Publications by authors named "Yang Gao"

1,887 Publications

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Merging C-H Activation and Strain-Release in Ruthenium-Catalyzed Isoindolinone Synthesis.

Org Lett 2021 Aug 4. Epub 2021 Aug 4.

School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, China.

The merger of strain-release of 1,2-oxazetidines with carboxylic acid directed C-H activation in catalytic synthesis of isoindolinones is reported for the first time. This reaction opens a new and sustainable avenue to prepare a range of structurally diverse isoindolinone skeletons from readily available benzoic acids. The success of late-stage functionalization of some bioactive acids, and concise synthesis of biologically important skeletons demonstrated its great synthetic potential in drug discovery. Mechanistic studies indicated a plausible C-H activation/β-carbon elimination/intramolecular cyclization cascade pathway.
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http://dx.doi.org/10.1021/acs.orglett.1c02131DOI Listing
August 2021

A sex-linked SNP mutation in amhr2 is responsible for male differentiation in obscure puffer (Takifugu obscurus).

Mol Biol Rep 2021 Aug 3. Epub 2021 Aug 3.

Department of Marine Biology, College of Oceanography, Hohai University, Nanjing, 210098, China.

Background: Anti-Mullerian hormone receptor type II (Amhr2) is a key receptor of Amh signaling in regulating gonad development. The amhr2 gene has been identified in numerous species, including a few teleost fishes. However, the roles of Amhr2 in Amh signaling in fish are poorly studied.

Methods And Results: In this study, an amhr2 homolog from obscure puffer (Takifugu obscurus) was identified, and its molecular characteristics were systematically analyzed. Expression analysis revealed that amhr2 was highly expressed in the gonads of adult pufferfish and significantly upregulated during sex differentiation. Significantly, a sex-linked SNP site was verified in obscure puffer amhr2. Females exhibited a homozygous genotype (C/C), while males possessed a heterozygous genotype (C/G), resulting in an amino acid variation (His/Asp384) in the kinase domain of Amhr2. Then, the functions of the different Amhr2 genotypes were further investigated. The male genotype protein (Amhr2) showed an enhanced ability to interact with the type I receptor (Bmpr1a) compared to the female genotype (Amhr2). The phosphorylation levels of Smads and activity of the target gene (id3) induced by the male genotype were also much higher than those induced by the female genotype. These results confirmed that the male genotype had an enhanced effect on the Amh signaling pathway compared with the female genotype.

Conclusions: This study provides direct experimental evidence for the roles of different Amhr2 genotypes in pufferfish and suggests that amhr2 is responsible for male sex differentiation in obscure puffer.
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http://dx.doi.org/10.1007/s11033-021-06606-4DOI Listing
August 2021

A three-component reaction of arynes, sodium sulfinates, and aldehydes toward 2-sulfonyl benzyl alcohol derivatives.

Org Biomol Chem 2021 Aug 3. Epub 2021 Aug 3.

School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China.

A novel three-component reaction of arynes, sodium sulfinates, and aldehydes under mild reaction conditions is described. This transformation provides a direct synthetic approach to 2-sulfonyl benzyl alcohol derivatives, which could be rapidly converted to diverse arylsulfur compounds via the transformation of the corresponding hydroxyl groups. Various aryne precursors, sodium arenesulfinates, and aromatic aldehydes can be effectively converted to the desired products in 40-84% yields (29 examples).
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http://dx.doi.org/10.1039/d1ob01229kDOI Listing
August 2021

MSC-Derived Exosomes can Enhance the Angiogenesis of Human Brain MECs and Show Therapeutic Potential in a Mouse Model of Parkinson's Disease.

Aging Dis 2021 Aug 1;12(5):1211-1222. Epub 2021 Aug 1.

1Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering of Chinese Academy of Medical Sciences, Beijing Key Laboratory, Beijing, China.

Parkinson's disease (PD) is the second most widespread neurodegenerative disorder in the world. It has been reported that exosomes derived from mesenchymal stem cells (MSCs) can contribute to the recovery of PD. However, the underlying mechanism remains poorly defined. In this study, proteomics and time-series analysis showed that exosomes derived from MSCs can keep human brain microvascular endothelial cells (HBMECs) in a transcriptionally active state, which may be beneficial for angiogenesis. Next, we found that MSC-derived exosomes can promote the angiogenesis of HBMECs by increasing the expression of ICAM1, and alleviate the damage caused by 1-methyl-4-phenylpyridinium (MPP+) in these cells. Accordingly, when ICAM1 was knocked down, the tube formation ability of HBMECs was obviously decreased. In addition, ICAM1 was found to promote the angiogenesis of HBMECs by activating the SMAD3 and P38MAPK signaling pathways. In a PD mouse model, MSC-derived exosomes were found to contribute to the recovery of PD by promoting ICAM1-related angiogenesis. These findings demonstrate that the exosome-ICAM1-SMAD3/P38MAPK axis can promote the angiogenesis of HBMECs, with possible therapeutic potential for PD.
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http://dx.doi.org/10.14336/AD.2020.1221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279521PMC
August 2021

p53 Inhibition Provides a Pivotal Protective Effect against Cerebral Ischemia-Reperfusion Injury via the Wnt Signaling Pathway.

Cerebrovasc Dis 2021 Aug 2:1-9. Epub 2021 Aug 2.

Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, China.

Introduction: Cerebral ischemia-reperfusion injury enhances brain injury and increases its morbidity and mortality. The purpose of our study was to further explore the specific pathogenesis of cerebral ischemia disease by studying the role of p53 in cerebral ischemia-reperfusion injury and its mechanism to provide a new target for the treatment of cerebral ischemia.

Methods: Middle cerebral artery occlusion (MCAo) was established in rats. The changes in p53 and apoptotic proteins in the rat model were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. The effects of p53 inhibitors on cerebral is-chemia-reperfusion injury in rats were evaluated by modified neurological severity score (mNSS) and infarct area. Subsequently, neural stem cells (NSCs) were isolated and cultured in vitro, and oxygen and glucose deprivation (OGD) was induced to establish an in vitro ischemia-reperfusion injury model. Cell viability and migration were detected by CCK-8 and transwell assays. Apoptosis of NSCs was detected by flow cytometry. Finally, protein expression in the Wnt pathway activated by p53 was detected by Western blotting.

Results: Compared with the sham group, p53 levels, mNSS, cerebral infarction area, and apoptosis were significantly increased in the MCAo group (p < 0.05). When the p53 inhibitor PFT-α was injected, the increase in these levels was reversed. Also, the viability and migration of cells decreased and apo-ptosis increased in the in vitro OGD model, whereas the viability, migration, and apoptosis were significantly reversed after the addition of p53 inhibitors (p < 0.05). Finally, p53 induced Wnt signaling pathway proteins β-catenin and cyclin D1 decrease in the MCAo group, while p53 inhibitors reversed their inhibitory effect on the Wnt signaling pathway.

Conclusion: We confirmed in vivo and in vitro that inhibition of p53 has a protective effect on the cerebral ischemia-reperfusion injury, which may be related to the activation of the Wnt signaling pathway.
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http://dx.doi.org/10.1159/000516889DOI Listing
August 2021

Acupotomy Contributes to Suppressing Subchondral Bone Resorption in KOA Rabbits by Regulating the OPG/RANKL Signaling Pathway.

Evid Based Complement Alternat Med 2021 26;2021:8168657. Epub 2021 Apr 26.

School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 100029, China.

Subchondral bone lesions, as the crucial inducement for accelerating cartilage degeneration, have been considered as the initiating factor and the potential therapeutic target of knee osteoarthritis (KOA). Acupotomy, the biomechanical therapy guided by traditional Chinese meridians theory, alleviates cartilage deterioration by correcting abnormal mechanics. Whether this mechanical effect of acupotomy inhibits KOA subchondral bone lesions is indistinct. This study aimed to investigate the effects of acupotomy on inhibiting subchondral bone resorption and to define the possible mechanism in immobilization-induced KOA rabbits. After KOA modeling, 8 groups of rabbits (4w/6w acupotomy, 4w/6w electroacupuncture, 4w/6w model, and 4w/6w control groups) received the indicated intervention for 3 weeks. Histological and bone histomorphometry analyses revealed that acupotomy prevented both cartilage surface erosion and subchondral bone loss. Further, acupotomy suppressed osteoclast activity and enhanced osteoblast activity in KOA subchondral bone, showing a significantly decreased expression of tartrate-resistant acid phosphatase (TRAP), matrix metalloproteinases-9 (MMP-9), and cathepsin K (Ctsk) and a significantly increased expression of osteocalcin (OCN); this regulation may be mediated by blocking the decrease in osteoprotegerin (OPG) and the increase in NF- receptor activated protein ligand (RANKL). These findings indicated that acupotomy inhibited osteoclast activity and promoted osteoblast activity to ameliorate hyperactive subchondral bone resorption and cartilage degeneration in immobilization-induced KOA rabbits, which may be mediated by the OPG/RANKL signaling pathway. Taken together, our results indicate that acupotomy may have therapeutic potential in KOA by restoring the balance between bone formation and bone resorption to attenuate subchondral bone lesions.
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http://dx.doi.org/10.1155/2021/8168657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298142PMC
April 2021

Patient-Derived Xenograft Models for Intrahepatic Cholangiocarcinoma and Their Application in Guiding Personalized Medicine.

Front Oncol 2021 13;11:704042. Epub 2021 Jul 13.

Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.

Background: Intrahepatic cholangiocarcinoma (ICC) remains one of the most intractable malignancies. The development of effective drug treatments for ICC is seriously hampered by the lack of reliable tumor models. At present, patient derived xenograft (PDX) models prove to accurately reflect the genetic and biological diversity required to decipher tumor biology and therapeutic vulnerabilities. This study was designed to investigate the establishment and potential application of PDX models for guiding personalized medicine and identifying potential biomarker for lenvatinib resistance.

Methods: We generated PDX models from 89 patients with ICC and compared the morphological and molecular similarities of parental tumors and passaged PDXs. The clinicopathologic features affecting PDX engraftment and the prognostic significance of PDX engraftment were analyzed. Drug treatment responses were analyzed in IMF-138, IMF-114 PDX models and corresponding patients. Finally, lenvatinib treatment response was examined in PDX models and potential drug resistance mechanism was revealed.

Results: Forty-nine PDX models were established (take rate: 55.1%). Successful PDX engraftment was associated with negative HbsAg (P = 0.031), presence of mVI (P = 0.001), poorer tumor differentiation (P = 0.023), multiple tumor number (P = 0.003), presence of lymph node metastasis (P = 0.001), and later TNM stage (P = 0.039). Moreover, patients with tumor engraftment had significantly shorter time to recurrence (TTR) (P < 0.001) and worse overall survival (OS) (P < 0.001). Multivariate analysis indicated that PDX engraftment was an independent risk factor for shortened TTR (HR = 1.84; 95% CI, 1.05-3.23; P = 0.034) and OS (HR = 2.13; 95% CI, 1.11-4.11; P = 0.024). PDXs were histologically and genetically similar to their parental tumors. We also applied IMF-138 and IMF-114 PDX drug testing results to guide clinical treatment for patients with ICC and found similar treatment responses. PDX models also facilitated personalized medicine for patients with ICC based on drug screening results using whole exome sequencing data. Additionally, PDX models reflected the heterogeneous sensitivity to lenvatinib treatment and CDH1 might be vital to lenvatinib-resistance.

Conclusion: PDX models provide a powerful platform for preclinical drug discovery, and potentially facilitate the implementation of personalized medicine and improvement of survival of ICC cancer patient.
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http://dx.doi.org/10.3389/fonc.2021.704042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315044PMC
July 2021

Rethinking the causes of extreme heavy winter PM pollution events in northern China.

Sci Total Environ 2021 Jun 24;794:148637. Epub 2021 Jun 24.

Key Lab of Marine Environment and Ecology, Ministry of Education, Ocean University of China, Qingdao 266100, China; Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266100, China; Institute for Advanced Ocean Study, Ocean University of China, Qingdao 266100, China. Electronic address:

It has been reported that air quality models largely underestimate PM concentrations during severe pollution events in China. In this study, the Models-3 Community Multi-scale Air Quality model (CMAQ) was employed to simulate PM concentrations in May-June (non-heating period) and in November-December (heating period) of 2013 in northern China, with a particular focus on determining the causes of the underestimation. Modeling results reproduced the mass concentrations of PM in approximately 50% of the non-heating and heating periods in Qingdao (referred to as the good periods), while the model performance was unsatisfactory during the remaining periods (the poor periods). In this respect, the overprediction of inorganic salts and the underprediction of organic matter in PM canceled each other out and resulted in a good simulation of PM concentrations during the good periods, whereas during poor periods, the bias of the planetary boundary layer height, wind direction, precipitation, and other factors caused inconsistencies between the simulated and observed PM concentrations. Sensitivity studies showed that the underestimation of primarily emitted particles from local emissions was likely the main cause of PM underpredictions during heavy haze days. Furthermore, our results implied that the assumption of the conditions of the gas-aerosol thermodynamic equilibria in the air quality model likely results in an overprediction of secondary PM inorganic salts (SO + NO + NH) during clear days. In contrast, during heavy pollution or heavy haze days, high concentrations of air pollutants theoretically rapidly leads to gas/particle chemical equilibrium and no overprediction of SO, NO, and NH concentrations. Nevertheless, the underestimation of primarily emitted particles from local sources during heavy haze days is yet to be explained and needs further investigation.
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http://dx.doi.org/10.1016/j.scitotenv.2021.148637DOI Listing
June 2021

Diagnostic and Prognostic Significance of miR-675-3p in Patients With Atherosclerosis.

Clin Appl Thromb Hemost 2021 Jan-Dec;27:10760296211024754

Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China.

In recent years, a rising number of studies have confirmed that microRNA (miRNA) plays a prominent role in the early diagnosis and prognostic value assessment of cardiovascular diseases. The current study was conducted to examine the expression of miR-675-3p in atherosclerosis (AS) patients and to evaluate its clinical diagnosis and prognostic value. 110 AS patients and 70 healthy controls were included in the study. Serum miR-675-3p levels were detected by quantitative real-time PCR (qRT-PCR). The clinical diagnostic significance of serum miR-675-3p in AS patients were investigated by the receiver operating characteristic (ROC) curve. The correlation between miRNA and carotid intima-media thickness (CIMT) was analyzed by the Spearman correlation coefficient. The prognostic significance of serum miR-675-3p was evaluated by the Kaplan-Meier method and Cox regression analysis. The patient's serum miR-675-3p was significantly increased than the healthy individuals ( < 0.05). An increase of carotid intima-media thickness (CIMT) was positively correlated with the promotion of serum miR-675-3p levels. The area under the ROC curve (AUC) was 0.918, with high sensitivity and specificity. miR-675-3p is a key independent predictor of cardiovascular adverse events in AS patients (HR = 5.375, 95%CI = 1.590-18.170, = 0.007), and patients with elevated miR-675-3p were more likely to have cardiovascular adverse events (log-rank = 0.030). Increased miR-675-3p can be used as a potential marker for the diagnosis of AS, and was associated with the poor prognosis of AS.
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http://dx.doi.org/10.1177/10760296211024754DOI Listing
July 2021

Coronary Evaluation Before Heart Valvular Surgery by Using Coronary Computed Tomographic Angiography Versus Invasive Coronary Angiography.

J Am Heart Assoc 2021 Aug 29;10(15):e019531. Epub 2021 Jul 29.

Department of Radiology Fuwai Hospital National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China.

Background Coronary computed tomography angiography (CCTA) is a noninvasive, less expensive, low-radiation alternative to invasive coronary angiography (ICA). ICA is recommended for coronary evaluation before heart valvular surgery, and the supporting evidence for CCTA is insufficient. Our study is a single-center, prospective cohort study designed to evaluate the feasibility of CCTA instead of ICA in detection of coronary artery disease before surgery. Methods and Results Heart valvular surgery candidates were consecutively enrolled between April 2017 and December 2018. Nine hundred fifty-eight patients in the CCTA group underwent CCTA primarily, and those with ≥50% coronary stenosis or uncertain diagnosis underwent subsequent ICA. One thousand five hundred twenty-five patients in the ICA group underwent ICA directly before surgery. Coronary artery bypass grafting decision was made by surgeons according to CCTA or ICA results. Most of the patients (78.8%) in the CCTA group avoided invasive angiography. Thirty-day mortality (0.7% versus 0.9%, =0.821), myocardial infarction (6.4% versus 6.9%, =0.680 ), and low cardiac output syndrome (4.2% versus 2.8%, =0.085) were similar in the CCTA and ICA groups. Median duration of follow-up was 19.3 months (interquartile range, 14.2-30.0 months), cumulative rates of mortality (2.6% versus 2.6%, =0.882) and major adverse cardiac events (9.6% versus 9.0%, =0.607) showed no difference between the 2 groups. Coronary evaluation expense was lower in the CCTA group ($149.6 versus $636.0, <0.001). Conclusions The strategy of using CCTA as a doorkeeper in coronary evaluation before heart valvular surgery showed noninferiority in identification of candidates for coronary artery bypass grafting and postoperative safety.
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http://dx.doi.org/10.1161/JAHA.120.019531DOI Listing
August 2021

Deep grey matter quantitative susceptibility mapping from small spatial coverages using deep learning.

Z Med Phys 2021 Jul 23. Epub 2021 Jul 23.

School of Information Technology and Electrical Engineering, University of Queensland, Brisbane, Australia. Electronic address:

Introduction: Quantitative Susceptibility Mapping (QSM) is generally acquired with full brain coverage, even though many QSM brain-iron studies focus on the deep grey matter (DGM) region only. Reducing the spatial coverage to the DGM vicinity can substantially shorten the scan time or enhance the spatial resolution without increasing scan time; however, this may lead to significant DGM susceptibility underestimation.

Method: A recently proposed deep learning-based QSM method, namely xQSM, is investigated to assess the accuracy of dipole inversion on reduced brain coverages. The xQSM method is compared with two conventional dipole inversion methods using simulated and in vivo experiments from 4 healthy subjects at 3T. Pre-processed magnetic field maps are extended symmetrically from the centre of globus pallidus in the coronal plane to simulate QSM acquisitions of difference spatial coverages, ranging from 100% (∼32mm) to 400% (∼128mm) of the actual DGM physical size.

Results: The proposed xQSM network led to the lowest DGM contrast loss in both simulated and in vivo subjects, with the smallest susceptibility variation range across all spatial coverages. For the digital brain phantom simulation, xQSM improved the DGM susceptibility underestimation more than 20% in small spatial coverages, as compared to conventional methods. For the in vivo acquisition, less than 5% DGM susceptibility error was achieved in 48mm axial slabs using the xQSM network, while a minimum of 112mm coverage was required for conventional methods. It is also shown that the background field removal process performed worse in reduced brain coverages, which further deteriorated the subsequent dipole inversion.

Conclusion: The recently proposed deep learning-based xQSM method significantly improves the accuracy of DGM QSM from small spatial coverages as compared with conventional QSM algorithms, which can shorten DGM QSM acquisition time substantially.
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http://dx.doi.org/10.1016/j.zemedi.2021.06.004DOI Listing
July 2021

Exploration of transmission chain and prevention of the recurrence of coronavirus disease 2019 in Heilongjiang Province due to in-hospital transmission.

World J Clin Cases 2021 Jul;9(20):5420-5426

Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin 150001, Heilongjiang Province, China.

The coronavirus disease 2019 (COVID-19) epidemic is a major public health emergency characterized by fast spread, a wide range of infections, and enormous control difficulty. Since the end of December 2019, Wuhan has become the first core infection area of China's COVID-19 outbreak. Since March 2020, the domestic worst-hit areas have moved to the Heilongjiang Province due to the increased number of imported COVID-19 cases. Herein, we reported the major COVID-19 outbreak, which caused a rebound of the epidemic in Harbin, China. After the rebound, different levels of causes for the recurrence of COVID-19, including city-level, hospital-level, and medical staff-level cause, were investigated. Meanwhile, corresponding countermeasures to prevent the recurrence of the epidemic were also carried out on the city level, hospital level, and medical staff level, which eventually showed the effect of infection control function in a pandemic. In this study, we described the complete transmission chain, analyzed the causes of the outbreak, and proposed corresponding countermeasures from our practical clinical experience, which can be used as a valuable reference for COVID-19 control.
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http://dx.doi.org/10.12998/wjcc.v9.i20.5420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281417PMC
July 2021

Sequential C-H activation enabled expedient delivery of polyfunctional arenes.

Chem Commun (Camb) 2021 Jul 23. Epub 2021 Jul 23.

School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, China.

Modular construction of polyfunctional arenes from abundant feedstocks stands as an unremitting pursue in synthetic chemistry, accelerating the discovery of drugs and materials. Herein, using the multiple C-H activation strategy with versatile imidate esters, the expedient delivery of molecular libraries of densely functionalized sulfur-containing arenes was achieved, which enabled the concise construction of biologically active molecules, such as Bipenamol.
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http://dx.doi.org/10.1039/d1cc03243gDOI Listing
July 2021

Accelerating quantitative susceptibility and R2* mapping using incoherent undersampling and deep neural network reconstruction.

Neuroimage 2021 Jul 16;240:118404. Epub 2021 Jul 16.

School of Information Technology and Electrical Engineering, University of Queensland, Brisbane, Australia. Electronic address:

Quantitative susceptibility mapping (QSM) and R2* mapping are MRI post-processing methods that quantify tissue magnetic susceptibility and transverse relaxation rate distributions. However, QSM and R2* acquisitions are relatively slow, even with parallel imaging. Incoherent undersampling and compressed sensing reconstruction techniques have been used to accelerate traditional magnitude-based MRI acquisitions; however, most do not recover the full phase signal, as required by QSM, due to its non-convex nature. In this study, a learning-based Deep Complex Residual Network (DCRNet) is proposed to recover both the magnitude and phase images from incoherently undersampled data, enabling high acceleration of QSM and R2* acquisition. Magnitude, phase, R2*, and QSM results from DCRNet were compared with two iterative and one deep learning methods on retrospectively undersampled acquisitions from six healthy volunteers, one intracranial hemorrhage and one multiple sclerosis patients, as well as one prospectively undersampled healthy subject using a 7T scanner. Peak signal to noise ratio (PSNR), structural similarity (SSIM), root-mean-squared error (RMSE), and region-of-interest susceptibility and R2* measurements are reported for numerical comparisons. The proposed DCRNet method substantially reduced artifacts and blurring compared to the other methods and resulted in the highest PSNR, SSIM, and RMSE on the magnitude, R2*, local field, and susceptibility maps. Compared to two iterative and one deep learning methods, the DCRNet method demonstrated a 3.2% to 9.1% accuracy improvement in deep grey matter susceptibility when accelerated by a factor of four. The DCRNet also dramatically shortened the reconstruction time of single 2D brain images from 36-140 seconds using conventional approaches to only 15-70 milliseconds.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118404DOI Listing
July 2021

Downregulation of miR-135b-5p Suppresses Progression of Esophageal Cancer and Contributes to the Effect of Cisplatin.

Front Oncol 2021 1;11:679348. Epub 2021 Jul 1.

Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.

Esophageal cancer (EC) is one of the commonest human cancers, which accompany high morbidity. MicroRNAs (miRNAs) play a pivotal role in various cancers, including EC. Our research aimed to reveal the function and mechanism of miR-135b-5p. Our research identified that miR-135b-5p was elevated in EC samples from TCGA database. Correspondingly real-time PCR assay also showed the miR-135b-5p is also higher expressed in Eca109, EC9706, KYSE150 cells than normal esophageal epithelial cells (Het-1A). CCK8, Edu, wound healing, Transwell assay, and western blot demonstrated miR-135b-5p inhibition suppresses proliferation, invasion, migration and promoted the apoptosis in Eca109 and EC9706 cells. Moreover, the miR-135b-5p inhibition also inhibited xenograft lump growth. We then predicted the complementary gene of miR-135b-5p using miRTarBase, TargetScan, and DIANA-microT. TXNIP was estimated as a complementary gene for miR-135b-5p. Luciferase report assay verified the direct binding site for miR-135b-5p and TXNIP. Real-time PCR and western blot assays showed that the inhibition of miR-135b-5p remarkably enhanced the levels of TXNIP in Eca109 and EC9706 cells. Furthermore, cisplatin (cis-diamminedichloroplatinum II, DDP) decreased miR-135b-5p expression and increased TXNIP expression. Enhanced expression of miR-135b-5p attenuated the inhibitory ability of cisplatin (cis-diamminedichloroplatinum II, DDP) in Eca109 cells, accompanied by TXNIP downregulation. In conclusion, the downregulation of miR-135b-5p suppresses the progression of EC through targeting TXNIP. MiR-135b-5p/TXNIP pathway contributes to the anti-tumor effect of DDP. These findings may provide new insight into the treatment of EC.
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http://dx.doi.org/10.3389/fonc.2021.679348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281352PMC
July 2021

Hydrogel-mesh composite for wound closure.

Proc Natl Acad Sci U S A 2021 Jul;118(28)

State Key Lab for Strength and Vibration of Mechanical Structures, Soft Machine Lab, School of Aerospace Engineering, Xi'an Jiaotong University, Xi'an 710049, China;

During operations, surgical mesh is commonly fixed on tissues through fasteners such as sutures and staples. Attributes of surgical mesh include biocompatibility, flexibility, strength, and permeability, but sutures and staples may cause stress concentration and tissue damage. Here, we show that the functions of surgical mesh can be significantly broadened by developing a family of materials called hydrogel-mesh composites (HMCs). The HMCs retain all the attributes of surgical mesh and add one more: adhesion to tissues. We fabricate an HMC by soaking a surgical mesh with a precursor, and upon cure, the precursor forms a polymer network of a hydrogel, in macrotopological entanglement with the fibers of the surgical mesh. In a surgery, the HMC is pressed onto a tissue, and the polymers in the hydrogel form covalent bonds with the tissue. To demonstrate the concept, we use a poly(-isopropylacrylamide) (PNIPAAm)/chitosan hydrogel and a polyethylene terephthalate (PET) surgical mesh. In the presence a bioconjugation agent, the chitosan and the tissue form covalent bonds, and the adhesion energy reaches above 100 J⋅m At body temperature, PNIPAAm becomes hydrophobic, so that the hydrogel does not swell and the adhesion is stable. Compared with sutured surgical mesh, the HMC distributes force over a large area. In vitro experiments are conducted to study the application of HMCs to wound closure, especially on tissues under high mechanical stress. The performance of HMCs on dynamic living tissues is further investigated in the surgery of a sheep.
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http://dx.doi.org/10.1073/pnas.2103457118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285977PMC
July 2021

A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies.

Signal Transduct Target Ther 2021 Jul 14;6(1):269. Epub 2021 Jul 14.

Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Intraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders, collectively termed as tauopathies, including the most common Alzheimer's disease (AD). Therefore, selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies. Here, we designed and synthesized a novel DEPhosphorylation TArgeting Chimera (DEPTAC) to specifically facilitate the binding of tau to Bα-subunit-containing protein phosphatase 2A (PP2A-Bα), the most active tau phosphatase in the brain. The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo. Further studies revealed that DEPTAC significantly improved microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368. Our data provide a strategy for selective removal of the hyperphosphorylated tau, which sheds new light for the targeted therapy of AD and related-tauopathies.
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http://dx.doi.org/10.1038/s41392-021-00669-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280143PMC
July 2021

Coseismic fault-slip distribution of the 2019 Ridgecrest Mw6.4 and Mw7.1 earthquakes.

Sci Rep 2021 Jul 9;11(1):14188. Epub 2021 Jul 9.

Xi'an Institute of Surveying and Mapping, Xi'an, 710054, Shaanxi, China.

The 2019 Ridgecrest, California seismic sequence, including an Mw6.4 foreshock and Mw7.1 mainshock, represent the largest regional seismic events within the past 20 years. To obtain accurate coseismic fault-slip distribution, we used precise positioning data of small earthquakes from January 2019 to October 2020 to determine the dip parameters of the eight fault geometry, and used the Interferometric Synthetic Aperture Radar (InSAR) data processed by Xu et al. (Seismol Res Lett 91(4):1979-1985, 2020) at UCSD to constrain inversion of the fault-slip distribution of both earthquakes. The results showed that all faults were sinistral strike-slips with minor dip-slip components, exception for dextral strike-slip fault F2. Fault-slip mainly occurred at depths of 0-12 km, with a maximum slip of 3.0 m. The F1 fault contained two slip peaks located at 2 km of fault S4 and 6 km of fault S5 depth, the latter being located directly above the Mw7.1hypocenter. Two slip peaks with maximum slip of 1.5 m located 8 and 20 km from the SW endpoint of the F2 fault were also identified, and the latter corresponds to the Mw6.4 earthquake. We also analyzed the influence of different inversion parameters on the fault slip distribution, and found that the slip momentum smoothing condition was more suitable for the inversion of the earthquakes slip distribution than the stress-drop smoothing condition.
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http://dx.doi.org/10.1038/s41598-021-93521-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270957PMC
July 2021

Integrated Analysis of microRNA and mRNA Transcriptome Reveals the Molecular Mechanism of Response to and .

Front Microbiol 2021 22;12:693574. Epub 2021 Jun 22.

Subcollege of Longping, Graduate School of Hunan University, Changsha, China.

(ToCV), is one of the most devastating cultivated tomato viruses, seriously threatened the growth of crops worldwide. As the vector of ToCV, the whitefly Mediterranean (MED) is mainly responsible for the rapid spread of ToCV. The current understanding of tomato plant responses to this virus and is very limited. To understand the molecular mechanism of the interaction between tomato, ToCV and , we adopted a next-generation sequencing approach to decipher miRNAs and mRNAs that are differentially expressed under the infection of and ToCV in tomato plants. Our data revealed that 6199 mRNAs were significantly regulated, and the differentially expressed genes were most significantly associated with the plant-pathogen interaction, the MAPK signaling pathway, the glyoxylate, and the carbon fixation in photosynthetic organisms and photosynthesis related proteins. Concomitantly, 242 differentially expressed miRNAs were detected, including novel putative miRNAs. Sly-miR159, sly-miR9471b-3p, and sly-miR162 were the most expressed miRNAs in each sample compare to control group. Moreover, we compared the similarities and differences of gene expression in tomato plant caused by infection or co-infection of and ToCV. Taken together, the analysis reported in this article lays a solid foundation for further research on the interaction between tomato, ToCV and , and provide evidence for the identification of potential key genes that influences virus transmission in tomato plants.
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http://dx.doi.org/10.3389/fmicb.2021.693574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258350PMC
June 2021

Bi-allelic mutations of DNAH10 cause primary male infertility with asthenoteratozoospermia in humans and mice.

Am J Hum Genet 2021 Jun 30. Epub 2021 Jun 30.

Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410000, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, China. Electronic address:

Multiple morphological abnormalities of the sperm flagella (MMAF)-induced asthenoteratozoospermia is a common cause of male infertility. Previous studies have identified several MMAF-associated genes, highlighting the condition's genetic heterogeneity. To further define the genetic causes underlying MMAF, we performed whole-exome sequencing in a cohort of 643 Chinese MMAF-affected men. Bi-allelic DNAH10 variants were identified in five individuals with MMAF from four unrelated families. These variants were either rare or absent in public population genome databases and were predicted to be deleterious by multiple bioinformatics tools. Morphological and ultrastructural analyses of the spermatozoa obtained from men harboring bi-allelic DNAH10 variants revealed striking flagellar defects with the absence of inner dynein arms (IDAs). DNAH10 encodes an axonemal IDA heavy chain component that is predominantly expressed in the testes. Immunostaining analysis indicated that DNAH10 localized to the entire sperm flagellum of control spermatozoa. In contrast, spermatozoa from the men harboring bi-allelic DNAH10 variants exhibited an absence or markedly reduced staining intensity of DNAH10 and other IDA components, including DNAH2 and DNAH6. Furthermore, the phenotypes were recapitulated in mouse models lacking Dnah10 or expressing a disease-associated variant, confirming the involvement of DNAH10 in human MMAF. Altogether, our findings in humans and mice demonstrate that DNAH10 is essential for sperm flagellar assembly and that deleterious bi-allelic DNAH10 variants can cause male infertility with MMAF. These findings will provide guidance for genetic counseling and insights into the diagnosis of MMAF-associated asthenoteratozoospermia.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.010DOI Listing
June 2021

Structural basis of the stereoselective formation of the spirooxindole ring in the biosynthesis of citrinadins.

Nat Commun 2021 07 6;12(1):4158. Epub 2021 Jul 6.

Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.

Prenylated indole alkaloids featuring spirooxindole rings possess a 3R or 3S carbon stereocenter, which determines the bioactivities of these compounds. Despite the stereoselective advantages of spirooxindole biosynthesis compared with those of organic synthesis, the biocatalytic mechanism for controlling the 3R or 3S-spirooxindole formation has been elusive. Here, we report an oxygenase/semipinacolase CtdE that specifies the 3S-spirooxindole construction in the biosynthesis of 21R-citrinadin A. High-resolution X-ray crystal structures of CtdE with the substrate and cofactor, together with site-directed mutagenesis and computational studies, illustrate the catalytic mechanisms for the possible β-face epoxidation followed by a regioselective collapse of the epoxide intermediate, which triggers semipinacol rearrangement to form the 3S-spirooxindole. Comparing CtdE with PhqK, which catalyzes the formation of the 3R-spirooxindole, we reveal an evolutionary branch of CtdE in specific 3S spirocyclization. Our study provides deeper insights into the stereoselective catalytic machinery, which is important for the biocatalysis design to synthesize spirooxindole pharmaceuticals.
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http://dx.doi.org/10.1038/s41467-021-24421-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260726PMC
July 2021

Twelve-month specific IgG response to SARS-CoV-2 receptor-binding domain among COVID-19 convalescent plasma donors in Wuhan.

Nat Commun 2021 07 6;12(1):4144. Epub 2021 Jul 6.

Sinopharm Wuhan Plasma-derived Biotherapies Co., Ltd, Wuhan, China.

To investigate the duration of humoral immune response in convalescent coronavirus disease 2019 (COVID-19) patients, we conduct a 12-month longitudinal study through collecting a total of 1,782 plasma samples from 869 convalescent plasma donors in Wuhan, China and test specific antibody responses. The results show that positive rate of IgG antibody against receptor-binding domain of spike protein (RBD-IgG) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the COVID-19 convalescent plasma donors exceeded 70% for 12 months post diagnosis. The level of RBD-IgG decreases with time, with the titer stabilizing at 64.3% of the initial level by the 9th month. Moreover, male plasma donors produce more RBD-IgG than female, and age of the patients positively correlates with the RBD-IgG titer. A strong positive correlation between RBD-IgG and neutralizing antibody titers is also identified. These results facilitate our understanding of SARS-CoV-2-induced immune memory to promote vaccine and therapy development.
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http://dx.doi.org/10.1038/s41467-021-24230-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260809PMC
July 2021

On-Orbit Robotic Grasping of a Spent Rocket Stage: Grasp Stability Analysis and Experimental Results.

Front Robot AI 2021 17;8:652681. Epub 2021 Jun 17.

STAR-Lab, Surrey Space Centre, University of Surrey, Guildford, United Kingdom.

The increased complexity of the tasks that on-orbit robots have to undertake has led to an increased need for manipulation dexterity. Space robots can become more dexterous by adopting grasping and manipulation methodologies and algorithms from terrestrial robots. In this paper, we present a novel methodology for evaluating the stability of a robotic grasp that captures a piece of space debris, a spent rocket stage. We calculate the Intrinsic Stiffness Matrix of a 2-fingered grasp on the surface of an Apogee Kick Motor nozzle and create a stability metric that is a function of the local contact curvature, material properties, applied force, and target mass. We evaluate the efficacy of the stability metric in a simulation and two real robot experiments. The subject of all experiments is a chasing robot that needs to capture a target AKM and pull it back towards the chaser body. In the V-REP simulator, we evaluate four grasping points on three AKM models, over three pulling profiles, using three physics engines. We also use a real robotic testbed with the capability of emulating an approaching robot and a weightless AKM target to evaluate our method over 11 grasps and three pulling profiles. Finally, we perform a sensitivity analysis to demonstrate how a variation on the grasping parameters affects grasp stability. The results of all experiments suggest that the grasp can be stable under slow pulling profiles, with successful pulling for all targets. The presented work offers an alternative way of capturing orbital targets and a novel example of how terrestrial robotic grasping methodologies could be extended to orbital activities.
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http://dx.doi.org/10.3389/frobt.2021.652681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247653PMC
June 2021

Selective Complex Precipitation for Ferro-Chrome Separation From Electroplating Sludge Leaching Solution.

Front Chem 2021 16;9:592407. Epub 2021 Jun 16.

School of Metallurgy and Chemical Engineering, Jiangxi University of Science and Technology, Ganzhou, China.

In this paper, aiming at the problem of chrome-iron separation in electroplating sludge, the separation of ferrochrome by complexation and precipitation with benzoic acid as complexing agent is achieved. The optimal conditions consisted of a 1: 3 molar ratio of Fe: CHCOOH, a reaction temperature of 30°C, a final pH of 2.5 and a reaction time of 2 min. The separation rate of the iron was 97.38% and the rate of loss of chromium was only 3.59%. The ferrochromium separation products were analyzed by XRD, fluorescence spectroscopy, infrared spectroscopy and H NMR Spectroscopy in order to study the mechanism of precipitation. The results showed that benzoic acid preferentially forms a complex with iron and iron benzoate precipitates with an increase pH. The iron benzoate crystals have a fine particle size, settle rapidly and are easy to filter. The separation of Cr /Fe was successful using our methodology.
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http://dx.doi.org/10.3389/fchem.2021.592407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241916PMC
June 2021

Effect of Electroacupuncture on Bladder Dysfunction via Regulation of MLC and MLCK Phosphorylation in a Rat Model of Type 2 Diabetes Mellitus.

Evid Based Complement Alternat Med 2021 10;2021:5558890. Epub 2021 Jun 10.

Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, China.

Previous studies observed have reported that electroacupuncture (EA) is effective in relieving diabetic bladder dysfunction (DBD); however, little is known about the mechanism. Therefore, we explored the effects and mechanisms of EA on DBD in streptozotocin-high-fat diet- (STZ-HFD-) induced diabetic rats. The Sprague-Dawley male rats were divided randomly into four groups: normal group, diabetes mellitus group (DM group), DM with EA treatment group (EA group), and DM with sham EA treatment group (sham EA group). After 8 weeks of EA treatment, the body weight, serum glucose, bladder weight, and cystometrogram were evaluated. The bladder wall thickness was examined by abdominal ultrasound imaging. After the transabdominal ultrasound measurements, hematoxylin-eosin (HE) staining was used to observe the bladder mucosa layer. The bladder detrusor smooth muscle cells (SMCs) and fibroblasts were observed under transmission electron microscopy (TEM). The phospho-myosin light chain (p-MLC), phospho-myosin light chain kinase (p-MLCK), and phospho-myosin phosphatase target subunit 1 (p-MYPT1) levels in the bladder were examined using Western blot. The bladder weight, serum glucose, bladder wall thickness, volume threshold for micturition, and postvoid residual (PVR) volume in the diabetic rats were significantly higher than those in the control animals. EA treatment significantly reduced the bladder weight, bladder wall thickness, volume threshold for micturition, and PVR volume in diabetic rats. EA caused a significant increase in the MLC dephosphorylation and MLCK phosphorylation levels in the group compared to the sham EA and model groups. EA reduced the infiltration of inflammatory cells in the bladder mucosa layer of diabetic rats. In addition, EA repaired the damaged bladder detrusor muscle of diabetic rats by reducing mitochondrial damage of the SMCs and fibroblasts. Therefore, EA could reduce the bladder hypertrophy to ameliorate DBD by reversing the impairment in the mucosa layer and detrusor SMCs, which might be mainly mediated by the regulation of p-MLC and p-MLCK levels.
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http://dx.doi.org/10.1155/2021/5558890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213478PMC
June 2021

In vitro anti-Toxoplasma gondii efficacy of synthesised benzyltriazole derivatives.

Onderstepoort J Vet Res 2021 Jun 11;88(1):e1-e8. Epub 2021 Jun 11.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro.

Toxoplasma gondii, an obligate intracellular parasite, is the aetiological agent of toxoplasmosis, a disease that affects approximately 25% - 30% of the world's population. At present, no safe and effective vaccine exists for the prevention of toxoplasmosis. Current treatment options for toxoplasmosis are active only against tachyzoites and may also cause bone marrow toxicity. To contribute to the global search for novel agents for the treatment of toxoplasmosis, we herein report the in vitro activities of previously synthesised benzyltriazole derivatives. The effects of these compounds against T. gondii in vitro were evaluated by using a expressing green fluorescent protein (GFP) type I strain parasite (RH-GFP) and a type II cyst-forming strain of parasite (PruΔku80Δhxgprt). The frontline antitubercular drug isoniazid, designated as Frans J. Smit -isoniazid (FJS-INH), was also included in the screening as a preliminary test in view of future repurposing of this agent. Of the compounds screened, FJS-302, FJS-303, FJS-403 and FJS-INH demonstrated 80% parasite growth inhibition with IC50 values of 5.6 µg/mL, 6.8 µg/µL, 7.0 µg/mL and 19.8 µg/mL, respectively. FJS-302, FJS-303 and FJS-403 inhibited parasite invasion and replication, whereas, sulphadiazine (SFZ), the positive control, was only effective against parasite replication. In addition, SFZ induced bradyzoite differentiation in vitro, whilst FJS-302, FJS-303 and FJS-403 did not increase the bradyzoite number. These results indicate that FJS-302, FJS-303 and FJS-403 have the potential to act as a viable source of antiparasitic therapeutic agents.
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http://dx.doi.org/10.4102/ojvr.v88i1.1898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252180PMC
June 2021

Identification of Arrhythmia by Using a Decision Tree and Gated Network Fusion Model.

Comput Math Methods Med 2021 29;2021:6665357. Epub 2021 May 29.

School of Information Engineering, Zhengzhou University, Zhengzhou 450001, China.

In recent years, deep learning (DNN) based methods have made leapfrogging level breakthroughs in detecting cardiac arrhythmias as the cost effectiveness of arithmetic power, and data size has broken through the tipping point. However, the inability of these methods to provide a basis for modeling decisions limits clinicians' confidence on such methods. In this paper, a Gate Recurrent Unit (GRU) and decision tree fusion model, referred to as (T-GRU), was designed to explore the problem of arrhythmia recognition and to improve the credibility of deep learning methods. The fusion model multipathway processing time-frequency domain featured the introduction of decision tree probability analysis of frequency domain features, the regularization of GRU model parameters and weight control to improve the decision tree model output weights. The MIT-BIH arrhythmia database was used for validation. Results showed that the low-frequency band features dominated the model prediction. The fusion model had an accuracy of 98.31%, sensitivity of 96.85%, specificity of 98.81%, and precision of 96.73%, indicating its high reliability and clinical significance.
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http://dx.doi.org/10.1155/2021/6665357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181111PMC
May 2021

Asymmetric activation of the calcium-sensing receptor homodimer.

Nature 2021 Jul 30;595(7867):455-459. Epub 2021 Jun 30.

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders. CaSR is a family C G-protein-coupled receptor that functions as an obligate homodimer, with each protomer composed of a Ca-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor.
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http://dx.doi.org/10.1038/s41586-021-03691-0DOI Listing
July 2021

G-protein activation by a metabotropic glutamate receptor.

Nature 2021 Jul 30;595(7867):450-454. Epub 2021 Jun 30.

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism. Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric G. Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6-TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound G can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6-TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation.
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http://dx.doi.org/10.1038/s41586-021-03680-3DOI Listing
July 2021

Research progress of indole compounds with potential antidiabetic activity.

Eur J Med Chem 2021 Jun 23;223:113665. Epub 2021 Jun 23.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China. Electronic address:

New types of antidiabetic agents are continually needed with diabetes becoming the epidemic in the world. Indole alkaloids play an important role in natural products owing to their variable structures and versatile biological activities like anticonvulsant, anti-inflammatory, antidiabetic, antimicrobial, and anticancer activities, which are a promising source of novel antidiabetic drugs discovery. The synthesized indole derivatives possess similar properties to natural indole alkaloids. In the last two decades, more and more indole derivatives have been designed and synthesized for searching their bioactivities. This present review describes comprehensive structures of indole compounds with the potential antidiabetic activity including natural indole alkaloids and the synthetic indole derivatives based on the structure classification, summarizes their approaches isolated from natural sources or by synthetic methods, and discusses the antidiabetic effects and the mechanisms of action. Furthermore, this review also provides briefly synthetic procedures of some important indole derivatives.
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http://dx.doi.org/10.1016/j.ejmech.2021.113665DOI Listing
June 2021
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