Publications by authors named "Hong Jiang"

2,518 Publications

  • Page 1 of 1

Oridonin inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia by inducing apoptosis and necroptosis.

Cell Death Discov 2021 Oct 18;7(1):297. Epub 2021 Oct 18.

School of Pharmaceutical Sciences, Tsinghua University, 100084, Beijing, China.

DNA (cytosine-5)-methyltransferase 3A (DNMT3A) mutations occur in ~20% of de novo acute myeloid leukemia (AML) patients, and >50% of these mutations in AML samples are heterozygous missense alterations within the methyltransferase domain at residue R882. DNMT3A R882 mutations in AML patients promote resistance to anthracycline chemotherapy and drive relapse. In this study, we performed high-throughput screening and identified that oridonin, an ent-kaurene diterpenoid extracted from the Chinese herb Rabdosia rubescens, inhibits DNMT3A R882 mutant leukemic cells at a low-micromolar concentration (IC = 2.1 µM) by activating both RIPK1-Caspase-8-Caspase-3-mediated apoptosis and RIPK1-RIPK3-MLKL-mediated necroptosis. The inhibitory effect of oridonin against DNMT3A R882 mutant leukemia cells can also be observed in vivo. Furthermore, oridonin inhibits clonal hematopoiesis of hematopoietic stem cells (HSCs) with Dnmt3a R878H mutation comparing to normal HSCs by inducing apoptosis and necroptosis. Overall, oridonin is a potential and promising drug candidate or lead compound targeting DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia.
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http://dx.doi.org/10.1038/s41420-021-00697-5DOI Listing
October 2021

Deficient immunoproteasome assembly drives gain of α-synuclein pathology in Parkinson's disease.

Redox Biol 2021 Oct 14;47:102167. Epub 2021 Oct 14.

Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China. Electronic address:

Aberrant α-synuclein (α-Syn) accumulation resulting from proteasome dysfunction is considered as a prominent factor to initiate and aggravate the neurodegeneration in Parkinson's disease (PD). Although the involvement of 26S proteasome in proteostasis imbalance has been widely accepted, our knowledge about the regulation of immunoproteasome function and its potential role in α-Syn pathology remains limited. Immunoproteasome abundance and proteolytic activities depend on the finely tuned assembly process, especially β-ring formation mediated by the only well-known chaperone proteasome maturation protein (POMP). Here, we identified that α-Syn overexpression was associated with a reduction in immunoproteasome function, which in turn limited the degradation of polo-like kinase 2 (PLK2), exacerbated α-Syn Ser129 phosphorylation and aggregation, ultimately leading to the neurodegeneration. These effects could be dramatically attenuated by β5i overexpression. Mechanistically, α-Syn suppressed the transcriptional regulation of POMP by nuclear factor erythroid 2-related factor 2 (NRF2), thereby preventing the assembly of immunoproteasome β subunits. Dopaminergic neurons-specific overexpression of NRF2-POMP axis effectively rescued the aggregation of α-Syn and PD-like phenotypes. These findings characterized abnormal immunoproteasome assembly as a key contributor governing α-Syn accumulation and neurodegeneration, which might open up a new perspective for the implication of immunoproteasome in PD and provide approaches of manipulating immunoproteasome assembly for therapeutic purposes.
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http://dx.doi.org/10.1016/j.redox.2021.102167DOI Listing
October 2021

Relationship Between Immunoinflammation and Coronary Physiology Evaluated by Quantitative Flow Ratio in Patients With Coronary Artery Disease.

Front Cardiovasc Med 2021 29;8:714276. Epub 2021 Sep 29.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.

The association between coronary physiology and immunoinflammation has not been investigated. We performed a retrospective study using quantitative flow ratio (QFR) to evaluate the interaction between immunoinflammatory biomarkers and coronary physiology. A total of 172 patients with CAD who underwent coronary arteriography (CAG) and QFR were continuously enrolled from May 2020 to February 2021. As a quantitative indicator of coronary physiology, QFR can reflect the functional severity of coronary artery stenosis. The target vessel measured by QFR was defined as that with the most severe lesions. Significant coronary anatomical stenosis was defined as 70% stenosis in the target vessel. Compared with the QFR > 0.8 group, interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were increased and CD3 and CD4 T lymphocyte counts were decreased in the QFR ≤ 0.8 group. In addition, patients with DS ≤ 70% had higher IL-6, IL-10, and TNF-α levels and decreased CD3 and CD4 T lymphocyte counts than those with DS > 70%. Logistic regression analysis indicated IL-6 to be an independent predictor of significant coronary functional and anatomic stenosis (odds ratio, 1.125; 95% CI, 1.059-1.196; < 0.001). Receiver operating characteristic (ROC) analyses showed that IL-6 > 6.36 was predictive of QFR ≤ 0.8 of the target vessel. The combination of IL-6, IL-10 and CD4 improved the value for predicting QFR ≤ 0.8 of the target vessel (AUC, 0.737; 95% CI, 0.661-0.810). Among immunoinflammatory biomarkers, IL-6 was independently associated with a higher risk of QFR ≤ 0.8 of the target vessel. The combination of immunoinflammatory biomarkers was highly predictive of significant coronary functional and anatomic stenosis.
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http://dx.doi.org/10.3389/fcvm.2021.714276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511462PMC
September 2021

Evaluation of Bivalirudin-Associated Major Adverse Cardiac and Hemorrhagic Events in Acute Coronary Syndrome Patients on Chronic Dialysis Following Percutaneous Coronary Intervention.

J Invasive Cardiol 2021 Oct 15. Epub 2021 Oct 15.

China-Japan Friendship Hospital, Yinghua Dongjie 2, Chaoyang District, Beijing 100029, China.

Background And Aim: Patients with chronic dialysis dependency undergoing percutaneous coronary intervention (PCI) are at a greater risk of hemorrhagic and ischemic events. Due to their exclusion from randomized clinical trials, the optimal antithrombotic regimen for this population remains unknown. Bivalirudin has been associated with fewer hemorrhagic complications than unfractionated heparin (UFH) in patients undergoing PCI. We evaluated major adverse cardiac event (MACE) and hemorrhagic event rates for an antithrombotic regimen using bivalirudin or UFH during PCI in acute coronary syndrome (ACS) patients with chronic dialysis dependency.

Methods: A retrospective study was performed, including 211 patients on dialysis undergoing PCI due to ACS from January 2014 to April 2019 at the China-Japan Friendship Hospital. Patients were divided into 2 groups based on anticoagulation regimen: the bivalirudin group (86 cases) or the UFH group (125 cases) during and after PCI. Statistical analyses were used to compare MACE and hemorrhagic events between groups at 30 days after PCI.

Results: No patients experienced stent thrombosis within 30 days after PCI regardless of anticoagulant. There was no difference in the incidence of MACE in the bivalirudin group compared with the UFH group (6.98% vs 8.80%, respectively; P>.05). The rate of hemorrhagic events in the bivalirudin group was significantly lower than in the UHP group (5.81% vs 18.4%, respectively; P<.05), particularly for rates of mild bleeding (4.65% vs 15.2%, respectively; P<.05). There were no significant differences in rates of severe bleeding between the bivalirudin and UFH groups (1.16% vs 4.00%, respectively; P>.05), although fewer severe hemorrhagic events occurred in the bivalirudin group.

Conclusion: Bivalirudin was associated with fewer bleeding events following PCI in individuals with end-stage renal disease on dialysis.
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October 2021

Accurate Prediction of Band Structure of FeS: A Hard Quest of Advanced First-Principles Approaches.

Front Chem 2021 28;9:747972. Epub 2021 Sep 28.

Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.

The pyrite and marcasite polymorphs of FeS have attracted considerable interests for their potential applications in optoelectronic devices because of their appropriate electronic and optical properties. Controversies regarding their fundamental band gaps remain in both experimental and theoretical materials research of FeS. In this work, we present a systematic theoretical investigation into the electronic band structures of the two polymorphs by using many-body perturbation theory with the approximation implemented in the full-potential linearized augmented plane waves (FP-LAPW) framework. By comparing the quasi-particle (QP) band structures computed with the conventional LAPW basis and the one extended by high-energy local orbitals (HLOs), denoted as LAPW + HLOs, we find that one-shot or partially self-consistent ( and , respectively) on top of the Perdew-Burke-Ernzerhof (PBE) generalized gradient approximation with a converged LAPW + HLOs basis is able to remedy the artifact reported in the previous calculations, and leads to overall good agreement with experiment for the fundamental band gaps of the two polymorphs. Density of states calculated from @PBE with the converged LAPW + HLOs basis agrees well with the energy distribution curves from photo-electron spectroscopy for pyrite. We have also investigated the performances of several hybrid functionals, which were previously shown to be able to predict band gaps of many insulating systems with accuracy close or comparable to . It is shown that the hybrid functionals considered in general fail badly to describe the band structures of FeS polymorphs. This work indicates that accurate prediction of electronic band structure of FeS poses a stringent test on state-of-the-art first-principles approaches, and the method based on semi-local approximation performs well for this difficult system if it is practiced with well-converged numerical accuracy.
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http://dx.doi.org/10.3389/fchem.2021.747972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506039PMC
September 2021

Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants.

J Am Coll Cardiol 2021 Oct;78(16):1603-1617

Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China. Electronic address:

Background: Two major forms of inherited J-wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS).

Objectives: This study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A.

Methods: Clinical evaluation and next-generation sequencing were performed in 262 probands with BrS and 104 with ERS. Nav1.5 and Kv4.3 channels were studied with the use of patch-clamp techniques. A computational model was used to investigate the protein structure.

Results: The SCN5A+ yield in ERS was significantly lower than in BrS (9.62% vs 22.90%; P = 0.004). Patients diagnosed with ERS displayed shorter QRS and QTc than patients with BrS. More than 2 pathogenic SCN5A variants were found in 5 probands. These patients displayed longer PR intervals and QRS duration and experienced more major arrhythmia events (MAE) compared with those carrying only a single pathogenic variant. SCN5A-L1412F, detected in a fever-induced ERS patient, led to total loss of function, destabilized the Nav1.5 structure, and showed a dominant-negative effect, which was accentuated during a febrile state. ERS-related SCN5A-G452C did not alter the inward sodium current (INa) when SCN5A was expressed alone, but when coexpressed with KCND3 it reduced peak INa by 44.52% and increased the transient outward potassium current (Ito) by 106.81%.

Conclusions: These findings point to SCN5A as a major susceptibility gene in ERS as much as it is in BrS, whereas the lower SCN5A+ ratio in ERS indicates the difference in underlying electrophysiology. These findings also identify the first case of fever-induced ERS and demonstrate a critical role of Ito in JWS and a higher risk for MAE in JWS probands carrying multiple pathogenic variants in SCN5A.
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http://dx.doi.org/10.1016/j.jacc.2021.08.024DOI Listing
October 2021

Saline-Aided Ultrasound Versus Upper Gastrointestinal Series in Neonates and Infants With Suspected Upper Gastrointestinal Obstruction: A Prospective Multicenter Comparative Study.

AJR Am J Roentgenol 2021 Oct 13. Epub 2021 Oct 13.

Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou 510080, P.R. China.

Use of upper gastrointestinal (UGI) series to diagnose UGI obstruction has raised concern in neonates and infants given increased radiation sensitivity by developing organs. To assess the diagnostic performance of saline-aided ultrasound for UGI obstruction in neonates and infants, in comparison with UGI series. This prospective multicenter study enrolled inpatients at three hospitals who were less than 1 year old and had suspected UGI obstruction between June 2015 and May 2018; patients with malrotation or pyloric stenosis on ultrasound were ineligible. Enrolled patients underwent both saline-aided ultrasound (saline administered by nasogastric tube) and UGI series. Surgical findings or at least one-year clinical follow-up served as reference for presence of UGI obstruction. Patients with UGI obstruction were classified in terms of level (proximal vs distal) and cause. Two radiologists independently interpreted saline-aided US examinations to assess interobserver agreement and then reached consensus. Two separate radiologists assessed upper GI series in consensus. Diagnostic performance for UGI obstruction presence and level was compared between modalities. Causes were assessed on saline-aided ultrasound. A total of 209 neonates were included (median age 5 days; 116 male, 93 female); 124 (59.3%) had UGI obstruction (proximal in 108). Saline-aided ultrasound exhibited strong interobserver agreement for obstruction presence (κ=0.87) and level (κ=0.85). For presence of UGI obstruction, accuracy, sensitivity, and specificity were 94.7%, 98.4%, and 89.4% for saline-aided US, versus 89.5%, 95.2%, and 81.5% for UGI series. For obstruction level, accuracy, sensitivity, and specificity were 91.9%, 97.2%, and 56.3% for saline-aided US, versus 87.1%, 92.6%, and 50.0% for UGI series. Accuracy for presence was significantly higher for saline-aided US (p=.02); otherwise, these metrics were not different between tests (p>.05). For causes of UGI obstruction (annual pancreas, duodenal web, duodenal atresia, and duodenal stenosis), accuracy of saline-aided US ranged from 75.0% to 94.1%. Saline-aided US has high diagnostic performance for presence and level of UGI obstruction in neonates and infants, comparing favorably versus UGI series. Saline-aided US may have additional utility in evaluating causes of obstruction. Saline-aided US may serve as an initial screening modality for UGI obstruction in neonates and infants.
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http://dx.doi.org/10.2214/AJR.21.26621DOI Listing
October 2021

Retinal microvascular and neuronal function in patients with multiple sclerosis: 2-year follow-up.

Mult Scler Relat Disord 2021 Oct 4;56:103314. Epub 2021 Oct 4.

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States. Electronic address:

Objective: To determine the longitudinal changes in retinal microstructure, microvasculature, microcirculation, and axonal and neuronal functions in patients with relapsing-remitting multiple sclerosis (RRMS) over the time course of about two years.

Methods: A total of 30 patients (60 eyes) with RRMS were followed for a period of 27 ± 6 months and evaluated with a battery of clinical tests including low contrast letter acuity (LCLA), intraretinal layer thicknesses by optical coherence tomography (OCT), ganglion cell function by steady-state pattern electroretinography (PERG), axonal function by polarization-sensitive OCT, volumetric vessel density (VVD) by OCT angiography, and retinal tissue perfusion (RTP) by retinal function imager.

Results: Axonal function measured as retinal nerve fiber layer birefringence in the temporal quadrant and vessel density in the deep vascular plexus were significantly decreased at 2-year follow-up (P < 0.05). Subgroup analyses showed that the increased retinal blood flow volume occurred in patients with no evidence of disease activity (NEDA), and with stable or improved visual function (P < 0.05). There was no significant difference in the expanded disability state scale, LCLA, RTP, VVD, or PERG measures between the two visits (P > 0.05).

Conclusion: To our best knowledge, this is the first 2-year prospective comprehensive study with a detailed assessment of retinal microstructure and neuronal functions in patients with RRMS. The recovery of retinal microcirculation occurred in patients with NEDA, and stable or improved visual function, suggesting these measurements as potential imaging biomarkers for monitoring disease progression.
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http://dx.doi.org/10.1016/j.msard.2021.103314DOI Listing
October 2021

Oral Supplementation With Butyrate Improves Myocardial Ischemia/Reperfusion Injury a Gut-Brain Neural Circuit.

Front Cardiovasc Med 2021 23;8:718674. Epub 2021 Sep 23.

Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, China.

Butyrate, a short-chain fatty acid (SCFA) produced by the intestinal microbiota, plays a protective role in cardiovascular diseases (CVDs), but the mechanisms involved in this process remain unelucidated. We aimed to explore the effect of butyrate on myocardial ischemia/reperfusion (I/R) injury through the gut-brain neural circuit. Rats were randomly divided into four groups: sham group (sham), I/R group (I/R), I/R+ butyrate group (butyrate), and I/R+ butyrate+ vagotomy group (vagotomy). The rats were treated with sodium butyrate for 4 weeks, and the gut-brain neural circuit was investigated by subdiaphragmatic vagotomy. Butyrate treatment significantly reduced the infarct size and decreased the expression of creatine kinase (CK), creatine kinase myocardial isoenzyme (CK-MB), and lactate dehydrogenase (LDH) compared with the values found for the I/R group. In addition, the I/R-induced increases in inflammation, oxidative stress, and apoptosis were attenuated by butyrate. However, the above-mentioned protective effects were diminished by subdiaphragmatic vagotomy. The RNA sequencing results also revealed that the butyrate-induced protective changes at the cardiac transcription level were reversed by vagotomy. An analysis of the heart rate variability (HRV) and the detection of norepinephrine (NE) showed that butyrate significantly inhibited the I/R-induced autonomic imbalance, but this inhibition was not observed in the vagotomy group. Butyrate treatment also suppressed the neural activity of the paraventricular nucleus (PVN) and superior cervical ganglion (SCG), and both of these effects were lost after vagotomy. Butyrate treatment significantly improves myocardial I/R injury via a gut-brain neural circuit, and this cardioprotective effect is likely mediated by suppression of the sympathetic nervous system.
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http://dx.doi.org/10.3389/fcvm.2021.718674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495014PMC
September 2021

Case Report: The Monogenic Familial Steroid-Resistant Nephrotic Syndrome Caused by a Novel Missense Mutation of Gene A593C in a Chinese Family.

Front Pediatr 2021 23;9:692727. Epub 2021 Sep 23.

Division of Nephrology, Department of Internal Medicine, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China.

Pathogenic variants in the gene encoding podocin in kidney podocytes are associated with autosomal recessive steroid-resistant nephrotic syndrome (SRNS) by disrupting podocyte function and the integrity of the glomerular filtration barrier. The outcome is generally poor by progressing into end-stage kidney disease (ESKD). With the help of gene diagnostics, we can further understand the role of podocin of podocytes in the development and progression of SRNS. However, the pathological mutation of and clinical relevance remain further elusive. Two siblings, a 15-year-old girl and her 10-year-old younger brother from a consanguineous Chinese family, presented with nephrotic syndrome. Both of them developed progressive proteinuria starting from the 5-year-old of age. The renal pathological lesions for them revealed focal segmental glomerulosclerosis (FSGS). There was no response to the glucocorticoid, calcineurin inhibitors, and rituximab treatment. The female affected patient received the hemodialysis treatment due to ESKD in June 2020; the male patient was still in follow-up presenting with SRNS. The mutational screening of the two patients and their parents using Trio whole-exome sequencing showed the gene missense mutation in exon 5 (A593C), for which the two siblings were homozygous and their parents confirmed heterozygous asymptomatic carriers. No other SRNS-related gene variants with the SRNS were determined. Pathological gene variants screening in children clinically suspected with SRNS might be helpful in the diagnosis as well as appropriate decisions on treatment strategies and prediction of prognosis.
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http://dx.doi.org/10.3389/fped.2021.692727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497038PMC
September 2021

Comparison of long-term clinical outcomes of percutaneous coronary intervention for chronic total occlusion between patients with and without diabetes mellitus: a single-center retrospective observational study.

Ann Palliat Med 2021 Sep;10(9):9993-10004

Cardiology Department of Integrated Traditional Chinese and Western Medicine, China-Japan Friendship Hospital, Beijing, China.

Background: The prognosis of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) between patients with diabetes mellitus (DM) and those without DM is unknown. This study aimed to investigate whether DM has adverse effects on CTO PCI patients.

Methods: This single-center retrospective study included consecutive patients who underwent PCI for CTO at the China-Japan Friendship Hospital (Beijing, China) between January 2016 and April 2019. The clinical outcomes during follow-up were compared between patients with DM and those without DM.

Results: The analysis included 187 patients (152 males) aged 62.6±11.5 years. A total of 99 participants (52.9%) had DM, which involved a higher body mass index (BMI) and triglyceride level than those without DM (P<0.05). Participants with DM and those without DM had similar PCI success rates (89.9% vs. 95.4%, respectively) and complete revascularization rates (82.8% vs. 84.1%, respectively). There were no significant differences between groups in the rates of all-cause mortality, cardiac death, major adverse cardiovascular events (MACEs), readmission, recurrence of angina, target vessel revascularization (TVR), or myocardial infarction (MI) during a median follow-up of 20.5 months. Multivariable logistic regression revealed that CTO in a coronary branch vessel was associated with higher odds of all-cause death (odds ratio (OR): 53.56; 95% confidence interval (CI): 2.48 to 1,155.41; P<0.05) and failure of PCI for CTO (OR: 5.40; 95% CI: 1.263 to 23.098; P<0.05). Additionally, PCI for single CTO was associated with lower odds of MACEs (OR: 0.300; 95% CI: 0.118 to 0.765; P<0.05).

Conclusions: The performance of PCI for CTO has a high success rate in both patients with DM and those without DM, and clinical outcomes are comparable between groups.
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http://dx.doi.org/10.21037/apm-21-2354DOI Listing
September 2021

Synthesis, structures and properties of hydrophobic Alkyltrimethoxysilane-Polyvinyltrimethoxysilane hybrid aerogels with different alkyl chain lengths.

J Colloid Interface Sci 2021 Sep 24;608(Pt 1):720-734. Epub 2021 Sep 24.

Microcellular Plastics Manufacturing Laboratory, Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario M5S 3G8, Canada. Electronic address:

Hypothesis: Alkyltrimethoxysilane (ATMS) is among most widely used silane coupling agents. These commercially available, reasonably priced chemicals are often utilized to improve the compatibility of inorganic surfaces with organic coatings. With three hydrolysable moieties, ATMS is an outstanding candidate for solving the hydrophilicity, moisture sensitivity and high cost of silica aerogels. However, ATMS has a non-hydrolysable alkyl chain that undergoes cyclization reactions. The alkyl chain prevents ATMS from being incorporated in aerogel structures. Polyvinyltrimethoxysilane (PVTMS) is a silica precursor that offers two types of crosslinking to the final aerogel product. This strong doubly-crosslinked network can potentially suppress the cyclization reactions of ATMS and include it in aerogel structure.

Experiments: PVTMS was used with ATMS having different alkyl lengths (3-16 carbons) and loadings (25 or 50 wt%) as the silica precursors. Acid and base catalysts were used to perform hydrolysis and condensation reactions on the mixture and ATMS:PVTMS aerogels were obtained via supercritical drying.

Findings: The incorporation of ATMS in the aerogels was approved by different characterization methods. Results showed that ATMS:PVTMS aerogels possess hydrophobicity (θ ∼ 130°), moisture resistance, varying surface area (44-916 m·g), meso/microporous structure and thermal insulation properties (λ ∼ 0.03 W·mK). These samples also showed excellent performance in oil and organic solvent adsorption.
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http://dx.doi.org/10.1016/j.jcis.2021.09.128DOI Listing
September 2021

Adjusting vascular permeability, leukocyte infiltration, and microglial cell activation to rescue dopaminergic neurons in rodent models of Parkinson's disease.

NPJ Parkinsons Dis 2021 Oct 8;7(1):91. Epub 2021 Oct 8.

Institute of Anatomy and Cell Biology, Medical College, Zhejiang University, Hangzhou, China.

Animal studies have indicated that increased blood-brain barrier (BBB) permeability and inflammatory cell infiltration are involved during the progression of Parkinson's disease (PD). This study used C16, a peptide that competitively binds to integrin αβ and inhibits inflammatory cell infiltration, as well as angiopoietin-1 (Ang-1), an endothelial growth factor crucial for blood vessel protection, to reduce inflammation and improve the central nervous system (CNS) microenvironment in murine models of PD. The combination of C16 and Ang-1 yielded better results compared to the individual drugs alone in terms of reducing dopaminergic neuronal apoptosis, ameliorating cognitive impairment, and electrophysiological dysfunction, attenuating inflammation in the CNS microenvironment, and improving the functional disability in PD mice or rats. These results suggest neuroprotective and anti-inflammatory properties of the C16 peptide plus Ang-1 in PD.
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http://dx.doi.org/10.1038/s41531-021-00233-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501121PMC
October 2021

Allicin protects against myocardial I/R by accelerating angiogenesis via the miR-19a-3p/PI3K/AKT axis.

Aging (Albany NY) 2021 Oct 4;13(19):22843-22855. Epub 2021 Oct 4.

Graduate School of Peking Union Medical College, Beijing 100730, China.

Objectives: Allicin is an allyl 2-propenethiosulfinate or diallyl thiosulfinate acid with cardioprotective effects in myocardial ischemia/reperfusion (MI/R) injury. This study aims to examine the underlying mechanism by which Allicin protects against MI/R.

Methods: C57BL6 mice were subjected to either sham or MI/R surgery, and mice in the Allicin group were injected with Allicin (5 mg/ml) before the induction of ischemia. The cardiac function and histopathology of experimental mice were evaluated by ultrasound quantification and Masson staining. We next measured the capillary angiogenesis of the peri-infarct area by Masson staining and immunohistochemical staining. The miRNA microarray was carried out to examine the expressed miRNAs in MI/R tissues and corresponding normal tissues. Real-time quantitative polymerase chain reaction (q-PCR) was performed to validate the selected miRNA-19α-3p gene expression. Besides, we evaluated the myocardial lactate dehydrogenase and COX-2 by immunofluorescence staining. The western blot analysis was used to evaluate the protein levels of p-AKT, p-PI3K, p-mTOR, COX-2, and VEGF protein in the Allicin and Model group. study, LPS stimulated Tie2 expressing macrophages were cultured in an ischemic buffer. We evaluated the accumulation of VEGF by fura-2/AM fluorescence. Besides, Western blotting was performed to examine the protein levels of p-PI3K, p-AKT, p-mTOR, VEGF, COX2, and MMP2. The PI3K inhibitor was applied to investigate whether Allicin-induced myocardial ischemia-reperfusion injury protection is mediated via the PI3K/AKT pathway. And the miR-19α-3p mimic/inhibitor were transfected to promote/inhibit the expression of miR-19a-3p for verifying the regulation of miR-19a-3p on PI3K pathway.

Results: Allicin pretreatment significantly improved I/R-induced cardiac function damage. Furthermore, Allicin could repress cardiac fibrosis, as evidenced by reduced areas of cardiac fibrosis. Allicin's effect on the MI/R was associated with increased capillary angiogenesis. Microarray analysis exposed that miR-19a-3p down-regulated PIK3CA (PI3K) expression by directly targeting the PIK3CA gene. The regulation of the angiogenesis pathway and gene miRNA-19a-3p might affect the Allicin-induced MI/R protection. Immunofluorescence staining revealed that COX-2 and myocardial lactate dehydrogenase were significantly increased after Allicin treatment. Furthermore, western blot analysis demonstrated that p-AKT, p-PI3K, p-mTOR, COX-2, and VEGF protein levels were also increased in the Allicin group. study, the protein levels of p-PI3K, p-AKT, p-mTOR, VEGF, COX2, and MMP2 were significantly increased in the Allicin-treated Tie2 expressing macrophages. These effects were partially reversed by PI3K inhibitor (Wortmannin) treatment. MiR-19α-3p plays an important role in myocardial I/R injury. It could regulate the activity of the PI3K-AKT pathway. And inhibition of miR-19a-3p promoted angiogenesis by regulating PI3K/AKT pathway.

Conclusions: Allicin pretreatment protects against myocardial I/R and activating the miR-19a-3p/PI3K/AKT pathway.
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http://dx.doi.org/10.18632/aging.203578DOI Listing
October 2021

Association between adiponectin-to-leptin ratio and heart rate variability in new-onset paroxysmal atrial fibrillation: A retrospective cohort study.

Ann Noninvasive Electrocardiol 2021 Oct 2:e12896. Epub 2021 Oct 2.

Hubei Key Laboratory of Cardiology, Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Wuhan, China.

Background: The adiponectin-to-leptin (A/L) ratio has been identified as a potential surrogate biomarker for metabolic disorders. However, it remains unknown whether the serum A/L ratio is associated with heart rate variability in paroxysmal atrial fibrillation (AF).

Methods: For this retrospective study, we included consecutive patients who underwent 24-h long-range electrocardiogram examination in our center for paroxysmal AF. The results of echocardiography, heart rate variability tests, and blood tests were also retrieved. Multivariate line regression analysis was performed to evaluate identify factors independently associated with heart rate variability.

Results: Among the 85 included patients with paroxysmal AF, the median A/L ratio was 1.71. Univariate analysis indicated that patients with a low A/L ratio (<1.71, n = 42) had a lower high-frequency (HF) power and a higher hs-CRP level, low-frequency (LF) power, and LF/HF ratio than those with a high A/L ratio (≥1.71, n = 43). Multivariate linear regression analysis showed that the serum leptin concentration was independently and positively associated with LF (β = 0.175, p = .028), while the serum adiponectin concentration was independently and positively associated with HF (β = 0.321, p = .001). Moreover, the A/L ratio was independently and negatively associated with the LF/HF ratio (β = -0.276, p = .007).

Conclusions: The A/L ratio was independently and negatively associated with the LF/HF ratio in patients with new-onset paroxysmal AF.
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http://dx.doi.org/10.1111/anec.12896DOI Listing
October 2021

Trends in regional morphological changes in the brain after the resolution of hypercortisolism in Cushing's disease: a complex phenomenon, not mere partial reversibility.

Endocr Connect 2021 Oct 25;10(11):1377-1386. Epub 2021 Oct 25.

Department of Neurosurgery, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

The adverse effects of hypercortisolism on the human brain have been highlighted in previous studies of Cushing's disease (CD). However, the relative alterations in regional hypercortisolism in the brain remain unclear. Thus, we investigated regional volumetric alterations in CD patients. We also analyzed the associations between these volumetric changes and clinical characteristics. The study participants comprised of active CD (n = 60), short-term-remitted CD (n = 28), and long-term-remitted CD (n = 32) patients as well as healthy control subjects (n = 66). Gray matter volumes (GMVs) were measured via voxel-based morphometry. The GMVs of substructures were defined using the automated anatomical labeling (AAL) atlas. Trends toward normalization in GMV were found in most brain substructures of CD patients. Different trends, including enlarged, irreversible, and unaffected, were observed in the other subregions, such as the amygdala, thalamus, and caudate. Morphological changes in GMVs after the resolution of hypercortisolism are a complex phenomenon; the characteristics of these changes significantly differ within the brain substructures.
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http://dx.doi.org/10.1530/EC-21-0385DOI Listing
October 2021

Carbon and nitrogen metabolism under nitrogen variation affects flavonoid accumulation in the leaves of .

PeerJ 2021 10;9:e12152. Epub 2021 Sep 10.

College of Forestry and Horticulture, Xinjiang Agriculture University, Urumuqi, China.

Flavonoids are phytochemicals present in medicinal plants and contribute to human health. , a species rich in flavonoids, has long been used in traditional medicine and as a food resource. N (nitrogen) fertilization can reduce flavonoid accumulation in . However, there is limited knowledge regarding N regulatory mechanisms. The aim of this study was to determine the effect of N availability on flavonoid biosynthesis in and to investigate the relationship between C (carbon) and N metabolism coupled with flavonoid synthesis under controlled conditions. seedlings were grown hydroponically under five different N levels (0, 0.625, 1.250, 2.500 and 5.000 mM). The related indexes of C, N and flavonoid metabolism of under N variation were measured and analysed. N availability (low and moderate N levels) regulates enzyme activities related to C and N metabolism, promotes the accumulation of carbohydrates, reduces N metabolite levels, and enhances the internal C/N balance. The flavonoid content in roots and stalks remained relatively stable, while that in leaves peaked at low or intermediate N levels. Flavonoids are closely related to phenylalanine ammonia-lyase (PAL), cinnamate 4-hydroxylase (C4H), 4-coumarate: coenzyme A ligase (4CL), and chalcone-thioase (CHS) activity, significantly positively correlated with carbohydrates and negatively correlated with N metabolites. Thus, C and N metabolism can not only control the distribution of C in amino acid and carbohydrate biosynthesis pathways but also change the distribution in flavonoid biosynthesis pathways, which also provides meaningful information for maintaining high yields while ensuring the nutritional value of crop plants.
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http://dx.doi.org/10.7717/peerj.12152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436962PMC
September 2021

Prevalence and determinants of frailty in older adult patients with chronic coronary syndrome: a cross-sectional study.

BMC Geriatr 2021 09 30;21(1):519. Epub 2021 Sep 30.

Department of Geriatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.

Background: Frailty is an expression of vulnerability and decline of physical, mental, and social activities, more commonly found in older adults. It is also closely related to the occurrence and poor prognosis of coronary artery disease (CAD). Little investigation has been conducted on the prevalence and determinants of frailty in older adult patients with chronic coronary syndrome (CCS).

Methods: A cross-sectional study was conducted, simple random sampling was used in this study. 218 older adults (age ≥ 60 years) with CCS with an inpatient admission number ending in 6 were randomly selected who hospitalized in Department of Geriatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, China, between January and December 2018. For measurement and assessment, we used the 5-item FRAIL scale (fatigue, resistance, ambulation, illnesses, and loss of weight), demographic characteristics, Barthel Index(BI), Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS-15), Mini Nutrition Assessment Shor-Form (MNA-SF), Morse Fall Scale (MFS), Caprini risk assessment, polypharmacy, and Numerical Rating Scale (NRS). Multivariate logistic regression analysis was used to confirme determinants.

Results: The FRAIL scale showed 30.3% of the subjects suffered from frailty. Determinants were aging (OR1.12; 95% CI 1.04 ~ 1.62), out-of-pocket (OR18.93; 95% CI 1.11 ~ 324.07), hearing dysfunction (OR9.43; 95% CI 1.61 ~ 55.21), MNA-SF score (OR0.71; CI 0.57 ~ 0.89), GDS-15 score (OR1.35; 95% CI 1.11 ~ 1.64), and Caprini score (OR1.34; 95% CI 1.06 ~ 1.70).

Conclusions: The FRAIL scale confirmed that the prevalence of frailty in patients with CCS was slightly lower than CAD. Aging, malnutrition, hearing dysfunction, depression, and VTE risk were significantly associated with frail for older adult patients with CCS. A comprehensive assessment of high-risk patients can help identify determinants for frailty progression. In the context of CCS, efforts to identify frailty are needed, as are interventions to limit or reverse frailty status in older CCS patients.
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http://dx.doi.org/10.1186/s12877-021-02426-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482732PMC
September 2021

Smartphone non-users experience disproportionately higher psychological distress than their counterparts: Mediations via psychosocial resources in a large sample of college students in China.

J Affect Disord 2021 Sep 22;296:41-48. Epub 2021 Sep 22.

Centre for Health Behaviours Research, JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China. Electronic address:

Background: Despite growing adoption of digital technologies, the gap between users and non-users (aka digital divide) persists. It is imperative to determine whether and how such a gap can lead to disparities in mental health outcomes among populations. However, few empirical studies have explored the effect of smartphone non-use on psychological well-being.

Methods: A large-scale cross-sectional survey was conducted among 26,951 college students in Shaanxi Province, China. Levels of depression and loneliness were first compared between smartphone non-users and their user counterparts. Based on the Conservation of Resources theory, structural equation modeling was then used to test the mediating roles of social support, quality of peer relationship, and self-esteem.

Results: Around 56.8% of smartphone non-users had probable depression and they reported significantly higher depressive symptoms (Cohen's d = 0.52) and loneliness (Cohen's d = 0.30) than users. The hypothesized mediation model was well supported with good model fit. Lower levels of social support, quality of peer relationship, and self-esteem fully mediated the total effect of smartphone non-use status on loneliness and explained 69.4% of the total effect on depression.

Limitations: Findings might be subject to self-reporting bias and limitations due to a cross-sectional design.

Conclusions: The study adds new evidence that the minority group of smartphone non-users exhibited disproportionately greater psychological distress than users resulting from lower supportive social relationships and positive sense of self. The findings inform the future investigation into digital divide in smartphone use/access and its negative impact on population's psychological well-being.
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http://dx.doi.org/10.1016/j.jad.2021.09.058DOI Listing
September 2021

Effect of CAG repeats on the age at onset of patients with spinocerebellar ataxia type 2 in China.

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2021 Aug;46(8):793-799

Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008.

Objectives: Spinocerebellar ataxia type 2 (SCA2) is one of the most common autosomal dominant ataxias in the world. Several reports revealed that CAG repeats in some polyQ-containing genes may affect the age at onset (AAO) of patients with SCA2, however, little studies were conducted among Chinese patients with SCA2. Thus, the aim of this study is to evaluate the effect of CAG repeats on the AAO of patients with SCA2 in China.

Methods: A total of 119 patients with SCA2 were enrolled and were divided into 2 groups according to their major phenotype: 17 patients from 9 families with Parkinson's syndrome were grouped as the Parkinson's disease-SCA2 (PD-SAC2); 91 patients from 66 SCA2 families and 11 sporadic SCA2 patients were grouped as the ataxia-SCA2 (A-SCA2). Blood samples were obtained from the subjects, and the CAG repeat length in ATXN2 and other (CAG)-containing genes was screened using fluorescent PCR. The Spearman's rank correlation between the CAG repeat length in (CAG)-containing genes and AAO was analyzed. Regression analysis was performed to investigate whether the CAG repeat length could explain the variant of AAO. A -test was used to compare the difference of CAG repeat length in (CAG)-containing genes between the PD-SAC2 and A-SCA2 groups.

Results: The CAG repeat length in the longer allele of ATXN2 was negatively correlated with AAO of SCA2 (=-0.251, <0.05), and the CAG repeat length could explain 41.7% of the variation of AAO. AAO negatively correlated with the CAG repeat length in the shorter allele of ATXN7 (=-0.251, =0.006) or in the longer allele of TBP gene (=-0.197, =0.034). A tendency of delay in the AAO was also observed in patients with SCA2 carrying the CAG repeat within the ATXN3, CACNA1A, ATXN7, TBP, and RAI1. In addition, we found that the CAG repeat length in ATXN7 and ATXN2 between the A-SCA2 and the PD-SCA2 groups was significantly different (both <0.05).

Conclusions: The CAG repeat in ATXN2 is a major genetic factor for the AAO of patients with SCA2 in China. The CAG repeat length in ATXN3, CACNA1A, ATXN7, TBP, and RAI1 genes might be a potential factor associated with the AAO of SCA2. The CAG repeat in ATXN7 might be a potential factor affecting the Parkinson's syndrome in SCA2.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2021.210230DOI Listing
August 2021

Identification of VCAN as Hub Gene for Diabetic Kidney Disease Immune Injury Using Integrated Bioinformatics Analysis.

Front Physiol 2021 7;12:651690. Epub 2021 Sep 7.

Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease in China. Tubular injury contributes to the progression of DKD. Our study was conducted to explore the differential gene expression profiles between kidneys from patients with DKD and kidney living donors (LDs). In total, seven DKD and eighteen LD gene expression profiles from the GSE104954 dataset were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were analyzed in R with the limma package. DEGs were uploaded to the g:Profiler online database to explore the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Ingenuity pathway analysis (IPA) was carried out using online IPA software. Weighted gene co-expression network analysis (WGCNA) was performed using the WGCNA R package. By integrating DEGs and genes from the top 1 phenotype-gene associated module, we determined the hub gene. We next tested the hub gene, VCAN, in the GSE30122 dataset. We also validated the versican levels in human kidney tissues, explored immune cell type enrichment using an online database xCell, and investigated the correlation between cell types and VCAN expression. A total of 563 DEGs was identified. A large number of pathways were involved in the immune response process according to the results of GO, KEGG, and IPA. Using WGCNA, we selected the lightcyan module in which genes showed the strongest correlation with the phenotype and smallest -value. We also identified VCAN as a hub gene by integrating DEG analysis and WGCNA. Versican expression was upregulated in human diabetic kidney tissue. Moreover, versican was speculated to play a role in immune injury according to the enrichment of functions and signaling pathways. VCAN transcript levels correlate with the assembly of immune cells in the kidney. Immune processes played an essential role in DKD tubulointerstitium injury. The hub gene VCAN contributed to this process.
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http://dx.doi.org/10.3389/fphys.2021.651690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454927PMC
September 2021

Oxidized LDL but not angiotensin II induces cardiomyocyte hypertrophic responses through the interaction between LOX-1 and AT receptors.

J Mol Cell Cardiol 2021 Sep 21;162:110-118. Epub 2021 Sep 21.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biological Science, Fudan University, Shanghai 200032, China. Electronic address:

It is well known that lectin-like oxidized low-density lipoprotein (ox-LDL) and its receptor LOX-1, angiotensin II (AngII) and its type 1 receptor (AT-R) play an important role in the development of cardiac hypertrophy. However, the molecular mechanism is not clear. In this study, we found that ox-LDL-induced cardiac hypertrophy was suppressed by inhibition of LOX-1 or AT1-R but not by AngII inhibition. These results suggest that the receptors LOX-1 and AT1-R, rather than AngII, play a key role in the role of ox-LDL. The same results were obtained in mice lacking endogenous AngII and their isolated cardiomyocytes. Ox-LDL but not AngII could induce the binding of LOX-1 and AT1-R; inhibition of LOX-1 or AT1-R but not AngII could abolish the binding of these two receptors. Overexpression of wild type LOX-1 with AT1-R enhanced ox-LDL-induced binding of two receptors and phosphorylation of ERKs, however, transfection of LOX-1 dominant negative mutant (lys266ala / lys267ala) or an AT1-R mutant (glu257ala) not only reduced the binding of two receptors but also inhibited the ERKs phosphorylation. Phosphorylation of ERKs induced by ox-LDL in LOX-1 and AT-R-overexpression cells was abrogated by an inhibitor of Gq protein rather than Jak2, Rac1 or RhoA. Genetically, an AT1-R mutant lacking Gq protein coupling ability inhibited ox-LDL induced ERKs phosphorylation. Furthermore, through bimolecular fluorescence complementation analysis, we confirmed that ox-LDL rather than AngII stimulation induced the direct binding of LOX-1 and AT-R. We conclude that direct binding of LOX-1 and AT1-R and the activation of downstream Gq protein are important mechanisms of ox-LDL-induced cardiomyocyte hypertrophy.
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http://dx.doi.org/10.1016/j.yjmcc.2021.09.006DOI Listing
September 2021

Immune-Related Multiple-Organs Injuries Following ICI Treatment With Tislelizumab in an Advanced Non-Small Cell Lung Cancer Patient: A Case Report.

Front Oncol 2021 2;11:664809. Epub 2021 Sep 2.

Department of Medical Oncology, Integrated Traditional Chinese and Western Medicine, China-Japan Friendship Hospital, Beijing, China.

Immune-related adverse events (irAEs) following treatment with immune checkpoint inhibitors (ICIs) can affect almost any organ systems. Multiple-organs irAEs are a rare occurrence which makes its management and treatment very challenging. This is a case report of a 71-year-old man with advanced non-small cell lung cancer (NSCLC) who developed multiple-organs irAEs (lung, muscle, myocardium, liver, and pituitary) after a single cycle (21 days) of the BGB-A317 (Tislelizumab). After more than two months of immunosuppression treatment with glucocorticoids, the tumor and inflammatory lesions in the lung were reduced. The levels of serum creatase, cardiac troponin T (TNT), and hepatic transaminase were also reduced. Four months after the termination of ICI therapy, the lung tumor reappeared in the previous site. This rare case report supplies several experiences in the management of multiple-organs irAEs, including full-scale monitoring of immunological indicators, early differential diagnosis, and prompt glucocorticoid therapy. This patient was not a candidate for the ICI re-challenge therapy due to the number and seriousness of irAEs. Multiple-organs irAEs add complexity to the management, and additional research is needed to develop optimal therapeutic guidelines.
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http://dx.doi.org/10.3389/fonc.2021.664809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443792PMC
September 2021

Prediction of in-hospital recurrence and false-negative results in patients with COVID-19 by red blood cell values on admission.

Exp Ther Med 2021 Nov 2;22(5):1250. Epub 2021 Sep 2.

Third Department of Infectious Diseases, Huoshenshan Hospital, Joint Logistics Support Force of The Chinese People's Liberation Army, Wuhan, Hubei 430101, P.R. China.

The clinical characteristics and risk factors of patients with coronavirus disease 2019 (COVID-19) with re-positive or false-negative test results have so far remained to be determined. The present study provides a cross-sectional observational study on 134 hospitalized patients selected from Huoshenshan Hospital (Wuhan, China) using cluster sampling. A total of 68 patients had reduced red blood cell (RBC) counts, 55 a decrease in the hemoglobin concentration (HBC) and 73 a decline in hematocrit (HCT). The false-negative rate of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA detection in pharyngeal swab specimens was 18.7%. The absolute lymphocyte count (ALC), RBC, HBC and HCT levels in false-negative patients were significantly higher than those in patients who tested positive for viral nucleic acids. Multivariate logistic regression analysis indicated that RBC [odds ratio (OR)=0.43, 95% CI: 0.18-0.99], HBC (OR=0.97, 95% CI: 0.94-0.99) and ALC (OR=0.43, 95% CI: 0.20-0.91) were the factors influencing the negative testing results for viral nucleic acid. The rate of re-positive patients was 16.4%. The white blood cell, RBC, HBC and HCT values in re-positive patients were lower than those in non-re-positive patients. The median (interquartile range) values for RBC, HBC and HCT of male re-positive patients were 3.95 (3.37, 4.2) x10/l, 123 (103, 133) g/l and 36.6 (31.1, 39.2)%, respectively, while the RBC, HBC and HCT of female re-positive patients were 3.54 (3.13, 3.74) x10/l, 115 (102, 118) g/l and 34.2 (28.5, 34.9)%, respectively. It was determined that RBC, HBC and HCT values had moderate accuracy in predicting SARS-CoV-2 recurrence in patients with COVID-19 using receiver operating curve analysis. The present study suggested that RBC may have an important role in the pathogenesis of COVID-19.
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http://dx.doi.org/10.3892/etm.2021.10685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438694PMC
November 2021

CRISPR/Cas9 mediated gene correction ameliorates abnormal phenotypes in spinocerebellar ataxia type 3 patient-derived induced pluripotent stem cells.

Transl Psychiatry 2021 09 17;11(1):479. Epub 2021 Sep 17.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a progressive autosomal dominant neurodegenerative disease caused by abnormal CAG repeats in the exon 10 of ATXN3. The accumulation of the mutant ataxin-3 proteins carrying expanded polyglutamine (polyQ) leads to selective degeneration of neurons. Since the pathogenesis of SCA3 has not been fully elucidated, and no effective therapies have been identified, it is crucial to investigate the pathogenesis and seek new therapeutic strategies of SCA3. Induced pluripotent stem cells (iPSCs) can be used as the ideal cell model for the molecular pathogenesis of polyQ diseases. Abnormal CAG expansions mediated by CRISPR/Cas9 genome engineering technologies have shown promising potential for the treatment of polyQ diseases, including SCA3. In this study, SCA3-iPSCs can be corrected by the replacement of the abnormal CAG expansions (74 CAG) with normal repeats (17 CAG) using CRISPR/Cas9-mediated homologous recombination (HR) strategy. Besides, corrected SCA3-iPSCs retained pluripotent and normal karyotype, which can be differentiated into a neural stem cell (NSCs) and neuronal cells, and maintained electrophysiological characteristics. The expression of differentiation markers and electrophysiological characteristics were similar among the neuronal differentiation from normal control iPSCs (Ctrl-iPSCs), SCA3-iPSCs, and isogenic control SCA3-iPSCs. Furthermore, this study proved that the phenotypic abnormalities in SCA3 neurons, including aggregated IC2-polyQ protein, decreased mitochondrial membrane potential (MMP) and glutathione expressions, increased reactive oxygen species (ROS), intracellular Ca concentrations, and lipid peroxidase malondialdehyde (MDA) levels, all were rescued in the corrected SCA3-NCs. For the first time, this study demonstrated the feasibility of CRISPR/Cas9-mediated HR strategy to precisely repair SCA3-iPSCs, and reverse the corresponding abnormal disease phenotypes. In addition, the importance of genetic control using CRISPR/Cas9-mediated iPSCs for disease modeling. Our work may contribute to providing a potential ideal model for molecular mechanism research and autologous stem cell therapy of SCA3 or other polyQ diseases, and offer a good gene therapy strategy for future treatment.
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http://dx.doi.org/10.1038/s41398-021-01605-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448778PMC
September 2021

The first national anesthesia workforce survey to inform future policymaking in China.

Authors:
Jiale Hu Hong Jiang

Lancet Reg Health West Pac 2021 Aug 20;13:100219. Epub 2021 Jul 20.

Medical Director, Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

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http://dx.doi.org/10.1016/j.lanwpc.2021.100219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350062PMC
August 2021

Effects of Ocufolin on retinal microvasculature in patients with mild non-proliferative diabetic retinopathy carrying polymorphisms of the MTHFR gene.

BMJ Open Diabetes Res Care 2021 09;9(1)

Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, USA

Introduction: To evaluate effects of Ocufolin on retinal microvasculature in mild non-proliferative diabetic retinopathy patients who carried methylenetetrahydrofolate reductase (MTHFR) polymorphisms (DR+MTHFRP).

Research Design And Methods: This is a prospective cohort study. Eight DR+MTHFRP (administrated Ocufolin for 6 months) and 15 normal controls (NCs) were recruited. MTHFR polymorphisms were subtyped as normal, C677T, or A1298C. Best-corrected visual acuity (BCVA) was evaluated. Retinal vessel density (VD) and microstructure were evaluated by optical coherence tomography angiography.

Results: BCVA and vascular indices of DR+MTHFRP at baseline were worse than those of NC and improved. Compared with baseline, DR+MTHFRP had significantly improved BCVA during follow-up period (p<0.05). VD of superficial vascular plexus was increased at 4 months (p=0.012), while VD of retinal vascular network did not change (p>0.05). Carriers of A1298C and C677T showed statistically significant increase in VD at all layers by 6 months, while carriers of C677T alone showed no significant change and carriers of A1298C alone showed decreased density from 4 months to 6 months. Microstructure did not change during the follow-up period.

Conclusion: A 6-month intake of Ocufolin is capable of reversing structural changes of microangiopathy in mild non-proliferative DR+MTHFRP. This suggests a novel way to address these impairments prior to catastrophic vision loss.
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http://dx.doi.org/10.1136/bmjdrc-2021-002327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442067PMC
September 2021

Morphine promotes microglial activation by upregulating the EGFR/ERK signaling pathway.

PLoS One 2021 14;16(9):e0256870. Epub 2021 Sep 14.

Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China.

Although they represent the cornerstone of analgesic therapy, opioids, such as morphine, are limited in efficacy by drug tolerance, hyperalgesia and other side effects. Activation of microglia and the consequent production of proinflammatory cytokines play a key pathogenic role in morphine tolerance, but the exact mechanisms are not well understood. This study aimed to investigate the regulatory mechanism of epidermal growth factor receptor (EGFR) on microglial activation induced by morphine in mouse microglial BV-2 cells. In this research, BV-2 cells were stimulated with morphine or pretreated with AG1478 (an inhibitor of EGFR). Expression levels of cluster of differentiation molecule 11b (CD11b), EGFR, and phospho-EGFR were detected by immunofluorescence staining. Cell signaling was assayed by Western blot. The migration ability of BV-2 cells was tested by Transwell assay. The production of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in the cell supernatant was determined by ELISA. We observed that the expression of CD11b induced by morphine was increased in a dose- and time- dependent manner in BV-2 cells. Phosphorylation levels of EGFR and ERK1/2, migration of BV-2 cells, and production of IL-1β and TNFα were markedly enhanced by morphine treatment. The activation, migration, and production of proinflammatory cytokines in BV-2 cells were inhibited by blocking the EGFR signaling pathway with AG1478. The present study demonstrated that the EGFR/ERK signaling pathway may represent a novel pharmacological strategy to suppress morphine tolerance through attenuation of microglial activation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256870PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439491PMC
September 2021

Blood Neurofilament Light Chain in Genetic Ataxia: A Meta-Analysis.

Mov Disord 2021 Sep 14. Epub 2021 Sep 14.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

Background: No comprehensive meta-analysis has ever been performed to assess the value of neurofilament light chain (NfL) as a biomarker in genetic ataxia.

Objective: We conducted a meta-analysis to summarize NfL concentration and evaluate its utility as a biomarker in genetic ataxia.

Methods: Studies were included if they reported NfL concentration of genetic ataxia. We used log (mean ± SD) NfL to describe mean raw value of NfL. The effect size of NfL between genetic ataxia and healthy controls (HC) was expressed by mean difference. Correlation between NfL and disease severity was calculated.

Results: We identified 11 studies of 624 HC and 1006 patients, here referred to as spinocerebellar ataxia (SCA1, 2, 3, 6, and 7), Friedreich ataxia (FRDA), and ataxia telangiectasia (A-T). The concentration of blood NfL (bNfL) elevated with proximity to expected onset, and progressively increased from asymptomatic to preclinical to clinical stage in SCA3. Compared with HC, bNfL levels were significantly higher in SCA1, 2, 3, and 7, FRDA, as well as A-T, and the difference increased with the advancing disease in SCA3. bNfL levels correlated with disease severity in SCA3. There was a significant correlation between bNfL and longitudinal progression in SCA3. Additionally, bNfL increased with age in HC, yet this is probably masked by higher disease-related effects on bNfL in genetic ataxia.

Conclusions: bNfL can be used as a potential biomarker to predict disease onset, severity, and progression of genetic ataxia. Reference-value setting of bNfL should be divided according to age. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28783DOI Listing
September 2021
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