Publications by authors named "Chen Jiang"

742 Publications

Endophilin A1 drives acute structural plasticity of dendritic spines in response to Ca2+/calmodulin.

J Cell Biol 2021 Jun 14;220(6). Epub 2021 May 14.

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Innovation Academy for Seed Design, Chinese Academy of Sciences, Beijing, China.

Induction of long-term potentiation (LTP) in excitatory neurons triggers a large transient increase in the volume of dendritic spines followed by decays to sustained size expansion, a process termed structural LTP (sLTP) that contributes to the cellular basis of learning and memory. Although mechanisms regulating the early and sustained phases of sLTP have been studied intensively, how the acute spine enlargement immediately after LTP stimulation is achieved remains elusive. Here, we report that endophilin A1 orchestrates membrane dynamics with actin polymerization to initiate spine enlargement in NMDAR-mediated LTP. Upon LTP induction, Ca2+/calmodulin enhances binding of endophilin A1 to both membrane and p140Cap, a cytoskeletal regulator. Consequently, endophilin A1 rapidly localizes to the plasma membrane and recruits p140Cap to promote local actin polymerization, leading to spine head expansion. Moreover, its molecular functions in activity-induced rapid spine growth are required for LTP and long-term memory. Thus, endophilin A1 serves as a calmodulin effector to drive acute structural plasticity necessary for learning and memory.
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http://dx.doi.org/10.1083/jcb.202007172DOI Listing
June 2021

Application of Textile Technology in Tissue Engineering: A review.

Acta Biomater 2021 May 4. Epub 2021 May 4.

School of Materials Science and Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Georgia Tech Manufacturing Institute, Georgia Institute of Technology, Atlanta, GA 30332, USA; H. Milton Stewart School of Industrial and System Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.

One of the key elements in tissue engineering is to design and fabricate scaffolds with tissue-like properties. Among various scaffold fabrication methods, textile technology has shown its unique advantages in mimicking human tissues' properties such as hierarchical, anisotropic, and strain-stiffening properties. As essential components in textile technology, textile patterns affect the porosity, architecture, and mechanical properties of textile-based scaffolds. However, the potential of various textile patterns has not been fully explored when fabricating textile-based scaffolds, and the effect of different textile patterns on scaffold properties has not been thoroughly investigated. This review summarizes textile technology development and highlights its application in tissue engineering to facilitate the broader application of textile technology, especially various textile patterns in tissue engineering. The potential of using different textile methods such as weaving, knitting, and braiding to mimic properties of human tissues is discussed, and the effect of process parameters in these methods on fabric properties is summarized. Finally, perspectives on future directions for explorations are presented. STATEMENT OF SIGNIFICANCE: : Recently, biomedical engineers have applied textile technology to fabricate scaffolds for tissue engineering applications. Various textile methods, especially weaving, knitting, and braiding, enables engineers to customize the physical, mechanical, and biological properties of scaffolds. However, most textile-based scaffolds only use simple textile patterns, and the effect of different textile patterns on scaffold properties has not been thoroughly investigated. In this review, we cover for the first time the effect of process parameters in different textile methods on fabric properties, exploring the potential of using different textile methods to mimic properties of human tissues. Previous advances in textile technology are presented, and future directions for explorations are presented, hoping to facilitate new breakthroughs of textile-based tissue engineering.
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http://dx.doi.org/10.1016/j.actbio.2021.04.047DOI Listing
May 2021

How Quality Control Systems AID Sec-Dependent Protein Translocation.

Front Mol Biosci 2021 13;8:669376. Epub 2021 Apr 13.

School of Biosciences and the Institute for Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom.

The evolutionarily conserved Sec machinery is responsible for transporting proteins across the cytoplasmic membrane. Protein substrates of the Sec machinery must be in an unfolded conformation in order to be translocated across (or inserted into) the cytoplasmic membrane. In bacteria, the requirement for unfolded proteins is strict: substrate proteins that fold (or misfold) prematurely in the cytoplasm prior to translocation become irreversibly trapped in the cytoplasm. Partially folded Sec substrate proteins and stalled ribosomes containing nascent Sec substrates can also inhibit translocation by blocking (i.e., "jamming") the membrane-embedded Sec machinery. To avoid these issues, bacteria have evolved a complex network of quality control systems to ensure that Sec substrate proteins do not fold in the cytoplasm. This quality control network can be broken into three branches, for which we have defined the acronym "AID": (i) of cytoplasmic intermediates through cotranslationally channeling newly synthesized Sec substrates to the Sec machinery; (ii) of folding Sec substrate proteins that transiently reside in the cytoplasm by molecular chaperones and the requirement for posttranslational modifications; (iii) of products that could potentially inhibit translocation. In addition, several stress response pathways help to restore protein-folding homeostasis when environmental conditions that inhibit translocation overcome the AID quality control systems.
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http://dx.doi.org/10.3389/fmolb.2021.669376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076867PMC
April 2021

Impact of Implant Surface Material and Microscale Roughness on the Initial Attachment and Proliferation of Primary Human Gingival Fibroblasts.

Biology (Basel) 2021 Apr 22;10(5). Epub 2021 Apr 22.

Competence Center for Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria.

Due to the rising demand for zirconia (Zr) based implant systems, it is important to understand the impact of Zr and titanium (Ti) implants and particularly their topography on soft tissue healing. As human gingival fibroblasts (hGFs) are the predominant cells in peri-implant soft tissue, we focused on examining the effect of implant material and surface roughness on hGFs' initial attachment, growth and the expression of proteins involved in the focal adhesion. hGFs isolated from eight healthy donors were cultured on the following surfaces: smooth titanium machined surface (TiM), smooth zirconia machined surface (ZrM), moderately rough titanium surface (SLA), or moderately rough zirconia surface (ZLA) for up to 14 days. The initial attachment of hGFs was evaluated by scanning electron microscopy. Cell proliferation/viability was assessed by cell counting kit 8. Focal adhesion and cytoskeleton were visualized by a focal adhesion staining kit. The gene expression of focal adhesion kinase (FAK), α-smooth muscle actin (α-SMA), and integrin subunits ITG-β1, ITG-β4, ITG-α4, ITG-α5, ITG-α6, was evaluated by qPCR. Cell proliferation/viability was slightly decreased by moderately rough surfaces, whereas no effect of surface material was observed. Cell morphology was strikingly different between differently treated surfaces: on machined surfaces, cells had elongated morphology and were attached along the grooves, whereas on moderately rough surfaces, cells were randomly attached. Surface roughness had a more pronounced effect on the gene expression compared to the surface material. The expression of FAK, α-SMA, ITG-β4, ITG-α5, and ITG-α6 was enhanced by moderately rough surfaces compared to smooth surfaces. Within the limitations of this in vitro study, it can be concluded that the behavior of primary hGFs is primarily affected by surface structure, whereas no apparent advantage of Zr over Ti could be observed.
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http://dx.doi.org/10.3390/biology10050356DOI Listing
April 2021

IsAb: a computational protocol for antibody design.

Brief Bioinform 2021 Apr 20. Epub 2021 Apr 20.

Computational Drug Abuse Research and Computational Chemogenomics Screening Center at the University of Pittsburgh, Pittsburgh, PA 15261, USA.

The design of therapeutic antibodies has attracted a large amount of attention over the years. Antibodies are widely used to treat many diseases due to their high efficiency and low risk of adverse events. However, the experimental methods of antibody design are time-consuming and expensive. Although computational antibody design techniques have had significant advances in the past years, there are still some challenges that need to be solved, such as the flexibility of antigen structure, the lack of antibody structural data and the absence of standard antibody design protocol. In the present work, we elaborated on an in silico antibody design protocol for users to easily perform computer-aided antibody design. First, the Rosetta web server will be applied to generate the 3D structure of query antibodies if there is no structural information available. Then, two-step docking will be used to identify the binding pose of an antibody-antigen complex when the binding information is unknown. ClusPro is the first method to be used to conduct the global docking, and SnugDock is applied for the local docking. Sequentially, based on the predicted binding poses, in silico alanine scanning will be used to predict the potential hotspots (or key residues). Finally, computational affinity maturation protocol will be used to modify the structure of antibodies to theoretically increase their affinity and stability, which will be further validated by the bioassays in the future. As a proof of concept, we redesigned antibody D44.1 and compared it with previously reported data in order to validate IsAb protocol. To further illustrate our proposed protocol, we used cemiplimab antibody, a PD-1 checkpoint inhibitor, as an example to showcase a step-by-step tutorial.
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http://dx.doi.org/10.1093/bib/bbab143DOI Listing
April 2021

Pancreatic Leiomyosarcoma With Schistosomiasis Hematobia: A Case Report and Literature Review.

Front Oncol 2021 31;11:638905. Epub 2021 Mar 31.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

Pancreatic leiomyosarcoma (PL) is a very rare, malignant neoplasm with a very poor prognosis. Here, we examine a novel case of PL with schistosomiasis hematobia. The patient had been initially misdiagnosed by the first magnetic resonance imaging (MRI). The second imaging examination demonstrated an enlarged heterogeneous tumor mass in the body-tail of pancreas. Following image analysis, the patient underwent a pancreatectomy, splenectomy and lymph node dissections. Sixteen months after the tumor resection, follow-up computed tomography (CT) and MRI revealed tumor metastasis in the liver and lung. PL has non-specific clinical manifestations and imaging characteristics, making early diagnosis very challenging. When it is difficult to distinguish between benign and malignant pancreatic lesions, short-term imaging follow-up is preferred. In this case report, we discuss the relationship between PL and schistosomiasis hematobia.
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http://dx.doi.org/10.3389/fonc.2021.638905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045707PMC
March 2021

Textile-based sandwich scaffold using wet electrospun yarns for skin tissue engineering.

J Mech Behav Biomed Mater 2021 Apr 8;119:104499. Epub 2021 Apr 8.

School of Materials Science and Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Georgia Tech Manufacturing Institute, Georgia Institute of Technology, Atlanta, GA, USA; H. Milton Stewart School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA, USA.

One of the key elements in tissue engineering is to design and fabricate scaffolds with tissue-like properties. However, mimicking the strain-stiffening property of human tissues by using synthetic materials is still a challenge in scaffold fabrication since most synthetic materials exhibit strain-softening behavior. To address this challenge, we propose a textile-based sandwich scaffold to mimic strain-stiffening behavior observed in human tissues. For this purpose, we first fabricate polycaprolactone (PCL) yarns by wet electrospinning. Then, we crochet PCL yarns into a textile fabric. Finally, we fabricate the sandwich scaffold by embedding the textile fabric inside two electrospun mats. The wet electrospun PCL yarns induce cellular alignment and elongation. The textile-based sandwich scaffold exhibits strain-stiffening behavior. By changing process parameters during the yarn fabrication and textile process, we can adjust the maximum stress of the scaffold from 5.40 to 8.83 MPa, the maximum strain from 0.89 to 1.69, and the elastic modulus from 2.9 to 10.31 MPa, all within the ranges of that of human skin. The scaffold is also able to support cell proliferation and infiltration after optimizing the thickness of the outer layers of the sandwich scaffold. This study validates the potential of the textile-based sandwich scaffold to mimic the physical, mechanical, and biological properties of human skin and other tissues.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104499DOI Listing
April 2021

The effects of Fushen Granule on the composition and function of the gut microbiota during Peritoneal Dialysis-Related Peritonitis.

Phytomedicine 2021 Jun 28;86:153561. Epub 2021 Mar 28.

Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, PR China. Electronic address:

Background: Peritoneal dialysis (PD) is an acknowledged treatment for patients with irreversible kidney failure. The treatment usually causes peritoneal dialysis-related peritonitis (PDRP), a common complication of PD that can lead to inadequate dialysis, gastrointestinal dysfunction, and even death. Recent studies indicated that Fushen Granule (FSG), a Chinese herbal formula, improves the treatment of PD. However, the mechanism of how FSG plays its role in the improvement is still unclear. Gut microbiota has been closely related to the development of various diseases. We carried out a randomized controlled trial to assess whether FSG can modulate the gut microbiota during PDRP treatment.

Methods: Forty-two PDRP patients were recruited into the clinical trial, and they were randomly divided into control(CON), probiotics(PRO) or Fushen granule group(FSG). To check whether FSG improve the PD treatment, we assessed the clinical parameters, including albumin(ALB), hemoglobin(HGB), blood urea nitrogen(BUN) and creatinine(CR). Fecal samples were collected before hospitalization and discharge, and stored at -80°C within 1 hour. And we assessed the microbial population and function by applying the 16S rRNA gene sequencing and functional enrichment analysis.

Results: Compared to control group, ALB is improved in both probiotics and FSG groups, while HGB is increased but BUN and CR is reduced in FSG group. Sequencing of 16S rRNA genes revealed that FSG and PRO affected the composition of the microbial community. FSG significantly increased a abundant represented by Bacteroides, Megamonas and Rothia, which was significantly correlated with the improvements in carbohydrate and amino acid metabolism.

Conclusions: This study demonstrates that FSG ameliorates the nutritional status and improves the quality of life by enriching beneficial bacteria associated with metabolism. These results indicate that FSG as alternative medicine is a promising treatment for patients with PDRP.
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http://dx.doi.org/10.1016/j.phymed.2021.153561DOI Listing
June 2021

Using Wet Electrospun PCL/Gelatin/CNT Yarns to Fabricate Textile-Based Scaffolds for Vascular Tissue Engineering.

ACS Biomater Sci Eng 2021 Apr 6. Epub 2021 Apr 6.

School of Materials Science and Engineering, Georgia Institute of Technology, 771 Ferst Dr NW, Atlanta 30332, Georgia, United States.

Incorporating conductive materials in scaffolds has shown advantages in regulating adhesion, mitigation, and proliferation of electroactive cells for tissue engineering applications. Among various conductive materials, carbon nanotubes (CNTs) have shown great promises in tissue engineering because of their good mechanical properties. However, the broad application of CNTs in tissue engineering is limited by current methods to incorporate CNTs in polymers that require miscible solvents to dissolve CNTs and polymers or CNT surface modification. These methods either limit polymer selections or adversely affect the properties of polymer/CNT composites. Here, we report a novel method to fabricate polymer/CNT composite yarns by electrospinning polycaprolactone/gelatin into a bath of CNT dispersion and extracting electrospun fibers out of the bath. The concentration of CNTs in the bath affects the thermal and mechanical properties and the yarns' degradation behavior. biological test results show that within a limited range of CNT concentrations in the bath, the yarns exhibit good biocompatibility and the ability to guide cell elongation and alignment. We also report the design and fabrication of a vascular scaffold by knitting the yarns into a textile fabric and combining the textile fabric with gelatin. The scaffold has similar mechanical properties to native vessels and supports cell proliferation. This work demonstrates that the wet electrospun polymer/CNT yarns are good candidates for constructing vascular scaffolds and provides a novel method to incorporate CNTs or other functional materials into biopolymers for tissue engineering applications.
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http://dx.doi.org/10.1021/acsbiomaterials.1c00097DOI Listing
April 2021

Cell-friendly photo-functionalized TiO nano-micro-honeycombs for selectively preventing bacteria and platelet adhesion.

Mater Sci Eng C Mater Biol Appl 2021 Apr 25;123:111996. Epub 2021 Feb 25.

Institute of Biomaterials and Surface Engineering, Key Lab. for Advanced Technologies of Materials, Ministry of Education, Southwest Jiaotong University, Chengdu 610031, China.

Titanium dioxide (TiO) is a widely used biomaterial. It is a great challenge to confer antibacterial and antithrombotic properties to TiO while maintaining its cell affinity. Here, we developed a new strategy to achieve the above goal by comprehensively controlling the chemical cues and geometrical cues of the surface of TiO. Using colloidal etching technology and UV irradiation treatment, we obtained the photofunctionalized nano-micro-honeycomb structured TiO. The honeycomb structured increased the photocatalytic activity of TiO, which endowed TiO with photo-induced superhydrophilicity to inhibit bacterial adhesion. The high photocatalytic activity also induced the strong photocatalytic oxidation of TiO surface organic adsorbates to suppress fibrinogen and platelet attachment. In addition, owing to the micropore trapping-isolation effect on the bacteria and the nano-frames' contact guidance effect on the growth and spreading of platelet pseudopods, the honeycomb structure also shows a considerable inhibiting effect on bacterial and platelet adhesion. Therefore, due to the controlled chemical and geometrical cues' synergistic effect, the photo-functionalized TiO honeycomb structure shows excellent bacterial-adhesion resistance and antithrombotic properties. More importantly, the photo-functionalized TiO honeycomb did not inhibit the adhesion and growth of endothelial cells (ECs) after culturing for 3 d, indicating a good cell affinity that the traditional antifouling surfaces do not possess.
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http://dx.doi.org/10.1016/j.msec.2021.111996DOI Listing
April 2021

Tumor innervation and clinical outcome in pancreatic cancer.

Sci Rep 2021 Apr 1;11(1):7390. Epub 2021 Apr 1.

School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, 2308, Australia.

Pancreatic cancer is a highly aggressive malignancy characterized by poor survival, recurrence after surgery and resistance to therapy. Nerves infiltrate the microenvironment of pancreatic cancers and contribute to tumor progression, however the clinicopathological significance of tumor innervation is unclear. In this study, the presence of nerves and their cross-sectional size were quantified by immunohistochemistry for the neuronal markers S-100, PGP9.5 and GAP-43 in a series of 99 pancreatic cancer cases versus 71 normal adjacent pancreatic tissues. A trend was observed between the presence of nerves in the tumor microenvironment of pancreatic cancer and worse overall patient survival (HR = 1.8, 95% CI 0.77-4.28, p = 0.08). The size of nerves, as measured by cross-sectional area, were significantly higher in pancreatic cancer than in the normal adjacent tissue (p = 0.002) and larger nerves were directly associated with worse patient survival (HR = 0.41, 95% CI 0.19-0.87, p = 0.04). In conclusion, this study suggests that the presence and size of nerves within the pancreatic cancer microenvironment are associated with tumor aggressiveness.
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http://dx.doi.org/10.1038/s41598-021-86831-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017010PMC
April 2021

Cytokine-induced killer cells/dendritic cells and cytokine-induced killer cells immunotherapy for the treatment of esophageal cancer: A meta-analysis.

Medicine (Baltimore) 2021 Apr;100(13):e24519

Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education)/ Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Xinjiang.

Objectives: This meta-analysis was designed to systematically evaluate whether autologous cytokine-induced killer cells (CIK) or dendritic cells and cytokine-induced killer cells (DC-CIK) immunotherapy combined with chemotherapy can improve the therapeutic effect and safety of chemotherapy in esophageal cancer (EC).

Materials And Methods: Randomized controlled trials (RCTs) were electronically searched databases including CNKI, WanFang, WeiPu, CBMDisc, PubMed, Web of Science, EMbase, the Cochrane Library, and Clinical Trials. The databases were searched for articles published until June 2019. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included literature. Meta-analysis was performed using RevMan5.3.

Results: Seventeen studies (1416 participants) were included. The differences between CIK/DC-CIK combination chemotherapy and chemotherapy alone were significant. The results displayed that the number of CD3+, CD4+, CD4+/CD8+, and NK cells was significantly increased after 1 to 2 weeks of treatment with CIK/DC-CIK cells in the treatment group (all P < .05). In addition, the results shown that 1-year overall survival was significantly prolonged (P < .0001) and quality of life was improved (P = .001) in EC chemotherapy combined with immunotherapy groups compared with conventional treatment. Furthermore, cytokine expression levels of interleukin 2 (IL-2), tumor necrosis factor α (TNF-α), and interleukin 12 (IL-12) were significantly increased (P = .0003) as well as the levels of immunoglobulins were elevated (P < .00001). Serum levels of tumor marker molecules, carcinoembryonic antigen (CEA), carbohydrate antigen (CA)-199, and CA-125 were lower in treatment groups than that of control groups (P < .00001). No fatal adverse reactions were noted (P = .04).

Conclusions: It is safe and effective for patients to use chemotherapy combined with CIK/DC-CIK immunotherapy. Immunotherapy can simultaneously improve the antitumor immune response. Specifically, DC-CIK cells can increase T lymphocyte subsets, CIK cells, NK cells, and immunoglobulins in peripheral blood to enhance antitumor immunity. Therefore, combination therapy enhances the immune function and improves the therapeutic efficacy of patients with EC.
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http://dx.doi.org/10.1097/MD.0000000000024519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021386PMC
April 2021

Development of double-positive thymocytes at single-cell resolution.

Genome Med 2021 Mar 26;13(1):49. Epub 2021 Mar 26.

Department of oncology, The First Affiliated Hospital of USTC, Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medicine, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230021, Anhui, China.

Background: T cells generated from thymopoiesis are essential for the immune system, and recent single-cell studies have contributed to our understanding of the development of thymocytes at the genetic and epigenetic levels. However, the development of double-positive (DP) T cells, which comprise the majority of thymocytes, has not been well investigated.

Methods: We applied single-cell sequencing to mouse thymocytes and analyzed the transcriptome data using Seurat. By applying unsupervised clustering, we defined thymocyte subtypes and validated DP cell subtypes by flow cytometry. We classified the cell cycle phases of each cell according to expression of cell cycle phase-specific genes. For immune synapse detection, we used immunofluorescent staining and ImageStream-based flow cytometry. We studied and integrated human thymocyte data to verify the conservation of our findings and also performed cross-species comparisons to examine species-specific gene regulation.

Results: We classified blast, rearrangement, and selection subtypes of DP thymocytes and used the surface markers CD2 and Ly6d to identify these subtypes by flow cytometry. Based on this new classification, we found that the proliferation of blast DP cells is quite different from that of double-positive cells and other cell types, which tend to exit the cell cycle after a single round. At the DP cell selection stage, we observed that CD8-associated immune synapses formed between thymocytes, indicating that CD8sp selection occurred among thymocytes themselves. Moreover, cross-species comparison revealed species-specific transcription factors (TFs) that contribute to the transcriptional differences of thymocytes from humans and mice.

Conclusions: Our study classified DP thymocyte subtypes of different developmental stages and provided new insight into the development of DP thymocytes at single-cell resolution, furthering our knowledge of the fundamental immunological process of thymopoiesis.
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http://dx.doi.org/10.1186/s13073-021-00861-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004397PMC
March 2021

BMP4/ALK3 deficiency leads to Meckel's cartilage truncation mimicking the mandible Tessier 30 cleft.

Oral Dis 2021 Mar 23. Epub 2021 Mar 23.

School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.

Objective: In chondrogenesis, BMP signaling was inferred to exhibit regional specificity during Meckel's cartilage morphogenesis. This study aimed to explore the differences in BMP signaling activity between different parts of Meckel's cartilage and the impacts of BMP4 or ALK3 deficiency on the development of Meckel's cartilage during embryogenesis.

Materials And Methods: The BRE-gal reporter mouse line was utilized to gain an overall picture of canonical BMP signaling activity, as assessed by X-gal staining. Mouse models lacking either Bmp4 or Alk3 in neural crest cells (Wnt1-Cre;Bmp4 and Wnt1-Cre;Alk3 ) were generated to explore the morphogenesis of Meckel's cartilage and the mandibular symphysis, as assessed by skeletal staining, histology, and immunostaining.

Results: Different parts of Meckel's cartilage exhibited activation of different combinations of BMP signaling pathways. In Wnt1-Cre;Bmp4 mutants, Sox9 condensation of the chondrogenic rostral process failed to form, and the V-shaped Runx2 tissue was split in the median mandibular symphysis. The Wnt1-Cre;Bmp4 and Wnt1-Cre;Alk3 mouse models both exhibited truncated Meckel's cartilage, aberrant mandibular intramembranous bone, and tongue muscle abnormalities.

Conclusions: The central hard-tissue loss of both mutant mouse models led to a mandibular symphysis cleft, mimicking the typical sign of the median mandible Tessier 30 cleft in humans.
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http://dx.doi.org/10.1111/odi.13855DOI Listing
March 2021

RALYL increases hepatocellular carcinoma stemness by sustaining the mRNA stability of TGF-β2.

Nat Commun 2021 03 9;12(1):1518. Epub 2021 Mar 9.

Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.

Growing evidences suggest that cancer stem cells exhibit many molecular characteristics and phenotypes similar to their ancestral progenitor cells. In the present study, human embryonic stem cells are induced to differentiate into hepatocytes along hepatic lineages to mimic liver development in vitro. A liver progenitor specific gene, RALY RNA binding protein like (RALYL), is identified. RALYL expression is associated with poor prognosis, poor differentiation, and metastasis in clinical HCC patients. Functional studies reveal that RALYL could promote HCC tumorigenicity, self-renewal, chemoresistance, and metastasis. Moreover, molecular mechanism studies show that RALYL could upregulate TGF-β2 mRNA stability by decreasing N6-methyladenosine (mA) modification. TGF-β signaling and the subsequent PI3K/AKT and STAT3 pathways, upregulated by RALYL, contribute to the enhancement of HCC stemness. Collectively, RALYL is a liver progenitor specific gene and regulates HCC stemness by sustaining TGF-β2 mRNA stability. These findings may inspire precise therapeutic strategies for HCC.
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http://dx.doi.org/10.1038/s41467-021-21828-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943813PMC
March 2021

Case Report: Intercostal Lymph Node Metastasis: A Case Report and Review of the Literature.

Front Oncol 2021 4;11:638948. Epub 2021 Mar 4.

Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, China.

The axillary lymph nodes are the primary group responsible for lymphatic drainage in the breast and, consequently, are the most common location for breast cancer metastasis. However, lymphatic pathways running from the breast, via intercostal spaces, to parasternal lymph vessels have also been identified. According to the American Joint Committee on Cancer eighth edition manual, regional lymph node metastasis normally travels to the ipsilateral axillary, supraclavicular, subclavicular, and internal mammary lymph nodes. The presence of intercostal metastasis is out the range of these regional lymph nodes. It is very rare for intercostal lymph nodes to be the extra-axillary site of metastasis in breast cancer, and it has been little reported on in the literature. Despite its rarity, it has the capacity to adversely affect the prognosis of breast cancer and drastically influence treatment choice. Here, we analyze such a case, with a patient receiving a radical mastectomy and metastatic intercostal lymph node dissection due to the presence of intercostal lymph node metastasis indicated via MRI. Furthermore, the potential application of preoperative 3-dimensional (3D) visualization and surgical planning is also discussed.
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http://dx.doi.org/10.3389/fonc.2021.638948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969973PMC
March 2021

Neuromodulation of the Pudendal Nerve Assisted by 3D Printed: A New Method of Neuromodulation for Lower Urinary Tract Dysfunction.

Front Neurosci 2021 26;15:619672. Epub 2021 Feb 26.

Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Electrical stimulation of peripheral nerves by implanted electrodes is an effective treatment for certain pelvic floor diseases. As well as intravesical electrical stimulation, this predominantly includes stimulation of the sacral nerve, tibial nerve, and pudendal nerve. The pudendal nerve is one of the main nerves that stimulate pelvic floor muscles, external urethral meatus, and the anal sphincter and pelvic organs, and it may have effects on frequent urination, urgency, dysuria, and perineal pain. It is difficult to locate because of its anatomical course, however, leading to difficulties fixing the electrode, which increases the difficulty of pudendal nerve electrical stimulation in clinical practice. In the current study 3D printed navigation was used to solve these problems. Combined with autopsy data and patient pelvic and nerve data, a personalized design was generated. Neural modulation of the pudendal nerve was achieved by implanting the lead with the guidance of 3D printed navigation. 3D printed navigation can maximize the phase II conversion rate, reduce the difficulty of surgery, shorten the operation time, reduce damage to additional organs and blood vessels, and increase the accuracy of electrode implantation, and it can be performed while the patient is awake. It is an accurate, reversible, efficient, and minimally invasive surgery.
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http://dx.doi.org/10.3389/fnins.2021.619672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952533PMC
February 2021

Biotransformation of Phlorizin by Eurotium cristatum to Increase the Antioxidant and Antibacterial Activity of Docynia indica Leaves.

Curr Microbiol 2021 Apr 8;78(4):1590-1601. Epub 2021 Mar 8.

College of Life Sciences, Sichuan Normal University, Longquan, No. 1819 Chen Long Avenue, Chengdu, 610101, People's Republic of China.

Docynia indica is used as a plant resource for both medicine and food in minority areas of southwestern China and Southeast of Asia, especially Docynia indica leaves, which are often used as a kind of functional tea in daily life. In our previous research, it has found that D. indica is rich in polyphenols (mainly phlorizin (PHZ)). Although PHZ is the first polyphenolic competitive inhibitor of sodium-dependent glucose transporters (SGLTs) to be discovered, the promotion and application of PHZ are limited due to its extremely low bioavailability. As a kind of aglycons, phloretin (PHT) possesses a better bioavailability and bioactivity than PHZ. Therefore, the conversion of PHZ to PHT in D. indica leaves by the method of biotransformation can be applied to solve the above issue. In this study, Aspergillus niger and Eurotium cristatum were used to transform PHZ to PHT in D. indica. Compared with Aspergillus niger, Eurotium cristatum can cause the equimolar conversion of PHZ to PHT. However, Aspergillus niger resulted in the complete degradation of PHZ. In the process of deep fermentation, PHZ in D. indica leaves was gradually biotransformed into PHT, and its content was as high as ~ 12% after fermentation. With the increase of PHT content, the antioxidant and antibacterial activity of Docynia indica leaves increased. By the acute toxicity evaluation, it was confirmed that Docynia indica leaves and Eurotium cristatum fermented leaves were much safer. These results indicate that Eurotium cristatum fermentation has the ability to transform the functional compounds in Docynia indica leaves and increase the antioxidant and antibacterial activity of Docynia indica, thus making it a substitute for PHT and functional tea.
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http://dx.doi.org/10.1007/s00284-021-02366-3DOI Listing
April 2021

Hair Loss Caused by Gain-Of-Function Mutant TRPV3 Is Associated with Premature Differentiation of Follicular Keratinocytes.

J Invest Dermatol 2021 Mar 3. Epub 2021 Mar 3.

Department of Dermatology, Peking University First Hospital, Beijing, China; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China; National Clinical Research Center for Skin and Immune Diseases, Beijing, China; Peking-Tsinghua Center for Life Sciences, Beijing, China; Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China. Electronic address:

Gain-of-function mutations in the TRPV3 gene can cause Olmsted syndrome characterized by palmoplantar and periorificial keratoderma, itch, and hair loss. The mechanism underlying the hair loss remains unclear. In this study, we engineered an Olmsted syndrome mouse model by introducing the point mutation G568V to the corresponding Trpv3 locus in the mice. These mice developed fully penetrant hair loss. The hair loss was associated with premature differentiation of follicular keratinocytes characterized by precocious degeneration of trichohyalin and keratins, increased production of deiminated proteins, elevated apoptosis, and attenuation of transcription regulators (Foxn1, Msx2, Dlx3, and Gata3) known to regulate hair follicle differentiation. These abnormalities occurred in the medial‒proximal region of the inner root sheath and the hair shaft, where Trpv3 is highly expressed, and correlated with an impaired formation of the hair canal and the hair shaft. The mutant Trpv3 mice also exhibited increased proliferation in the outer root sheath, accelerated hair cycle, reduction of hair follicle stem cells, and miniaturization of regenerated hair follicles. Findings from this study suggest that precocious maturation of postmitotic follicular keratinocytes drives hair loss in patients with Olmsted syndrome.
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http://dx.doi.org/10.1016/j.jid.2020.11.036DOI Listing
March 2021

COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas.

Cell 2021 04 3;184(7):1895-1913.e19. Epub 2021 Feb 3.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China.

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.
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http://dx.doi.org/10.1016/j.cell.2021.01.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857060PMC
April 2021

Effects of KAI gene expression on ferroptosis in pancreatic cancer cells.

Mol Med Rep 2021 02 22;23(2). Epub 2020 Dec 22.

Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110840, P.R. China.

The specific role and mechanism of ferroptosis in the development of pancreatic cancer (PC) remain to be elucidated. The present study aimed to investigate the effects of the overexpression of the KAI1 gene on the ferroptosis of the human PC cell line MIA PaCa‑2. MIA PaCa‑2 cells infected with pCMV‑KAI1 and selected by G418 and KAI1 protein were analyzed by western blotting. The MIA PaCa‑2 cells with a stable expression of the KAI1 gene were termed MIA PaCa‑2‑KAI1. The proliferative capacities of MIA PaCa‑2 and MIA PaCa‑2‑KAI1 cells were detected using Cell Counting Kit‑8. The reactive oxygen species (ROS) in the cells were compared by flow cytometry. The expressions of ferroportin (FPN) and glutathione peroxidase 4 (GPX4) protein were analyzed by western blotting. The KAI1 stable expression cell line was confirmed and relabeled as MIA PaCa‑2‑KAI1. No significant differences in the proliferation of MIA PaCa‑2 and MIA PaCa‑2‑KAI1 were identified. Following treatment with a ferroptosis blocker, the increase in the proliferation of MIA PaCa‑2‑KAI1 (from 2.06±0.02 to 2.75±0.02) was more evident compared with MIA PaCa‑2 (from 2.94±0.02 to 2.95±0.02; P<0.05). The ROS in MIA PaCa‑2‑KAI1 was significantly higher compared with MIA PaCa‑2 (P<0.05). FPN and GPX4 protein demonstrated higher expression levels in MIA PaCa‑2‑KAI1 compared with MIA PaCa‑2. Moreover, KAI1 exerted an obvious promotion effect on FPN expression. This study identified that the high expression of the KAI1 gene promoted the occurrence of ferroptosis in PC cells through its extensive effect on FPN and GPX4. KAI1‑induced ferroptosis did not significantly inhibit the proliferation of PC cells.
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http://dx.doi.org/10.3892/mmr.2020.11802DOI Listing
February 2021

Mechanochemical control of epidermal stem cell divisions by B-plexins.

Nat Commun 2021 02 26;12(1):1308. Epub 2021 Feb 26.

Institute of Pharmacology, University of Marburg, Marburg, Germany.

The precise spatiotemporal control of cell proliferation is key to the morphogenesis of epithelial tissues. Epithelial cell divisions lead to tissue crowding and local changes in force distribution, which in turn suppress the rate of cell divisions. However, the molecular mechanisms underlying this mechanical feedback are largely unclear. Here, we identify a critical requirement of B-plexin transmembrane receptors in the response to crowding-induced mechanical forces during embryonic skin development. Epidermal stem cells lacking B-plexins fail to sense mechanical compression, resulting in disinhibition of the transcriptional coactivator YAP, hyperproliferation, and tissue overgrowth. Mechanistically, we show that B-plexins mediate mechanoresponses to crowding through stabilization of adhesive cell junctions and lowering of cortical stiffness. Finally, we provide evidence that the B-plexin-dependent mechanochemical feedback is also pathophysiologically relevant to limit tumor growth in basal cell carcinoma, the most common type of skin cancer. Our data define a central role of B-plexins in mechanosensation to couple cell density and cell division in development and disease.
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http://dx.doi.org/10.1038/s41467-021-21513-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910479PMC
February 2021

An Instrumented Cochlea Model for the Evaluation of Cochlear Implant Electrical Stimulus Spread.

IEEE Trans Biomed Eng 2021 Feb 15;PP. Epub 2021 Feb 15.

Cochlear implants use electrical stimulation of the auditory nerve to restore the sensation of hearing to deaf people. Unfortunately, the stimulation current spreads extensively within the cochlea, resulting in "blurring" of the signal, and hearing that is far from normal. Current spread can be indirectly measured using the implant electrodes for both stimulating and sensing, but this provides incomplete information near the stimulating electrode due to electrode-electrolyte interface effects. Here, we present a 3D-printed "unwrapped" physical cochlea model with integrated sensing wires. We integrate resistors into the walls of the model to simulate current spread through the cochlear bony wall, and "tune" these resistances by calibration with an in-vivo electrical measurement from a cochlear implant patient. We then use this model to compare electrical current spread under different stimulation modes including monopolar, bipolar and tripolar configurations. Importantly, a trade-off is observed between stimulation amplitude and current focusing among different stimulation modes. By combining different stimulation modes and changing intracochlear current sinking configurations in the model, we explore this trade-off between stimulation amplitude and focusing further. These results will inform clinical strategies for use in delivering speech signals to cochlear implant patients.
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http://dx.doi.org/10.1109/TBME.2021.3059302DOI Listing
February 2021

Interpenetrating interfaces for efficient perovskite solar cells with high operational stability and mechanical robustness.

Nat Commun 2021 Feb 12;12(1):973. Epub 2021 Feb 12.

School of Engineering, Brown University, Providence, 02912, RI, USA.

The perovskite solar cell has emerged rapidly in the field of photovoltaics as it combines the merits of low cost, high efficiency, and excellent mechanical flexibility for versatile applications. However, there are significant concerns regarding its operational stability and mechanical robustness. Most of the previously reported approaches to address these concerns entail separate engineering of perovskite and charge-transporting layers. Herein we present a holistic design of perovskite and charge-transporting layers by synthesizing an interpenetrating perovskite/electron-transporting-layer interface. This interface is reaction-formed between a tin dioxide layer containing excess organic halide and a perovskite layer containing excess lead halide. Perovskite solar cells with such interfaces deliver efficiencies up to 22.2% and 20.1% for rigid and flexible versions, respectively. Long-term (1000 h) operational stability is demonstrated and the flexible devices show high endurance against mechanical-bending (2500 cycles) fatigue. Mechanistic insights into the relationship between the interpenetrating interface structure and performance enhancement are provided based on comprehensive, advanced, microscopic characterizations. This study highlights interface integrity as an important factor for designing efficient, operationally-stable, and mechanically-robust solar cells.
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http://dx.doi.org/10.1038/s41467-021-21292-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881119PMC
February 2021

Evaluation of serum ATX and LPA as potential diagnostic biomarkers in patients with pancreatic cancer.

BMC Gastroenterol 2021 Feb 10;21(1):58. Epub 2021 Feb 10.

Department of Gastroenterology, General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenyang, 110840, Liaoning Province, China.

Background: Pancreatic cancer (PC) is a devastating disease that has a poor prognosis and a total 5-year survival rate of around 5%. The poor prognosis of PC is due in part to a lack of suitable biomarkers that can allow early diagnosis. The lysophospholipase autotaxin (ATX) and its product lysophosphatidic acid (LPA) play an essential role in disease progression in PC patients and are associated with increased morbidity in several types of cancer. In this study, we evaluated both the potential role of serum LPA and ATX as diagnostic markers in PC and their prognostic value for PC either alone or in combination with CA19-9.

Methods: ATX, LPA and CA19-9 levels were evaluated using ELISA of serum obtained from PC patients (n = 114) healthy volunteers (HVs: n = 120) and patients with benign pancreatic diseases (BPDs: n = 94).

Results: Serum levels of ATX, LPA and CA19-9 in PC patients were substantially higher than that for BPD patients or HVs (p < 0.001). The sensitivity of LPA in early phase PC was 91.74% and the specificity of ATX was 80%. The levels of ATX, LPA and CA19-9 were all substantially higher for early stage PC patients compared to levels in serum from BPD patients and HVs. The diagnostic efficacy of CA19-9 for PC was significantly enhanced by the addition of ATX and LPA (p = 0.0012).

Conclusion: Measurement of LPA and ATX levels together with CA19-9 levels can be used for early detection of PC and diagnosis of PC in general.
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http://dx.doi.org/10.1186/s12876-021-01635-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877052PMC
February 2021

induces epithelial-mesenchymal transition in gastric carcinogenesis via the AKT/GSK3β signaling pathway.

Oncol Lett 2021 Feb 4;21(2):165. Epub 2021 Jan 4.

Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.

() is a main risk factor for gastric cancer (GC). Epithelial-mesenchymal transition (EMT) is involved in the development and progression of -associated GC. However, the exact molecular mechanism of this process remains unclear. The AKT/GSK3β signaling pathway has been demonstrated to promote EMT in several types of cancer. The present study investigated whether infection induced EMT, and promoted the development and metastasis of cancer in the normal gastric mucosa, and whether this process was dependent on AKT activation. The expression levels of the EMT-associated proteins, including E-cadherin and N-cadherin, were determined in 165 gastric mucosal samples of different disease stages by immunohistochemical analysis. The expression levels of E-cadherin, N-cadherin, AKT, phosphorylated (p-)AKT (Ser473), GSK3β and p-GSK3β (Ser9) were further determined in -infected Mongolian gerbil gastric tissues and cells co-cultured with by immunohistochemical analysis and western blotting. The results indicated that the expression levels of the epithelial marker E-cadherin were decreased, whereas the expression levels of the mesenchymal marker N-cadherin were increased during gastric carcinogenesis. Their expression levels were associated with infection. Furthermore, infection resulted in downregulation of E-cadherin expression and upregulation of N-cadherin expression in Mongolian gerbils and GES-1 cells. In addition, an investigation of the associated mechanism of action revealed that p-AKT (Ser473) and p-GSK3β (Ser9) were activated in GES-1 cells following co-culture with . Furthermore, following pretreatment of the cells with the AKT inhibitor VIII, the expression levels of E-cadherin, N-cadherin, p-AKT and p-GSK3β did not show significant differences between GES-1 cells that were co-cultured with or without . The levels of p-AKT and p-GSK3β were increased in -infected Mongolian gerbils. In conclusion, the present study demonstrated that infection activated AKT and resulted in the phosphorylation and inactivation of GSK3β, which in turn promoted early stage EMT. These effects were AKT-dependent. This mechanism may serve as a prerequisite for GC development.
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http://dx.doi.org/10.3892/ol.2021.12426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798028PMC
February 2021

Association of air pollution and greenness with carotid plaque: A prospective cohort study in China.

Environ Pollut 2021 Jan 15;273:116514. Epub 2021 Jan 15.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.

Previous studies indicated that exposure to air pollution was associated with the progress of atherosclerosis, but evidence is very limited in China and even in the world. This study aims to assess the associations of long-term exposures to air pollution and greenness with the occurrence of carotid plaque. Participants of this cohort study were urban residents and office workers who visited Hebei General Hospital for routine physical examination annually from September 2016 through to December 2018. Eligible participants were people diagnosed the absence of carotid plaque clinically at their first hospital visit and were followed up at their second or third hospital visit. Exposure to particulate matter with aerodynamic diameter less than 2.5 μm (PM), nitrogen dioxide (NO) and ozone (O) were estimated using an inverse distance weighted (IDW) method. The level of greenness was assessed using the Normalized Difference Vegetation Index (NDVI) and Enhanced Vegetation Index (EVI). The associations were evaluated using Cox proportional hazards regression models. Among 4,137 participants, 575 showed the occurrence of carotid plaque during the follow-up period. After controlling for potential confounders, the hazard ratios (HRs) and 95% confidence intervals (95%CIs) of carotid plaque associated with per interquartile range (IQR) increase in PM, NO, and O were 1.78 (1.55, 2.03), 1.32 (1.14, 1.53) and 1.99 (1.71, 2.31), respectively. Increased EVI and NDVI were significantly associated with lower risk of carotid plaque [HR (and 95%CI): 0.84 (0.77, 0.93) and 0.87 (0.80, 0.94)]. PM significantly mediated 80.47% or 93.00% of the estimated association between EVI or NDVI and carotid plaque. In light of the significant associations between air pollution, greenness and carotid plaque in this study, continued efforts are needed to curb air pollution and plan more green space considering their effects on vascular disease.
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http://dx.doi.org/10.1016/j.envpol.2021.116514DOI Listing
January 2021

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Mol Psychiatry 2021 Jan 22. Epub 2021 Jan 22.

HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
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http://dx.doi.org/10.1038/s41380-020-01006-9DOI Listing
January 2021

Na , K -ATPase participates in the protective mechanism of rat cerebral ischemia-reperfusion through the interaction with glutamate transporter-1.

Fundam Clin Pharmacol 2021 Jan 22. Epub 2021 Jan 22.

Department of Neurosurgery, Hengshui Fifth People's Hospital, Hebei, China.

Glutamate excitotoxicity in cerebral ischemia/reperfusion is an important cause of neurological damage. The aim of this study was to investigate the mechanism of Na+, K+-ATPase (NKA) involved in l ow concentration of ouabain (Oua, activating NKA)-induced protection of rat cerebral ischemia-reperfusion injury. The 2,3,5-triphenyltetrazolium chloride (TTC) staining and neurological deficit scores (NDS) were performed to evaluate rat cerebral injury degree respectively at 2 h, 6 h, 1 d and 3 d after reperfusion of middle cerebral artery occlusion (MCAO) 2 h in rats. NKA α1/α2 subunits and glutamate transporter-1 (GLT-1) protein expression were investigated by Western blotting. The cerebral infarct volume ratio were evidently decreased in Oua group vs MCAO/R group at 1 d and 3 d after reperfusion of 2 h MCAO in rats (*p < 0.05 ). Moreover, NDS were not significantly different (p > 0.05 ). NKA α1 was decreased at 6 h and 1 d after reperfusion of 2 h MCAO in rats, and was improved in Oua group. However, NKA α1 and α2 were increased at 3 d after reperfusion of 2 h MCAO in rats, and was decreased in Oua group. GLT-1 was decreased at 6 h, 1 d and 3 d after reperfusion of 2 h MCAO in rats, and was improved in Oua group. These data indicated that l ow concentration of Oua could improve MCAO/R injury through probably changing NKA α1/α2 and GLT-1 protein expression, then increasing GLT-1 function and promoting Glu transport and absorption, which could be useful to determine potential therapeutic strategies for patients with stroke. Low concentration of Oua improved rat MCAO/R injury via NKA α1/α2 and GLT-1.
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http://dx.doi.org/10.1111/fcp.12652DOI Listing
January 2021