Miracle-dz/UniFAR-FTUs huggingface dataset:
Spirometric Response to Bronchodilator and Eucapnic Voluntary Hyperpnea in Adults With Asthma

BACKGROUND: The spirometric response to fast-acting bronchodilator is used clinically to diagnose asthma and in clinical research to verify its presence. However, bronchodilator responsiveness does not correlate with airway hyper-responsiveness measured with the direct-acting stimulus of methacholine, demonstrating that bronchodilator responsiveness is a problematic method for diagnosing asthma. The relationship between bronchodilator responsiveness and airway hyper-responsiveness assessed with indirect-acting stimuli is not known. METHODS: Retrospectively, the spirometric responses to inhaled bronchodilator and a eucapnic voluntary hyperpnea challenge (EVH) were compared in 39 non-smoking adult subjects with asthma (26 male, 13 female; mean ± SD age 26.9 ± 7.8 y; mean ± SD body mass index 26.3 ± 4.7 kg/m2). All subjects met one or both of 2 criteria: ≥ 12% and 200 mL increase in FEV1 after inhaled bronchodilator, and ≥ 10% decrease in FEV1 after an EVH challenge. RESULTS: Overall, FEV1 increased by 9.9 ± 7.9% after bronchodilator (3.93 ± 0.97 to 4.28 ± 0.91 L, P < .001) and decreased by 23.9 ± 15.0% after the EVH challenge (3.89 ± 0.89 to 2.96 ± 0.88 L, P < .001). However, the change in FEV1 after bronchodilator did not correlate with the change after EVH challenge (r = 0.062, P = .71). Significant bronchodilator responsiveness predicted a positive response to EVH challenge in 9 of 33 subjects (sensitivity 27%). Following EVH, the change in FEV1 strongly correlated with the change in FVC (FEV1 percent change vs FVC percent change, r = 0.831, P < .001; FEV1 ΔL vs FVC ΔL, r = 0.799, P < .001). CONCLUSIONS: These results extend previous findings that demonstrate a lack of association between bronchodilator responsiveness and methacholine responsiveness. Given the poor concordance between the spirometric response to fast-acting bronchodilator and the EVH challenge, these findings suggest that the airway response to inhaled β2-agonist must be interpreted with caution and in the context of its determinants and limitations.
Thermal acclimation increases the stability of a predator–prey interaction in warmer environments

Global warming over the next century is likely to alter the energy demands of consumers and thus the strengths of their interactions with their resources. The subsequent cascading effects on population biomasses could have profound effects on food web stability. One key mechanism by which organisms can cope with a changing environment is phenotypic plasticity, such as acclimation to warmer conditions through reversible changes in their physiology. Here, we measured metabolic rates and functional responses in laboratory experiments for a widespread predator–prey pair of freshwater invertebrates, sampled from across a natural stream temperature gradient in Iceland (4–18℃). This enabled us to parameterize a Rosenzweig–MacArthur population dynamical model to study the effect of thermal acclimation on the persistence of the predator–prey pairs in response to warming. Acclimation to higher temperatures either had neutral effects or reduced the thermal sensitivity of both metabolic and feeding rates for the predator, increasing its energetic efficiency. This resulted in greater stability of population dynamics, as acclimation to higher temperatures increased the biomass of both predator and prey populations with warming. These findings indicate that phenotypic plasticity can act as a buffer against the impacts of environmental warming. As a consequence, predator–prey interactions between ectotherms may be less sensitive to future warming than previously expected, but this requires further investigation across a broader range of interacting species.
Extending the allelic spectrum at noncoding risk loci of orofacial clefting

Genome‐wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease‐relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single‐molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree‐ and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology.
Rosmarinic acid protects mice from imiquimod induced psoriasis‐like skin lesions by inhibiting the IL‐23/Th17 axis via regulating Jak2/Stat3 signaling pathway

IL‐23/Th17 (IL‐17) axis plays a critical role in psoriasis. Rosmarinic acid (RA) was proved the inhibitory effect of T cell infiltration in the skin. However, whether and how RA has beneficial effects on psoriasis did not really know yet. So lipopolysaccharide (LPS)‐induced abnormal proliferation Hacat cell line and Imiquimod (IMQ)‐induced psoriasis‐like mouse dermatitis were used to assess the pharmacological effects and mechanisms of RA by Psoriasis Area Severity Index (PASI) score, histopathology, flow cytometry, reverse transcription‐polymerase chain reaction (RT‐PCR) and western blotting. The results showed that RA inhibited LPS‐induced aberrant expression of Hacat cell line, and significantly alleviated IMQ‐induced skin inflammation. Although RA had no obviously effect on the ratio of epidermal Langerhans cell (LC) and LC migration from the skin to the skin draining lymph nodes, RA inhibited the expression of IL‐23 in skin lesions, as well as reduced the differentiation of Th17 cells and producing of IL‐17A by down regulating the transcriptor factor RORγt and JAK2/Stat3 signal pathway, comparing to IMQ treated group. The findings suggest that RA inhibits psoriasis‐like skin inflammation in vivo and in vitro by reducing the expression of IL‐23, inhibiting Th17 dominated inflammation and down regulating the Jak2/Stat3 signal pathway.
An Oncolytic Virus Expressing IL15/IL15Rα Combined with Off-the-Shelf EGFR-CAR NK Cells Targets Glioblastoma

The combination of an oncolytic virus expressing the IL15/IL15Rα complex and frozen, ready-to-use EGFR-CAR NK cells elicits strong antitumor responses in glioblastoma. IL15 is a pleiotropic cytokine with multiple roles that improve immune responses to tumor cells. Oncolytic viruses (OV) specifically lyse tumors and activate immune responses. Systemic administration of IL15 or its complex with the IL15Rα and chimeric antigen receptor (CAR) natural killer (NK) cells are currently being tested in the clinic. Here, we generated a herpes simplex 1–based OV-expressing human IL15/IL15Rα sushi domain fusion protein (named OV-IL15C), as well as off-the-shelf EGFR-CAR NK cells, and studied their monotherapy and combination efficacy in vitro and in multiple glioblastoma (GBM) mouse models. In vitro, soluble IL15/IL15Rα complex was secreted from OV-IL15C–infected GBM cells, which promoted GBM cytotoxicity and improved survival of NK and CD8+ T cells. Frozen, readily available off-the-shelf EGFR-CAR NK cells showed enhanced killing of tumor cells compared with empty vector–transduced NK cells. In vivo, OV-IL15C significantly inhibited tumor growth and prolonged survival of GBM-bearing mice in the presence of CD8+ T cells compared with parental OV. OV-IL15C plus EGFR-CAR NK cells synergistically suppressed tumor growth and significantly improved survival compared with either monotherapy, correlating with increased intracranial infiltration and activation of NK and CD8+ T cells and elevated persistence of CAR NK cells in an immunocompetent model. Collectively, OV-IL15C and off-the-shelf EGFR-CAR NK cells represent promising therapeutic strategies for GBM treatment to improve the clinical management of this devastating disease. Significance: The combination of an oncolytic virus expressing the IL15/IL15Rα complex and frozen, ready-to-use EGFR-CAR NK cells elicits strong antitumor responses in glioblastoma.
Detection and Analysis of Proteins Modified by O‐Linked N‐Acetylglucosamine

O‐GlcNAc is a common post‐translational modification of nuclear, mitochondrial, and cytoplasmic proteins that regulates normal physiology and the cell stress response. Dysregulation of O‐GlcNAc cycling is implicated in the etiology of type II diabetes, heart failure, hypertension, and Alzheimer's disease, as well as cardioprotection. These protocols cover simple and comprehensive techniques for detecting proteins modified by O‐GlcNAc and studying the enzymes that add or remove O‐GlcNAc. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC.
Converging Roles of the Aryl Hydrocarbon Receptor in Early Embryonic Development, Maintenance of Stemness and Tissue Repair.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor well-known for its adaptive role as a sensor of environmental toxicants and mediator of the metabolic detoxification of xenobiotic ligands. In addition, a growing body of experimental data has provided indisputable evidence that the AHR regulates critical functions of cell physiology and embryonic development. Recent studies have shown that the naïve AHR-i.e., unliganded to xenobiotics but activated endogenously-has a crucial role in maintenance of embryonic stem cell pluripotency, tissue repair and regulation of cancer stem cell stemness. Depending on the cellular context, AHR silences the expression of pluripotency genes Oct4 and Nanog and potentiates differentiation, while curtailing cellular plasticity and stemness. In these processes, AHR-mediated contextual responses and outcomes are dictated by changes of interacting partners in signaling pathways, gene networks, and cell type-specific genomic structures. In this review, we focus on AHR-mediated changes of genomic architecture as an emerging mechanism for the AHR to regulate gene expression at the transcriptional level. Collective evidence places this receptor as a physiological hub connecting multiple biological processes whose disruption impacts on embryonic development, tissue repair and maintenance or loss of stemness.
Articulating the Trauma-Informed Theory of Individual Health Behavior.

Exposure to trauma increases the risk of engaging in detrimental health behaviors such as tobacco and substance use. In response, the United States Substance Abuse and Mental Health Services Administration developed Trauma-Informed Care (TIC), an organizational framework for improving the provision of behavioral health care to account for the role exposure to trauma plays in patients' lives. We adapt TIC to introduce a novel theory of behavior change, the Trauma-Informed Theory of Individual Health Behavior (TTB). TTB posits that individual capacity to undertake intentional health-promoting behavior change is dependent on three factors: 1) the forms and severity of trauma they have been and are exposed to; 2) how this trauma physiologically manifests (i.e., the trauma response); and 3) resilience to undertake behavior change despite this trauma response. We define each of these factors and their relationships to one another. We anticipate that the introduction of TTB will provide a foundation for developing theory-driven research, interventions, and policies that improve behavioral health outcomes in trauma-affected populations. This article is protected by copyright. All rights reserved.
A systematic review on nomophobia prevalence: Surfacing results and standard guidelines for future research

Background Mobile phones allow us to stay connected with others and provide us a sense of security. We can work, chat with family and friends, take pictures, buy clothes or books, and even control home appliances. They play such a significant role in our lives that we feel anxious without them. In some cases, the relationship between humans and these communication devices have become problematic. Nomophobia (NMP) is the fear of becoming incommunicable, separated from the mobile phone and losing connection to the Internet. Since this social phobia was coined in the first decade of the XXI century, a growing number of studies have studied it and reported the prevalence of this technology-related problem. However, this research activity has generated mixed results regarding how we assess and report nomophobia and who may be at a higher risk of suffering or developing it. Methods We conducted a systematic review of 108 studies published in English and Spanish and collected them in Parsifal. We searched for assessment and prevalence data on nomophobia. Also, we looked at gender and age differences to identify risk factors and see if these differences exist and emerge worldwide. Results In this study, we find that women and younger individuals suffer more from nomophobia. The disparity in reporting the prevalence of nomophobia is enormous since the percentages of “at-risk” participants go from 13% to 79%, and participants suffering from it are between 6% and 73%, being the score in the range of 45.5 and 93.82. Within the group of nomophobic people, moderate cases vary between 25.7% and 73.3%, and severe cases, between 1% and 87%. Such disparity is due to differences in assessment criteria. Females and young people seem to be more vulnerable to nomophobia although methodological disparity makes it difficult to reach definitive conclusions. We conclude our review by recommending some common guidelines for guiding future research.
Evolutionary, proteomic, and experimental investigations suggest the extracellular matrix of cumulus cells mediates fertilization outcomes

Abstract Studies of fertilization biology often focus on sperm and egg interactions. However, before gametes interact, mammalian sperm must pass through the cumulus layer; in mice, this consists of several thousand cells tightly glued together with hyaluronic acid and other proteins. To better understand the role of cumulus cells and their extracellular matrix, we perform proteomic experiments on cumulus oophorus complexes (COCs) in house mice (Mus musculus), producing over 24,000 mass spectra to identify 711 proteins. Seven proteins known to stabilize hyaluronic acid and the extracellular matrix were especially abundant (using spectral counts as an indirect proxy for abundance). Through comparative evolutionary analyses, we show that three of these evolve rapidly, a classic signature of genes that influence fertilization rate. Some of the selected sites overlap regions of the protein known to impact function. In a follow-up experiment, we compared COCs from females raised in two different social environments. Female mice raised in the presence of multiple males produced COCs that were smaller and more resistant to dissociation by hyaluronidase compared to females raised in the presence of a single male, consistent with a previous study that demonstrated such females produced COCs that were more resistant to fertilization. Although cumulus cells are often thought of as enhancers of fertilization, our evolutionary, proteomic, and experimental investigations implicate their extracellular matrix as a potential mediator of fertilization outcomes. Summary sentence Cumulus cell protein identification reveals potential roles in fertilization outcomes. Graphical Abstract
A Generalized Partially Confirmatory Factor Analysis Framework with Mixed Bayesian Lasso Methods

Abstract This research extends the partially confirmatory approach to accommodate mixed types of data and missingness in a unified framework that can address a wide range of the confirmatory-exploratory continuum in factor analysis. A mix of Bayesian adaptive and covariance Lasso procedures was developed to estimate model parameters and regularize the loading structure and local dependence simultaneously. Several model variants were offered with different constraints for identification. The less-constrained variant can achieve sufficient condition for the more-powerful variant, although loading estimates associated with local dependence can be inflated. Parameter recovery was satisfactory, but the information on local dependence was partially lost with categorical data or missingness. A real-life example illustrated how the models can be used to obtain a more discernible loading pattern and to identify items that do not measure what they are supposed to measure. The proposed methodology has been implemented in the R package LAWBL.
Loss of CPAP in developing mouse brain and its functional implication in human primary microcephaly.

Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by small brain size with mental retardation. CPAP/CENPJ, a known microcephaly gene, plays a key role in centriole biogenesis. Here, we generated a previously unreported conditional knockout allele in the mouse Cpap gene. Our results showed that conditional Cpap deletion preferentially induces formation of monopolar spindles in radial glia progenitors (RGPs) and causes robust apoptosis that severely disrupts embryonic brains. Interestingly, microcephalic brains with reduced apoptosis are detected in the conditional Cpap gene-deleted mice, which lose only one allele of p53, while simultaneous removal of p53 and Cpap rescues RGPs death. Furthermore, Cpap deletion leads to cilia loss, RGPs mislocalization, junctional integrity disruption, massive heterotopia, and severe cerebellar hypoplasia. Together, these findings indicate that complete CPAP loss leads to severe and complex phenotypes in developing mouse brain, and provide new insights into the causes of MCPH.
The prevalence of novel periodontal pathogens and bacterial complexes in Stage II generalized periodontitis based on 16S rRNA next generation sequencing

Abstract Objective: To define the subgingival microbial profile associated with Stage II generalized periodontitis using next-generation sequencing and to determine the relative abundance of novel periodontal pathogens and bacterial complexes. Methodology: Subgingival biofilm samples were collected from 80 subjects diagnosed with Stage II generalized periodontitis. Bacterial DNA was extracted, and 16S rRNA-based bacterial profiling via next-generation sequencing was carried out. The bacterial composition and diversity of microbial communities based on the age and sex of the patients were analyzed. The bacterial species were organized into groups: bacterial complexes (red, orange, purple, yellow, and green), novel periodontal pathogens, periodontal health-related species, and unclassified periodontal species. The results were analyzed and statistically evaluated. Results: The highest number of bacteria belonged to the phylum Bacteroidetes and Firmicutes. In terms of relative abundance, the orange complex represented 18.99%, novel bacterial species (Fretibacterium spp. and Saccharibacteria spp.) comprised 17.34%, periodontal health-related species accounted for 16.75% and unclassified periodontal species represented (Leptotrichia spp. and Selenomonas spp.) 15.61%. Novel periodontal pathogens had outweighed the periodontal disease-related red complex (5.3%). The one-sample z-test performed was statistically significant at p<0.05. The Beta diversity based on the unweighted UniFrac distance at the species level demonstrated a total variance of 15.77% based on age and 39.19% on sex, which was not statistically significant. Conclusion: The bacterial species corresponding to the disease-related orange complex and novel periodontal pathogens are predominant in Stage II generalized periodontitis.
Differential expression profiles of miRNAs and their putative targets in Schistosoma mansoni during its life cycle

BACKGROUND Schistosomiasis is a disease caused by Schistosoma. Due to its complex life cycle, evolutionary position and sexual dimorphism, schistosomes have several mechanisms of gene regulation. MicroRNAs (miRNAs) are short endogenous RNAs that regulate gene expression at the post-transcriptional level by targeting mRNA transcripts. OBJECTIVES Here, we tested 12 miRNAs and identified their putative targets using a computational approach. METHODS We performed the expression profiles of a set of miRNAs and their putative targets during the parasite’s life cycle by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). FINDINGS Our results showed differential expression patterns of the mature miRNAs sma-miR-250; sma-miR-92a; sma-miR-new_4-3p; sma-miR-new_4-5p; sma-miR-new_5-5p; sma-miR-new_12-5p; sma-miR-new_13-3p and sma-miR-new_13-5p. Interestingly, many of the putative target genes are linked to oxidative phosphorylation and are up-regulated in adult-worms, which led us to suggest that miRNAs might play important roles in the post-transcriptional regulation of genes related to energetic metabolism inversion during parasite development. It is noteworthy that the expression of sma-miR-new_13-3p exhibited a negative correlation on SmNADH:ubiquinone oxidoreductase complex I. MAIN CONCLUSIONS Our analysis revealed putative miRNA genes related to important biological processes, such as transforming growth factor beta (TGF-β) signaling, proteasome regulation, glucose and lipid metabolism, immune system evasion and transcriptional regulation.
A functional in vitro cell-free system for studying DNA repair in isolated nuclei

ABSTRACT Assessment of DNA repair is an important endpoint measurement when studying the biochemical mechanisms of the DNA damage response and when investigating the efficacy of chemotherapy, which often uses DNA-damaging compounds. Numerous in vitro methods to biochemically characterize DNA repair mechanisms have been developed so far. However, such methods have some limitations, which are mainly due to the lack of chromatin organization in the DNA templates used. Here we describe a functional cell-free system to study DNA repair synthesis in vitro, using G1-phase nuclei isolated from human cells treated with different genotoxic agents. Upon incubation in the corresponding damage-activated cytosolic extracts, containing biotinylated dUTP, nuclei were able to initiate DNA repair synthesis. The use of specific DNA synthesis inhibitors markedly decreased biotinylated dUTP incorporation, indicating the specificity of the repair response. Exogenously added human recombinant PCNA protein, but not the sensors of UV-DNA damage DDB2 and DDB1, stimulated UVC-induced dUTP incorporation. In contrast, a DDB2PCNA− mutant protein, unable to associate with PCNA, interfered with DNA repair synthesis. Given its responsiveness to different types of DNA lesions, this system offers an additional tool to study DNA repair mechanisms. This article has an associated First Person interview with the first author of the paper. Summary: A simple and effective cell-free assay can be used for the detection, analysis and quantification of DNA repair mechanisms.