Miracle-dz/UniFAR-FTUs huggingface dataset:
Bacteroides Fragilis Polysaccharide A Ameliorates Abnormal Voriconazole Metabolism Accompanied With the Inhibition of TLR4/NF-κB Pathway

The antifungal agent voriconazole (VRC) exhibits extreme inter-individual and intra-individual variation in terms of its clinical efficacy and toxicity. Inflammation, as reflected by C-reactive protein (CRP) concentrations, significantly affects the metabolic ratio and trough concentrations of voriconazole. Bacteroides fragilis (B. fragilis) is an important component of the human intestinal microbiota. Clinical data have shown that B. fragilis abundance is comparatively higher in patients not presenting with adverse drug reactions, and inflammatory cytokine (IL-1β) levels are negatively correlated with B. fragilis abundance. B. fragilis natural product capsular polysaccharide A (PSA) prevents various inflammatory disorders. We tested the hypothesis that PSA ameliorates abnormal voriconazole metabolism by inhibiting inflammation. Germ-free animals were administered PSA intragastrically for 5 days after lipopolysaccharide (LPS) stimulation. Their blood and liver tissues were collected to measure VRC concentrations. PSA administration dramatically improved the resolution phase of LPS-induced hepatic VRC metabolism and inflammatory factor secretion. It reversed inflammatory lesions and alleviated hepatic pro-inflammatory factor secretion. Both in vitro and in vivo data demonstrate that PSA reversed LPS-induced IL-1β secretion, downregulated the TLR4/NF-κB signaling pathway and upregulated CYP2C19 and P-gp. To the best of our knowledge, this study is the first to show that PSA from the probiotic B. fragilis ameliorates abnormal voriconazole metabolism by inhibiting TLR4-mediated NF-κB transcription and regulating drug metabolizing enzyme and transporter expression. Thus, PSA could serve as a clinical adjunct therapy.
Hypoglycemia Associated With Drug–Drug Interactions in Patients With Type 2 Diabetes Mellitus Using Dipeptidylpeptidase-4 Inhibitors

Background: Dipeptidylpeptidase-4 inhibitors (DPP-4i′s) are considered to be safe for patients with type 2 diabetes mellitus (T2DM). However, little is known about drug–drug interactions between DPP-4i′s and concurrent medications. Methods: Data on patients using DPP-4i′s for T2DM during 2011–2017 were retrieved from Chang Gung Research database provided by Chang Gung Memorial Hospital. Patients were excluded if they were aged <30 years or >90 years; had incomplete demographic data; had insulinoma; or had records of concomitant insulin use. A generalized estimating equation–based Poisson model was employed for statistical analysis. The primary outcome was hypoglycemia events. Results: We retrieved data on a total of 97,227 patients using DPP-4i′s. After patients were excluded according to the mentioned criteria, the remaining 77,047 DPP-4i users were studied (mean age 64 ± 12 years, men 54.4%). The most common medications coprescribed with DPP4is over all person-quarters were acetaminophen, simvastatin, fluvastatin, and colchicine (all >20,000 person-quarters). The combinations of a DPP-4i with bumetanide, captopril, colchicine, acetaminophen, cotrimoxazole, and pantoprazole were associated with an increased risk of hypoglycemia. Compared with the ratios observed for person-quarters of DPP-4i use alone (reference category), the adjusted prevalence ratios per 100 person-years of hypoglycemia for person-quarters of DPP-4i use in combination with bumetanide, captopril, colchicine, acetaminophen, cotrimoxazole, and pantoprazole were 2.44 (95% confidence interval [CI], 1.78–3.36), 2.97 (95% CI, 2.26–3.90), 1.87 (95% CI, 1.44–2.42), 2.83 (95% CI, 2.44–3.29), 2.27 (95% CI, 1.27–4.04), and 3.03 (95% CI, 1.96–4.68), respectively. Conclusion: Among patients taking DPP-4i′s for T2DM, concurrent use of such inhibitors with bumetanide, captopril, acetaminophen, and pantoprazole was associated with an increased risk of hypoglycemia compared with the use of DPP-4i′s alone. Physicians prescribing DPP-4i′s should consider the potential risks associated with their concomitant use with other drugs.
Personality and Mind-Wandering Self-Perception: The Role of Meta-Awareness

Mind-wandering is a psychological process involving the emergence of spontaneous thoughts in daily life. Research has shown that mind-wandering influences diverse psychological outcomes; however, less is known about possible individual differences that may drive mind-wandering. In this study, we argue that personality traits, expressed in neuroticism and openness to experience, may lead to the individual’s self-perception of their mind-wandering activity, due to meta-awareness processes. In a three-wave survey study with 273 college students, we gathered data which supported a positive association of both neuroticism and openness to experience with mind-wandering self-perception, mediated by the individual’s meta-awareness. Thus, this study contributes to the literature on spontaneous thinking by showing that mind-wandering processes may be a function of individual differences expressed in personality traits.
Biosynthesis of Silver Nanoparticles by Aspergillus terreus: Characterization, Optimization, and Biological Activities

In this study, mycelial filtrate of Aspergillus terreus BA6 was used to reduce AgNO3 to form silver nanoparticles (AgNPs). The effect of seven independent variables on the diameter of AgNPs was studied by applying design of experiments (DOE). At optimal conditions, the diameter of AgNPs was reduced by approximately 26.7% compared to the basal culture condition and AgNO3 concentration was found to be the most significant factor affecting the diameter of AgNPs. A. terreus nano-Ag was characterized using UV-visible spectroscopy, transmission electron microscopy, energy dispersive X-ray (EDX), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and Zeta potential. The maximum UV absorption was obtained at 420 nm and the microscopic results showed particles with narrow size distribution ranging from 7 to 23 nm. XRD pattern of AgNPs revealed four diffraction peaks of metallic silver and the EDX spectrum showed a strong signal attributed to Ag nano-crystals. AgNPs mycofabricated by A. terreus showed potent minimum inhibitory concentration (MIC) and broad minimum bactericidal/fungicidal concentration (MBC/MFC) against 12 reference microorganisms. The MIC and MBC/MFC values of AgNPs were 0.312 to 1.25 μg/ml and 0.625 to 10 μg/ml, respectively. Nevertheless, AgNPs did not demonstrate any antagonistic activity against Coxsackie B virus. The in vitro cytotoxicity of the mycosynthesized AgNPs showed significant antitumor activity against adenocarcinoma epithelial cells from human breast cancer (Mcf-7) cell line with an inhibitory concentration (IC50) of 87.5 μg/ml.
Stress and the Brain: An Emerging Role for Selenium

The stress response is an important tool in an organism’s ability to properly respond to adverse environmental conditions in order to survive. Intense acute or chronic elevation of glucocorticoids, a class of stress hormone, can have deleterious neurological effects, however, including memory impairments and emotional disturbances. In recent years, the protective role of the antioxidant micronutrient selenium against the negative impact of externally applied stress has begun to come to light. In this review, we will discuss the effects of stress on the brain, with a focus on glucocorticoid action in the hippocampus and cerebral cortex, and emerging evidence of an ability of selenium to normalize neurological function in the context of various stress and glucocorticoid exposure paradigms in rodent models.
School Violence and Teacher Professional Engagement: A Cross-National Study

School violence research has mainly focused on the impact on students. Very few studies, even fewer from a cross-cultural perspective, have examined the relationships between school violence and teacher professional engagement, and the role played by teacher self-efficacy and school climate related factors. The present study utilizes a SEM research methodology to analyze the 2013 TALIS data. The purpose is to understand and compare the relationships in four different cultural contexts; the U.S., England, South Korea, and Mexico. Results indicate, on average, that the significant and negative impacts of school violence on teacher professional engagement are partly mediated by teacher self-efficacy. The negativity of school violence is significantly alleviated by enhancing participation among school stakeholders and improving teacher–student relationships. The relationships among the factors apply across all four cultural systems, though, the effects of factors and variables vary to a degree. The paper also discusses other relevant issues and differences as well as their implications.
Proteomic Analysis of the Parasitic Cnidarian Ceratonova shasta (Cnidaria: Myxozoa) Reveals Diverse Roles of Actin in Motility and Spore Formation

Myxozoans are widely distributed aquatic obligate endoparasites that were recently recognized as belonging within the phylum Cnidaria. They have complex life cycles with waterborne transmission stages: resistant, infectious spores that are unique to myxozoans. However, little is known about the processes that give rise to these transmission stages. To understand the molecular underpinnings of spore formation, we conducted proteomics on Ceratonova shasta, a highly pathogenic myxozoan that causes severe mortalities in wild and hatchery-reared salmonid fishes. We compared proteomic profiles between developmental stages from inside the fish host, and the mature myxospore, which is released into the water where it drifts passively, ready to infect the next host. We found that C. shasta contains 2,123 proteins; representing the first proteomic catalog of a myxozoan myxospore. Analysis of proteins differentially expressed between developing and mature spore stages uncovered processes that are active during spore formation. Our data highlight dynamic changes in the actin cytoskeleton, which provides myxozoan developmental stages with mobility through lamellipodia and filopodia, whereas in the mature myxospore the actin network supports F-actin stabilization that reinforces the transmission stage. These findings provide molecular insight into the myxozoan life cycle stages and, particularly, into the process of sporogenesis.
TRIM21, a New Component of the TRAIL-Induced Endogenous Necrosome Complex

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a well-known apoptosis inducer and a potential anticancer agent. When caspases and inhibitors of apoptosis proteins (IAPs) are inhibited, TRAIL induces necroptosis. Molecular mechanisms of necroptosis rely on kinase activation, and on the formation of a necrosome complex, bringing together the receptor-interacting protein kinases 1 and 3 (RIPK1, RIPK3), and the mixed lineage kinase domain-like protein (MLKL). In this study, mass spectrometry approach allowed to identify the tripartite motif containing 21 (TRIM21), an E3 ubiquitin-protein ligase as a new partner of the endogenous TRAIL-induced necrosome. Alteration of TRIM21 expression level, obtained by transient transfection of HT29 or HaCat cells with TRIM21-targeted siRNAs or cDNA plasmids coding for TRIM21 demonstrated that TRIM21 is a positive regulator of TRAIL-induced necroptosis. Furthermore, the invalidation of TRIM21 expression in HT29 cells by CRISPR-Cas9 technology also decreased cell sensitivity to TRAIL-induced necroptosis, a shortcoming associated with a reduction in MLKL phosphorylation, the necroptosis executioner. Thus, TRIM21 emerged as a new partner of the TRAIL-induced necrosome that positively regulates the necroptosis process.
Using Stakeholder Perceptions to Inform Future Efforts to Implement Mental Health First Aid Training in China: A Qualitative Study

Background: The Mental Health First Aid (MHFA) training program has been widely implemented in many high-income countries. Evidence on the adaptation of this and other similar programs in resource-constrained settings like China is very limited. This study aimed to explore the views of key stakeholders on the implementation issues and contextual factors relevant to the scale-up of MHFA in China. Methods: Informed by the Consolidated Framework for Implementation Research, five implementation domains of intervention characteristics, characteristics of individuals, contextual adaptation, outer and inner setting, and implementation process were investigated through semi-structured in-depth interviews. Twenty-four stakeholders with diverse expertise in the Chinese mental health system were interviewed. Transcripts were coded using NVivo 12 software and thematically analyzed. Results: Fifteen themes and 52 sub-themes were identified in relation to the five domains. Participants saw MHFA as meeting the need for more evidence-based interventions to improve population mental health. Previous participants in MHFA training were satisfied with the course, but their intentions to help and levels of self-efficacy varied. Contextual adaptation of course content, delivery formats, and financing models, was seen as essential. External health policies and some socioeconomic factors (e.g., improved living conditions) were perceived as potential enablers of scalability. Low levels of engagement in health interventions and lack of supportive social norms were identified as potential barriers while executive support, quality control, and sustainable funding were viewed as facilitators of implementation. Conclusion: MHFA training meets some very important current societal and public health needs in China. To achieve its potential impact, significant contextual adaptation is required, particularly in terms of course content, delivery formats, and financing models. Overcoming low levels of engagement in community-based mental health interventions and combating stigma will also be critical for its scale-up.
The Promise of the Zebrafish Model for Parkinson’s Disease: Today’s Science and Tomorrow’s Treatment

The second most prevalent neurodegenerative disorder in the elderly is Parkinson’s disease (PD). Its etiology is unclear and there are no available disease-modifying medicines. Therefore, more evidence is required concerning its pathogenesis. The use of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is the basis of most animal models of PD. MPTP is metabolized by monoamine oxidase B (MAO B) to MPP + and induces the loss of dopaminergic neurons in the substantia nigra in mammals. Zebrafish have been commonly used in developmental biology as a model organism, but owing to its perfect mix of properties, it is now emerging as a model for human diseases. Zebrafish (Danio rerio) are cheap and easy to sustain, evolve rapidly, breed transparent embryos in large amounts, and are readily manipulated by different methods, particularly genetic ones. Furthermore, zebrafish are vertebrate species and mammalian findings obtained from zebrafish may be more applicable than those derived from genetic models of invertebrates such as Drosophila melanogaster and Caenorhabditis elegans. The resemblance cannot be taken for granted, however. The goal of the present review article is to highlight the promise of zebrafish as a PD animal model. As its aminergic structures, MPTP mode of action, and PINK1 roles mimic those of mammalians, zebrafish seems to be a viable model for studying PD. The roles of zebrafish MAO, however, vary from those of the two types of MAO present in mammals. The benefits unique to zebrafish, such as the ability to perform large-scale genetic or drug screens, should be exploited in future experiments utilizing zebrafish PD models.
Sedentary Life and Reduced Mastication Impair Spatial Learning and Memory and Differentially Affect Dentate Gyrus Astrocyte Subtypes in the Aged Mice

To explore the impact of reduced mastication and a sedentary lifestyle on spatial learning and memory in the aged mice, as well as on the morphology of astrocytes in the molecular layer of dentate gyrus (MolDG), different masticatory regimens were imposed. Control mice received a pellet-type hard diet, while the reduced masticatory activity group received a pellet diet followed by a powdered diet, and the masticatory rehabilitation group received a pellet diet, followed by powder diet and then a pellet again. To mimic sedentary or active lifestyles, mice were housed in an impoverished environment of standard cages or in an enriched environment. The Morris Water Maze (MWM) test showed that masticatory-deprived group, regardless of environment, was not able to learn and remember the hidden platform location, but masticatory rehabilitation combined with enriched environment recovered such disabilities. Microscopic three-dimensional reconstructions of 1,800 glial fibrillary acidic protein (GFAP)-immunolabeled astrocytes from the external third of the MolDG were generated using a stereological systematic and random sampling approach. Hierarchical cluster analysis allowed the characterization into two main groups of astrocytes with greater and lower morphological complexities, respectively, AST1 and AST2. When compared to compared to the hard diet group subjected to impoverished environment, deprived animals maintained in the same environment for 6 months showed remarkable shrinkage of astrocyte branches. However, the long-term environmental enrichment (18-month-old) applied to the deprived group reversed the shrinkage effect, with significant increase in the morphological complexity of AST1 and AST2, when in an impoverished or enriched environment. During housing under enriched environment, complexity of branches of AST1 and AST2 was reduced by the powder diet (pellet followed by powder regimes) in young but not in old mice, where it was reversed by pellet diet (pellet followed by powder and pellet regime again). The same was not true for mice housed under impoverished environment. Interestingly, we were unable to find any correlation between MWM data and astrocyte morphological changes. Our findings indicate that both young and aged mice subjected to environmental enrichment, and under normal or rehabilitated masticatory activity, preserve spatial learning and memory. Nonetheless, data suggest that an impoverished environment and reduced mastication synergize to aggravate age-related cognitive decline; however, the association with morphological diversity of AST1 and AST2 at the MolDG requires further investigation.
Neuromodulation Effect of Very Low Intensity Transcranial Ultrasound Stimulation on Multiple Nuclei in Rat Brain

Objective Low-intensity transcranial ultrasound stimulation (TUS) is a non-invasive neuromodulation technique with high spatial resolution and feasible penetration depth. To date, the mechanisms of TUS modulated neural oscillations are not fully understood. This study designed a very low acoustic intensity (AI) TUS system that produces considerably reduced AI Ultrasound pulses (ISPTA < 0.5 W/cm2) when compared to previous methods used to measure regional neural oscillation patterns under different TUS parameters. Methods We recorded the local field potential (LFP) of five brain nuclei under TUS with three groups of simulating parameters. Spectrum estimation, time-frequency analysis (TFA), and relative power analysis methods have been applied to investigate neural oscillation patterns under different stimulation parameters. Results Under PRF, 500 Hz and 1 kHz TUS, high-amplitude LFP activity with the auto-rhythmic pattern appeared in selected nuclei when ISPTA exceeded 12 mW/cm2. With TFA, high-frequency energy (slow gamma and high gamma) was significantly increased during the auto-rhythmic patterns. We observed an initial plateau in nuclei response when ISPTA reached 16.4 mW/cm2 for RPF 500 Hz and 20.8 mW/cm2 for RPF 1 kHz. The number of responding nuclei started decreasing while ISPTA continued increasing. Under 1.5 kHz TUS, no auto-rhythmic patterns have been observed, but slow frequency power was increased during TUS. TUS inhibited most of the frequency band and generated obvious slow waves (theta and delta band) when stimulated at RPF = 1.5 kHz, ISPTA = 8.8 mW/cm2. Conclusion These results demonstrate that very low intensity Transcranial Ultrasound Stimulation (VLTUS) exerts significant neuromodulator effects under specific parameters in rat models and may be a valid tool to study neuronal physiology.
Random Fields in Physics, Biology and Data Science

A random field is the representation of the joint probability distribution for a set of random variables. Markov fields, in particular, have a long standing tradition as the theoretical foundation of many applications in statistical physics and probability. For strictly positive probability densities, a Markov random field is also a Gibbs field, i.e., a random field supplemented with a measure that implies the existence of a regular conditional distribution. Markov random fields have been used in statistical physics, dating back as far as the Ehrenfests. However, their measure theoretical foundations were developed much later by Dobruschin, Lanford and Ruelle, as well as by Hammersley and Clifford. Aside from its enormous theoretical relevance, due to its generality and simplicity, Markov random fields have been used in a broad range of applications in equilibrium and non-equilibrium statistical physics, in non-linear dynamics and ergodic theory. Also in computational molecular biology, ecology, structural biology, computer vision, control theory, complex networks and data science, to name but a few. Often these applications have been inspired by the original statistical physics approaches. Here, we will briefly present a modern introduction to the theory of random fields, later we will explore and discuss some of the recent applications of random fields in physics, biology and data science. Our aim is to highlight the relevance of this powerful theoretical aspect of statistical physics and its relation to the broad success of its many interdisciplinary applications.
Potential Mimicry of Viral and Pancreatic β Cell Antigens Through Non-Spliced and cis-Spliced Zwitter Epitope Candidates in Type 1 Diabetes

Increasing evidence suggests that post-translational peptide splicing can play a role in the immune response under pathological conditions. This seems to be particularly relevant in Type 1 Diabetes (T1D) since post-translationally spliced epitopes derived from T1D-associated antigens have been identified among those peptides bound to Human Leucocyte Antigen (HLA) class I and II complexes. Their immunogenicity has been confirmed through CD4+ and CD8+ T cell-mediated responses in T1D patients. Spliced peptides theoretically have a large sequence variability. This might increase the frequency of viral-human zwitter peptides, i.e. peptides that share a complete sequence homology irrespective of whether they originate from human or viral antigens, thereby impinging upon the discrimination between self and non-self antigens by T cells. This might increase the risk of autoimmune responses triggered by viral infections. Since enteroviruses and other viral infections have historically been associated with T1D, we investigated whether cis-spliced peptides derived from selected viruses might be able to trigger CD8+ T cell-mediated autoimmunity. We computed in silico viral-human non-spliced and cis-spliced zwitter epitope candidates, and prioritized peptide candidates based on: (i) their binding affinity to HLA class I complexes, (ii) human pancreatic β cell and medullary thymic epithelial cell (mTEC) antigens’ mRNA expression, (iii) antigen association with T1D, and (iv) potential hotspot regions in those antigens. Neglecting potential T cell receptor (TCR) degeneracy, no viral-human zwitter non-spliced peptide was found to be an optimal candidate to trigger a virus-induced CD8+ T cell response against human pancreatic β cells. Conversely, we identified some zwitter peptide candidates, which may be produced by proteasome-catalyzed peptide splicing, and might increase the likelihood of pancreatic β cells recognition by virus-specific CD8+ T cell clones, therefore promoting β cell destruction in the context of viral infections.