bluuebunny/crossref_metadata_2025_split huggingface dataset:
The epigenetic regulator G9a attenuates stress-induced resistance and metabolic transcriptional programs across different stressors and species
Authors: Riahi Human , Fenckova Michaela , Goruk Kayla J. , Schenck Annette , Kramer Jamie M. 
Published: May 2021

Abstract
Background
Resistance and tolerance are two coexisting defense strategies for fighting infections. Resistance is mediated by signaling pathways that induce transcriptional activation of resistance factors that directly eliminate the pathogen. Tolerance refers to adaptations that limit the health impact of a given pathogen burden, without targeting the infectious agent. The key players governing immune tolerance are largely unknown. In Drosophila, the histone H3 lysine 9 (H3K9) methyltransferase G9a was shown to mediate tolerance to virus infection and oxidative stress (OS), suggesting that abiotic stresses like OS may also evoke tolerance mechanisms. In response to both virus and OS, stress resistance genes were overinduced in Drosophila G9a mutants, suggesting an intact but overactive stress response. We recently demonstrated that G9a promotes tolerance to OS by maintaining metabolic homeostasis and safeguarding energy availability, but it remained unclear if this mechanism also applies to viral infection, or is conserved in other species and stress responses. To address these questions, we analyzed publicly available datasets from Drosophila, mouse, and human in which global gene expression levels were measured in G9a-depleted conditions and controls at different time points upon stress exposure.

Results
In all investigated datasets, G9a attenuates the transcriptional stress responses that confer resistance against the encountered stressor. Comparative analysis of conserved G9a-dependent stress response genes suggests that G9a is an intimate part of the design principles of stress resistance, buffering the induction of promiscuous stress signaling pathways and stress-specific resistance factors. Importantly, we find stress-dependent downregulation of metabolic genes to also be dependent on G9a across all of the tested datasets.

Conclusions
These results suggest that G9a sets the balance between activation of resistance genes and maintaining metabolic homeostasis, thereby ensuring optimal organismal performance during exposure to diverse types of stress across different species. We therefore propose G9a as a potentially conserved master regulator underlying the widely important, yet poorly understood, concept of stress tolerance.
Extremes of age are associated with differences in the expression of selected pattern recognition receptor genes and ACE2, the receptor for SARS-CoV-2: implications for the epidemiology of COVID-19 disease
Authors: Bickler Stephen W. , Cauvi David M. , Fisch Kathleen M. , Prieto James M. , Sykes Alicia G. , Thangarajah Hariharan , Lazar David A. , Ignacio Romeo C. , Gerstmann Dale R. , Ryan Allen F. , Bickler Philip E. , De Maio Antonio 
Published: May 2021

Abstract
Background
Older aged adults and those with pre-existing conditions are at highest risk for severe COVID-19 associated outcomes.

Methods
Using a large dataset of genome-wide RNA-seq profiles derived from human dermal fibroblasts (GSE113957) we investigated whether age affects the expression of pattern recognition receptor (PRR) genes and ACE2, the receptor for SARS-CoV-2.

Results
Extremes of age are associated with increased expression of selected PRR genes, ACE2 and four genes that encode proteins that have been shown to interact with SAR2-CoV-2 proteins.

Conclusions
Assessment of PRR expression might provide a strategy for stratifying the risk of severe COVID-19 disease at both the individual and population levels.
Nonlinear relationship between visceral adiposity index and lung function: a population-based study
Authors: Wang Yide , Li Zheng , Li Fengsen 
Published: May 2021

Abstract
Background
As one of the critical indicators of obesity, the interaction between visceral fat content and lung disease is the focus of current research. However, the exact relationship between Visceral adipose index (VAI) and lung function is not fully understood. The purpose of this study was to evaluate the relationship between VAI and lung function,

Methods
Our study included all participants from the baseline survey population in Xinjiang in the Natural Population Cohort Study in Northwest China. A field survey was conducted in rural areas of Moyu County, Xinjiang, China, between 35 and 74 years old from June to December 2018. We collected standard questionnaires and completed physical examinations, visceral fat tests, and lung function measurements.

Results
The study included 2367 participants with a mean VAI of 10.35 ± 4.35, with males having a significantly higher VAI than females: 13.17 ± 3.91 vs. 7.58 ± 2.65. The piecewise linear spline models indicated a significant threshold effect between lung function and VAI in the general population and the males population, showing an inverted U-shaped curve. But there was no significant association between VAI and lung function in females. FEV1% predicted and FVC% predicted increased with the increase of VAI (β 0.76; 95% CI 0.30, 1.21) and (β 0.50; 95% CI 0.06, 0.94) in males with VAI ≤ 14, while FEV1% predicted and FVC% predicted decreased with the increase of VAI (β − 1.17; 95% CI − 1.90, − 0.45) and (β − 1.36; 95% CI − 2.08, − 0.64) in males with VAI ≥ 15.

Conclusions
The relationship between lung function and VAI in male participants showed an inverted U-shaped curve, with the turning point of VAI between 14 and 15. The association between visceral fat and lung function was more robust in males than in females.
Development of an automated platform for the optimal production of glycoconjugate vaccines expressed in Escherichia coli
Authors: Samaras Jasmin J. , Mauri Marta , Kay Emily J. , Wren Brendan W. , Micheletti Martina 
Published: May 2021

AbstractProtein Glycan Coupling Technology (PGCT) uses purposely modified bacterial cells to produce recombinant glycoconjugate vaccines. This vaccine platform holds great potential in this context, namely due to its modular nature, the simplified production process in comparison to traditional chemical conjugation methods, and its amenability to scaled-up operations. As a result, a considerable reduction in production time and cost is expected, making PGCT-made vaccines a suitable vaccine technology for low-middle income countries, where vaccine coverage remains predominantly low and inconsistent. This work aims to develop an integrated whole-process automated platform for the screening of PGCT-made glycoconjugate vaccine candidates. The successful translation of a bench scale process for glycoconjugate production to a microscale automated setting was achieved. This was integrated with a numerical computational software that allowed hands-free operation and a platform adaptable to biological variation over the course of a production process. Platform robustness was proven with both technical and biological replicates and subsequently the platform was used to screen for the most favourable conditions for production of a pneumococcal serotype 4 vaccine candidate. This work establishes an effective automated platform that enabled the identification of the most suitable E. coli strain and genetic constructs to be used in ongoing early phase research and be further brought into preclinical trials.
Effect of plasma vitamin C levels on Parkinson’s disease and age at onset: a Mendelian randomization study
Authors: Liu Haijie , Zhang Yan , Zhang Haihua , Wang Longcai , Wang Tao , Han Zhifa , Wu Liyong , Liu Guiyou 
Published: May 2021

AbstractBackgroundUntil now, epidemiological evidence regarding the association between vitamin C intake (both diet and supplements) and Parkinson’s disease (PD) remains inconsistent. Hence, it is necessary to establish the causal link between vitamin C levels and PD, and further develop effective therapies or prevention.MethodsWe selected 11 newly identified plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (n = 52,018) as the effective instrumental variables, and extracted their corresponding GWAS summary statistics from PD (33,674 PD cases and 449,056 controls) and PD age at onset (AAO) (n = 28,568). We then performed a Mendelian randomization (MR) study to evaluate the causal association of plasma vitamin C levels with PD and PD AAO using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test.ResultsWe did not observe any significant association between genetically increased vitamin C levels and PD. Interestingly, we found a reduced trend of PD AAO (1.134 years) with 1 SD genetically increased vitamin C levels using IVW (beta = − 1.134, 95% CI: [− 2.515, 0.248],P = 0.108). Importantly, this trend was further successfully verified using both weighted median and MR-Egger. Each 1 SD genetically increased vitamin C levels could reduce PD AAO 1.75 and 2.592 years using weighted median (beta = − 1.750, 95% CI: [− 3.396, − 0.105],P = 0.037) and MR-Egger (beta = − 2.592, 95% CI: [− 4.623, − 0.560],P = 0.012).ConclusionsWe demonstrated the causal association between genetically increased plasma vitamin C levels and reduced PD AAO in people of European descent. Randomized controlled trials are required to clarify whether diet intake or supplement, or both could reduce the AAO of PD.
Clinical characteristics and genetic analysis of A20 haploinsufficiency
Authors: Zhang Dan , Su Gaixiu , Zhou Zhixuan , Lai Jianming 
Published: May 2021

Abstract
Purpose
To evaluate the clinical and genetic characteristics of 3 children with Haploinsufficiency of A20 (HA20). Methods:The clinical and genetic testing data of 3 children with HA20 treated at Capital Institute of Pediatrics (CIP) between August 2016 and October 2019 were retrospectively analysed.

Result
Patient 1 presented with arthritis and inflammatory bowel disease, patient 2 presented with axial spinal arthritis and lupus-like syndrome, and patient 3 presented with recurrent oral ulcers, gastrointestinal ulcers, and perianal abscesses. Regarding laboratory tests, patients were found to have elevated white blood cell (WBC) count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The CRP and ESR was reported to be high in all the patients. The WBC was reported to be high in patient 1 and 3. Patient 2 was positive for antinuclear antibodies, anti-Sjögren’s syndrome antigen A, dsDNA, rheumatoid factor and Coombs test. Genetic testing showed that all three patients had heterozygous mutation in TNFAIP3 gene. As for the treatment, patient 1 was treated with TNFα antagonist, patient 2 was treated with TNF α antagonist and sulfasalazine, and patient 3 was treated with corticosteroids and thalidomide. Patients 1 and 2 were followed for four and 3 months, respectively. There was an improvement in joint and gastrointestinal symptoms; inflammatory indices and rheumatoid factor (RF) were normal, and dsDNA and Coombs test became negative. Patient 3 was treated at another hospital and showed gradual improvement in oral ulcers and perianal abscesses.

Conclusion
HA20 is a single-gene auto-inflammatory disease caused by mutation in tumour necrosis factor (TNF)-α-induced protein 3 (TNFAIP3) gene. It may present as Behçet-like syndrome and resemble various other autoimmune diseases as well. Corticosteroids and immunosuppressive agents are effective treatments, and cytokine antagonists can be used in refractory cases. Whole-exome genetic testing should be proactively performed for children with early-age onset or Behçet-like syndrome to achieve early diagnosis and accurate treatment.
Cerebral microemboli in mini-sternotomy compared to mini- thoracotomy for aortic valve replacement: a cross sectional cohort study
Authors: Bozhinovska Marija , Jenko Matej , Stupica Gordana Taleska , Klokočovnik Tomislav , Kšela Juš , Jelenc Matija , Podbregar Matej , Fabjan Andrej , Šoštarič Maja 
Published: May 2021

AbstractBackgroundRecently adopted mini-thoracotomy approach for surgical aortic valve replacement has shown benefits such as reduced pain and shorter recovery, compared to more conventional mini-sternotomy access. However, whether limited exposure of the heart and ascending aorta resulting from an incision in the second intercostal space may lead to increased intraoperative cerebral embolization and more prominent postoperative neurologic decline, remains inconclusive. The aim of our study was to assess potential neurological complications after two different minimal invasive surgical techniques for aortic valve replacement by measuring cerebral microembolic signal during surgery and by follow-up cognitive evaluation.MethodsTrans-cranial Doppler was used for microembolic signal detection during aortic valve replacement performed via mini-sternotomy and mini-thoracotomy. Patients were evaluated using Addenbrooke’s Cognitive Examination Revised Test before and 30 days after surgical procedure.ResultsA total of 60 patients were recruited in the study. In 52 patients, transcranial Doppler was feasible. Of those, 25 underwent mini-sternotomy and 27 had mini-thoracotomy. There were no differences between groups with respect to sex, NYHA class distribution, Euroscore II or aortic valve area. Patients in mini-sternotomy group were younger (60.8 ± 14.4 vs.72 ± 5.84,p = 0.003), heavier (85.2 ± 12.4 vs.72.5 ± 12.9,p = 0.002) and had higher body surface area (1.98 ± 0.167 vs. 1.83 ± 0.178,p = 0.006). Surgery duration was longer in mini-sternotomy group compared to mini-thoracotomy (158 ± 24 vs. 134 ± 30 min,p < 0.001, respectively). There were no differences between groups in microembolic load, length of ICU or total hospital stay. Total microembolic signals count was correlated with cardiopulmonary bypass duration (5.64, 95%CI 0.677–10.60,p = 0.027). Addenbrooke’s Cognitive Examination Revised Test score decreased equivalently in both groups (p = 0.630) (MS: 85.2 ± 9.6 vs. 82.9 ± 11.4,p = 0.012; MT: 85.2 ± 9.6 vs. 81.3 ± 8.8,p = 0.001).ConclusionThere is no difference in microembolic load between the groups. Total intraoperative microembolic signals count was associated with cardiopulmonary bypass duration. Age, but not micorembolic signals load, was associated with postoperative neurologic decline.Trial registry numberclinicaltrials.gov,NCT0269778614.
The genetic basis of classical galactosaemia in Polish patients
Authors: Jezela-Stanek Aleksandra , Bauer Anna , Wertheim-Tysarowska Katarzyna , Bal Jerzy , Rygiel Agnieszka Magdalena , Sykut-Cegielska Jolanta 
Published: May 2021

AbstractClassic galactosemia (OMIM #230400) is an autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the galactose-1-phosphate uridylyltransferase gene (GALT; 606999) on chromosome 9p13. Its diagnosis is established by detecting elevated erythrocyte galactose-1-phosphate concentration, reduced erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity. Biallelic pathogenic variants in the GALT gene is confirmed by DNA analysis. Our paper presents molecular characteristics of 195 Polish patients diagnosed with galactosemia I, intending to expand the current knowledge of this rare disease's molecular etiology. To the best of our knowledge, the described cohort of galactosemia patients is the largest single-center cohort presented so far.
Providing trial results to participants in phase III pragmatic effectiveness RCTs: a scoping review
Authors: Bruhn Hanne , Cowan Elle-Jay , Campbell Marion K. , Constable Lynda , Cotton Seonaidh , Entwistle Vikki , Humphreys Rosemary , Innes Karen , Jayacodi Sandra , Knapp Peter , South Annabelle , Gillies Katie 
Published: May 2021

Abstract
Background
There is an ethical imperative to offer the results of trials to those who participated. Existing research highlights that less than a third of trials do so, despite the desire of participants to receive the results of the trials they participated in. This scoping review aimed to identify, collate, and describe the available evidence relating to any aspect of disseminating trial results to participants.

Methods
A scoping review was conducted employing a search of key databases (MEDLINE, EMBASE, PsycINFO, and the Cumulative Index to Nursing & Allied Health Literature (CINAHL) from January 2008 to August 2019) to identify studies that had explored any aspect of disseminating results to trial participants. The search strategy was based on that of a linked existing review. The evidence identified describes the characteristics of included studies using narrative description informed by analysis of relevant data using descriptive statistics.

Results
Thirty-three eligible studies, including 12,700 participants (which included patients, health care professionals, trial teams), were identified and included. Reporting of participant characteristics (age, gender, ethnicity) across the studies was poor. The majority of studies investigated dissemination of aggregate trial results. The most frequently reported mode of disseminating of results was postal. Overall, the results report that participants evaluated receipt of trial results positively, with reported benefits including improved communication, demonstration of appreciation, improved retention, and engagement in future research. However, there were also some concerns about how well the dissemination was resourced and done, worries about emotional effects on participants especially when reporting unfavourable results, and frustration about the delay between the end of the trial and receipt of results.

Conclusions
This scoping review has highlighted that few high-quality evaluative studies have been conducted that can provide evidence on the best ways to deliver results to trial participants. There have been relatively few qualitative studies that explore perspectives from diverse populations, and those that have been conducted are limited to a handful of clinical areas. The learning from these studies can be used as a platform for further research and to consider some core guiding principles of the opportunities and challenges when disseminating trial results to those who participated.
Moving online: young people and parents’ experiences of adolescent eating disorder day programme treatment during the COVID-19 pandemic
Authors: Brothwood Phillipa Louise , Baudinet Julian , Stewart Catherine S. , Simic Mima 
Published: May 2021

Abstract
Background
This study examined the experiences of young people and their parents who attended an intensive day treatment programme for eating disorders online during the global COVID-19 pandemic.

Methods
Online questionnaires were completed by 14 adolescents (12–18 years) and their parents (n = 19). The questionnaires included a mixture of rating questions (Likert scale) and free text responses. Free text responses were analysed using reflexive thematic analysis.

Results
Three main themes were identified: 1) New discoveries, 2) Lost in translation and 3) The best of a bad situation. This study provides insight into the benefits and pitfalls of online treatment delivery in the adolescent day programme context, which has rapidly had to become part of the everyday therapeutic practice. Results indicate that there are advantages and disadvantages to this, and that parents and young people’s views differed.

Conclusions
This study suggests that the increased accessibility provided by online working does not necessarily translate to increased connection. Given the importance of therapeutic alliance in treatment outcomes, this will be an important consideration for future developments of online intensive treatments.
Pharmacokinetic-pharmacodynamic modelling of atazanavir in hair among adolescents on antiretroviral treatment in Zimbabwe
Authors: Ngara Bernard , Zvada Simbarashe , Chawana Tariro Dianah , Nhachi Charles Fungai Brian , Rusakaniko Simbarashe 
Published: May 2021

Abstract
Background
Drug potency is a pharmacological parameter defining dose or concentration of drug required to obtain 50% of the drug’s maximal effect. Pharmacokinetic-pharmacodynamic modelling and simulation allows estimation of potency and evaluate strategies improving treatment outcome. The objective of our study is to determine potency of atazanavir in hair, defined as atazanavir level in hair associated with 50% probability of failing to achieve viral load below 1000 copies/ml among adolescents, and explore the effect of participant specific variables on potency.

Methods
A secondary analysis was performed on data from a previous study conducted in HIV-infected adolescents failing 2nd line ART from Harare central hospital, Zimbabwe, between 2015 and 2016. We simulated atazanavir concentrations in hair using NONMEM (version 7.3) ADVAN 13, based on a previously established pharmacokinetic model. Logistic regression methods were used for PKPD analysis. Simulations utilising PKPD model focused on estimation of potency and exploring the effect of covariates.

Results
The potency of atazanavir in hair was found to be 4.5 ng/mg hair before adjusting for covariate effects. Participants at three months follow-up, reporting adequate adherence, having normal BMI-for-age, and cared for by mature guardians had increased potency of atazanavir in hair of 2.6 ng/mg, however the follow-up event was the only statistically significant factor at 5% level.

Conclusion
Atazanavir in hair in the range 2.6 to 4.5 ng/mg is associated with above 50% probability of early viral load suppression. Adherence monitoring to adolescents with lower potency of atazanavir is recommended. The effect self-reported adherence level, BMI-for-age, and caregiver status require further evaluation.
Using tri-axial accelerometer loggers to identify spawning behaviours of large pelagic fish
Authors: Clarke Thomas M. , Whitmarsh Sasha K. , Hounslow Jenna L. , Gleiss Adrian C. , Payne Nicholas L. , Huveneers Charlie 
Published: May 2021

Abstract
Background
Tri-axial accelerometers have been used to remotely describe and identify in situ behaviours of a range of animals without requiring direct observations. Datasets collected from these accelerometers (i.e. acceleration, body position) are often large, requiring development of semi-automated analyses to classify behaviours. Marine fishes exhibit many “burst” behaviours with high amplitude accelerations that are difficult to interpret and differentiate. This has constrained the development of accurate automated techniques to identify different “burst” behaviours occurring naturally, where direct observations are not possible.

Methods
We trained a random forest machine learning algorithm based on 624 h of accelerometer data from six captive yellowtail kingfish during spawning periods. We identified five distinct behaviours (swim, feed, chafe, escape, and courtship), which were used to train the model based on 58 predictive variables.

Results
Overall accuracy of the model was 94%. Classification of each behavioural class was variable; F1 scores ranged from 0.48 (chafe) – 0.99 (swim). The model was subsequently applied to accelerometer data from eight free-ranging kingfish, and all behaviour classes described from captive fish were predicted by the model to occur, including 19 events of courtship behaviours ranging from 3 s to 108 min in duration.

Conclusion
Our findings provide a novel approach of applying a supervised machine learning model on free-ranging animals, which has previously been predominantly constrained to direct observations of behaviours and not predicted from an unseen dataset. Additionally, our findings identify typically ambiguous spawning and courtship behaviours of a large pelagic fish as they naturally occur.