Publications by authors named "Yu Huang"

1,994 Publications

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Synergistic Effect of Bio-Inspired Nanochannels: Hydrophilic DNA Probes at Inner Wall and Hydrophobic Coating at Outer Surface for Highly Sensitive Detection.

Small 2022 Aug 18:e2201925. Epub 2022 Aug 18.

Key Laboratory of Bio-Inspired Smart Interfacial Science and Technology of the Ministry of Education, School of Chemistry and Environment, Beihang University, Beijing, 100191, P. R. China.

During the past few decades, bio-inspired nanochannels have been well developed and applied in biosensing, energy transfer, separation, and so on. Here, inspired by the synergistic effect of biological nanopores, biomimetic solid-state nanochannels with hydrophilic DNA probes at the inner wall ([email protected] ) and hydrophobic coating at the outer surface ([email protected] ) are designed. To demonstrate their prompted sensing properties, Hg and its specific probe are selected as target and hydrophilic DNA probes, respectively. Compared with the traditional solid-state nanochannels with hydrophilic probes distributed on both the inner wall and outer surface, the nanochannels with [email protected] [email protected] significantly decrease the limit of detection (LOD) by 10 -fold. The obvious improvement of sensitivity (with LOD of 1 nM) is attributed to the synergistic effect: [email protected] results in the nanochannel's effective diameter decrease and [email protected] induces a specific sensing target. Meanwhile, nanomolar detection of Hg in human serum and in vivo fish muscle are achieved. Through molecular dynamics simulation, the synergistic effect can be confirmed by ion fluxes increasement; the relative carbon nanotube increases from 135.64% to 135.84%. This work improves the understanding of nanochannels' synergistic effect and provides a significant insight for nanochannels with improved sensitivity.
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http://dx.doi.org/10.1002/smll.202201925DOI Listing
August 2022

Short-Term Outcomes of Tri-Staple Versus Universal Staple in Laparoscopic Anterior Resection of Rectal and Distal Sigmoid Colonic Cancer: A Matched-Pair Analysis.

World J Surg 2022 Aug 17. Epub 2022 Aug 17.

Division of Colorectal Surgery, Changzheng Hospital, Navy Medical University, No. 415, Fengyang Road, Shanghai, China.

Background: Anastomotic leakage is a serious complication in laparoscopic colorectal surgeries. To resolve this problem, a new stapling technology (Tri-staple) is developed. In this study, we aim to compare the short-term outcomes of Tri-staple versus Universal staple in laparoscopic anterior resection of rectal and distal sigmoid colonic cancer.

Methods: A total of 446 patients were admitted to our hospital and received laparoscopic anterior resection for rectal and distal sigmoid colonic cancer between January 2016 and December 2020. Among them, Tri-staples were used in 202 patients, and the Universal staples were used in 244 patients. Propensity score matching was performed, followed by a comparison between the two groups (Tri-staple vs. Universal staple) in the incidences of anastomotic leakage, bleeding, and reoperation.

Results: In total, 270 patients were included in this retrospective cohort study by the propensity score matching, with each group having 135 patients. Tri-staple group had a significant lower incidence of anastomotic leakage compared with the Universal staple group (4.44% vs. 11.11%, P < 0.05). The reoperation rate was also lower in Tri-staple group than the Universal staple group (3.70% vs. 8.15%, P < 0.05). The anastomotic bleeding rates, average postoperative hospital stay, average drain indwelling period, and average fasting period had no statistical differences between the two groups.

Conclusion: The usage of Tri-staple in laparoscopic anterior resection of rectal and distal sigmoid colonic cancer is associated with lower postoperative complications compared with Universal staple. Future high-quality randomized controlled trials are needed to confirm our findings.
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http://dx.doi.org/10.1007/s00268-022-06704-9DOI Listing
August 2022

A Novel Constraint-based Knee-guided Neuroevolutionary Algorithm for Context-specific ECG Early Classification.

IEEE J Biomed Health Inform 2022 Aug 17;PP. Epub 2022 Aug 17.

Cardiovascular diseases (CVDs) are considered the greatest threat to human life according to World Health Organization. Early classification of CVDs and the appropriate follow-up treatment are crucial for preventing sudden deaths. Electrocardiogram (ECG) is one of the most common non-invasive tools used to evaluate the state of the heart, which can be exploited to automatically diagnose as well. However, the importance of diagnosing CVDs is varying in different context-specific scenarios. For example, ST-segment elevation (STE) is an acute myocardial infarction indicator for patients associated with chest pain and cardiac biomarker. In in-hospital healthcare, STE should be diagnosed with a higher priority than the other phenotypes of ECG. Hence, the context-specific requirements should be considered in ECG early classification problems. We formalize the ECG early classification problem as the context-specific time series classification problem. We propose a novel Constraint-based Knee-guided Neuroevolutionary Algorithm (CKNA) based on the Snippet Policy Networks V2 to solve this problem. To validate the proposed method, we perform a series of experiments on two public ECG datasets under various context-specific simulated scenarios after consulting with physicians specializing in the area. Experimental results show that CKNA significantly improves the average recall of disease classification by 5.5% compared to the competing baseline under user-specified requirements. Moreover, experimental results prove that CKNA presents a feasible solution for the early classifying of cardiac arrhythmias under different user-specified scenarios.
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http://dx.doi.org/10.1109/JBHI.2022.3199377DOI Listing
August 2022

Assessing volatile organic compounds exposure and prostate-specific antigen: National Health and Nutrition Examination Survey, 2001-2010.

Front Public Health 2022 29;10:957069. Epub 2022 Jul 29.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Volatile organic compounds (VOCs) are a large group of chemicals widely used in people's daily routines. Increasing evidence revealed the VOCs' accumulating toxicity. However, the VOCs toxicity in male prostate has not been reported previously. Thus, we comprehensively evaluated the association between VOCs and prostate-specific antigen (PSA).

Methods: A total of 2016 subjects were included in our study from the National Health and Nutrition Examination Survey with VOCs, PSA, and other variables among U.S. average population. We constructed XGBoost Algorithm Model, Regression Model, and Generalized linear Model (GAM) to analyze the potential association. Stratified analysis was used to identify high-risk populations.

Results: XGBoost Algorithm model identified blood chloroform as the most critical variable in the PSA concentration. Regression analysis suggested that blood chloroform was a positive association with PSA, which showed that environmental chloroform exposure is an independent risk factor that may cause prostate gland changes [β, (95% CI), = 0.007, (0.003, 0.011), 0.00019]. GAM observed the linear relationship between blood chloroform and PSA concentration. Meanwhile, blood chloroform linear correlated with water chloroform in the lower dose range, indicating that the absorption of water may be the primary origin of chloroform. Stratified associations analysis identified the high-risk group on the chloroform exposures.

Conclusion: This study revealed that blood chloroform was positively and independently associated with total PSA level, suggesting that long-term environmental chloroform exposure may cause changes in the prostate gland.
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http://dx.doi.org/10.3389/fpubh.2022.957069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9372286PMC
August 2022

Pathophysiology of RAGE in inflammatory diseases.

Front Immunol 2022 29;13:931473. Epub 2022 Jul 29.

Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.

The receptor for advanced glycation end products (RAGE) is a non-specific multi-ligand pattern recognition receptor capable of binding to a range of structurally diverse ligands, expressed on a variety of cell types, and performing different functions. The ligand-RAGE axis can trigger a range of signaling events that are associated with diabetes and its complications, neurological disorders, cancer, inflammation and other diseases. Since RAGE is involved in the pathophysiological processes of many diseases, targeting RAGE may be an effective strategy to block RAGE signaling.
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http://dx.doi.org/10.3389/fimmu.2022.931473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9373849PMC
August 2022

Serotonin system is partially involved in immunomodulation of Nile tilapia () immune cells.

Front Immunol 2022 28;13:944388. Epub 2022 Jul 28.

College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Zhanjiang, China.

Serotonin (5-hydroxytryptamine) is a well-known neurotransmitter affecting emotion, behavior, and cognition. Additionally, numerous immunomodulatory functions of serotonin have been discovered in mammals. However, the regulatory role of the serotonin system in fish immunity remains unclear. In this study, various serotonergic markers in Nile tilapia () were identified and characterized. The involvement of the serotonin system during bacterial infection was investigated. Moreover, the expression characteristics and specific functions of serotonergic markers within Nile tilapia immune cells were also assessed. Overall, 22 evolutionarily conserved serotonergic marker genes in Nile tilapia were cloned and characterized. Transcriptional levels of these molecules were most abundant in the brain, and their transcripts were induced during infection. Nevertheless, few serotonergic markers exist on Nile tilapia immune cells, and no distinct immunomodulation effect was observed during an immune response. The present study lays a theoretical foundation for further investigation of the immunological mechanisms in fish as well as the evolution of the serotonin system in animals.
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http://dx.doi.org/10.3389/fimmu.2022.944388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366525PMC
August 2022

Effects of 4-DAMP on allergic rhinitis in guinea pigs and its potential mechanism.

Ann Transl Med 2022 Jul;10(14):774

Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Background: Allergic rhinitis (AR) is a non-infectious chronic inflammatory disease of the nasal mucosa mainly mediated by immunoglobulin E (IgE), which seriously affects the life quality of affected patients. This study aimed to observe the effects of 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP; a selective M3 receptor antagonist) on ovalbumin (OVA)-induced AR guinea pigs, and to explore its potential mechanism of involvement.

Methods: An AR model was established by inducing male guinea pigs (4-6 weeks of age) with OVA. AR guinea pigs were randomly divided into a model group, 0.6 mg/kg ipratropium bromide (IB) group, 0.12 and 0.6 mg/kg 4-DAMP group (n=18). The 0.6 mg/kg IB group, 0.12 and 0.6 mg/kg 4-DAMP group animals were treated with IB (0.6 mg/kg) and 4-DAMP (0.12 or 0.6 mg/kg) by intranasal instillation per nostril daily. Animals in the model group and normal group were treated with saline as control. The AR symptom scores were counted and nasal secretion weights were measured. Histopathological methods were used to observe nasal mucosa. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of histamine and cytokines. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expressions of mucin 5AC (MUC5AC), matrix metalloproteinase 9 (MMP9), and epidermal growth factor receptor (EGFR).

Results: Compared with model group animals, the AR symptom scores and nasal secretion weights of animals treated with 4-DAMP were reduced significantly, goblet cell metaplasia was reversed, and eosinophil infiltration was visibly alleviated. The levels of histamine and cytokines in nasal lavage fluid (NLF) were decreased, and the protein and messenger RNA (mRNA) expressions of MUC5AC, MMP9, and EGFR were inhibited.

Conclusions: Treatment with 4-DAMP has a certain effect on AR, especially for mucus hypersecretion, which provides a new idea for clinical treatment of AR.
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http://dx.doi.org/10.21037/atm-22-2998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9372692PMC
July 2022

Plasma metabolomic profiles of dementia: a prospective study of 110,655 participants in the UK Biobank.

BMC Med 2022 08 15;20(1):252. Epub 2022 Aug 15.

Department of Ophthalmology, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China.

Background: Plasma metabolomic profile is disturbed in dementia patients, but previous studies have discordant conclusions.

Methods: Circulating metabolomic data of 110,655 people in the UK Biobank study were measured with nuclear magnetic resonance technique, and incident dementia records were obtained from national health registers. The associations between plasma metabolites and dementia were estimated using Cox proportional hazard models. The 10-fold cross-validation elastic net regression models selected metabolites that predicted incident dementia, and a 10-year prediction model for dementia was constructed by multivariable logistic regression. The predictive values of the conventional risk model, the metabolites model, and the combined model were discriminated by comparison of area under the receiver operating characteristic curves (AUCs). Net reclassification improvement (NRI) was used to estimate the change of reclassification ability when adding metabolites into the conventional prediction model.

Results: Amongst 110,655 participants, the mean (standard deviation) age was 56.5 (8.1) years, and 51 186 (46.3%) were male. A total of 1439 (13.0%) developed dementia during a median follow-up of 12.2 years (interquartile range: 11.5-12.9 years). A total of 38 metabolites, including lipids and lipoproteins, ketone bodies, glycolysis-related metabolites, and amino acids, were found to be significantly associated with incident dementia. Adding selected metabolites (n=24) to the conventional dementia risk prediction model significantly improved the prediction for incident dementia (AUC: 0.824 versus 0.817, p =0.042) and reclassification ability (NRI = 4.97%, P = 0.009) for identifying high risk groups.

Conclusions: Our analysis identified various metabolomic biomarkers which were significantly associated with incident dementia. Metabolomic profiles also provided opportunities for dementia risk reclassification. These findings may help explain the biological mechanisms underlying dementia and improve dementia prediction.
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http://dx.doi.org/10.1186/s12916-022-02449-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377110PMC
August 2022

In Situ Reconstructed Zn doped Fe Ni OOH Catalyst for Efficient and Ultrastable Oxygen Evolution Reaction at High Current Densities.

Small 2022 Aug 12:e2203710. Epub 2022 Aug 12.

Department of Materials Science and Engineering, Southern University of Science and Technology, Shenzhen, 518055, China.

Developing FeOOH as a robust electrocatalyst for high output oxygen evolution reaction (OER) remains challenging due to its low conductivity and dissolvability in alkaline conditions. Herein, it is demonstrated that the robust and high output Zn doped NiOOH-FeOOH (Zn-Fe Ni )OOH catalyst can be derived by electro-oxidation-induced reconstruction from the pre-electrocatalyst of Zn modified Ni metal/FeOOH film supported by nickel foam (NF). In situ Raman and ex situ characterizations elucidate that the pre-electrocatalyst undergoes dynamic reconstruction occurring on both the catalyst surface and underneath metal support during the OER process. That involves the Fe dissolution-redeposition and the merge of Zn doped FeOOH with in situ generated NiOOH from NF support and NiZn alloy nanoparticles. Benefiting from the Zn doping and the covalence interaction of FeOOH-NiOOH, the reconstructed electrode shows superior corrosion resistance, and enhanced catalytic activity as well as bonding force at the catalyst-support interface. Together with the feature of superaerophobic surface, the reconstructed electrode only requires an overpotential of 330 mV at a high-current-density of 1000 mA cm and maintains 97% of its initial activity after 1000 h. This work provides an in-depth understanding of electrocatalyst reconstruction during the OER process, which facilitates the design of high-performance OER catalysts.
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http://dx.doi.org/10.1002/smll.202203710DOI Listing
August 2022

The White Matter Rounds experience: The importance of a multidisciplinary network to accelerate the diagnostic process for adult patients with rare white matter disorders.

Front Neurol 2022 25;13:928493. Epub 2022 Jul 25.

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.

Introduction: Adult genetic leukoencephalopathies are rare neurological disorders that present unique diagnostic challenges due to their clinical and radiological overlap with more common white matter diseases, notably multiple sclerosis (MS). In this context, a strong collaborative multidisciplinary network is beneficial for shortening the diagnostic odyssey of these patients and preventing misdiagnosis. The White Matter Rounds (WM Rounds) are multidisciplinary international online meetings attended by more than 30 physicians and scientists from 15 participating sites that gather every month to discuss patients with atypical white matter disorders. We aim to present the experience of the WM Rounds Network and demonstrate the value of collaborative multidisciplinary international case discussion meetings in differentiating and preventing misdiagnoses between genetic white matter diseases and atypical MS.

Methods: We retrospectively reviewed the demographic, clinical and radiological data of all the subjects presented at the WM Rounds since their creation in 2013.

Results: Seventy-four patients (mean age 44.3) have been referred and discussed at the WM Rounds since 2013. Twenty-five (33.8%) of these patients were referred by an MS specialist for having an atypical presentation of MS, while in most of the remaining cases, the referring physician was a geneticist (23; 31.1%). Based on the WM Rounds recommendations, a definite diagnosis was made in 36/69 (52.2%) patients for which information was available for retrospective review. Of these diagnosed patients, 20 (55.6%) had a genetic disease, 8 (22.2%) had MS, 3 (8.3%) had both MS and a genetic disorder and 5 (13.9%) had other non-genetic conditions. Interestingly, among the patients initially referred by an MS specialist, 7/25 were definitively diagnosed with MS, 5/25 had a genetic condition (e.g., X-linked adrenoleukodystrophy and hereditary small vessel diseases like Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and -related disorder), and one had both MS and a genetic demyelinating neuropathy. Thanks to the WM Rounds collaborative efforts, the subjects who currently remain without a definite diagnosis, despite extensive investigations performed in the clinical setting, have been recruited in research studies aimed at identifying novel forms of genetic MS mimickers.

Conclusions: The experience of the WM Rounds Network demonstrates the benefit of collective discussions on complex cases to increase the diagnostic rate and decrease misdiagnosis in patients with rare or atypical white matter diseases. Networks of this nature allow physicians and scientists to compare and share information on challenging cases from across the world, provide a basis for future multicenter research studies, and serve as model for other rare diseases.
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http://dx.doi.org/10.3389/fneur.2022.928493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9359417PMC
July 2022

lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis.

Open Med (Wars) 2022 25;17(1):1338-1349. Epub 2022 Jul 25.

Emergency Department, Taizhou People's Hospital, No. 366 Taihu Road, Taizhou Pharmaceutical High-Tech Zone, Taizhou 225300, Jiangsu Province, China.

This study aimed to investigate the role and mechanism of long non-coding RNA (lncRNA) WT1 antisense RNA (WT1-AS) in cerebral ischemic stroke. The Starbase database and dual-luciferase reporter gene assay were used to analyze the interaction between lncRNA WT1 antisense RNA (lncRNA WT1-AS) and microRNA-186-5p (miR-186-5p). Reverse transcription-quantitative PCR analysis was performed to determine lncRNA WT1-AS and miR-186-5p levels. An oxygen glucose deprivation (OGD)-induced SH-SY5Y cell injury model was established. Cell viability and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and flow cytometric assays, respectively. Caspase 3 activity was evaluated using a caspase 3 activity detection kit. The results showed that miR-186-5p is a direct target of the lncRNA WT1-AS. In addition, lncRNA WT1-AS levels were downregulated and miR-186-5p levels were upregulated in the blood samples of patients with ischemic stroke and OGD-induced SH-SY5Y cells. WT1-AS overexpression promoted OGD-induced cell viability and reduced the cell apoptosis and caspase 3 activity. However, these effects were reversed by miR-186-5p overexpression. Furthermore, the results demonstrated that the X-linked inhibitor of apoptosis (XIAP) was directly targeted by miR-186-5p. Similarly, transfection with the miR-186-5p inhibitor reduced OGD-induced neuronal damage by upregulating XIAP expression. In conclusion, lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury in cerebral ischemic stroke through the miR-186-5p/XIAP axis.
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http://dx.doi.org/10.1515/med-2022-0528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9319664PMC
July 2022

Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.

J Clin Immunol 2022 Aug 10. Epub 2022 Aug 10.

Department of Medicine, St Vincent's Hospital, University of Melbourne, Vic, Fitzroy, Australia.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.
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http://dx.doi.org/10.1007/s10875-022-01312-7DOI Listing
August 2022

Transcription Factor GATA4 Regulates Cell Type-Specific Splicing Through Direct Interaction With RNA in Human Induced Pluripotent Stem Cell-Derived Cardiac Progenitors.

Circulation 2022 Aug 8:CIRCULATIONAHA121057620. Epub 2022 Aug 8.

Gladstone Institutes, San Francisco, CA (L.Z., K.C., B.G-T., Y-S.A., R.T., N.R.S., L.L., P.Z., Y.H., A.P., F.K., A.P., N.S., A.H., M.W.C., C.A.G., J.v.B., R.H., B.R.C., B.G.B., N.J.K., K.S.P., D.S.).

Background: GATA4 (GATA-binding protein 4), a zinc finger-containing, DNA-binding transcription factor, is essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Defects in alternative splicing are associated with many heart diseases, yet relatively little is known about how cell type- or cell state-specific alternative splicing is achieved in the heart. Here, we show that GATA4 regulates cell type-specific splicing through direct interaction with RNA and the spliceosome in human induced pluripotent stem cell-derived cardiac progenitors.

Methods: We leveraged a combination of unbiased approaches including affinity purification of GATA4 and mass spectrometry, enhanced cross-linking with immunoprecipitation, electrophoretic mobility shift assays, in vitro splicing assays, and unbiased transcriptomic analysis to uncover GATA4's novel function as a splicing regulator in human induced pluripotent stem cell-derived cardiac progenitors.

Results: We found that GATA4 interacts with many members of the spliceosome complex in human induced pluripotent stem cell-derived cardiac progenitors. Enhanced cross-linking with immunoprecipitation demonstrated that GATA4 also directly binds to a large number of mRNAs through defined RNA motifs in a sequence-specific manner. In vitro splicing assays indicated that GATA4 regulates alternative splicing through direct RNA binding, resulting in functionally distinct protein products. Correspondingly, knockdown of GATA4 in human induced pluripotent stem cell-derived cardiac progenitors resulted in differential alternative splicing of genes involved in cytoskeleton organization and calcium ion import, with functional consequences associated with the protein isoforms.

Conclusions: This study shows that in addition to its well described transcriptional function, GATA4 interacts with members of the spliceosome complex and regulates cell type-specific alternative splicing via sequence-specific interactions with RNA. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.057620DOI Listing
August 2022

Immunogenicity of a vaccinia virus-based severe acute respiratory syndrome coronavirus 2 vaccine candidate.

Front Immunol 2022 22;13:911164. Epub 2022 Jul 22.

NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, and Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines provide essential tools for the control of the COVID-19 pandemic. A number of technologies have been employed to develop SARS-CoV-2 vaccines, including the inactivated SARS-CoV-2 particles, mRNA to express viral spike protein, recombinant spike proteins, and viral vectors. Here, we report the use of the vaccinia virus Tiantan strain as a vector to express the SARS-CoV-2 spike protein. When it was used to inoculate mice, robust SARS-CoV-2 spike protein-specific antibody response and T-cell response were detected. Sera from the vaccinated mice showed strong neutralizing activity against the ancestral Wuhan SARS-CoV-2, the variants of concern (VOCs) B.1.351, B.1.617.2, and the emerging B.1.1.529 (omicron). This finding supports the possibility of developing a new type of SARS-CoV-2 vaccine using the vaccinia virus vector.
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http://dx.doi.org/10.3389/fimmu.2022.911164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353262PMC
August 2022

Real-time fluorescent cholangiography with indocyanine green in laparoscopic cholecystectomy: a randomized controlled trial to establish the optimal indocyanine green dose within 30 min preoperatively.

Surg Today 2022 Aug 3. Epub 2022 Aug 3.

Department of Surgery, Guangzhou First People's Hospital, No. 1 Panfu Road, Yuexiu District, Guangzhou, 510180, Guangdong, China.

Purpose: To establish the optimal dose of indocyanine green (ICG) to administer intravenously 30 min before laparoscopic cholecystectomy (LC).

Methods: In this randomized controlled trial (RCT), patients undergoing LC for cholecystitis, cholelithiasis, and/or cholecystic polyps were randomized into four groups given four different ICG doses (0.025, 0.1, 0.25, 2.5 mg). Using OptoMedic endoscopy combined with a near-infrared fluorescent imaging system, we evaluated the fluorescence intensity (FI) of the common bile duct and liver at three timepoints: before surgical dissection of the cystohepatic triangle, before clipping of the cystic duct, and before closure. The bile duct-to-liver ratio (BLR) of the FI was analyzed to assess the cholangiography effect.

Results: Sixty-four patients were allocated to one of four groups, with 40 patients included in the final analysis. Generally, with increasing ICG doses, the levels of FI in the bile duct and liver increased gradually at each of the three timepoints. Before surgical dissection of the cystohepatic triangle, 0.1-mg ICG showed the highest BLR (F = 3.47, p = 0.0259). Before clipping the cystic duct and before closure, the 0.025- and 0.1-mg groups showed a higher BLR than the 0.25- and 2.5-mg groups (p < 0.05). When setting the ideal cholangiography at a BLR ≥ 1, ≥ 3, or ≥ 5, the 0.1-mg group showed the highest qualified case number at the three timepoints.

Conclusions: The intravenous administration of 0.1-mg ICG, 30 min before LC, is significantly better for fluorescent cholangiography of the extrahepatic biliary structures before dissection and clipping of the cystohepatic triangle.

Trial Registration: This study was registered in the Chinese Clinical Trial Registry (ChiCTR) (ChiCTR2200057933).
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http://dx.doi.org/10.1007/s00595-022-02563-yDOI Listing
August 2022

Association between dual sensory impairment and risk of mortality: a cohort study from the UK Biobank.

BMC Geriatr 2022 08 1;22(1):631. Epub 2022 Aug 1.

Department of Ophthalmology, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China.

Background: Dual sensory impairment is affecting over 10% of older adults worldwide. However, the long-term effect of dual sensory impairment (DSI) on the risk of mortality remains controversial. We aim to investigate the impact of single or/and dual sensory impairment on the risk of mortality in a large population-based sample of the adult in the UK with 14-years of follow-up.

Methods: This population-based prospective cohort study included participants aged 40 and over with complete records of visual and hearing functions from the UK Biobank study. Measurements of visual and hearing functions were performed at baseline examinations between 2006 and 2010, and data on mortality was obtained by 2021. Dual sensory impairment was defined as concurrent visual and hearing impairments. Cox proportional hazards regression models were employed to evaluate the impact of sensory impairment (dual sensory impairment, single visual or hearing impairment) on the hazard of mortality.

Results: Of the 113,563 participants included in this study, the mean age (standard deviation) was 56.8 (8.09) years, and 61,849 (54.5%) were female. At baseline measurements, there were 733 (0.65%) participants with dual sensory impairment, 2,973 (2.62%) participants with single visual impairment, and 13,560 (11.94%) with single hearing impairment. After a follow-up period of 14 years (mean duration of 11 years), 5,992 (5.28%) participants died from all causes. Compared with no sensory impairment, dual sensory impairment was significantly associated with an estimated 44% higher hazard of mortality (hazard ratio: 1.44 [95% confidence interval, 1.11-1.88], p = 0.007) after multiple adjustments.

Conclusions: Individuals with dual sensory impairment were found to have an independently 44% higher hazard of mortality than those with neither sensory impairment. Timely intervention of sensory impairment and early prevention of its underlying causes should help to reduce the associated risk of mortality.
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http://dx.doi.org/10.1186/s12877-022-03322-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9341066PMC
August 2022

Low Expression Levels of CXCL12, CXCR4, and CXCR 7 in Peripheral Blood and Decidual Tissues are Associated with Miscarriage in Women.

Immunol Invest 2022 Aug 1:1-13. Epub 2022 Aug 1.

Department of Obstetrics and Gynecology, Qingdao Women and Children's Hospital, Shandong University, Qingdao, Shandong, P.R. China.

Miscarriage can cause significant physical and psychological harm to women. The stromal cell-derived factor 1 (SDF-1, also known as CXCL12)/C-X-C motif chemokine receptor 4 (CXCR4) and C-X-C motif chemokine receptor 7 (CXCR7) axis can promote the proliferation and invasion of trophoblast cells in early pregnancy, and maintain immune tolerance at the maternal-fetal interface to aid with pregnancy success. From our findings, the serum CXCL12 level of women who have miscarried (n = 25) was significantly lower than that of healthy early pregnancy women (n = 20) by ELISA ( < .001). Additionally, CXCL12 levels in normal non-pregnant women (n = 20) were significantly lower than those in early pregnancy women ( < .001) and women who have miscarried ( < .001). Quantitative real-time PCR detected no significant difference in the mRNA transcription levels of CXCR4 and CXCR7 in the decidua tissues of women with early pregnancy (n = 20) and miscarriage (n = 20) ( = .724,  = .281, respectively). However, Western blot and immunohistochemistry of CXCR4 and CXCR7 in decidual tissue of women who have miscarried (n = 20) were significantly lower than those in early pregnancy women (n = 20) ( < .05 for both). Therefore, we believe that the increased serum CXCL12 levels in pregnant offspring may benefit normal pregnancy maintenance. The low level of CXCL12 in peripheral blood and the low expression of CXCR4 and CXCR7 proteins in decidua may be associated with the occurrence of early spontaneous abortion, and the clinical application value of serum CXCL12 in predicting adverse pregnancy outcomes is worth further exploring.
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http://dx.doi.org/10.1080/08820139.2022.2106871DOI Listing
August 2022

CEO Overconfidence, Corporate Governance, and R&D Smoothing in Technology-Based Entrepreneurial Firms.

Front Psychol 2022 13;13:944117. Epub 2022 Jul 13.

School of Management, Shanghai University, Shanghai, China.

The intertemporal stability of research and development (R&D) investment is a key issue in successfully promoting the continuation of innovation activities under high uncertainty in entrepreneurship. R&D smoothing helps firms to navigate the uncertainties of the external environment and maintain the stability of their investments in innovation. Chief executive officers (CEOs) are the most important decision-makers in firms' strategic planning. However, overconfident CEOs may overlook the importance of their firms' strategic actions on innovative activities. Drawing on upper echelons theory, this paper examines how CEO overconfidence affects firms' R&D smoothing. Using a sample of firms listed in China's Growth Enterprises Market between 2013 and 2020, this study finds that CEO overconfidence has a significant negative impact on R&D smoothing. Furthermore, our findings reveal that firms' internal control quality and institutional investor monitoring can mitigate the negative association between CEO overconfidence and R&D smoothing. Our findings provide new insights into the micro-level theoretical explanations for R&D smoothing and offer practical implications for technology-based entrepreneurial firms.
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http://dx.doi.org/10.3389/fpsyg.2022.944117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9326171PMC
July 2022

Endothelial UCP2 Is a Mechanosensitive Suppressor of Atherosclerosis.

Circ Res 2022 Aug 28;131(5):424-441. Epub 2022 Jul 28.

Department of Biomedical Sciences, City University of Hong Kong, China (C.K.C., L.H., Y.P., Y.H.).

Background: Inflamed endothelial cells (ECs) trigger atherogenesis, especially at arterial regions experiencing disturbed blood flow. UCP2 (Uncoupling protein 2), a key mitochondrial antioxidant protein, improves endothelium-dependent relaxation in obese mice. However, whether UCP2 can be regulated by shear flow is unknown, and the role of endothelial UCP2 in regulating inflammation and atherosclerosis remains unclear. This study aims to investigate the mechanoregulation of UCP2 expression in ECs and the effect of UCP2 on endothelial inflammation and atherogenesis.

Methods: In vitro shear stress simulation system was used to investigate the regulation of UCP2 expression by shear flow. EC-specific Ucp2 knockout mice were used to investigate the role of UCP2 in flow-associated atherosclerosis.

Results: Shear stress experiments showed that KLF2 (Krüppel-like factor 2) mediates fluid shear stress-dependent regulation of UCP2 expression in human aortic and human umbilical vein ECs. Unidirectional shear stress, statins, and resveratrol upregulate whereas oscillatory shear stress and proinflammatory stimuli inhibit UCP2 expression through altered KLF2 expression. KLF2 directly binds to UCP2 promoter to upregulate its transcription in human umbilical vein ECs. UCP2 knockdown induced expression of genes involved in proinflammatory and profibrotic signaling, resulting in a proatherogenic endothelial phenotype. EC-specific deletion promotes atherogenesis and collagen production. Additionally, we found endothelial deficiency aggravates whereas adeno-associated virus-mediated EC- overexpression inhibits carotid atherosclerotic plaque formation in disturbed flow-enhanced atherosclerosis mouse model. RNA-sequencing analysis revealed FoxO1 (forkhead box protein O1) as the major proinflammatory transcriptional regulator activated by UCP2 knockdown, and FoxO1 inhibition reduced vascular inflammation and disturbed flow-enhanced atherosclerosis. We showed further that UCP2 level is critical for phosphorylation of AMPK (AMP-activated protein kinase), which is required for UCP2-induced inhibition of FoxO1.

Conclusions: Altogether, our studies uncover that UCP2 is novel mechanosensitive gene under the control of fluid shear stress and KLF2 in ECs. UCP2 expression is critical for endothelial proinflammatory response and atherogenesis. Therapeutic strategies enhancing UCP2 level may have therapeutic potential against atherosclerosis.
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http://dx.doi.org/10.1161/CIRCRESAHA.122.321187DOI Listing
August 2022

Targeting PDE4B (Phosphodiesterase-4 Subtype B) for Cardioprotection in Acute Myocardial Infarction via Neutrophils and Microcirculation.

Circ Res 2022 Aug 28;131(5):442-455. Epub 2022 Jul 28.

State Key Laboratory of Cardiovascular Disease (Q.W., C.X., L.Z., Y.Z., Z.P., H.C., H.R., F.C., X.N., X.Y., S.H., M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Timely and complete restoration of blood flow is the most effective intervention for patients with acute myocardial infarction. However, the efficacy is limited by myocardial ischemia-reperfusion (MI/R) injury. PDE4 (phosphodiesterase-4) hydrolyzes intracellular cyclic adenosine monophosphate and it has 4 subtypes A-D. This study aimed to delineate the role of PDE4B (phosphodiesterase-4 subtype B) in MI/R injury.

Methods: Mice were subjected to 30-minute coronary artery ligation, followed by 24-hour reperfusion. Cardiac perfusion was assessed by laser Doppler flow. Vasomotor reactivities were determined in mouse and human coronary (micro-)arteries.

Results: Cardiac expression of PDE4B, but not other PDE4 subtypes, was increased in mice following reperfusion. PDE4B was detected primarily in endothelial and myeloid cells of mouse and human hearts. PDE4B deletion strikingly reduced infarct size and improved cardiac function 24-hour or 28-day after MI/R. PDE4B in bone marrow-derived cells promoted MI/R injury and vascular PDE4B further exaggerated this injury. Mechanistically, PDE4B mediated neutrophil-endothelial cell interaction and PKA (protein kinase A)-dependent expression of cell adhesion molecules, neutrophil cardiac infiltration, and release of proinflammatory cytokines. Meanwhile, PDE4B promoted coronary microcirculatory obstruction and vascular permeability in MI/R, without affecting flow restriction-induced thrombosis. PDE4B blockade increased flow-mediated vasodilatation and promoted endothelium-dependent dilatation of coronary arteries in a PKA- and nitric oxide-dependent manner. Furthermore, postischemia administration with piclamilast, a PDE4 pan-inhibitor, improved cardiac microcirculation, suppressed inflammation, and attenuated MI/R injury in mice. Incubation with sera from patients with acute myocardial infarction impaired acetylcholine-induced relaxations in human coronary microarteries, which was abolished by PDE4 inhibition. Similar protection against MI/R-related coronary injury was recapitulated in mice with PDE4B deletion or inhibition, but not with the pure vasodilator, sodium nitroprusside.

Conclusions: PDE4B is critically involved in neutrophil inflammation and microvascular obstruction, leading to MI/R injury. Selective inhibition of PDE4B might protect cardiac function in patients with acute myocardial infarction designated for reperfusion therapy.
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http://dx.doi.org/10.1161/CIRCRESAHA.122.321365DOI Listing
August 2022

Targeting transcription in heart failure via CDK7/12/13 inhibition.

Nat Commun 2022 07 27;13(1):4345. Epub 2022 Jul 27.

Gladstone Institutes, San Francisco, CA, USA.

Heart failure with reduced ejection fraction (HFrEF) is associated with high mortality, highlighting an urgent need for new therapeutic strategies. As stress-activated cardiac signaling cascades converge on the nucleus to drive maladaptive gene programs, interdicting pathological transcription is a conceptually attractive approach for HFrEF therapy. Here, we demonstrate that CDK7/12/13 are critical regulators of transcription activation in the heart that can be pharmacologically inhibited to improve HFrEF. CDK7/12/13 inhibition using the first-in-class inhibitor THZ1 or RNAi blocks stress-induced transcription and pathologic hypertrophy in cultured rodent cardiomyocytes. THZ1 potently attenuates adverse cardiac remodeling and HFrEF pathogenesis in mice and blocks cardinal features of disease in human iPSC-derived cardiomyocytes. THZ1 suppresses Pol II enrichment at stress-transactivated cardiac genes and inhibits a specific pathologic gene program in the failing mouse heart. These data identify CDK7/12/13 as druggable regulators of cardiac gene transactivation during disease-related stress, suggesting that HFrEF features a critical dependency on transcription that can be therapeutically exploited.
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http://dx.doi.org/10.1038/s41467-022-31541-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329381PMC
July 2022

Primary Antibiotic Resistance of in Different Regions of China: A Systematic Review and Meta-Analysis.

Pathogens 2022 Jul 12;11(7). Epub 2022 Jul 12.

Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology &Hepatology NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200120, China.

Aim: Understanding the prevalence of antibiotic resistance can provide reliable information for selecting treatment options. The goal of this meta-analysis was to observe the primary antibiotic resistance of () in different regions and time periods of China.

Method: We searched PubMed, EMBASE, Chinese Biomedical databases and the China National Knowledge Infrastructure from inception to 20 February 2022. Data on the prevalence of primary resistance at various time points were included. A random-effect model was established to calculate the pooled antibiotic resistance.

Results: In total, 2150 articles were searched, with 70 meeting the inclusion criteria. The resistance to clarithromycin, metronidazole, levofloxacin amoxicillin, tetracycline and furazolidone in 2016-2020 were 34% (95% CI: 30-39%), 78% (95% CI: 73-84%), 35% (95% CI: 30-40%), 3% (95% CI: 1-5%), 2% (95%CI: 1-4%) and 1% (95% CI: 0-4%), respectively. Clarithromycin showed regional difference, as the resistance was higher in northern (37%, 95% CI: 32-41%) and western China (35%, 95% CI: 17-54%) than that in southern (24%, 95% CI: 17-32%) and eastern China (24%, 95% CI: 20-28%).

Conclusion: The resistance of to clarithromycin and metronidazole was high and increased over time, whereas resistance to levofloxacin, amoxicillin, tetracycline and furazolidone remained stable.
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http://dx.doi.org/10.3390/pathogens11070786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316315PMC
July 2022

Association of Retinal Age Gap With Arterial Stiffness and Incident Cardiovascular Disease.

Stroke 2022 Jul 26:101161STROKEAHA122038809. Epub 2022 Jul 26.

Department of Ophthalmology, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China (Z.Z., X.S., Y.H., X.Z., S.T., H.Y., X.Y., M.H.).

Background: Retinal parameters could reflect systemic vascular changes. With the advances of deep learning technology, we have recently developed an algorithm to predict retinal age based on fundus images, which could be a novel biomarker for aging and mortality. Therefore, we aim to investigate associations of retinal age gap with arterial stiffness index and incident cardiovascular disease (CVD).

Methods: A deep learning model was trained based on 19 200 fundus images of 11 052 participants without any medical history at baseline to predict the retinal age. Retinal age gap (retinal age predicted minus chronological age) was generated for the remaining 35 917 participants. Regression models were used to assess the association between retinal age gap and arterial stiffness index. Cox proportional hazards regression models and restricted cubic splines were used to explore the association between retinal age gap and incident CVD.

Results: We found each 1-year increase in retinal age gap was associated with increased arterial stiffness index (β=0.002 [95% CI, 0.001-0.003]; <0.001). After a median follow-up of 5.83 years (interquartile range: 5.73-5.97), 675 (2.00%) developed CVD. In the fully adjusted model, each 1-year increase in retinal age gap was associated with a 3% increase in the risk of incident CVD (hazard ratio=1.03 [95% CI, 1.01-1.06]; =0.014). In the restricted cubic splines analysis, the risk of incident CVD increased significantly when retinal age gap reached 1.21 (hazard ratio=1.05 [95% CI, 1.00-1.10]; -overall <0.0001; -nonlinear=0.0681).

Conclusions: We found that retinal age gap was significantly associated with arterial stiffness index and incident CVD events, supporting the potential of this novel biomarker in identifying individuals at high risk of future CVD events.
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http://dx.doi.org/10.1161/STROKEAHA.122.038809DOI Listing
July 2022

Graphene-nanopocket-encaged PtCo nanocatalysts for highly durable fuel cell operation under demanding ultralow-Pt-loading conditions.

Nat Nanotechnol 2022 Jul 25. Epub 2022 Jul 25.

Department of Materials Science and Engineering, University of California, Los Angeles, Los Angeles, CA, USA.

The proton exchange membrane fuel cell (PEMFC) as an attractive clean power source can promise a carbon-neutral future, but the widespread adoption of PEMFCs requires a substantial reduction in the usage of the costly platinum group metal (PGM) catalysts. Ultrafine nanocatalysts are essential to provide sufficient catalytic sites at a reduced PGM loading, but are fundamentally less stable and prone to substantial size growth in long-term operations. Here we report the design of a graphene-nanopocket-encaged platinum cobalt ([email protected]) nanocatalyst with good electrochemical accessibility and exceptional durability under a demanding ultralow PGM loading (0.070 mg cm) due to the non-contacting enclosure of graphene nanopockets. The [email protected] delivers a state-of-the-art mass activity of 1.21 A mg, a rated power of 13.2 W mg and a mass activity retention of 73% after an accelerated durability test. With the greatly improved rated power and durability, we project a 6.8 g loading for a 90 kW PEMFC vehicle, which approaches that used in a typical catalytic converter.
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http://dx.doi.org/10.1038/s41565-022-01170-9DOI Listing
July 2022

mA Regulator-Based Methylation Modification Patterns Characterized by Distinct Tumor Microenvironment Immune Profiles in Rectal Cancer.

Front Oncol 2022 6;12:879405. Epub 2022 Jul 6.

Jiangxi Province Key Laboratory of Laboratory Medicine, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China.

Background: Previous studies reported the related role of RNA n6-methyladenosine (m6A) modification in tumorigenesis and development. However, it is not clear whether m6A modification also plays a potential role in the immune regulation of rectal cancer (RC) and the formation of tumor microenvironment.

Methods: In this study, we screened 23 m6A regulatory factors from 369 rectal cancer specimens, further determined the modification patterns of m6A in RC, and systematically linked these modification patterns with the characteristics of TME cell infiltration. The principal component analysis (PCA) algorithm was used to evaluate the m6A modification pattern of a single tumor related to immune response.

Results: Three different m6A modification patterns were found in the measurement results, which are related to different clinical results and biological pathways. TME identification results show that the identified m6A pattern is closely related to immune characteristics. According to the m6Ascore extracted from m6A-related signature genes, RC patients were divided into high and low score subgroups combined with tumor mutation burden. Patients with high tumor mutation burden and higher m6Ascore have a significant survival advantage and enhanced immune infiltration. Further analysis showed that patients with higher m6Ascore had higher PD-L1 expression levels and showed better immune response and lasting clinical benefits.

Conclusions: M6A modification plays a crucial role in the formation of TME diversity and complexity. The evaluation of the m6A modification mode will help us to enhance our understanding of the characteristics of TME infiltration and provide new insights for more effective immunotherapy strategies.
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http://dx.doi.org/10.3389/fonc.2022.879405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299953PMC
July 2022

Effects of black carbon aerosol on air quality and vertical meteorological factors in early summer in Beijing.

Sci Total Environ 2022 Jul 21;847:157529. Epub 2022 Jul 21.

School of Earth and Space Sciences, University of Science and Technology of China, Hefei, China.

Black carbon (BC) aerosols have effects on the atmospheric thermal vertical structure due to its radiation absorption characteristics, hereby influencing the boundary layer characteristics and pollutant diffusion. This study focuses on the BC effects under different atmospheric conditions on air quality and vertical meteorological conditions. Four days flight observation combined with surface wind profiler radar data were used to investigate the vertical profiles of BC and wind speed over Beijing urban area in early summer. The vertical profiles of BC concentration and wind speed in the boundary layer had a negative correlation, both having abrupt changes near the boundary layer height under stagnant weather conditions. The chemical transport model showed the increase of BC under stagnant conditions could cause aggravation of the stability of the boundary layer, thereby increasing the accumulation of pollutants. In particular, BC leads to the changes in the temperature profile, which will modify relative humidity and indirectly lead to the changes in the vertical profile of aerosol optical properties. However, if the early accumulation of BC was absent under more turbulent conditions, the effects of BC on air quality and meteorological conditions were limited.
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http://dx.doi.org/10.1016/j.scitotenv.2022.157529DOI Listing
July 2022

Implementation of NUDT15 genotyping to prevent Azathioprine-induced leukopenia for patients with autoimmune disorders in Chinese population.

Clin Pharmacol Ther 2022 Jul 22. Epub 2022 Jul 22.

Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan.

Azathioprine (AZA) is commonly used for many autoimmune disorders; however, the limitation of its clinical use is due to potential toxicities, including severe leukopenia. Recent studies have identified genetic NUDT15 variants strongly associated with AZA-induced leukopenia in Asians. This study aimed to investigate the strength of above genetic association and evaluate the usefulness of prospective screening of the NUDT15 variants to prevent AZA-induced leukopenia in Chinese patients. AZA-induced leukopenia patients with autoimmune disorders were enrolled from multiple medical centers in Taiwan/China between 2012~2017 to determine the strength of genetic association of NUDT15 or TPMT variants by whole exome sequencing (WES). Furthermore, a prospective study was conducted between 2018~2021 to investigate the incidence of AZA-induced leukopenia with and without genetic screening. The WES result showed the genetic variants of NUDT15 R139C (rs116855232) (P=3.7×10 , odd ratios [OR]=21.7, 95% confidence interval [95% CI]=12.1-38.8) and NUDT15 rs746071566 (P=4.2×10 , OR=7.1, 95% CI=3.7-13.7), but not TPMT, were associated with AZA-induced leukopenia and NUDT15 R139C variant shows the highest sensitivity with 92.5%. Furthermore, the targeted screening of 1,013 participants for NUDT15 R139C enabled those identified as carriers to use alternative immunosuppressants. This strategy resulted in a significant decrease in the incidence of AZA-induced leukopenia compared to historical incidence (incidence rate=from 7.6% decreased to 0.4%; P=9.3×10 ). In conclusion, the NUDT15 R139C variant was strongly associated with AZA-induced leukopenia in Chinese patients. The genetic screening of NUDT15 R139C followed by use of alternative immunosuppressants in identified carriers effectively decreased the incidence of AZA leukopenia for patients with autoimmune disorders.
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http://dx.doi.org/10.1002/cpt.2716DOI Listing
July 2022

A Fibrinogen-Mimicking, Activated-Platelet-Sensitive Nanocoacervate Enhances Thrombus Targeting and Penetration of Tissue Plasminogen Activator for Effective Thrombolytic Therapy.

Adv Healthc Mater 2022 Jul 21:e2201265. Epub 2022 Jul 21.

Department of Chemical Engineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.

The development of a fibrinolytic system with long circulation time, high thrombus targeting, efficient thrombus penetration, effective thrombolysis, and minimal hemorrhagic risk remains a major challenge. Herein, inspired by fibrinogen binding to activated platelets in thrombosis, this article reports a fibrinogen-mimicking, activated-platelet-sensitive nanocoacervate to enhance thrombus penetration of tissue plasminogen activator (tPA) for targeted thrombolytic therapy. This biomimetic nanothrombolytic system, denoted as [email protected], is constructed by "one-pot" coacervation through electrostatic interactions between positively charged arginine-glycine-aspartic acid (RGD)-grafted chitosan (RGD-Chi) and negatively charged tPA. Flow cytometry and confocal laser scanning microscopy measurements show targeting of [email protected] to activated platelets. Controlled tPA release triggered by activated platelets at a thrombus site is demonstrated. Its targeted fibrinolytic and thrombolytic activities are measured in in vitro models. The pharmacokinetic profiles show that [email protected] can significantly prolong circulation time compared to free tPA. In a mouse tail thrombus model, [email protected] displays efficient thrombus targeting and penetration, enabling a complete vascular recanalization as confirmed by the fluorescence imaging, histochemical assay, and laser speckle contrast imager. Consequently, [email protected] induces a substantial enhancement in thrombolysis with minimal hemorrhagic risk compared to free tPA. This simple, effective, and safe platform holds great promise for the development of thrombolytic nanomedicines.
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http://dx.doi.org/10.1002/adhm.202201265DOI Listing
July 2022

Cyanophycin Granule Polypeptide: a Neglected High Value-Added Biopolymer, Synthesized in Activated Sludge on a Large Scale.

Appl Environ Microbiol 2022 07 7;88(14):e0074222. Epub 2022 Jul 7.

Key Laboratory of the Three Gorges Reservoir Region's Eco-Environments of MOE, Chongqing Universitygrid.190737.b, Chongqing, China.

Recovery of microbial synthetic polymers with high economic value and market demand in activated sludge has attracted extensive attention. This work analyzed the synthesis of cyanophycin granule peptide (CGP) in activated sludge and its adsorption capacity for heavy metals and dyes. The distribution and expression of synthetic genes for eight biopolymers in two wastewater treatment plants (WWTPs) were analyzed by metagenomics and metatranscriptomics. The results indicate that the abundance and expression level of CGP synthase () are similar to those of polyhydroxyalkanoate polymerase, implying high synthesis of CGP in activated sludges. CGP in activated sludge is mainly polymerized from aspartic acid and arginine, and its secondary structure is mainly β-sheet. The crude yields of CGP are as high as 104 ± 26 and 76 ± 13 mg/g dry sludge in winter and in summer, respectively, comparable to those of polyhydroxyalkanoate and alginate. CGP has a stronger adsorption capacity for anionic pollutants (Cr (VI) and methyl orange) than for cationic pollutants because it is rich in guanidine groups. This study highlights prospects for recovery and application of CGP from WWTPs. The conversion of organic pollutants into bioresources by activated sludge can reduce the carbon dioxide emission of wastewater treatment plants. Identification of new high value-added biopolymers produced by activated sludge is beneficial to recover bioresources. Cyanophycin granule polypeptide (CGP), first discovered in cyanobacteria, has unique chemical and material properties suitable for industrial food, medicine, cosmetics, water treatment, and agriculture applications. Here, we revealed for the first time that activated sludge has a remarkable ability to produce CGP. These findings could further facilitate the conversion of wastewater treatment plants into resource recycling plants.
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http://dx.doi.org/10.1128/aem.00742-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317870PMC
July 2022

A case of CIC-rearranged sarcoma with CIC-LEUTX gene fusion in spinal cord.

Neuropathology 2022 Jul 20. Epub 2022 Jul 20.

Department of Pathology, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China.

A 16-year-old male was admitted to the hospital for weakness of both lower extremities. Magnetic resonance imaging revealed an intraspinal extramedullary subdural mass at the thoracic 9 level. Microscopically, the tumor cells were small to medium sized and round to ovoid in shape. They were distributed in diffuse sheets or showed nodular appearance. The nucleus of the tumor had mild-to-moderate atypia, with vesicular chromatin and prominent nucleoli. A smaller proportion of tumor cells demonstrated rhabdoid morphology. Focal myxoid stromal change was present, in which tumor cells exhibited spindle shapes. Approximately two mitoses were counted per 10 high-power fields. No necrosis was observed. The tumor cells were focal positive for CD99; multifocal positive for WT1; diffuse positive for nestin, synaptophysin, and D2-40; partial positive for GFAP; focal positive for desmin and SSTR2; and scattered positive for S-100 protein. The Ki-67 labeling index was approximately 20%. Genetic testing revealed CIC-LEUTX gene fusion. Considering the patient's history, clinical data, pathological findings and genetic findings, we rendered a rare tumor named CIC-rearranged sarcoma with CIC-LEUTX gene fusion.
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http://dx.doi.org/10.1111/neup.12850DOI Listing
July 2022
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