Miracle-dz/UniFAR-FTUs huggingface dataset:
The Role of Iron, Its Metabolism and Ferroptosis in Traumatic Brain Injury

Traumatic brain injury (TBI) is a structural and physiological disruption of brain function caused by external forces. It is a major cause of death and disability for patients worldwide. TBI includes both primary and secondary impairments. Iron overload and ferroptosis highly involved in the pathophysiological process of secondary brain injury. Ferroptosis is a form of regulatory cell death, as increased iron accumulation in the brain leads to lipid peroxidation, reactive oxygen species (ROS) production, mitochondrial dysfunction and neuroinflammatory responses, resulting in cellular and neuronal damage. For this reason, eliminating factors like iron deposition and inhibiting lipid peroxidation may be a promising therapy. Iron chelators can be used to eliminate excess iron and to alleviate some of the clinical manifestations of TBI. In this review we will focus on the mechanisms of iron and ferroptosis involving the manifestations of TBI, broaden our understanding of the use of iron chelators for TBI. Through this review, we were able to better find novel clinical therapeutic directions for further TBI study.
Towards Data-Driven Real-Time Hybrid Simulation: Adaptive Modeling of Control Plants

We present a method for control in real-time hybrid simulation (RTHS) that relies exclusively on data processing. Our approach bypasses conventional control techniques, which presume availability of a mathematical model for the description of the control plant (e.g., the transfer system and the experimental substructure) and applies a simple plug 'n play framework for tuning of an adaptive inverse controller for use in a feedforward manner, avoiding thus any feedback loops. Our methodology involves (i) a forward adaptation part, in which a noise-free estimate of the control plant's dynamics is derived; (ii) an inverse adaptation part that performs estimation of the inverse controller; and (iii) the integration of a standard polynomial extrapolation algorithm for the compensation of the delay. One particular advantage of the method is that it requires tuning of a limited set of hyper-parameters (essentially three) for proper adaptation. The efficacy of our framework is assessed via implementation on a virtual RTHS (vRTHS) benchmark problem that was recently made available to the community. The attained results indicate that data-driven RTHS may form a competitive alternative to conventional control.
Control of Gut Inflammation by Modulation of Purinergic Signaling

Inflammatory bowel disease (IBD) is a serious inflammatory condition of the gastrointestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are two of the most common IBD manifestations and are both associated with unfettered inflammation, often refractory to conventional immunosuppressive treatment. In both conditions, imbalance between effector and regulatory cell immune responses has been documented and is thought to contribute to disease pathogenesis. Purinergic signaling is a known modulator of systemic and local inflammation and growing evidences point to extracellular ATP/adenosine imbalance as a key determinant factor in IBD-associated immune dysregulation. In vitro and pre-clinical studies suggest a role for both ATP (P2) and adenosine (P1) receptors in dictating onset and severity of the disease. Moreover, our experimental data indicate ENTPD1/CD39 and CD73 ectoenzymes as pivotal modulators of intestinal inflammation, with clear translational importance. Here we will provide an updated overview of the current knowledge on the role of the purinergic signaling in modulating immune responses in IBD. We will also review and discuss the most promising findings supporting the use of purinergic-based therapies to correct immune dysregulation in CD and UC.
Reporting quality of trend analyses in leading medicine and oncology journals

Trend analyses are critical for assessing changes and predicting future of epidemiological parameters. Recent trend-analysis guidelines recommended reporting slopes or beta/coefficient if possible. American Statistical Association and others recommended reporting effect-size. However, reporting of these statistics in trend analyses was largely unclear. We searched the Pubmed for the articles published during Jan. 1, 2008 to Dec. 31, 2018, whose titles included “trend” or “trends” among the following medicine and oncology journals: Ann Intern Med, Ann Oncol, BMJ, J Clin Oncol, J Natl Cancer Inst, JAMA Oncol, JAMA, Lancet, Lancet Oncol and N Engl J Med. We examined proportions of the trend analyses in leading medicine and oncology journals, that reported p-value, effect-size or beta/coefficient/Annual percent change (APC), and identified associated factors. Among the 398 identified reports of trend analysis published during 2008-2018, there were 297 qualified reports, including 38 (12.8%) analyses using non-parametric model, 226 (76.1%) analyses using (piece-wise) linear model, 32 (10.8%) analyses using non-linear parametric model and 1 (0.3%) analyses using semi-parametric model (Cox regression). In these analyses, 193 (66.0%) and 216 (72,7%) analyses reported P-value and effect-size, respectively. Among the 226 trend analyses using linear model, 169 (74.8%) reported p-value, 183 (81.0%) reported effect-size, 94 (41.6%) reported APC and 34 (15.0%) reported Beta/coefficient. Only 13 (5.8%) analyses reported neither p-value/effect size nor beta/coefficient/APC. In multivariable regression models, author affiliation with epidemiology department or statistics department was associated with reporting effect-size, and U.S. senior-authors (versus non-U.S.) more likely reported p-value. No factors were linked to reporting APC. In summary, reporting quality of the included trend analyses was overall good. However, reporting p-value or effect-size did not change with publication years, and reporting APC or Beta/coefficient was uncommon. Additional works and training appear warranted to improve reporting quality of trend analyses.
scLink: Inferring Sparse Gene Co-expression Networks from Single-cell Expression Data

A system-level understanding of the regulation and coordination mechanisms of gene expression is essential to understanding the complexity of biological processes in health and disease. With the rapid development of single-cell RNA sequencing technologies, it is now possible to investigate gene interactions in a cell-type-specific manner. Here we propose the scLink method, which uses statistical network modeling to understand the co-expression relationships among genes and to construct sparse gene co-expression networks from single-cell gene expression data. We use both simulation and real data studies to demonstrate the advantages of scLink and its ability to improve single-cell gene network analysis. The source code used in this article is available at https://github.com/Vivianstats/scLink.
A Toolbox for Site-Specific Labeling of RecQ Helicase With a Single Fluorophore Used in the Single-Molecule Assay

Fluorescently labeled proteins can improve the detection sensitivity and have been widely used in a variety of biological measurements. In single-molecule assays, site-specific labeling of proteins enables the visualization of molecular interactions, conformational changes in proteins, and enzymatic activity. In this study, based on a flexible linker in the Escherichia coli RecQ helicase, we established a scheme involving a combination of fluorophore labeling and sortase A ligation to allow site-specific labeling of the HRDC domain of RecQ with a single Cy5 fluorophore, without inletting extra fluorescent domain or peptide fragment. Using single-molecule fluorescence resonance energy transfer, we visualized that Cy5-labeled HRDC could directly interact with RecA domains and could bind to both the 3′ and 5′ ends of the overhang DNA dynamically in vitro for the first time. The present work not only reveals the functional mechanism of the HRDC domain, but also provides a feasible method for site-specific labeling of a domain with a single fluorophore used in single-molecule assays.
The neuropeptide SMYamide, a SIFamide paralog, is expressed by salivary gland innervating neurons in the American cockroach and likely functions as a hormone

The SMYamide genes are paralogs of the SIFamide genes and code for neuropeptides that are structurally similar to SIFamide. In the American cockroach, Periplanea americana, the SMYamide gene is specifically expressed in the SN2 neurons that innervate the salivary glands and are known to produce action potentials during feeding. The innervation of the salivary glands by the SN2 neurons is such that one has to expect that on activation of these neurons significant amounts of SMYamide will be released into the hemolymph, thus suggesting that SMYamide also functions as a hormone. In the Periplaneta genome there are two putative SIFamide receptors and these are both expressed not only in the central nervous system and the salivary gland, but also in the gonads and other peripheral tissues. This reinforces the hypothesis that SMYamide also has an endocrine function in this species.
Successive Immunization With Epitope-Decreasing Dengue Antigens Induced Conservative Anti-Dengue Immune Responses

Repeated homologous antigen immunization has been hypothesized to hinder antibody diversification, whereas sequential immunization with heterologous immunogens can educate B cell differentiations towards conserved residues thereby facilitating the generation of cross-reactive immunity. In this study, we developed a sequential vaccination strategy that utilized epitope-decreasing antigens to reinforce the cross-reactivity of T and B cell immune responses against all four serotypes dengue virus. The epitope-decreasing immunization was implemented by sequentially inoculating mice with antigens of decreasing domain complexity that first immunized with DENV1 live-attenuated virus, following by the Envelope protein (Env), and then Env domain III (EDIII) subunit protein. When compared to mice immunized with DENV1 live-attenuated virus three times, epitope-decreasing immunization induced higher TNF-α CD8+ T cell immune response against consensus epitopes. Epitope-decreasing immunization also significantly improved neutralizing antibody response to heterologous serotypes. Moreover, this sequential approach promoted somatic hypermutations in the immunoglobulin gene of antigen-specific memory B cells in comparison to repeated immunization. This proof-of-concept work on epitope-decreasing sequential vaccination sheds light on how successively exposing the immune system to decreasing-epitope antigens can better induce cross-reactive antibodies.
Muscle Twitch Kinetics Are Dependent on Muscle Group, Disease State, and Age in Duchenne Muscular Dystrophy Mouse Models

Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by the lack of functional dystrophin protein. In muscular dystrophy preclinical research, it is pertinent to analyze the force of the muscles affected by the disease to assess pathology and potential effectiveness of therapeutic interventions. Although muscles function at sub-maximal levels in vivo, maximal tetanic contractions are most commonly used to assess and report muscle function in muscular dystrophy studies. At submaximal activation, the kinetics of contraction and relaxation are heavily impacted by the kinetics of the single twitch. However, maximal tetanic force is often the main, if not sole, outcome measured in most studies, while contractile kinetics are rarely reported. To investigate the effect of muscle disease on twitch contraction kinetics, isolated diaphragm and extensor digitorum longus (EDL) muscles of 10-, 20-week, “het” (dystrophin deficient and utrophin haplo-insufficient), and 52-week mdx (dystrophin deficient) mice were analyzed and compared to wild-type controls. We observed that twitch contractile kinetics are dependent on muscle type, age, and disease state. Specific findings include that diaphragm from wildtype mice has a greater time to 50% relaxation (RT50) than time to peak tension (TTP) compared to the het and mdx dystrophic models, where there is a similar TTP compared to RT50. Diaphragm twitch kinetics remain virtually unchanged with age, while the EDL from het and mdx mice initially has a greater RT50 than TTP, but the TTP increases with age. The difference between EDL contractile kinetics of dystrophic and wildtype mice is more prominent at young age. Differences in kinetics yielded greater statistical significance compared to previously published force measurements, thus, using kinetics as an outcome parameter could potentially allow for use of smaller experimental groups in future study designs. Although this study focused on DMD models, our findings may be applicable to other skeletal muscle conditions and diseases.
Circular RNA Involved in the Protective Effect of Malva sylvestris L. on Myocardial Ischemic/Re-Perfused Injury

Ischemic heart disease has become a major health challenge worldwide. Malva sylvestris L. (MS) is a traditional herbal medicine with anti-inflammatory properties and have been used as antioxidant and anti- inflammatory agent in infectious diseases and inflammatory diseases.In this study, we aimed at elucidating the mechanism of MS against ischemia-reperfusion (I/R)–induced injury in vivo and in vitro. The I/R animal model in rats and oxygen glucose deprivation/re-oxygenation (OGD/Re) model in H9c2 cells were used in this study. MS was used to pre-treat the rats and cells. Electrocardiogram, histology staining, qPCR, ELISA, CCK-8, and circRNA microarray were performed. We found that pre-treatment with MS extract attenuate OGD/Re-induced cell apoptosis and cell viability inhibition in H9c2 cells. In addition, pre-treatment with MS protected against I/R injury in vivo. The protective effects of MS pre-treatment were associated with inflammatory genes expression and cytokines release. Further mechanistic investigation revealed that MS protected cardiomyocytes through regulating circular RNA (circRNA). We identified a novel circRNA circ003593 that mediated the protective role of MS in vitro through NLRP3 complex, which was associated with reperfusion injury salvage kinase (RISK) signaling pathway. Conclusion: this study is the first time to demonstrate the protective role of MS on I/R injury. Our findings reveal a novel circRNA circ003593-mediated the protective role of MS through NLRP3 inflammasome. Circ003593 may serve as a potential therapeutic target for ischemic heart diseases.
Two-Target Quantitative PCR To Predict Library Composition for Shallow Shotgun Sequencing

When determining human microbiota composition, shotgun sequencing is a powerful tool that can generate large amounts of data. However, in sample compositions with low or variable microbial density, shallowing sequencing can negatively affect resulting data. ABSTRACT When determining human microbiota composition, shotgun sequencing is a powerful tool that can generate high-resolution taxonomic and functional information at once. However, the technique is limited by missing information about host-to-microbe ratios observed in different body compartments. This limitation makes it difficult to plan shotgun sequencing assays, especially in the context of high sample multiplexing and limited sequencing output and is of particular importance for studies employing the recently described shallow shotgun sequencing technique. In this study, we evaluated the use of a quantitative PCR (qPCR)-based assay to predict host-to-microbe ratio prior to sequencing. Combining a two-target assay involving the bacterial 16S rRNA gene and the human beta-actin gene, we derived a model to predict human-to-microbe ratios from two sample types, including stool samples and oropharyngeal swabs. We then validated it on two independently collected sample types, including rectal swabs and vaginal secretion samples. This assay enabled accurate prediction in the validation set in a range of sample compositions between 4% and 98% nonhuman reads and observed proportions varied between −18.8% and +19.2% from the expected values. We hope that this easy-to-use assay will help researchers to plan their shotgun sequencing experiments in a more efficient way. IMPORTANCE When determining human microbiota composition, shotgun sequencing is a powerful tool that can generate large amounts of data. However, in sample compositions with low or variable microbial density, shallowing sequencing can negatively affect microbial community metrics. Here, we show that variable sequencing depth decreases measured alpha diversity at differing rates based on community composition. We then derived a model that can determine sample composition prior to sequencing using quantitative PCR (qPCR) data and validated the model using a separate sample set. We have included a tool that uses this model to be available for researchers to use when gauging shallow sequencing viability of samples.
D1, not D2, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa

Levodopa is the Parkinson’s disease standard-of-care, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral “dopamine agonist” matches the efficacy of levodopa. Although there are consistent data in both primate models and in Parkinson’s disease showing that selective high intrinsic activity D1 agonists can equal levodopa, there are no data on whether such compounds would be effective in severe disease when levodopa efficacy is lower or even absent. We compared two approved antiparkinson drugs (levodopa and the D2/3 agonist bromocriptine) with the experimental selective D1 full agonist dihydrexidine in two severely parkinsonian MPTP-treated non-human primates. Bromocriptine caused no discernable improvement in parkinsonian signs, whereas levodopa caused a small transient improvement in one of the two subjects. Conversely, the full D1 agonist dihydrexidine caused a dramatic improvement in both subjects, decreasing parkinsonian signs by ca. 75%. No attenuation of dihydrexidine effects was observed when the two subjects were pretreated with the D2 antagonist remoxipride. These data provide evidence that selective D1 agonists may provide profound antiparkinson symptomatic relief even when the degree of nigrostriatal degeneration is so severe that current drugs are ineffective. Until effective disease-modifying therapies are discovered, high intrinsic activity D1 agonists may offer a major therapeutic advance in improving the quality of life, and potentially the longevity, of late stage Parkinson’s patients.
Ouabain Suppresses IL-6/STAT3 Signaling and Promotes Cytokine Secretion in Cultured Skeletal Muscle Cells

The cardiotonic steroids (CTS), such as ouabain and marinobufagenin, are thought to be adrenocortical hormones secreted during exercise and the stress response. The catalytic α-subunit of Na,K-ATPase (NKA) is a CTS receptor, whose largest pool is located in skeletal muscles, indicating that muscles are a major target for CTS. Skeletal muscles contribute to adaptations to exercise by secreting interleukin-6 (IL-6) and plethora of other cytokines, which exert paracrine and endocrine effects in muscles and non-muscle tissues. Here, we determined whether ouabain, a prototypical CTS, modulates IL-6 signaling and secretion in the cultured human skeletal muscle cells. Ouabain (2.5–50 nM) suppressed the abundance of STAT3, a key transcription factor downstream of the IL-6 receptor, as well as its basal and IL-6-stimulated phosphorylation. Conversely, ouabain (50 nM) increased the phosphorylation of ERK1/2, Akt, p70S6K, and S6 ribosomal protein, indicating activation of the ERK1/2 and the Akt-mTOR pathways. Proteasome inhibitor MG-132 blocked the ouabain-induced suppression of the total STAT3, but did not prevent the dephosphorylation of STAT3. Ouabain (50 nM) suppressed hypoxia-inducible factor-1α (HIF-1α), a modulator of STAT3 signaling, but gene silencing of HIF-1α and/or its partner protein HIF-1β did not mimic effects of ouabain on the phosphorylation of STAT3. Ouabain (50 nM) failed to suppress the phosphorylation of STAT3 and HIF-1α in rat L6 skeletal muscle cells, which express the ouabain-resistant α1-subunit of NKA. We also found that ouabain (100 nM) promoted the secretion of IL-6, IL-8, GM-CSF, and TNF-α from the skeletal muscle cells of healthy subjects, and the secretion of GM-CSF from cells of subjects with the type 2 diabetes. Marinobufagenin (10 nM), another important CTS, did not alter the secretion of these cytokines. In conclusion, our study shows that ouabain suppresses the IL-6 signaling via STAT3, but promotes the secretion of IL-6 and other cytokines, which might represent a negative feedback in the IL-6/STAT3 pathway. Collectively, our results implicate a role for CTS and NKA in regulation of the IL-6 signaling and secretion in skeletal muscle.
Emotional State During Tasting Affects Emotional Experience Differently and Robustly for Novel and Familiar Foods

Emotional state during food consumption is expected to affect food pleasantness. We hypothesize that a negative emotional state reduces food pleasantness and more so for novel foods than for familiar foods because novel foods have not yet been associated with previous emotions. Furthermore, we expect this effect to be stronger when judging the food again from memory without tasting. We induced a positive emotional state in 34 participants by telling them that they earned a monetary bonus and induced a negative emotional state in 35 other participants by subjecting them to a social stress test. After this emotion induction, both groups tasted and rated a (for them) novel soup (sumashi soup) and a familiar soup (vegetable soup). Several explicit and implicit measures of food pleasantness (rated valence, EsSense25, willingness-to-take-home and sip size) indicated that while the negative emotion group did not experience the soups as less pleasant than the positive emotion group, there was an interaction between food familiarity and emotional group. The positive emotion group experienced novel and familiar soups as equally pleasant, whereas the negative emotion group experienced the novel soup as relatively unpleasant and the familiar soup as pleasant. The latter result is consistent with a comforting effect of a familiar taste in a stressful situation. This effect remained in the ratings given 1 week later based on memory and even after retasting. Our results show that emotional state affects food pleasantness differently for novel and familiar foods and that such an effect can be robust.
Comparative Neurobiology of Biogenic Amines in Animal Models in Deuterostomes

We review the occurrence of biogenic amines and their potential role as neurotransmitters in the nervous system of three groups of invertebrate deuterostomes: tunicates, cephalochordates, and echinoderms. In addition to an overview of biogenic amines in each subphylum, we focus on a few species, including the sea squirts Ciona intestinalis, C. robusta, C. savignyi, and Phallusia mammillata (tunicates), the lancelets Branchiostoma lanceolatum and Branchiostoma floridae (cephalochordates), and the sea urchin Strongylocentrotus purpuratus (echinoderms). We chose these species as they are the most studied invertebrate deuterostomes in the field of evolutionary developmental biology (EvoDevo). Providing a comparative picture of the expression and role of neurotransmitters in deuterostomes will contribute to understanding the evolution of these neural signaling systems. Such an approach represents a new frontier of comparative neuroanatomy and neurobiology, and a prerequisite to uncover the homology of neuronal structures and circuits in deuterostomes with such diverse body plan organization and complexity.