bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brusatol Sensitizes Endometrial Hyperplasia and Cancer to Progestin by Suppressing Nrf2-Tet1-AKR1C1-Mediated Progestin Metabolism
Authors: Hu Meiyan , Sun Di , Yu Jing , Fu Yue , Qin Zuoshu , Huang Baozhu , Zhang Qiuju , Chen Xiong , Wei Youheng , Zhu Huiting , Wang Yue , Feng Youji , Zheng Wenxin , Liao Hong , Li Jingjie , Wu Sufang , Zhang Zhenbo 
Published: May 2021

Abstract
BackgroundProgestin resistance is the main obstacle for the conservative therapy to maintain fertility in women with endometrial hyperplasia and cancer. Up to 30% of endometrial cancers fail to respond to progestin, a rate that has not significantly changed due to the lack of a detailed understanding of progestin resistance.MethodsCell Counting Kit-8 (CCK-8) assays were used to detect the synergistic effects of brusatol in combination with progestin. Using commercial kits, the conversion of progestin to 20α-dihydroxyprogesterone following btusatol treatment or AKR1C1 silence was investigated. The correlation betwwen AKR1C1 expression profile and prgestin response was further analyzed in paired endometrial hyperplasia and cancer samples from the same individuals before and after progestin therapy. The effects of brusatol-mediated reversal of progestin resistance was explored in both mouse xenograft and human organoid models. DNA dot blot, HMeDIP, and dural-luciferase reporter assays were performed to uncover the mechanism through which brusatol inhibits AKR1C1 and sensitizes endometrial hyperplasia and cancer to progestin.ResultsBrusatol sensitizes endometrial cancer cell to progestin by downregulating the expression of Nrf2 and its target AKR1C1. Increased AKR1C1 facilitated production of 20-α-dihydroxyprogeserone and was associated with declined progesterone. Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth. Aberrant overexpression of AKR1C1 was found in paired endometrial hyperplasia and cancer samples from the same individuals with progestin resistance, whereas attenuated or loss of AKR1C1 was observed in post-treatment samples with well progestin response as compared with paired pre-treatment tissues. Tet1 was identified as a novel Nrf2 target gene. It in turn upregulated AKR1C1 expression by increasing hydroxymethylation levels in its promoter regions. ConclusionsWe found that Nrf2-Tet1-AKR1C1 axis plays an essential role in progestin resistance, and brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing Nrf2-Tet1-AKR1C1-mediated progestin metabolism. Our findings suggest that AKR1C1 expression pattern may serve as an important biomarker of progestin resistance in endometrial hyperplasia and cancer .
The Burden of Drug Resistant Tuberculosis in a predominantly nomadic population in Uganda. A Mixed Methods Study
Authors: Simbwa Brenda Nakafeero , Katana Elizabeth B. , Nabatanzi Sandra , Sendaula Emmanuel , Karamagi Charles A. , Kalyango Joan N. , Opio Denis , Laker Eva A.O. , Katamba Achilles , Worodria William , Ictho Jerry , Lochoro Peter 
Published: May 2021

Abstract
Background: Emergence of Drug Resistant Tuberculosis (DR-TB) has aggravated the Tuberculosis (TB) public health burden worldwide and especially in low income settings. We present findings from a predominantly nomadic population in Karamoja, Uganda with a high-TB burden (3,500 new cases annually) and sought to determine the prevalence, patterns, factors associated with DR-TB. Methods: We used mixed methods of data collection. We enrolled 6890 participants who were treated for tuberculosis in a programmatic setting between January 2015 and April 2018. A cross sectional study and a matched case control study with conditional logistic regression and robust standard errors respectively were used to the determine prevalence and factors associated with DR-TB. The qualitative methods included focus group discussions, in-depth interviews and key informant interviews. Results: The overall prevalence of DR-TB was 41/6890 (0.6%) with 4/64197 (0.1%) among the new and 37/2693 (1.4%) among the previously treated TB patients respectively. The drug resistance patterns observed in the region were mainly rifampicin mono resistant (68.3%) and Multi Drug-Resistant Tuberculosis (31.7%). Factors independently associated with DR-TB were previous TB treatment, adjusted odds ratio (aOR) 13.070 (95%CI: 1.552 – 110.135) and drug stock-outs aOR 0.027 (95%CI: 0.002-0.364). The nomadic lifestyle, substance use, congested homesteads and poor health worker attitudes were a great challenge to effective treatment of TB. Conclusion: Despite having the highest national TB incidence, Karamoja still has a low DR-TB prevalence. Previous TB treatment and drug stock outs were associated with DR-TB. Regular supply of anti TB medications and health education may help to stem the burden of TB disease in this nomadic population.
Expression and Purification of the Extracellular Domain of Luteinizing Hormone Receptor From Ovis Aries Testicle
Authors: Villalpando-Aguilar Jose Luis , López-Rosas Itzel , Montero-Pardo Arnulfo , Azuara-Liceaga Elisa Irene , Valencia-Méndez Javier de Jesus , Trejo-Muñoz Cynthia R. , Cetzal-Ix William Rolando , Kubli-Garfias Carlos 
Published: May 2021

Abstract
The luteinizing hormone receptor (LHR) is a glycoprotein member of the G protein-coupled receptor superfamily. Physiologically, this receptor participates in corpus luteum formation and ovulation in females. In males, it acts in testosterone synthesis and spermatogenesis and is involved in some fertility disorders. RNA was extracted from Ovis aries testicles, and the corresponding cDNA was synthesized to amplify the lhr gene, termed lhr-bed here, consisting of 762 bp that encodes 273 amino acids of the extracellular domain of LHR. Thus, the lhr-bed was cloned into pJET1.2/blunt, subcloned into the pCOLD II expression vector and finally transformed into E. coli BL21 cells. Since the induced rLHR-Bed protein was found in the insoluble fraction, the purification protocol was modified as follows: induction at 25°C, denaturing conditions (8 M UREA and 0.1% CHAPS) and refolding in the column to increase solubility. The rLHR-Bed expression was corroborated by western blotting and mass spectrometry (MS) analysis. This successful method to obtain the recombinant LHR extracellular domain yields 0.2 mg/L of the protein with approximately 90% purity from a single chromatographic purification step. The present approach demonstrates the feasibility of obtaining large quantities of rLHR-Bed. This might be useful to accomplish future studies regarding the structure and functional analysis of the binding interplay with its ligand luteinizing hormone and its isoforms. Additionally, this biotechnological strategy might be used to improve and to develop new drugs for the treatment of reproductive disorders and might also be applied to species reproduction in the livestock industry.
Design and Analysis of a Novel MEMS Piezoresistive Pressure Sensor with Annular Groove Membrane and Centre Mass for Low Pressure Measurements
Authors: SAHAY ROHAN , HIRWANI JAGRITI , Jindal Sumit Kumar , K SREEKANTH P , KUMAR AJAY 
Published: May 2021

Abstract
Purpose: Micro Electronic Mechanical System (MEMS) based pressure sensors have found their use in multiple applications lately in the field of healthcare, automotive etc. These sensors however face a trade-off between sensitivity and linearity which limits sensor performance. The proposed design aims to achieve an enhanced sensor performance by alleviating the sensitivity and linearity trade-off.Methods: Novel structures such as annular grooves and center mass have been introduced for providing better sensor performance along with membrane dimension optimization. Annular grooves generate Stress Concentrated Regions (SCRs) on membrane surface on application of external pressure which enhances sensor sensitivity while center mass provides partial stiffening of the membrane and hence reduces non-linearity.Results: The proposed sensor achieves a low non-linearity error of 0.15% FSS with a well-balanced sensitivity of 28.0 mV/V/psi. Conclusion: The proposed novel sensor structure achieves a relatively better performance in comparison to conventional membrane variants. With a high sensitivity and appreciable linearity, the novel structure proves to be ideal for low pressure measurements in the range (0-5)KPa.
The effect of Curcumin on Multi-Level Immune Checkpoint Blockade and T Cell Dysfunction in Head and Neck Cancer
Authors: Liu Lihua , Lim Mi Ae , Jung Seung-Nam , Oh Chan , Won Ho-Ryun , Jin Yan Li , Piao Yudan , Kim Hae Jong , Chang Jae Won , Koo Bon Seok 
Published: May 2021

Abstract
BackgroundDespite recent advances in understanding the complex immunologic dysfunction in the tumor microenvironment (TME), fewer than 20% of patients with head and neck squamous cell carcinoma (HNSCC) respond to immune checkpoint blockade (ICB). Thus, it is important to understand how inhibitory IC receptors maintain the suppressed dysfunctional TME, and to develop more effective combination immunotherapy. This study evaluated the immune-modulating effects of Curcumin, which has well-established anti-cancer and chemopreventive properties, and its long-term safety as a phytochemical drug.MethodsWe carried out the western blot and small interfering RNA (siRNA) transfection assayto evaluate the effects of Curcumin on IC ligands and IC ligands function in HNSCC. Through T-cell cytotoxicity assay and measurements of cytokine secretion, we assessed the effects of combination of Curcumin with programmed death-ligand 1 (PD-L1) Ab on cancer cell killing. Flow cytometry were used to analyze the effects of Curcumin on the expression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain3 (TIM-3) on CD4, CD8 and Treg. Immunofluorescence, immunohistochemistry and western blot were used to detecte the cytokine (IFN-γ, Granzyme B), IC receptors (PD-1 and TIM-3) and its ligands (PD-L1, PD-L2, Galectin-9) in xenograft mouse model and 4-nitroquinoline-1-oxide (4-NQO) oral cancer model. ResultsWe found that Curcumin decreased the expression of IC ligands such as PD-L1, PD-L2, and Galectin-9 in HNSCC, leading to regulation of epithelial-to-mesenchymal transition-associated tumor invasion. Curcumin also effectively restored the ability of CD8+ cytotoxic T cells to lyse cancer cells. To evaluate the effect of Curcumin on the TME further, the 4-NQO oral cancer model was used. Curcumin increased T-cell proliferation, tumor-infiltrating lymphocytes (TILs), and effector cytokines, and decreased the expression of PD-1, TIM-3, suppressive IC receptors and their ligands (PD-L1, PD-L2, and Galectin-9) in the TME, implying reinvigoration of the exhausted CD8+ T cells. In addition, Curcumin inhibited expression of CD4+CD25+FoxP3+ Treg cells as well as PD-1 and TIM-3. ConclusionsThese results show that Curcumin reinvigorates defective T cells via multiple (PD-1 and TIM-3) and multi-level (IC receptors and its ligands) IC axis suppression, thus providing a rationale to combine Curcumin with conventional targeted therapy or ICB as a multi-faceted approach for treating patients with HNSCC.
Nucleus Accumbens Dopamine D3 Receptor Regulates Microglial M1 Polarization Through Akt Signaling Pathway in the Depressive-Like Behavior
Authors: Wang Jing , Lai Simin , Wang Rui , Zhou Ting , Dong Nan , Zhu Li , Chen Teng , Chen Yanjiong 
Published: May 2021

Abstract
Background: Nucleus accumbens (NAc) inflammation is implicated in the development and progression of depression but the underlying mechanism remains largely unclear. We previously reported that dopamine D3 receptor (D3R) expressed in the NAc strongly correlated with inflammation-related depression. The objective of the present study is to determine the exact mechanism of D3R in the NAc inflammation relevant depression.Methods: Bilateral NAc injection of Lipopolysaccharide (LPS)-induced NAc inflammation mouse model was used to explore the relationship between NAc inflammation and depressive-like behaviors. Either conditional knockout of D3R in the NAc in the adult mice or restoration of D3R expression in the NAc in D3R mutant mice was applied to investigate the effects of D3R in the NAc on depressive disorders. The exact molecular mechanism of D3R in the NAc inflammation-induced depressive-like phenotype was ascertained by in vivo and in vitro studies. Results: NAc inflammation induced by intra-NAc LPS triggered a series of depressive-like disorders, and the interaction of D3R and microglia activation involved in the NAc inflammation-induced depressive-like phenotype. We observed that selective knock-down of D3R in the NAc elicited the depressive-like behaviors, but re-expression of D3R in the NAc alleviated the depressive-like behaviors established by D3R mutation. Finally, D3R in the NAc mediated microglial polarization to M1 phenotype mainly through Akt signaling pathway. Conclusions: These findings provide direct evidence that not only NAc inflammation but also down-regulation of D3R in the NAc has a role in regulation the initiation and development of depression, and indicate that D3R negatively regulated microglial M1 polarization mainly via Akt signaling pathway that may be involved in the NAc inflammation and thereby depressive-like behaviors.
Automatic Evaluation of Strephenopodia Based on Plantar Pressure and Machine Learning: A Pilot Study
Authors: Nong Jinjin , Zhou Zikang , Xian Xiaoming , Huang Guowei , Li Peiwen , Xie Longhan 
Published: May 2021

Abstract
Purpose Stroke patients often suffer from strephenopodia because of high muscle tension or muscle spasms, which seriously affect their walking ability and rehabilitation. During the treatment of strephenopodia, there are practical demands for convenient, automatic, and quantitative assessments of the angle of strephenopodia. However, existing strephenopodia detection methods, including traditional clinical gait analysis, gait video analysis and plantar pressure systems, suffer from object obstruction or require complex setups. In this paper, we proposed a novel methodology for automatically predicting the angles of strephenopodia based on a gait analysis system using machine learning methods.Methods Plantar pressure distribution data from thirty healthy participants were recorded during walking on the Zebris FDM-THM instrumented treadmill and were processed to generate 15 gait features. The right ankle angles on the coronal plane were measured by the Vicon system to provide a detailed description and explanation of strephenopodia walking. Three machine learning methods were implemented to build stochastic function mapping from gait features to strephenopodia angles.Results This study showed good reliability and precision prediction of the angle of strephenopodia [determination coefficient (R2)\(\ge\)0.80]. Gaussian process regression (GPR) exhibited the best regression performance [R2 = 0.93, mean root-mean-square error (RMSE) = 0.67].Conclusion The study results showed that this strephenopodia-detection method is not only convenient to implement but also has high accuracy and outperforms previous reports. Measurements derived from the gait analysis system are proper estimators of the angle of strephenopodia and should be considered to improve diagnosis and assessment of the stroke population.
Description of a Novel Fameshifting Site in the 5'UTR of SARS-CoV-2 as a Potential Drug Target
Authors: Garcia-Moran Emilio , Hernandez Marta , Abad David , Eiros Jose Maria 
Published: May 2021

Abstract
SARS-CoV-2 is an enveloped positive-sense single-stranded RNA coronavirus that causes COVID-19 whose present outbreak has cost a high number of casualties throughout the world. The aim of this work was to scan the SARS-CoV-2 genome in search for new therapeutic targets. We found a sequence in the 5'UTR (NC 045512:74-130), consisting of a typical heptamer next to a structured region that may cause frameshifting. The potential biological value of this region is shown by its similarity with other coronaviruses related with SARS-CoV and its sequence conservation within isolates from SARS-CoV-2. We have predicted the secondary structure of the region by means of different bioinformatic tools. We have chosen a probable secondary structure to proceed with a 3D reconstruction of the structured segment. We carried out virtual docking on the 3D structure to look for a binding site and then for drug ligands from a database of lead compounds. Several molecules that would probably administered as oral drugs show promising binding affinity within the structured region and so it would be possible interfere the potential regulatory role of our sequence of interest.
Identification of Candidate Biomarkers Associated with Ovarian Cancer Progression and Prognosis by Integrated Microarray Analysis
Authors: Xiaohong Chen , Jiachun Xin , Zhijun Feng , Hui Cai , Shouye Ma , Huifang Wu 
Published: May 2021

Abstract
Ovarian cancer (OC) is one of the most common gynecological malignancies, with high mortality and few prognostic biomarkers. This study aimed to identify differentially expressed genes (DEGs) relevant to the prognosis of ovarian cancer. First, we performed differential analysis on GSE38666, GSE14407, GSE27651 and GSE18520 expression profile datasets from the Gene Expression Omnibus (GEO) database and obtained 638 DEGs using a Venn diagram tool. Second, we constructed a protein–protein interaction (PPI) network with the STRING database and used the Molecular Complex Detection (MCODE) plugin in Cytoscape software to perform gene cluster analyses for 269 upregulated and 367 downregulated DEGs, respectively. Based on the results of gene cluster analyses, we selected two gene clusters of upregulated DEGs with network scores of > 10 and two gene clusters of downregulated DEGs with scores of > 5 for further functional analysis with the clusterProfiler package. In addition, we analyzed the effect of genes from those clusters on the overall survival (OS) and progression-free survival (PFS) of OC patients based on Kaplan–Meier Plotter and PrognoScan databases. The gene clusters of upregulated DEGs are involved mainly in cell division and cell proliferation, and the genes of downregulated DEGs primarily participate in the TGF-β signaling pathway and various metabolic processes. Via cross-validation of survival analysis, we identified four hub genes (AURKA, CDCA5, CEP55 and UBE2C) that correlated with ovarian cancer OS and PFS, which derived from the upregulated DEGs. Patients with these four hub genes trended toward worse OS and PFS than patients with low expression. Unfortunately, no significantly prognosis-related genes were detected among downregulated clusters. The mRNA expression of these four genes were analysed using the Oncomine and GEPIA databases, and the result revealed that the mRNA expression of AURKA,CDCA5,CEP55 and UBE2C was greatly upregulated in OC tissues compare with normal tissues. The gene set/pathway primarily showed alterations in amplification and deep deletion, and correlation analysis indicated significant positive correlations between AURKA, CDCA5, CEP55 and UBE2C. Nevertheless, for clarifying the protein expression levels of the four prognostic genes, the staining of the immunohistochemistry (IHC) were obtained base on the Human Protein Atlas, and was showed the proteins levels of these four genes was significantly elevated in patients with OC. Our results revealed that these four hub genes may mediate ovarian cancer development and have valuable clinical potential as prognostic biomarkers for OC patients.
Diet of the earliest modern humans in East Asia
Authors: Wu Yan , Tao Dawei , Wu Xiujie , Liu Wu 
Published: May 2021

Abstract
Reconstructing diet can offer an improved understanding of the origin and evolution of modern humans. However, the diet of early modern humans in East Asia is poorly understood. Starch analysis of dental calculus is harmless to precious fossil hominins and provides the most direct evidence of plant food sources in early modern human dietary records. In this paper, we examined starch grains in dental calculus from Fuyan Cave hominins in Daoxian (South China), which were the earliest modern humans in East Asia. Our results reveal the earliest direct evidence of a hominin diet made of acorns, roots, tubers, grass seeds, and other yet-unidentified plants in marine isotope stage 5 between 120–80 ka. Our study also provides the earliest evidence that acorns may have played an important role in subsistence strategies. There may have been a long-lasting tradition of using these plants during the Late Pleistocene in China. Plant foods would have been a plentiful source of carbohydrates that greatly increased energy availability to human tissues with high glucose demands, such as the brain, red blood cells, and developing fetuses. Furthermore, a variety of starch grains retrieved from dental calculus revealed that Fuyan cave hominins were able to consume a diet that fulfilled their physiological requirements in the late Middle and early Upper Pleistocene. Our study both provides the earliest direct dietary evidence from modern humans in China and helps elucidate the evolutionary advantages of early modern humans in the late Middle and early Upper Pleistocene.
Comparative Efficacy and Safety of the Moxibustion for the Treatment of Coronavirus Disease 2019 (COVID-19): Protocol for a Systematic Review and Meta-analysis.
Authors: Gao Juan , Zhou Xiujuan , Xie Hongyan , Gao hong , Fu xiaoxu , Peng sihan , Xu guiping , Xie Chunguang 
Published: May 2021

Abstract
Background Coronavirus disease 2019 (COVID-19) has spread from its origins to the world and become a pandemic since late 2019. It predominantly damages the lungs and causes diffuse alveolar injury with edema, cellular fibroblasts and hyaline membrane formation, resulting in acute respiratory insufficiency, respiratory failure, sepsis, acute heart injury, heart failure and other severe complications. It is also reported that moxibustion can effectively modify the negative emotions and relieve the symptoms of chest distress and impaired appetite for the patient with COVID-19. The main objective of current research is to make an assessment for effectiveness and safety of the moxibustion as an important complementary and alternative therapeutic method for COVID-19.Methods and analysis Articles for the systematic literature will be located at the MEDLINE, OVID, EMBASE, CNKI, CBM, NTR, Chi CTR databases. With no restriction about language, manual search will be conducted for potential eligible articles as supplements. Any randomized controlled trials (RCTs) with any moxibustion interventions issued by the therapeutic regimen on all patients diagnosed with COVID-19 will be included. We will include the published studies with no restriction about language. All study records of the title and abstract identified by the search strategies will be directly imported and assessed based on the eligibility criteria. Risk of individual studies for the methodological quality of eligible RCTs will be assessed with the tool from the Cochrane Collaboration’s risk of bias tool.Discussion The purpose of this study is to conduct a systematic review and meta-analysis of the efficacy and safety of moxibustion as a complementary and alternative treatment for COVID-19.No studies have investigated whether moxibustion will relieve clinical symptoms and shorten the length of hospitalization time.To the best of our knowledge, this is the first systematic review and meta-analysis program designed to update the currently available evidence. Despite the fact of controversial views in using moxibustion, if this study confirms its efficacy and safety, it could provide a better guide for clinical practice around the world.Systematic review registrationPROSPERO CRD42020176572.