Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting cannabinoid receptor 2 (CB2) limits collagen production—An in vitro study in a primary culture of human fibroblasts

Previous studies showed that cannabinoid 2 (CB2) receptor is involved in skin inflammation, fibrogenesis and re‐epithelialization in mice, indicating that this receptor may be implicated in wound healing. Thus, topical use of cannabinoids may have a role in local fibrotic and wound healing diseases such as scars or keloids. We investigate the effect of the CB2 selective receptor agonist (6aR,10aR)‐3‐(1,1‐Dimethylbutyl)‐6a,7,10,10a‐tetrahydro‐6,6,9‐trimethyl‐6H‐dibenzo[b,d]pyran (JWH133) and the CB2 selective receptor antagonist (6‐Iodo‐2‐methyl‐1‐[2‐(4‐morpholinyl)ethyl]‐1H‐indol‐3‐yl)(4‐methoxyphenyl)‐methanone (AM630), on primary cultures of human fibroblasts. Primary cultures of adult human fibroblasts were obtained from abdominal human skin samples. Fibroblasts pretreated with JWH133 and/or AM630 were stimulated with TGF‐β (10 ng/ml). Fibroblast activation into myofibroblasts was quantified by the expression of alpha‐smooth muscle actin (α‐SMA) using Immunocytochemistry and Western Blot assays. Collagen content was quantified with the Sirius red staining assay. Upon human fibroblasts stimulation with TGF‐β, a significant increase on α‐SMA and CB2 receptor expression was observed. In these cells, JWH133 decreased α‐SMA expression and collagen content. However, this effect was not observed in resting human fibroblasts. AM630 decreased α‐SMA expression and collagen content in both resting and activated fibroblasts. This effect was time‐ and concentration‐dependent with an IC50 value of 11 μM. The CB2 receptor appears to be involved in fibroblast repair during skin wound healing in humans, as TGF‐β increases CB2 receptor expression and JWH133 produces an anti‐fibrotic effect in human fibroblasts. AM630 also showed an anti‐fibrotic effect hypothesizing that other cannabinoid receptors, such as TRPV, may be involved in this response.
The four category systematic approach for selecting patients for face transplantation

Abstract There is a need for a systematic approach to evaluate patients for potential face transplantation (FT). Ten patients with severe facial defects treated between 1995 and 2017 formed the study group. Data was collected from patient charts and clinical, radiological and laboratory examinations. Facial deficiencies were subdivided into four different categories: anatomical region (10 facial subunits), facial function, aesthetic defect (range 0–9-worst), and impact on health-related quality of life (HRQoL) (15D questionnaire, range 0–1). Immunological status and possible contraindications were also evaluated. Defect aetiology consisted of burns (4), ballistic injury (3), blunt injury (1), blast injury (1), and neurofibromatosis type I (1). All patients had central facial deficiencies and 6 patients had 8 to 10 injured facial subunits. All patients had at least partial loss of facial function. The mean aesthetic disfigurement score was 6.4. The median lowering of 15D score was −0.107. None were significantly sensitized although four patients had relative contraindications and one patient had an absolute contraindication for FT. Three patients with a severe overall facial deficiency were considered as potential FT candidates. We herein propose a comprehensive and systematic tool to evaluate potential candidates for FT. This approach includes assessment of 4 key categories: anatomical regions affected, facial function, aesthetics, and HRQoL.
Volume Reduction: Which Dose is Sufficient to Retain Resistance Training Adaptations in Older Women?

Abstract We compared the effects of different resistance training (RT) volume reduction strategies on muscular strength and lean soft-tissue (LST) in older women. Fifty-seven physically independent women (>60 years) performed a 20-week pre-conditioning phase of a standardized whole-body RT program (eight exercises, three sets, 8–12 repetitions, three sessions a week), and were then randomly assigned to one of the following conditions: reduced volume for a single set (RV1, n=20) or two sets (RV2, n=19), or maintained volume of three sets (MV, n=18) for 8 weeks (specific training phase). Muscular strength in the chest press, leg extension, and preacher curl exercises was determined by one-repetition maximum tests. A dual-energy X-ray absorptiometry device was used to estimate LST. An increase in muscular strength (16.3–32.1%) and LST (3.2–7.9%) was observed after the pre-conditioning phase. There was an increase in chest press for all groups (9.4–16.7%) after the specific training phase. In contrast, only MV increased significantly in the leg extension (4.4%). No between-group differences were revealed for LST in the specific training phase. Our results suggest that reduced RT volume from three to one set per exercise for 8 weeks seems sufficient to retain neuromuscular adaptations in older women.
Social sentiment segregation: Evidence from Twitter and Google Trends in Chile during the COVID-19 dynamic quarantine strategy

The Chilean health authorities have implemented a sanitary strategy known as dynamic quarantine or strategic quarantine to cope with the COVID-19 pandemic. Under this system, lockdowns were established, lifted, or prolonged according to the weekly health authorities’ assessment of municipalities’ epidemiological situation. The public announcements about the confinement situation of municipalities country-wide are made typically on Tuesdays or Wednesdays before noon, have received extensive media coverage, and generated sharp stock market fluctuations. Municipalities are the smallest administrative division in Chile, with each city broken down typically into several municipalities. We analyze social media behavior in response to the confinement situation of the population at the municipal level. The dynamic quarantine scheme offers a unique opportunity for our analysis, given that municipalities display a high degree of heterogeneity, both in size and in the socioeconomic status of their population. We exploit the variability over time in municipalities’ confinement situations, resulting from the dynamic quarantine strategy, and the cross-sectional variability in their socioeconomic characteristics to evaluate the impact of these characteristics on social sentiment. Using event study and panel data methods, we find that proxies for social sentiment based on Twitter queries are negatively related (more pessimistic) to increases in the number of confined people, but with a statistically significant effect concentrated on people from the wealthiest cohorts of the population. For indicators of social sentiment based on Google Trends, we found that search intensity during the periods surrounding government announcements is positively related to increases in the total number of confined people. Still, this effect does not seem to be dependent on the segments of the population affected by the quarantine. Furthermore, we show that the observed heterogeneity in sentiment mirrors heterogeneity in stock market reactions to government announcements. We provide evidence that the observed stock market behavior around quarantine announcements can be explained by the number of people from the wealthiest segments of the population entering or exiting lockdown.
Gene–Environment Interactions in Developmental Neurotoxicity: a Case Study of Synergy between Chlorpyrifos and CHD8 Knockout in Human BrainSpheres

Background: Autism spectrum disorder (ASD) is a major public health concern caused by complex genetic and environmental components. Mechanisms of gene–environment (G×E) interactions and reliable biomarkers associated with ASD are mostly unknown or controversial. Induced pluripotent stem cells (iPSCs) from patients or with clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9)-introduced mutations in candidate ASD genes provide an opportunity to study (G×E) interactions. Objectives: In this study, we aimed to identify a potential synergy between mutation in the high-risk autism gene encoding chromodomain helicase DNA binding protein 8 (CHD8) and environmental exposure to an organophosphate pesticide (chlorpyrifos; CPF) in an iPSC-derived human three-dimensional (3D) brain model. Methods: This study employed human iPSC-derived 3D brain organoids (BrainSpheres) carrying a heterozygote CRISPR/Cas9-introduced inactivating mutation in CHD8 and exposed to CPF or its oxon-metabolite (CPO). Neural differentiation, viability, oxidative stress, and neurite outgrowth were assessed, and levels of main neurotransmitters and selected metabolites were validated against human data on ASD metabolic derangements. Results: Expression of CHD8 protein was significantly lower in CHD8 heterozygous knockout (CHD8+/−) BrainSpheres compared with CHD8+/+ ones. Exposure to CPF/CPO treatment further reduced CHD8 protein levels, showing the potential (G×E) interaction synergy. A novel approach for validation of the model was chosen: from the literature, we identified a panel of metabolic biomarkers in patients and assessed them by targeted metabolomics in vitro. A synergistic effect was observed on the cholinergic system, S-adenosylmethionine, S-adenosylhomocysteine, lactic acid, tryptophan, kynurenic acid, and α-hydroxyglutaric acid levels. Neurite outgrowth was perturbed by CPF/CPO exposure. Heterozygous knockout of CHD8 in BrainSpheres led to an imbalance of excitatory/inhibitory neurotransmitters and lower levels of dopamine. Discussion: This study pioneered (G×E) interaction in iPSC-derived organoids. The experimental strategy enables biomonitoring and environmental risk assessment for ASD. Our findings reflected some metabolic perturbations and disruption of neurotransmitter systems involved in ASD. The increased susceptibility of CHD8+/− BrainSpheres to chemical insult establishes a possibly broader role of (G×E) interaction in ASD. https://doi.org/10.1289/EHP8580
Measures of Function and Structure to Determine Phenotypic Features, Natural History, and Treatment Outcomes in Inherited Retinal Diseases.

Inherited retinal diseases (IRDs) are at the forefront of innovative gene-specific treatments because of the causation by single genes, the availability of microsurgical access for treatment delivery, and the relative ease of quantitative imaging and vision measurement. However, it is not always easy to choose a priori, from scores of potential measures, an appropriate subset to evaluate efficacy outcomes considering the wide range of disease stages with different phenotypic features. This article reviews measurements of visual function and retinal structure that our group has used over the past three decades to understand the natural history of IRDs. We include measures of light sensitivity, retinal structure, mapping of natural fluorophores, evaluation of pupillary light reflex, and oculomotor control. We provide historical context and examples of applicability. We also review treatment trial outcomes using these measures of function and structure. Expected final online publication date for the Annual Review of Vision Science, Volume 7 is September 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Hidden Markov Modeling Reveals Prolonged "Baseline" State and Shortened Antagonistic State across the Adult Lifespan.

The brain networks undergo functional reorganization across the whole lifespan, but the dynamic patterns behind the reorganization remain largely unclear. This study models the dynamics of spontaneous activity of large-scale networks using hidden Markov model (HMM), and investigates how it changes with age on two adult lifespan datasets of 176/157 subjects (aged 20-80 years). Results for both datasets showed that 1) older adults tended to spend less time on a state where default mode network (DMN) and attentional networks show antagonistic activity, 2) older adults spent more time on a "baseline" state with moderate-level activation of all networks, accompanied with lower transition probabilities from this state to the others and higher transition probabilities from the others to this state, and 3) HMM exhibited higher sensitivity in uncovering the age effects compared with temporal clustering method. Our results suggest that the aging brain is characterized by the shortening of the antagonistic instances between DMN and attention systems, as well as the prolongation of the inactive period of all networks, which might reflect the shift of the dynamical working point near criticality in older adults.
Search Behavior Regarding Cancer Susceptibility Genes Using a Clinical Decision Support Tool for Gene-Specific Penetrance: Content Analysis

Background Genetic testing for germline cancer susceptibility genes is widely available. The Ask2Me.org (All Syndromes Known to Man Evaluator) tool is a clinical decision support tool that provides evidence-based risk predictions for individuals with pathogenic variants in cancer susceptibility genes. Objective The aim of this study was to understand the search behavior of the Ask2Me.org tool users, identify the patterns of queries entered, and discuss how to further improve the tool. Methods We analyzed the Ask2Me.org user-generated queries collected between December 12, 2018, and October 8, 2019. The gene frequencies of the user-generated queries were compared with previously published panel testing data to assess the correspondence between usage and prevalence of pathogenic variants. The frequencies of prior cancer in the user-generated queries were compared with the most recent US population–based cancer incidence. Results A total of 10,085 search queries were evaluated. The average age submitted in the queries was 48.8 (SD 16.5) years, and 84.1% (8478/10,085) of the submitted queries were for females. BRCA2 (1671/10,085, 16.6%), BRCA1 (1627/10,085, 16.1%), CHEK2 (994/10,085, 9.9%), ATM (662/10,085, 6.6%), and APC (492/10,085, 4.9%) were the top 5 genes searched by users. There was a strong linear correlation between genes queried by users and the frequency of pathogenic variants reported in published panel testing data (r=0.95, r2=0.90, P<.001). Over half of the queries (5343/10,085, 53.0%) included a prior personal history of cancer. The frequencies of prior cancers in the queries on females were strongly correlated with US cancer incidences (r=0.97, r2=0.95, P<.001), while the same correlation was weaker among the queries on males (r=0.69, r2=0.47, P=.02). Conclusions The patients entered in the Ask2Me.org tool are a representative cohort of patients with pathogenic variants in cancer susceptibility genes in the United States. While a majority of the queries were on breast cancer susceptibility genes, users also queried susceptibility genes with lower prevalence, which may represent a transformation from single gene testing to multigene panel testing. Owing to these changing tides, more efforts are needed to improve evidence-based clinical decision support tools to better aid clinicians and their practice.
Punch Grafting for the Management of Hard-to-Heal Diabetic Foot Ulcers: A Prospective Case Series

Punch grafting is an alternative treatment to enhance wound healing which has been associated with promising clinical outcomes in various leg and foot wound types. We aimed to evaluate the clinical outcomes of punch grafting as a treatment for hard-to-heal diabetic foot ulcers (DFUs). Six patients with chronic neuropathic or neuroischemic DFUs with more than 6 months of evolution not responding to conventional treatment were included in a prospective case series between May 2017 and December 2020. All patients were previously debrided using an ultrasound-assisted wound debridement and then, grafted with 4 to 6 mm punch from the donor site that was in all cases the anterolateral aspect of the thigh. All patients were followed up weekly until wound healing. Four (66.7%) DFUs were located in the heel, 1 (16.7%) in the dorsal aspect of the foot and 1 (16.7%) in the Achilles tendon. The median evolution time was 172 (interquartile range [IQR], 25th-75th; 44-276) weeks with a median area of 5.9 (IQR; 1.87-37.12) cm2 before grafting. Complete epithelization was achieved in 3 (50%) patients at 12 weeks follow-up period with a mean time of 5.67 ± 2.88 weeks. Two of the remaining patients achieved wound healing at 32 and 24 weeks, respectively, and 1 patient showed punch graft unsuccessful in adhering. The median time of wound healing of all patients included in the study was 9.00 (IQR; 4.00-28.00) weeks. The wound area reduction (WAR) at 4 weeks was 38.66% and WAR at 12 weeks was 88.56%. No adverse effects related to the ulcer were registered through the follow-up period. Autologous punch graft is an easy procedure that promotes healing, achieving wound closure in chronic DFUs representing an alternative of treatment for hard-to-heal DFUs in which conservative treatment has been unsuccessful.
Dietary raffinose ameliorates hepatic lipid accumulation induced by cholic acid via modulation of enterohepatic bile acid circulation in rats

Abstract Enterohepatic circulation of 12α-hydroxylated (12αOH) bile acid (BA) is enhanced depending on the energy intake in high-fat diet-fed rats. Such BA metabolism can be reproduced using a diet supplemented with cholic acid (CA), which also induces simple steatosis, without inflammation and fibrosis, accompanied by some other symptoms that are frequently observed in the condition of non-alcoholic fatty liver in rats. We investigated whether supplementation of the diet with raffinose (Raf) improves hepatic lipid accumulation induced by the CA-fed condition in rats. After acclimation to the AIN-93-based control diet, male Wistar rats were fed diets supplemented with a combination of Raf (30 g/kg diet) and/or CA (0·5 g/kg diet) for 4 weeks. Dietary Raf normalised hepatic TAG levels (two-way ANOVA P < 0·001 for CA, P = 0·02 for Raf and P = 0·004 for interaction) in the CA-supplemented diet-fed rats. Dietary Raf supplementation reduced hepatic 12αOH BA concentration (two-way ANOVA P < 0·001 for CA, P = 0·003 for Raf and P = 0·03 for interaction). The concentration of 12αOH BA was reduced in the aortic and portal plasma. Raf supplementation increased acetic acid concentration in the caecal contents (two-way ANOVA P = 0·001 as a main effect). Multiple regression analysis revealed that concentrations of aortic 12αOH BA and caecal acetic acid could serve as predictors of hepatic TAG concentration (R 2 = 0·55, P < 0·001). However, Raf did not decrease the secondary 12αOH BA concentration in the caecal contents as well as the transaminase activity in the CA diet-fed rats. These results imply that dietary Raf normalises hepatic lipid accumulation via suppression of enterohepatic 12αOH BA circulation.
Interplay of the RNA Exosome Complex and RNA-Binding Protein Ssd1 in Maintaining Cell Wall Stability in Yeast

Stressful conditions such as high temperatures can compromise cellular integrity and cause bursting. In microorganisms surrounded by a cell wall, such as yeast, the cell wall is the primary shield that protects cells from environmental stress. ABSTRACT Yeast cell wall stability is important for cell division and survival under stress conditions. The expression of cell-wall-related proteins is regulated by several pathways involving RNA-binding proteins and RNases. The multiprotein RNA exosome complex provides the 3′→5′ exoribonuclease activity that is critical for maintaining the stability and integrity of the yeast cell wall under stress conditions such as high temperatures. In this work, we show that the temperature sensitivity of RNA exosome mutants is most pronounced in the W303 genetic background due to the nonfunctional ssd1-d allele. This gene encodes the RNA-binding protein Ssd1, which is involved in the posttranscriptional regulation of cell-wall-related genes. Expression of the functional SSD1-V allele from its native genomic locus or from a centromeric plasmid suppresses the growth defects and aberrant morphology of RNA exosome mutant cells at high temperatures or upon treatment with cell wall stressors. Moreover, combined inactivation of the RNA exosome catalytic subunit Rrp6 and Ssd1 results in a synthetically sick phenotype of cell wall instability, as these proteins may function in parallel pathways (i.e., via different mRNA targets) to maintain cell wall stability. IMPORTANCE Stressful conditions such as high temperatures can compromise cellular integrity and cause bursting. In microorganisms surrounded by a cell wall, such as yeast, the cell wall is the primary shield that protects cells from environmental stress. Therefore, remodeling its structure requires inputs from multiple signaling pathways and regulators. In this work, we identify the interplay of the RNA exosome complex and the RNA-binding protein Ssd1 as an important factor in the yeast cell wall stress response. These proteins operate in independent pathways to support yeast cell wall stability. This work highlights the contribution of RNA-binding proteins in the regulation of yeast cell wall structure, providing new insights into yeast physiology.
Self-Esteem as a Mediator between Life Satisfaction and Depression among Cardiovascular Disease Patients

This study explores the association between life satisfaction and depression among patients with cardiovascular diseases and whether this association is mediated by self-esteem. A cross-sectional study was conducted in a third-grade hospital. We examined 300 patients with cardiovascular diseases with a mean age of 62.00 years (females, 133). Life satisfaction was associated with depression. Adding self-esteem to the model weakened the strength of the association between the two. Moreover, 34.2% of the effect of life satisfaction on depression could be explained by self-esteem. We found that self-esteem could totally explain the effect of life satisfaction on depression among patients with cardiovascular diseases.
The InDel variants of sheep IGF2BP1 gene are associated with growth traits

Abstract Insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) plays positive roles in the growth, proliferation of cells and early embryos development by binding mRNA targets. Recently, it had been shown that some polymorphic loci within IGF2BP1 gene were associated with growth traits in animals, especially in goats. Therefore, it has been hypothesized that some variants within IGF2BP1 gene may be also involved in growth traits of sheep. Nine insertion/deletion (InDel) mutations within IGF2BP1 were identified and three loci were polymorphic. Meanwhile, the association analyses between three InDels and growth traits were carried out in 745 sheep. The results showed that all InDels included 5 bp InDel in downstream region, 9 bp InDel in intron 4 and 15 bp InDel in intron 2 within IGF2BP1 were significantly associated with growth traits (p<.05). Furthermore, at 5 and 9 bp InDel loci, the individuals of heterozygous genotype (ID) had superior growing performance especially at body weight (BW). In all, three InDels were crucial variants correlated with growth traits and could be applied in marker-assisted selection (MAS) in sheep.