bluuebunny/crossref_metadata_2025_split huggingface dataset:
Health and economic burden of respiratory syncytial virus (RSV) disease and the cost-effectiveness of potential interventions against RSV among children under 5 years in 72 Gavi-eligible countries
Authors: Li Xiao , Willem Lander , Antillon Marina , Bilcke Joke , Jit Mark , Beutels Philippe 
Published: April 2020

AbstractBackgroundRespiratory syncytial virus (RSV) frequently causes acute lower respiratory infection in children under 5, representing a high burden in Gavi-eligible countries (mostly low-income and lower-middle-income). Since multiple RSV interventions, including vaccines and monoclonal antibody (mAb) candidates, are under development, we aim to evaluate the key drivers of the cost-effectiveness of maternal vaccination and infant mAb for 72 Gavi countries.MethodsA static Multi-Country Model Application for RSV Cost-Effectiveness poLicy (MCMARCEL) was developed to follow RSV-related events monthly from birth until 5 years of age. MCMARCEL was parameterised using country- and age-specific demographic, epidemiological, and cost data. The interventions’ level and duration of effectiveness were guided by the World Health Organization’s preferred product characteristics and other literature. Maternal vaccination and mAb were assumed to require single-dose administration at prices assumed to align with other Gavi-subsidised technologies. The effectiveness and the prices of the interventions were simultaneously varied in extensive scenario analyses. Disability-adjusted life years (DALYs) were the primary health outcomes for cost-effectiveness, integrated with probabilistic sensitivity analyses and Expected Value of Partially Perfect Information analysis.ResultsThe RSV-associated disease burden among children in these 72 countries is estimated at an average of 20.8 million cases, 1.8 million hospital admissions, 40 thousand deaths, 1.2 million discounted DALYs, and US$611 million discounted direct costs. Strategy ‘mAb’ is more effective due to its assumed longer duration of protection versus maternal vaccination, but it was also assumed to be more expensive. Given all parameterised uncertainty, the optimal strategy of choice tends to change for increasing willingness to pay (WTP) values per DALY averted from the current situation to maternal vaccination (at WTP > US$1000) to mAB (at WTP > US$3500). The age-specific proportions of cases that are hospitalised and/or die cause most of the uncertainty in the choice of optimal strategy. Results are broadly similar across countries.ConclusionsBoth the maternal and mAb strategies need to be competitively priced to be judged as relatively cost-effective. Information on the level and duration of protection is crucial, but also more and better disease burden evidence—especially on RSV-attributable hospitalisation and death rates—is needed to support policy choices when novel RSV products become available.
A novel fungal beta-propeller phytase from nematophagous Arthrobotrys oligospora: characterization and potential application in phosphorus and mineral release for feed processing
Authors: Hou Xianjuan , Shen Zhen , Li Na , Kong Xiaowei , Sheng Kangliang , Wang Jingmin , Wang Yongzhong 
Published: April 2020

AbstractPhytases are widely utilized in feed industry to increase the utilization of phosphorus, minerals, and amino acids for improvement of animal and human nutrition. At present, all known β-propeller phytases (BPP) have been generated from bacteria, particularly Bacillus. In this work we report for the first time a new fungal-derived BPP phytase. We identified a phytase highly differentially expressed only in the parasitic stage of a nematophagous fungus, Arhtrobotrys oliogospora, during the development of the 3D traps. We found that this phytase was homologous to the known bacterial BPP phytase, thus we referred the new phytase to Aophytase. The heterologous expression of codon-optimized Aophytase gene in Pichia pastoris was successfully investigated to yield recombinant Aophytase (r-Aophytase) with high specific enzyme activity of 74.71 U/mg, much higher than those of recombinant BPP phytases derived bacteria. The kinetic parameters of the r-Aophytase, the optimum pH and temperature, as well as the effects of surfactant, EDTA and different ions on its enzyme activity were further investigated. The potential utilization of r-Aophytase in feed processing was finally explored. We found that the optimal pH value was about 7.5, and the optimal temperature was 50 °C.; r-Aophytase significantly increased the release of inorganic phosphorus from soybean meal, and improved the release of soluble minerals from the durum wheat flour and finger millet flour. The findings indicate its potential utilization in the feed processing to ameliorate nutritional value of cereals and animal feed in the future.
The effects of statins on dental and oral health: a review of preclinical and clinical studies
Authors: Tahamtan Shabnam , Shirban Farinaz , Bagherniya Mohammad , Johnston Thomas P. , Sahebkar Amirhossein 
Published: April 2020

AbstractThe statin family of drugs are safe and effective therapeutic agents for the treatment of arteriosclerotic cardiovascular disease (CVD). Due to a wide range of health benefits in addition to their cholesterol lowering properties, statins have recently attracted significant attention as a new treatment strategy for several conditions, which are not directly related to normalizing a lipid profile and preventing CVD. Statins exert a variety of beneficial effects on different aspects of oral health, which includes their positive effects on bone metabolism, their anti-inflammatory and antioxidant properties, and their potential effects on epithelization and wound healing. Additionally, they possess antimicrobial, antiviral, and fungicidal properties, which makes this class of drugs attractive to the field of periodontal diseases and oral and dental health. However, to the best of our knowledge, there has been no comprehensive study to date, which has investigated the effects of statin drugs on different aspects of dental and oral health. Therefore, the primary objective of this paper was to review the effect of statins on dental and oral health. Results of our extensive review have indicated that statins possess remarkable and promising effects on several aspects of dental and oral health including chronic periodontitis, alveolar bone loss due to either extraction or chronic periodontitis, osseointegration of implants, dental pulp cells, orthodontic tooth movement, and orthodontic relapse, tissue healing (wound/bone healing), salivary gland function, and finally, anti-cancer effects. Hence, statins can be considered as novel, safe, inexpensive, and widely-accessible therapeutic agents to improve different aspects of dental and oral health.
Benefits and limitations of humanized mice in HIV persistence studies
Authors: Marsden Matthew D. 
Published: April 2020

AbstractSignificant advances in the treatment of HIV infection have been made in the last three decades. Antiretroviral therapy (ART) is now potent enough to prevent virus replication and stop disease progression. However, ART alone does not cure the infection, primarily because HIV can persist in stable long-term reservoir cells including latently-infected CD4 + T cells. A central goal of the HIV research field is to devise strategies to eliminate these reservoirs and thereby develop a cure for HIV. This requires robust in vivo model systems to facilitate both the further characterization of persistent HIV reservoirs and evaluation of methods for eliminating latent virus. Humanized mice have proven to be versatile experimental models for studying many basic aspects of HIV biology. These models consist of immunodeficient mice transplanted with human cells or tissues, which allows development of a human immune system that supports robust infection with HIV. There are many potential applications for new generations of humanized mouse models in investigating HIV reservoirs and latency, but these models also involve caveats that are important to consider in experimental design and interpretation. This review briefly discusses some of the key strengths and limitations of humanized mouse models in HIV persistence studies.
Analysis of reassortant and intragenic recombination in Cypovirus
Authors: Zhang Zhendong , Li Ning , Hou Chengxiang , Gao Kun , Tang Xudong , Guo Xijie 
Published: April 2020

AbstractCypoviruses (CPVs) are RNA viruses with segmented double-stranded genome and major pathogens of various insects, including economic insects like silkworms and pest insects for agricultural crops and forests. Genome reassortment and recombination are common phenomenon for viruses as a mechanism to expand host range and increase virulence. In the present study, we analyzed the reassortant and recombination events for CPVs. The results showed that two genome segments (S1 and S4) of BmCPV1-YN shared higher nucleotide identity with the corresponding segment of BmCPV1-I while others were all more closely to BmCPV1-SZ, suggesting BmCPV1-YN was originated from reassortant events between BmCPV1-I and BmCPV1-SZ. Recombination analyses revealed that S6 of BmCPV1-YN was a recombinant segment derived from BmCPV1-I and BmCPV1-SZ, and S10 of DpCPV1 was a recombinant segment emerged from BmCPV1-I and LdCPV1. Our findings provide the evidence for the fact that CPVs could undergo reassortant and recombinant events and enrich the knowledge about etiology and molecular epidemiology of CPVs.
Comparison of CTVHR and organs at risk contours between TRUS and MR images in IB cervical cancers: a proof of concept study
Authors: Mendez Lucas C. , Ravi Ananth , Martell Kevin , Raziee Hamid , Alayed Yasir , Wronski Matt , Paudel Moti , Barnes Elizabeth , Taggar Amandeep , Wong C. S. , Leung Eric 
Published: April 2020

Abstract
Purpose
To compare CTVHR and OAR dimensions and inter-rater agreement between magnetic resonance (MR) and trans-rectal ultrasound (TRUS) images in IB cervical cancer patients.

Methods
IB cervical cancer patients treated with (chemo)radiotherapy plus MR-guided brachytherapy (BT) were prospectively enrolled in this study. Radiation oncologists contoured CTVHR and OARs in pre-BT MR images (MRI) and intra-operative TRUS images. These contours were subsequently compared in regard to volume and dimension. Contour inter-rater agreement analysis was also investigated using kappa index (KI). Stata 15.0 was used for statistical analysis and a p-value < 0.05 was considered statistically significant.

Results
TRUS CTVHR volumes were statistically smaller than the respective MRI contoured volumes. TRUS CTVHR thickness was found to be consistently smaller than MRI contours in all patients. No statistical difference was seen in width and height between the two different imaging modalities. MRI contours had a median KI of 0.66 (range: 0.56–0.77) while TRUS-based contours had a median KI of 0.64 (range: 0.47–0.77). Bladder and rectum had very satisfactory KI in both imaging modalities. Vaginal contours had moderate agreement in MR (0.52) and in TRUS images (0.58).

Conclusion
TRUS images allow good visualization of CTVHR and OARs in IB cervical cancer patients. Inter-rater contour variability was comparable between TRUS and MR images. TRUS is a promising modality on its own for image-guided BT.
Impact of adjuvant radiotherapy on the survival of women with optimally resected stage III endometrial cancer in the era of modern radiotherapy: a retrospective study
Authors: Chen Jenny Ling-Yu , Huang Yu-Sen , Huang Chao-Yuan , Hsu Che-Yu , Lan Keng-Hsueh , Cheng Wen-Fang , Kuo Sung-Hsin 
Published: April 2020

Abstract
Background
The optimal adjuvant treatment for stage III endometrial cancer in the era of modern radiotherapy remains undefined. We investigated the benefit of adjuvant radiotherapy for women who underwent optimal resection for stage III endometrial cancer in the era of modern radiotherapy.

Methods
We retrospectively reviewed patients with endometrial cancer who were treated between 2010 and 2018. Adjuvant treatment included radiotherapy by modern radiotherapy techniques (intensity-modulated or volumetric modulated arc radiotherapy), chemotherapy, or both. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method and analyzed via multivariate Cox proportional hazards models.

Results
One hundred sixty-one patients were initially included (52, 9, and 100 with stages IIIA, IIIB, and IIIC cancer, respectively); 154 patients (96%) received adjuvant therapy. Such adjuvant treatment was associated with improved RFS (p = 0.014) and OS (p = 0.044) over surgery alone. Adjuvant radiotherapy by modern radiotherapy techniques led to low incidence of acute (25%) and chronic (7%) grade ≥ 2 gastrointestinal toxicity. On univariate analysis, non-endometrioid histology and grade 3 status were associated with higher risks of tumor recurrence and death, whereas adjuvant radiotherapy alone or in combination chemotherapy reduced their risks. On multivariate analysis, non-endometrioid histology was associated with increased recurrence (hazard ratio [HR], 2.95; p = 0.009), whereas adjuvant radiotherapy alone or with chemotherapy was associated with lower recurrence (HR, 0.62; p = 0.042). Patients > 60 years of age (p = 0.038) as well as those with endometrioid histology (p = 0.045), lymphovascular space invasion (p = 0.031), and ≥ 2 positive lymph nodes (p = 0.044) benefited most from adjuvant radiotherapy.

Conclusions
Modern adjuvant radiotherapy (intensity-modulated or volumetric modulated arc radiotherapy) alone or with chemotherapy should be considered for women with optimally resected stage III endometrial cancer.

Trial registration
ClinicalTrials.gov, NCT04251676. Registered 24 January 2020. Retrospectively registered.
MicroRNA-1202 plays a vital role in osteoarthritis via KCNQ1OT1 has-miR-1202-ETS1 regulatory pathway
Authors: Liu Changzeng , Gao Jianming , Su Guangyan , Xiang Yang , Wan Le 
Published: April 2020

AbstractBackgroundThis study aimed to explore the molecular mechanism of osteoarthritis (OA) and provide information about new genes as potential targets for OA treatment.MethodsGene expression profile of GSE105027, including 12 OA serum samples (OA group) and 12 healthy serum samples (ctrl group), was downloaded. The differentially expressed miRNAs (DEMs) as well as miRNA-mRNAs interactions were investigated, followed by function and pathway investigation. Then the protein-protein interaction (PPI) network was performed. Furthermore, the long non-coding RNA (lncRNA)-miRNA-mRNA interactions (competing endogenous RNAs, ceRNAs) were investigated.ResultsA total of 17 downregulated miRNAs were revealed between OA and ctrl groups. These DEMs such as has-miR-1202 were mainly enriched in GO functions like histone acetyltransferase binding and KEGG pathways like cellular senescence. The integrated PPI network analysis showed that has-miR-1202, has-miR-33b-3p, has-miR-940, has-miR-4284, and has-miR-4281 were 5 downregulated miRNAs in this network. Furthermore, the lncRNA-miRNA-mRNA interactions such as KCNQ1OT1-has-miR-1202-ETS1 were revealed in the present ceRNA network.ConclusionKey DEMs such as miR-33b-3p, miR-940, and miR-1202 may be involved in OA. miR-1202 may regulate OA development via histone acetyltransferase pathway binding function and cellular senescence pathway. Furthermore, KCNQ1OT1-has-miR-1202-ETS1 might be vital for the process of OA.
Identification of a novel Shank2 transcriptional variant in Shank2 knockout mouse model of autism spectrum disorder
Authors: Lee Yong-Seok , Yu Nam-Kyung , Chun Jeewan , Yang Jung-eun , Lim Chae-Seok , Kim Hyopil , Park Gaeun , Lee Jin-A , Lee Kyungmin , Kaang Bong-Kiun , Lee Jae-Hyung 
Published: April 2020

AbstractAutism spectrum disorder (ASD) is a group of neurodevelopmental disorders that are highly heterogeneous in clinical symptoms as well as etiologies. Mutations in SHANK2 are associated with ASD and accordingly, Shank2 knockout mouse shows ASD-like behavioral phenotypes, including social deficits. Intriguingly, two lines of Shank2 knockout (KO) mouse generated by deleting different exons (exon 6–7 or exon 7) showed distinct cellular phenotypes. Previously, we compared gene expressions between Shank2 KOs lacking exon 6–7 (e6–7 KO) and KOs lacking exon 7 (e7 KO) by performing RNA-seq. In this study, we expanded transcriptomic analyses to identify novel transcriptional variants in the KO mice. We found prominent expression of a novel exon (exon 4′ or e4’) between the existing exons 4 and 5 in the Shank2 e6–7 KO model. Expression of the transcriptional variant harboring this novel exon was confirmed by RT-PCR and western blotting. These findings suggest that the novel variant may function as a modifier gene, which contributes to the differences between the two Shank2 mutant lines. Furthermore, our result further represents an example of genetic compensation that may lead to phenotypic heterogeneity among ASD patients with mutations in the same gene.
Cullin-7 (CUL7) is overexpressed in glioma cells and promotes tumorigenesis via NF-κB activation
Authors: Xu Jianye , Zhang Zongpu , Qian Mingyu , Wang Shaobo , Qiu Wei , Chen Zihang , Sun Zhongzheng , Xiong Ye , Wang Chaochao , Sun Xiaopeng , Zhao Rongrong , Xue Hao , Li Gang 
Published: April 2020

Abstract
Background
Cullin-7 (CUL7) is a member of the DOC domain-containing cullin family and is involved in the regulation of cell transformation. However, the clinical significance, potential mechanism and upstream regulators of CUL7 in malignant gliomas remain to be determined.

Methods
Expression level data and clinical information were obtained via the Cancer Genome Atlas (TCGA) database, the Chinese Glioma Genome Atlas (CGGA) database, immunohistochemistry (IHC) and western blot analysis. Gene set enrichment analysis (GSEA) was used to explore the potential molecular mechanisms of CUL7. RNA silencing was performed using siRNA or lentiviral constructs in U87MG and U251 glioma cell lines and GSC267 glioma stem cells. CUL7 overexpression was performed using the GV141-CUL7 plasmid construct. In addition, overexpression of miR-3940-5p was performed and validated by quantitative real-time PCR (qRT-PCR). Cells were characterized in vitro or in vivo to evaluate their molecular status, cell proliferation, invasion, and migration by Cell Counting Kit (CCK)-8, EdU, flow cytometry, colony formation, Transwell and 3D tumour spheroid invasion assays. Coimmunoprecipitation (co-IP) and western blotting were performed to test the mechanisms of activation of the NF-κB signalling pathway.

Results
High CUL7 expression was associated with a high tumour grade, a mesenchymal molecular glioma subtype and a poor prognosis in patients. Gene silencing of CUL7 in U87MG and U251 cells significantly inhibited tumour growth, invasion and migration in vitro and in vivo. Western blot analysis revealed that cyclin-dependent kinase inhibitors and epithelial-mesenchymal transition (EMT) molecular markers changed under CUL7 silencing conditions. In contrast, CUL7 overexpression promoted tumour growth, invasion and migration. Gene set enrichment analysis (GSEA) and western blot analysis revealed that CUL7 was positively associated with the NF-κB pathway. Moreover, with coimmunoprecipitation assays, we discovered that CUL7 physically associated with MST1, which further led to ubiquitin-mediated MST1 protein degradation, which promoted activation of the NF-κB signalling pathway. Finally, CUL7 was found to be downregulated by miR-3940-5p, which suppressed the development of gliomas.

Conclusions
Our findings indicate that CUL7 plays a significant role in promoting tumorigenesis via NF-κB activation and that it can be negatively regulated by miR-3940-5p in human gliomas. Furthermore, CUL7 might be a candidate molecular target for the treatment of glioma.
Leveraging biological and statistical covariates improves the detection power in epigenome-wide association testing
Authors: Huang Jinyan , Bai Ling , Cui Bowen , Wu Liang , Wang Liwen , An Zhiyin , Ruan Shulin , Yu Yue , Zhang Xianyang , Chen Jun 
Published: April 2020

AbstractBackgroundEpigenome-wide association studies (EWAS), which seek the association between epigenetic marks and an outcome or exposure, involve multiple hypothesis testing. False discovery rate (FDR) control has been widely used for multiple testing correction. However, traditional FDR control methods do not use auxiliary covariates, and they could be less powerful if the covariates could inform the likelihood of the null hypothesis. Recently, many covariate-adaptive FDR control methods have been developed, but application of these methods to EWAS data has not yet been explored. It is not clear whether these methods can significantly improve detection power, and if so, which covariates are more relevant for EWAS data.ResultsIn this study, we evaluate the performance of five covariate-adaptive FDR control methods with EWAS-related covariates using simulated as well as real EWAS datasets. We develop an omnibus test to assess the informativeness of the covariates. We find that statistical covariates are generally more informative than biological covariates, and the covariates of methylation mean and variance are almost universally informative. In contrast, the informativeness of biological covariates depends on specific datasets. We show that the independent hypothesis weighting (IHW) and covariate adaptive multiple testing (CAMT) method are overall more powerful, especially for sparse signals, and could improve the detection power by a median of 25% and 68% on real datasets, compared to the ST procedure. We further validate the findings in various biological contexts.ConclusionsCovariate-adaptive FDR control methods with informative covariates can significantly increase the detection power for EWAS. For sparse signals, IHW and CAMT are recommended.