bluuebunny/crossref_metadata_2025_split huggingface dataset:
A NOTCH1/LSD1/BMP2 co-regulatory network mediated by miR-137 negatively regulates osteogenesis of human adipose-derived stem cells
Authors: Fan Cong , Ma Xiaohan , Wang Yuejun , Lv Longwei , Zhu Yuan , Liu Hao , Liu Yunsong 
Published: July 2021

Abstract
Background
MicroRNAs have been recognized as critical regulators for the osteoblastic lineage differentiation of human adipose-derived stem cells (hASCs). Previously, we have displayed that silencing of miR-137 enhances the osteoblastic differentiation potential of hASCs partly through the coordination of lysine-specific histone demethylase 1 (LSD1), bone morphogenetic protein 2 (BMP2), and mothers against decapentaplegic homolog 4 (SMAD4). However, still numerous molecules involved in the osteogenic regulation of miR-137 remain unknown. This study aimed to further elucidate the epigenetic mechanisms of miR-137 on the osteogenic differentiation of hASCs.

Methods
Dual-luciferase reporter assay was performed to validate the binding to the 3′ untranslated region (3′ UTR) of NOTCH1 by miR-137. To further identify the role of NOTCH1 in miR-137-modulated osteogenesis, tangeretin (an inhibitor of NOTCH1) was applied to treat hASCs which were transfected with miR-137 knockdown lentiviruses, then together with negative control (NC), miR-137 overexpression and miR-137 knockdown groups, the osteogenic capacity and possible downstream signals were examined. Interrelationships between signaling pathways of NOTCH1-hairy and enhancer of split 1 (HES1), LSD1 and BMP2-SMADs were thoroughly investigated with separate knockdown of NOTCH1, LSD1, BMP2, and HES1.

Results
We confirmed that miR-137 directly targeted the 3′ UTR of NOTCH1 while positively regulated HES1. Tangeretin reversed the effects of miR-137 knockdown on osteogenic promotion and downstream genes expression. After knocking down NOTCH1 or BMP2 individually, we found that these two signals formed a positive feedback loop as well as activated LSD1 and HES1. In addition, LSD1 knockdown induced NOTCH1 expression while suppressed HES1.

Conclusions
Collectively, we proposed a NOTCH1/LSD1/BMP2 co-regulatory signaling network to elucidate the modulation of miR-137 on the osteoblastic differentiation of hASCs, thus providing mechanism-based rationale for miRNA-targeted therapy of bone defect.
The tRNA-derived fragment 5026a inhibits the proliferation of gastric cancer cells by regulating the PTEN/PI3K/AKT signaling pathway
Authors: Zhu Linwen , Li Zhe , Yu Xiuchong , Ruan Yao , Shen Yijing , Shao Yongfu , Zhang Xinjun , Ye Guoliang , Guo Junming 
Published: July 2021

Abstract
Background
Recently, tRNA-derived fragments (tRFs) have been shown to serve important biological functions. However, the role of tRFs in gastric cancer has not been fully elucidated. This study aimed to identify the tumor suppressor role of tRF-5026a (tRF-18-79MP9P04) in gastric cancer.

Methods
Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was first used to detect tRF-5026a expression levels in gastric cancer tissues and patient plasma. Next, the relationship between tRF-5026a levels and clinicopathological features in gastric cancer patients was assessed. Cell lines with varying tRF-5026a levels were assessed by measuring tRF-5026a using qRT-PCR. After transfecting cell lines with a tRF-5026a mimic or inhibitor, cell proliferation, colony formation, migration, apoptosis, and cell cycle were evaluated. The expression levels of related proteins in the PTEN/PI3K/AKT pathway were also analyzed by Western blotting. Finally, the effect of tRF-5026a on tumor growth was tested using subcutaneous tumor models in nude mice.

Results
tRF-5026a was downregulated in gastric cancer patient tissues and plasma samples. tRF-5026a levels were closely related to tumor size, had a certain diagnostic value, and could be used to predict overall survival. tRF-5026a was also downregulated in gastric cancer cell lines. tRF-5026a inhibited the proliferation, migration, and cell cycle progression of gastric cancer cells by regulating the PTEN/PI3K/AKT signaling pathway. Animal experiments showed that upregulation of tRF-5026a effectively inhibited tumor growth.

Conclusions
tRF-5026a (tRF-18-79MP9P04) is a promising biomarker for gastric cancer diagnostics and has tumor suppressor effects mediated through the PTEN/PI3K/AKT signaling pathway.
miR-20a-5p contributes to osteogenic differentiation of human dental pulp stem cells by regulating BAMBI and activating the phosphorylation of Smad5 and p38
Authors: Cen Xiao , Pan Xuefeng , Zhang Bo , Huang Wei , Pei Fang , Luo Tao , Huang Xinqi , Liu Jun , Zhao Zhihe 
Published: July 2021

AbstractBackgroundHuman dental pulp stem cells (hDPSCs) are the preferable choice of seed cells for craniomaxillofacial bone tissue regeneration. As a member of the miR-17-92 cluster, miR-20a-5p functions as an important regulator during bone remodeling. This study aimed to investigate the roles and mechanisms of miR-20a-5p during osteogenesis of hDPSCs.MethodsQuantitative reverse transcription-polymerase chain reaction (qRT-PCR) was conducted to determine the expression of miR-20a-5p during osteogenesis of hDPSCs. We interfered with the expression of miR-20a-5p in hDPSCs to clarify the function of miR-20a-5p on osteogenesis both in vitro and vivo. Direct bind sites between miR-20a-5p and BAMBI were confirmed by dual-luciferase reporter assay, and the underlying mechanisms were investigated with cell co-transfections.ResultsThe expression of miR-20a-5p was showed to be upregulated during osteogenesis of hDPSCs. Inhibition of miR-20a-5p could weaken the intensity of ALP/ARS staining and downregulate the expression of mRNAs and proteins of osteogenic markers, while overexpression of miR-20a-5p could enhance the intensity of ALP/ARS staining and the expression of osteogenic markers. Both micro-CT reconstruction images and histological results showed that miR-20a-5p could promote the regeneration of calvarial defects. miR-20a-5p directly targeted bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), and the latter one was an inhibitor of hDPSC osteogenesis. Silencing BAMBI partially reversed the suppression effect of miR-20a-5p knockdown on osteogenesis. Phosphorylation of Smad5 and p38 was decreased when miR-20a-5p was silenced, whereas p-Smad5 and p-p38 were upregulated when miR-20a-5p was overexpressed or BAMBI was silenced.ConclusionsIt is demonstrated that miR-20a-5p functioned as a regulator of BAMBI to activate the phosphorylation of Smad5 and p38 during osteogenic differentiation of hDPSCs.
Risk factors for norovirus infection in healthcare workers during nosocomial outbreaks: a cross-sectional study
Authors: Torén Kjell , Schiöler Linus , Nenonen Nancy P. , Hannoun Charles , Roth Anette , Andersson Lars-Magnus , Westin Johan , Bergström Tomas 
Published: July 2021

AbstractBackgroundNorovirus outbreaks cause severe medico-socio-economic problems affecting healthcare workers and patients. The aim of the study was to investigate prevalence of norovirus infection and risk factors for infection in healthcare workers during nosocomial outbreaks.MethodsA cross-sectional study of norovirus infections in healthcare workers was performed in seven outbreak wards in a large university hospital. Packs (swab for rectal sampling, and questionnaire) were posted to healthcare workers on notification of a ward outbreak. Rectal samples were examined with norovirus-specific real-time PCR. Replies from questionnaires were analysed using logistic regression models with norovirus genogroup (G)II positive findings as dependent variable. The results are expressed as odds ratios (OR) with 95% confidence intervals (CI). Sequencing and phylogenetic analyses (1040 nucleotides) were used to characterize norovirus strains from healthcare workers. Cluster analyses included norovirus GII.4 strains detected in ward patients during the ongoing outbreaks.ResultsOf 308 packs issued to healthcare workers, 129 (42%) were returned. norovirus GII was detected in 26 healthcare workers (20.2%). Work in cohort care (OR 4.8, 95% CI 1.4–16.3), work in wards for patients with dementia (OR 13.2, 95% CI 1.01–170.7), and having diarrhoea, loose stools or other gastrointestinal symptoms the last week (OR 7.7, 95% CI 2.5–27.2) were associated with increased norovirus prevalence in healthcare workers. Sequencing revealed norovirus GII.4 in healthcare workers samples, and strains detected in healthcare workers and ward patients during a given ward outbreak showed ≥ 99% similarity.ConclusionNorovirus positive findings in healthcare workers were strongly associated with symptomatic infection, close contact with sick patients, and dementia nursing.
Sequence type 17 is a predictor of subsequent bacteremia in vancomycin-resistant Enterococcus faecium-colonized patients: a retrospective cohort study
Authors: Kim Si-Ho , Cho Sun Young , Kim Hye Mee , Huh Kyungmin , Kang Cheol-In , Peck Kyong Ran , Chung Doo Ryeon 
Published: July 2021

Abstract
Background
Sequence type (ST) 17 vancomycin-resistant Enterococcus faecium (VREF) is frequently isolated in nosocomial settings. The aim of this study was to identify whether ST17 contributes to subsequent bacteremia more often than other STs among hospitalized patients carrying VREF.

Methods
A retrospective cohort study was conducted in patients carrying ST17 VREF and those with non-ST17 VREF. Rectal screening according to hospital policy was used to identify patients with VREF. Subsequent VREF bacteremia events within a year of detection of colonization were recorded. Cox regression analysis was used to adjust the covariates involved in determining the association between ST17 and subsequent bacteremia events.

Results
The cohorts comprised 52 patients with ST17 and 169 patients with non-ST17 VREF. One-year VREF bacteremia-free rates were 85.9% and 90.2%, respectively. In multivariate analysis, ST17 was associated with subsequent bacteremia at an adjusted hazard risk (aHR) of 4.02 (95% confidence interval [CI], 1.32–12.29). Liver transplantation (aHR, 40.08; 95% CI, 4.87–329.76) and hematologic malignancy (aHR, 20.97; 95% CI, 4.87–87.82) were also significant. All cases of subsequent bacteremia in ST17 VREF carriers were caused by ST17; however, subsequent bacteremia in non-ST17 carriers was often caused by ST17 or another ST variant.

Conclusions
A specific genotype, ST17 is a predictor of subsequent bacteremia in hospitalized patients carrying VREF. Patients with a hematologic malignancy and those receiving a liver transplant are also at high risk. More targeted strategies may be needed to prevent VREF infection in hospitals.
Multi-level determinants of failure to receive timely and complete measles vaccinations in Southwest China: a mixed methods study
Authors: Tang Xian-Yan , Cheng Man , Geater Alan , Deng Qiu-Yun , Zhong Ge , Lin Yue-Dong , Chen Ning , Lan Tao , Jiang Long-Yan , Zhu Man-Tong , Li Qiao 
Published: July 2021

Abstract
Background
Measles outbreaks re-emerged in 2013–2014 in Guangxi Zhuang Autonomous Region of China, where measles immunisation coverage is high. The discrepancy between the vaccination coverage and outbreaks indicates that timeliness is crucial, yet there is limited knowledge on the health system barriers to timely vaccination. Using integrated evidence at the household, village clinic, and township hospital levels, this study aimed to identify the determinants of failure in receiving timely measles vaccinations among children in rural Guangxi.

Methods
A multi-stage stratified cluster sampling survey with a nested qualitative study was conducted among children aged 18–54 months in Longan, Zhaoping, Wuxuan, and Longlin counties of Guangxi from June to August 2015. The status of timely vaccinations for the first dose of measles-containing vaccine (MCV1) and the second dose of measles-containing vaccine (MCV2) was verified via vaccination certificates. Data on household-level factors were collected using structured questionnaires, whereas data on village and township-level factors were obtained through in-depth interviews and focus group discussions. Determinants of untimely measles vaccinations were identified using multilevel logistic regression models.

Results
A total of 1216 target children at the household level, 120 villages, and 20 township hospitals were sampled. Children were more likely to have untimely vaccination when their primary guardian had poor vaccination knowledge [MCV1, odds ratio (OR) = 1.72; MCV2, OR = 1.51], had weak confidence in vaccines (MCV1, OR = 1.28–4.58; MCV2, OR = 1.42–3.12), had few practices towards vaccination (MCV1, OR = 12.5; MCV2, OR = 3.70), or had low satisfaction with vaccination service (MCV1, OR = 2.04; MCV2, OR = 2.08). This trend was also observed in children whose village doctor was not involved in routine vaccination service (MCV1, OR = 1.85; MCV2, OR = 2.11) or whose township hospital did not provide vaccination notices (MCV1, OR = 1.64; MCV2, OR = 2.05), vaccination appointment services (MCV1, OR = 2.96; MCV2, OR = 2.74), sufficient and uniformly distributed sessions for routine vaccination (MCV1, OR = 1.28; MCV2, OR = 1.17; MCV1, OR = 2.08), or vaccination service on local market days (MCV1, OR = 2.48).

Conclusions
Guardians with poor knowledge, weak beliefs, and little practice towards vaccination; non-involvement of village doctors in routine vaccinations; and inconvenient vaccination services in township hospitals may affect timely measles vaccinations among children in rural China.

Graphical abstract
Supportive and demanding managerial circumstances and associations with excellent workability: a cross-sectional study of Swedish school principals
Authors: Persson Roger , Leo Ulf , Arvidsson Inger , Nilsson Kerstin , Österberg Kai , Håkansson Carita 
Published: July 2021

AbstractBackgroundThe leadership of principals is important for school, teacher and student related outcomes. To be capable of doing their work (i.e., having sufficient workability), school principals need proper organisational preconditions, motivation, and good health. It is therefore concerning that some studies suggest that principals have a work situation that risks taxing their health and reducing their workability. However, few studies have examined the psychosocial working conditions of principals and no study has gauged principals’ workability. Accordingly, we decided to examine Swedish principals’ workability and their perceptions of eight demanding and five supportive managerial circumstances as well as the associations between managerial circumstances and reports of excellent workability.MethodsThe participants comprised 2219 Swedish principals (78% women) who completed a cross-sectional web survey in 2018. A brief version of the Gothenburg Manager Stress Inventory (GMSI-Mini) gauged managerial circumstances. Workability was assessed with the workability score (0–10; WAS). Unadjusted and adjusted logistic regression analyses were used to examine associations between managerial circumstances and reports of excellent workability (WAS ≥ 9). Covariates were: length of work experience as a principal, school level, self-rated health, and general self-efficacy.ResultsThe results showed that circa 30% of the principals reported excellent workability. The GMSI-Mini results showed that role conflicts, resource deficits, and having to harbour co-workers’ frustrations were the most frequently encountered managerial demands. Meanwhile, cooperating co-workers, supportive manager colleagues, and a supportive private life were the most supportive managerial circumstances. Adjusted logistic regression analyses showed that role conflicts and role demands were associated with an increased likelihood of reporting less than excellent workability. In contrast, supportive managerial colleagues, a supportive private life and supportive organisational structures were associated with an increased likelihood of reporting excellent workability.ConclusionCirca 30% of the participating principals perceived their workability to be excellent. Reducing role demands, clarifying the principals’ areas of responsibility and accountability in relation to other actors in the governing chain (role conflicts), striving for increased role clarity, and striving to find ways to separate work and private life, seem to be promising intervention areas if increasing principals’ workability is desired.
Antiangiogenic therapy reverses the immunosuppressive breast cancer microenvironment
Authors: Chen Wuzhen , Shen Lesang , Jiang Jingxin , Zhang Leyi , Zhang Zhigang , Pan Jun , Ni Chao , Chen Zhigang 
Published: July 2021

AbstractTumor angiogenesis induces local hypoxia and recruits immunosuppressive cells, whereas hypoxia subsequently promotes tumor angiogenesis. Immunotherapy efficacy depends on the accumulation and activity of tumor-infiltrating immune cells (TIICs). Antangiogenic therapy could improve local perfusion, relieve tumor microenvironment (TME) hypoxia, and reverse the immunosuppressive state. Combining antiangiogenic therapy with immunotherapy might represent a promising option for the treatment of breast cancer. This article discusses the immunosuppressive characteristics of the breast cancer TME and outlines the interaction between the tumor vasculature and the immune system. Combining antiangiogenic therapy with immunotherapy could interrupt abnormal tumor vasculature-immunosuppression crosstalk, increase effector immune cell infiltration, improve immunotherapy effectiveness, and reduce the risk of immune-related adverse events. In addition, we summarize the preclinical research and ongoing clinical research related to the combination of antiangiogenic therapy with immunotherapy, discuss the underlying mechanisms, and provide a view for future developments. The combination of antiangiogenic therapy and immunotherapy could be a potential therapeutic strategy for treatment of breast cancer to promote tumor vasculature normalization and increase the efficiency of immunotherapy.
Tree mortality and regeneration of Euphrates poplar riparian forests along the Tarim River, Northwest China
Authors: Keram Ayjamal , Halik Ümüt , Aishan Tayierjiang , Keyimu Maierdang , Jiapaer Kadeliya , Li Guolei 
Published: July 2021

Abstract
Background
Tree mortality and regeneration (seedling and sapling recruitment) are essential components of forest dynamics in arid regions, especially where subjected to serious eco-hydrological problems. In recent decades, the mortality of the Euphrates poplar (Populus euphratica) along the Tarim River in Northwest China has increased. However, few studies have quantified the causes of mortality and regeneration in this azonal riparian forest type.

Methods
The present study describes the annual hydrological response of tree mortality and regeneration in forest gaps. A total of 60 canopy gaps were investigated in six replicate grid plots (50 m × 50 m) and the annual runoff and water consumption data during the period of 1955–2016 were collected from hydrological stations in the middle reaches of the Tarim River. We compared the regeneration density of seedlings and saplings within the canopy gap areas (CGAs), undercanopy areas (UCAs), and uncovered riverbank areas (RBAs) through detailed field investigation.

Results
Our study found that the mortality of young and middle-aged gap makers has increased remarkably over recent decades, particularly since the year 1996. The main results indicated that regional water scarcity was the primary limiting factor for long-term changes in tree mortality, as shown by a significant correlation between the diameter at breast height (DBH) of dead trees and the annual surface water. The average density (or regeneration rate) of seedlings and saplings was highest in the RBAs, intermediate in the CGAs, and lowest in the UCAs. Compared with the UCAs, the CGAs promote tree regeneration to some extent by providing favorable conditions for the survival and growth of seedlings and saplings, which would otherwise be suppressed in the understory. Furthermore, although the density of seedlings and saplings in the CGAs was not as high as in the RBAs, the survival rate was higher in the CGAs than in the RBAs.

Conclusion
Forest canopy gaps in floodplain areas can play a decisive role in the long-term germination and regeneration of plant species. However, as a typical phreatophyte in this hyper-arid region, the ecosystem structure, functions and services of this fragile P. euphratica floodplain forests are threatened by a continuous decrease of water resources, due to excessive water use for agricultural irrigation, which has resulted in a severe reduction of intact poplar forests. Furthermore, the survival of seedlings and saplings is influenced by light availability and soil water at the regional scale. Our findings suggest that policymakers may need to reconsider the restoration and regeneration measures implemented in riparian P. euphratica forests to improve flood water efficiency and create canopy gaps. Our results provide with valuable reference information for the conservation and sustainable development of floodplain forest ecosystems.
Estimating a global demand model for soybean traffic through the Panama Canal
Authors: Ho Javier , Bernal Paul 
Published: July 2021

AbstractThis study attempts to fit a global demand model for soybean traffic through the Panama Canal using Ordinary Least Square. Most of the soybean cargo through the interoceanic waterway is loaded on the U.S. Gulf and East Coast ports -mainly destined to East Asia, especially China-, and represented about 34% of total Panama Canal grain traffic between fiscal years 2010–19. To estimate the global demand model for soybean traffic, we are considering explanatory variables such as effective toll rates through the Panama Canal, U.S. Gulf- Asia and U.S. Pacific Northwest- Asia freight rates, Baltic Dry Index, bunker costs, soybean export inspections from the U.S. Gulf and Pacific Northwest, U.S. Gulf soybean basis levels, Brazil’s soybean exports and average U.S. dollar index. As part of the research, we are pursuing the estimation of the toll rate elasticity of vessels transporting soybeans via the Panama Canal. Data come mostly from several U.S. Department of Agriculture sources, Brazil’s Secretariat of Foreign Trade (SECEX) and from Panama Canal transit information. Finally, after estimation of the global demand model for soybean traffic, we will discuss the implications for future soybean traffic through the waterway, evaluating alternative routes and sources for this trade.