (NH)-white patients, NH-black patients with breast (HR = 1.27, 95% CI: 1.26 to 1.29), ovarian (HR = 1.20, 95% CI: 1.17 to 1.23), prostate (HR = 1.31, 95% CI: 1.30 to 1.33), colorectal (HR = 1.11, 95% CI: 1.10 to 1.12) or pancreatic (HR = 1.03, 95% CI: 1.02 to 1.05) cancers had significantly elevated mortality, while Asians (13-31%) and Hispanics (13-19%) had lower mortality for all cancers. Racial/ethnic disparities were observed across all strata of access to care related factors and modified by those factors. NH-black and NH-white disparities were most evident among patients with high SES or those with private insurance, while Hispanic/Asian versus NH-white disparities were more evident among patients with low SES or those with no/poor insurance. Racial/ethnic mortality disparities for major cancers exist across all patient groups with different access to care levels. The influence of SES or insurance on mortality disparity follows different patterns for racial/ethnic minorities versus NH-whites. Our study highlights the need for racial/ethnic-specific strategies to reduce the mortality disparities for major cancers.
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http://dx.doi.org/10.3390/cancers14143390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9318931PMC
July 2022

Associations between circulating proteins and risk of breast cancer by intrinsic subtypes: a Mendelian randomisation analysis.

Br J Cancer 2022 Jul 26. Epub 2022 Jul 26.

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: The aetiologic role of circulating proteins in the development of breast cancer subtypes is not clear. We aimed to examine the potential causal effects of circulating proteins on the risk of breast cancer by intrinsic-like subtypes within the Mendelian randomisation (MR) framework.

Methods: MR was performed using summary statistics from two sources: the INTERVAL protein quantitative trait loci (pQTL) Study (1890 circulating proteins and 3301 healthy individuals) and the Breast Cancer Association Consortium (BCAC; 106,278 invasive cases and 91,477 controls). The inverse-variance (IVW)-weighted method was used as the main analysis to evaluate the associations between genetically predicted proteins and the risk of five different intrinsic-like breast cancer subtypes and the weighted median MR method, the Egger regression, the MR-PRESSO, and the MRLocus method were performed as secondary analysis.

Results: We identified 98 unique proteins significantly associated with the risk of one or more subtypes (Benjamini-Hochberg false discovery rate < 0.05). Among them, 51 were potentially specific to luminal A-like subtype, 14 to luminal B/Her2-negative-like, 11 to triple negative, 3 to luminal B-like, and 2 to Her2-enriched-like breast cancer (n = 81). Associations for three proteins (ICAM1, PLA2R1 and TXNDC12) showed evident heterogeneity across the subtypes. For example, higher levels of genetically predicted ICAM1 (per unit of increase) were associated with an increased risk of luminal B/HER2-negative-like cancer (OR = 1.06, 95% CI = 1.03-1.08, BH-FDR = 2.43 × 10) while inversely associated with triple-negative breast cancer with borderline significance (OR = 0.97, 95% CI = 0.95-0.99, BH-FDR = 0.065, P < 0.005).

Conclusions: Our study found potential causal associations with the risk of subtypes of breast cancer for 98 proteins. Associations of ICAM1, PLA2R1 and TXNDC12 varied substantially across the subtypes. The identified proteins may partly explain the heterogeneity in the aetiology of distinct subtypes of breast cancer and facilitate the personalised risk assessment of the malignancy.
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http://dx.doi.org/10.1038/s41416-022-01923-2DOI Listing
July 2022

Current understanding of the interactions between metal ions and Apolipoprotein E in Alzheimer's disease.

Neurobiol Dis 2022 Jul 22;172:105824. Epub 2022 Jul 22.

Department of Anatomy, Histology and Embryology, School of Medicine, Shenzhen University, Shenzhen, China. Electronic address:

Alzheimer's disease (AD), the most common type of dementia in the elderly, is a chronic and progressive neurodegenerative disorder with no effective disease-modifying treatments to date. Studies have shown that an imbalance in brain metal ions, such as zinc, copper, and iron, is closely related to the onset and progression of AD. Many efforts have been made to understand metal-related mechanisms and therapeutic strategies for AD. Emerging evidence suggests that interactions of brain metal ions and apolipoprotein E (ApoE), which is the strongest genetic risk factor for late-onset AD, may be one of the mechanisms for neurodegeneration. Here, we summarize the key points regarding how metal ions and ApoE contribute to the pathogenesis of AD. We further describe the interactions between metal ions and ApoE in the brain and propose that their interactions play an important role in neuropathological alterations and cognitive decline in AD.
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http://dx.doi.org/10.1016/j.nbd.2022.105824DOI Listing
July 2022

Characteristics of HBV Novel Serum Markers across Distinct Phases in Treatment-Naïve Chronic HBV-Infected Patients.

Dis Markers 2022 14;2022:4133283. Epub 2022 Jul 14.

Intervention and Cell Therapy Center, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518035 Guangdong Province, China.

Methods: A total of 111 patients in total from different disease phases were recruited, including 21 in immune-tolerant (IT) phase, 49 in immune-clearance (IC) phases, 29 in immune-control or low replicative (LR) phase, and 12 in reactivation phases. Serum HBV RNA, anti-HBc, HBcrAg, and intrahepatic covalently closed circular DNA (cccDNA) were quantified and each of these indicator's correlation with liver inflammation was analyzed.

Results: HBeAg-positive individuals had significant higher serum levels of HBV RNA and HBcrAg than those who were HBeAg negative, similar to that of serum HBV DNA. Comparatively, HBV RNA ( =0.79, < 0.01) and HBcrAg ( =0.78, < 0.01) had almost same higher overall correlation with the cccDNA, as that of HBV DNA ( =0.81, < 0.01). Serum anti-HBc level ( = -0.52, < 0.05) is negatively correlated with cccDNA level at IT phase rather than the other three phases. When set the cutoff value at 4.00 log IU/mL, serum anti-HBc showed potential to indicate liver inflammation, with AUC as 0.79 and the specificities as 78.85% for HBeAg positive, and with AUC as 0.72 and the specificities as 62.16% for HBeAg-negative patients, respectively.

Conclusions: In treatment-naïve patients, levels of serological markers HBV RNA and HBcrAg could mirror intrahepatic cccDNA level, but were not superior to HBV DNA level. Serum anti-HBc level had certain potential to be used as a predicting marker for liver inflammation.
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http://dx.doi.org/10.1155/2022/4133283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303147PMC
July 2022

Therapeutic Strategies For Tay-Sachs Disease.

Front Pharmacol 2022 5;13:906647. Epub 2022 Jul 5.

National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United States.

Tay-Sachs disease (TSD) is an autosomal recessive disease that features progressive neurodegenerative presentations. It affects one in 100,000 live births. Currently, there is no approved therapy or cure. This review summarizes multiple drug development strategies for TSD, including enzyme replacement therapy, pharmaceutical chaperone therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell replacement therapy. and systems are described to assess the efficacy of the aforementioned therapeutic strategies. Furthermore, we discuss using MALDI mass spectrometry to perform a high throughput screen of compound libraries. This enables discovery of compounds that reduce GM2 and can lead to further development of a TSD therapy.
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http://dx.doi.org/10.3389/fphar.2022.906647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294361PMC
July 2022

Pathogenic variant in ACTL7A causes severe teratozoospermia characterized by bubble-shaped acrosomes and male infertility.

Mol Hum Reprod 2022 Jul;28(8)

Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, China.

Teratozoospermia is a common factor associated with male infertility. However, teratozoospermia characterized by bubble-shaped acrosomes (BSAs) has not yet been identified in men and the causative genes are unknown. The present study is of a patient with severe teratozoospermia characterized by BSA and carrying a variant (c.1204G>A, p.Gly402Ser) of actin-like 7A (ACTL7A). For further verification, we generated an Actl7a-mutated mouse model (p.Gly407Ser) carrying an equivalent variant to that in the patient. We found that homozygous Actl7a-mutated (Actl7aMut/Mut) male mice were sterile, and all their sperm showed acrosomal abnormalities. We detected by transmission electron microscopy that during acrosomal biogenesis, the acrosome detaches from the nuclear membrane in Actl7aMut/Mut mice. Furthermore, mutant ACTL7A failed to attach to the acroplaxome and was discharged by cytoplasmic droplets, which led to the absence of ACTL7A in epididymal spermatozoa in mice. The mutant sperm failed to activate the oocyte, and sperm-borne oocyte activation factor phospholipase C zeta (PLCζ) discharge accompanied by ACTL7A was observed, leading to total fertilization failure (TFF). Immunoprecipitation followed by liquid chromatography-mass spectrometry showed that several differentially expressed proteins participate in acrosome assembly and actin filament organization. Furthermore, assisted oocyte activation by calcium ionophore exposure successfully overcame TFF in the couple with an ACTL7A pathogenic variant. Our study defined a novel phenotype of an acrosomal abnormality characterized by BSA, revealed the underlying mechanism of a pathogenic variant in ACTL7A and provided a genetic marker and potential therapeutic option for male infertility.
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http://dx.doi.org/10.1093/molehr/gaac028DOI Listing
July 2022

Rituximab plus cladribine versus R-CHOP in frontline management of marginal zone lymphoma in China: a propensity-score matched multicenter study.

Ann Hematol 2022 Jul 20. Epub 2022 Jul 20.

Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China.

Marginal zone lymphoma (MZL) is an uncommon subtype of non-Hodgkin lymphoma (NHL). Combination of rituximab and cladribine (R-2CdA) is a potential option for indolent NHL (iNHL) and mantle cell lymphoma (MCL) patients. The goal of this multicenter retrospective study was to assess the efficacy and safety of R-2CdA in MZL to support consensus-reaching in first-line therapy in advanced-stage patients. We searched electronic medical records databases of eight centers in China. Between November 2014 and December 2019, 183 symptomatic advanced MZL patients (42 treated with R-2CdA and 141 with rituximab plus cyclophosphamide, adriamycin, vincristine, and prednisone [R-CHOP]) were identified. After propensity score matching (PSM) (1:1) to adjust for clinical characteristics, 39 patients from each treatment arm were selected. The overall response rate (ORR) (84.6% vs. 94.9%, P = 0.263) and complete response rate (59.0% vs. 66.7%, P = 0.487) were comparable between two protocols. Neither progression-free survival (PFS), including the 5-year PFS (67.7% vs. 56.1%, P = 0.352), nor overall survival was improved by R-2CdA versus R-CHOP. However, R-2CdA was more tolerable than R-CHOP in MZL patients regarding grade 3/4 hematological adverse events (odds ratio [OR] 0.565, 95% confidence interval [CI] neutropenic fever (OR 0.795, 95% CI 0.678-0.932), and infections (OR 0.800, 95% CI 0.640-1.000). Overall, our study demonstrated that R-2CdA is potentially as effective as but safer than R-CHOP in advanced MZL.
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http://dx.doi.org/10.1007/s00277-022-04919-3DOI Listing
July 2022

How to distinguish thoracic and cervical lymph nodes during minimally invasive esophagectomy.

Thorac Cancer 2022 Jul 18. Epub 2022 Jul 18.

Key labortatory of Cardio-Thoracic Surgery (Fujian Medical university), Fujian Province University, Fuzhou, China.

Purpose: In this article, we aimed to reconstruct the cervical-thoracic junction plane (CTJP) using a three-dimensional (3D) reconstruction system. Thus, the CTJP can be judged during surgery to better distinguish cervical-thoracic lymph nodes.

Methods: We included patients in Fujian Medical University Union Hospital from December 2019 to March 2020. All patients underwent a thin-slice and enhanced computed tomography scan of the chest with 3D reconstruction using the IQQA system (EDDA technology) to reconstruct the CTJP, brachiocephalic trunk, right common carotid artery, and right subclavian artery. The distance from the intersection of the right subclavian artery and the CTJP to the origin of the right subclavian artery (ORSA) was measured, and the relationship between this distance and the patient's sex, BMI and height was analyzed.

Results: Seventy-three patients were enrolled, of whom 12 had ORSA above the CTJP, while 61 had ORSA below the plane. There was a significant difference in age between the two groups (p = 0.04), compared with height, weight and BMI (p > 0.05). In 61 patients with the ORSA below the CTJP, the average distance was 24.7 ± 7.6 mm. The difference between the distance and BMI (p = 0.02) was statistically significant, and it was increased with increasing BMI.

Conclusions: The relationship between the ORSA and CTJP can be clarified through 3D reconstruction. The cervical-thoracic recurrent laryngeal nerve lymph nodes can be distinguished clearly in minimally invasive esophagectomy, contributing to the accurate N staging of middle-thoracic esophageal cancer.
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http://dx.doi.org/10.1111/1759-7714.14554DOI Listing
July 2022

Predictive Value of Clinical and Pathological Characteristics for Metastatic Radioactive Iodine-Refractory Differentiated Thyroid Carcinoma: A 16-year Retrospective Study.

Front Endocrinol (Lausanne) 2022 28;13:930180. Epub 2022 Jun 28.

Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.

Purpose: To assess predictive value of clinical and pathological characteristics for metastatic radioactive iodine-refractory differentiated thyroid carcinoma (RAIR-DTC) in early stage retrospectively.

Methods: We studied 199 metastatic DTC patients who were divided into two groups (TgAb negative and TgAb positive). The stimulated Tg (Sti-Tg) at the first and second radioiodine therapy (RIT) were defined as Sti-Tg1 and Sti-Tg2, the suppressed Tg (Sup-Tg) were designated as Sup-Tg1 and Sup-Tg2, while the TgAb were defined as TgAb1 and TgAb2, respectively. Univariate analysis and Logistic regression were used to investigate the effects of 13 observed factors to predict RAIR-DTC.

Results: In TgAb negative group, ROC curve analysis showed that cut-off values of age, Sti-Tg2/Sti-Tg1 and Sup-Tg2/Sup-Tg1 to predict RAIR-DTC were 40 years old, 57.0% and 81.0%, respectively. Age, extrathyroid invasion, Sti-Tg2/Sti-Tg1, Sup-Tg2/Sup-Tg1 and BRAF gene mutation were proved to be independent factors predicting RAIR-DTC. In TgAb-positive group, ROC curve analysis showed that cut-off values of age, TgAb1 and TgAb2/TgAb1 to predict RAIR-DTC were 55 years old, 297 IU/ml (14.8 times higher than the upper limit) and 53.6%, respectively.

Conclusions: For TgAb-negative DTC, age over 40, extraglandular invasion, mutated BRAF gene, Sti-Tg decreased less than 43%, and Sup-Tg decreased less than 19% after the first two courses of RIT were independent predictors for RAIR-DTC. For TgAb-positive DTC, age over 55, extraglandular invasion, mutated BRAF gene, distant metastasis before RIT, TgAb level 14.8 times higher than the upper limit, TgAb dropped less than 46.4% after two courses of RIT were influencing factors.
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http://dx.doi.org/10.3389/fendo.2022.930180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9281388PMC
July 2022

Progressive assembly of multi-domain protein structures from cryo-EM density maps.

Nat Comput Sci 2022 Apr 28;2(4):265-275. Epub 2022 Apr 28.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.

Progress in cryo-electron microscopy has provided the potential for large-size protein structure determination. However, the success rate for solving multi-domain proteins remains low because of the difficulty in modelling inter-domain orientations. Here we developed domain enhanced modeling using cryo-electron microscopy (DEMO-EM), an automatic method to assemble multi-domain structures from cryo-electron microscopy maps through a progressive structural refinement procedure combining rigid-body domain fitting and flexible assembly simulations with deep-neural-network inter-domain distance profiles. The method was tested on a large-scale benchmark set of proteins containing up to 12 continuous and discontinuous domains with medium- to low-resolution density maps, where DEMO-EM produced models with correct inter-domain orientations (template modeling score (TM-score) >0.5) for 97% of cases and outperformed state-of-the-art methods. DEMO-EM was applied to the severe acute respiratory syndrome coronavirus 2 genome and generated models with average TM-score and root-mean-square deviation of 0.97 and 1.3 Å, respectively, with respect to the deposited structures. These results demonstrate an efficient pipeline that enables automated and reliable large-scale multi-domain protein structure modelling from cryo-electron microscopy maps.
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http://dx.doi.org/10.1038/s43588-022-00232-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9281201PMC
April 2022

Synthesis and anti-SARS-CoV-2 activity of deuterated GS-441524 analogs.

Tetrahedron Lett 2022 Aug 9;104:154012. Epub 2022 Jul 9.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.

The COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuing to spread around the world. GS-441524 is the parent nucleoside of remdesivir which is the first drug approved for the treatment of COVID-19, and demonstrates strong activity against SARS-Cov-2 in vitro and in vivo. Herein, we reported the synthesis of a series of deuterated GS-441524 analogs, which had deuterium atoms up to five at the ribose and the nucleobase moieties. Compared to GS-441524, all the deuterated compounds showed similar inhibitory activities against SARS-CoV-2 in vitro.
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http://dx.doi.org/10.1016/j.tetlet.2022.154012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9270844PMC
August 2022
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