bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma
Authors:   U-BIOPRED Consortium, Kermani Nazanin Zounemat , Song Woo-Jung , Badi Yusef , Versi Ali , Guo Yike , Sun Kai , Bhavsar Pank , Howarth Peter , Dahlen Sven-Erik , Sterk Peter J. , Djukanovic Ratko , Adcock Ian M. , Chung Kian Fan 
Published: January 2021

Abstract
Background
Patients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells.

Methods
We examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels.

Results
ACE2 levels were significantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing samples, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterised by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes.

Conclusion
Levels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.
Comprehensive elaboration of glycemic variability in diabetic macrovascular and microvascular complications
Authors: Sun Bao , Luo Zhiying , Zhou Jiecan 
Published: January 2021

AbstractDiabetes mellitus is the major risk factor for the development of macrovascular and microvascular complications. It is increasingly recognized that glycemic variability (GV), referring to oscillations in blood glucose levels and representing either short-term or long-term GV, is involved in the pathogenesis of diabetic complications and has emerged as a possible independent risk factor for them. In this review, we summarize the metrics and measurement of GV in clinical practice, as well as comprehensively elaborate the role and related mechanisms of GV in diabetic macrovascular and microvascular complications, aiming to provide the mechanism-based therapeutic strategies for clinicians to manage diabetes mellitus.
Effects of liraglutide on diastolic function parameters in patients with type 2 diabetes and coronary artery disease: a randomized crossover study
Authors: Kumarathurai Preman , Sajadieh Ahmad , Anholm Christian , Kristiansen Ole P. , Haugaard Steen B. , Nielsen Olav W. 
Published: January 2021

AbstractBackgroundDiastolic dysfunction is highly prevalent in patients with type 2 diabetes mellitus (T2DM) and is associated with overweight, glucose dysregulation and coronary artery disease (CAD). The GLP-1 receptor agonist, liraglutide, has shown to induce weight loss and improve metabolic factors, thus modulating factors associated with diastolic dysfunction. We have previously reported the effects of liraglutide on systolic function, and in this current study we explore the effects of liraglutide on diastolic function parameters in patients with stable CAD, preserved left ventricular ejection fraction (LVEF), and newly diagnosed T2DM.MethodsThirty subjects were randomized to liraglutide or placebo intervention for 12 + 12-weeks in this double-blind cross-over study. 2D-echocardiography using tissue velocity imaging was used for assessment of diastolic function parameters. Early diastolic filling velocity (E), late atrial filling velocity (A), E-wave deceleration time (EDT) and E/A ratio was assessed from the pulse wave (PW)-Doppler velocity recording of the mitral inflow. Peak early diastolic annular velocities (e′) was measured from color tissue doppler images.ResultsLiraglutide, when compared to placebo, induced a significant reduction in average e′ and lateral e′ velocities (– 0.57 cm/s [– 1.05 to − 0.08] and –0.74 cm/s [–1.32 to –0.15], respectively). Adjusted for the concomitant increase in HR (+ 6.16 bpm [0.79 to 11.54], the changes were not significant. No significant changes in other diastolic function parameters were observed.ConclusionsLiraglutide therapy did not improve any diastolic function parameters in subjects with T2DM, CAD, and preserved LVEF. Instead, a deterioration in e’ was observed, which was associated to an increase in heart rate induced by liraglutide therapy.Trial registrationClinical Trial Registration:http://www.clinicaltrials.gov(unique identifier: NCT01595789) (first submitted May 8, 2012)
Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF
Authors: Bode David , Semmler Lukas , Wakula Paulina , Hegemann Niklas , Primessnig Uwe , Beindorff Nicola , Powell David , Dahmen Raphael , Ruetten Hartmut , Oeing Christian , Alogna Alessio , Messroghli Daniel , Pieske Burkert M. , Heinzel Frank R. , Hohendanner Felix 
Published: January 2021

Abstract
Background
Sodium–glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF.

Methods
17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca2+ transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca2+ release were recorded by ratiometric microscopy using Ca2+-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca2+ buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student’s t-test, as applicable.

Results
Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca2+ release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca2+] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium–calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca2+ buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca2+ accumulation upon glycolytic inhibition.

Conclusion
The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca2+-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca2+ buffer capacity, diastolic Ca2+ accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.
The damage and tolerance mechanisms of Phaffia rhodozyma mutant strain MK19 grown at 28 °C
Authors: Miao Li-Li , Chi Shuang , Hou Ting-Ting , Liu Zhi-Pei , Li Ying 
Published: January 2021

Abstract
Background
Phaffia rhodozyma has many desirable properties for astaxanthin production, including rapid heterotrophic metabolism and high cell densities in fermenter culture. The low optimal temperature range (17–21 °C) for cell growth and astaxanthin synthesis in this species presents an obstacle to efficient industrial-scale astaxanthin production. The inhibition mechanism of cell growth at > 21 °C in P. rhodozyma have not been investigated.

Results
MK19, a mutant P. rhodozyma strain grows well at moderate temperatures, its cell growth was also inhibited at 28 °C, but such inhibition was mitigated, and low biomass 6 g/L was obtained after 100 h culture. Transcriptome analysis indicated that low biomass at 28 °C resulted from strong suppression of DNA and RNA synthesis in MK19. Growth inhibition at 28 °C was due to cell membrane damage with a characteristic of low mRNA content of fatty acid (f.a.) pathway transcripts (acc, fas1, fas2), and consequent low f.a. content. Thinning of cell wall and low mannose content (leading to loss of cell wall integrity) also contributed to reduced cell growth at 28 °C in MK19. Levels of astaxanthin and ergosterol, two end-products of isoprenoid biosynthesis (a shunt pathway of f.a. biosynthesis), reached 2000 µg/g and 7500 µg/g respectively; ~2-fold higher than levels at 21 or 25 °C. Abundance of ergosterol, an important cell membrane component, compensated for lack of f.a., making possible the biomass production of 6 g/L for MK19 at 28 °C.

Conclusions
Inhibition of growth of P. rhodozyma at 28 °C results from blocking of DNA, RNA, f.a., and cell wall biosynthesis. In MK19, abundant ergosterol made possible biomass production 6 g/L at 28 °C. Significant accumulation of astaxanthin and ergosterol indicated an active MVA pathway in MK19 at 28 °C. Strengthening of the MVA pathway can be a feasible metabolic engineering approach for enhancement of astaxanthin synthesis in P. rhodozyma. The present findings provide useful mechanistic insights regarding adaptation of P. rhodozyma to 28 °C, and improved understanding of feasible metabolic engineering techniques for industrial scale astaxanthin production by this economically important yeast species.
Whole genome sequencing and metabolomics analyses reveal the biosynthesis of nerol in a multi-stress-tolerant Meyerozyma guilliermondii GXDK6
Authors: Mo Xueyan , Cai Xinghua , Hui Qinyan , Sun Huijie , Yu Ran , Bu Ru , Yan Bing , Ou Qian , Li Quanwen , He Sheng , Jiang Chengjian 
Published: January 2021

Abstract
Background
Nerol (C10H18O), an acyclic monoterpene, naturally presents in plant essential oils, and is used widely in food, cosmetics and pharmaceuticals as the valuable fragrance. Meanwhile, chemical synthesis is the only strategy for large-scale production of nerol, and the disadvantages of chemical synthesis greatly limit the production and its application. These defects drive the interests of researchers shift to the production of nerol by eco-friendly methods known as biosynthesis methods. However, the main technical bottleneck restricting the biosynthesis of nerol is the lacking of corresponding natural aroma-producing microorganisms.

Results
In this study, a novel multi-stress-tolerant probiotics Meyerozymaguilliermondii GXDK6 with aroma-producing properties was identified by whole genome sequencing and metabolomics technology. GXDK6 showed a broad pH tolerance in the range of 2.5–10.0. The species also showed salt tolerance with up to 12% NaCl and up to 18% of KCl or MgCl2. GXDK6 exhibited heavy-metal Mn2+ tolerance of up to 5494 ppm. GXDK6 could also ferment with a total of 21 kinds of single organic matter as the carbon source, and produce abundant aromatic metabolites. Results from the gas chromatography–mass spectrometry indicated the production of 8–14 types of aromatic metabolites (isopentanol, nerol, geraniol, phenylethanol, isobutanol, etc.) when GXDK6 was fermented up to 72 h with glucose, sucrose, fructose, or xylose as the single carbon source. Among them, nerol was found to be a novel aromatic metabolite from GXDK6 fermentation, and its biosynthesis mechanism had also been further revealed.

Conclusion
A novel aroma-producing M. guilliermondii GXDK6 was identified successfully by whole genome sequencing and metabolomics technology. GXDK6 showed high multi-stress-tolerant properties with acid–base, salty, and heavy-metal environments. The aroma-producing mechanism of nerol in GXDK6 had also been revealed. These findings indicated the aroma-producing M. guilliermondii GXDK6 with multi-stress-tolerant properties has great potential value in the fermentation industry.
YAP manipulates proliferation via PTEN/AKT/mTOR-mediated autophagy in lung adenocarcinomas
Authors: Xu Wei , Zhang Mingjiong , Li Yue , Wang Yu , Wang Kai , Chen Qiaoyu , Zhang Runjie , Song Weiwei , Huang Qiqing , Zhao Weihong , Wu Jianqing 
Published: January 2021

Abstract
Background
Autophagy is a double-edged sword during the initiation and progression of multiple tumors. The Hippo pathway effector YAP has been proved to be involved in autophagy processes. The present study aimed to investigate how YAP regulates cell proliferation via autophagy in lung adenocarcinomas (LUAD).

Methods
Data of LUAD chip GSE43458 was obtained from Gene Expression Omnibus (GEO). RT-qPCR and Western blot were performed to assess YAP expression in LUAD cell lines. CCK-8 assay, xenograft tumor model, immunochemistry and GFP-mRFP-LC3 fusion proteins were utilized to evaluate the effect of YAP on autophagy of LUAD cells in vitro and in vivo. Autophagy inhibitor treatment and rescue experiments were carried out to elucidate the mechanism by which YAP manipulates autophagy in LUAD cells.

Results
YAP was significantly overexpressed in samples of LUAD patients and its expression level is related to 5-year survival. YAP manipulated the proliferation and autophagy in A549 and H1299 LUAD cells. YAP could induce activation of Akt/mTOR signaling pathway via suppressing PTEN in a Hippo-pathway-dependent manner. 3-Methyladenine impeded autophagy flux and promoted the proliferation in vitro and in vivo.

Conclusions
Hippo pathway critical transcriptional coactivators YAP manipulates the proliferation of lung adenocarcinoma, which is regulated by PTEN/AKT/mTOR autophagic signaling.
MicroRNA regulation of cancer stem cells in the pathogenesis of breast cancer
Authors: Niu Tong , Zhang Weiwei , Xiao Wei 
Published: January 2021

AbstractBreast cancer is the most common cancer among women and accounts for 30% of all female malignancies worldwide. Breast cancer stem cells (BCSCs) are a small population of breast cancer cells that exhibit multiple characteristics including differentiation capacity, self-renewal and therapeutic resistance. Recently, BCSCs have attracted attention due to their modulation of breast tumor behaviors and drug resistance. miRNAs are small noncoding mRNAs involved in virtually all biological processes, including stem cell development, maintenance and differentiation. In breast cancer, miRNAs appear to be multi-faceted since they can act as either suppressors or oncogenes to regulate breast cancer progression. This review summarizes the critical roles of miRNAs in regulating multiple signaling pathways such as Wnt/β-catenin, Notch, PI3K/AKT/mTOR, BMI-1 and STAT3 that are important for the BCSC maintenance.
ADAM10 is involved in the oncogenic process and chemo-resistance of triple-negative breast cancer via regulating Notch1 signaling pathway, CD44 and PrPc
Authors: Cheng Yuanyuan , Lin Lishuang , Li Xiaoyan , Lu Aiqi , Hou Chenjian , Wu Qian , Hu Xiaomu , Zhou Zhongwen , Chen Zhongqing , Tang Feng 
Published: January 2021

AbstractBackgroundTriple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat, because it is so aggressive with shorter survival. Chemotherapy remains the standard treatment due to the lack of specific and effective molecular targets. The aim of the present study is to investigate the potential roles of A Disintegrin and Metalloproteinase 10 (ADAM10) on TNBC cells and the effects of combining ADAM10 expression and neoadjuvant chemotherapy treatment (NACT) to improve the overall survival in breast cancer patients.MethodsUsing a series of breast cancer cell lines, we measured the expression of ADAM10 and its substrates by quantitative real-time PCR assay (qRT-PCR) and western blot analysis. Cell migration and invasion, cell proliferation, drug sensitivity assay, cell cycle and apoptosis were conducted in MDA-MB-231 cells cultured with ADAM10 siRNA. The effect of ADAM10 down-regulation by siRNA on its substrates was assessed by western blot analysis. We performed immunohistochemical staining for ADAM10 in clinical breast cancer tissues in 94 patients receiving NACT.ResultsThe active form of ADAM10 was highly expressed in TNBC cell lines. Knockdown of ADAM10 in MDA-MB-231 cells led to a significant decrease in cell proliferation, migration, invasion and the IC50value of paclitaxel and adriamycin, while induced cell cycle arrest and apoptosis. And these changes were correlated with down-regulation of Notch signaling, CD44 and cellular prion protein (PrPc). In clinical breast cancer cases, a high ADAM10 expression in pre-NACT samples was strongly associated with poorer response to NACT and shorter overall survival.ConclusionsThese data suggest the previously unrecognized roles of ADAM10 in contributing to the progression and chemo-resistance of TNBC.
Variation of physical durability between LLIN products and net use environments: summary of findings from four African countries
Authors: Kilian Albert , Obi Emmanuel , Mansiangi Paul , Abílio Ana Paula , Haji Khamis Ameir , Blaufuss Sean , Olapeju Bolanle , Babalola Stella , Koenker Hannah 
Published: January 2021

Abstract
Background
Physical durability of long-lasting-insecticidal nets (LLIN) is an important aspect of the effectiveness of LLIN as a malaria prevention tool, but there is limited data on performance across locations and products. This secondary analysis of data from the VectorWorks project from 10 sites in four African countries involving six LLIN brands provides such data.

Methods
A total of 4672 campaign nets from 1976 households were recruited into prospective cohort studies 2–6 months after distribution through campaigns and followed for 3 years in Mozambique, Nigeria, DRC and Zanzibar, Tanzania. LLIN products included two 100 denier polyester LLIN (DawaPlus® 2.0, PermaNet® 2.0) distributed in five sites and four 150 denier polyethylene LLIN (Royal Sentry®, MAGNet®, DuraNet©, Olyset™ Net) distributed in five sites. Primary outcome was LLIN survival in serviceable condition and median survival in years. Net use environment and net care variables were collected during four household surveys. Determinants of physical durability were explored by survival analysis and Cox regression models with risk of failure starting with the first hanging of the net.

Results
Definite outcomes for physical durability were obtained for 75% of study nets. After 31 to 37 months survival in serviceable condition varied between sites by 63 percentage-points, from 17 to 80%. Median survival varied by 3.7 years, from 1.6 to 5.3 years. Similar magnitude of variation was seen for polyethylene and polyester LLIN and for the same brand. Cox regression showed increasing net care attitude in combination with exposure to net related messages to be the strongest explanatory variable of survival. However, differences between countries also remained significant. In contrast, no difference was seen for LLIN material types.

Conclusions
Variation in net use environment and net care is the main reason for differences in the physical durability of LLIN products in different locations. While some of these factors have been identified to work across countries, other factors remain poorly defined and further investigation is needed in this area. Grouping LLIN brands by similar textile characteristics, such as material or yarn strength, is insufficient to distinguish LLIN product performance suggesting a more differentiated, composite metric is needed.
Molecular characterization of G6PD mutations reveals the high frequency of G6PD Aures in the Lao Theung population
Authors: Sanephonasa Amkha , Cheepsunthorn Chalisa Louicharoen , Khaminsou Naly , Savongsy Onekham , Nuchprayoon Issarang , Leecharoenkiat Kamonlak 
Published: January 2021

AbstractBackgroundThe prevalence and genotypes of G6PD deficiency vary worldwide, with higher prevalence in malaria endemic areas. The first-time assessment of G6PD deficiency prevalence and molecular characterization ofG6PDmutations in the Lao Theung population were performed in this study.MethodsA total of 252 unrelated Lao Theung participants residing in the Lao People’s Democratic Republic (PDR) were recruited. All participant samples were tested for G6PD enzyme activity andG6PDgene mutations. The amplification refractory mutation system (ARMS)-PCR for detecting G6PD Aures was developed.ResultsTheG6PDmutations were detected in 11.51% (29/252) of the participants. Eight G6PD mutations were detected. The G6PD Aures was the most common mutation identified in this cohort, which represented 58.62% (17/29) of all mutation. The mutation pattern was homogenous, predominantly involving the G6PD Aures mutation (6.75%), followed by 1.19% G6PD Union and 0.79% each G6PD Jammu, G6PD Mahidol and G6PD Kaiping. One subject (0.4%) each carried G6PD Viangchan and G6PD Canton. Interestingly, one case of coinheritance of G6PD Aures and Quing Yan was detected in this cohort. Based on levels of G6PD enzyme activity, the prevalence of G6PD deficiency in the Lao Theung population was 9.13% (23/252). The prevalence of G6PD deficient males and females (activity < 30%) in the Lao Theung population was 6.41% (5/78) and 1.72% (3/174), respectively, and the prevalence of G6PD intermediate (activity 30–70%) was 5.95% (15/252).ConclusionsThe G6PD Aures mutation is highly prevalent in the Lao Theung ethnic group. The common G6PD variants in continental Southeast Asian populations, G6PD Viangchan, Canton, Kaiping, Union and Mahidol, were not prevalent in this ethnic group. The technical simplicity of the developed ARMS-PCR will facilitate the final diagnosis of the G6PD Aures.