Publications by authors named "Shao Li"

445 Publications

The dilemmas in the diagnosis and management of angular pregnancy.

Taiwan J Obstet Gynecol 2021 May;60(3):582-583

Department of Ultrasonography, Ningbo First Hospital, Ningbo, Zhejiang, China.

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http://dx.doi.org/10.1016/j.tjog.2021.03.040DOI Listing
May 2021

Scorpion venom peptide SVHRSP ameliorates 6-OHDA-induced neurotoxicity and neuroinflammation: potential role of Na 1.6 inhibition in microglia.

Br J Pharmacol 2021 Apr 22. Epub 2021 Apr 22.

National-Local Joint Engineering Research Center for Drug Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, No 9 Western Section, Lvshun South Road, Dalian City, P.R. China, 116044.

Background And Purpose: Microglia-related inflammation is associated with the pathology of Parkinson's disease (PD). Functional voltage-gated sodium channels (VGSCS) are involved in regulating microglial function. Here, we aim to investigate the effects of SVHRSP (scorpion venom heat-resistant synthesized peptide) on 6-OHDA-induced PD-like mouse model and reveal its underlying mechanism.

Experimental Approach: Unilateral brain injection of 6-OHDA was performed to establish PD mouse model. After behavior test, brain tissuses were collected for morphological analysis and protein/gene expression examination. Primary microglia culture was used to investigate the role of sodium channel Na 1.6 in the regulation of microglia inflammation by SVHRSP.

Key Results: SVHRSP treatment attenuated motor deficits, dopaminergic neurodegeneration, activation of glial cells as well expression of pro-inflammatory cytokines induced by 6-OHDA lesion. Primary microglia activation and the production of pro-inflammatory cytokines induced by lipopolysaccharide (LPS) were also suppressed by SVHRSP treatment. In addition, SVHRSP could inhibit mitogen-activated protein kinases (MAPKs) pathway which plays pivotal roles in the pro-inflammatory response. Notably, SVHRSP treatment suppressed the over-expression of microglial Na 1.6 induced by 6-OHDA and LPS. Finally, it was shown that the anti-inflammatory effect of SVHRSP in microglia was Na 1.6 dependent and was related to suppression of sodium current and probably the consequent Na /Ca exchange.

Conclusion And Implications: SVHRSP might inhibit neuroinflammation and protect dopaminergic neurons via down-regulating microglial Na 1.6 and subsequently suppressing intracellular Ca accumulation to attenuate the activation of MAPKs signaling pathway in microglia.
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http://dx.doi.org/10.1111/bph.15502DOI Listing
April 2021

SRC-1 Deficiency Increases Susceptibility of Mice to Depressive-Like Behavior After Exposure to CUMS.

Neurochem Res 2021 Apr 21. Epub 2021 Apr 21.

Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.

Steroid receptor coactivator 1 (SRC-1) is one of the coactivators recruited by the nuclear receptors (NRs) when NRs are activated by steroid hormones, such as glucocorticoid. SRC-1 is abundant in hippocampus and hypothalamus and is also related to some major risk factors for depression, implicated by its reduced expression after stress and its effect on hypothalamus-pituitary-adrenal gland axis function. However, whether SRC-1 is involved in the formation of depression remains unclear. In this study, we firstly established chronic unpredictable stress (CUS) to induce depressive-like behaviors in mice and found that SRC-1 expression was reduced by CUS. A large number of studies have shown that neuroinflammation is associated with stress-induced depression and lipopolysaccharide (LPS) injection can lead to neuroinflammation and depressive-like behaviors in mice. Our result indicated that LPS treatment also decreased SRC-1 expression in mouse brain, implying the involvement of SRC-1 in the process of inflammation and depression. Next, we showed that the chronic unpredictable mild stress (CUMS) failed to elicit the depressive-like behaviors and dramatically promoted the expression of SRC-1 in brain of wild type mice. What's more, the SRC-1 knockout mice were more susceptible to CUMS to develop depressive-like behaviors and presented the changed expression of glucocorticoid receptor. However, SRC-1 deficiency did not affect the microglia activation induced by CUMS. Altogether, these results indicate a correlation between SRC-1 level and depressive-like behaviors, suggesting that SRC-1 might be involved in the development of depression induced by stress.
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http://dx.doi.org/10.1007/s11064-021-03316-yDOI Listing
April 2021

PTEN loss correlates with T cell exclusion across human cancers.

BMC Cancer 2021 Apr 19;21(1):429. Epub 2021 Apr 19.

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood.

Methods: Utilizing The Cancer Genome Atlas (TCGA) and publicly available dataset of immunotherapy, we explored the correlation of PTEN expressing level or genomic loss with tumor immune microenvironment and response to immunotherapy. We further investigated the involvement of PI3K-AKT-mTOR pathway activation, which is known to be the subsequent effect of PTEN loss, in the immune microenvironment modulation.

Results: We reveal that PTEN mRNA expression is significantly positively correlated with CD4/CD8A gene expression and T cells infiltration especially T helpers cells, central memory T cell and effector memory T cells in multiples tumor types. Genomic loss of PTEN is associated with reduced CD8+ T cells, type 1 T helper cells, and increased type 2 T helper cells, immunosuppressed genes (e.g. VEGFA) expression. Furthermore, T cell exclusive phenotype is also observed in tumor with PI3K pathway activation or genomic gain in PIK3CA or PIK3CB. PTEN loss and PI3K pathway activation correlate with immunosuppressive microenvironment, especially in terms of T cell exclusion. PTEN loss predict poor therapeutic response and worse survival outcome in patients receiving immunotherapy.

Conclusion: These data brings insight into the role of PTEN loss in T cell exclusion and immunotherapy resistance, and inspires further research on immune modulating strategy to augment immunotherapy.
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http://dx.doi.org/10.1186/s12885-021-08114-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054401PMC
April 2021

Effects of CcpA against salt stress in Lactiplantibacillus plantarum as assessed by comparative transcriptional analysis.

Appl Microbiol Biotechnol 2021 May 14;105(9):3691-3704. Epub 2021 Apr 14.

School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai, People's Republic of China.

Lactiplantibacillus plantarum is frequently exposed to salt stress during industrial applications. Catabolite control protein (CcpA) controls the transcription of many genes, but its role in the response to salt stress remains unclear. In this study, we used transcriptome analyses to investigate differences in the logarithmic growth phases of Lactiplantibacillus plantarum ST-III and its ccpA-knockout mutant when grown with or without salt and glycine betaine (GB). The deletion of ccpA significantly affected bacterial growth under different conditions. Among the comparisons, the highest proportion of differentially expressed genes (64%) was observed in the comparison between the wild-type and ccpA mutant grown with NaCl, whereas the lowest proportion (6%) was observed in the comparison between the ccpA mutant strain cultures grown with NaCl alone or with GB together. Transcriptomic analyses showed that CcpA could regulate GB uptake, activate iron uptake, produce acetyl-CoA, and affect fatty acid composition to maintain membrane lipid homeostasis in the adaptation of high-salinity conditions. Conclusively, these results demonstrate the importance of CcpA as a master regulator of these processes in response to salt stress, and provide new insights into the complex regulatory network of lactic acid bacteria. KEY POINTS: • The absence of CcpA significantly affected growth of L. plantarum and its response to salt stress. • CcpA regulates compatible solutes absorption and ions transport to resist salt stress. • CcpA alters fatty acids composition to maintain membrane lipid homeostasis towards salt stress.
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http://dx.doi.org/10.1007/s00253-021-11276-0DOI Listing
May 2021

Decreased excitatory drive onto hilar neuronal nitric oxide synthase expressing interneurons in chronic models of epilepsy.

Brain Res 2021 Apr 5;1764:147467. Epub 2021 Apr 5.

Department of Physiology, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, China.

Excitation-inhibition imbalance of GABAergic interneurons is predisposed to develop chronic temporal lobe epilepsy (TLE). We have previously shown that virtually every neuronal nitric oxide synthase (nNOS)-positive cell is a GABAergic inhibitory interneuron in the denate gyrus. The present study was designed to quantify the number of nNOS-containing hilar interneurons using stereology in pilocapine- and kainic acid (KA)-exposed transgenic adult mice that expressed GFP under the nNOS promoter. In addition, we studied the properties of miniature excitatory postsynaptic current (mEPSC) and paired-pulse response ratio (PPR) of evoked EPSC in nNOS interneurons using whole cell recording techniques. Results showed that there were fewer nNOS-immunoreactive interneurons of chronically epileptic animals. Importantly, patch-clamp recordings revealed reduction in mEPSC frequency, indicating diminished global excitatory input. In contrast, PPR of evoked EPSC following the granule cell layer stimulation was increased in epileptic animals suggesting reduced neurotransmitter release from granule cell input. In summary, we propose that impaired excitatory drive onto hippocampal nNOS interneurons may be implicated in the development of refractory epilepsy.
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http://dx.doi.org/10.1016/j.brainres.2021.147467DOI Listing
April 2021

Network pharmacology to explore the anti-inflammatory mechanism of Xuebijing in the treatment of sepsis.

Phytomedicine 2021 May 17;85:153543. Epub 2021 Mar 17.

Institute for TCM-X, MOE Key Laboratory of Bioinformatics, Bioinformatics Division, BNRist, Department of Automation, Tsinghua University, 100084 Beijing, China. Electronic address:

Background: Xuebijing (XBJ) is a traditional Chinese patent medicine for sepsis. However, the mechanism of action (MoA) of XBJ on sepsis remain unclear.

Purpose: Elucidate the MoA of XBJ for treating sepsis based on network pharmacology.

Study Design: Integrate computational prediction, experimental validation and literature reported clinical results analysis based on network pharmacology.

Methods: Computationally, representative compounds of XBJ were characterized by LC-MS/MS and the target profiles of each compound were identified using network-based method. Compounds from XBJ were compared with FDA approved drugs or experimental agents for sepsis by hierarchical clustering of target profile. Key biological functional modules of XBJ for treating sepsis were identified by enrichment analysis. Differential expressed analysis for each biological functional module was conducted from sepsis related public omics datasets. Herb-biological functional module network was constructed to reveal part of the traditional combinatorial rules of herbs for modules. Experimentally, the action of XBJ compounds on genes in biological functional module was validated by detecting quantitative transcriptional profiling and sepsis animal model. Clinically, combined with the clinical results recorded in literature, computational and experimental results were used to interpret the anti-inflammatory effect of XBJ for treating sepsis.

Results: The target profiles of compound cover most of the compound's related biomolecules reported in literature, which can characterize the comprehensive function of compound. XBJ has similar pharmacological effect as FDA approved drugs or experimental agents. Four key biological functional modules including inflammation, immune, cell apoptosis and coagulation of XBJ for treating sepsis were identified. Cell line experimental results show that part of ingredients in XBJ regulate the expression of genes in inflammation modules as predicted. Animal experiments show that compounds from XBJ could reduce the expression level of IL-1β. Combined with literature reported clinical results, XBJ was found to exert anti-inflammatory effect through regulating the NF-kappa B signaling pathway.

Conclusion: The network pharmacology framework integrating computational prediction, experimental validation and literature reported clinical results analysis provides a novel approach for analyzing MoA of XBJ for treating sepsis.
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http://dx.doi.org/10.1016/j.phymed.2021.153543DOI Listing
May 2021

SIRT2 ablation inhibits glucose-stimulated insulin secretion through decreasing glycolytic flux.

Theranostics 2021 4;11(10):4825-4838. Epub 2021 Mar 4.

Department of Endocrine and Metabolic Diseases/ Shanghai institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

Sirtuins are NAD-dependent protein deacylases known to have protective effects against age-related diseases such as diabetes, cancer, and neurodegenerative disease. SIRT2 is the only primarily cytoplasmic isoform and its overall role in glucose homeostasis remains uncertain. SIRT2-knockout (KO) rats were constructed to evaluate the role of SIRT2 in glucose homeostasis. The effect of SIRT2 on β-cell function was detected by investigating the morphology, insulin secretion, and metabolomic state of islets. The deacetylation and stabilization of GKRP in β-cells by SIRT2 were determined by western blot, adenoviral infection, and immunoprecipitation. SIRT2-KO rats exhibited impaired glucose tolerance and glucose-stimulated insulin secretion (GSIS), without change in insulin sensitivity. SIRT2 deficiency or inhibition by AGK2 decreased GSIS in isolated rat islets, with lowered oxygen consumption rate. Adenovirus-mediated overexpression of SIRT2 enhanced insulin secretion from rat islets. Metabolomics analysis revealed a decrease in metabolites of glycolysis and tricarboxylic acid cycle in SIRT2-KO islets compared with control islets. Our study further demonstrated that glucokinase regulatory protein (GKRP), an endogenous inhibitor of glucokinase (GCK), was expressed in rat islets. SIRT2 overexpression deacetylated GKRP in INS-1 β-cells. SIRT2 knockout or inhibition elevated GKRP protein stability in islet β-cells, leading to an increase in the interaction of GKRP and GCK. On the contrary, SIRT2 inhibition promoted the protein degradation of ALDOA, a glycolytic enzyme. SIRT2 ablation inhibits GSIS through blocking GKRP protein degradation and promoting ALDOA protein degradation, resulting in a decrease in glycolytic flux.
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http://dx.doi.org/10.7150/thno.55330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978320PMC
March 2021

Deciphering the Pharmacological Mechanisms of Guizhi-Fuling Capsule on Primary Dysmenorrhea Through Network Pharmacology.

Front Pharmacol 2021 3;12:613104. Epub 2021 Mar 3.

Department of Automation, Institute for TCM-X, MOE Key Laboratory of Bioinformatics/Bioinformatics Division, BNRIST, Tsinghua University, Beijing, China.

Guizhi-Fuling capsule (GZFLC), originated from a classical traditional Chinese herbal formula Guizhi-Fuling Wan, has been clinically used for primary dysmenorrhea in China. Nonetheless, the underlying pharmacological mechanisms of GZFLC remain unclear. The integration of computational and experimental methods of network pharmacology might be a promising way to decipher the mechanisms. In this study, the target profiles of 51 representative compounds of GZFLC were first predicted by a high-accuracy algorithm, drugCIPHER-CS, and the network target of GZFLC was identified. Then, potential functional modules of GZFLC on primary dysmenorrhea were investigated using functional enrichment analysis. Potential bioactive compounds were recognized by hierarchical clustering analysis of GZFLC compounds and first-line anti-dysmenorrhea drugs. Furthermore, the potential anti-dysmenorrhea mechanisms of GZFLC were verified through enzyme activity assays and immunofluorescence tests. Moreover, effects of GZFLC on primary dysmenorrhea were evaluated in oxytocin-induced dysmenorrhea murine model. In the network target analysis, GZFLC may act on five functional modules of pain, inflammation, endocrine, blood circulation and energy metabolism. Integrating computational and experimental approaches, we found that GZFLC significantly inhibited the writhing response and reduced the degree of uterine lesions in oxytocin-induced dysmenorrhea murine model. Furthermore, GZFLC may partially alleviate primary dysmenorrhea by inhibiting cyclooxygenase 2 (COX2) and downregulating MAPK signaling pathway. Consequently, GZFLC presented pain relief and sustained benefits for primary dysmenorrhea. This study could provide a scientific approach for deciphering pharmacological mechanisms of herbal formulae through network pharmacology.
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http://dx.doi.org/10.3389/fphar.2021.613104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966503PMC
March 2021

Bioconversion variation of ginsenoside CK mediated by human gut microbiota from healthy volunteers and colorectal cancer patients.

Chin Med 2021 Mar 17;16(1):28. Epub 2021 Mar 17.

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China.

Background: Ginsenoside CK (GCK) serves as the potential anti-colorectal cancer (CRC) protopanaxadiol (PPD)-type saponin, which could be mainly bio-converted to yield PPD by gut microbiota. Meanwhile, the anti-CRC effects of GCK could be altered by gut microbiota due to their different diversity in CRC patients. We aimed to investigate the bioconversion variation of GCK mediated by gut microbiota from CRC patients by comparing with healthy subjects.

Methods: Gut microbiota profiled by 16S rRNA gene sequencing were collected from healthy volunteers and CRC patients. GCK was incubated with gut microbiota in vitro. A LC-MS/MS method was validated to quantify GCK and PPD after incubation at different time points.

Results: The bioconversion of GCK in healthy subjects group was much faster than CRC group, as well as the yield of PPD. Moreover, significant differences of PPD concentration between healthy subjects group and CRC group could be observed at 12 h, 48 h and 72 h check points. According to 16S rRNA sequencing, the profiles of gut microbiota derived from healthy volunteers and CRC patients significantly varied, in which 12 differentially abundant taxon were found, such as Bifidobacterium, Roseburia, Bacteroides and Collinsella. Spearman's correlation analysis showed bacteria enriched in healthy subjects group were positively associated with the biotransformation of GCK, while bacteria enriched in CRC group displayed non correlation character. Among them, Roseburia which could secrete β-glycosidase showed the strongest positive association with the bioconversion of GCK.

Conclusions: The bioconversion of GCK in healthy subjects was much faster than CRC patients mediated by gut microbiota, which might alter the anti-CRC effects of GCK.
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http://dx.doi.org/10.1186/s13020-021-00436-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968294PMC
March 2021

Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications.

Nat Commun 2021 03 12;12(1):1618. Epub 2021 Mar 12.

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

Cytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19.
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http://dx.doi.org/10.1038/s41467-021-21907-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955129PMC
March 2021

Audio-Visual Causality and Stimulus Reliability Affect Audio-Visual Synchrony Perception.

Front Psychol 2021 18;12:629996. Epub 2021 Feb 18.

Department of Psychology, Sun Yat-sen University, Guangzhou, China.

People can discriminate the synchrony between audio-visual scenes. However, the sensitivity of audio-visual synchrony perception can be affected by many factors. Using a simultaneity judgment task, the present study investigated whether the synchrony perception of complex audio-visual stimuli was affected by audio-visual causality and stimulus reliability. In Experiment 1, the results showed that audio-visual causality could increase one's sensitivity to audio-visual onset asynchrony (AVOA) of both action stimuli and speech stimuli. Moreover, participants were more tolerant of AVOA of speech stimuli than that of action stimuli in the high causality condition, whereas no significant difference between these two kinds of stimuli was found in the low causality condition. In Experiment 2, the speech stimuli were manipulated with either high or low stimulus reliability. The results revealed a significant interaction between audio-visual causality and stimulus reliability. Under the low causality condition, the percentage of "synchronous" responses of audio-visual intact stimuli was significantly higher than that of visual_intact/auditory_blurred stimuli and audio-visual blurred stimuli. In contrast, no significant difference among all levels of stimulus reliability was observed under the high causality condition. Our study supported the synergistic effect of top-down processing and bottom-up processing in audio-visual synchrony perception.
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http://dx.doi.org/10.3389/fpsyg.2021.629996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930005PMC
February 2021

Hand Hygiene Knowledge and Self-Reported Hand Washing Behaviors among Restaurant Kitchen Chefs in Jiangsu Province, China.

Int J Environ Res Public Health 2021 02 22;18(4). Epub 2021 Feb 22.

Business School of Yangzhou University, Yangzhou 225001, China.

Inadequate hand washing among chefs is a major contributor to outbreaks of foodborne illnesses originating in restaurants. Although many studies have evaluated hand hygiene knowledge (HHK) and self-reported hand washing behaviors (HWBs) in restaurant workers in different countries, little is known about HHK and HWBs in restaurant kitchen chefs, particularly in China. In this study, we interviewed 453 restaurant kitchen chefs in Jiangsu Province in China regarding their HHK and HWBs and used Chi-square tests (Fisher exact tests), pairwise comparisons, and linear regression models to analyze the responses and identify determinants of HHK and HWBs. Results reveal that less frequent hand washing after leaving work temporarily and after touching used cutlery were the main issues among restaurant kitchen chefs in Jiangsu Province. Kitchen hands had lower levels of HHK and engaged less frequently in good HWBs than the other type of chefs. Furthermore, working in a large restaurant and having worked in the restaurant industry for a longer amount of time were correlated with better HHK and HWBs. These findings suggest that close attention should be paid to the HWBs of chefs during food preparation, that kitchen hands are the key group of restaurant kitchen workers who need training in HHK, and that regulatory activities should focus on small-scale restaurants.
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http://dx.doi.org/10.3390/ijerph18042149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926436PMC
February 2021

Structural and Functional Dysbiosis of Fecal Microbiota in Chinese Patients With Alzheimer's Disease.

Front Cell Dev Biol 2020 4;8:634069. Epub 2021 Feb 4.

Department of Geriatrics, Lishui Second People's Hospital, Lishui, China.

Increasing evidence suggests that gut dysbiosis plays vital roles in a variety of gut-brain disorders, such as Alzheimer's disease (AD). However, alterations of the gut microbiota as well as their correlations with cognitive scores and host immunity have remained unclear in well-controlled trials on Chinese AD patients. In this study, samples from 100 AD patients, and 71 age- and gender-matched, cognitively normal controls were obtained to explore the structural and functional alterations of the fecal microbiota targeting the V3-V4 region of the 16S rRNA gene by MiSeq sequencing, and to analyze their associations with clinical characteristics. Our data demonstrated a remarkably reduction in the bacterial diversity and alterations in the taxonomic composition of the fecal microbiota of the AD patients. Interestingly, the abundant butyrate-producing genera such as decreased significantly, where this was positively correlated with such clinical indicators as the MMSE, WAIS, and Barthel scores in the AD patients. On the contrary, abundant lactate-producing genera, such as , increased prominently, and were inversely correlated with these indicators. This shift in the gut dysbiosis of the microbiota, from being butyrate producers to lactate producers, contributed to immune disturbances in the host that could be used as non-invasive biomarkers to distinguish the controls from the AD patients. Moreover, several predicted functional modules, including the biosynthesis and the metabolism of fatty acids, that were altered in the microbiota of the AD patients could be utilized by the bacteria to produce immunomodulatory metabolites. Our study established the structural and functional dysbiosis of fecal microbiota in AD patients, and the results suggest the potential for use of gut bacteria for the early, non-invasive diagnosis of AD, personalized treatment, and the development of tailor-made probiotics designed for Chinese AD patients.
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http://dx.doi.org/10.3389/fcell.2020.634069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889981PMC
February 2021

HP1c regulates development and gut homeostasis by suppressing Notch signaling through Su(H).

EMBO Rep 2021 Apr 17;22(4):e51298. Epub 2021 Feb 17.

Gene Regulatory Lab, School of Medicine, Tsinghua University, Beijing, China.

Notch signaling and epigenetic factors are known to play critical roles in regulating tissue homeostasis in most multicellular organisms, but how Notch signaling coordinates with epigenetic modulators to control differentiation remains poorly understood. Here, we identify heterochromatin protein 1c (HP1c) as an essential epigenetic regulator of gut homeostasis in Drosophila. Specifically, we observe that HP1c loss-of-function phenotypes resemble those observed after Notch signaling perturbation and that HP1c interacts genetically with components of the Notch pathway. HP1c represses the transcription of Notch target genes by directly interacting with Suppressor of Hairless (Su(H)), the key transcription factor of Notch signaling. Moreover, phenotypes caused by depletion of HP1c in Drosophila can be rescued by expressing human HP1γ, suggesting that HP1γ functions similar to HP1c in Drosophila. Taken together, our findings reveal an essential role of HP1c in normal development and gut homeostasis by suppressing Notch signaling.
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http://dx.doi.org/10.15252/embr.202051298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024896PMC
April 2021

Fecal Fungal Dysbiosis in Chinese Patients With Alzheimer's Disease.

Front Cell Dev Biol 2020 28;8:631460. Epub 2021 Jan 28.

Department of Geriatrics, Lishui Second People's Hospital, Lishui, China.

Gut bacterial dysbiosis plays a vital role in the development of Alzheimer's disease (AD). However, our understanding of alterations to the gut fungal microbiota and their correlations with host immunity in AD is still limited. Samples were obtained from 88 Chinese patients with AD, and 65 age- and gender-matched, cognitively normal controls. Using these samples, we investigated the fungal microbiota targeting internal transcribed spacer 2 (ITS2) rRNA genes using MiSeq sequencing, and analyzed their associations with the host immune response. Our data demonstrated unaltered fungal diversity but altered taxonomic composition of the fecal fungal microbiota in the AD patients. The analysis of the fungal microbiota was performed using 6,585,557 high-quality reads (2,932,482 reads from the controls and 3,653,075 from the AD patients), with an average of 43,042 reads per sample. We found that several key differential fungi such as and were enriched in the AD patients, while decreased significantly. Interestingly, and were positively correlated with IP-10 and TNF-α levels. In contrast, was negatively correlated with IL-8 and IFN-γ levels, and was negatively correlated with TNF-α level. PiCRUSt analysis revealed that lipoic acid metabolism, starch and sucrose metabolism were significantly decreased in the AD fungal microbiota. This study is the first to demonstrate fecal fungal dysbiosis in stable AD patients at a deeper level, and to identify the key differential fungi involved in regulating host systemic immunity. The analysis of the fungal microbiota in AD performed here may provide novel insights into the etiopathogenesis of AD and pave the way for improved diagnosis and treatment of AD.
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http://dx.doi.org/10.3389/fcell.2020.631460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876328PMC
January 2021

TCM network pharmacology: A new trend towards combining computational, experimental and clinical approaches.

Chin J Nat Med 2021 Jan;19(1):1-11

Institute for TCM-X, MOE Key Laboratory of Bioinformatics/Bioinformatics Division, BNRIST, Department of Automation, Tsinghua University, Beijing 100084, China. Electronic address:

Traditional Chinese medicine (TCM) is a precious treasure of the Chinese nation and has unique advantages in the prevention and treatment of diseases. The holistic view of TCM coincides with the new generation of medical research paradigm characterized by network and system. TCM gave birth to a new method featuring holistic and systematic "network target", a core theory and method of network pharmacology. TCM is also an important research object of network pharmacology. TCM network pharmacology, which aims to understand the network-based biological basis of complex diseases, TCM syndromes and herb treatments, plays a critical role in the origin and development process of network pharmacology. This review introduces new progresses of TCM network pharmacology in recent years, including predicting herb targets, understanding biological foundation of diseases and syndromes, network regulation mechanisms of herbal formulae, and identifying disease and syndrome biomarkers based on biological network. These studies show a trend of combining computational, experimental and clinical approaches, which is a promising direction of TCM network pharmacology research in the future. Considering that TCM network pharmacology is still a young research field, it is necessary to further standardize the research process and evaluation indicators to promote its healthy development.
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http://dx.doi.org/10.1016/S1875-5364(21)60001-8DOI Listing
January 2021

Root Endophytic Fungal Community and Carbon and Nitrogen Stable Isotope Patterns Differ among Species (Orchidaceae).

J Fungi (Basel) 2021 Jan 20;7(2). Epub 2021 Jan 20.

Shanghai Chenshan Plant Science Research Center, Chinese Academy of Sciences, Chenshan Botanical Garden, Shanghai 201620, China.

Orchids of the genus are well-known ornamental plants and sources of traditional medicine in Asia that rely on the symbiotic relationship with root endophytic fungi throughout their whole life cycle. However, little is known about their fungal partners, infection pattern, and pathways of carbon gain. We investigated carbon and nitrogen stable isotope patterns in different organs of three species, identified the root endophytic fungal community composition, and determined mycorrhizal colonization rates. The three species were comprised by a polyphyletic group which belongs to different trophic modes, such as saprotroph, pathotroph, and symbiotroph; however, the dominant species and their abundances varied among spp. Mycorrhizal infection rates also varied among species, with (65% ± 25%) being significantly higher than those of (35% ± 16%) and (22% ± 13%). Compared with surrounding autotrophic plants, all spp. were significantly enriched in C with to a significantly higher level than other two species. Among different organs, stems had higher δC values, while leaves and flowers had higher δN and total N content values across all three species. Our results indicate that the symbiotic relationship of and its root endophytic fungi is not strictly specific. Although mycorrhizal infection rates were highly variable, the three species had the same infection pattern with hyphae penetrating the cortex cell by the pathway cell. Different species have different strategies for C allocation among plant organs. These findings provide new insights into the ecological adaptation of orchids and will contribute to germplasm conservation and sustainable utilization.
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http://dx.doi.org/10.3390/jof7020069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909265PMC
January 2021

Advancements in stem cell-derived hepatocyte-like cell models for hepatotoxicity testing.

Stem Cell Res Ther 2021 Jan 25;12(1):84. Epub 2021 Jan 25.

Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China.

Drug-induced liver injury (DILI) is one of the leading causes of clinical trial failures and high drug attrition rates. Currently, the commonly used hepatocyte models include primary human hepatocytes (PHHs), animal models, and hepatic cell lines. However, these models have disadvantages that include species-specific differences or inconvenient cell extraction methods. Therefore, a novel, inexpensive, efficient, and accurate model that can be applied to drug screening is urgently needed. Owing to their self-renewable ability, source abundance, and multipotent competence, stem cells are stable sources of drug hepatotoxicity screening models. Because 3D culture can mimic the in vivo microenvironment more accurately than can 2D culture, the former is commonly used for hepatocyte culture and drug screening. In this review, we introduce the different sources of stem cells used to generate hepatocyte-like cells and the models for hepatotoxicity testing that use stem cell-derived hepatocyte-like cells.
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http://dx.doi.org/10.1186/s13287-021-02152-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836452PMC
January 2021

Genome-wide association study on Northern Chinese identifies KLF2, DOT1L and STAB2 associated with systemic lupus erythematosus.

Rheumatology (Oxford) 2021 Jan 25. Epub 2021 Jan 25.

Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

Objectives: To identify novel genetic loci associated with systemic lupus erythematosus (SLE) and to evaluate potential genetic differences between ethnic Chinese and European populations in SLE susceptibility.

Methods: A new genome-wide association study (GWAS) was conducted from Jining, North China, on 1,506 individuals (512 SLE cases and 994 matched healthy controls). The association results were meta-analyzed with existing data on Chinese populations from Hong Kong, Guangzhou and Central China, as well as GWAS results from four cohorts of European ancestry. A total of 26 774 individuals (9,310 SLE cases and 17 464 controls) were included in this study.

Results: Meta-analysis on four Chinese cohorts identifies KLF2 as a novel locus associated with SLE (rs2362475;OR = 0.85, P = 2.00E-09). KLF2 is likely an Asian-specific locus as no evidence of association was detected in the four European cohorts (OR = 0.98, p = 0.58), with evidence of heterogeneity (p = 0.0019) between the two ancestral groups. Meta-analyses of results from both Chinese and Europeans identify STAB2 (rs10082873; OR = 0.89, P = 4.08E-08) and DOT1L (rs4807205; OR = 1.12, P = 8.17E-09) as trans-ancestral association loci, surpassing the genome-wide significance.

Conclusions: We identified three loci associated with SLE, with KLF2 a likely Chinese-specific locus, highlighting the importance of studying diverse populations in SLE genetics. We hypothesize that DOT1L and KLF2 are plausible SLE treatment targets, with inhibitors of DOT1L and inducers of KLF2 already available clinically.
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http://dx.doi.org/10.1093/rheumatology/keab016DOI Listing
January 2021

Fecal Fungi Dysbiosis in Nonalcoholic Fatty Liver Disease.

Obesity (Silver Spring) 2021 Feb;29(2):350-358

Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.

Objective: Nonalcoholic fatty liver disease (NAFLD) can systematically harm more aspects of human health than just the liver. In addition to the potential roles of the gut microbiota in NAFLD, commensal fungi can functionally replace intestinal bacteria in maintaining the host immune response in the gut by reversing disease susceptibility. Therefore, gut commensal fungi should be studied to help understand NAFLD.

Methods: The fungal compositions of 79 patients with NAFLD and 34 matched healthy subjects were studied via internal transcribed spacer sequencing. In the NAFLD group, 32 patients underwent liver biopsies to evaluate the associations between gut fungi and NAFLD development.

Results: The fungal microbiota distribution was skewed in the patients with NAFLD. The relative abundances of Talaromyces, Paraphaeosphaeria, Lycoperdon, Curvularia, Phialemoniopsis, Paraboeremia, Sarcinomyces, Cladophialophora, and Sordaria were higher in patients with NAFLD, whereas the abundances of Leptosphaeria, Pseudopithomyces, and Fusicolla were decreased. Patients with NAFLD exhibited more co-occurring fungal intrakingdom correlations. Several fungi were found to be associated with liver injury, lipid metabolism, and the development of NAFLD.

Conclusions: This study found that gut fungi may play some roles in NAFLD development. Research on gut fungi may be of great value in diagnosing and monitoring NAFLD.
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http://dx.doi.org/10.1002/oby.23073DOI Listing
February 2021

Design, synthesis and biological evaluation of novel benzoxaborole derivatives as potent PDE4 inhibitors for topical treatment of atopic dermatitis.

Eur J Med Chem 2021 Mar 12;213:113171. Epub 2021 Jan 12.

Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 21009, China. Electronic address:

In this work, a series of structurally novel benzoxaborole derivatives were designed, synthesized and biologically evaluated as PDE4 inhibitors for battling atopic dermatitis (AD). Among them, the majority exhibited superior PDE4B inhibitory activities to that of the lead compound Crisaborole, an approved PDE4 inhibitor. In particular, 72, the most potent PDE4B inhibitor throughout this series, displayed 136-fold improved enzymatic activity (IC = 0.42 nM) as compared to Crisaborole (IC = 57.20 nM), along with favorable isoform specificity. In the phorbol ester (PMA)-induced mouse ear oedema model, 72 exerted remarkably greater efficacy than Crisaborole at the same dosage (P < 0.05). Moreover, the ointment of 72 exerted dramatically enhanced therapeutic potency than the ointment of Crisaborole (P < 0.05) in the calcipotriol-induced mouse AD model. In addition to the potent in vitro and in vivo activity, 72 displayed favorable safety in the repeated oral dose toxicity study and did not exhibit phototoxicity. With the above attractive biological performance, 72 is worthy of further functional investigation as a novel anti-AD therapeutic agent.
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http://dx.doi.org/10.1016/j.ejmech.2021.113171DOI Listing
March 2021

Molecular Entrapment of Polymers by Pyrogallol[4]arenes.

J Am Chem Soc 2021 01 6;143(2):693-698. Epub 2021 Jan 6.

Department of Chemistry, University of Missouri, Columbia, Missouri 65211, United States.

Macromolecular recognition systems are difficult to construct because extremely high recognition ability is required to form a stable host-guest complex toward macromolecules. Herein, we report a novel host-guest recognition motif based on C-propylpyrogallol[4]arene () and a commercially available polymer, polyethylene glycol (PEG). The results show that can selectively entrap PEG with higher molecular weights to form bilayered host-guest complex structures. Interestingly, this host-guest recognition is strong enough that is able to adsorb PEG from an aqueous solution efficiently.
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http://dx.doi.org/10.1021/jacs.0c12685DOI Listing
January 2021

Self-Assembly of a Semiconductive and Photoactive Heterobimetallic Metal-Organic Capsule.

Angew Chem Int Ed Engl 2021 May 24;60(19):10516-10520. Epub 2021 Mar 24.

Department of Chemistry, University of Missouri, 601 S. College Ave., Columbia, MO, 65211, USA.

We report the synthesis of a novel metal-organic capsule constructed from six pyrogallol[4]arene macrocycles, which are switched together by 16 Fe and 16 Co ions. This supramolecular structure is the first instance of a spheroidal heterometallic nanocage assembled through a one-step metal-ligand coordination approach. This new assembly also demonstrates an important proof of concept through the formation of multiple heterometallic metal-metal interactions within the capsule framework. Photophysical and electrochemical studies of self-assembled capsule films indicate their potential as semiconductors. These materials display unexpected photoelectric conversion properties, thus representing an emergent phenomenon in discrete metal-organic supramolecular assemblies.
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http://dx.doi.org/10.1002/anie.202016077DOI Listing
May 2021

Alterations of the Fecal Microbiota in Chinese Patients With Multiple Sclerosis.

Front Immunol 2020 16;11:590783. Epub 2020 Dec 16.

Department of Laboratory Medicine, Lishui Second People's Hospital, Lishui, China.

Mounting evidence indicates that alterations in the intestinal microbiota may be associated with neurological disorders such as multiple sclerosis (MS). MS is a putative autoimmune disease of the central nervous system. However, it has not been determined whether the intestinal microbiota and host immune status are altered in Chinese patients with stable MS. In our study, 22 Chinese patients with stable MS and 33 healthy controls were enrolled for fecal microbiota analysis and host immunity evaluation. The microbial diversity and composition, bacterial co-occurrence correlations, predictive functional profiles, and microbiota-cytokine correlations between the two groups were compared. We observed that while the overall structure of the fecal microbiota did not change significantly, the abundances of several key functional bacteria, primarily , decreased remarkably. and could be used to distinguish between patients with MS and healthy controls with an area under the curve of 0.832. PiCRUSt analysis revealed that genes associated with fructose, mannose, and fatty acid metabolism were significantly enriched in the MS microbiota. In addition, we also observed that the levels of several pro- and anti-inflammatory cytokines and chemokines, such as IL-1ra, IL-8, IL-17, and TNF-α changed observably, and the abundances of key functional bacteria like butyrate producers correlated with the changes in the cytokine levels. Our present study indicated that altered composition of the fecal microbiota might play vital roles in the etiopathogenesis of MS by regulating host immunity, which suggests that microbiota-targeting patient-tailored early intervention techniques might serve as novel therapeutic approaches for MS.
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http://dx.doi.org/10.3389/fimmu.2020.590783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772405PMC
December 2020

Global, Regional, and National Burden of Chronic Myeloid Leukemia, 1990-2017: A Systematic Analysis for the Global Burden of Disease Study 2017.

Front Oncol 2020 15;10:580759. Epub 2020 Dec 15.

Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Background: With the advent of tyrosine kinase inhibitors (TKIs), the prognosis of chronic myeloid leukemia (CML) seems to have dramatically improved over the last two decades. Accurate information of the global burden of CML is critical for direct health policy and healthcare resource allocation in the era of high-cost TKI therapy.

Objective: This study aimed to evaluate the health burden of CML at global, regional, and national levels from 1990 to 2017.

Methods: We collected data of CML between 1990 and 2017 from the Global Burden of Disease (GBD) study 2017 including, annual incidence, disease-related mortality, and disability-adjusted life-years (DALY), and the corresponding age-standardized rates (ASRs). To summarize the results, countries were categorized by sociodemographic index (SDI) quintiles and 21 GBD regions.

Results: In 2017, an estimated 34,179 [95% Uncertainty Interval (UI), 31,516-36,714) incident cases of CML were recorded, and 24,054 (95%UI, 22,233-26,072) CML-related deaths were reported worldwide. Both, the age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR) steadily decreased from 1990 to 2017, with estimated annual percentage changes (EAPCs) of -2.39 (95%UI, -8.13-3.71) and -2.74 (95%UI, -9.31-4.31), respectively. The global incidence and mortality of CML in males were higher than that in females. The ASRs varied substantially across regions, with the highest burden in Andean Latin America, Central Sub-Saharan Africa, and Southeast Asia. Besides, the ASRs decreased most obviously in the high-SDI regions compared to non-high-SDI regions. Moreover, the lower the SDI, the higher was the proportion of deaths in the younger age groups.

Conclusion: Despite the decreasing trends of ASRs of CML from 1990 to 2017, the health-related burden of CML remains a challenge for the low-SDI regions. These findings highlight that appropriate strategies should be adopted in low-SDI countries to reduce the ASRs of CML.
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http://dx.doi.org/10.3389/fonc.2020.580759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770240PMC
December 2020

Temporal Variation in Community Composition of Root Associated Endophytic Fungi and Carbon and Nitrogen Stable Isotope Abundance in Two Species (Orchidaceae).

Plants (Basel) 2020 Dec 24;10(1). Epub 2020 Dec 24.

Shanghai Chenshan Plant Science Research Center, Chinese Academy of Sciences, Chenshan Botanical Garden, Shanghai 201620, China.

Mycorrhizae are an important energy source for orchids that may replace or supplement photosynthesis. Most mature orchids rely on mycorrhizae throughout their life cycles. However, little is known about temporal variation in root endophytic fungal diversity and their trophic functions throughout whole growth periods of the orchids. In this study, the community composition of root endophytic fungi and trophic relationships between root endophytic fungi and orchids were investigated in and at different phenological stages using stable isotope natural abundance analysis combined with molecular identification analysis. We identified 467 OTUs assigned to root-associated fungal endophytes, which belonged to 25 orders in 10 phyla. Most of these OTUs were assigned to saprotroph (143 OTUs), pathotroph-saprotroph (63 OTUs) and pathotroph-saprotroph-symbiotroph (18 OTUs) using FunGuild database. Among these OTUs, about 54 OTUs could be considered as putative species of orchid mycorrhizal fungi (OMF). For both species, significant temporal variation was observed in the diversity of root endophytic fungi. The florescence and emergence periods had higher fungal community richness of total species and endemic species than did other periods. Both species were dominated by Agaricomycetes and Basidiomycota fungi throughout the whole year; however, their abundances varied between two species and among phenological stages. Meanwhile, the ranges of C and N natural abundance were also highly dynamic across all growth stages of species. Compared with the surrounding autotrophic plants, significant C enrichments (εC) were found across all phenological stages, while significant N enrichment in the florescence period and strong N depletion during the fruiting period were found for both species. We can deduce that both species obtained carbon from root endophytic fungi during the whole year. Additionally, the temporal varying tendency of root endophytic fungal diversity was consistent with C enrichments, which was also accord with the nutritional requirement of plant.
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http://dx.doi.org/10.3390/plants10010018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824424PMC
December 2020

Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195).

J Med Chem 2021 01 24;64(1):644-661. Epub 2020 Dec 24.

La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate ( (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of .
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http://dx.doi.org/10.1021/acs.jmedchem.0c01652DOI Listing
January 2021

Two-dimensional GaO monolayer with tunable band gap and high hole mobility.

Phys Chem Chem Phys 2021 Jan;23(1):666-673

School of Materials, Zhengzhou University of Aeronautics, Zhengzhou 450015, China.

By means of density functional theory and unbiased structure search computations, we systematically investigated the stability and electronic properties of a new Ga2O2 monolayer. The phonon spectra and ab initio molecular dynamics simulations show that the Ga2O2 monolayer is dynamically and thermally stable. Moreover, it also shows superior open-air stability. In particular, the Ga2O2 monolayer is an indirect semiconductor with a wide band gap of 2.752 eV and high hole mobility of 4720 cm2 V-1 s-1. Its band gap can be tuned flexibly in a large range by applied strain and layer control. It exhibits high absorption coefficients (>105 cm-1) in the ultraviolet region. The combined novel electronic properties of the Ga2O2 monolayer imply that it is a highly promising material for future applications in electronics and optoelectronics.
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http://dx.doi.org/10.1039/d0cp05171cDOI Listing
January 2021

A novel three-TMH Na/H antiporter and the functional role of its oligomerization.

J Mol Biol 2021 01 3;433(2):166730. Epub 2020 Dec 3.

Department of Microbiology and Biotechnology, College of Life Sciences, Northeast Agricultural University, No. 600 Changjiang Road, Xiangfang District, Harbin 150030, China. Electronic address:

Na/Hantiportersare a category of ubiquitous transmembrane proteins with various important physiological roles in almost all living organisms ranging from bacteria to humans. However, the knowledge of novel Na/Hantiporters remains to be broadened, and the functional roles ofoligomerization in theseantiportershave not yet been thoroughly understood. Here, we reported functional analysis of an unknown transmembrane protein composed of 103 amino acid residues. This protein was found to function as a Na(Li, K)/H antiporter. To the best of our knowledge, this antiporter is the minimal one of known Na/Hantiporters and thus designated as NhaM to represent the minimal Na/Hantiporter. NhaM and its homologs have not yet been classified into any protein family. Based on phylogenetic analysis and protein alignment, we propose NhaM and its homologs to constitute a novel transporter family designated as NhaM family. More importantly, we found that NhaM is assembled with parallel protomers into a homo-oligomer and oligomerization is vital for the function of this antiporter. This implies that NhaM may adopt and require an oligomer structure for its normal function to create a similar X-shaped structure to that of the NhaA fold. Taken together, current findings not only present the proposal of a novel transporter family but also positively contribute to the functional roles of oligomerization in Na/Hantiporters.
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http://dx.doi.org/10.1016/j.jmb.2020.166730DOI Listing
January 2021