Miracle-dz/UniFAR-FTUs huggingface dataset:
Assessment of the Carcinogenic Potential of Pretomanid in Transgenic Tg.rasH2 Mice

Pretomanid is a nitroimidazooxazine antimycobacterial drug that was approved as part of a three-drug oral regimen, consisting of bedaquiline, pretomanid, and linezolid, for 6-months treatment of adults with pulmonary extensively drug-resistant tuberculosis or with complicated forms of multidrug-resistant tuberculosis by the food and drug administration in the United States and regulatory bodies in over 10 other countries. Nitroaromatic compounds as a class carry a risk of genotoxicity and potential carcinogenicity based on reactive metabolite formation. A battery of good laboratory practice genotoxicity studies on pretomanid indicated that the compound was not genotoxic, however its hydroxy imidazole metabolite (M50) was genotoxic in the Ames assay. To assess the in vivo carcinogenic potential of pretomanid, hemizygous Tg.rasH2 mice were administered pretomanid once daily by oral gavage for 26 weeks. Male mice were given pretomanid in vehicle at doses of 0, 5, 15 and 40 mg/kg/day and female mice were given pretomanid in vehicle at doses of 0, 10, 30 and 80 mg/kg/day. Positive control mice of both sexes received intraperitoneal injections of urethane at 1000 mg/kg on Days 1, 3 and 5. There were no pretomanid-related early deaths, tumors, non-neoplastic microscopic findings, or gross necropsy findings at any dose level. The positive control gave the anticipated response of lung tumors. Oral administration of pretomanid to mice produced plasma exposure to the parent compound (high dose AUC of pretomanid 3 times the clinical AUC at the maximum recommended human dose) and exposure to the M50 metabolite (less than 10% of pretomanid) at all dose levels in both sexes. These data show that pretomanid was not carcinogenic in a transgenic mouse model at systemic exposures greater than human therapeutic exposures.
Measures of tracheal lesions are more discriminatory and reproducible indications of chronic respiratory disease caused by Mycoplasma gallisepticum in poultry

ABSTRACT Mycoplasma gallisepticum is the primary causative agent of chronic respiratory disease in poultry, and vaccination is the measure most commonly used for its control. Pathological changes caused by M. gallisepticum are mainly observed in the trachea and air sacs, but assessment of air sac lesions is subjective. Standardized parameters for evaluation of pathological changes, and their reproducibility and discrimination in uninfected and infected groups, are critical when assessing the efficacy of M. gallisepticum vaccination. This study reviewed and critically appraised the published literature on evaluation of vaccine efficacy against pathological changes caused by M. gallisepticum in poultry in the trachea and air sacs. A search of four electronic databases, with subsequent manual filtering, identified 23 eligible papers published since 1962 describing the assessment of histopathological changes in the trachea using tracheal lesion scores and/or measurement of tracheal mucosal thicknesses and assessment of gross air sac lesions using lesion scores. Measurement of tracheal lesions proved a more reliable and robust method of assessing disease induced by M. gallisepticum when compared to assessment of air sac lesions, highlighting the importance of including assessment of tracheal lesions as the primary outcome variable in vaccine efficacy studies. In addition, this study also identified the necessity for use of a standardized model for evaluation and reporting on M. gallisepticum vaccines to minimize variations between vaccine efficacy studies and to allow direct comparisons between them. RESEARCH HIGHLIGHTS Tracheal and air sac lesions have been used to assess M. gallisepticum vaccine efficacy. The specific parameters and statistical tests used to compare tracheal and air sac lesions vary greatly. Measures of tracheal lesions are more discriminatory than measures of air sac lesions. A standardized model is needed to evaluate vaccines against infection with M. gallisepticum.
Contextual factors and business strategy choice: The case of us hospitals

US hospitals are struggling with how to compete and remain viable in an increasingly turbulent and competitive environment. Using Porter’s generic strategies and resource dependence theory, this study examined the relationship between environmental factors and business strategy choice among U.S. hospitals. The study used longitudinal data from 2006 to 2016 of US urban, general acute care hospitals from the American Hospital Association Annual Survey, Medicare cost reports, and Area Health Resource File. Multinomial regression was used to analyze the data. and Discussion: Our findings showed four types of hospital strategy: cost-leadership, differentiation, hybrid, and stuck-in-the-middle. A greater number of physicians (county-level) increases the likelihood of pursuing differentiation and hybrid strategy. On the other hand, a higher older adult population (65 years+) increases the likelihood of pursuing a cost-leadership strategy. Similarly, lower competition and higher Medicare Advantage penetration increases the likelihood of pursuing cost-leadership over hybrid strategy. An increase in the unemployment rate decreases the likelihood of pursuing differentiation and cost-leadership strategies versus the hybrid strategy. Finally, hospitals pursuing a differentiation strategy tended to be larger, teaching, and not-for-profit. The results showed the importance of environmental and organizational factors in predicting the strategy choice of hospitals.
Multilevel methods for elliptic problems on domains not resolved by the coarse grid

Elliptic boundary value problems are frequently posed on complicated domains, which cannot be covered by a simple coarse initial grid as is needed for multigrid-like iterative methods. In the present article, this problem is resolved for selfadjoint second order problems and Dirichlet boundary conditions. The idea is to construct appropriate subspace decompositions of the corresponding finite element spaces by way of an embedding of the domain under consideration into a simpler domain like a square or a cube. Then the general theory of subspace correction methods can be applied.
Shifts in morphological covariation and evolutionary rates across multiple acquisitions of the trap‐jaw mechanism in Strumigenys

A long‐standing question in comparative biology is how the evolution of biomechanical systems influences morphological evolution. The need for functional fidelity implies that the evolution of such systems should be associated with tighter morphological covariation, which may promote or dampen rates of morphological evolution. I examine this question across multiple evolutionary origins of the trap‐jaw mechanism in the genus Strumigenys. Trap‐jaw ants have latch‐mediated, spring‐actuated systems that amplify the power output of their mandibles. I use Bayesian estimates of covariation and evolutionary rates to test the hypotheses that the evolution of this high‐performance system is associated with tighter morphological covariation in the head and mandibles relative to nontrap‐jaw forms and that this leads to shifts in rates of morphological evolution. Contrary to these hypotheses, there is no evidence of a large‐scale shift to higher covariation in trap‐jaw forms, while different traits show both increased and decreased evolutionary rates between forms. These patterns may be indicative of many‐to‐one mapping and/or mechanical sensitivity in the trap‐jaw LaMSA system. Overall, it appears that the evolution of trap‐jaw forms in Strumigenys did not require a correlated increase in morphological covariation, partly explaining the proclivity with which the system has evolved.
Bared‐teeth displays in bonobos (Pan paniscus): An assessment of the power asymmetry hypothesis

Facial expressions are key to navigating social group life. The Power Asymmetry Hypothesis of Motivational Emancipation predicts that the type of social organization shapes the meaning of communicative displays in relation to an individual's dominance rank. The bared‐teeth (BT) display represents one of the most widely observed communicative signals across primate species. Studies in macaques indicate that the BT display in despotic species is often performed unidirectionally, from low‐ to high‐ranking individuals (signaling submission), whereas the BT display in egalitarian species is usually produced irrespective of dominance (mainly signaling affiliation and appeasement). Despite its widespread presence, research connecting BT displays to the power asymmetry hypothesis outside the Macaca genus remains scarce. To extend this knowledge, we investigated the production of BT in relation to social dominance in dyadic interactions (N = 11,377 events) of 11 captive bonobos (Pan paniscus). Although adult bonobos were more despotic than previously suggested in the literature, BT displays were produced irrespective of dominance rank. Moreover, while adults produced the BT exclusively during socio‐sexual interactions, especially during periods of social tension, immature bonobos produced the BT in a wider number of contexts. As such, the results indicate that the communicative meaning of the BT display is consistent with signaling appeasement, especially in periods of social tension. Moreover, the BT display does not seem to signal social status, supporting the prediction for species with a high degree of social tolerance. These results advance our understanding of the origins of communicative signals and their relation to species' social systems.
Cardiac remodelling in association with left ventricular dyssynchrony and systolic dysfunction in patients with coronary artery disease

In patients with coronary artery disease (CAD), ischaemic cardiomyopathy may result in progressive cardiac remodelling and left ventricular (LV) dysfunction. Myocardial perfusion imaging (MPI) can be used to quantify LV size and shape, mechanical dyssynchrony (LVMD) and ejection fraction (EF) as well as myocardial ischaemia and injury extents. We investigated the prevalence of LV remodelling (LVR) in patients with CAD and the relationship between LVR, LVMD and EF.
Automatic auditory processing features in distinct subtypes of patients at clinical high risk for psychosis: Forecasting remission with mismatch negativity

Individuals at clinical high risk (CHR) for psychosis exhibit a compromised mismatch negativity (MMN) response, which indicates dysfunction of pre‐attentive deviance processing. Event‐related potential and time‐frequency (TF) information, in combination with clinical and cognitive profiles, may provide insight into the pathophysiology and psychopathology of the CHR stage and predict the prognosis of CHR individuals. A total of 92 individuals with CHR were recruited and followed up regularly for up to 3 years. Individuals with CHR were classified into three clinical subtypes demonstrated previously, specifically 28 from Cluster 1 (characterized by extensive negative symptoms and cognitive deficits), 31 from Cluster 2 (characterized by thought and behavioral disorganization, with moderate cognitive impairment), and 33 from Cluster 3 (characterized by the mildest symptoms and cognitive deficits). Auditory MMN to frequency and duration deviants was assessed. The event‐related spectral perturbation (ERSP) and inter‐trial coherence (ITC) were acquired using TF analysis. Predictive indices for remission were identified using logistic regression analyses. As expected, reduced frequency MMN (fMMN) and duration MMN (dMMN) responses were noted in Cluster 1 relative to the other two clusters. In the TF analysis, Cluster 1 showed decreased theta and alpha ITC in response to deviant stimuli. The regression analyses revealed that dMMN latency and alpha ERSP to duration deviants, theta ITC to frequency deviants and alpha ERSP to frequency deviants, and fMMN latency were significant MMN predictors of remission for the three clusters. MMN variables outperformed behavioral variables in predicting remission of Clusters 1 and 2. Our findings indicate relatively disrupted automatic auditory processing in a certain CHR subtype and a close affinity between these electrophysiological indexes and clinical profiles within different clusters. Furthermore, MMN indexes may serve as predictors of subsequent remission from the CHR state. These findings suggest that the auditory MMN response is a potential neurophysiological marker for distinct clinical subtypes of CHR.
Altered adipose tissue macrophage populations in people with HIV on integrase inhibitor-containing antiretroviral therapy

Objective: Antiretroviral therapy (ART) extends the life of people with HIV (PWH), but these individuals are at increased risk for obesity, dyslipidemia, diabetes, and cardiovascular disease. These comorbidities may be a consequence of HIV-related chronic inflammation and/or adverse effects of ART on tissue regulatory adipose tissue macrophages (ATMs). We sought to determine the effects of HIV/ART on metabolically beneficial ATM populations and functions. Design: We examined subcutaneous ATMs from PWH on integrase inhibitor-containing ART (n = 5) and uninfected persons (n = 9). We complemented these studies with ex vivo and in vitro analyses of peripheral blood mononuclear cell (PBMC) and murine macrophage lipid metabolism and fatty acid oxidation gene expression. Methods: ATM populations were examined by flow cytometry. Macrophage lipid metabolism and fatty acid oxidation gene expression were examined by Seahorse assay and quantitative PCR. Results: Adipose tissue from PWH had reduced populations of metabolically activated CD9+ ATMs compared to that of uninfected controls (P < 0.001). PBMCs of PWH had lower fatty acid metabolism compared to those of uninfected controls (P < 0.01). Analysis of murine macrophages revealed that dolutegravir reduced lipid metabolism (P < 0.001) and increased expression of the fatty acid beta-oxidation enzyme enoyl-CoA hydratase, short chain 1 (P < 0.05). Conclusions: We report the loss of metabolically beneficial ATM populations in PWH on ART, altered fatty acid metabolism of blood immune cells, and evidence that dolutegravir alters macrophage fatty acid metabolism. Future studies should examine direct or indirect effects and mechanisms of dolutegravir, and other integrase inhibitors and ART classes, on fatty acid beta-oxidation.
Examining the role of information integration in the continued influence effect using an event segmentation approach

Misinformation regarding the cause of an event often continues to influence an individual’s event-related reasoning, even after they have received a retraction. This is known as the continued influence effect (CIE). Dominant theoretical models of the CIE have suggested the effect arises primarily from failures to retrieve the correction. However, recent research has implicated information integration and memory updating processes in the CIE. As a behavioural test of integration, we applied an event segmentation approach to the CIE paradigm. Event segmentation theory suggests that incoming information is parsed into distinct events separated by event boundaries, which can have implications for memory. As such, when an individual encodes an event report that contains a retraction, the presence of event boundaries should impair retraction integration and memory updating, resulting in an enhanced CIE. Experiments 1 and 2 employed spatial event segmentation boundaries in an attempt to manipulate the ease with which a retraction can be integrated into a participant’s mental event model. While Experiment 1 showed no impact of an event boundary, Experiment 2 yielded evidence that an event boundary resulted in a reduced CIE. To the extent that this finding reflects enhanced retrieval of the retraction relative to the misinformation, it is more in line with retrieval accounts of the CIE.
Generation and Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus: A Core-Shell Model

We focus our research on how the core-shell organization controls behavior of the suprachiasmatic nucleus (SCN), how the core and shell are synchronized to the environment, what impact they have on the behavior of the SCN under different lighting conditions, and what mechanisms disrupt synchronization. To this end, we use a reduced Kuramoto model, with parameters inferred from experimental observations and calibrated for mice, and perform a detailed comparison between the model and experimental data under light-dark (LD), dark-dark (DD), and light-light (LL) conditions. The operating limits of free-running and entrained SCN activity under symmetric LD cycles are analyzed, with particular focus on the phenomena of anticipation and dissociation. Results reveal that the core-shell organization of the SCN enables anticipation of future events over circadian cycles. The model predicts the emergence of a second (dissociated) rhythm for large and small LD periods. Our results are in good qualitative and quantitative agreement with experimental observations of circadian dissociation. We further describe SCN activity under LL conditions and show that our model satisfies Aschoff’s first rule, according to which the endogenous free-running circadian period observed under complete darkness will shorten in diurnal animals and lengthen in nocturnal animals under constant light. Our results strongly suggest that the Kuramoto model captures essential features of synchronization and entrainment in the SCN. Moreover, our approach is easily extendible to an arbitrary number of groups, with dynamics described by explicit equations for the group phase and synchronization index. Viewed together, the reduced Kuramoto model presents itself as a useful tool for exploring open problems in the study of circadian rhythms, one that can account for evolving views of the circadian system’s organization, including peripheral clocks and inter-hemispheric interaction, and can be translated to other nocturnal and diurnal animals, including humans.
Sleep duration irregularity is associated with elevated blood pressure in young adults

ABSTRACT Sleep irregularity (i.e., highly variable sleep patterns) is an emerging risk factor for cardiometabolic disease. Though irregular sleep patterns are common among young adults, the cardiometabolic health (CMH) repercussions of sleep irregularity in this population are unclear. We examined associations between sleep duration and irregularity with measures of CMH in 44 (24 M/20 F, 23 ± 5y, BMI 26 ± 4 kg/m2, blood pressure (BP): 125/71 ± 14/9 mmHg) young adults. Participants wore actigraphy monitors for seven-days and sleep duration irregularity was operationalized as the standard deviation of nightly sleep duration (sleep SD). CMH variables of interest included brachial and aortic BP, arterial stiffness (cf-PWV), augmentation index (AIx75), and fasting blood glucose and lipids. Associations between sleep duration and sleep SD with CMH variables were assessed via correlations adjusted for sex and BMI. Sleep duration generally was not associated with CMH indices. However, sleep SD was associated with brachial systolic (r = 0.433, p = .027) and diastolic BP (r = 0.415, p = .035). Similarly, sleep duration SD was associated with aortic systolic BP (r = 0.447, p = .022). Our findings show that sleep irregularity, but not duration, is associated with higher brachial and central BP in young adults. Abbreviations: AIx75: augmentation index at a heart rate of 75 beats per minute; BP: blood pressure; CMH: cardiometabolic health; cf-PWV: carotid-femoral pulse wave velocity; DXA: dual x-ray absorptiometry; mg/dl: milligrams per deciliter; PWA: pulse wave analysis; PWV: pulse wave velocity; sleep duration SD: standard deviation of nightly sleep duration
Indoor Built Environment and Older Adults’ Activity: A Systematic Review

Abstract Although the physical environment can influence people’s activity, there are few knowledge syntheses for indoor environments and older adults’ daily life routines. Therefore, we conducted a systematic review of peer-reviewed evidence to inform future research and practice. Inclusion criteria were studies with any research designs, across all years and languages focused on older adults 60 years of age or more, on physical activity/sedentary behaviour and the indoor environment. After searching five databases, two authors completed title/abstract and full-text screening. The last search was on December 19, 2020. We screened 1,367 citations, and included 23 studies situated in private or collective dwellings (e.g., assisted living). We identified physical activity-supportive indoor features across three domains: campus (e.g., amenities, pathways), building (e.g., area, floor level), and fixtures (e.g., elevators, hallways). Knowledge of indoor environmental factors for older adults’ engagement in daily activities can guide future research and policy on housing design.
The small subunit of Rubisco and its potential as an engineering target

Abstract Rubisco catalyses the first rate-limiting step in CO2 fixation and is responsible for the vast majority of organic carbon present in the biosphere. The function and regulation of Rubisco remain an important research topic and a longstanding engineering target to enhance the efficiency of photosynthesis for agriculture and green biotechnology. The most abundant form of Rubisco (Form I) consists of eight large and eight small subunits, and is found in all plants, algae, cyanobacteria, and most phototrophic and chemolithoautotrophic proteobacteria. Although the active sites of Rubisco are located on the large subunits, expression of the small subunit regulates the size of the Rubisco pool in plants and can influence the overall catalytic efficiency of the Rubisco complex. The small subunit is now receiving increasing attention as a potential engineering target to improve the performance of Rubisco. Here we review our current understanding of the role of the small subunit and our growing capacity to explore its potential to modulate Rubisco catalysis using engineering biology approaches.
Florida Obsessive‐Compulsive Inventory and Children's Florida Obsessive Compulsive Inventory: A reliability generalization meta‐analysis

Abstract Background The Florida Obsessive Compulsive Inventory (FOCI) and its pediatric version, the Children's Florida Obsessive Compulsive Inventory (C‐FOCI), are instruments for evaluating obsessive‐compulsive symptomatology. Method A reliability generalization meta‐analysis was conducted to estimate an average reliability of the scores and to identify study characteristics that explained the heterogeneity among scores. Using Kuder–Richardson 20 (KR‐20) and Cronbach's α, a total of 23 and 20 independent samples were included in the meta‐analysis for the FOCI and C‐FOCI. Results We found an average KR‐20 of 0.826 for the FOCI's Symptom Checklist and an α of 0.882 FOCI's Symptom Severity. An average KR‐20 of 0.740 was found for the C‐FOCI's Symptom Checklist, while an average α of 0.794 was found for the C‐FOCI's Symptom Severity. Moderator analyses showed that the source of the coefficients (i.e., whether they were reported by the authors of the primary study or estimated by the meta‐analysts) was an important variable for the FOCI Symptom Severity, and that the focus of the study (i.e., whether it was psychometric or applied) and the sample size were relevant for the C‐FOCI Symptom Checklist. Conclusions Considering that the FOCI and C‐FOCI are scales characterized by their brevity and ease of use, and the reliabilities obtained here, both scales are well suited for screening purposes.