bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transformer 2β Regulates the Alternative Splicing of Cell Cycle Regulator Genes to Promote Ovarian Cancer Cell Progression
Authors: Fu Peiying , Zhou Ting , Chen Dong , Wang ShiXuan , Liu Ronghua 
Published: September 2021

Abstract
Background: Late-stage ovarian cancer (OV) has a poor prognosis and a high metastasis rate, but the underlying molecular mechanism is ambiguous. RNA binding proteins (RBPs) play important roles in posttranscriptional regulation in the contexts of neoplasia and tumor metastasis. Results: In this study, we explored the molecular functions of a canonical RBP, TRA2B, in cancer cells. TRA2B knockdown in HeLa cells and whole-transcriptome sequencing (RNA-seq) experiments revealed that the TRA2B-regulated alternative splicing (AS) profile was tightly associated with the mitotic cell cycle, apoptosis, and several cancer pathways. Moreover, hundreds of genes were regulated by TRA2B at the expression level, and their functions were enriched in cell proliferation, cell adhesion and angiogenesis, which are related to cancer progression. We also observed that AS regulation and expression regulation occurred independently by integrating the alternatively spliced and differentially expressed genes. We then explored and validated the carcinogenic functions of TRA2B by knocking down its expression in OV cells. In vivo, a high expression level of TRA2B was associated with a poor prognosis in OV patients. Conclusions: We demonstrated the important roles of TRA2B in ovarian neoplasia and OV progression and identified the underlying molecular mechanisms, facilitating the targeted treatment of OV in the future.
As a Novel Tumor Suppressor, LHPP Promotes Apoptosis by Inhibiting the PI3K/AKT Signaling Pathway in Oral Squamous Cell Carcinoma
Authors: Liu Shanshan , Gao Wenzhen , Lu Yupu , Zhou Qin , Su Rongjian , Hasegawa Tomoka , Du Juan , Li Minqi 
Published: September 2021

Abstract
Background: Oral squamous cell carcinoma (OSCC) refers to the malignant tumor of the head and neck with a highest morbidity. It exhibits a poor prognosis and unsatisfactory treatment, which is partially attributed to delayed diagnosis. As indicated from existing reports, the protein histidine phosphatase LHPP acts as a vital factor in tumorigenesis in liver, lung, bladder, breast and pancreatic tumor tissues. Thus far, the expression level of LHPP in OSCC has been rarely studied, and its functional mechanism remains unclear. Methods: DEG analysis, OSCC cell lines and OSCC samples were used to detect the expression of LHPP in adjacent normal and cancerous tissues and its relationship with OSCC differentiation. Immunofluorescence staining was used to detect the over-expressed LHPP in OSCC cell lines. The cell counting kit 8 test, EdU proliferation test, scratch test, invasion test, single clone formation test, mouse xenograft tumor model HE staining and immunohistochemistry were used to estimate the biological characteristics of LHPP in OSCC in vivo and in vitro. GO and KEGG enrichment analysis and LHPP transcription factor analysis were used to further predict the role of LHPP and its related genes. The Western blotting assay, real-time PCR analysis and flow cytometry determined the inhibitory mechanism of LHPP in OSCC cells.Results: LHPP was down-regulated in OSCC tissues and cells than that in normal oral mucosa tissues and cells, LHPP expressing also displays a close association with the degree differentiation of OSCC. LHPP is capable of significantly inhibiting OSCC cells from proliferating, migrating and invading. The increase in LHPP expression facilitated OSCC cell apoptosis through PI3K/AKT signaling pathway.Conclusion: LHPP is a novel tumor suppressor which promotes apoptosis by inhibiting the PI3K/AKT signaling pathway in OSCC, indicating that LHPP is a new diagnostic marker and therapeutic target for OSCC.
Phenylboronic Acid Conjugated to Doxorubicin for the Treatment of Hepatocellular Carcinoma Through Transcatheter Arterial Chemoembolization
Authors: Kang Byung-Yoon , Kim Sung Min , Hur Wonhee , Roh Pu Reun , Han Ji Won , Sung Pil Soo , Tak Eunyoung , Kim Won Jong , Jin Long , Chun Ho Jong , Yoon Seung Kew 
Published: September 2021

Abstract
Background: Anticancer strategies using nanocarrier systems via the enhanced permeability and retention (EPR) effect and tumor targeting have been explored in various cancers. In previous studies, the anticancer effect of polymerized phenylboronic acid-conjugated doxorubicin (pPBA-Dox) nanocomplexes was confirmed in various cancers, and their anticancer effect and tumor targeting ability was confirmed in hepatocellular carcinoma (HCC).This study aimed to determine the anticancer effect and changes in the liver immune cell population and function after pPBA-Dox nanocomplex infusion through transcatheter arterial chemoembolization (TACE), which is a locoregional therapy (LRT), in HCC. TACE was performed in a rat liver cancer model, and the anticancer effects, immune cell populations and functional changes were confirmed after 1 week. Magnetic resonance imaging (MRI) and flow cytometry (FACS) were performed to analyze the anticancer effect and immune cell population and function. Results: In HCC, the infusion of pPBA-Dox nanocomplexes through TACE had a stronger anticancer effect than conventional doxorubicin (Dox) and it promoted the infiltration and activation of CD4+ and CD8+ T cells in the liver. Conclusions: This study provides insight into novel targeted therapies using nanocomplexes for the treatment of HCC.
JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder
Authors: Li Heli , Wang Xinyuan , Hu Cong , Li Hao , Xu Zhuoshuo , Lei Ping , Luo Xiaoping , Hao Yan 
Published: September 2021

Abstract
Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is characterized by marked genetic heterogeneity. This study aimed to use gene expression datasets to explore candidate hub genes for ASD. Methods: In this study, two independent microarray datasets of the cerebellum of children with ASD were integratively analysed using NetworkAnalyst to screen crucial candidate genes and related signalling pathways. Upregulation of the two hub genes was validated by other datasets and an ASD mouse model. Results: NetworkAnalyst identified two upregulated genes as the most crucial genes in the cerebellum of children with ASD: Jun proto-oncogene (JUN) and platelet-derived growth factor receptor alpha (PDGFRA). According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, genes associated with JUN in the cerebellum highlight the pathways of Th17 cell differentiation and Th1 and Th2 cell differentiation. Genes associated with PDGFRA in the cerebellum were enriched in the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance and Rap1 signalling pathways. The analysis of all the differentially expressed genes (DEGs) of the two datasets using gene set enrichment analysis (GSEA) demonstrated the involvement of the IL-17 signalling pathway, which is related to the expression of JUN and PDGFRA. ImmuCellAI found that elevated expression of JUN and PDGFRA correlated with the abundance of Th17 and monocytes, suggesting that JUN and PDGFRA could regulate Th17 cell activation and monocyte infiltration. Our ASD mouse model of maternal immune activation demonstrated that JUN and PDGFRA were upregulated in ASD mice. Limitations: The function of JUN and PDGFRA in patients of ASD and different ASD mouse models require explore and validation, and the results should be replicated in more patients with ASD. Conclusions: JUN and PDGFRA are crucial candidate genes and related to the IL-17 signalling pathway in ASD patients.
It's in the Eye of the Beholder: Ocular Ultrasound Enhanced Monitoring of Neurotoxicity after CAR T-cell therapy
Authors: Garcia-Robledo Juan Esteban , Valencia-Sanchez Cristina , Knox Molly G. , Goodman Brent P. , Rosenthal Allison , Castro Januario E. , Patel Bhavesh 
Published: September 2021

Abstract
Usually used in emergency settings, bedside sonographic measurement of optic nerve sheath diameter can aid in diagnosing elevated intracranial pressure. We report a case of a 26-year-old male hospitalized for CAR T-cell therapy with Axicabtagene Ciloleucel for treatment of relapsed diffuse large B-cell lymphoma, who developed progressive symptoms of immune effector cell-associated neurotoxicity syndrome. Fundoscopic examination suggested the presence of blurred optic disc margins. Bedside ocular ultrasound revealed wide optic nerve sheath diameters and bulging optic discs bilaterally. The patient had a ventriculostomy placed for monitoring and received treatment with steroids and mannitol, as well as tocilizumab. After 7 days in the ICU, the patient recovered with no evidence of long-term neurological deficits.
Lipopolysaccharide Acting Via Toll Like Receptor 4 Transactivates The TGF-β Receptor in Vascular Smooth Muscle cells
Authors: Afroz Rizwana , Kumarapperuma Hirushi , Mohamad Raafat , Little Peter J , Kamato Danielle 
Published: September 2021

Abstract
Toll-like receptors (TLRs) recognise pathogen‑associated molecular patterns, which allow the detection of microbial infection by host cells. Bacterial derived toxin lipopolysaccharide activates TLR4 and leads to the activation of the Smad2 transcription factor. The phosphorylation of the Smad2 transcription factor is the result of the activation of the transforming growth factor-β receptor 1 (TGFBR1). Therefore, we sought to investigate LPS via TLR4 mediated Smad2C phosphorylation dependent on the (trans)activation of the TGFBR1. The invitro used human aortic vascular smooth muscle cells (HA-VSMCs) to assess the implications of TLR4 (trans)activation of the TGFBR1 in vascular pathophysiology. We show that LPS mediated Smad2 carboxy-terminal phosphorylation is inhibited in the presence of TGFBR1 inhibitor SB431542 in HA-VSMCs. Treatment with MyD88 and TRIF pathways antagonists does not affect LPS mediated phosphorylation of Smad2C; however, LPS mediated Smad2 phosphorylation was inhibited in the presence of MMP inhibitor, GM6001 and unaffected in the presence of ROCK inhibitor Y27632. LPS via transactivation of the TGFBR1 stimulates PAI-1 mRNA expression. TLRs are first in line to respond to exogenous invading substances and endogenous molecules; our findings characterise a novel signalling pathway in the context of cell biology. Identifying TLR transactivation of the TGFBR1 may provide future insight into the detrimental implications of pathogens in pathophysiology.
Determination of Anti-Phospholipase A2 and Anti-Thrombospondin Type 1 Domain-Containing Protein 7A in Latin Patients With Membranous Nephropathy
Authors: Battaini L. C. , Ranzani O. T. , Marçal L. J. , Antonangelo L. , Jorge L.B. , Bitencourt C.D. , Woronik V. , Malheiros D.M.A. , Yu L 
Published: September 2021

Abstract
BACKGROUND

Membranous nephropathy (MN) is caused by antibodies against podocyte antigens, of which the type M receptor of phospholipase A2 (PLA2R) and thrombospondin type-1 domain containing 7 A (THSD7A) are the mostly studied. The objectives of this study were to determine anti-PLA2R and anti-THSD7A serum antibodies and anti-PLA2R renal tissue prevalence in a Latin population with primary MN and to evaluate their role as biomarkers for disease activity. Additionally, the performance of the two available serum diagnostic methods - ELISA and indirect immunofluorescence - was evaluated for the diagnosis of MN.
METHODS

Fifty-nine patients, 29 MN, 18 lupus membranous nephropathy (LMN) and 12 focal and segmental glomerulosclerosis (FSGS) were evaluated for serum antibodies. Renal biopsies were also evaluated for the presence of anti-PLA2R. Twenty-one patients with MN were followed for 1 year.
RESULTS

Patients with LMN and FSGS were negative for both antibodies. All 29 MN were negative for anti-THSD7A; 16 MN were positive by ELISA and/or IFI, and 3 MN patients were positive only by IFI. Thus, ELISA test showed a 45% sensitivity and 97% specificity while the IFI showed a 55% and 100%, respectively. In patients with less than a year between biopsy and antibody collection, sensitivity increased to 79% and maintained specificity. Positive correlations were observed between the anti-PLA2R ELISA titer and proteinuria. Among the 28 MN renal biopsies, 20 presented anti-PLA2R positive staining, a 72% sensitivity.
CONCLUSIONS

The determination of anti-PLA2R antibodies in the Latin population showed similar rates as reported in other populations, and the IFI test presented greater sensitivity. A lower rate of remission was found among those with anti-PLA2R positive tests.
Remodeling of Conformational Dynamics Enhances Catalytic Activities of M1 Zinc-metallopeptidases from Lanthipeptide Biosynthesis
Authors: zhao chang , Sheng Wang-Jian , wang ying , Zheng Jie , Xie Xiangqian , Liang Yong , wei wanqing , Bao Rui , Wang Huan 
Published: September 2021

Abstract
Lanthipeptides are an important group of natural products with diverse biological functions, and their biosynthesis requires the removal of N-terminal leader peptides (LPs) by designated proteases. LanPM1 enzymes, a subgroup of M1 zinc-metallopeptidases, are recently identified as bifunctional proteases with both endo- and aminopeptidase activities to remove LPs of class III and class IV lanthipeptides. Herein, we report the biochemical and structural characterization of EryP as the LanPM1 enzyme from the biosynthesis of class III lanthipeptide erythreapeptin. We determined X-ray crystal structures of EryP in three conformational states, the open, intermediate and closed states and identified a unique inter-domain Ca binding site as a regulatory element to modulate its domain dynamics and proteolytic activity. Inspired by the regulatory Ca binding, we develop a strategy to engineer LanPM1 enzymes for enhanced catalytic activities by strengthening inter-domain associations and driving the conformational equilibrium toward their closed forms.
Resveratrol Blocks Retrotransposition of LINE-1 Through PPAR α and Sirtuin-6
Authors: Okudaira Noriyuki , Ishizaka Yukihito , Tamamori-Adachi Mimi 
Published: September 2021

Abstract
The retroelement long interspersed element-1 (LINE-1 or L1) comprises about 17% of the human genome. L1 retrotransposition is known to cause genomic instability and related disorders, and resveratrol suppresses this retrotransposition; however, the underlying mechanism is still not elucidated. Recent observations showed that low-molecular-weight compounds might induce L1 retrotransposition through unknown mechanisms. This study aimed to determine polyphenol resveratrol (RV)’s effect on L1-RTP (retrotransposition) in somatic cells. Surprisingly, RV completely blocked L1-RTP. Experiments using the PPARα inhibitor GW6471 or siRNA-mediated PPARα depletion showed that RV-mediated L1-RTP’s inhibition depended on peroxisome proliferator-activated receptor α (PPARα). We demonstrated that RV inhibits p38 and CREB phosphorylation, which are involved in MAPK signaling, and the L1-ORF1 protein’s chromatin recruitment. Furthermore, RV increased the expression of sirtuin-6 (SIRT6), which inhibited the activation of L1. The sirtuins family, SIRT1, SIRT6, and SIRT7, but not SIRT3, are involved in RV-mediated inhibition of L1-RTP. Overall, our findings suggest that RV directly modulates PPARα-mediated L1-RTP in somatic cells and that MAPK signaling interacts with SIRT1, SIRT6, and SIRT7 closely and may play a role in preventing human diseases such as cancer.
First Evidence of the Implication of Cuticular Based Mechanisms in Aedes Aegypti Populations Resistant To Pyrethroids and DDT in Cameroon
Authors: TCHAMEN Borel DJIAPPI , Mariette Nana-Ndjangwo Stella , Balabanidou Vasileia , Mavridis Konstantinos , Idene Makoudjou , Parfait Awono-Ambene , Wondji Charles , Timoléon Tchuinkam , Vontas John , Christophe Antonio-Nkondjio 
Published: September 2021

Abstract
Pyrethroid resistance is now expanding in the two main arboviruses vectors Aedes aegypti and Aedes albopictus from Cameroon. Although recent studies suggested the implication of target site (kdr) resistance and overexpression of detoxification enzymes as key mechanisms, the implication of additional mechanisms such as cuticular resistance has not been investigated. The present study assesses the possible implication of cuticle in Aedes species resistance to pyrethroids. High cuticular hydrocarbon (CHC) content was detected in Ae. aegypti populations from Douala and Yaoundé. The difference (38% increase) between the Douala and susceptible populations was found to be statistically significant.The study confirms the implication of cuticular-based mechanisms in resistant to pyrethroids and DDT Aedes aegypti mosquitoes from Cameroon.
Variations of Habitat Quality and Ecological Risk and Their Correlations With Landscape Metrics in a Robust Human Disturbed Coastal Region
Authors: Han Huiqing , Su Zhihua , Yang Guangbin 
Published: September 2021

Abstract
As impacted by strong intense human activity disturbance, the landscape pattern change significantly affects the habitat quality and ecological risk level in the coastal regions. Though numerous researches were conducted in coastal habitat quality and ecological risk, the correlations of habitat quality and ecological risk with landscape metrics in coastal regions have been rarely reported. A scientific question should be addressed is the scientific basis for the sustainable development of coastal regions. Accordingly, Xinggang town, a coastal region in southern China, was selected as a typical coastal region disturbed by robust human activities. Given high-precision remote sensing data, the temporal-spatial variations of habitat quality and ecological risk in the coastal region were analyzed by adopting the methods of InVEST model and ecological risk index, and the correlations of habitat quality and ecological risk with landscape metrics were examined. As indicated from the results, the deterioration of habitat quality and the increase in ecological risk in the coastal region under the disturbance of human activities exhibited obvious distance gradients. The gradient area close to the coastline was the area with the prominent variations of habitat quality and ecological risk. Most landscape metrics were positively correlated with habitat quality and ecological risk, and the correlations were different in a range of distance gradients. Under the rapid urbanization in the coastal region, the rapid expansion of built-up land and the decrease of natural landscapes significantly impacted the landscape pattern index and then altered the habitat quality and ecological risk level.
Putting Together the Puzzle of Ion Transfer in Single-Digit Carbon Nanotubes: Ab Initio Meets Mean-Field
Authors: Neklyudov Vadim , Freger Viatcheslav 
Published: September 2021

Abstract
Nature employs channel proteins to selectively pass water across cell membranes, which inspires search for bio-mimetic analogues. Carbon nanotube porins (CNTPs) are intriguing mimics of water channels, yet ion transport in CNTPs still poses questions. As alternative to continuum models, here we present a molecular mean-field model, computing ab initio all required thermodynamic quantities for KCl salt and H+ and OH- ions present in water. Starting from water transfer, the model considers transfer of free ions, along with ion-pair formation to address ion-ion interactions. High affinity to hydroxide, suggested by experiments and making it dominant charge carrier in CNTP, is revealed as an exceptionally favorable transfer of KOH pairs. Nevertheless, free ions, coexisting with less mobile ion-pairs, apparently control ion transport. The model explains well the observed effects of salt concentration and pH on conductivity, transport numbers, anion permeation and its activation energies, and current rectification. The proposed approach is extendable to other sub-nanochannels and help design novel osmotic materials and devices.
Identifying Extreme COVID-19 Mortality Risks in English Small Areas: A Disease Cluster Approach
Authors: Adin Aritz , Congdon Peter , Santafe Guzman , Ugarte Maria Dolores 
Published: September 2021

Abstract
The COVID-19 pandemic is having a huge impact worldwide and has highlighted the extent of health inequalities between countries but also in small areas within a country. Identifying areas with high mortality is important both of public health mitigation in COVID-19 outbreaks, and of longer term efforts to tackle social inequalities in health. In this paper we consider different statistical models and an extension of a recent method to analyze COVID-19 related mortality in English small areas during the first wave of the epidemic in the first half of 2020. We seek to identify hotspots, and where they are most geographically concentrated, taking account of observed area factors as well as spatial correlation and clustering in regression residuals, while also allowing for spatial discontinuities. Results show an excess of COVID-19 mortality cases in small areas surrounding London and in other small areas in North-East and and North-West of England. Models alleviating spatial confounding show ethnic isolation, air quality and area morbidity covariates having a significant and broadly similar impact on COVID-19 mortality, whereas nursing home location seems to be slightly less important.
A Comprehensive Evaluation Between Dexmedetomidine and Midazolam for Intraoperative Sedation in the Elderly: Protocol for a Systematic Review and Meta-analysis of Randomized Controlled Trials
Authors: Huang Chunxia , Li Zunjiang , Long Yingxin , Li Dongli , Huang Manhua , Ding Banghan , Zhu Wei 
Published: September 2021

Abstract
Background: The sedative effect of intraoperative sedation in elderly surgery exerts critical influence on the prognosis. Comparison on the safety and efficacy between Dexmedetomidine and Midazolam in many clinical randomized controlled trials (RCTs) were inconsistent and suspicious. We aimed to comprehensively evaluate the safety and efficacy between Dexmedetomidine and Midazolam for intraoperative sedation in the elderly via meta-analysis and systematic reviews.Methods: RCTs regarding to the comparison of sedative effects and safety between Dexmedetomidine and Midazolam in elderly patients (aged ≥ 60 years) will be comprehensively searched from 2000.10 to 2021.05 through 4 English databases and 4 Chinese databases. After extraction in duplicate, the systematic review and meta-analysis will be performed on the primary outcomes (hemodynamic changes, sedative effect, cognitive function) and secondary outcomes (analgesic effect, surgical characteristics, complications or adverse reactions) for assessing the two therapy methods using Review manage software (Version 5.3). Sensitivity analysis will be conducted to evaluate the heterogeneity of the results, funnel plot and Egger’s test will be performed to analyze publication bias of the included studies, and test sequential analysis will be applied to assess the robustness and reliability of preliminary meta-analysis results. Finally, rating quality of evidence and strength of recommendations on the meta results will be summarized by rating quality of evidence and strength of recommendations (GRADE) approach. Discussion: This systematic review and meta-analysis will evaluate the safety and efficacy between Dexmedetomidine and Midazolam for intraoperative sedation in the elderly, it will give an insight on the application of Dexmedetomidine and Midazolam, and will provide evidences-based reference for clinical decision makings.Systematic review registration: PROSPERO (CRD42021221897).