Publications by authors named "Jiali Wang"

261 Publications

Long noncoding RNA DGCR5 involves in tumorigenesis of esophageal squamous cell carcinoma via SRSF1-mediated alternative splicing of Mcl-1.

Cell Death Dis 2021 Jun 7;12(6):587. Epub 2021 Jun 7.

Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University, 050035, Shijiazhuang, Hebei, China.

Long noncoding RNAs (lncRNAs) emerge as essential roles in the regulation of alternative splicing (AS) in various malignancies. Serine- and arginine-rich splicing factor 1 (SRSF1)-mediated AS events are the most important molecular hallmarks in cancer. Nevertheless, the biological mechanism underlying tumorigenesis of lncRNAs correlated with SRSF1 in esophageal squamous cell carcinoma (ESCC) remains elusive. In this study, we found that lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) was upregulated in ESCC clinical samples, which associated with poor prognosis. Through RNA interference and overexpression approaches, we confirmed that DGCR5 contributed to promote ESCC cell proliferation, migration, and invasion while inhibited apoptosis in vitro. Mechanistically, DGCR5 could directly bind with SRSF1 to increase its stability and thus stimulate alternative splicing events. Furthermore, we clarified that SRSF1 regulated the aberrant splicing of myeloid cell leukemia-1 (Mcl-1) and initiated a significant Mcl-1L (antiapoptotic) isoform switch, which contributed to the expression of the full length of Mcl-1. Moreover, the cell-derived xenograft (CDX) model was validated that DGCR5 could facilitate the tumorigenesis of ESCC in vivo. Collectively, our findings identified that the key biological role of lncRNA DGCR5 in alternative splicing regulation and emphasized DGCR5 as a potential biomarker and therapeutic target for ESCC.
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http://dx.doi.org/10.1038/s41419-021-03858-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184765PMC
June 2021

Successful prenatal therapy of anti-CD36-mediated severe FNAIT by deglycosylated antibodies in a novel murine model.

Blood 2021 May 26. Epub 2021 May 26.

Guangzhou Blood Centre, China.

Recent studies have demonstrated that maternal anti-CD36 antibodies represent a frequent cause of fetal/neonatal alloimmune thrombocytopenia (FNAIT) in Asian and African populations. However, little is known about the pathomechanism and antenatal treatment of anti-CD36-mediated FNAIT. Here, we established a novel animal model to examine the clinical features of pups from immunized Cd36-/- female mice after breeding with wild-type male mice. Mild thrombocytopenia was observed, but high pup mortality was also documented (40.26%). IVIG (1 g/kg) administration on days 7, 12, and 17 to immunized Cd36-/- mothers after breeding reduced fetal death (12.70%). However, delaying the IVIG administration series on days 10, 15, and 20 did not reduce fetal death (40.00%). In contrast, injection of deglycosylated anti-CD36 (deg-anti-CD36) polyclonal antibodies (5 mg/kg) on days 10, 15, and 20 significantly reduced fetal death (5.26%). Subsequently, monoclonal antibodies (mAbs) against mouse CD36 were developed, and one clone producing high-affinity anti-CD36 (termed 32-106) effectively inhibited maternal antibody binding and was therefore selected. Using the same approach of deg-anti-CD36, the administration of deg-32-106 significantly reduced fetal death (2.17%). Furthermore, immunized Cd36-/- mothers showed placenta deficiency. Accordingly, maternal anti-CD36 antibodies inhibited angiogenesis of placenta endothelial cells, which could be restored by deg-32-106. In summary, maternal anti-CD36 antibodies caused a high frequency of fetal death in our animal model, associated with placental dysfunction. This deleterious effect could be diminished by the antenatal administration of IVIG and deg-mAb 32-106. Interestingly, treatment with deg-32-106 appears more beneficial considering the lower dose, later start of treatment, and therapy success.
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http://dx.doi.org/10.1182/blood.2021011131DOI Listing
May 2021

Moderate to Severe Marrow Fibrosis As a More Advanced Risk Factor for MDS and MDS-AML Patients With Excess of Blasts Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 May 18. Epub 2021 May 18.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.

Marrow fibrosis (MF) is usually accompanied with primary myelodysplastic syndromes (MDS) and no consensus has been reached on the relationship between MF and prognosis. We retrospectively analyzed 239 MDS and MDS derived acute myeloid leukemia patients with known grade of MF who received allogeneic stem cell transplantation (allo-HSCT). Of these, it included 121 (50.6%) without fibrosis (MF-0), 81 (33.9%) with mild fibrosis (MF-1), 37 (15.5%) with moderate to severe fibrosis (MF-2/3). MF-2/3 was associated with more pronounced dysmegakaryopoiesis (P =.002), more frequent karyotype abnormality (P = .039) and increased leukemic transformation. Spliceosome and ras pathway mutation occurred more frequently in patients with MF-2/3. After allo-HSCT, neutrophil and platelet engraftment was significantly delayed in patients with MF-2/3 than those with MF-1 and MF-0 (P = .031, P = .05, respectively). The estimated 3-year overall survival (OS) rates and disease-free survival (DFS) rates were significantly lower in patients with MF-2/3 than in those with MF-0 or MF-1 (P = .018, P = .018, respectively). Notably, in the subgroup of patients with more than 10% bone marrow blasts, MF-2/3 was independently associated with shorter OS and DFS (P = .012, P = .012, respectively) and has improved outcomes for these patients who achieved complete remission (CR) before allo-HSCT. Overall, MF-2/3 as an additional risk factor have the inferior prognosis for MDS and MDS-AML patients with bone marrow blasts ≥10%. Using pretransplantation cytoreductive therapy to obtain CR for these patients may benefit from allo-HSCT.
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http://dx.doi.org/10.1016/j.jtct.2021.05.006DOI Listing
May 2021

Biodegradable magnesium pins enhanced the healing of transverse patellar fracture in rabbits.

Bioact Mater 2021 Nov 27;6(11):4176-4185. Epub 2021 Apr 27.

Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China.

Displaced fractures of patella often require open reduction surgery and internal fixation to restore the extensor continuity and articular congruity. Fracture fixation with biodegradable magnesium (Mg) pins enhanced fracture healing. We hypothesized that fixation with Mg pins and their degradation over time would enhance healing of patellar fracture radiologically, mechanically, and histologically. Transverse patellar fracture surgery was performed on thirty-two 18-weeks old female New Zealand White Rabbits. The fracture was fixed with a pin made of stainless steel or pure Mg, and a figure-of-eight stainless steel band wire. Samples were harvested at week 8 or 12, and assessed with microCT, tensile testing, microindentation, and histology. Microarchitectural analysis showed that Mg group showed 12% higher in the ratio of bone volume to tissue volume at week 8, and 38.4% higher of bone volume at week 12. Tensile testing showed that the failure load and stiffness of Mg group were 66.9% and 104% higher than the control group at week 8, respectively. At week 12, Mg group was 60.8% higher in ultimate strength than the control group. Microindentation showed that, compared to the Control group, Mg group showed 49.9% higher Vickers hardness and 31% higher elastic modulus at week 8 and 12, respectively. At week 12, the new bone of Mg group remodelled to laminar bone, but those of the control group remained woven bone-like. Fixation of transverse patellar fracture with Mg pins and its degradation enhanced new bone formation and mechanical properties of the repaired patella compared to the Control group.
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http://dx.doi.org/10.1016/j.bioactmat.2021.03.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099917PMC
November 2021

Expression levels and activation status of Yap splicing isoforms determine self-renewal and differentiation potential of embryonic stem cells.

Stem Cells 2021 May 2. Epub 2021 May 2.

Laboratory of Stem Cell & Developmental Biology, Department of Histology and Embryology, Army Medical University, Chongqing, People's Republic of China.

Yap is the key effector of Hippo signaling; however, its role in embryonic stem cells (ESCs) remains controversial. Here, we identify two Yap splicing isoforms (Yap472 and Yap488), which show equal expression levels but heterogeneous distribution in ESCs. Knockout (KO) of both isoforms reduces ESC self-renewal, accelerates pluripotency exit but arrests terminal differentiation, while overexpression of each isoform leads to the reverse phenotype. The effect of both Yap isoforms on self-renewal is Teads-dependent and mediated by c-Myc. Nonetheless, different isoforms are found to affect overlapping yet distinct genes, and confer different developmental potential to Yap-KO cells, with Yap472 exerting a more pronounced biological effect and being more essential for neuroectoderm differentiation. Constitutive activation of Yaps, particularly Yap472, dramatically upregulates p53 and Cdx2, inducing trophectoderm trans-differentiation even under self-renewal conditions. These findings reveal the combined roles of different Yap splicing isoforms and mechanisms in regulating self-renewal efficiency and differentiation potential of ESCs.
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http://dx.doi.org/10.1002/stem.3389DOI Listing
May 2021

Design, synthesis and antibacterial evaluation of ocotillol derivatives with polycyclic nitrogen-containing groups.

Future Med Chem 2021 Jun 30;13(12):1025-1039. Epub 2021 Apr 30.

School of Pharmacy, Key Laboratory of Molecular Pharmacology & Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System & Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR.

With the increasing abuse of antibacterial drugs, multidrug-resistant bacteria have become a burden on human health and the healthcare system. To find alternative compounds effective against hospital-acquired methicillin-resistant  (HA-MRSA), novel derivatives of ocotillol were synthesized. Ocotillol derivatives with polycyclic nitrogen-containing groups were synthesized and evaluated for antibacterial activity. Compounds exhibited potent antibacterial activity against HA-MRSA, with MIC = 8-64 μg/ml. Additionally, a combination of compound and the commercially available antibiotic kanamycin showed synergistic inhibitory effects, with a fractional inhibitory concentration index of ≤0.375. Compound has a strong inhibitory effect, and this derivative has potential for use as a pharmacological tool to explore antibacterial mechanisms.
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http://dx.doi.org/10.4155/fmc-2020-0364DOI Listing
June 2021

Enhancement of ferroelectricity and homogeneity of orthorhombic phase in HfZrOthin films.

Nanotechnology 2021 May 26;32(33). Epub 2021 May 26.

Guangdong Provincial Key Laboratory of Quantum Engineering and Quantum Materials and Institute for Advanced Materials, South China Academy of Advanced Optoelectronics, South China Normal University, Guangzhou 510006, People's Republic of China.

By adoption of a high permittivity ZrOcapping layer (ZOCL), enhanced ferroelectric properties were achieved in the HfZrO(HZO) thin films. For HZO thin film with 10 Å ZOCL, the 2value can reach as high as ∼43.1C cmunder a sweep electric field of 3 MV cm. In addition, a reduced coercive field of 1.5 MV cmwas observed, which is comparable to that of HZO with metallic CL. Furthermore, the homogeneity of ferroelectric orthorhombic phase in HZO films was observed to be clearly increased, as evidenced by nanoscale piezoelectric force microscopy measurements. These results demonstrate that ZOCL is very favorable for high performance ferroelectric HZO films and their future device applications.
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http://dx.doi.org/10.1088/1361-6528/abfc70DOI Listing
May 2021

Description of a new species of the genus emMaua/em Distant (Hemiptera, Cicadidae) from China.

Zootaxa 2021 Mar 26;4949(3):zootaxa.4949.3.8. Epub 2021 Mar 26.

Key Laboratory of Plant Protection Resources and Pest Management, Ministry of Education, Entomological Museum, Northwest AF University, Yangling, Shaanxi 712100, China..

A new species, Maua squeala sp. nov., is described from China. This species is similar to M. affinis Distant, 1905 and M. palawanensis Duffels, 2009, but can be distinguished by the shorter and more slender body of the new species, the lateral fasciae on the mesonotum and the shape of the male genitalia. The intraspecific variation of this species is discussed based on morphological observation combined with sequences of partial mitochondrial COI gene (DNA barcoding) of individuals exhibiting different morphological characters.
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http://dx.doi.org/10.11646/zootaxa.4949.3.8DOI Listing
March 2021

Chondroblastoma of the patella with secondary aneurysmal bone cyst, an easily misdiagnosed bone tumor:a case report with literature review.

BMC Musculoskelet Disord 2021 Apr 23;22(1):381. Epub 2021 Apr 23.

Ningxia Medical University, 1160 Shengli Street, Xingqing District, Yinchuan, 750004, People's Republic of China.

Background: Chondroblastoma (CB) is a rare, primary, benign bone tumor that commonly affects men aged 15-20 years. It is usually detected in the epiphysis of the long bones, such as the proximal femur, humerus, and tibia. The patella is an infrequent site. CB with secondary aneurysmal bone cyst (ABC) is extremely rare in the patella, which can be easily confused with other common bone tumors of the patella. Thus, it is necessary to make the right diagnosis to get a good outcome.

Case Presentation: We have presented here the case of a 30-year-old man who was suffering from anterior knee pain for the past 6 months that had aggravated 2 weeks before the presentation. Osteolytic bone destruction in the patella could be detected in both his X-ray and computed tomography (CT) examinations, while the magnetic resonance imaging (MRI) detected a fluid level. Accordingly, secondary ABC was presumed. We diagnosed the condition as giant cell tumor (GCT) with secondary ABC and, accordingly, performed curettage inside the focus region with autogenous bone grafting following the patient's medical history, physical manifestations, results of physical and ancillary examinations, and the disease characteristics. However, the intraoperative and postoperative outcomes indicated that the patient's histopathology was consistent with that of typical CB, suggesting a definitive error in diagnosis. Accordingly, the patient was finally diagnosed with patella CB along with secondary ABC.

Conclusions: Past studies have demonstrated that the 3 commonest bone tumors affecting the patella are GCT, CB, and ABC. CB with secondary ABC can be easily misdiagnosed as GCT with secondary ABC or ABC. Performing incision biopsy or excision biopsy and conducting histological examination may be the most effective method for suspected CB with secondary ABC.
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http://dx.doi.org/10.1186/s12891-021-04262-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066474PMC
April 2021

Observing spontaneous, accelerated substrate binding in molecular dynamics simulations of glutamate transporters.

PLoS One 2021 23;16(4):e0250635. Epub 2021 Apr 23.

Department of Chemistry, Binghamton University, Binghamton, New York, United States of America.

Glutamate transporters are essential for removing the neurotransmitter glutamate from the synaptic cleft. Glutamate transport across the membrane is associated with elevator-like structural changes of the transport domain. These structural changes require initial binding of the organic substrate to the transporter. Studying the binding pathway of ligands to their protein binding sites using molecular dynamics (MD) simulations requires micro-second level simulation times. Here, we used three methods to accelerate aspartate binding to the glutamate transporter homologue Gltph and to investigate the binding pathway. 1) Two methods using user-defined forces to prevent the substrate from diffusing too far from the binding site. 2) Conventional MD simulations using very high substrate concentrations in the 0.1 M range. The final, substrate bound states from these methods are comparable to the binding pose observed in crystallographic studies, although they show more flexibility in the side chain carboxylate function. We also captured an intermediate on the binding pathway, where conserved residues D390 and D394 stabilize the aspartate molecule. Finally, we investigated glutamate binding to the mammalian glutamate transporter, excitatory amino acid transporter 1 (EAAT1), for which a crystal structure is known, but not in the glutamate-bound state. Overall, the results obtained in this study reveal new insights into the pathway of substrate binding to glutamate transporters, highlighting intermediates on the binding pathway and flexible conformational states of the side chain, which most likely become locked in once the hairpin loop 2 closes to occlude the substrate.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250635PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064580PMC
April 2021

Urgent Need of Integrated Health and Social Care to Alleviate High Psychological Distress in People with Disabilities: A Cross-Sectional National Representative Survey in Australia.

Risk Manag Healthc Policy 2021 15;14:1541-1550. Epub 2021 Apr 15.

Faculty of Health Science, University of Sydney, Sydney, Australia.

Objective: To investigate factors in association with high psychological distress in people with disabilities.

Methods: We used the 2015 national survey on disability in Australia to derive the representative study population of 7936 people with disabilities aged 18+ years. The Kessler Psychological Distress Scale (K10) was used to define high psychological distress (scores ≥22). The explanatory variables included socioeconomic status, physical health, social relationships and environment factors. Adjusted Odds Ratios (ORs) and 95% Confidence Intervals (CIs) were evaluated using weighted Logistic regression models with lasso techniques.

Results: Approximately 21 in 100 study participants experienced high psychological distress. The risk of high psychological distress decreased with age and high educational attainment. Having non-English speaking background (2.31; 1.87-2.85) and need for assistance in cognitive or emotional tasks (3.25; 2.65-3.98) were independently significantly associated with high psychological distress in people with disabilities. Delay seeing a GP was associated with a 2-fold risk increase.

Conclusion: Integrated healthcare and social support are warranted with appropriate targeting to improve mental health outcomes in people with disabilities.
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http://dx.doi.org/10.2147/RMHP.S291004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055466PMC
April 2021

Systematic optimization of the yeast cell factory for sustainable and high efficiency production of bioactive ginsenoside compound K.

Synth Syst Biotechnol 2021 Jun 31;6(2):69-76. Epub 2021 Mar 31.

CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, 300 Fenglin Rd, Shanghai, 200032, China.

Ginsenoside Compound K (CK) has been recognized as a major functional component that is absorbed into the systemic circulation after oral administration of ginseng. CK demonstrates diverse bioactivities. A phase I clinical study indicated that CK was a potential candidate for arthritis therapy. However, a phase II clinical study was suspended because of the high cost associated with the present CK manufacturing approach, which is based on the traditional planting-extracting-biotransforming process. We previously elucidated the complete CK biosynthetic pathway and realized for the first time biosynthesis of CK from glucose by engineered yeast. However, CK production was not sufficient for industrial application. Here, we systematically engineered to achieve high titer production of CK from glucose using a previously constructed protopanaxadiol (PPD)-producing chassis, optimizing UGTPg1 expression, improving UDP-glucose biosynthesis, and tuning down UDP-glucose consumption. Our final engineered yeast strain produced CK with a titer of 5.74 g/L in fed-batch fermentation, which represents the highest CK production in microbes reported to date. Once scaled-up, this high titer microbial biosynthesis platform will enable a robust and stable supply of CK, thus facilitating study and medical application of CK.
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http://dx.doi.org/10.1016/j.synbio.2021.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040117PMC
June 2021

Protein Corona Formation: Characterizations, Effects on Engineered Nanoparticles' Biobehaviors, and Applications.

Front Bioeng Biotechnol 2021 31;9:646708. Epub 2021 Mar 31.

School of Pharmacy, Nantong University, Nantong, China.

Understanding the basic interactions between engineered nanoparticles (ENPs) and biological systems is essential for evaluating ENPs' safety and developing better nanomedicine. Profound interactions between ENPs and biomolecules such as proteins are inevitable to occur when ENPs are administered or exposed to biological systems, for example, through intravenous injection, oral, or respiration. As a key component of these interactions, protein corona (PC) is immediately formed surrounding the outlayer of ENPs. PC formation is crucial because it gives ENPs a new biological identity by altering not only the physiochemical properties, but also the biobehaviors of ENPs. In the past two decades, most investigations about PC formation were carried out with systems which could not represent the true events occurring within systems. Most recently, studies of PC formation were reported, and it was found that the protein compositions and structures were very different from those formed . Herein, we provide an in-time review of the recent investigations of this PC formation of ENPs. In this review, commonly used characterization methods and compositions of PC are summarized firstly. Next, we highlight the impacts of the PC formation on absorption, blood circulation, biodistribution, metabolism, and toxicity of administered ENPs. We also introduce the applications of modulating PC formation in nanomedicine. We further discuss the challenges and future perspectives.
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http://dx.doi.org/10.3389/fbioe.2021.646708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044820PMC
March 2021

Rhombencephalitis due to infection with GQ1b antibody positivity and multiple intracranial hemorrhage: a case report and literature review.

J Int Med Res 2021 Apr;49(4):300060521998568

Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

is a Gram-positive facultative intracellular bacterium that causes central nervous system infection. We report a case of rhombencephalitis caused by infection, which mimicked Bickerstaff's brainstem encephalitis, and GQ1b antibody positivity and multiple intracranial foci were observed. A 68-year-old male patient presented with a nonspecific prodrome of faintness, forehead tightness, and walking instability. This was followed by progressive cranial nerve palsies, limb weakness, cerebellar signs, hyperpyrexia, and impaired consciousness. Brain imaging showed multiple abnormal brainstem and cerebellar signals that were accompanied by blood infiltration without any lesion enhancement. Serum GQ1b antibody positivity led to an initial diagnosis of Bickerstaff's brainstem encephalitis, which was treated with immunosuppressive therapy with limited efficacy. A pathogen examination helped confirm infection. A combination of meropenem and trimethoprim-sulfamethoxazole therapy was applied and the patient recovered without sequelae. The symptoms and imaging of rhombencephalitis are nonspecific. Accurate diagnosis and prompt treatment of this condition are essential. Whether infection triggers an autoimmune response remains unclear.
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http://dx.doi.org/10.1177/0300060521998568DOI Listing
April 2021

Clinical translation and challenges of biodegradable magnesium-based interference screws in ACL reconstruction.

Bioact Mater 2021 Oct 12;6(10):3231-3243. Epub 2021 Mar 12.

School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, 510006, China.

As one of the most promising fixators developed for anterior cruciate ligament (ACL) reconstruction, biodegradable magnesium (Mg)-based interference screws have gained increasing attention attributed to their appropriate modulus and favorable biological properties during degradation after surgical insertion. However, its fast degradation and insufficient mechanical strength have also been recognized as one of the major causes to limit their further application clinically. This review focused on the following four parts. Firstly, the advantages of Mg or its alloys over their counterparts as orthopaedic implants in the fixation of tendon grafts in ACL reconstruction were discussed. Subsequently, the underlying mechanisms behind the contributions of Mg ions to the tendon-bone healing were introduced. Thirdly, the technical challenges of Mg-based interference screws towards clinical trials were discussed, which was followed by the introduction of currently used modification methods for gaining improved corrosion resistance and mechanical properties. Finally, novel strategies including development of Mg/Titanium (Ti) hybrid fixators and Mg-based screws with innovative structure for achieving clinically customized therapies were proposed. Collectively, the advancements in the basic and translational research on the Mg-based interference screws may lay the foundation for exploring a new era in the treatment of the tendon-bone insertion (TBI) and related disorders.
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http://dx.doi.org/10.1016/j.bioactmat.2021.02.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966853PMC
October 2021

Population pharmacokinetics and individual analysis of daptomycin in kidney transplant recipients.

Eur J Pharm Sci 2021 Jul 24;162:105818. Epub 2021 Mar 24.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address:

Background: Little is known about the population pharmacokinetics (PPK) of daptomycin in kidney transplant patients. The present study established a pharmacokinetic model for daptomycin in kidney transplant patients in China and examinee the important factors affecting the pharmacokinetic parameters of daptomycin.

Methods: The study population included 49 kidney transplant patients with 537 daptomycin concentrations. The PPK model of daptomycin was developed using a nonlinear mixed-effects model, a two-compartment structural model, and a mixed residual error model. The stability and predictive ability of the final model were evaluated based on bootstrapping, visual prediction checks and normalized prediction distribution errors.

Results: Glomerular filtration rate (GFR) and total body weight significantly affected clearance, and body weight influenced the central volume of distribution. The average clearance of the population was 0.316 L/h, the central volume of distribution was 6.04 L, the intercompartmental clearance was 2.31 L/h, and the peripheral volume of distribution was 2.46 L. Based on the established model and the target of area under curve (AUC)/minimum inhibition concentration (MIC) ≥666, we developed a recommended dose regimen for kidney transplant patients according to their renal function and weight. The daily doses were 4.0±0.31, 4.7±0.36, 5.1±0.40, 5.5±0.43, 5.8±0.45, and 6.1±0.48 mg/kg when the GFRs were 15, 30, 45, 60, 75, and 90 ml/min/1.73 m, respectively.

Conclusion: This study provides a reference for individualized daptomycin administration in kidney transplant recipients, and it is a valuable resource for improving the treatment effect and reducing the toxic effects of daptomycin.
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http://dx.doi.org/10.1016/j.ejps.2021.105818DOI Listing
July 2021

Analysis of survey on menstrual disorder among teenagers using Gaussian copula model with graphical lasso prior.

PLoS One 2021 18;16(3):e0248340. Epub 2021 Mar 18.

Research School of Finance, Actuarial Studies and Statistics, College of Business and Economics, The Australian National University, Canberra, ACT, Australia.

A high prevalence of menstrual disturbance has been reported among teenage girls, and research shows that there are delays in diagnosis of endometriosis among young girls. Using data from the Menstrual Disorder of Teenagers Survey (administered in 2005 and 2016), we propose a Gaussian copula model with graphical lasso prior to identify cohort differences in menstrual characteristics and to predict endometriosis. The model includes random effects to account for clustering by school, and we use the extended rank likelihood copula model to handle variables of mixed-type. The graphical lasso prior shrinks the elements in the precision matrix of a Gaussian distribution to encourage a sparse graphical structure, where the level of shrinkage is adaptable based on the strength of the conditional associations among questions in the survey. Applying our proposed model to the menstrual disorder data set, we found that menstrual disturbance was more pronouncedly reported over a decade, and we found some empirical differences between those girls with higher risk of developing endometriosis and the general population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248340PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971494PMC
March 2021

Characteristics of Gln368Ter Myocilin Variant and Influence of Polygenic Risk on Glaucoma Penetrance in the UK Biobank.

Ophthalmology 2021 Mar 10. Epub 2021 Mar 10.

Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; Ocular Genomics Institute, Harvard Medical School, Boston, Massachusetts.

Purpose: MYOC (myocilin) mutations account for 3% to 5% of primary open-angle glaucoma (POAG) cases. We aimed to understand the true population-wide penetrance and characteristics of glaucoma among individuals with the most common MYOC variant (p.Gln368Ter) and the impact of a POAG polygenic risk score (PRS) in this population.

Design: Cross-sectional population-based study.

Participants: Individuals with the p.Gln368Ter variant among 77 959 UK Biobank participants with fundus photographs (FPs).

Methods: A genome-wide POAG PRS was computed, and 2 masked graders reviewed FPs for disc-defined glaucoma (DDG).

Main Outcome Measures: Penetrance of glaucoma.

Results: Two hundred individuals carried the p.Gln368Ter heterozygous genotype, and 177 had gradable FPs. One hundred thirty-two showed no evidence of glaucoma, 45 (25.4%) had probable/definite glaucoma in at least 1 eye, and 19 (10.7%) had bilateral glaucoma. No differences were found in age, race/ethnicity, or gender among groups (P > 0.05). Of those with DDG, 31% self-reported or had International Classification of Diseases codes for glaucoma, whereas 69% were undiagnosed. Those with DDG had higher medication-adjusted cornea-corrected intraocular pressure (IOPcc) (P < 0.001) vs. those without glaucoma. This difference in IOPcc was larger in those with DDG with a prior glaucoma diagnosis versus those not diagnosed (P < 0.001). Most p.Gln368Ter carriers showed IOP in the normal range (≤21 mmHg), although this proportion was lower in those with DDG (P < 0.02) and those with prior glaucoma diagnosis (P < 0.03). Prevalence of DDG increased with each decile of POAG PRS. Individuals with DDG demonstrated significantly higher PRS compared with those without glaucoma (0.37 ± 0.97 vs. 0.01 ± 0.90; P = 0.03). Of those with DDG, individuals with a prior diagnosis of glaucoma had higher PRS compared with undiagnosed individuals (1.31 ± 0.64 vs. 0.00 ± 0.81; P < 0.001) and 27.5 times (95% confidence interval, 2.5-306.6) adjusted odds of being in the top decile of PRS for POAG.

Conclusions: One in 4 individuals with the MYOC p.Gln368Ter mutation demonstrated evidence of glaucoma, a substantially higher penetrance than previously estimated, with 69% of cases undetected. A large portion of p.Gln368Ter carriers, including those with DDG, have IOP in the normal range, despite similar age. Polygenic risk score increases disease penetrance and severity, supporting the usefulness of PRS in risk stratification among MYOC p.Gln368Ter carriers.
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http://dx.doi.org/10.1016/j.ophtha.2021.03.007DOI Listing
March 2021

Plasma metabolites, especially lipid metabolites, are altered in pregnant women with gestational diabetes mellitus.

Clin Chim Acta 2021 Jun 9;517:139-148. Epub 2021 Mar 9.

Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of China. Electronic address:

Background And Aims: Gestational diabetes mellitus (GDM) is a pathological condition of glucose intolerance associated with adverse pregnancy outcomes and increased risk of developing maternal type 2 diabetes later in life. Metabolomics is finding increasing use in the study of GDM. To date, GDM-specific metabolomic changes have not been completely elucidated.

Materials And Methods: In this pilot study, metabolomics fingerprinting data, obtained by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS), of 54 healthy pregnant women and 49 patients with GDM at the second and third gestational trimesters were analyzed. Multilevel statistical methods were used to process complex metabolomic data from the retrospective cohorts.

Results: Using univariate analysis (p < 0.05), 41 metabolites were identified as having the most significant differences between these two groups. Lipid metabolites, particularly glycerophospholipids, were the most prevalent class of altered compounds. In addition, metabolites with previously unknown connection to GDM - such as monoacylglycerol, dihydrobiopterin, and 13S-hydroxyoctadecadienoic acid - were identified with strong discriminative power. The main metabolic pathways affected by GDM included glycerophospholipid metabolism, linoleic acid metabolism, and D-arginine and D-ornithine metabolism.

Conclusion: Our data provide a comprehensive overview of metabolite changes at different stages of pregnancy, which offers further insights into the pathogenesis of GDM.
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http://dx.doi.org/10.1016/j.cca.2021.02.023DOI Listing
June 2021

Early-onset of type 2 diabetes mellitus is a risk factor for diabetic nephropathy progression: a biopsy-based study.

Aging (Albany NY) 2021 03 3;13(6):8146-8154. Epub 2021 Mar 3.

Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.

Several studies show that patients with early-onset diabetes have higher risk of diabetic complications than those diagnosed in middle age. However, whether early-onset of type 2 diabetes mellitus (T2DM) is a risk factor for diabetic nephropathy (DN) progression remains unclear, especially a lack of data in biopsy-confirmed cohort. In This study, we enrolled 257 patients with T2DM and biopsy-confirmed DN to investigate the role of early-onset T2DM in DN progression. Participants were divided into two groups according to the age of T2DM diagnosis: early-onset group (less than 40 years) and later-onset group (40 years or older). We found that patients with early-onset T2DM had higher glomerular grades and arteriolar hyalinosis scores than those in later-onset group. After adjusted for confounding factors, early-onset of T2DM remained an independent predictor of end-stage renal disease (ESRD) for patients with DN. In conclusion, although with the comparable renal function and proteinuria, patients with early-onset T2DM and DN had worse renal pathological changes than those with later-onset. Early-onset of T2DM might be an important predictor of ESRD for patients with DN, which called more attention to early supervision and prevention for patients with early-onset T2DM and DN.
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http://dx.doi.org/10.18632/aging.202624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034912PMC
March 2021

Association between atherosclerotic cardiovascular diseases risk and renal outcome in patients with type 2 diabetes mellitus.

Ren Fail 2021 Dec;43(1):477-487

Division of Nephrology, West China Hospital of Sichuan University, Chengdu, China.

Aims: Chronic kidney disease (CKD) and diabetes mellitus increase atherosclerotic cardiovascular diseases (ASCVD) risk. However, the association between renal outcome of diabetic kidney disease (DKD) and ASCVD risk is unclear.

Methods: This retrospective study enrolled 218 type 2 diabetic patients with biopsy-proven DKD, and without known cardiovascular diseases. Baseline characteristics were obtained and the 10-year ASCVD risk score was calculated using the Pooled Cohort Equation (PCE). Renal outcome was defined as progression to end-stage renal disease (ESRD). The association between ASCVD risk and renal function and outcome was analyzed with logistic regression and Cox analysis.

Results: Among all patients, the median 10-year ASCVD risk score was 14.1%. The median of ASCVD risk score in CKD stage 1, 2, 3, and 4 was 10.9%, 12.3%, 16.5%, and 14.8%, respectively ( = 0.268). Compared with patients with lower ASCVD risk (<14.1%), those with higher ASCVD risk had lower eGFR, higher systolic blood pressure, and more severe renal interstitial inflammation. High ASCVD risk (>14.1%) was an independent indicator of renal dysfunction in multivariable-adjusted logistic analysis (OR, 3.997; 95%CI, 1.385-11.530;  = 0.010), though failed to be an independent risk factor for ESRD in patients with DKD in univariate and multivariate Cox analysis.

Conclusions: DKD patients even in CKD stage 1 had comparable ASCVD risk score to patients in CKD stage 2, 3, and 4. Higher ASCVD risk indicated severe renal insufficiency, while no prognostic value of ASVCD risk for renal outcome was observed, which implied macroangiopathy and microangiopathy in patients with DKD were related, but relatively independent.
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http://dx.doi.org/10.1080/0886022X.2021.1893186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946063PMC
December 2021

Linking the Dynamic Chemical State of Catalysts with the Product Profile of Electrocatalytic CO Reduction.

Angew Chem Int Ed Engl 2021 Mar 7. Epub 2021 Mar 7.

Department of Chemistry, National (Taiwan) University, Taipei, 10617, Taiwan.

The promoted activity and enhanced selectivity of electrocatalysts is commonly ascribed to specific structural features such as surface facets, morphology, and atomic defects. However, unraveling the factors that really govern the direct electrochemical reduction of CO (CO RR) is still very challenging since the surface state of electrocatalysts is dynamic and difficult to predict under working conditions. Moreover, theoretical predictions from the viewpoint of thermodynamics alone often fail to specify the actual configuration of a catalyst for the dynamic CO RR process. Herein, we re-survey recent studies with the emphasis on revealing the dynamic chemical state of Cu sites under CO RR conditions extracted by in situ/operando characterizations, and further validate a critical link between the chemical state of Cu and the product profile of CO RR. This point of view provides a generalizable concept of dynamic chemical-state-driven CO RR selectivity that offers an inspiration in both fundamental understanding and efficient electrocatalysts design.
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http://dx.doi.org/10.1002/anie.202017181DOI Listing
March 2021

Knockdown of sorcin increases HEI-OC1 cell damage induced by cisplatin in vitro.

Arch Biochem Biophys 2021 04 3;701:108752. Epub 2021 Mar 3.

ENT Institute and Otorhinolaryngology Department, Affiliated Eye and ENT Hospital, Fudan University and Key Laboratory of Hearing Medicine of National Health and Family Planning Commission (NHFPC), Shanghai, 200031, China. Electronic address:

Hearing loss caused by ototoxic drugs is a kind of acquired hearing loss. Cisplatin is one of the most commonly used drugs and its main action sites are hair cells (HCs). Sorcin is a drug-resistant calcium-binding protein belonging to the small penta-EF-hand protein family. Sorcin is highly expressed in many tissues, including bone, heart, brain, lung, and skin tissues. Single-cell RNA sequencing showed that sorcin was expressed in the outer HCs of mice, but its role remained unknown. We also found that sorcin was highly expressed in the cytoplasm of cochlear HCs and HEI-OC1 cells. After cisplatin injury, the expression of sorcin in HCs and HEI-OC1 cells decreased significantly. SiRNA transfection technology was used to knock down the expression of sorcin. The results showed that the number of apoptotic cells, the expression of cleaved caspased-3, and the expression of Bax increased while the anti-apoptotic factor Bcl-2 decreased in the siRNA-Sorcin + CIS group. The observed increase in apoptosis was related to the increase of reactive oxygen species (ROS) and the destruction of the mitochondrial membrane potential (MMP). Finally, we found that the downregulated sorcin worked by activating the P-ERK1/2 signaling pathway. Overall, this study showed that sorcin can be used as a new target to prevent the ototoxicity of platinum drugs.
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http://dx.doi.org/10.1016/j.abb.2021.108752DOI Listing
April 2021

Comparisons between self-reported and interview-verified psychotic-like experiences in adolescents.

Early Interv Psychiatry 2021 Feb 16. Epub 2021 Feb 16.

Department of Social Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China.

Aim: The 15-item positive subscale of the Community Assessment of Psychic Experiences (CAPE-P15) has been widely used for measuring self-reported psychotic-like experiences (PLEs). However, its validity has not been well established. This study aimed to explore the consistency of self-reported PLEs (PLEs-S) and interview-verified PLEs (PLEs-I) based on the same items of the CAPE-P15.

Methods: A total of 1255 college students completed the CAPE-P15 for measuring lifetime and current PLEs. Half of the students with high-risk scores and 5% of the rest were interviewed through telephone. Telephone interviews were based on the items of the CAPE-P15 using the symptom criteria for attenuated positive symptom syndrome.

Results: When considering the presence of PLEs only, all κ values and correspondence rates (CRs) fell below the thresholds. However, there was adequate consistency for lifetime PLEs when associated distress was also considered in self-report (κ = .432, CR = 90.0%). Among three factors, only bizarre experiences (BEs) showed adequate diagnostic accuracy in detecting lifetime PLEs when combined with distress. Cut-off points of 1.30 (sensitivity of 89.2% and specificity of 92.3%) and 1.57 (sensitivity of 79.2% and specificity of 73.8%) for frequency scores were found to best identify genuine PLEs during lifetime and in the past month, respectively.

Conclusions: Although the validity of the CAPE-P15 for genuine PLEs is unsatisfactory, the scale showed much better diagnostic accuracy when combined with associated distress, especially for detecting lifetime PLEs. Self-report items on BEs may be more sensitive and specific when identifying PLEs in late adolescence.
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http://dx.doi.org/10.1111/eip.13132DOI Listing
February 2021

U0126 pretreatment inhibits cisplatin-induced apoptosis and autophagy in HEI-OC1 cells and cochlear hair cells.

Toxicol Appl Pharmacol 2021 03 9;415:115447. Epub 2021 Feb 9.

ENT Institute and Otorhinolaryngology Department, Affiliated Eye and ENT Hospital, Fudan University and Key Laboratory of Hearing Medicine of National Health and Family Planning Commission (NHFPC), Shanghai 200031, China. Electronic address:

Deafness is the most common sensory disorder in the world. Ototoxic drugs are common inducing factors of sensorineural hearing loss, and cochlear hair cell (HC) damage is the main concern of the present studies. Cisplatin is a widely used, highly effective antitumor drug, but some patients have experienced irreversible hearing loss as a result of its application. This hearing loss is closely related to HC apoptosis and autophagy. U0126 is a specific inhibitor of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signaling pathway and has neuroprotective effects. For example, the neuroprotective effect of U0126 on ischemic stroke has been widely recognized. In neural cells, U0126 can prevent death due to excess glutamate, dopamine, or zinc ions. However, no studies of U0126 and ototoxic drug-induced injury have been reported to date. In the present study, we found that U0126 pretreatment significantly reduced the apoptosis and autophagy of HCs in auditory House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear HCs. In addition, U0126 reduced the cisplatin-induced production of reactive oxygen species as well as the cisplatin-induced decrease in the mitochondrial membrane potential. These findings suggest that U0126 may be a potential therapeutic candidate for the prevention of cisplatin-induced ototoxicity.
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http://dx.doi.org/10.1016/j.taap.2021.115447DOI Listing
March 2021

Hsa_circ_0043278 Inhibits Tumorigenesis and is Downregulated in Colorectal Cancer.

Cancer Manag Res 2021 3;13:965-975. Epub 2021 Feb 3.

Department of Oncology and Hematology, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, People's Republic of China.

Purpose: Circular RNAs are novel endogenous RNAs, which are considered to play a role in tumorigenesis. Nevertheless, the role as well as clinical diagnostic value of most circular RNAs in colorectal cancer are still unclear.

Materials And Methods: We investigated the circular RNA microarray containing expression profiles in samples of colorectal cancer patients by bioinformatics. The consequence indicated that hsa_circ_0043278 was strongly downregulated. We then measured the expression level of hsa_circ_0043278 in tissue samples of colorectal cancer by quantitative real-time polymerase chain reaction. Besides, we also explored the expression condition of the circular RNA in colorectal cancer cell lines including HCT116, SW620, and SW480. Cell counting kit-8, colony formation, and transwell assays, as well as flow cytometry, were applied to detect changes in cell proliferation, migration, apoptosis, and cell cycle progression.

Results: We discovered that circular RNA hsa_circ_0043278 was significantly downregulated in tumor samples ( < 0.0001) as well as cell lines ( < 0.05). The value of the area under the receiver operating characteristic curve was 0.71, with a sensitivity of 0.72 and specificity of 0.70 ( = 0.0006). Moreover, we found that overexpression of hsa_circ_0043278 suppressed proliferation and migratory abilities while promoting apoptosis in colorectal cancer cells.

Conclusion: Our findings revealed that hsa_circ_0043278 inhibited the tumorigenesis of colorectal cancer and could be a potential biomarker for colorectal cancer diagnosis. Besides, it hopes to become a target for treatment.
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http://dx.doi.org/10.2147/CMAR.S289775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868253PMC
February 2021

Pre-Steady-State Kinetics and Reverse Transport in Rat Glutamate Transporter EAAC1 with an Immobilized Transport Domain.

Neurochem Res 2021 Feb 6. Epub 2021 Feb 6.

Department of Chemistry, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY, 13902, USA.

Plasma membrane glutamate transporters move glutamate across the cell membrane in a process that is thought to involve elevator-like movement of the transport domain relative to the static trimerization domain. Conformational changes associated with this elevator-like movement have been blocked by covalent crosslinking of cysteine pairs inserted strategically in several positions in the transporter structure, resulting in inhibition of steady-state transport activity. However, it is not known how these crosslinking restraints affect other partial reactions of the transporter that were identified based on pre-steady-state kinetic analysis. Here, we re-examine two different introduced cysteine pairs in the rat glutamate transporter EAAC1 recombinantely expressed in HEK293 cells, W440C/K268C and K64C/V419C, with respect to the molecular mechanism of their impairment of transporter function. Pre-steady-state kinetic studies of glutamate-induced partial reactions were performed using laser photolysis of caged glutamate to achieve sub-millisecond time resolution. Crosslinking of both cysteine pairs abolished steady-state transport current, as well as the majority of pre-steady-state glutamate-induced charge movements, in both forward and reverse transport mode, suggesting that it is not only the elevator-like movement associated with translocation, but also other transporter partial reactions that are inhibited. In contrast, sodium binding to the empty transporter, and glutamate-induced anion conductance were still intact after the W440C/K268C crosslink. Our results add to the previous mechanistic view of how covalent restraints of the transporter affect function and structural changes linked to individual steps in the transport cycle.
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http://dx.doi.org/10.1007/s11064-021-03247-8DOI Listing
February 2021

In Situ Identifying the Dynamic Structure behind Activity of Atomically Dispersed Platinum Catalyst toward Hydrogen Evolution Reaction.

Small 2021 Apr 3;17(16):e2005713. Epub 2021 Feb 3.

Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan.

Single-atom catalysts (SAs) with the maximum atom utilization and breakthrough activities toward hydrogen evolution reaction (HER) have attracted considerable research interests. Uncovering the nature of single-atom metal centers under operating electrochemical condition is highly significant for improving their catalytic performance, yet is poorly understood in most studies. Herein, Pt single atoms anchoring on the nitrogen-carbon substrate (Pt /N-C) as a model system are utilized to investigate the dynamic structure of Pt single-atom centers during the HER process. Via in situ/operando synchrotron X-ray absorption spectroscopy and X-ray photoelectron spectroscopy, an intriguing structural reconstruction at atomic level is identified in the Pt /N-C when it is subjected to the repetitive linear sweep voltammetry and cyclic voltammetry scanning. It demonstrates that the PtN bonding tends to be weakened under cathodic potentials, which induces some Pt single atoms to dynamically aggregate into forming small clusters during the HER reaction. More importantly, experimental evidence and/or indicator is offered to correlate the observed Tafel slope with the dynamic structure of Pt catalysts. This work provides an evident understanding of SAs under electrocatalytic process and offers informative insights into constructing efficient catalysts at atomic level for electrochemical water-splitting system.
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http://dx.doi.org/10.1002/smll.202005713DOI Listing
April 2021

COVID-19-related medical research: a meta-research and critical appraisal.

BMC Med Res Methodol 2021 01 4;21(1). Epub 2021 Jan 4.

Paris Translational Research Epidemiology and Biostatistics Department, Hôpital Necker, 149 rue de Sèvres, 75015, Paris, France.

Background: Since the start of the COVID-19 outbreak, a large number of COVID-19-related papers have been published. However, concerns about the risk of expedited science have been raised. We aimed at reviewing and categorizing COVID-19-related medical research and to critically appraise peer-reviewed original articles.

Methods: The data sources were Pubmed, Cochrane COVID-19 register study, arXiv, medRxiv and bioRxiv, from 01/11/2019 to 01/05/2020. Peer-reviewed and preprints publications related to COVID-19 were included, written in English or Chinese. No limitations were placed on study design. Reviewers screened and categorized studies according to i) publication type, ii) country of publication, and iii) topics covered. Original articles were critically appraised using validated quality assessment tools.

Results: Among the 11,452 publications identified, 10,516 met the inclusion criteria, among which 7468 (71.0%) were peer-reviewed articles. Among these, 4190 publications (56.1%) did not include any data or analytics (comprising expert opinion pieces). Overall, the most represented topics were infectious disease (n = 2326, 22.1%), epidemiology (n = 1802, 17.1%), and global health (n = 1602, 15.2%). The top five publishing countries were China (25.8%), United States (22.3%), United Kingdom (8.8%), Italy (8.1%) and India (3.4%). The dynamic of publication showed that the exponential growth of COVID-19 peer-reviewed articles was mainly driven by publications without original data (mean 261.5 articles ± 51.1 per week) as compared with original articles (mean of 69.3 ± 22.3 articles per week). Original articles including patient data accounted for 713 (9.5%) of peer-reviewed studies. A total of 576 original articles (80.8%) showed intermediate to high risk of bias. Last, except for simulation studies that mainly used large-scale open data, the median number of patients enrolled was of 102 (IQR = 37-337).

Conclusions: Since the beginning of the COVID-19 pandemic, the majority of research is composed by publications without original data. Peer-reviewed original articles with data showed a high risk of bias and included a limited number of patients. Together, these findings underscore the urgent need to strike a balance between the velocity and quality of research, and to cautiously consider medical information and clinical applicability in a pressing, pandemic context. SYSTEMATIC REVIEW REGISTRATION: https://osf.io/5zjyx/.
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http://dx.doi.org/10.1186/s12874-020-01190-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780085PMC
January 2021

Identification of novel Taz isoforms and functional comparison in pluripotency maintenance of mouse embryonic stem cells.

Gene 2021 Mar 29;773:145383. Epub 2020 Dec 29.

Laboratory of Stem Cell & Developmental Biology, Department of Histology and Embryology, Army Medical University, Chongqing 400038, China. Electronic address:

Alternative splicing (AS) is a key process to expand the diversity of mRNA and protein from the genome and it is crucial for fate determination of embryonic stem cells (ESCs) by encoding isoforms with different functions to regulate the balance between pluripotency maintenance and differentiation. Since the role of the Hippo pathway in ESCs is controversial, there may be novel isoforms of Taz, a key effector of the Hippo pathway, previously unknown to us. Here, we identified three variants of Taz in mESCs. Apart from the canonical Taz1185, there were also two novel variants, Taz402 and Taz1086. We found their structure and subcellular localization to be different, while they could all interact with TEAD2 with similar binding affinities and activate transcription. Under the LIF condition, overexpression of them all induced apoptosis and differentiation of mESCs, among which the phenotype of Taz1086 was the most dramatic. Taken together, we discovered novel variants of Taz and compared their structure and functional differences in mESC pluripotency maintenance. These findings will help us to understand the Taz gene and clarify its role in mESC.
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http://dx.doi.org/10.1016/j.gene.2020.145383DOI Listing
March 2021