Publications by authors named "Jiang Zhu"

818 Publications

Coupled protein synthesis and ribosome-guided piRNA processing on mRNAs.

Nat Commun 2021 Oct 13;12(1):5970. Epub 2021 Oct 13.

Center for RNA Biology: From Genome to Therapeutics, Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, 14642, USA.

PIWI-interacting small RNAs (piRNAs) protect the germline genome and are essential for fertility. piRNAs originate from transposable element (TE) RNAs, long non-coding RNAs, or 3´ untranslated regions (3´UTRs) of protein-coding messenger genes, with the last being the least characterized of the three piRNA classes. Here, we demonstrate that the precursors of 3´UTR piRNAs are full-length mRNAs and that post-termination 80S ribosomes guide piRNA production on 3´UTRs in mice and chickens. At the pachytene stage, when other co-translational RNA surveillance pathways are sequestered, piRNA biogenesis degrades mRNAs right after pioneer rounds of translation and fine-tunes protein production from mRNAs. Although 3´UTR piRNA precursor mRNAs code for distinct proteins in mice and chickens, they all harbor embedded TEs and produce piRNAs that cleave TEs. Altogether, we discover a function of the piRNA pathway in fine-tuning protein production and reveal a conserved piRNA biogenesis mechanism that recognizes translating RNAs in amniotes.
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http://dx.doi.org/10.1038/s41467-021-26233-8DOI Listing
October 2021

Leukemic progenitor cells enable immunosuppression and post-chemotherapy relapse via IL-36-inflammatory monocyte axis.

Sci Adv 2021 Oct 8;7(41):eabg4167. Epub 2021 Oct 8.

Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated with Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China.

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http://dx.doi.org/10.1126/sciadv.abg4167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500518PMC
October 2021

Quantitative Proteomic Analysis for High- and Low-Aflatoxin-Yield Strains Isolated From Natural Environments.

Front Microbiol 2021 21;12:741875. Epub 2021 Sep 21.

State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan National Laboratory for Optoelectronics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Huazhong University of Science and Technology, Wuhan, China.

The molecular mechanisms underlying aflatoxin production have been well-studied in strains of the fungus () under artificial conditions. However, aflatoxin biosynthesis has rarely been studied in strains isolated from field conditions with different aflatoxin-producing ability. In the present study, tandem mass tag (TMT) labeling and high-performance liquid chromatography (HPLC) coupled with tandem-mass spectrometry analysis were used for proteomic quantification in natural isolates of high- and low-aflatoxin-yield strains. Additionally, findings obtained using the TMT-labeling method were validated using the high-resolution multiple reaction monitoring (MRM-HR) method. In total, 4,363 proteins were quantified, among which 1,045 proteins were differentially expressed between the high- and low-aflatoxin-yield strains. Bioinformatics analysis showed that the up-regulated proteins were significantly enriched in carbon-related metabolism and the biosynthesis of secondary metabolites, whereas the down-regulated proteins were enriched in oxidative phosphorylation. Moreover, GST proteins were found to be significantly down-regulated in high-yield strains; this result contradicted previous findings obtained from strains grown under artificial conditions. In summary, our study provides novel insights into aflatoxin regulation in under field conditions and could facilitate the development of various strategies for the effective control of aflatoxin contamination in food crops.
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http://dx.doi.org/10.3389/fmicb.2021.741875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491651PMC
September 2021

ALCAM-EGFR Interaction Regulates Myelomagenesis.

Blood Adv 2021 Sep 30. Epub 2021 Sep 30.

Department of Hematology, West China Hospital/State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China.

Multiple myeloma, a plasma cell malignancy in the bone marrow, remains largely incurable with currently available therapeutics. In this study, we discovered that the activated-leukocyte-cell-adhesion-molecule (ALCAM) interacted with epidermal growth factor receptor (EGFR), and regulated myelomagenesis. ALCAM was a negative regulator of myeloma clonogenicity. ALCAM expression was positively correlated with patients' survival. ALCAM-knockdown myeloma cells displayed enhanced colony formation in the presence of bone marrow stromal cells (BMSCs). BMSCs supported myeloma colony formation by secreted epidermal growth factor (EGF), which bound with its receptor (EGFR) on myeloma cells and activated Mek/Erk cell signaling, PI3K/Akt cell signaling and hedgehog pathway. ALCAM could also bind with EGFR, block EGF from binding to EGFR, and abolish EGFR-initiated cell signaling. Hence, our study identifies ALCAM as a novel negative regulator of myeloma pathogenesis.
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http://dx.doi.org/10.1182/bloodadvances.2021004695DOI Listing
September 2021

Untargeted metabolomic analysis of urine samples for diagnosis of inherited metabolic disorders.

Funct Integr Genomics 2021 Sep 28. Epub 2021 Sep 28.

Newborn Screening Center, Chongqing Health Center for Women and Children, Longshan Road 120th, Yubei District, Chongqing, 401147, People's Republic of China.

Metabolomics has become an important tool for clinical research, especially for analyzing inherited metabolic disorders (IMDs). The purpose of this study was to explore the performance of metabolomics in diagnosing IMDs using an untargeted metabolomic approach. A total of 40 urine samples were collected: 20 samples from healthy children and 20 from pediatric patients, of whom 13 had confirmed IMDs and seven had suspected IMDs. Samples were analyzed by Orbitrap mass spectrometry in positive and negative mode alternately, coupled with ultra-high liquid chromatography. Raw data were processed using Compound Discovery 2.0 ™ and then exported for partial least squares discriminant analysis (PLS-DA) by SIMCA-P 14.1. After comparing with m/zCloud and chemSpider libraries, compounds with similarity above 80% were selected and normalized for subsequent relative quantification analysis. The uncommon compounds discovered were analyzed based on the Kyoto Encyclopedia of Genes and Genomes to explore their possible metabolic pathways. All IMDs patients were successfully distinguished from controls in the PLS-DA. Untargeted metabolomics revealed a broader metabolic spectrum in patients than what is observed using routine chromatographic methods for detecting IMDs. Higher levels of certain compounds were found in all 13 confirmed IMD patients and 5 of 7 suspected IMD patients. Several potential novel markers emerged after relative quantification. Untargeted metabolomics may be able to diagnose IMDs from urine and may deepen insights into the disease by revealing changes in various compounds such as amino acids, acylcarnitines, organic acids, and nucleosides. Such analyses may identify biomarkers to improve the study and treatment of IMDs.
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http://dx.doi.org/10.1007/s10142-021-00804-wDOI Listing
September 2021

Integrated Metabolomics and Transcriptomics Analyses Reveal Histidine Metabolism Plays an Important Role in Imiquimod-Induced Psoriasis-like Skin Inflammation.

DNA Cell Biol 2021 Oct 28;40(10):1325-1337. Epub 2021 Sep 28.

Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Psoriasis is a chronic inflammatory skin disease characterized by massive keratinocyte proliferation and immune cell infiltration into the epidermis. However, the specific mechanisms underlying the development of psoriasis remain unclear. Untargeted metabolomics and transcriptomics have been used separately to profile biomarkers and risk genes in the serum of psoriasis patients. However, the integration of metabolomics and transcriptomics to identify dysregulated metabolites and genes in the psoriatic skin is lacking. In this study, we performed an untargeted metabolomics analysis of imiquimod (IMQ)-induced psoriasis-like mice and healthy controls, and found that levels of a total of 4,188 metabolites differed in IMQ-induced psoriasis-like mice compared with those in control mice. Metabolomic data analysis using MetaboAnalyst showed that the metabolic pathways of primary metabolites, such as folate biosynthesis and galactose metabolism, were significantly altered in the skin of mice after treatment with IMQ. Furthermore, IMQ treatment also significantly altered metabolic pathways of secondary metabolites, including histidine metabolism, in mouse skin tissues. The metabolomic results were verified by transcriptomics analysis. RNA-seq results showed that (HDC) mRNA levels were significantly upregulated after IMQ treatment. Targeted inhibition of histamine biosynthesis process using HDC-specific inhibitor, pinocembrin (PINO), significantly alleviated epidermal thickness, downregulated the expression of interleukin (IL)-17A and IL-23, and inhibited the infiltration of immune cells during IMQ-induced psoriasis-like skin inflammation. In conclusion, our study offers a validated and comprehensive understanding of metabolism during the development of psoriasis and demonstrated that PINO could protect against IMQ-induced psoriasis-like skin inflammation.
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http://dx.doi.org/10.1089/dna.2021.0465DOI Listing
October 2021

Structural Investigations on the SH3b Domains of Autolysin through NMR Spectroscopy and Structure Simulation Enlighten the Cell Wall Binding Function.

Molecules 2021 Sep 21;26(18). Epub 2021 Sep 21.

State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, Wuhan 430071, China.

autolysin (CpAcp) is a peptidoglycan hydrolase associated with cell separation, division, and growth. It consists of a signal peptide, ten SH3b domains, and a catalytic domain. The structure and function mechanisms of the ten SH3bs related to cell wall peptidoglycan binding remain unclear. Here, the structures of CpAcp SH3bs were studied through NMR spectroscopy and structural simulation. The NMR structure of SH3b6 was determined at first, which adopts a typical β-barrel fold and has three potential ligand-binding pockets. The largest pocket containing eight conserved residues was suggested to bind with peptide ligand in a novel model. The structures of the other nine SH3bs were subsequently predicted to have a fold similar to SH3b6. Their ligand pockets are largely similar to those of SH3b6, although with varied size and morphology, except that SH3b1/2 display a third pocket markedly different from those in other SH3bs. Thus, it was supposed that SH3b3-10 possess similar ligand-binding ability, while SH3b1/2 have a different specificity and additional binding site for ligand. As an entirety, ten SH3bs confer a capacity for alternatively binding to various peptidoglycan sites in the cell wall. This study presents an initial insight into the structure and potential function of CpAcp SH3bs.
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http://dx.doi.org/10.3390/molecules26185716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470621PMC
September 2021

Analysis of the spatial distribution of Aedes albopictus in an urban area of Shanghai, China.

Parasit Vectors 2021 Sep 26;14(1):501. Epub 2021 Sep 26.

Department of Infectious Disease Control, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, 200336, China.

Background: Aedes albopictus is a vector of major arboviral diseases and a primary pest in tropical and temperate regions of China. In most cities of China, the current monitoring system for the spread of Ae. albopictus is based on the subdistrict scale and does not consider spatial distribution for analysis of species density. Thus, the system is not sufficiently accurate for epidemic investigations, especially in large cities.

Methods: This study used an improved surveillance program, with the mosquito oviposition trap (MOT) method, integrating the actual monitoring locations to investigate the temporal and spatial distribution of Ae. albopictus abundance in an urban area of Shanghai, China from 2018 to 2019. A total of 133 monitoring units were selected for surveillance of Ae. albopictus density in the study area, which was composed of 14 subdistricts. The vector abundance and spatial structure of Ae. albopictus were predicted using a binomial areal kriging model based on eight MOTs in each unit. Results were compared to the light trap (LT) method of the traditional monitoring scheme.

Results: A total of 8,192 MOTs were placed in the study area in 2018, and 7917 (96.6%) were retrieved, with a positive rate of 6.45%. In 2019, 22,715 (97.0%) of 23,408 MOTs were recovered, with a positive rate of 5.44%. Using the LT method, 273 (93.5%) and 312 (94.5%) adult female Ae. albopictus were gathered in 2018 and 2019, respectively. The Ae. albopictus populations increased slowly from May, reached a peak in July, and declined gradually from September. The MOT positivity index (MPI) showed significant positive spatial autocorrelation across the study area, whereas LT collections indicated a nonsignificant spatial autocorrelation. The MPI was suitable for spatial interpolation using the binomial areal kriging model and showed different hot spots in different years.

Conclusions: The improved surveillance system integrated with a geographical information system (GIS) can improve our understanding of the spatial and temporal distribution of Ae. albopictus in urban areas and provide a practical method for decision-makers to implement vector control and mosquito management.
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http://dx.doi.org/10.1186/s13071-021-05022-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474869PMC
September 2021

Distinct immune signatures discriminate between asymptomatic and presymptomatic SARS-CoV-2 subjects.

Cell Res 2021 Sep 24. Epub 2021 Sep 24.

Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Institute of Respiratory Diseases, School of Medicine, Shanghai Jiao-Tong University, Shanghai, China.

Increasing numbers of SARS-CoV-2-positive (SARS-CoV-2) subjects are detected at silent SARS-CoV-2 infection stage (SSIS). Yet, SSIS represents a poorly examined time-window wherein unknown immunity patterns may contribute to the fate determination towards persistently asymptomatic or overt disease. Here, we retrieved blood samples from 19 asymptomatic and 12 presymptomatic SARS-CoV-2 subjects, 47 age/gender-matched patients with mild or moderate COVID-19 and 27 normal subjects, and interrogated them with combined assays of 44-plex CyTOF, RNA-seq and Olink. Notably, both asymptomatic and presymptomatic subjects exhibited numerous readily detectable immunological alterations, while certain parameters including more severely decreased frequencies of CD107a classical monocytes, intermediate monocytes, non-classical monocytes and CD62L CD8 T cells, reduced plasma STC1 level but an increased frequency of CD4 NKT cells combined to distinguish the latter. Intercorrelation analyses revealed a particular presymptomatic immunotype mainly manifesting as monocytic overactivation and differentiation blockage, a likely lymphocyte exhaustion and immunosuppression, yielding mechanistic insights into SSIS fate determination, which could potentially improve SARS-CoV-2 management.
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http://dx.doi.org/10.1038/s41422-021-00562-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461439PMC
September 2021

DICER activates autophagy and promotes cisplatin resistance in non-small cell lung cancer by binding with let-7i-5p.

Acta Histochem 2021 Sep 17;123(7):151788. Epub 2021 Sep 17.

Second People's Hospital of Jingmen, Jingmen, Hubei 448000, PR China. Electronic address:

Objective: Drug resistance is the main obstacle in the treatment of non-small cell lung cancer (NSCLC). This study aimed to explore the mechanism of DICER in NSCLC resistance and its downstream signaling pathways.

Methods: The A549 cisplatin (DDP)-resistant strain A549/DDP was established. A549/DDP cells were transfected with DICER- and let-7i-5p-related vectors, and treated with autophagy activator rapamycin. The cell viability and apoptosis were tested by CCK-8 assay and flow cytometry, respectively. The formation of autophagosomes was observed with a transmission electron microscopy. RT-qPCR and Western blot assay were conducted to detect expression levels of DICER, let-7i-5p, autophagy-related proteins, and the PI3K/AKT/mTOR pathway-related proteins. The dual luciferase reporter gene assay was implemented to confirm the targeted binding of DICER and let-7i-5p.

Results: DICER was highly expressed in DDP-resistant NSCLC tissues and cells, and DICER could target and negatively regulate the expression of let-7i-5p. DDP treatment could inhibit the viability and promote cell apoptosis of A549/DDP cells. Downregulation of DICER in A549/DDP cells exhibited a decrease of cell viability, a decreased ratio of LC3-II/LC3-I and autophagosomes, together with an elevation of cell apoptosis rate and the phosphorylation levels of PI3K/AKT/mTOR. Treatment of rapamycin and let-7i-5p inhibitor reversed the effects of downregulated DICER in cell viability, ratio of LC3-II/LC3-I, autophagosomes, cell apoptosis rate and the phosphorylation levels of PI3K/AKT/mTOR in A549/DDP cells.

Conclusion: Our research suggests that DICER promotes autophagy and DDP resistance in NSCLC through downregulating let-7i-5p, and inhibits the activation of PI3K/AKT/mTOR pathway.
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http://dx.doi.org/10.1016/j.acthis.2021.151788DOI Listing
September 2021

Development and validation of a novel classification scheme for combining pathological T stage and log odds of positive lymph nodes for colon cancer.

Eur J Surg Oncol 2021 Sep 9. Epub 2021 Sep 9.

Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China; Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. Electronic address:

Aim: Log Odds of Positive Lymph Nodes (LODDS) have a better predictive ability than N stage for colon cancer. However, the prognostic value of developing a novel prognostic classification by combining T stage and LODDS (TLODDS) for colon cancer remains unknown. Therefore, in the present study, we aimed to develop a TLODDS classification for colon cancer, and assess whether or not the novel TLODDS classification could improve survival stratification by comparing its discrimination, model-fitting, and net benefits, with the American Joint Committee on Cancer (AJCC) Tumor/Node/Metastasis (TNM) classification.

Methods: 45,558 Western colon cancers were identified in the Surveillance, Epidemiology, and End Results database as a training set. A novel LODDS stage was established and patients with similar survival rates were grouped by combining T and LODDS stages to develop a novel TLODDS classification. The TLODDS classification was further assessed in a Chinese validation set of 3,515 colon cancers and an application set of 3,053 rectal cancers.

Results: We developed a novel TLODDS classification that incorporated 7 stages: stage I (T1LODDS1), IIA (T2LODDS1, T1LODDS2, T1LODDS3), IIB (T2LODDS2-3, T3LODDS1, T1LODDS4), IIC (T3LODDS2, T2LODDS4, T4aLODDS1), IIIA (T3LODDS3, T1-2LODDS5, T4bLODDS1, T4aLODDS2), IIIB (T3LODDS4-5, T4aLODDS3-4, T4bLODDS2) and IIIC (T4bLODDS3-5, T4aLODDS5). In the training set, it showed significantly better discrimination (area under the receiver operating characteristic (ROC) curve, 0.691 vs. 0.664, P < 0.001), better model-fitting (Akaike information criteria, 265,644 vs. 267,410), and superior net benefits, than the latest AJCC TNM classification. The predictive performance of the TLODDS classification was further validated in colon cancers and was successfully applied in rectal cancers with regards to both overall and disease-free survival.

Conclusions: The TLODDS classification has better discriminatory ability, model-fitting, and net benefits than the existing TNM classification, and represents an alternative to the current TNM classifications for colon and rectal cancers.
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http://dx.doi.org/10.1016/j.ejso.2021.09.005DOI Listing
September 2021

Antibiotic Combined with Epitope-Specific Monoclonal Antibody Cocktail Protects Mice Against Bacteremia and Acute Pneumonia from Methicillin-Resistant Infection.

J Inflamm Res 2021 30;14:4267-4282. Epub 2021 Aug 30.

National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University, Chongqing, 400038, People's Republic of China.

Purpose: We previously reported that monoclonal antibody (mAb) cocktail improves survival in infection. In this study, we used acute pneumonia model and lethal sepsis model to investigate the efficacy of antibiotic combined with epitope-specific mAb cocktail in treating MRSA252 infection.

Methods: MRSA252 was challenged by tail vein injection or tracheal intubation to establish sepsis model or pneumonia model. One hour after infection, the mice received a single intravenous injection of normal saline, vancomycin, and vancomycin combined monoclonal antibody, linezolid alone or linezolid combined monoclonal antibody. Daily record survival rate (total 7 days), bacterial load, histology, cytokine analysis of serum and alveolar lavage fluid, and in vitro determination of the neutralizing ability of antibodies to SEB toxin and Hla toxin explained the mechanism of antibody action.

Results: The mAb cocktail combined with low doses of vancomycin or linezolid improved survival rates in acute pneumonia model (70%, 80%) and lethal sepsis model (80%, 80%). Epitope-specific monoclonal antibodies reduced bacterial colonization in the kidneys and lungs of mice and inhibited the biological functions of the toxins Hla and SEB in vitro. Compared to the antibiotic alone or PBS groups, the combination group had higher levels of IL-1α, IL-1β and IFN-γ and lower levels of IL-6, IL-10, TNF-α. Further, the combination of antibiotic and mAb cocktail improved infection survival against the clinical MRSA isolates in a lethal sepsis model.

Conclusion: This study demonstrates a novel method to treat people with low immunity against drug-resistant infections.
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http://dx.doi.org/10.2147/JIR.S325286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415768PMC
August 2021

GPR40 Agonist Ameliorate Pathological Neuroinflammation of Alzheimer's Disease via the Modulation of Gut Microbiota and Immune System, a Mini-Review.

Neurotox Res 2021 Sep 10. Epub 2021 Sep 10.

Department of Nephrology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

Alzheimer's disease (AD) is a central disease with high incidence, and its pathological process is closely associated with changes of some biological indicators in the periphery. Among them, the intestinal flora mainly causes a series of pathological changes such as inflammation through the immune system, which may contribute to the pathological process of AD. In this paper, we mainly focused the relationship between gut microbiota and immune system disorder in the neuropathology of AD, underlining the significance of the advanced mechanism of inflammatory response and providing a new direction for the treatment of AD.
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http://dx.doi.org/10.1007/s12640-021-00408-zDOI Listing
September 2021

Cardiomyocyte Stim1 Deficiency Exacerbates Doxorubicin Cardiotoxicity by Magnification of Endoplasmic Reticulum Stress.

J Inflamm Res 2021 14;14:3945-3958. Epub 2021 Aug 14.

Intensive Care Unit, People's Hospital of Xishuangbanna Dai Nationality Autonomous Prefecture, Jinghong City, 666100, Yunnan, People's Republic of China.

Introduction: Doxorubicin (Dox) is an effective anticancer agent; however, its cardiotoxicity remains a challenge. Dysfunction of intracellular calcium ion (Ca) is implicated in the process of Dox-induced cardiomyocyte apoptosis. Although store-operated Ca entry (SOCE) is suggested to be responsible for Ca entry in cardiomyocytes, the direct role of store-operated Ca channels in Dox-related cardiomyocyte apoptosis is unknown.

Materials And Methods: Cardiomyocyte Stim1-specific knockout or overexpression mice were treated with Dox. Cardiomyocytes were pretreated with Stim1 adenovirus or siRNA followed by Dox incubation in vitro. Cardiac function and underlying mechanisms echocardiography were assessed via immunofluorescence, flow cytometry, real-time PCR, Western blotting and immunoprecipitation.

Results: We observed the inhibition of Stim1 expression, association of Stim1 to Orai1 or Trpc1, and SOCE in Dox-treated mouse myocardium and cardiomyocytes. Orai1 and Trpc1 expression remained unchanged. Cardiomyocyte-specific deficiency of Stim1 exacerbated Dox-induced cardiac dysfunction and myocardial apoptosis. However, specific overexpression of Stim1 in the myocardium was associated with amelioration of cardiac dysfunction and myocardial apoptosis. In vitro, STIM1 knockdown potentiated Dox-induced AC16 human cardiomyocyte apoptosis. This apoptosis was attenuated by STIM1 upregulation. Moreover, STIM1 downregulation enhanced Dox-induced endoplasmic reticulum (ER) stress in cardiomyocytes. In contrast, STIM1 overexpression inhibited the activation of the above molecular markers of ER stress. Immunoprecipitation assay showed that STIM1 interacted with GRP78 in cardiomyocytes. This interaction was attenuated in response to Dox treatment.

Conclusion: Our data demonstrate that cardiomyocyte STIM1 binding to GRP78 ameliorates Dox cardiotoxicity by inhibiting pro-apoptotic ER stress.
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http://dx.doi.org/10.2147/JIR.S304520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373307PMC
August 2021

Improving cerebral microvascular image quality of optical coherence tomography angiography with deep learning-based segmentation.

J Biophotonics 2021 Aug 12:e202100171. Epub 2021 Aug 12.

Key Laboratory of the Ministry of Education for Optoelectronic Measurement Technology and Instrument, Beijing Information Science and Technology University, Beijing, China.

Optical coherence tomography angiography (OCTA) can map the microvascular networks of the cerebral cortices with micrometer resolution and millimeter penetration. However, the high scattering of the skull and the strong noise in the deep imaging region will distort the vasculature projections and decrease the OCTA image quality. Here, we proposed a deep learning-based segmentation method based on a U-Net convolutional neural network to extract the cortical region from the OCT image. The vascular networks were then visualized by three OCTA algorithms. The image quality of the vasculature projections was assessed by two metrics, including the peak signal-to-noise ratio (PSNR) and the contrast-to-noise ratio (CNR). The results show the accuracy of the cortical segmentation was 96.07%. The PSNR and CNR values increased significantly in the projections of the selected cortical regions. The OCTA incorporating the deep learning-based cortical segmentation can efficiently improve the image quality and enhance the vasculature clarity.
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http://dx.doi.org/10.1002/jbio.202100171DOI Listing
August 2021

L-Theanine Alleviates IMQ-Induced Psoriasis Like Skin Inflammation by Downregulating the Production of IL-23 and Chemokines.

Front Pharmacol 2021 26;12:719842. Epub 2021 Jul 26.

Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Psoriasis, the most common skin inflammatory disease, is characterized by massive keratinocyte proliferation and immune cell infiltration into epidermis. L-Theanine (L-THE), a nonproteinogenic amino acid derived from green tea (Camellia sinensis), has been proved to possess the properties of anti-inflammatory, antidepressants and neuroprotective. However, whether L-THE has a therapeutic effect on psoriasis is still unknown. In this study, we found that the epidermal thickness and inflammatory response were significantly reduced in Imiquimod (IMQ)-induced psoriasis mice by applying with L-THE on mice skin. The expression of proliferation and inflammation associated genes such as , and was also downregulated by L-THE. Furthermore, L-THE inhibited the production of IL-23 in dendritic cells (DCs) after IMQ treatment, and decreased the levels of chemokines in keratinocytes treated with IL-17A by downregulating the expression of IL-17RA. RNA-seq and KEGG analysis revealed that L-THE significantly regulated the expression of IL-17A and NF-κB signaling pathway-associated genes. Metabolomics analysis displayed that L-THE promoted propanoate metabolism which has been reported to inhibit the activity of TH17 cells. Therefore, our results demonstrated that L-THE significantly decreases the levels of IL-23 and chemokines, and attenuates IMQ-induced psoriasis like skin inflammation by inhibiting the activation of NF-κB and IL-17A signaling pathways, and promoting the propanoate metabolism. Our findings suggest that topical applied L-THE can be used as a topical drug candidate for the treatment of psoriasis or as an adjuvant treatment of ustekinumab or secukinumab to prevent the relapse of psoriasis.
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http://dx.doi.org/10.3389/fphar.2021.719842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350042PMC
July 2021

RSPH14 regulates the proliferation, cell cycle progression, and apoptosis of non-small cell lung cancer cells.

FEBS Open Bio 2021 Oct 25;11(10):2715-2726. Epub 2021 Aug 25.

Department of Esophageal Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center of Cancer, Tianjin, China.

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, and it is characterized by a high incidence. It is important to understand the molecular mechanisms that determine the progression and metastasis of NSCLC in order to develop more effective therapies and identify novel diagnostic indicators of NSCLC. RSPH14 has been reported to be related to multiple human diseases, including duodenal adenocarcinoma and meningiomas, but the role of RSPH14 in NSCLC remains unclear. The present study aimed to investigate the molecular function and clinical significance of RSPH14 in NSCLC. Analyses of public datasets and clinical samples demonstrated that RSPH14 expression was upregulated in NSCLC samples compared with normal samples. In addition, high RSPH14 expression was associated with a shorter overall survival time in patients with NSCLC. Notably, RSPH14 knockdown suppressed the proliferation and cell cycle progression and enhanced the apoptosis of NSCLC cells. Mechanically, tandem mass tag analysis demonstrated that RSPH14 can affect multiple processes, including the AMPK signaling pathway, calcium ion import regulation, glucose transmembrane transporter activity, and glucose transmembrane transport. Taken together, the results of the present study suggest that RSPH14 may be a promising prognostic factor and therapeutic target for NSCLC.
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http://dx.doi.org/10.1002/2211-5463.13266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487038PMC
October 2021

Sustained Attention Deficits in Adults With Juvenile-Onset Type 1 Diabetes Mellitus.

Psychosom Med 2021 Oct;83(8):906-912

From the Medical Psychological Center (Zou, Y. Liu, J. Zhu, C. Li, Du, X. Zhu), The Second Xiangya Hospital, Central South University; Medical Psychological Institute of Central South University (X. Zhu); National Clinical Research Center for Mental Disorders (X. Zhu), The Second Xiangya Hospital; Department of Psychology (He) and Hunan Key Laboratory of Children's Psychological Development and Brain Cognitive Science (He), Hunan First Normal University; National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology (Zou, Y. Liu, Xie, Zhou, X. Li), The Second Xiangya Hospital of Central South University; Xiangya School of Nursing (F. Liu), Central South University, Hunan Province; and Department of Nutrition (Huang), The Second Xiangya Hospital, Central South University, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan Province, China.

Objective: This study aimed to investigate whether patients with juvenile-onset type 1 diabetes mellitus (T1DM) have poorer sustained attention than their counterparts with adult-onset T1DM, and whether there is a relationship between diabetes-related variables and sustained attention.

Methods: This study included 76 participants with juvenile-onset T1DM, 68 participants with adult-onset T1DM, and 85 healthy controls (HCs). All participants completed the Sustained Attention to Response Task, Beck Depression Inventory-II, and the Chinese version of the Wechsler Adult Intelligence Scale.

Results: The juvenile-onset group showed more omission errors (p = .007) than the adult-onset group and shorter reaction time (p = .005) than HCs, whereas the adult-onset group showed no significant differences compared with HCs. Hierarchical linear regression analysis revealed that the age of onset was associated with omission errors in T1DM participants (β = -0.275, t = -2.002, p = .047). In the juvenile-onset group, the omission error rate were associated with the history of severe hypoglycemia (β = 0.225, t = 1.996, p = .050), whereas reaction time was associated with the age of onset (β = -0.251, t = -2.271, p = .026). Fasting blood glucose levels were significantly associated with reaction time in both the juvenile-onset and adult-onset groups (β = -0.236, t = -2.117, p = .038, and β = 0.259, t = 2.041, p = .046, respectively).

Conclusions: Adults with juvenile-onset T1DM have sustained attention deficits in contrast to their adult-onset counterparts, suggesting that the disease adversely affects the developing brain. Both the history of severe hypoglycemia and fasting blood glucose levels are factors associated with sustained attention impairment. Early diagnosis and treatment in juvenile patients are required to prevent the detrimental effects of diabetes.
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http://dx.doi.org/10.1097/PSY.0000000000000992DOI Listing
October 2021

Preclinical Mechanisms of Topical PRN473, a Bruton Tyrosine Kinase Inhibitor, in Immune-Mediated Skin Disease Models.

Immunohorizons 2021 07 29;5(7):581-589. Epub 2021 Jul 29.

Principia Biopharma Inc., a Sanofi Company, South San Francisco, CA.

The expression of Bruton tyrosine kinase (BTK) in B cells and innate immune cells provides essential downstream signaling for BCR, Fc receptors, and other innate immune cell pathways. The topical covalent BTK inhibitor PRN473 has shown durable, reversible BTK occupancy with rapid on-rate and slow off-rate binding kinetics and long residence time, resulting in prolonged, localized efficacy with low systemic exposure in vivo. Mechanisms of PRN473 include inhibition of IgE (FcεR)-mediated activation of mast cells and basophils, IgG (FcγR)-mediated activation of monocytes, and neutrophil migration. In vivo, oral PRN473 was efficacious and well tolerated in the treatment of canine pemphigus foliaceus. In this study, we evaluated in vitro selectivity and functionality, in vivo skin Ab inflammatory responses, and systemic pharmacology with topically administered PRN473. Significant dose-dependent inhibition of IgG-mediated passive Arthus reaction in rats was observed with topical PRN473 and was maintained when given 16 h prior to challenge, reinforcing extended activity with once-daily administration. Similarly, topical PRN473 resulted in significant dose-dependent inhibition of the mouse passive cutaneous anaphylaxis IgE-mediated reaction. Multiday treatment with topical PRN473 in rodents resulted in low-to-no systemic accumulation, suggesting that efficacy was mainly due to localized exposure. Reduced skin Ab inflammatory activity was also confirmed with oral PRN473. These preclinical studies provide a strong biologic basis for targeting innate immune cell responses locally in the skin, with rapid onset of action following once-daily topical PRN473 administration and minimal systemic exposure. Dose-dependent inhibition in these preclinical models of immune-mediated skin diseases support future clinical studies.
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http://dx.doi.org/10.4049/immunohorizons.2100063DOI Listing
July 2021

Metabolic Engineering of Aspartic Acid Supply Modules for Enhanced Production of Bacitracin in .

ACS Synth Biol 2021 09 29;10(9):2243-2251. Epub 2021 Jul 29.

State Key Laboratory of Biocatalysis and Enzyme Engineering, Environmental Microbial Technology Center of Hubei Province, College of Life Sciences, Hubei University, Wuhan, 430062, PR China.

Bacitracin, a type of cyclic dodecapeptide antibiotic mainly produced by , is widely used in fields of veterinary drug and feed additive. Modularization of metabolic pathways based on the concept of synthetic biology has been widely used in the efficient synthesis of target products. Here, we want to improve bacitracin production through strengthening aspartic acid (Asp) supply in DW2. First, exogenous Asp addition assays implied that strengthening Asp supply benefited bacitracin production. Second, Asp synthetic pathways were strengthened via overexpressing aspartate dehydrogenase AspD and asparaginase AnsB, attaining recombinant strain DW2-ASP2, and bacitracin yield produced by DW2-ASP2 was 862.81 U/mL, increased by 14.05% compared with that of DW2 (756.49 U/mL). Then, to improve precursor oxaloacetate (OAA) accumulation for Asp synthesis, pyruvate carboxylase PycA and carbonic anhydrase EcaA were co-overexpressed in DW2-ASP2, and malic enzyme gene was deleted to weak overflow metabolism of tricarboxylic acid, and the attained strain DW2-ASP7 showed further increased bacitracin production from 862.81 to 989.23 U/mL. Subsequently, transporter YveA was identified as an Asp exporter, and bacitracin yield was increased to 1025.26 U/mL via deleting , attaining strain DW2-ASP9. Finally, Asp ammonia-lyase gene was disrupted to weaken Asp degradation, and bacitracin yield of attained strain DW2-ASP10 reached 1059.86 U/mL, increased by 40.10% compared to DW2. Taken together, this research demonstrated that metabolic engineering of Asp metabolic modules is an efficient strategy for enhancing bacitracin production, and these strategies could also be applied in the production of other peptide-related metabolites.
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http://dx.doi.org/10.1021/acssynbio.1c00154DOI Listing
September 2021

Neuronal VCP loss of function recapitulates FTLD-TDP pathology.

Cell Rep 2021 Jul;36(3):109399

Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivate VCP in murine postnatal forebrain neurons (VCP conditional knockout [cKO]). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulates features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.
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http://dx.doi.org/10.1016/j.celrep.2021.109399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383344PMC
July 2021

Alterations in Gut Vitamin and Amino Acid Metabolism are Associated with Symptoms and Neurodevelopment in Children with Autism Spectrum Disorder.

J Autism Dev Disord 2021 Jul 14. Epub 2021 Jul 14.

Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Childhood Nutrition and Health, Chongqing, 400014, China.

Metabolic disturbance may be implicated in the pathogenesis of autism. This study aimed to investigate the gut metabolomic profiles of autistic children and to analyze potential interaction between gut metabolites with autistic symptoms and neurodevelopment levels. We involved 120 autistic and 60 neurotypical children. Autistic symptoms and neurodevelopment levels were assessed. Fecal samples were analyzed using untargeted liquid chromatography-tandem mass spectrometry methods. Our results showed the metabolic disturbances of autistic children involved in multiple vitamin and amino acid metabolism pathways, with the strongest enrichment identified for tryptophan metabolism, retinol metabolism, cysteine-methionine metabolism, and vitamin digestion and absorption. Differential gut metabolites were correlated to autistic symptoms and neurodevelopment levels. Our findings improved the understanding of the perturbations of metabolome networks in autism.
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http://dx.doi.org/10.1007/s10803-021-05066-wDOI Listing
July 2021

Iron-Catalyzed Diborylation of Unactivated Aliphatic -Dihalogenoalkenes: Synthesis of 1,2-Bis(boryl)alkanes.

Org Lett 2021 Jul 7;23(14):5565-5570. Epub 2021 Jul 7.

Sichuan Key Laboratory of Medical Imaging, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China.

Herein, we report the first example of iron-catalyzed defluoroborylation of unactivated -difluoroalkenes, -dichloroalkenes, and -dibromoalkenes, providing the 1,2-bis(boryl)alkanes in moderate to good yield. This transformation has high regioselectivity, wide substrate scope, and excellent functional group compatibility. Preliminary mechanistic studies indicate that double β-F elimination is involved in the catalytic cycle, and the 1,1-diborylated alkenes might be intermediates in this iron-catalyzed 1,2-diborylation reaction.
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http://dx.doi.org/10.1021/acs.orglett.1c01967DOI Listing
July 2021

Inflammatory monocytes promote pre-engraftment syndrome and tocilizumab can therapeutically limit pathology in patients.

Nat Commun 2021 07 6;12(1):4137. Epub 2021 Jul 6.

Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Unrelated cord blood transplantation (UCBT) is an effective treatment for hematopoietic disorders. However, this attractive approach is frequently accompanied by pre-engraftment syndrome (PES), severe cases of PES are associated with enhanced mortality and morbidity, but the pathogenesis of PES remains unclear. Here we show that GM-CSF produced by cord blood-derived inflammatory monocytes drives PES pathology, and that monocytes are the main source of IL-6 during PES. Further, we report the outcome of a single arm, single-center clinical study of tocilizumab in the treatment of steroid-refractory severe PES patients (www.chictr.org.cn ChiCTR1800015472). The study met the primary outcome measure since none of the patients was nonrelapse death during the 100 days follow-up. The study also met key secondary outcomes measures of neutrophil engraftment and hematopoiesis. These findings offer a therapeutic strategy with which to tackle PES and improve nonrelapse mortality.
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http://dx.doi.org/10.1038/s41467-021-24412-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260612PMC
July 2021

Vitamin a deficiency and sleep disturbances related to autism symptoms in children with autism spectrum disorder: a cross-sectional study.

BMC Pediatr 2021 07 3;21(1):299. Epub 2021 Jul 3.

Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Child Nutrition and Health, Chongqing, PR China.

Background: Vitamin A deficiency (VAD) and sleep disturbances have been reported in children with autism spectrum disorder (ASD). The influence of vitamin A (VA) levels on sleep regulation and sleep disturbances in ASD has garnered concern. The present study aimed to characterize the association of VA levels with sleep disturbances in children with ASD.

Methods: This cross-sectional study compared children with ASD (n = 856) to typically developing children (TDC; n = 316). We used the Children's Sleep Habits Questionnaire to assess sleep disturbances, Childhood Autism Rating Scale to evaluate the severity of autism symptoms, and Autism Behavior Checklist and Social Responsiveness Scale to assess autism behaviors. Serum VA levels were estimated using high-performance liquid chromatography. Multivariable linear regression and two-way analysis of variance were performed to investigate if VAD was related to sleep disturbances in children with ASD.

Results: Children with ASD had lower serum VA levels and a higher prevalence of sleep disturbances than TDC did. The incidence of VAD in ASD children with sleep disturbances was higher, and the symptoms more severe than those without sleep disturbances and TDC. Interestingly, the interaction between VAD and sleep disturbances was associated with the severity of autism symptoms.

Conclusion: VAD and sleep disturbances are associated with the core symptoms of ASD in children. Regular monitoring of sleep and VA levels may be beneficial for children with ASD.

Trial Registration: Chinese Clinical Trial Registry, registration number: ChiCTR-ROC-14005442 , registration date: December 9th 2014.
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http://dx.doi.org/10.1186/s12887-021-02775-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254303PMC
July 2021

Straw-Based Activated Carbon: Optimization of the Preparation Procedure and Performance of Volatile Organic Compounds Adsorption.

Materials (Basel) 2021 Jun 14;14(12). Epub 2021 Jun 14.

Key Lab for Green Chemical Technology of Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.

Straw is one of the largest agricultural biowastes and a potential alternative precursor of activated carbon. Activated carbon prepared from different types of straw have great differences in structure and adsorption performance. In order to explore the performance of different straw-based activated carbon in volatile organic compounds adsorption, five common straws were selected as potential source materials for the preparation of SAC. The straw-based activated carbons were prepared and characterized via a thermo-gravimetric analysis, scanning electron microscope and the Brunauer-Emmett-Teller method. Among the five straw-based activated carbons, millet straw-derived activated carbon exhibited superior properties in S, S and adsorption capacities of both toluene and ethyl acetate. Furthermore, the preparation process of millet straw activated carbon was optimized via response surface methodology, using carbonization temperature, carbonization time and impregnation ratio as variables and toluene adsorption capacity, ethyl acetate adsorption capacity and activated carbon yield as responses. The optimal preparation conditions include a carbonization temperature of 572 °C, carbonization time of 1.56 h and impregnation ratio (ZnCl/PM, /) of 1.60, which was verified experimentally, resulting in millet straw activated carbon with a toluene adsorption capacity of 321.9 mg/g and ethyl acetate adsorption capacity of 240.4 mg/g. Meanwhile, the adsorption isothermals and regeneration performance of millet straw activated carbon prepared under the optimized conditions were evaluated. The descriptive ability of the isothermals via the Redlich-Peterson equation suggests a heterogeneous surface on millet straw activated carbon. Recyclability testing has shown that millet straw activated carbon maintained a stable adsorption capacity throughout the second to fifth cycles. The results of this work indicate that millet straw activated carbon may be a potential volatile organic compound adsorbent for industrial application.
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http://dx.doi.org/10.3390/ma14123284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232107PMC
June 2021

Multiple Genetic Mutations Related to Insecticide Resistance are Detected in Field Kazakhstani House Flies (Muscidae: Diptera).

J Med Entomol 2021 Jul 1. Epub 2021 Jul 1.

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.

The house fly (Musca domestica Linnaeus) is an important disease vector. Insecticide resistance is an obstacle to effective house fly control. Previous studies have demonstrated that point mutations in acetylcholinesterase (Ace), carboxylesterase (MdαE7) and voltage-sensitive sodium channel (Vssc), and over-expression of CYP6D1v1 confer insecticide resistance in the house fly. However, information about the status and underlying mechanisms of insecticide resistance in Kazakhstani house flies is lacking. In this study, we investigated the occurrence of genetic mutations associated with insecticide resistance in field house flies collected at six different locations in southern Kazakhstan. Four mutations (V260L, G342A/V, and F407Y) in Ace and three mutations (G137D and W251L/S) in MdαE7 were detected with appreciable frequencies. Notably, haplotypes carrying triple-loci mutations in Ace and double mutations in MdαE7 were found in Kazakhstan. The L1014H and L1014F mutations in Vssc, and CYP6D1v1 resistance allele were detected at a low frequency in some of the six investigated house fly populations. Phylogenetic analyses of haplotypes supported multiple origins of resistance mutations in Ace and MdαE7. These observations suggest that house flies in southern Kazakhstan may exhibit significant resistance to organophosphates and carbamates. Regular monitoring of insecticide resistance is recommended to achieve effective house fly control by chemical agents in southern Kazakhstan.
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http://dx.doi.org/10.1093/jme/tjab110DOI Listing
July 2021

Neutralizing Antibodies Induced by First-Generation gp41-Stabilized HIV-1 Envelope Trimers and Nanoparticles.

mBio 2021 06 22;12(3):e0042921. Epub 2021 Jun 22.

Department of Integrative Structural and Computational Biology, The Scripps Research Institutegrid.214007.0, La Jolla, California, USA.

The immunogenicity of gp41-stabilized HIV-1 BG505 envelope (Env) trimers and nanoparticles (NPs) was recently assessed in mice and rabbits. Here, we combined Env-specific B-cell sorting and repertoire sequencing to identify neutralizing antibodies (NAbs) from immunized animals. A panel of mouse NAbs was isolated from mice immunized with a 60-meric I3-01 NP presenting 20 stabilized trimers. Three mouse NAbs potently neutralized BG505.T332N by recognizing a glycan epitope centered in the C3/V4 region on BG505 Env, as revealed by electron microscopy (EM), X-ray crystallography, and epitope mapping. A set of rabbit NAbs was isolated from rabbits immunized with a soluble trimer and a 24-meric ferritin NP presenting 8 trimers. Neutralization assays against BG505.T332N variants confirmed that potent rabbit NAbs targeted previously described glycan holes on BG505 Env and accounted for a significant portion of the autologous NAb response in both the trimer and ferritin NP groups. Last, we examined NAb responses that were induced by non-BG505 Env immunogens. We determined a 3.4-Å-resolution crystal structure for the clade C transmitted/founder (T/F) Du172.17 Env with a redesigned heptad repeat 1 (HR1) bend in gp41. This clade C Env, in a soluble trimer form and in a multivalent form with 8 trimers attached to ferritin NP, and the gp41-stabilized clade A Q482-d12 Env trimer elicited distinct NAb responses in rabbits, with notable differences in neutralization breadth. Although eliciting a broad NAb response remains a major challenge, our study provides valuable information on an HIV-1 vaccine design strategy that combines gp41 stabilization and NP display. Self-assembling protein nanoparticles (NPs) presenting BG505 envelope (Env) trimers can elicit tier 2 HIV-1-neutralizing antibody (NAb) responses more effectively than soluble trimers. In the present study, monoclonal NAbs were isolated from previously immunized mice and rabbits for structural and functional analyses, which revealed that potent mouse NAbs recognize the C3/V4 region and small NP-elicited rabbit NAbs primarily target known glycan holes on BG505 Env. This study validates the gp41 stabilization strategy for HIV-1 Env vaccine design and highlights the challenge in eliciting a broad NAb response.
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http://dx.doi.org/10.1128/mBio.00429-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262854PMC
June 2021

Mn(II) Complex of Lipophilic Group-Modified Ethylenediaminetetraacetic Acid (EDTA) as a New Hepatobiliary MRI Contrast Agent.

J Med Chem 2021 07 21;64(13):9182-9192. Epub 2021 Jun 21.

Department of Radiotherapy, Sichuan Cancer Hospital & Institute, Chengdu 610041, China.

Liver-specific contrast agents (CAs) can improve the Magnetic resonance imaging (MRI) detection of focal and diffuse liver lesions by increasing the lesion-to-liver contrast. A novel Mn(II) complex, Mn-BnO-TyrEDTA, with a lipophilic group-modified ethylenediaminetetraacetic acid (EDTA) structure as a ligand to regulate its behavior in vivo, is superior to Gd-EOB-DTPA in terms of a liver-specific MRI contrast agent. An MRI study on mice demonstrated that Mn-BnO-TyrEDTA can be rapidly taken up by hepatocytes with a combination of hepatobiliary and renal clearance pathways. Bromosulfophthalein (BSP) inhibition imaging, biodistribution, and cellular uptake studies confirmed that the mechanism of hepatic targeting of Mn-BnO-TyrEDTA is the hepatic uptake of the amphiphilic anion contrast agent mediated by organic anion transporting polypeptides (OATPs) expressed by functional hepatocytes.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00393DOI Listing
July 2021

Elevated circRNAs circ_0000745, circ_0001531 and circ_0001640 in human whole blood: Potential novel diagnostic biomarkers for breast cancer.

Exp Mol Pathol 2021 Aug 15;121:104661. Epub 2021 Jun 15.

Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, Jinan 250012, Shandong, People's Republic of China. Electronic address:

Background And Objectives: Increasing studies have shown that circular RNAs (circRNAs) have great diagnostic potential in cancer. Here, we examined whether the blood circRNAs could be promising candidates as diagnostic biomarkers in breast cancer.

Methods: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to detect levels of five circRNAs (circ_0000501, circ_0000745, circ_0001531, circ_0001640 and circ_0001978) in 129 patients with breast cancer, 19 patients with benign breast tumor and 13 healthy controls. The diagnostic accuracy of circRNAs was assessed using the receiver operating characteristic (ROC) curve. A circRNA-miRNA-mRNA network was constructed based on bioinformatic analysis.

Results: QRT-PCR validated that circ_0000745, circ_0001531 and circ_0001640 were upregulated in breast cancer, compared with benign tumor and healthy control. ROC curve analysis revealed that circ_0000745, circ_0001531 and circ_0001640 had good diagnostic potential. Notably, a signature comprising the three circRNAs showed better diagnostic potential, with the area under curve (AUC) of 0.9130 (P < 0.0001). And a circRNA-miRNA-mRNA network revealed that the circRNAs could participate in complex regulated network and thus involve in cancer development and progression.

Conclusions: Taken together, our findings support the potential of circ_0000745, circ_0001531, circ_0001640 and the three-circRNA signature as biomarkers for breast cancer diagnosis.
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http://dx.doi.org/10.1016/j.yexmp.2021.104661DOI Listing
August 2021
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