bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protocol for the Controlled evaLuation of Angiotensin Receptor blockers for COVID-19 respIraTorY disease (CLARITY): a randomised controlled trial
Authors: Hockham Carinna , Kotwal Sradha , Wilcox Arlen , Bassi Abhinav , McGree James , Pollock Carol , Burrell Louise M. , Bathla Nikita , Kunigari Mallikarjuna , Rathore Vinay , John Michael , Lin Enmoore , Jenkins Christine , Ritchie Angus , McLachlan Andrew , Snelling Thomas , Jones Mark , Jha Vivekanand , Jardine Meg ,   on behalf of the CLARITY Investigators
Published: August 2021

Abstract
Background
SARS-CoV-2 binds to membrane-bound angiotensin-converting enzyme 2 (ACE2) which may result in downregulation of membrane-bound ACE2. ACE2 is a key regulator of the renin-angiotensin system (RAS) and is responsible for degrading angiotensin II and thereby counteracting its pro-inflammatory, pro-fibrotic effects mediated through the angiotensin II type 1 receptor (AT1R). As AT1R is directly blocked by angiotensin receptor blockers (ARBs), these agents may offer a safe, low-cost solution for reducing COVID-19 respiratory outcomes.

Methods and discussion
CLARITY is a pragmatic, adaptive, two-arm, multi-centre, comparative effectiveness phase III randomised controlled trial that examines whether ARBs reduce COVID-19 severity among high-risk patients. Recruiting in India and Australia, the trial will compare treatment with a maximum tolerated daily dose of an ARB to standard of care. Treatment allocation is blinded in India but open-label in Australia due to interruptions to placebo supply in the latter. The primary endpoint is a 7-point ordinal scale of clinical states, ranging from no limitation of activities (category 1) to death (category 7), assessed on day 14. Secondary outcomes include the 7-point scale assessed at day 28 and 28- and 90-day mortality. The design adapts the sample size based on accumulating data via frequent interim analyses and the use of predictive probability to determine whether the current sample size is sufficient or continuing accrual would be futile. The trial commenced recruitment on 18 August 2020.

Trial registration
ClinicalTrials.gov, NCT04394117. Registered on 19 May 2020. Clinical Trial Registry of India: CTRI/2020/07/026831)
2-Hydroxybenzylamine (2-HOBA) to prevent early recurrence of atrial fibrillation after catheter ablation: protocol for a randomized controlled trial including detection of AF using a wearable device
Authors: O’Neill Matthew J. , Yoneda Zachary T. , Crawford Diane M. , Ye Fei , Ao Mingfang , Pitchford Lisa M. , Rathmacher John A. , Murray Katherine T. , Akers Wendell S. , Roden Dan M. , Michaud Gregory F. , Shoemaker M. Benjamin 
Published: August 2021

Abstract
Background
Although catheter ablation is an effective therapy for atrial fibrillation (AF), the most common cardiac arrhythmia encountered in clinical practice, AF ablation generates inflammation and oxidative stress in the early postoperative period predisposing to recurrence of AF. Isolevuglandins (IsoLGs) are reactive lipid mediators of oxidative stress injury that rapidly react with endogenous biomolecules to compromise their function. 2-Hydroxybenzylamine (2-HOBA), a potent small molecule scavenger of IsoLGs, sequesters the reactive species as inert adducts. This mechanism, coupled with reported safety in humans, supports the investigation of 2-HOBA as a novel therapeutic to reduce AF caused by oxidative stress, such as that which occurs after catheter ablation. Accordingly, we seek to test the hypothesis that treatment with 2-HOBA will decrease early recurrence of AF and other atrial arrhythmias following AF ablation by decreasing IsoLG adducts with native biomolecules.

Methods
The proposed trial will randomly assign 162 participants undergoing cryo- or radiofrequency catheter ablation for AF to 2-HOBA (N = 81) or placebo (N = 81). Individuals will begin the study drug 3 days prior to ablation and continue for 28 days. Participants will be given a wearable smartwatch capable of detecting and recording atrial arrhythmias. They will be instructed to record ECGs daily with additional ECGs if they experience symptoms of AF or when alerted by the smartwatch AF detection alarm. The primary clinical endpoint will be an episode of AF, atrial tachycardia, or atrial flutter lasting 30 s or more within 28 days post-AF ablation. Secondary measures will be the change in IsoLG adduct levels from blood samples collected immediately pre-ablation and post-ablation and reduction in AF burden as calculated from the smartwatch.

Discussion
The proposed trial will test the hypothesis that 2-HOBA reduces post-ablation atrial arrhythmias through sequestration of reactive IsoLG species. The results of this study may improve the understanding of the role of IsoLGs and oxidative stress in AF pathogenesis and provide evidence to advance 2-HOBA and related compounds as a new therapeutic strategy to treat AF.

Trial registration
ClinicalTrials.gov NCT04433091. Registered on June 3, 2020.
Rational engineering of Saccharomyces cerevisiae towards improved tolerance to multiple inhibitors in lignocellulose fermentations
Authors: Brandt Bianca A. , García-Aparicio Maria D. P. , Görgens Johann F. , van Zyl Willem H. 
Published: August 2021

Abstract
Background
The fermentation of lignocellulose hydrolysates to ethanol requires robust xylose-capable Saccharomycescerevisiae strains able to operate in the presence of microbial inhibitory stresses. This study aimed at developing industrial S.cerevisiae strains with enhanced tolerance towards pretreatment-derived microbial inhibitors, by identifying novel gene combinations that confer resistance to multiple inhibitors (thus cumulative inhibitor resistance phenotype) with minimum impact on the xylose fermentation ability. The strategy consisted of multiple sequential delta-integrations of double-gene cassettes containing one gene conferring broad inhibitor tolerance (ARI1, PAD1 or TAL1) coupled with an inhibitor-specific gene (ADH6, FDH1 or ICT1). The performances of the transformants were compared with the parental strain in terms of biomass growth, ethanol yields and productivity, as well as detoxification capacities in a synthetic inhibitor cocktail, sugarcane bagasse hydrolysate as well as hardwood spent sulphite liquor.

Results
The first and second round of delta-integrated transformants exhibited a trade-off between biomass and ethanol yield. Transformants showed increased inhibitor resistance phenotypes relative to parental controls specifically in fermentations with concentrated spent sulphite liquors at 40% and 80% v/v concentrations in 2% SC media. Unexpectedly, the xylose fermentation capacity of the transformants was reduced compared to the parental control, but certain combinations of genes had a minor impact (e.g. TAL1 + FDH1). The TAL1 + ICT1 combination negatively impacted on both biomass growth and ethanol yield, which could be linked to the ICT1 protein increasing transformant susceptibility to weak acids and temperature due to cell membrane changes.

Conclusions
The integration of the selected genes was proven to increase tolerance to pretreatment inhibitors in synthetic or industrial hydrolysates, but they were limited to the fermentation of glucose. However, some gene combination sequences had a reduced impact on xylose conversion.
Risk of dementia in patients with toxoplasmosis: a nationwide, population-based cohort study in Taiwan
Authors: Yang Hung-Yi , Chien Wu-Chien , Chung Chi-Hsiang , Su Ruei-Yu , Lai Chung-Yu , Yang Chuan-Chi , Tzeng Nian-Sheng 
Published: August 2021

Abstract
Background
Approximately 25–30% of individuals worldwide are infected with Toxoplasma gondii (T. gondii), which is difficult to detect in its latent state. We aimed to evaluate the association between toxoplasmosis, the risk of dementia, and the effects of antibiotics in Taiwan.

Methods
This nationwide, population-based, retrospective cohort study was conducted using the Longitudinal Health Insurance Database containing the records of 2 million individuals retrieved from Taiwan’s National Health Insurance Research Database. Fine–Gray competing risk analysis was used to determine the risk for the development of dementia in the toxoplasmosis cohort relative to the non-toxoplasmosis cohort. A sensitivity analysis was also conducted. The effects of antibiotics (sulfadiazine or clindamycin) on the risk of dementia were also analyzed.

Results
We enrolled a total of 800 subjects, and identified 200 patients with toxoplasmosis and 600 sex- and age-matched controls without toxoplasmosis infection in a ratio of 1:3, selected between 2000 and 2015. The crude hazard ratio (HR) of the risk of developing dementia was 2.570 [95% confidence interval (CI) = 1.511–4.347, P < 0.001]. After adjusting for sex, age, monthly insurance premiums, urbanization level, geographical region, and comorbidities, the adjusted HR was 2.878 (95% CI = 1.709–4.968, P < 0.001). Sensitivity analysis revealed that toxoplasmosis was associated with the risk of dementia even after excluding diagnosis in the first year and the first 5 years. The usage of sulfadiazine or clindamycin in the treatment of toxoplasmosis was associated with a decreased risk of dementia.

Conclusions
This finding supports the evidence that toxoplasmosis is associated with dementia and that antibiotic treatment against toxoplasmosis is associated with a reduced risk of dementia. Further studies are necessary to explore the underlying mechanisms of these associations.

Graphical Abstract
The parasite Schistocephalus solidus secretes proteins with putative host manipulation functions
Authors: Berger Chloé Suzanne , Laroche Jérôme , Maaroufi Halim , Martin Hélène , Moon Kyung-Mee , Landry Christian R. , Foster Leonard J. , Aubin-Horth Nadia 
Published: August 2021

Abstract
Background
Manipulative parasites are thought to liberate molecules in their external environment, acting as manipulation factors with biological functions implicated in their host’s physiological and behavioural alterations. These manipulation factors are part of a complex mixture called the secretome. While the secretomes of various parasites have been described, there is very little data for a putative manipulative parasite. It is necessary to study the molecular interaction between a manipulative parasite and its host to better understand how such alterations evolve.

Methods
Here, we used proteomics to characterize the secretome of a model cestode with a complex life cycle based on trophic transmission. We studied Schistocephalus solidus during the life stage in which behavioural changes take place in its obligatory intermediate fish host, the threespine stickleback (Gasterosteus aculeatus). We produced a novel genome sequence and assembly of S. solidus to improve protein coding gene prediction and annotation for this parasite. We then described the whole worm’s proteome and its secretome during fish host infection using LC–MS/MS.

Results
A total of 2290 proteins were detected in the proteome of S. solidus, and 30 additional proteins were detected specifically in the secretome. We found that the secretome contains proteases, proteins with neural and immune functions, as well as proteins involved in cell communication. We detected receptor-type tyrosine-protein phosphatases, which were reported in other parasitic systems to be manipulation factors. We also detected 12 S. solidus-specific proteins in the secretome that may play important roles in host–parasite interactions.

Conclusions
Our results suggest that S. solidus liberates molecules with putative host manipulation functions in the host and that many of them are species-specific.

Graphical abstract
Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan
Authors: Rosa-Teijeiro Chloé , Wagner Victoria , Corbeil Audrey , d’Annessa Ilda , Leprohon Philippe , do Monte-Neto Rubens L. , Fernandez-Prada Christopher 
Published: August 2021

Abstract
Background
The evolution of drug resistance is one of the biggest challenges in leishmaniasis and has prompted the need for new antileishmanial drugs. Repurposing of approved drugs is a faster and very attractive strategy that is gaining supporters worldwide. Different anticancer topoisomerase 1B (TOP1B) inhibitors have shown strong antileishmanial activity and promising selective indices, supporting the potential repurposing of these drugs. However, cancer cells and Leishmania share the ability to become rapidly resistant. The aim of this study was to complete a whole-genome exploration of the effects caused by exposure to topotecan in order to highlight the potential mechanisms deployed by Leishmania to favor its survival in the presence of a TOP1B inhibitor.

Methods
We used a combination of stepwise drug resistance selection, whole-genome sequencing, functional validation, and theoretical approaches to explore the propensity of and potential mechanisms deployed by three independent clones of L. infantum to resist the action of TOP1B inhibitor topotecan.

Results
We demonstrated that L. infantum is capable of becoming resistant to high concentrations of topotecan without impaired growth ability. No gene deletions or amplifications were identified from the next-generation sequencing data in any of the three resistant lines, ruling out the overexpression of efflux pumps as the preferred mechanism of topotecan resistance. We identified three different mutations in the large subunit of the leishmanial TOP1B (Top1BF187Y, Top1BG191A, and Top1BW232R). Overexpression of these mutated alleles in the wild-type background led to high levels of resistance to topotecan. Computational molecular dynamics simulations, in both covalent and non-covalent complexes, showed that these mutations have an effect on the arrangement of the catalytic pentad and on the interaction of these residues with surrounding amino acids and DNA. This altered architecture of the binding pocket results in decreased persistence of topotecan in the ternary complex.

Conclusions
This work helps elucidate the previously unclear potential mechanisms of topotecan resistance in Leishmania by mutations in the large subunit of TOP1B and provides a valuable clue for the design of improved inhibitors to combat resistance in both leishmaniasis and cancer. Our data highlights the importance of including drug resistance evaluation in drug discovery cascades.

Graphical abstract
Functional significance of gain-of-function H19 lncRNA in skeletal muscle differentiation and anti-obesity effects
Authors: Li Yajuan , Zhang Yaohua , Hu Qingsong , Egranov Sergey D. , Xing Zhen , Zhang Zhao , Liang Ke , Ye Youqiong , Pan Yinghong , Chatterjee Sujash S. , Mistretta Brandon , Nguyen Tina K. , Hawke David H. , Gunaratne Preethi H. , Hung Mien-Chie , Han Leng , Yang Liuqing , Lin Chunru 
Published: August 2021

Abstract
Background
Exercise training is well established as the most effective way to enhance muscle performance and muscle building. The composition of skeletal muscle fiber type affects systemic energy expenditures, and perturbations in metabolic homeostasis contribute to the onset of obesity and other metabolic dysfunctions. Long noncoding RNAs (lncRNAs) have been demonstrated to play critical roles in diverse cellular processes and diseases, including human cancers; however, the functional importance of lncRNAs in muscle performance, energy balance, and obesity remains elusive. We previously reported that the lncRNA H19 regulates the poly-ubiquitination and protein stability of dystrophin (DMD) in muscular dystrophy.

Methods
Here, we identified mouse/human H19-interacting proteins using mouse/human skeletal muscle tissues and liquid chromatography–mass spectrometry (LC-MS). Human induced pluripotent stem-derived skeletal muscle cells (iPSC-SkMC) from a healthy donor and Becker Muscular Dystrophy (BMD) patients were utilized to study DMD post-translational modifications and associated proteins. We identified a gain-of-function (GOF) mutant of H19 and characterized the effects on myoblast differentiation and fusion to myotubes using iPSCs. We then conjugated H19 RNA gain-of-function oligonucleotides (Rgof) with the skeletal muscle enrichment peptide agrin (referred to as AGR-H19-Rgof) and evaluated AGR-H19-Rgof’s effects on skeletal muscle performance using wild-type (WT) C57BL/6 J mice and its anti-obesity effects using high-fat diet (HFD)- and leptin deficiency-induced obese mouse models.

Results
We demonstrated that both human and mouse H19 associated with DMD and that the H19 GOF exhibited enhanced interaction with DMD compared to WT H19. DMD was found to associate with serine/threonine-protein kinase MRCK alpha (MRCKα) and α-synuclein (SNCA) in iPSC-SkMC derived from BMD patients. Inhibition of MRCKα and SNCA-mediated phosphorylation of DMD antagonized the interaction between H19 and DMD. These signaling events led to improved skeletal muscle cell differentiation and myotube fusion. The administration of AGR-H19-Rgof improved the muscle mass, muscle performance, and base metabolic rate of WT mice. Furthermore, mice treated with AGR-H19-Rgof exhibited resistance to HFD- or leptin deficiency-induced obesity.

Conclusions
Our study suggested the functional importance of the H19 GOF mutant in enhancing muscle performance and anti-obesity effects.
Physical and psychological health outcomes of a sitting light volleyball intervention program on adults with physical disabilities: a non-randomized controlled pre-post study
Authors: Leung Ka-Man , Chung Pak-Kwong , Chu William , Ng Kwok 
Published: August 2021

Abstract
Background
People with physical disabilities (PWPD) have limited opportunities to participate in sport activities. Sitting light volleyball (SLVB) is an adapted sport that combines light volleyball and paralympic sitting volleyball. This study examined the effectiveness of an SLVB intervention program to improve the physical and psychological health outcomes of PWPD in Hong Kong, China.

Methods
Thirty-two PWPD [13 women; SLVB group, n = 18; control group (CG), n = 14] with an average age of 48.89 years (SD = 14.42 years) participated in a 16-week intervention consisting of basic SLVB skills, and they also received instructions on the required posture, team tactics, and SLVB rules. Physical (i.e., muscular strength, muscular endurance, body composition, flexibility, and aerobic endurance) and psychological (i.e., physical activity enjoyment and quality of life) health outcomes were measured before and after the intervention.

Results
Individuals in the SLVB group exhibited statistically significant improvements in cardiovascular endurance [F(1,29) = 4.23, p = .049], body composition [F(1,23) = 6.67, p = .017], and physical activity enjoyment [F(1,29) = 16.94, p = .001] compared with adults in the CG.

Conclusions
Participating in SLVB has physical and psychological benefits for adults with physical disabilities in this study.
Registration number of trial registry: The trial is registered at chictr.org.cn, number ChiCTR2000032971 on 17/05/2020.
Propionic acid disrupts endocytosis, cell cycle, and cellular respiration in yeast
Authors: Micalizzi Emma W. , Golshani Ashkan , Smith Myron L. 
Published: August 2021

Abstract
Objective
We previously identified propionic acid as a microbially-produced volatile organic compound with fungicidal activity against several pathogenic fungi. The purpose of this work is to better understand how propionic acid affects fungi by examining some of the effects of this compound on the yeast cell.

Results
We show that propionic acid causes a dramatic increase in the uptake of lucifer yellow in yeast cells, which is consistent with enhanced endocytosis. Additionally, using a propidium iodide assay, we show that propionic acid treatment causes a significant increase in the proportion of yeast cells in G1 and a significant decrease in the proportion of cells in G2, suggesting that propionic acid causes a cell cycle arrest in yeast. Finally, we show that the reduction of MTT is attenuated in yeast cells treated with propionic acid, indicating that propionic acid disrupts cellular respiration. Understanding the effects of propionic acid on the yeast cell may aid in assessing the broader utility of this compound.
Application of bacteriophage as food preservative to control enteropathogenic Escherichia coli (EPEC)
Authors: Waturangi Diana Elizabeth , Kasriady Cecillia Pingkan , Guntama Geofany , Sahulata Amelinda Minerva , Lestari Diana , Magdalena Stella 
Published: August 2021

Abstract
Objectives
This study was conducted to characterize lytic bacteriophages infecting enteropathogenic Escherichia coli (EPEC) on several types of food and analyze their ability as phage biocontrol to be used as a food preservative. Characterization was done for bacteriophage morphology and stability, along with the determination of minimum multiplicity of infection (miMOI), and application of bacteriophage in the food matrix.

Results
Out of the five samples, BL EPEC bacteriophage exhibited the highest titer of 2.05  ×  109 PFU/mL, with a wide range of pH tolerance, and high thermal tolerance. BL EPEC also showed the least reduction after 168 h of incubation, with a rate of 0.90  ×  10–3 log10 per hour. Bacteriophages from BL EPEC and CS EPEC showed an ideal value of miMOI of 0.01. As a food preservative, BL EPEC bacteriophage was able to reduce bacteria in food samples with a reduction above 0.24 log10 in lettuce and approximately 1.84 log10 in milk. From this study we found that BL EPEC bacteriophage showed the greatest potential to be used as phage biocontrol to improve food safety