Miracle-dz/UniFAR-FTUs huggingface dataset:
Sesame lignans upregulate glutathione S-transferase expression and downregulate microRNA-669c-3p

Oxidative stress is associated with aging and pathologies such as cardiovascular diseases, Alzheimer’s disease, and cancer. Glutathione S-transferase (GST), a family of detoxification enzymes, plays a crucial role in countering oxidative stress. Therefore, there is a need for the development of physiologically functional foods and agricultural products, which enhance GST activity. Sesamin and episesamin are major lignans in refined sesame oil that exhibit beneficial properties including antioxidative stress effects. A previous study showed that sesamin upregulated GST activity. This study aimed to elucidate the mechanism underlying the GST activity enhancement elicited by sesame lignans. C57BL/6J mice were orally administered 20 mg/kg body weight sesame lignans (sesamin:episesamin=1:1) for 7 days. Oral administration of sesame lignans increased the GST activity in the mouse liver. Furthermore, the lignans upregulated GSTA1, GSTA4, and GSTM4 protein expression. Microarray analysis revealed that sesame lignans changed the expression of various microRNAs (miRNAs) (84 upregulated, 19 downregulated). We also found 16 miRNAs, including miR-669c-3p, that may negatively regulate GST expression among the 19 miRNAs with reduced expression caused by the sesame lignans. miR-669c is reportedly negatively correlated with GST. Additionally, we transfected NMuLi cells with an miR-669c-3p mimic and evaluated the effect of miR-669c-3p on GST mRNA and protein expressions. The results showed that the miR-669c-3p mimic suppressed the mRNA and protein levels of GSTA4 and GSTM4. In conclusion, sesame lignans increased GST protein expression and activity and downregulated miRNAs, including miR-669c-3p, which is a possible suppressor of GST.
Feasibility and preliminary efficacy for morning bright light therapy to improve sleep and plasma biomarkers in US Veterans with TBI. A prospective, open-label, single-arm trial

Mild traumatic brain injury (TBI) is associated with persistent sleep-wake dysfunction, including insomnia and circadian rhythm disruption, which can exacerbate functional outcomes including mood, pain, and quality of life. Present therapies to treat sleep-wake disturbances in those with TBI (e.g., cognitive behavioral therapy for insomnia) are limited by marginal efficacy, poor patient acceptability, and/or high patient/provider burden. Thus, this study aimed to assess the feasibility and preliminary efficacy of morning bright light therapy, to improve sleep in Veterans with TBI (NCT03578003). Thirty-three Veterans with history of TBI were prospectively enrolled in a single-arm, open-label intervention using a lightbox (~10,000 lux at the eye) for 60-minutes every morning for 4-weeks. Pre- and post-intervention outcomes included questionnaires related to sleep, mood, TBI, post-traumatic stress disorder (PTSD), and pain; wrist actigraphy as a proxy for objective sleep; and blood-based biomarkers related to TBI/sleep. The protocol was rated favorably by ~75% of participants, with adherence to the lightbox and actigraphy being ~87% and 97%, respectively. Post-intervention improvements were observed in self-reported symptoms related to insomnia, mood, and pain; actigraphy-derived measures of sleep; and blood-based biomarkers related to peripheral inflammatory balance. The severity of comorbid PTSD was a significant positive predictor of response to treatment. Morning bright light therapy is a feasible and acceptable intervention that shows preliminary efficacy to treat disrupted sleep in Veterans with TBI. A full-scale randomized, placebo-controlled study with longitudinal follow-up is warranted to assess the efficacy of morning bright light therapy to improve sleep, biomarkers, and other TBI related symptoms.
Similarities, differences, and possible interactions between hepatitis E and hepatitis C viruses: Relevance for research and clinical practice

Hepatitis E virus (HEV) and hepatitis C virus (HCV) are both RNA viruses with a tropism for liver parenchyma but are also capable of extrahepatic manifestations. Hepatitis E is usually a viral acute fecal-oral transmitted and self-limiting disease presenting with malaise, jaundice, nausea and vomiting. Rarely, HEV causes a chronic infection in immunocompromised persons and severe fulminant hepatitis in pregnant women. Parenteral HCV infection is typically asymptomatic for decades until chronic complications, such as cirrhosis and cancer, occur. Despite being two very different viruses in terms of phylogenetic and clinical presentations, HEV and HCV show many similarities regarding possible transmission through organ transplantation and blood transfusion, pathogenesis (production of antinuclear antibodies and cryoglobulins) and response to treatment with some direct-acting antiviral drugs. Although both HEV and HCV are well studied individually, there is a lack of knowledge about coinfection and its consequences. The aim of this review is to analyze current literature by evaluating original articles and case reports and to hypothesize some interactions that can be useful for research and clinical practice.
Digital interventions for smoking abstinence: a systematic review and meta-analysis of randomized control trials

Abstract Objectives Technological advancements have improved patients’ health and clinical care through digital interventions. This study investigated the effects of digital interventions on smoking abstinence. Methods PubMed, the Cochrane Library, and Scopus were systematically searched from inception until December 2021. Meta-analysis was carried out using a random-effects model. The degree of heterogeneity, quality, and publication bias of the selected studies was further evaluated. Results A total of 43 randomized control trial studies were eligible for this study. 38,814 participants from 18 countries were included in the analysis. Digital interventions on seven-day point prevalence abstinence (1 month) showed increased smoking abstinence. The odds ratio was 2.02 and confidence interval (CI) was 1.67–2.43; p < 0.001; I 2 = 55.1%) . The result for a 30-day point prevalence abstinence (1 month) was 1.63 (CI 1.09–2.46; p = 0.018; I 2 = 0%). Digital intervention also had a significant effect on continuous abstinence (odds ratio = 1.68; CI 1.29–2.18; p < 0.001; I 2 = 70.1%) and prolonged abstinence (odds ratio = 1.60; CI 1.19–2.15; p = 0.002; I 2 = 53.6%). There was evidence of heterogeneity and publication bias. Conclusions Digital interventions led to increased smoking abstinence and can be a valuable tool in smoking cessation. Further research is required to evaluate the long-term impact of digital interventions on outcomes related to smoking cessation.
Pre-Existing Frailty is Unrelated to Progression of Diffuse Subcortical Damage of Vascular Origin: A Longitudinal Prospective Study in Community-Dwelling Older Adults

Background: Both frailty and white matter hyperintensities (WMH) of presumed vascular origin are associated with enhanced expression of inflammatory biomarkers. Therefore, it is possible that pre-existing frailty predisposes to WMH progression. However, this relationship has not been explored. This population-based longitudinal prospective study aimed to assess the impact of frailty on subsequent progression of WMH in community-dwelling older adults living in rural Ecuador. Methods: Participants of the Atahualpa Project Cohort received baseline frailty assessment and brain MRIs. Frailty was evaluated by means of the Edmonton Frail Scale (EFS). WMH were graded according to the modified Fazekas scale. Individuals who received a follow-up brain MRI were included. Poisson regression models were fitted to assess the differential rate of WMH progression according to EFS score, after adjusting for demographics, level of education, and cardiovascular risk factors. Results: The study included 263 individuals aged ≥60 years (mean age: 65.7 ± 6.2 years; 57% women). The mean EFS score at baseline was 4 ± 2.3 points. Follow-up MRIs after a median follow-up of 6.5 years showed WMH progression in 103 (39%) individuals. The EFS score at baseline was associated with WMH progression in unadjusted analysis (P = .006). However, significance was not achieved in a multivariate Poisson regression model adjusted for relevant covariates (IRR: 1.07; 95% C.I.: 0.97-1.18; P = .192). Conclusions: Study results do not support an independent relationship between frailty and WMH progression, adjusting for the confounding effect of aging.
In vitro human cell‐based aneugen molecular mechanism assay

This laboratory previously described an in vitro human cell‐based assay and data analysis scheme that discriminates common molecular targets responsible for chemical‐induced in vitro aneugenicity: tubulin destabilization, tubulin stabilization, and inhibition of Aurora kinases (Bernacki et al., Toxicol. Sci. 170 [2019] 382–393). The current report describes updated procedures that simplify benchtop processing and data analysis methods. For these experiments, human lymphoblastoid TK6 cells were exposed to each of 25 aneugens over a range of concentrations in the presence of fluorescent paclitaxel (488 Taxol). After a 4 h treatment period, cells were lysed and nuclei were stained with a nucleic acid dye and labeled with fluorescent antibodies against phospho‐histone H3 (p‐H3). Flow cytometric analyses revealed several unique signatures: tubulin stabilizers caused increased frequencies of p‐H3‐positive events with concentration‐dependent increases in 488 Taxol‐associated fluorescence; tubulin destabilizers caused increased frequencies of p‐H3‐positive events with concomitant decreases in 488 Taxol‐associated fluorescence; and Aurora kinase B inhibitors caused reduced frequencies of p‐H3‐positive events and lower median fluorescent intensities of p‐H3‐positive events. These results demonstrate a simple rubric based on 488 Taxol‐ and p‐H3‐associated metrics can reliably discriminate between several commonly encountered aneugenic molecular mechanisms.
Common Microscale and Macroscale Principles of Connectivity in the Human Brain

The brain requires efficient information transfer between neurons and large-scale brain regions. Brain connectivity follows predictable organizational principles. At the cellular level, larger supragranular pyramidal neurons have larger, more branched dendritic trees, more synapses, and perform more complex computations; at the macroscale, region-to-region connections display a diverse architecture with highly connected hub areas facilitating complex information integration and computation. Here, we explore the hypothesis that the branching structure of large-scale region-to-region connectivity follows similar organizational principles as the neuronal scale. We examine microscale connectivity of basal dendritic trees of supragranular pyramidal neurons (300+) across 10 cortical areas in five human donor brains (1 male, 4 female). Dendritic complexity was quantified as the number of branch points, tree length, spine count, spine density, and overall branching complexity. High-resolution diffusion-weighted MRI was used to construct white matter trees of corticocortical wiring. Examining complexity of the resulting white matter trees using the same measures as for dendritic trees shows heteromodal association areas to have larger, more complex white matter trees than primary areas (p < 0.0001) and macroscale complexity to run in parallel with microscale measures, in terms of number of inputs (r = 0.677, p = 0.032), branch points (r = 0.797, p = 0.006), tree length (r = 0.664, p = 0.036), and branching complexity (r = 0.724, p = 0.018). Our findings support the integrative theory that brain connectivity follows similar principles of connectivity at neuronal and macroscale levels and provide a framework to study connectivity changes in brain conditions at multiple levels of organization. SIGNIFICANCE STATEMENT Within the human brain, cortical areas are involved in a wide range of processes, requiring different levels of information integration and local computation. At the cellular level, these regional differences reflect a predictable organizational principle with larger, more complexly branched supragranular pyramidal neurons in higher order regions. We hypothesized that the 3D branching structure of macroscale corticocortical connections follows the same organizational principles as the cellular scale. Comparing branching complexity of dendritic trees of supragranular pyramidal neurons and of MRI-based regional white matter trees of macroscale connectivity, we show that macroscale branching complexity is larger in higher order areas and that microscale and macroscale complexity go hand in hand. Our findings contribute to a multiscale integrative theory of brain connectivity.
Accuracy of conversion formula for effect sizes: A Monte Carlo simulation

In meta‐analysis, effect sizes often need to be converted into a common metric. For this purpose conversion formulas have been constructed; some are exact, others are approximations whose accuracy has not yet been systematically tested. We performed Monte Carlo simulations where samples with pre‐specified population correlations between the x and y‐variables were drawn from a normally distributed population. A number of commonly used effect size measures and statistics were calculated from each sample. Using several available conversion formula these statistics were converted into Pearson r and Cohen's d and compared to r and d calculated directly from the original data. Converted values were systematically lower than the directly calculated values. While conversions to d were quite accurate, some of the conversions to r resulted in large biases. These systematic errors can in most cases be adjusted for by simply multiplying the converted values with a corresponding correction factor.
SOX18-associated gene signature predicts sepsis outcome.

OBJECTIVES Sepsis is a critical medical condition associated with an high mortality. Currently, there are no reliable diagnostic or prognostic biomarkers to evaluate sepsis outcomes. SRY (sex-determining region on the Y chromosome)-box transcription factor 18 (SOX18) is an endothelial barrier protective protein, and a decreased level of SOX18 expression is involved in disruption of human endothelial cell barrier integrity. Over-expression of SOX18 attenuates the bacterial lipopolysaccharide (LPS)-mediated disruption of the vascular barrier and is associated with favorable prognosis. The utility of SOX18-related genes as biomarkers in sepsis is uncertain. METHODS Transcriptomic analysis was used to profile the PBMC samples of patients with sepsis across two Gene Expression Omnibus (GEO) datasets with survival data. An 84-gene signature was derived from discovery datasets that correlated with SOX18 gene expression and sepsis survival. RESULTS Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed Th1 and Th2 cell differentiation, Cytokine-cytokine receptor interaction, and T cell receptor signaling pathways as the most significantly enriched KEGG pathways among 84 genes. A severity score based on the gene expression of 84 genes was allocated to each patient. A notable increase was detected in sepsis patients compared to healthy controls in both discovery and validation cohorts. SOX18-associated gene signature discriminated severe cases from mild cases and performed significantly better than both random 84-gene sets from whole genomes or sepsis survival-related genes. Furthermore, we obtained an 18-gene signature from screening these 84 genes in a LASSO model, which performed better in both discovery and validation cohorts. CONCLUSIONS Data support SOX18-associated gene signatures as a prognostic biomarker for sepsis.
Toyota Motor Energy Analysis and Modeling

Acknowledgements We would like to thank our advisor Dr. Gale Boyd for his time advising on this project, for providing us with a background of the auto industry and for support when we struggled to find solutions. Executive Summary The automobile manufacturing industry in the U.S. uses over 800 trillion British Thermal Units (Btus) of energy and spends about $3.6 billion on it each year. As a leading automobile manufacturing corporation, our client Toyota Motor Engineering & Manufacturing North America, Inc. (Toyota) seeks opportunities to improve their accuracy in predicting manufacture energy use. With a better understanding of future energy use, Toyota will be able to identify energy efficiency opportunities and improve the overall budgeting accuracy at corporate level. To accomplish this goal, this project uses five years of historical energy consumption data to test existing energy models and identify possible improvements that can be done on a process and plant level. The products of this study include revised energy models for manufacture energy use and administrative energy use for both electricity and total energy consumption. Toyota could use our models as a reliable reference to predict future energy performance.
No sex-related differences in infarct size, no-reflow and protection by ischaemic preconditioning in Göttingen minipigs.

AIMS Female sex has been proposed to be cardioprotective per se. Studies with myocardial ischaemia/reperfusion and infarct size as endpoint have demonstrated cardioprotection in female, castrated male and male pigs. These studies are difficult to compare, given the different pig strains, models, durations of ischaemia and methods of infarct size quantification. The few studies using both female and male pigs reported no differences in infarct size and cardioprotection. We therefore prospectively compared infarct size in Göttingen minipigs undergoing ischaemia/reperfusion (I/R) without and with ischaemic preconditioning (IPC) between female, castrated male and male pigs. METHODS AND RESULTS In a prospective, randomised approach, 28 Göttingen open-chest, anaesthetised minipigs underwent 60 min ischaemia by distal left anterior descending artery (LAD) occlusion and 180 min reperfusion without and with IPC by 3 cycles of 5 min LAD occlusion/10 min reperfusion. Infarct size with I/R was not different between female, castrated male and male pigs (45±8 vs. 45±13 vs. 41±9% area at risk), as was the reduction in infarct size with IPC (25±11 vs. 30±8 vs. 19±10% area at risk). Also, the area of no-reflow was not different between female, castrated male and male pigs with I/R (57±13 vs. 35±7 vs. 47±26% infarct size) or IPC (4±10 vs.12±20 vs. 0±0% infarct size). Phosphorylation of signal transducer and activator of transcription 3 was increased at 10 min reperfusion by IPC but not by I/R to the same extent in female, castrated male and male pigs (198±30 vs. 230±165 vs. 179±107% of baseline). CONCLUSION Our data do not support the notion of sex- or castration-related differences in infarct size, coronary microvascular injury and cardioprotection by ischaemic preconditioning. TRANSLATIONAL PERSPECTIVE The translation of successful preclinical studies on cardioprotection to the benefit of patients with reperfused myocardial infarction has been difficult. The difficulties have been attributed to confounders such as co-morbidities and co-medications which patients typically have but animals don´t, but also to age and sex. Notably, female sex has been considered as protective per se. We have now, using our established and clinically relevant pig model of reperfused acute myocardial infarction and ischaemic preconditioning as the most robust cardioprotective intervention looked for sex-related differences of infarct size, no-reflow and cardioprotection by ischaemic preconditioning in a prospectively powered approach but found none such difference.
More Prominent Nonlinear Mixed Selectivity in the Dorsolateral Prefrontal than Posterior Parietal Cortex

Abstract Neurons in the dorsolateral prefrontal cortex (dlPFC) and posterior parietal cortex (PPC) are activated by different cognitive tasks and respond differently to the same stimuli depending on task. The conjunctive representations of multiple tasks in nonlinear fashion in single neuron activity, is known as nonlinear mixed selectivity (NMS). Here, we compared NMS in a working memory task in areas 8a and 46 of the dlPFC and 7a and lateral intraparietal cortex (LIP) of the PPC in macaque monkeys. NMS neurons were more frequent in dlPFC than in PPC and this was attributed to more cells gaining selectivity in the course of a trial. Additionally, in our task, the subjects’ behavioral performance improved within a behavioral session as they learned the session-specific statistics of the task. The magnitude of NMS in the dlPFC also increased as a function of time within a single session. On the other hand, we observed minimal rotation of population responses and no appreciable differences in NMS between correct and error trials in either area. Our results provide direct evidence demonstrating a specialization in NMS between dlPFC and PPC and reveal mechanisms of neural selectivity in areas recruited in working memory tasks.
Combining human and machine intelligence for clinical trial eligibility querying

Abstract Objective To combine machine efficiency and human intelligence for converting complex clinical trial eligibility criteria text into cohort queries. Materials and Methods Criteria2Query (C2Q) 2.0 was developed to enable real-time user intervention for criteria selection and simplification, parsing error correction, and concept mapping. The accuracy, precision, recall, and F1 score of enhanced modules for negation scope detection, temporal and value normalization were evaluated using a previously curated gold standard, the annotated eligibility criteria of 1010 COVID-19 clinical trials. The usability and usefulness were evaluated by 10 research coordinators in a task-oriented usability evaluation using 5 Alzheimer’s disease trials. Data were collected by user interaction logging, a demographic questionnaire, the Health Information Technology Usability Evaluation Scale (Health-ITUES), and a feature-specific questionnaire. Results The accuracies of negation scope detection, temporal and value normalization were 0.924, 0.916, and 0.966, respectively. C2Q 2.0 achieved a moderate usability score (3.84 out of 5) and a high learnability score (4.54 out of 5). On average, 9.9 modifications were made for a clinical study. Experienced researchers made more modifications than novice researchers. The most frequent modification was deletion (5.35 per study). Furthermore, the evaluators favored cohort queries resulting from modifications (score 4.1 out of 5) and the user engagement features (score 4.3 out of 5). Discussion and Conclusion Features to engage domain experts and to overcome the limitations in automated machine output are shown to be useful and user-friendly. We concluded that human–computer collaboration is key to improving the adoption and user-friendliness of natural language processing.