Publications by authors named "Geng Tian"

234 Publications

Offspring production of ovarian organoids derived from spermatogonial stem cells by defined factors with chromatin reorganization.

J Adv Res 2021 Nov 17;33:81-98. Epub 2021 Mar 17.

Renji Hospital, Key Laboratory for the Genetics of Developmental & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, China.

Introduction: Fate determination of germline stem cells remains poorly understood at the chromatin structure level.

Objectives: Our research hopes to develop successful offspring production of ovarian organoids derived from spermatogonial stem cells (SSCs) by defined factors.

Methods: The offspring production from oocytes transdifferentiated from mouse SSCs with tracking of transplanted SSCs in vivo, single cell whole exome sequencing, and in 3D cell culture reconstitution of the process of oogenesis derived from SSCs. The defined factors were screened with ovarian organoids. We uncovered extensive chromatin reorganization during SSC conversion into induced germline stem cells (iGSCs) using high throughput chromosome conformation.

Results: We demonstrate successful production of offspring from oocytes transdifferentiated from mouse spermatogonial stem cells (SSCs). Furthermore, we demonstrate direct induction of germline stem cells (iGSCs) differentiated into functional oocytes by transduction of , , and and inactivation of in SSCs after screening with ovarian organoids. We uncovered extensive chromatin reorganization during SSC conversion into iGSCs, which was highly similar to female germline stem cells. We observed that although topologically associating domains were stable during SSC conversion, chromatin interactions changed in a striking manner, altering 35% of inactive and active chromosomal compartments throughout the genome.

Conclusion: We demonstrate successful offspring production of ovarian organoids derived from SSCs by defined factors with chromatin reorganization. These findings have important implications in various areas including mammalian gametogenesis, genetic and epigenetic reprogramming, biotechnology, and medicine.
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http://dx.doi.org/10.1016/j.jare.2021.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463929PMC
November 2021

An efficient method to identify virus-specific TCRs for TCR-T cell immunotherapy against virus-associated malignancies.

BMC Immunol 2021 09 28;22(1):65. Epub 2021 Sep 28.

Department of Research and Development, Shenzhen Institute for Innovation and Translational Medicine, Shenzhen International Biological Valley-Life Science Industrial Park, Dapeng New District, Shenzhen, China.

Adoptive transfer of T cells genetically engineered with a T cell receptor (TCR) is a promising cancer treatment modality that requires the identification of TCRs with good characteristics. Most T cell cloning methods involve a stringent singularization process, which necessitates either tedious hands-on operations or high cost. We present an efficient and nonstringent cloning approach based on existing techniques. We hypothesize that after elimination of most nonspecific T cells, a clonotype with high quality could outcompete other clonotypes and finally form a predominant population. This TCR identification method can be used to clone virus-specific TCRs efficiently from cancer patients and is easily adoptable by any laboratory.
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http://dx.doi.org/10.1186/s12865-021-00455-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480097PMC
September 2021

Enhancement of Oxytocin in the Medial Prefrontal Cortex Reverses Behavioral Deficits Induced by Repeated Ketamine Administration in Mice.

Front Neurosci 2021 10;15:723064. Epub 2021 Sep 10.

Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, China.

Ketamine is a popular recreational substance of abuse that induces persistent behavioral deficits. Although disrupted oxytocinergic systems have been considered to modulate vulnerability to developing drugs of abuse, the involvement of central oxytocin in behavioral abnormalities caused by chronic ketamine has remained largely unknown. Herein, we aimed to investigate the potential role of oxytocin in the medial prefrontal cortex (mPFC) in social avoidance and cognitive impairment resulting from repeated ketamine administration in mice. We found that ketamine injection (5 mg/kg, i.p.) for 10 days followed by a 6-day withdrawal period induced behavioral disturbances in social interaction and cognitive performance, as well as reduced oxytocin levels both at the periphery and in the mPFC. Repeated ketamine exposure also inhibited mPFC neuronal activity as measured by a decrease in c-fos-positive cells. Furthermore, direct microinjection of oxytocin into the mPFC reversed the social avoidance and cognitive impairment following chronic ketamine exposure. In addition, oxytocin administration normalized ketamine-induced inflammatory cytokines including TNF-α, IL-6, and IL-1β levels. Moreover, the activation of immune markers such as neutrophils and monocytes, by ketamine was restored in oxytocin-treated mice. Finally, the reversal effects of oxytocin on behavioral performance were blocked by pre-infusion of the oxytocin receptor antagonist atosiban into the mPFC. These results demonstrate that enhancing oxytocin signaling in the mPFC is a potential pathway to reverse social avoidance and cognitive impairment caused by ketamine, partly through inhibition of inflammatory stimulation.
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http://dx.doi.org/10.3389/fnins.2021.723064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462509PMC
September 2021

Identifying Breast Cancer-Related Genes Based on a Novel Computational Framework Involving KEGG Pathways and PPI Network Modularity.

Front Genet 2021 16;12:596794. Epub 2021 Aug 16.

Academician Workstation, Changsha Medical University, Changsha, China.

Complex diseases, such as breast cancer, are often caused by mutations of multiple functional genes. Identifying disease-related genes is a critical and challenging task for unveiling the biological mechanisms behind these diseases. In this study, we develop a novel computational framework to analyze the network properties of the known breast cancer-associated genes, based on which we develop a random-walk-with-restart (RCRWR) algorithm to predict novel disease genes. Specifically, we first curated a set of breast cancer-associated genes from the Genome-Wide Association Studies catalog and Online Mendelian Inheritance in Man database and then studied the distribution of these genes on an integrated protein-protein interaction (PPI) network. We found that the breast cancer-associated genes are significantly closer to each other than random, which confirms the modularity property of disease genes in a PPI network as revealed by previous studies. We then retrieved PPI subnetworks spanning top breast cancer-associated KEGG pathways and found that the distribution of these genes on the subnetworks are non-random, suggesting that these KEGG pathways are activated non-uniformly. Taking advantage of the non-random distribution of breast cancer-associated genes, we developed an improved RCRWR algorithm to predict novel cancer genes, which integrates network reconstruction based on local random walk dynamics and subnetworks spanning KEGG pathways. Compared with the disease gene prediction without using the information from the KEGG pathways, this method has a better prediction performance on inferring breast cancer-associated genes, and the top predicted genes are better enriched on known breast cancer-associated gene ontologies. Finally, we performed a literature search on top predicted novel genes and found that most of them are supported by at least wet-lab experiments on cell lines. In summary, we propose a robust computational framework to prioritize novel breast cancer-associated genes, which could be used for further and experimental validation.
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http://dx.doi.org/10.3389/fgene.2021.596794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415302PMC
August 2021

Application of Circulating Tumor DNA as a Biomarker for Non-Small Cell Lung Cancer.

Front Oncol 2021 5;11:725938. Epub 2021 Aug 5.

Genetron Health (Beijing) Co. Ltd., Beijing, China.

Background: Non-small cell lung cancer (NSCLC) is one of the most prevalent causes of cancer-related death worldwide. Recently, there are many important medical advancements on NSCLC, such as therapies based on tyrosine kinase inhibitors and immune checkpoint inhibitors. Most of these therapies require tumor molecular testing for selecting patients who would benefit most from them. As invasive biopsy is highly risky, NSCLC molecular testing based on liquid biopsy has received more and more attention recently.

Objective: We aimed to introduce liquid biopsy and its potential clinical applications in NSCLC patients, including cancer diagnosis, treatment plan prioritization, minimal residual disease detection, and dynamic monitoring on the response to cancer treatment.

Method: We reviewed recent studies on circulating tumor DNA (ctDNA) testing, which is a minimally invasive approach to identify the presence of tumor-related mutations. In addition, we evaluated potential clinical applications of ctDNA as blood biomarkers for advanced NSCLC patients.

Results: Most studies have indicated that ctDNA testing is critical in diagnosing NSCLC, predicting clinical outcomes, monitoring response to targeted therapies and immunotherapies, and detecting cancer recurrence. Moreover, the changes of ctDNA levels are associated with tumor mutation burden and cancer progression.

Conclusion: The ctDNA testing is promising in guiding the therapies on NSCLC patients.
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http://dx.doi.org/10.3389/fonc.2021.725938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375502PMC
August 2021

A nanoselenium-coating biomimetic cytomembrane nanoplatform for mitochondrial targeted chemotherapy- and chemodynamic therapy through manganese and doxorubicin codelivery.

J Nanobiotechnology 2021 Jul 30;19(1):227. Epub 2021 Jul 30.

Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China.

The cell membrane is widely considered as a promising delivery nanocarrier due to its excellent properties. In this study, self-assembled Pseudomonas geniculate cell membranes were prepared with high yield as drug nanocarriers, and named BMMPs. BMMPs showed excellent biosafety, and could be more efficiently internalized by cancer cells than traditional red cell membrane nanocarriers, indicating that BMMPs could deliver more drug into cancer cells. Subsequently, the BMMPs were coated with nanoselenium (Se), and subsequently loaded with Mn ions and doxorubicin (DOX) to fabricate a functional nanoplatform (BMMP-Mn/Se/DOX). Notably, in this nanoplatform, Se nanoparticles activated superoxide dismutase-1 (SOD-1) expression and subsequently up-regulated downstream HO levels. Next, the released Mn ions catalyzed HO to highly toxic hydroxyl radicals (·OH), inducing mitochondrial damage. In addition, the BMMP-Mn/Se nanoplatform inhibited glutathione peroxidase 4 (GPX4) expression and further accelerated intracellular reactive oxygen species (ROS) generation. Notably, the BMMP-Mn/Se/DOX nanoplatform exhibited increased effectiveness in inducing cancer cell death through mitochondrial and nuclear targeting dual-mode therapeutic pathways and showed negligible toxicity to normal organs. Therefore, this nanoplatform may represent a promising drug delivery system for achieving a safe, effective, and accurate cancer therapeutic plan.
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http://dx.doi.org/10.1186/s12951-021-00971-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325191PMC
July 2021

Urinary exosomal circular RNAs of sex chromosome origin are associated with gender-related risk differences of clinicopathological features in patients with IgA nephropathy.

J Nephrol 2021 Jul 22. Epub 2021 Jul 22.

Department of Nephrology, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, Jilin, China.

Background: There are arguments for individualized treatments and the necessity of non-invasive biomarkers for patients with IgA nephropathy (IgAN) according to gender, but the rationale remains unclear. We aimed to investigate the relationship between urine exosomal circular RNA (circRNA) levels, related genes, clinical features, and renal pathological features in IgA nephropathy patients of different genders.

Methods: Clinicopathological data from patients of different genders from a multicenter cohort were retrospectively analyzed. We used the Oxford classification to examine the severity of pathological damage in these patients. We compared clinical features and renal pathologies between IgAN patients of different genders. Using findings of urine exosomal circRNAs from male IgAN patients, we analyzed the relationship between this factor, the regulated genes located on the sex chromosomes, and renal pathologies.

Results: A total of 502 IgAN patients were included. The proportion of male patients with crescent formation was higher than that of females (p = 0.019). Multivariate logistic regression analysis showed that proteinuria was an independent marker for crescent formation in male and female patients with IgAN, while smoking and higher low-density lipoprotein cholesterol (LDL-C) levels were independent risk factors for crescent formation in males alone. Urine exosomal circRNA chrY:15478147-15481229- located on the Y chromosome in male patients was negatively correlated with the expressions of UTY in specific regions of the Y chromosome.

Conclusion: Compared with female patients, males with IgAN had more severe renal dysfunction and a higher probability of glomerular crescent formation. Urine exosomal circRNA chrY:15478147-15481229- might participate in the pathogenesis of IgAN in male patients by altering UTY expressions.
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http://dx.doi.org/10.1007/s40620-021-01118-7DOI Listing
July 2021

Cascaded filter deterministic lateral displacement microchips for isolation and molecular analysis of circulating tumor cells and fusion cells.

Lab Chip 2021 08 5;21(15):2881-2891. Epub 2021 Jul 5.

CAS Key Laboratory of Health Informatics, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.

Precise isolation and analysis of circulating tumor cells (CTCs) from blood samples offer considerable potential for cancer research and personalized treatment. Currently, available CTC isolation approaches remain challenging in the quest for simple strategies to achieve cell isolation with both high separation efficiency and high purity, which limits the use of captured CTCs for downstream analyses. Here, we present a filter deterministic lateral displacement concept to achieve one-step and label-free CTC isolation with high throughput. Unlike conventional deterministic lateral displacement (DLD) devices, the proposed method uses a hydrodynamic cell sorting design by incorporating a filtration concept into a DLD structure, and enables high-throughput and clog-free isolation by a cascaded microfluidic design. The cascaded filter-DLD (CFD) design demonstrated enhanced performance for size-based cell separation, and achieved high separation efficiency (>96%), high cell purity (WBC removal rate 99.995%), high cell viability (>98%) and high processing rate (1 mL min). Samples from lung cancer patients were analyzed using the CFD-Chip, CTCs and tumor cell-leukocyte fusion cells were efficiently collected, and changes in CTC levels were used for treatment response monitoring. The CFD-Chip platform isolated CTCs with good viability, enabling direct downstream analysis with single-cell RNA sequencing. Transcriptome analysis of enriched CTCs identified new subtypes of CTCs such as tumor cell-leukocyte fusion cells, providing insights into cancer diagnostics and therapeutics.
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http://dx.doi.org/10.1039/d1lc00360gDOI Listing
August 2021

Large-Scale Identification of T-Cell Epitopes Derived From Severe Acute Respiratory Syndrome Coronavirus 2 for the Development of Peptide Vaccines Against Coronavirus Disease 2019.

J Infect Dis 2021 09;224(6):956-966

Department of Research and Development, Shenzhen Institute for Innovation and Translational Medicine, Shenzhen International Biological Valley-Life Science Industrial Park, Dapeng New District, Shenzhen, China.

Background: Coronavirus disease 2019 (COVID-19) continues to be a major public health challenge globally. The identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived T-cell epitopes is of critical importance for peptide vaccines or diagnostic tools of COVID-19.

Methods: In this study, several SARS-CoV-2-derived human leukocyte antigen (HLA)-I binding peptides were predicted by NetMHCpan-4.1 and selected by Popcover to achieve pancoverage of the Chinese population. The top 5 ranked peptides derived from each protein of SARS-CoV-2 were then evaluated using peripheral blood mononuclear cells from unexposed individuals (negative for SARS-CoV-2 immunoglobulin G).

Results: Seven epitopes derived from 4 SARS-CoV-2 proteins were identified. It is interesting to note that most (5 of 7) of the SARS-CoV-2-derived peptides with predicted affinities for HLA-I molecules were identified as HLA-II-restricted epitopes and induced CD4+ T cell-dependent responses. These results complete missing pieces of pre-existing SARS-CoV-2-specific T cells and suggest that pre-existing T cells targeting all SARS-CoV-2-encoded proteins can be discovered in unexposed populations.

Conclusions: In summary, in the current study, we present an alternative and effective strategy for the identification of T-cell epitopes of SARS-CoV-2 in healthy subjects, which may indicate an important role in the development of peptide vaccines for COVID-19.
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http://dx.doi.org/10.1093/infdis/jiab324DOI Listing
September 2021

Lower growth arrest-specific 5 level in endometrium is related to endometriosis via promoting cell proliferation and angiogenesis.

Kaohsiung J Med Sci 2021 Sep 17;37(9):776-783. Epub 2021 Jun 17.

Center for Reproductive Medicine, The Fourth Hospital of Shijiazhuang, Gynecology and Obstetrics Hospital Affiliated to Hebei Medical University, Shijiazhuang, Heibei, China.

Long noncoding RNAs are a group of more than 200 nt, nonprotein coding RNAs, some of which are dysregulated in many pathophysiological processes including endometriosis. This study aims to clarify the roles of dysregulated growth arrest-specific 5 (GAS5) in patients with endometriosis, and unveil the underlying mechanisms. We obtained endometrium samples from 37 patients with endometriosis and 23 controls without endometriosis. Primary endometrial stromal cells (ESCs) and endothelial cells were separated from the endometrium. Levels of GAS5 were quantified using quantitative real-time polymerase chain reaction, and levels of p27, cleaved caspase-3, cleaved poly (ADP-Ribose) polymerase 1, vascular endothelial growth factor A, tissue inhibitor of metalloproteinases 3 (TIMP3), and trypsin-modified soy protein 10 were assessed by immunoblotting. Cell viability was examined using MTT assays, and the cell cycle and apoptosis were analyzed by flow cytometry. Endothelial cell tube formation capacity was assayed in vitro. GAS5 and p27 levels were found lower in the endometrium samples from patients with endometriosis. Primary ESCs from patients with endometriosis had increased viability, reduced apoptosis, and a relatively uncontrolled cell cycle. Gain- and loss-of-function studies confirmed that GAS5 regulated p27 expression in ESCs. Furthermore, GAS5 level was relatively low in primary endothelial cells from patients with endometriosis and GAS5 acted as an angiogenesis inhibitor by regulating the miR-181c-TIMP3 axis. Thus, lower GAS5 level in endometrium might be related to endometriosis by regulating cell proliferation, apoptosis, cell cycle, and angiogenesis.
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http://dx.doi.org/10.1002/kjm2.12408DOI Listing
September 2021

Infrared-Light-Responsive Controlled-Release Pesticide Using Hollow Carbon [email protected] Glycol/α-Cyclodextrin Gel.

J Agric Food Chem 2021 Jun 17;69(25):6981-6988. Epub 2021 Jun 17.

Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, People's Republic of China.

Controlled release of pesticides by light regulation is one of the most viable strategies recently developed for the highly efficient utilization of agrochemicals. Herein, we report an infrared-light-responsive pesticide delivery system for the controlled release of imidacloprid (IMI) by preparation of functional hollow carbon microspheres (HCMs). After IMI loading and surface functionalization with polyethylene glycol (PEG) and α-cyclodextrin (α-CD), IMI was sequestered in the pesticide system (denoted as HCMs/IMI/PEG/α-CD) as a result of the formation of a PEG/α-CD gel network. Upon the irradiation of infrared light, HCMs with high photothermal conversion efficiency (42.8%) raised the local temperature effectively, leading to the collapse of the gel network and the release of IMI. In comparison to the amount of pesticide release (29%) under sunlight, it could reach 77% driven by infrared light, which was an intriguing improvement. Consequently, HCMs/IMI/PEG/α-CD under infrared light showed significantly higher pest control efficacy on corn borers by 125% than itself alone. This work provides a promising method to intentionally regulate pesticide release and enhance utilization efficiency.
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http://dx.doi.org/10.1021/acs.jafc.1c01265DOI Listing
June 2021

Spermidine induces cytoprotective autophagy of female germline stem cells in vitro and ameliorates aging caused by oxidative stress through upregulated sequestosome-1/p62 expression.

Cell Biosci 2021 Jun 7;11(1):107. Epub 2021 Jun 7.

Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, China.

Background: Autophagy is required for oogenesis and plays a critical role in response to aging caused by oxidative stress. However, there have been no reports on regulation of cytoprotective autophagy in female germline stem cells (FGSCs) in response to aging caused by oxidative stress.

Results: We found that Spermidine (SPD) significantly increased protein expression of autophagy markers microtubule-associated protein 1 light chain 3 beta-II (MAP1LC3B-II/LC3B-II) and sequestosome-1/p62 (SQSTM1/p62), and evoked autophagic flux in FGSCs. Moreover, SPD increased the number and viability of FGSCs in vitro. Further, we found that SPD significantly reduced basal or hydrogen peroxide (HO)-induced up-regulated protein expression of the aging markers, cyclin dependent kinase inhibitor 2A (p16/CDKN2A) and tumor protein 53 (p53). After knockdown of p62 in FGSCs, p16 protein levels were significant higher compared with controls. However, protein p16 levels were not significantly changed in p62 knockdown FGSCs with SPD treatment compared with without SPD. Moreover, SPD significantly changed the expression of autophagy-related genes and pathways in FGSCs, as shown by bioinformatics analysis of RNA sequencing data. Additionally, SPD significantly inhibited AKT/mTOR phosphorylation.

Conclusions: SPD induces cytoprotective autophagy in FGSCs in vitro and ameliorates cellular senescence of FGSCs induced by HO. Furthermore, SPD can ameliorate cellular senescence of FGSCs through p62. SPD might induce autophagy in FGSCs via the PI3K/Akt pathway. Our findings could be helpful for delaying aging of female germ cells due to oxidative stress and preserving female fertility.
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http://dx.doi.org/10.1186/s13578-021-00614-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186080PMC
June 2021

Evaluating DNA Methylation, Gene Expression, Somatic Mutation, and Their Combinations in Inferring Tumor Tissue-of-Origin.

Front Cell Dev Biol 2021 3;9:619330. Epub 2021 May 3.

Academician Workstation, Changsha Medical University, Changsha, China.

Carcinoma of unknown primary (CUP) is a type of metastatic cancer, the primary tumor site of which cannot be identified. CUP occupies approximately 5% of cancer incidences in the United States with usually unfavorable prognosis, making it a big threat to public health. Traditional methods to identify the tissue-of-origin (TOO) of CUP like immunohistochemistry can only deal with around 20% CUP patients. In recent years, more and more studies suggest that it is promising to solve the problem by integrating machine learning techniques with big biomedical data involving multiple types of biomarkers including epigenetic, genetic, and gene expression profiles, such as DNA methylation. Different biomarkers play different roles in cancer research; for example, genomic mutations in a patient's tumor could lead to specific anticancer drugs for treatment; DNA methylation and copy number variation could reveal tumor tissue of origin and molecular classification. However, there is no systematic comparison on which biomarker is better at identifying the cancer type and site of origin. In addition, it might also be possible to further improve the inference accuracy by integrating multiple types of biomarkers. In this study, we used primary tumor data rather than metastatic tumor data. Although the use of primary tumors may lead to some biases in our classification model, their tumor-of-origins are known. In addition, previous studies have suggested that the CUP prediction model built from primary tumors could efficiently predict TOO of metastatic cancers (Lal et al., 2013; Brachtel et al., 2016). We systematically compared the performances of three types of biomarkers including DNA methylation, gene expression profile, and somatic mutation as well as their combinations in inferring the TOO of CUP patients. First, we downloaded the gene expression profile, somatic mutation and DNA methylation data of 7,224 tumor samples across 21 common cancer types from the cancer genome atlas (TCGA) and generated seven different feature matrices through various combinations. Second, we performed feature selection by the Pearson correlation method. The selected features for each matrix were used to build up an XGBoost multi-label classification model to infer cancer TOO, an algorithm proven to be effective in a few previous studies. The performance of each biomarker and combination was compared by the 10-fold cross-validation process. Our results showed that the TOO tracing accuracy using gene expression profile was the highest, followed by DNA methylation, while somatic mutation performed the worst. Meanwhile, we found that simply combining multiple biomarkers does not have much effect in improving prediction accuracy.
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http://dx.doi.org/10.3389/fcell.2021.619330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126648PMC
May 2021

Genomic variation, origin tracing, and vaccine development of SARS-CoV-2: A systematic review.

Innovation (N Y) 2021 May 11;2(2):100116. Epub 2021 May 11.

Genetic Testing Center, Academician Workstation, Changsha Medical University, Changsha 410219, China.

COVID-19 has spread globally to over 200 countries with more than 40 million confirmed cases and one million deaths as of November 1, 2020. The SARS-CoV-2 virus, leading to COVID-19, shows extremely high rates of infectivity and replication, and can result in pneumonia, acute respiratory distress, or even mortality. SARS-CoV-2 has been found to continue to rapidly evolve, with several genomic variants emerging in different regions throughout the world. In addition, despite intensive study of the spike protein, its origin, and molecular mechanisms in mediating host invasion are still only partially resolved. Finally, the repertoire of drugs for COVID-19 treatment is still limited, with several candidates still under clinical trial and no effective therapeutic yet reported. Although vaccines based on either DNA/mRNA or protein have been deployed, their efficacy against emerging variants requires ongoing study, with multivalent vaccines supplanting the first-generation vaccines due to their low efficacy against new strains. Here, we provide a systematic review of studies on the epidemiology, immunological pathogenesis, molecular mechanisms, and structural biology, as well as approaches for drug or vaccine development for SARS-CoV-2.
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http://dx.doi.org/10.1016/j.xinn.2021.100116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110321PMC
May 2021

A Systematic Analysis on COVID-19 Patients in Inner Mongolia Based on Dynamic Monitoring.

Biomed Res Int 2021 20;2021:5559187. Epub 2021 Apr 20.

Department of Pulmonary and Critical Care Medicine/Key Laboratory of National Health Commission for the Diagnosis & Treatment of COPD, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, China.

COVID-19 has spread globally with over 90,000,000 incidences and 1,930,000 deaths by Jan 11, 2021, which poses a big threat to public health. It is urgent to distinguish COVID-19 from common pneumonia. In this study, we reported multiple clinical feature analyses on COVID-19 in Inner Mongolia for the first time. We dynamically monitored multiple clinical features of all 75 confirmed COVID-19 patients, 219 pneumonia patients, and 68 matched healthy people in Inner Mongolia. Then, we studied the association between COVID-19 and clinical characteristics, based on which to construct a novel logistic regression model for predicting COVID-19. As a result, among the tested clinical characteristics, WBC, hemoglobin, C-reactive protein (CRP), ALT, and Cr were significantly different between COVID-19 patients and patients in other groups. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.869 for the logistic regression model using multiple factors associated with COVID-19. Furthermore, the CRP reaction showed five different time-series patterns with one-peak and double-peak modes. In conclusion, our study identified a few clinical characteristics significantly different between COVID-19 patients and others in Inner Mongolia. The features can be used to establish a reliable logistic regression model for predicting COVID-19.
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http://dx.doi.org/10.1155/2021/5559187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059476PMC
May 2021

Novel circGFRα1 Promotes Self-Renewal of Female Germline Stem Cells Mediated by mA Writer METTL14.

Front Cell Dev Biol 2021 12;9:640402. Epub 2021 Apr 12.

Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Renji Hospital, School of Medicine, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.

Circular RNAs (circRNAs) play important roles in the self-renewal of stem cells. However, their significance and regulatory mechanisms in female germline stem cells (FGSCs) are largely unknown. Here, we identified an -methyladenosine (mA)-modified circRNA, circGFRα1, which is highly abundant in mouse ovary and stage-specifically expressed in mouse FGSC development. Knockdown of circGFRα1 in FGSCs significantly reduced their self-renewal. In contrast, overexpression of circGFRα1 enhanced FGSC self-renewal. Mechanistically, circGFRα1 promotes FGSC self-renewal by acting as a competing endogenous RNA (ceRNA) that sponges miR-449, leading to enhanced GFRα1 expression and activation of the glial cell derived neurotrophic factor (GDNF) signaling pathway. Furthermore, circGFRα1 acts as a ceRNA based on METTL14-mediated cytoplasmic export through the GGACU motif. Our study should help to understand the mechanisms regulating germ cell development, add new evidence on the mechanism of action of circRNA, and deepen our understanding of the development of FGSCs.
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http://dx.doi.org/10.3389/fcell.2021.640402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076159PMC
April 2021

Vascular endothelial growth factor B inhibits insulin secretion in MIN6 cells and reduces Ca and cyclic adenosine monophosphate levels through PI3K/AKT pathway.

World J Diabetes 2021 Apr;12(4):480-498

Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China.

Background: Type 2 diabetes (T2D) is characterized by insufficient insulin secretion caused by defective pancreatic β-cell function or insulin resistance, resulting in an increase in blood glucose. However, the mechanism involved in this lack of insulin secretion is unclear. The level of vascular endothelial growth factor B (VEGF-B) is significantly increased in T2D patients. The inactivation of VEGF-B could restore insulin sensitivity in db/db mice by reducing fatty acid accumulation. It is speculated that VEGF-B is related to pancreatic β-cell dysfunction and is an important factor affecting β-cell secretion of insulin. As an model of normal pancreatic β-cells, the MIN6 cell line can be used to analyze the mechanism of insulin secretion and related biological effects.

Aim: To study the role of VEGF-B in the insulin secretion signaling pathway in MIN6 cells and explore the effect of VEGF-B on blood glucose regulation.

Methods: The MIN6 mouse pancreatic islet β-cell line was used as the model system. By administering exogenous VEGF-B protein or knocking down VEGF-B expression in MIN6 cells, we examined the effects of VEGF-B on insulin secretion, Ca and cyclic adenosine monophosphate (cAMP) levels, and the insulin secretion signaling pathway.

Results: Exogenous VEGF-B inhibited the secretion of insulin and simultaneously reduced the levels of Ca and cAMP in MIN6 cells. Exogenous VEGF-B also reduced the expression of phospholipase C gamma 1 (PLCγ1), phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), and other proteins in the insulin secretion pathway. Upon knockdown of VEGF-B, MIN6 cells exhibited increased insulin secretion and Ca and cAMP levels and upregulated expression of PLCγ1, PI3K, AKT, and other proteins.

Conclusion: VEGF-B can regulate insulin secretion by modulating the levels of Ca and cAMP. VEGF-B involvement in insulin secretion is related to the expression of PLCγ1, PI3K, AKT, and other signaling proteins. These results provide theoretical support and an experimental basis for the study of VEGF-B in the pathogenesis of T2D.
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http://dx.doi.org/10.4239/wjd.v12.i4.480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040075PMC
April 2021

Structures of chaperone-associated assembly intermediates reveal coordinated mechanisms of proteasome biogenesis.

Nat Struct Mol Biol 2021 05 12;28(5):418-425. Epub 2021 Apr 12.

Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.

The proteasome mediates most selective protein degradation. Proteolysis occurs within the 20S core particle (CP), a barrel-shaped chamber with an αββα configuration. CP biogenesis proceeds through an ordered multistep pathway requiring five chaperones, Pba1-4 and Ump1. Using Saccharomyces cerevisiae, we report high-resolution structures of CP assembly intermediates by cryogenic-electron microscopy. The first structure corresponds to the 13S particle, which consists of a complete α-ring, partial β-ring (β2-4), Ump1 and Pba1/2. The second structure contains two additional subunits (β5-6) and represents a later pre-15S intermediate. These structures reveal the architecture and positions of Ump1 and β2/β5 propeptides, with important implications for their functions. Unexpectedly, Pba1's N terminus extends through an open CP pore, accessing the CP interior to contact Ump1 and the β5 propeptide. These results reveal how the coordinated activity of Ump1, Pba1 and the active site propeptides orchestrate key aspects of CP assembly.
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http://dx.doi.org/10.1038/s41594-021-00583-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160580PMC
May 2021

Influences of puff protocols and upper airway anatomy on cannabis pharmacokinetics: A CFPD-PK study.

Comput Biol Med 2021 05 13;132:104333. Epub 2021 Mar 13.

Office of Pharmaceutical Quality, Center for Drug Evaluation Research, US Food and Drug Administration, USA.

Predicting the optimal administration doses of the inhaled Δ9-tetrahydrocannabinol (THC), i.e., one of the major natural compounds in cannabis, is critical for maximizing the therapeutic outcomes and minimizing the toxic side effects. Thus, it is essential to developing an aerosol dosimetry model to simulate the transport, deposition, and translocation of inhaled THC aerosols from the human respiratory system to the systemic region. In this study, a computational fluid-particle dynamics (CFPD) plus pharmacokinetics (PK) model was developed and validated to quantify the localized vapor and particle uptake rates of THC and the resultant THC-plasma concentrations using two human upper airway geometries. In addition, two different puff protocols (4.0/10.0 s and 1.6/11.4 s as the inhalation/holding time ratios) were employed, associated with two different inhaled THC doses (2.0 mg and 8.82 mg, respectively). The computational results demonstrated that multiple parameters had noticeable influences on THC particle deposition and vapor absorption in the upper airways, as well as the resultant pharmacokinetic behaviors. These factors include anatomical features of the upper airway, puff flow rate, duration, and holding time. The results indicated that puff protocol with 4.0/10.0 s inhalation/holding time ratio would be recommended if the treatment needs THC delivery to the deeper lung. Furthermore, the inhaled THC dose had a dominant effect on the THC-plasma PK profiles, which could override the influences of anatomical variability and puff protocols. The developed CFPD-PK modeling framework has the potential to provide localized lung absorption data and PK profiles for in vitro-in vivo correlation, as well as supporting the development and assessment of drug products containing cannabis or cannabis-derived compounds.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104333DOI Listing
May 2021

Prioritizing antiviral drugs against SARS-CoV-2 by integrating viral complete genome sequences and drug chemical structures.

Sci Rep 2021 03 18;11(1):6248. Epub 2021 Mar 18.

School of Computer Science, Hunan University of Technology, Zhuzhou, 412007, China.

The outbreak of a novel febrile respiratory disease called COVID-19, caused by a newfound coronavirus SARS-CoV-2, has brought a worldwide attention. Prioritizing approved drugs is critical for quick clinical trials against COVID-19. In this study, we first manually curated three Virus-Drug Association (VDA) datasets. By incorporating VDAs with the similarity between drugs and that between viruses, we constructed a heterogeneous Virus-Drug network. A novel Random Walk with Restart method (VDA-RWR) was then developed to identify possible VDAs related to SARS-CoV-2. We compared VDA-RWR with three state-of-the-art association prediction models based on fivefold cross-validations (CVs) on viruses, drugs and virus-drug associations on three datasets. VDA-RWR obtained the best AUCs for the three fivefold CVs, significantly outperforming other methods. We found two small molecules coming together on the three datasets, that is, remdesivir and ribavirin. These two chemical agents have higher molecular binding energies of - 7.0 kcal/mol and - 6.59 kcal/mol with the domain bound structure of the human receptor angiotensin converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein, respectively. Interestingly, for the first time, experimental results suggested that navitoclax could be potentially applied to stop SARS-CoV-2 and remains to further validation.
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http://dx.doi.org/10.1038/s41598-021-83737-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973547PMC
March 2021

The role of Elabela in kidney disease.

Int Urol Nephrol 2021 Sep 8;53(9):1851-1857. Epub 2021 Mar 8.

Department of Nephrology, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, Jilin, China.

Elabela, also known as Toddler or Apela, is a recently discovered hormonal peptide containing 32 amino acids. Elabela is a ligand of the apelin receptor (APJ). APJ is a G protein-coupled receptor widely expressed throughout body, and together with its cognate ligand, apelin, it plays an important role in various physiological processes including cardiovascular functions, angiogenesis and fluid homeostasis. Elabela also participates in embryonic development and pathophysiological processes in adulthood. Elabela is highly expressed in undifferentiated embryonic stem cells and regulates endoderm differentiation and cardiovascular system development. During differentiation, Elabela is highly expressed in pluripotent stem cells and in adult renal collecting ducts and loops, where it functions to maintain water and sodium homeostasis. Other studies have also shown that Elabela plays a crucial role in the pathogenesis of kidney diseases. This review addresses the role of Elabela in kidney diseases including renal ischemia/reperfusion injury, hypertensive nephropathy, diabetic nephropathy, and cardiorenal syndrome.
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http://dx.doi.org/10.1007/s11255-021-02790-1DOI Listing
September 2021

Identification of Tumor Tissue of Origin with RNA-Seq Data and Using Gradient Boosting Strategy.

Biomed Res Int 2021 17;2021:6653793. Epub 2021 Feb 17.

School of Mathematics and Statistics, Hainan Normal University, Haikou 570100, China.

Background: Cancer of unknown primary (CUP) is a type of malignant tumor, which is histologically diagnosed as a metastatic carcinoma while the tissue-of-origin cannot be identified. CUP accounts for roughly 5% of all cancers. Traditional treatment for CUP is primarily broad-spectrum chemotherapy; however, the prognosis is relatively poor. Thus, it is of clinical importance to accurately infer the tissue-of-origin of CUP.

Methods: We developed a gradient boosting framework to trace tissue-of-origin of 20 types of solid tumors. Specifically, we downloaded the expression profiles of 20,501 genes for 7713 samples from The Cancer Genome Atlas (TCGA), which were used as the training data set. The RNA-seq data of 79 tumor samples from 6 cancer types with known origins were also downloaded from the Gene Expression Omnibus (GEO) for an independent data set.

Results: 400 genes were selected to train a gradient boosting model for identification of the primary site of the tumor. The overall 10-fold cross-validation accuracy of our method was 96.1% across 20 types of cancer, while the accuracy for the independent data set reached 83.5%.

Conclusion: Our gradient boosting framework was proven to be accurate in identifying tumor tissue-of-origin on both training data and independent testing data, which might be of practical usage.
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http://dx.doi.org/10.1155/2021/6653793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904362PMC
May 2021

A Novel XGBoost Method to Infer the Primary Lesion of 20 Solid Tumor Types From Gene Expression Data.

Front Genet 2021 3;12:632761. Epub 2021 Feb 3.

Department of Breast Surgical Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China.

Purpose: Establish a suitable machine learning model to identify its primary lesions for primary metastatic tumors in an integrated learning approach, making it more accurate to improve primary lesions' diagnostic efficiency.

Methods: After deleting the features whose expression level is lower than the threshold, we use two methods to perform feature selection and use XGBoost for classification. After the optimal model is selected through 10-fold cross-validation, it is verified on an independent test set.

Results: Selecting features with around 800 genes for training, the -score of a 10-fold CV of training data can reach 96.38%, and the -score of test data can reach 83.3%.

Conclusion: These findings suggest that by combining tumor data with machine learning methods, each cancer has its corresponding classification accuracy, which can be used to predict primary metastatic tumors' location. The machine-learning-based method can be used as an orthogonal diagnostic method to judge the machine learning model processing and clinical actual pathological conditions.
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http://dx.doi.org/10.3389/fgene.2021.632761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886791PMC
February 2021

Differential expression analysis of urinary exosomal circular RNAs in patients with IgA nephropathy.

Nephrology (Carlton) 2021 May 11;26(5):432-441. Epub 2021 Feb 11.

Department of Nephrology, The Second Hospital of Jilin University, Changchun, China.

Aims: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease to cause end-stage kidney disease. This study investigated the difference in urinary exosomal circular RNA (circRNA) expression profiles between patients with IgAN and healthy controls (HCs), for better understanding of gene regulation in exosomes of IgAN patients.

Methods: A pairwise comparison of urinary circRNA expression profiles between IgAN patients and HCs was performed using methods, including high-throughput sequencing and quantitative polymerase chain reaction. Moreover, the potential functions of differentially expressed circRNAs (DECs) in IgAN were investigated by gene ontology (GO) enrichment analysis; Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis; and the circRNA-miRNA-mRNA network.

Results: We identified 450 upregulated and 26 downregulated circRNAs in the IgAN patients. GO analysis showed that these enriched circRNAs might regulate primary miRNA processing, the ability of angiotensin receptor binding, and stress fibre function. KEGG analysis suggested these DECs may be closely associated with the phosphoinositide-3-kinase-protein kinase B/Akt (PI3K-Akt) signalling pathways. Network analysis revealed the relationship between circRNAs and their target genes.

Conclusion: The identified DECs may be useful for both researches on molecular aetiology of IgAN and development of potentially novel non-invasive biomarkers of IgAN.
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http://dx.doi.org/10.1111/nep.13855DOI Listing
May 2021

Protective Role of a New Polysaccharide Extracted from in Mice with Ulcerative Colitis Induced by Dextran Sulphate Sodium.

Biomed Res Int 2021 2;2021:8878633. Epub 2021 Jan 2.

Geneis Beijing Co., Ltd., Beijing 100102, China.

is a traditional Chinese herbal medicine for treating intestinal inflammation. The extraction method of polysaccharide (LJP) has been developed previously by our research group. In this study, a Fourier transform infrared spectrometer (FT-IR) was used to perform a qualitative analysis of LJP and a precolumn derivatization high-performance liquid chromatography (HPLC) ((Palo Alto, CA, USA) method was used to explore the monosaccharide composition of LJP. Then, we studied the effect of LJP on the intestinal flora and immune functions of dextran sulfate sodium- (DSS-) induced colitis ulcerative mouse models. The results showed that LJP was consisted of 6 types of monosaccharides and had the characteristic absorption of typical polysaccharides. LJP can increase significantly the weight, organ index, serum cytokines (interleukin, tumor necrosis factor, and interferon-), secretory immunoglobulin A (SIgA) concentration, and natural killer (NK) cell and cytotoxic lymphocyte (CTL) activities in DSS-treated mice. The results of intestinal flora showed that a high dose (150 mg kg) of LJP had the best effects on improving the intestinal probiotics ( and ) and antagonizing the pathogenic bacteria ( and ). In addition, the measurement results of the spleen lymphocyte apoptosis confirmed from another perspective that LJP had protective effects of immune cells for DSS-treated mice.
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http://dx.doi.org/10.1155/2021/8878633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801063PMC
May 2021

Comparison of RNA mA and DNA methylation profiles between mouse female germline stem cells and STO cells.

Mol Ther Nucleic Acids 2021 Mar 26;23:431-439. Epub 2020 Nov 26.

Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan 750004, China.

N-methyladenosine (mA) methylation modification is the most prevalent and abundant internal modification of eukaryotic mRNAs. Increasing evidence has shown that mRNA mA plays important roles in the development of stem cells. However, to the best of our knowledge, no reports about the roles of mRNA mA in mouse female germline stem cells (mFGSCs) have been published. In this study, we compared the genome-wide profiles of mRNA mA methylation and DNA methylation between FGSCs and sandosinbred mice (SIM) embryo-derived thioguanine and ouabain-resistant (STO) cells. qRT-PCR revealed that the expression levels of mRNA mA-related genes (, , , , , and ) in FGSCs were significantly higher than those in STO cells. mA RNA immunoprecipitation sequencing (MeRIP-seq) data further showed that the unique mA-methylated mRNAs in FGSCs and STO cells were related to cell population proliferation and somatic development, respectively. Additionally, knockdown of inhibited FGSC self-renewal. Comparison of methylated DNA immunoprecipitation sequencing (MeDIP-seq) results between FGSCs and STO cells identified that DNA methylation contributed to FGSC proliferation by suppressing the somatic program. These results suggested that mA regulated FGSC self-renewal possibly through mA binding protein YTHDF1, and DNA methylation repressed somatic programs in FGSCs to maintain FGSC characteristics.
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http://dx.doi.org/10.1016/j.omtn.2020.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803632PMC
March 2021

Development of an RTD-Based Flowsheet Modeling Framework for the Assessment of In-Process Control Strategies.

AAPS PharmSciTech 2021 Jan 5;22(1):25. Epub 2021 Jan 5.

Office of Pharmaceutical Quality, Center for Drug Evaluation Research, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA.

Continuous manufacturing (CM) is an emerging technology which can improve pharmaceutical manufacturing and reduce drug product quality issues. One challenge that needs to be addressed when adopting CM technology is material traceability through the entire continuous process, which constitutes one key aspect of control strategy. Residence time distribution (RTD) plays an important role in material traceability as it characterizes the material spreading through the process. The propagation of upstream disturbances could be predictively tracked through the entire process by convolution of the disturbance and the RTD. The present study sets up the RTD-based modeling framework in a commonly used process modeling environment, gPROMS, and integrates it with existing modules and built-in tools (e.g., parameter estimation). Concentration calculations based on the convolution integral requires access to historical stream property information, which is not readily available in flowsheet modeling platforms. Thus, a novel approach is taken whereby a partial differential equation is used to propagate and store historical data as the simulation marches forward in time. Other stream properties not modeled by an RTD are determined in auxiliary modules. To illustrate the application of the framework, an integrated RTD-auxiliary model for a continuous direct compression manufacturing line was developed. An excellent agreement was found between the model predictions and experiments. The validated model was subsequently used to assess in-process control strategies for feeder and material traceability through the process. Our simulation results show that the employed modeling approach facilitates risk-based assessment of the continuous line by promoting our understanding on the process.
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http://dx.doi.org/10.1208/s12249-020-01913-8DOI Listing
January 2021

Revealing the Interactions Between Diabetes, Diabetes-Related Diseases, and Cancers Based on the Network Connectivity of Their Related Genes.

Front Genet 2020 14;11:617136. Epub 2020 Dec 14.

Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Treatment, Guangzhou, China.

Diabetes-related diseases (DRDs), especially cancers pose a big threat to public health. Although people have explored pathological pathways of a few common DRDs, there is a lack of systematic studies on important biological processes (BPs) connecting diabetes and its related diseases/cancers. We have proposed and compared 10 protein-protein interaction (PPI)-based computational methods to study the connections between diabetes and 254 diseases, among which a method called DIconnectivity_eDMN performs the best in the sense that it infers a disease rank (according to its relation with diabetes) most consistent with that by literature mining. DIconnectivity_eDMN takes diabetes-related genes, other disease-related genes, a PPI network, and genes in BPs as input. It first maps genes in a BP into the PPI network to construct a BP-related subnetwork, which is expanded (in the whole PPI network) by a random walk with restart (RWR) process to generate a so-called expanded modularized network (eMN). Since the numbers of known disease genes are not high, an RWR process is also performed to generate an expanded disease-related gene list. For each eMN and disease, the expanded diabetes-related genes and disease-related genes are mapped onto the eMN. The association between diabetes and the disease is measured by the reachability of their genes on all eMNs, in which the reachability is estimated by a method similar to the Kolmogorov-Smirnov (KS) test. DIconnectivity_eDMN achieves an area under receiver operating characteristic curve (AUC) of 0.71 for predicting both Type 1 DRDs and Type 2 DRDs. In addition, DIconnectivity_eDMN reveals important BPs connecting diabetes and DRDs. For example, "respiratory system development" and "regulation of mRNA metabolic process" are critical in associating Type 1 diabetes (T1D) and many Type 1 DRDs. It is also found that the average proportion of diabetes-related genes interacting with DRDs is higher than that of non-DRDs.
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http://dx.doi.org/10.3389/fgene.2020.617136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767993PMC
December 2020

[Protective effect of taurine against formaldehyde-induced male reproductive toxicity in adult male rats].

Zhonghua Nan Ke Xue 2020 Sep;26(9):777-782

Guizhou Medical University, Guiyang, Guizhou 550004, China.

Objective: To study the effect of taurine on the reproductive toxicity damage induced by formaldehyde (FM) in adult male rats.

Methods: Forty-eight SD adult male rats were equally randomized into a normal control, an FM poisoning (FMP), a taurine intervention (TI), and an TI+FMP group. The control rats were given normal diet and gavage of saline, the rats of the FMP group treated intraperitoneally with FM at 10 mg/kg qd alt, those of the TI group intragastrically with taurine at 100 mg/kg qd, and those of the TI+FMP group with both FM and taurine at the above doses. After 30 days of treatment, the blood of the abdominal cardinal vein of the rats was extracted for measurement of the levels of serum hormones, the body weight, testis weight and testicular coefficient obtained, the testis tissue subjected to HE staining, and the expressions of Bcl-2 and Bax determined by Western blot.

Results: There were no statistically significant differences among the four groups of rats in the body weight, testis weight or testicular coefficient (P > 0.05). The rats in the FMP group showed obviously decreased testicular spermatogenic cells and disordered layers and loose structure of seminiferous tubules, which were basically restored to normal after taurine intervention. Compared with the normal controls, the animals of the TI group exhibited no significant abnormality, but those of the FMP group presented markedly reduced levels of serum T, LH and FSH (P < 0.05), and dramatically increased level of Gonadotropin-releasing hormone (GnRH) (P < 0.01). The levels of serum hormones were all significantly improved (P < 0.05) and that of the apoptotic protein Bax basically returned to normal (P < 0.05) after taurine intervention.

Conclusions: Taurine has a certain protective effect against male reproductive toxicity caused by formaldehyde.
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September 2020

Identifying cortical specific long noncoding RNAs modified by mA RNA methylation in mouse brains.

Epigenetics 2020 Dec 23:1-17. Epub 2020 Dec 23.

Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen, China.

Proper development of the mammalian cerebral cortex relies on precise gene expression regulation. Increasing evidence shows that cortical development is regulated by both mRNAs and long noncoding RNAs (lncRNAs), which also are modified by -methyladenosine (mA). Patterns of mA-methylation in lncRNAs in the developing cortex have not been uncovered. Here we reveal differentially expressed lncRNAs and report stage-specific mA-methylation patterns in lncRNAs expressed in mouse embryonic (E) and postnatal (P) cortices using RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation (MeRIP) sequencing. Many lncRNAs show temporal differential expression, and display genic distribution in the genome. Interestingly, we detect temporal-specific mA-methylation with consensus mA motif GGACU in the last exon in most lncRNAs. And mA methylation levels of lncRNAs are positively correlated with the transcript abundance of lncRNAs that have no significantly differential expression in E- and P-stages. Furthermore, the transcript abundance has a positive correlation between the mA genic lncRNAs and their nearest mA methylated mRNAs. Our work reveals a fundamental expression reference of lncRNAs and their nearest mRNAs, and highlights an importance of mA-mediated epitranscriptomic modifications in lncRNAs that are temporally expressed in the developing cortex.
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http://dx.doi.org/10.1080/15592294.2020.1861170DOI Listing
December 2020
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