Miracle-dz/UniFAR-FTUs huggingface dataset:
Atypical structures of GAA/TTC trinucleotide repeats underlying Friedreich’s ataxia: DNA triplexes and RNA/DNA hybrids

Abstract Expansion of the GAA/TTC repeats in the first intron of the FXN gene causes Friedreich’s ataxia. Non-canonical structures are linked to this expansion. DNA triplexes and R-loops are believed to arrest transcription, which results in frataxin deficiency and eventual neurodegeneration. We present a systematic in silico characterization of the possible DNA triplexes that could be assembled with GAA and TTC strands; the two hybrid duplexes [r(GAA):d(TTC) and d(GAA):r(UUC)] in an R-loop; and three hybrid triplexes that could form during bidirectional transcription when the non-template DNA strand bonds with the hybrid duplex (collapsed R-loops, where the two DNA strands remain antiparallel). For both Y·R:Y and R·R:Y DNA triplexes, the parallel third strand orientation is more stable; both parallel and antiparallel protonated d(GA+A)·d(GAA):d(TTC) triplexes are stable. Apparent contradictions in the literature about the R·R:Y triplex stability is probably due to lack of molecular resolution, since shifting the third strand by a single nucleotide alters the stability ranking. In the collapsed R-loops, antiparallel d(TTC+)·d(GAA):r(UUC) is unstable, while parallel d(GAA)·r(GAA):d(TTC) and d(GA+A)·r(GAA):d(TTC) are stable. In addition to providing new structural perspectives for specific therapeutic aims, our results contribute to a systematic structural basis for the emerging field of quantitative R-loop biology.
Pesticide exposure and risk of cardiovascular disease: A systematic review

ABSTRACT The increase in pesticide consumption has a negative health impact. Studies point to an association between exposure to pesticides and cardiovascular disease (CVD), one of the leading causes of world mortality. This review synthesize evidence on the association between occupational exposure and environmental contamination by pesticides with CVDs from 1750 references databases (EBSCO, Medline, Science Direct, Scielo, Lilacs and Ovid) without date or language restriction. Selected 24 articles by PRISMA and Downs & Black methodologies, were included from inclusion criteria: original studies (case-control, cohort or cross-sectional design); clear CVD definition and exposure to pesticides; representative sample of the target population. The results show the occupational exposure to pesticides chlorpyrifos, coumafos, carbofuran, ethylene bromide, mancozeb, ziram, metalaxyl, pendimethalin and trifluralin was associated a risk of 1.8 to 3.2 for acute myocardial infarction. Primaphos, fenitrothion, malathion and deltamethrin pesticides were associated with a blood pressure increase. Environmental contamination by tetrachlorodibenzo-p-dioxin was associated with CVD with risk of 1.09 to 2.78 and organochlorine, 1.19 to 4.54; heavy metals, arsenic, trimethylarsine and dimethylarsinic acid with atherosclerosis and systemic arterial hypertension. These findings point to the association between exposure to pesticides and CVD, signaling the importance of greater rigor in the public policy related to pesticides.
Reward Enhances Pain Discrimination in Humans

The notion that reward inhibits pain is a well-supported observation in both humans and animals, allowing suppression of pain reflexes to acquired rewarding stimuli. However, a blanket inhibition of pain by reward would also impair pain discrimination. In contrast, early counterconditioning experiments implied that reward might actually spare pain discrimination. To test this hypothesis, we investigated whether discriminative performance was enhanced or inhibited by reward. We found in adult human volunteers (N = 25) that pain-based discriminative ability is actually enhanced by reward, especially when reward is directly contingent on discriminative performance. Drift-diffusion modeling shows that this relates to an augmentation of the underlying sensory signal strength and is not merely an effect of decision bias. This enhancement of sensory-discriminative pain-information processing suggests that whereas reward can promote reward-acquiring behavior by inhibition of pain in some circumstances, it can also facilitate important discriminative information of the sensory input when necessary.
Evaluating the capacity of species distribution modeling to predict the geographic distribution of the mangrove community in Mexico

Mangroves are highly productive ecosystems that provide important environmental services, but have been impacted massively in recent years by human activities. Studies of mangroves have focused on their ecology and function at local or landscape scales, but little has been done to understand their broader distributional patterns or the environmental factors that determine those distributions. Species distribution models (SDMs), have been used to estimate potential distributions of hundreds of species, yet no SDM studies to date have assessed mangrove community distributions in Mexico (the country with the fourth largest extent of this ecosystem). We used maximum entropy approaches to model environmental suitability for mangrove species distributions in the country, and to identify the environmental factors most important in determining those distributions. We also evaluated whether this modeling approach is adequate to estimate mangrove distribution as a community across Mexico. Best models were selected based on statistical significance (AUC ratio), predictive performance (omission error of 5%), and model complexity (Akaike criterion); after this evaluation, only one model per species met the three evaluation criteria. Environmental variable sets that included distance to coast yielded significantly better models; variables with strongest contributions included elevation, temperature of the coldest month, and organic carbon content of soil. Based on our results, we conclude that SDMs can be used to map mangrove communities in Mexico, but that results can be improved at local scales with inclusion of local variables (salinity, hydroperiod and microtopography), field validations, and remote sensing data.
Systematic Reconstruction of the Complete Two-Component Sensorial Network in Staphylococcus aureus

Bacteria are able to sense environmental conditions and respond accordingly. Their sensorial system relies on pairs of sensory and regulatory proteins, known as two-component systems (TCSs). The majority of bacteria contain dozens of TCSs, each of them responsible for sensing and responding to a different range of signals. Traditionally, the function of each TCS has been determined by analyzing the changes in gene expression caused by the absence of individual TCSs. Here, we used a bacterial strain deprived of the complete TC sensorial system to introduce, one by one, the active form of every TCS. This gain-of-function strategy allowed us to identify the changes in gene expression conferred by each TCS without interference of other members of the family. ABSTRACT In bacteria, adaptation to changes in the environment is mainly controlled through two-component signal transduction systems (TCSs). Most bacteria contain dozens of TCSs, each of them responsible for sensing a different range of signals and controlling the expression of a repertoire of target genes (regulon). Over the years, identification of the regulon controlled by each individual TCS in different bacteria has been a recurrent question. However, limitations associated with the classical approaches used have left our knowledge far from complete. In this report, using a pioneering approach in which a strain devoid of the complete nonessential TCS network was systematically complemented with the constitutively active form of each response regulator, we have reconstituted the regulon of each TCS of S. aureus in the absence of interference between members of the family. Transcriptome sequencing (RNA-Seq) and proteomics allowed us to determine the size, complexity, and insulation of each regulon and to identify the genes regulated exclusively by one or many TCSs. This gain-of-function strategy provides the first description of the complete TCS regulon in a living cell, which we expect will be useful to understand the pathobiology of this important pathogen. IMPORTANCE Bacteria are able to sense environmental conditions and respond accordingly. Their sensorial system relies on pairs of sensory and regulatory proteins, known as two-component systems (TCSs). The majority of bacteria contain dozens of TCSs, each of them responsible for sensing and responding to a different range of signals. Traditionally, the function of each TCS has been determined by analyzing the changes in gene expression caused by the absence of individual TCSs. Here, we used a bacterial strain deprived of the complete TC sensorial system to introduce, one by one, the active form of every TCS. This gain-of-function strategy allowed us to identify the changes in gene expression conferred by each TCS without interference of other members of the family.
Standardisations internationale et régionale des épreuves immuno-enzymatiques : méthodes, intérêts et limites

Les techniques immuno-enzymatiques (enzyme-linked immunosorbent assay : ELISA) utilisees pour le diagnostic des maladies infectieuses ont fait l'objet de nombreuses etudes de standardisation visant une meilleure reproductibilite des tests, l'expression des resultats, le choix du seuil de positivite et des echantillons de reference. Il apparait que la standardisation internationale des reactifs et des protocoles est necessaire pour permettre les controles de qualite et la comparaison des resultats entre laboratoires, mais que l'interpretation des resultats peut se heurter a des differences importantes selon le secteur geographique etudie. Partant de ces travaux, et a la lumiere du modele de l'ELISA indirecte pour la recherche des anticorps diriges contre #Trypanosoma vivax# chez les bovins, l'auteur propose de realiser la standardisation internationale des reactifs, du protocole et du mode d'expression des resultats ELISA a l'aide d'echantillons de reference internationaux. En revanche, pour la standardisation locale, il est propose de realiser : l'echantillonnage des populations de reference locales ; l'etablissement des frequences de distribution des populations locales infectee et non infectee ; le choix de temoins representatifs des populations locales (echantillons de reference secondaires) ; l'expression des resultats de la reaction par rapport a ces temoins ; l'etablissement d'un controle interne de qualite fonde sur la reponse des temoins ; la determination du seuil de positivite selon les exigences de l'utilisateur ; l'adaptation du seuil de positivite selon la prevalence observee dans le secteur geographique etudie. Ces mesures permettent de determiner la sensibilite et la specificite du test dans la population etudiee et, lorsque la prevalence de l'infection est connue, de calculer les valeurs predictives du test. (Resume d'auteur)
Understanding resource utilization and mortality in COPD to support policy making: A microsimulation study

Chronic obstructive pulmonary disease (COPD) poses a significant but heterogeneous burden to individuals and healthcare systems. Policymakers develop targeted policies to minimize this burden but need personalized tools to evaluate novel interventions and target them to subpopulations most likely to benefit. We developed a platform to identify subgroups that are at increased risk of emergency department visits, hospitalizations and mortality and to provide stratified patient input in economic evaluations of COPD interventions. We relied on administrative and survey data from Ontario, Canada and applied a combination of microsimulation and multi-state modeling methods. We illustrated the functionality of the platform by quantifying outcomes across smoking status (current, former, never smokers) and by estimating the effect of smoking cessation on resource use and survival, by comparing outcomes of hypothetical cohorts of smokers who quit at diagnosis and smokers that continued to smoke post diagnosis. The cumulative incidence of all-cause mortality was 37.9% (95% CI: 34.9, 41.4) for never smokers, 34.7% (95% CI: 32.1, 36.9) for current smokers, and 46.4% (95% CI: 43.6, 49.0) for former smokers, at 14 years. Over 14 years, smokers who did not quit at diagnosis had 16.3% (95% CI: 9.6, 38.4%) more COPD-related emergency department visits than smokers who quit at diagnosis. In summary, we combined methods from clinical and economic modeling to create a novel tool that policymakers and health economists can use to inform future COPD policy decisions and quantify the effect of modifying COPD risk factors on resource utilization and morality.
Fractal analysis of muscle activity patterns during locomotion: pitfalls and how to avoid them.

Time-dependent physiological data sets are often difficult to interpret objectively. Biosignals such as electromyogram, electroencephalogram or single-neuron recordings can be interpreted using various linear and nonlinear methods. Each analysis technique aims at the explanation of different data features that might be visible or not to the naked eye. Here, we used linear decomposition based on machine learning to extract motor primitives (the time-dependent coefficients of muscle synergies) from the hindlimb electromyographic activity of mice during normal and mechanically perturbed locomotion. We set out to investigate the effects of calculation parameters and data quality on two nonlinear metrics derived from fractal analysis: The Higuchi's fractal dimension (HFD) and the Hurst exponent (H). Both HFD and H proved to be exceptionally sensitive to changes in motor primitives induced by external perturbations to locomotion. We discuss the potential pitfalls that might arise from fractal analysis by using examples based on surrogate data. We conclude giving some simple, data-driven suggestions to reduce the chance of misinterpretations when metrics such as HFD and H are applied to any biological signal containing elements of periodicity.
Evaluation of protein requirements for juvenile growth and effect of dietary protein levels on post-juvenile growth and reproduction of zebrafish (Danio rerio)

Despite the increasing utilisation of zebrafish as research model and the investment in its large-scale production, zebrafish rearing conditions are still based on subjective experience and conditions found for other aquacultured species. Since standardization and optimization of rearing conditions are fundamental to ensure reproducibility and reliability of research outputs, it is indispensable to perform studies especially designed to define specific conditions for zebrafish rearing. This necessarily includes the evaluation of nutritional requirements of zebrafish and the subsequent formulation of a standard diet. In view of these considerations, the present work aiming at (1) assessing dietary protein requirement for juvenile growth of zebrafish, and (2) assessing the effect of dietary protein levels on post-juvenile growth and reproductive performance of zebrafish. In a first experiment ten isoenergetic diets containing between 15% and 60% of protein were formulated in order to estimate the protein requirements for zebrafish juvenile. Dietary protein requirements were estimated at about 37% for maximum weight gain, 47% for maximum nitrogen retention, and 45% for maximum energy retention. A daily ration of 33.6 g kg of a diet containing 37% of protein and a daily ration of 29.1 g kg of a diet containing 47% of protein will promote respectively maximum weight gain and maximum nitrogen retention in zebrafish juvenile. In a second experiment four isoenergetic diets containing between 30% and 60% of protein were formulated in order to evaluate the effect of dietary protein levels on growth and reproductive performance of zebrafish post-juveniles. Neither growth nor the reproductive performance of zebrafish post-juvenile was significantly influenced by tested dietary protein levels, suggesting that relatively low dietary protein levels can be used in zebrafish husbandry at this stage. In our opinion, overall results should be viewed as a contribution towards the formulation of standard diets for zebrafish juvenile and post-juvenile stages, aiming the general standardization of zebrafish husbandry.
Feeling the heat: source–sink mismatch as a mechanism underlying the failure of thermal tolerance

ABSTRACT A mechanistic explanation for the tolerance limits of animals at high temperatures is still missing, but one potential target for thermal failure is the electrical signaling off cells and tissues. With this in mind, here I review the effects of high temperature on the electrical excitability of heart, muscle and nerves, and refine a hypothesis regarding high temperature-induced failure of electrical excitation and signal transfer [the temperature-dependent deterioration of electrical excitability (TDEE) hypothesis]. A central tenet of the hypothesis is temperature-dependent mismatch between the depolarizing ion current (i.e. source) of the signaling cell and the repolarizing ion current (i.e. sink) of the receiving cell, which prevents the generation of action potentials (APs) in the latter. A source–sink mismatch can develop in heart, muscles and nerves at high temperatures owing to opposite effects of temperature on source and sink currents. AP propagation is more likely to fail at the sites of structural discontinuities, including electrically coupled cells, synapses and branching points of nerves and muscle, which impose an increased demand of inward current. At these sites, temperature-induced source–sink mismatch can reduce AP frequency, resulting in low-pass filtering or a complete block of signal transmission. In principle, this hypothesis can explain a number of heat-induced effects, including reduced heart rate, reduced synaptic transmission between neurons and reduced impulse transfer from neurons to muscles. The hypothesis is equally valid for ectothermic and endothermic animals, and for both aquatic and terrestrial species. Importantly, the hypothesis is strictly mechanistic and lends itself to experimental falsification. Summary: A modified hypothesis about high temperature-induced failure of electrically excitable tissues is discussed; briefly, initiation and conduction of action potentials is impaired by temperature-dependent mismatch between active and passive properties of the cell membrane.
The current status of orthodontic education in U.S. pediatric dental residencies.

PURPOSE/OBJECTIVES The purpose of this study was to survey the current status of orthodontic education at pediatric dental residencies in the United States. A similar survey was conducted >10 years ago. With changing healthcare politics, social demands, and technology, it is important to have current information about dental education. METHODS A 23-item anonymous survey was sent to individual pediatric dental residency program directors via Qualtrics email software. The survey was sent a total of 4 times over an 8-week period. If the surveys were not completed in a predetermined amount of time, they were resent to those who had not yet completed them. RESULTS There were 34 responders for a 24% response rate. Of the respondents, 73% reported teaching biomechanics of tooth movement, and 45% reported teaching 2 × 4 mechanics to "marginally acceptable" level. Early (91%) to late mixed dentition (77%) is the most commonly treated orthodontic case. While most programs do not require a minimum number of orthodontic cases for graduation (85%), residents' understanding of growth and development is mostly (71%) evaluated through the results of the American Board of Pediatric Dentistry Qualifying Examination. CONCLUSION This study summarizes the current climate of the orthodontic education component in U.S. pediatric dental residencies.
Root system architecture analysis in Mesembryanthemum crystallinum (ice plant) seedlings reveals characteristic root halotropic response

ABSTRACT One of the major environmental stress factors that affect root growth is salinity. Arabidopsis thaliana, a glycophyte, shows halotropism, whereby it alters the direction of root growth in a non-gravitropic pattern to evade high soil salinity. Asymmetric auxin distribution regulated by the relocation of auxin-efflux carrier proteins is a key cellular event in the halotropic response. However, there are no reports of halotropism in halophytes. Here, we investigated root growth traits in Mesembryanthemum crystallinum (ice plant), under high salinity conditions. We hypothesized that ice plant roots would show halotropic responses different from those of Arabidopsis. Notably, similar to halotropism observed in Arabidopsis, ice plant roots showed continuous root bending under salinity stress. However, the root elongation rate did not change in ice plants. Expression analyses of several genes revealed that auxin transport might be partially involved in ice plant halotropism. This study enhances our understanding of halophyte root adaptation to high salinity stress. Summary: Halotropism is one of the key root growth traits that facilitates adaptation to saline soil conditions. The halophyte Mesembryanthemum crystallinum (ice plant), exhibited halotropic root growth under high salinity conditions.
Does Fibre-fix provided to people with irritable bowel syndrome who are consuming a low FODMAP diet improve their gut health, gut microbiome, sleep and mental health? A double-blinded, randomised controlled trial

Introduction A diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) is an effective way to reduce gut symptoms in people with irritable bowel syndrome (IBS). This diet reduces the intake of fermentable fibres, leading to changes of the gut microbiota and insufficient fermentation in the large bowel, resulting in reduced production of short-chain fatty acids (SCFAs), such as butyrate, which has unfavourable implications for gut health, sleep and mental health. This study will examine the effect of Fibre-fix, a supplement containing a mix of dietary fibres, on the human gut microbiome composition, fermentative capacity, sleep, quality of life (QOL) and mental health of people with IBS who consume a low FODMAP diet (LFD). Methods and analysis A randomised, double-blind, placebo-controlled, study design is proposed to examine whether Fibre-fix added to an existing LFD may help modulate gastrointestinal function, improve markers of sleep, mental health and promote QOL in patients with IBS. Participants will provide stool and blood samples, daily bowel symptoms diaries and 3-day diet records. Additionally, they will complete validated questionnaires relating to FODMAP intake, sleep, mental health and QOL before and after a 3-week intervention. Gut health will be assessed via faecal microbiome composition, faecal pH and SCFA levels. Alteration of sleep will be recorded using an actigraphy device worn by all participants over the whole study. Multivariate analysis will be used to examine the gut microbiome and repeated measures Analysis of variance (ANOVA) will be used for dependent variables from questionnaires related to bowel symptoms, stool type, sleep, mental health and QOL to assess the differences between intervention and control groups after adjustment for confounding variables. Ethics and dissemination Ethics approval was obtained from the Human Research Ethics Committee of Edith Cowan University (2019-00619-YAN). Results will be disseminated in peer-review journal publications, and conference presentations. Participants will be provided with a summary of findings once the study is completed. If Fibre-fix is shown to result in favourable changes in gut microbial composition, SCFA production, sleep and mental well-being without exacerbating symptoms, this will provide additional dietary management options for those with IBS following an LFD. Trial registration number ACTRN12620000032954.