Miracle-dz/UniFAR-FTUs huggingface dataset:
miR-26b inhibits isoproterenol-induced cardiac fibrosis via the Keap1/Nrf2 signaling pathway

A critical event in cardiac fibrosis is the transformation of cardiac fibroblasts (CFs) into myofibroblasts. MicroRNAs (miRNAs) have been reported to be critical regulators in the development of cardiac fibrosis. However, the underlying molecular mechanisms of action of miRNA (miR)-26b in cardiac fibrosis have not yet been extensively studied. In the present study, the expression levels of miR-26b were downregulated in isoproterenol (ISO)-treated cardiac tissues and CFs. Moreover, miR-26b overexpression inhibited the cell viability of ISO-treated CFs and decreased the protein levels of collagen I and α-smooth muscle actin (α-SMA). Furthermore, bioinformatics analysis and dual luciferase reporter assays indicated that Kelch-like ECH-associated protein 1 (Keap1) was the target of miR-26b, and that its expression levels were decreased in miR-26b-treated cells. In addition, Keap1 overexpression reversed the inhibitory effects of miR-26b on ISO-induced cardiac fibrosis, as demonstrated by cell viability, and the upregulation of collagen I and α-SMA expression levels. Furthermore, inhibition of Keap1 expression led to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which induced the transcriptional activation of antioxidant/detoxifying proteins in order to protect against cardiac fibrosis. Taken together, the data demonstrated that miR-26b attenuated ISO-induced cardiac fibrosis via the Keap-mediated activation of Nrf2.
Conducting a Cost-Benefit Analysis of Transitional Care Programmes: The Key Challenges and Recommendations

Transitional care encompasses a range of services designed to promote care integration as patients transfer between different locations or different levels of care. Transitional care programmes have been proven to produce positive outcomes in reducing hospital readmissions and improving patients’ health outcomes. However, little is known about the benefits of the programmes on healthcare cost and the published results have been inconsistent. With increasing healthcare expenditures and limited public healthcare resources, cost-benefit analyses become paramount in informing healthcare resource allocation decisions. This perspective paper describes the approaches used in estimating the total costs of a bundle of transitional care services from an academic medical centre, identifies the key methodological challenges encountered in the process of cost-benefit analysis, and recommends potential solutions to tackle these challenges. By providing a comprehensive perspective on the methodological challenges, this paper encourages program evaluators to take these possible challenges into consideration for future cost-benefit analyses.
Efflux Pumps Contribute to Intrinsic Clarithromycin Resistance in Clinical, Mycobacterium abscessus Isolates

Purpose The emergence of clarithromycin resistance is a challenge in treating Mycobacterium abscessus infections. Known mechanisms that contribute to intrinsic clarithromycin resistance focus on rrl gene-related mutations, but resistant clinical isolates often exhibit an inconsistent rrl genotype. Patients and Methods In this study, 194 clinical Mycobacterium abscessus isolates were collected from patients with lung infections and the whole genome of each isolate was sequenced. A comprehensive examination of the molecular mechanisms underlying intrinsic clarithromycin resistance was performed, combining MIC determination, comparative genome sequence analysis and qRT-PCR. Results Of the 194 isolates, 13 (6.7%) were clarithromycin resistant; only seven of these harbored a rrl 2270/2271 mutation. The remaining six resistant isolates did not exhibit a specific resistance-associated mutation in the clarithromycin target-site genes, rrl, rplC, rplD and rplV, or in the rrl modification gene erm(41). qRT-PCR analysis showed that the increased expression of the efflux pump genes, MAB_2355c, MAB_1409c and MAB_1846, as well as their positive regulatory gene whiB7, consistently correlated with increased clarithromycin resistance. The presence of efflux pump inhibitors significantly decreased the MIC of clarithromycin for nonsusceptible isolates, especially the intrinsic resistant isolates that exhibited no rrl 2270/2271 mutation. Conclusion These findings indicate that efflux pumps play a prominent role in the intrinsic resistance of M. abscessus to clarithromycin, complementing other known resistance mechanisms.
Cardiomyocyte Calcium Ion Oscillations—Lessons From Physics

We review a theoretical, coarse-grained description for cardiomyocytes calcium dynamics that is motivated by experiments on RyR channel dynamics and provides an analogy to other spontaneously oscillating systems. We show how a minimal model, that focuses on calcium channel and pump dynamics and kinetics, results in a single, easily understood equation for spontaneous calcium oscillations (the Van-der-Pol equation). We analyze experiments on isolated RyR channels to quantify how the channel dynamics depends both on the local calcium concentration, as well as its temporal behavior (“adaptation”). Our oscillator model analytically predicts the conditions for spontaneous oscillations, their frequency and amplitude, and how each of those scale with the small number of relevant parameters related to calcium channel and pump activity. The minimal model is easily extended to include the effects of noise and external pacing (electrical or mechanical). We show how our simple oscillator predicts and explains the experimental observations of synchronization, “bursting” and reduction of apparent noise in the beating dynamics of paced cells. Thus, our analogy and theoretical approach provides robust predictions for the beating dynamics, and their biochemical and mechanical modulation.
A Review of the Anti-Inflammatory Effects of Rosmarinic Acid on Inflammatory Diseases

Inflammatory diseases are caused by abnormal immune responses and are characterized by an imbalance of inflammatory mediators and cells. In recent years, the anti-inflammatory activity of natural products has attracted wide attention. Rosmarinic acid (RosA) is a water-soluble phenolic compound that is an ester of caffeic acid and 3, 4-dihydroxyphenyl lactic acid. It is discovered in many plants, like those of the Boraginaceae and Lamiaceae families. RosA has a wide range of pharmacological effects, including anti-oxidative, anti-apoptotic, anti-tumorigenic, and anti-inflammatory effects. The anti-inflammatory effects of RosA have been revealed through in vitro and in vivo studies of various inflammatory diseases like arthritis, colitis, and atopic dermatitis. This article mainly describes the preclinical research of RosA on inflammatory diseases and depicts a small amount of clinical research data. The purpose of this review is to discuss the anti-inflammatory effects of RosA in inflammatory diseases and its underlying mechanism.
Nordihydroguaiaretic Acid: From Herbal Medicine to Clinical Development for Cancer and Chronic Diseases

Nordihydroguaiaretic acid (NDGA) is a phenolic lignan obtained from Larrea tridentata, the creosote bush found in Mexico and USA deserts, that has been used in traditional medicine for the treatment of numerous diseases such as cancer, renal, cardiovascular, immunological, and neurological disorders, and even aging. NDGA presents two catechol rings that confer a very potent antioxidant activity by scavenging oxygen free radicals and this may explain part of its therapeutic action. Additional effects include inhibition of lipoxygenases (LOXs) and activation of signaling pathways that impinge on the transcription factor Nuclear Factor Erythroid 2-related Factor (NRF2). On the other hand, the oxidation of the catechols to the corresponding quinones my elicit alterations in proteins and DNA that raise safety concerns. This review describes the current knowledge on NDGA, its targets and side effects, and its synthetic analogs as promising therapeutic agents, highlighting their mechanism of action and clinical projection towards therapy of neurodegenerative, liver, and kidney disease, as well as cancer.
Dynamic Modeling and Simulation of a Body Weight Support System

This paper proposes a body weight support (BWS) system with a series elastic actuator (SEA) to facilitate walking assistance and motor relearning during gait rehabilitation. This system comprises the following: a mobile platform that ensures movement of the system on the ground, a BWS mechanism with an SEA that is capable of providing the desired unloading force, and a pelvic brace to smooth the pelvis motions. The control of the body weight support is realized by an active weight-offload method, and a dynamic model of the BWS system with offload mass of a human is conducted to simulate the control process and optimize the parameters. Preliminary results demonstrate that the BWS system can provide the desired support force and vertical motion of the pelvis.
Binding Options for the Small Subunit-Like Domain of Cyanobacteria to Rubisco

Two proteins found in cyanobacteria contain a C-terminal domain with homology to the small subunit of rubisco (RbcS). These small subunit-like domains (SSLDs) are important features of CcmM, a protein involved in the biogenesis of carboxysomes found in all β-cyanobacteria, and a rubisco activase homolog [activase-like protein of cyanobacteria (ALC)] found in over a third of sequenced cyanobacterial genomes. Interaction with rubisco is crucial to the function of CcmM and is believed to be important to ALC as well. In both cases, the SSLD aggregates rubisco, and this nucleation event may be important in regulating rubisco assembly and activity. Recently, two independent studies supported the conclusion that the SSLD of CcmM binds equatorially to L8S8 holoenzymes of rubisco rather than by displacing an RbcS, as its structural homology would suggest. We use sequence analysis and homology modeling to examine whether the SSLD from the ALC could bind the large subunit of rubisco either via an equatorial interaction or in an RbcS site, if available. We suggest that the SSLD from the ALC of Fremyella diplosiphon could bind either in a vacant RbcS site or equatorially. Our homology modeling takes into account N-terminal residues not represented in available cryo-electron microscopy structures that potentially contribute to the interface between the large subunit of rubisco (RbcL) and RbcS. Here, we suggest the perspective that binding site variability as a means of regulation is plausible and that the dynamic interaction between the RbcL, RbcS, and SSLDs may be important for carboxysome assembly and function.
Extending Burk Dehority’s Perspectives on the Role of Ciliate Protozoa in the Rumen

Dr. Burk Dehority was an international expert on the classification and monoculture of ruminal ciliated protozoa. We have summarized many of the advancements in knowledge from his work but also in his scientific way of thinking about interactions of ruminal ciliates with the entire rumen microbial community and animal host. As a dedication to his legacy, an electronic library of high-resolution images and video footage catalogs numerous species and techniques involved in taxonomy, isolation, culture, and ecological assessment of ruminal ciliate species and communities. Considerable promise remains to adapt these landmark approaches to harness eukaryotic cell signaling technology with genomics and transcriptomics to assess cellular mechanisms regulating growth and responsiveness to ruminal environmental conditions. These technologies can be adapted to study how protozoa interact (both antagonism and mutualism) within the entire ruminal microbiota. Thus, advancements and limitations in approaches used are highlighted such that future research questions can be posed to study rumen protozoal contribution to ruminant nutrition and productivity.
Quantitative and Dynamic MRI Measures of Peripheral Vascular Function

The endothelium regulates and mediates vascular homeostasis, allowing for dynamic changes of blood flow in response to mechanical and chemical stimuli. Endothelial dysfunction underlies many diseases and is purported to be the earliest pathologic change in the progression of atherosclerotic disease. Peripheral vascular function can be interrogated by measuring the response kinetics following induced ischemia or exercise. In the presence of endothelial dysfunction, there is a blunting and delay of the hyperemic response, which can be measured non-invasively using a variety of quantitative magnetic resonance imaging (MRI) methods. In this review, we summarize recent developments in non-contrast, proton MRI for dynamic quantification of blood flow and oxygenation. Methodologic description is provided for: blood oxygenation-level dependent (BOLD) signal that reflect combined effect of blood flow and capillary bed oxygen content; arterial spin labeling (ASL) for quantification of regional perfusion; phase contrast (PC) to quantify arterial flow waveforms and macrovascular blood flow velocity and rate; high-resolution MRI for luminal flow-mediated dilation; and dynamic MR oximetry to quantify oxygen saturation. Overall, results suggest that these dynamic and quantitative MRI methods can detect endothelial dysfunction both in the presence of overt cardiovascular disease (such as in patients with peripheral artery disease), as well as in sub-clinical settings (i.e., in chronic smokers, non-smokers exposed to e-cigarette aerosol, and as a function of age). Thus far, these tools have been relegated to the realm of research, used as biomarkers of disease progression and therapeutic response. With proper validation, MRI-measures of vascular function may ultimately be used to complement the standard clinical workup, providing additional insight into the optimal treatment strategy and evaluation of treatment efficacy.
Methods for Monitoring for the Population Consequences of Disturbance in Marine Mammals: A Review

Assessing the non-lethal effects of disturbance and their population-level consequences is a significant ecological and conservation challenge, because it requires extensive baseline knowledge of behavioral patterns, life-history and demography. However, for many marine mammal populations, this knowledge is currently lacking and it may take decades to fill the gaps. During this time, undetected population declines may occur. In this study we identify methods that can be used to monitor populations subject to disturbance and provide insights into the processes through which disturbance may affect them. To identify and address the knowledge gaps highlighted above, we reviewed the literature to identify suitable response variables and methods for monitoring these variables. We also used existing models of the population consequences of disturbance (PCoD) to identify demographic characteristics (e.g., the proportion of immature animals in the population, or the ratio of calves/pups to mature females) that may be strongly correlated with population status and therefore provide early warnings of future changes in abundance. These demographic characteristics can be monitored using established methods such as visual surveys combined with photogrammetry, and capture-recapture analysis. Individual health and physiological variables can also inform PCoD assessment and can be monitored using photogrammetry, remote tissue sampling, hands-on assessment and individual tracking. We then conducted a workshop to establish the relative utility and feasibility of all these approaches for different groups of marine mammal species. We describe how future marine mammal monitoring programs can be designed to inform population-level analysis.
Effects of in ovo Inoculation of Multi-Strain Lactobacilli on Cytokine Gene Expression and Antibody-Mediated Immune Responses in Chickens

This study was conducted to investigate the effects of various doses of a multi-strain lactobacilli mixture (Lactobacillus salivarius, Lactobacillus reuteri, Lactobacillus crispatus, and Lactobacillus johnsonii) on the innate and adaptive immune responses in broiler chickens. At embryonic day eighteen, 200 eggs were injected with PBS, or three different doses of a multi-strain lactobacilli mixture (1 × 105, 1 × 106, and 1 × 107 CFU/egg, P1, P2, and P3 respectively) along with a group of negative control. On days 5 and 10 post-hatch, cecal tonsil, bursa of fabricius, and spleen were collected for gene expression and cellular analysis. On days 14 and 21 post-hatch, birds were immunized intramuscularly with both sheep red blood cells (SRBC) and keyhole limpet hemocyanin (KLH). Serum samples were collected on days 0, 7, 14, and 21 after primary immunization. The results demonstrated that lactobacilli inoculation increased the splenic expression of cytokines, including interferon (IFN)-α, IFN-β, IFN-γ, interleukin (IL)-8, and IL-12 on day 5 post-hatch compared to the control group (PBS). However, in cecal tonsils, lactobacilli treatment downregulated the expression of IL-6 on day 5 post-hatch and IL-2 and IL-8 on day 10 post-hatch. No significant differences were observed in the expression of cytokine genes in the bursa except for IL-13 which was upregulated in lactobacilli-treated groups P2 and P3 on days 5 and 10 post-hatch. Flow cytometry analysis showed that the percentage of KUL01, CD4+ and CD8+ splenocytes was not affected by treatments. In addition, no significant differences were observed for antibody titers against SRBC. However, lactobacilli treatment (P1, P2, and P3) was found to increase IgM titers on day 21 post-primary immunization compared to controls. Furthermore, in ovo injection of the highest dose of probiotics (1 × 107, P3) increased serum IgG titers against KLH on day 7 post-primary immunization. In conclusion, this study demonstrated that that in ovo administration of lactobacilli can improve antibody-mediated immune responses and differentially modulate cytokine expression in mucosal and systemic lymphoid tissues of chickens.
Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation

The hERG (human-ether-à-go-go-related gene) channel underlies the rapid delayed rectifier current, Ikr, in the heart, which is essential for normal cardiac electrical activity and rhythm. Slow deactivation is one of the hallmark features of the unusual gating characteristics of hERG channels, and plays a crucial role in providing a robust current that aids repolarization of the cardiac action potential. As such, there is significant interest in elucidating the underlying mechanistic determinants of slow hERG channel deactivation. Recent work has shown that the hERG channel S4 voltage sensor is stabilized following activation in a process termed relaxation. Voltage sensor relaxation results in energetic separation of the activation and deactivation pathways, producing a hysteresis, which modulates the kinetics of deactivation gating. Despite widespread observation of relaxation behaviour in other voltage-gated K+ channels, such as Shaker, Kv1.2 and Kv3.1, as well as the voltage-sensing phosphatase Ci-VSP, the relationship between stabilization of the activated voltage sensor by the open pore and voltage sensor relaxation in the control of deactivation has only recently begun to be explored. In this review, we discuss present knowledge and questions raised related to the voltage sensor relaxation mechanism in hERG channels and compare structure-function aspects of relaxation with those observed in related ion channels. We focus discussion, in particular, on the mechanism of coupling between voltage sensor relaxation and deactivation gating to highlight the insight that these studies provide into the control of hERG channel deactivation gating during their physiological functioning.
Biotransformation of Phthalate Plasticizers and Bisphenol A by Marine-Derived, Freshwater, and Terrestrial Fungi

Phthalate esters (PEs, Phthalates) are environmentally ubiquitous as a result of their extensive use as plasticizers and additives in diverse consumer products. Considerable concern relates to their reported xenoestrogenicity and consequently, microbial-based attenuation of environmental PE concentrations is of interest to combat harmful downstream effects. Fungal PE catabolism has received less attention than that by bacteria, and particularly fungi dwelling within aquatic environments remain largely overlooked in this respect. We have compared the biocatalytic and biosorptive removal rates of di-n-butyl phthalate (DBP) and diethyl phthalate (DEP), chosen to represent two environmentally prominent PEs of differing structure and hydrophobicity, by marine-, freshwater-, and terrestrial-derived fungal strains. Bisphenol A, both an extensively used plastic additive and prominent environmental xenoestrogen, was included as a reference compound due to its well-documented fungal degradation. Partial pathways of DBP metabolization by the ecophysiologically diverse asco- and basidiomycete strains tested were proposed with the help of UPLC-QTOF-MS analysis. Species specific biochemical reaction steps contributing to DBP metabolism were also observed. The involved reactions include initial cytochrome P450-dependent monohydroxylations of DBP with subsequent further oxidation of related metabolites, de-esterification via either hydrolytic cleavage or cytochrome P450-dependent oxidative O-dealkylation, transesterification, and demethylation steps - finally yielding phthalic acid as a central intermediate in all pathways. Due to the involvement of ecophysiologically and phylogenetically diverse filamentous and yeast-like fungi native to marine, freshwater, and terrestrial habitats the results of this study outline an environmentally ubiquitous pathway for the biocatalytic breakdown of plastic additives. Beyond previous research into fungal PE metabolism which emphasizes hydrolytic de-esterification as the primary catabolic step, a prominent role of cytochrome P450 monooxygenase-catalyzed reactions is established.
Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development

About 20% of total cancer cases are associated to infections. To date, seven human viruses have been directly linked to cancer development: high-risk human papillomaviruses (hrHPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and human T-lymphotropic virus 1 (HTLV-1). These viruses impact on several molecular mechanisms in the host cells, often resulting in chronic inflammation, uncontrolled proliferation, and cell death inhibition, and mechanisms, which favor viral life cycle but may indirectly promote tumorigenesis. Recently, the ability of oncogenic viruses to alter autophagy, a catabolic process activated during the innate immune response to infections, is emerging as a key event for the onset of human cancers. Here, we summarize the current understanding of the molecular mechanisms by which human oncogenic viruses regulate autophagy and how this negative regulation impacts on cancer development. Finally, we highlight novel autophagy-related candidates for the treatment of virus-related cancers.