Miracle-dz/UniFAR-FTUs huggingface dataset:
Bile Goes Viral

Laboratory cultivation of viruses is critical for determining requirements for viral replication, developing detection methods, identifying drug targets, and developing antivirals. Several viruses have a history of recalcitrance towards robust replication in laboratory cell lines, including human noroviruses and hepatitis B and C viruses. These viruses have tropism for tissue components of the enterohepatic circulation system: the intestine and liver, respectively. The purpose of this review is to discuss how key enterohepatic signaling molecules, bile acids (BAs), and BA receptors are involved in the replication of these viruses and how manipulation of these factors was useful in the development and/or optimization of culture systems for these viruses. BAs have replication-promoting activities through several key mechanisms: (1) affecting cellular uptake, membrane lipid composition, and endocytic acidification; (2) directly interacting with viral capsids to influence binding to cells; and (3) modulating the innate immune response. Additionally, expression of the Na+-taurocholate cotransporting polypeptide BA receptor in continuous liver cell lines is critical for hepatitis B virus entry and robust replication in laboratory culture. Viruses are capable of hijacking normal cellular functions, and understanding the role of BAs and BA receptors, components of the enterohepatic system, is valuable for expanding our knowledge on the mechanisms of norovirus and hepatitis B and C virus replication.
Restoration of Vitamin D Levels Improves Endothelial Function and Increases TASK-Like K+ Currents in Pulmonary Arterial Hypertension Associated with Vitamin D Deficiency

Background: Vitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We hypothesize that recovering optimal levels of vitD in an animal model of PAH previously depleted of vitD improves the hemodynamics, the endothelial dysfunction and the ionic remodeling. Methods: Male Wistar rats were fed a vitD-free diet for five weeks and then received a single dose of Su5416 (20 mg/Kg) and were exposed to vitD-free diet and chronic hypoxia (10% O2) for three weeks to induce PAH. Following this, vitD deficient rats with PAH were housed in room air and randomly divided into two groups: (a) continued on vitD-free diet or (b) received an oral dose of 100,000 IU/Kg of vitD plus standard diet for three weeks. Hemodynamics, pulmonary vascular remodeling, pulmonary arterial contractility, and K+ currents were analyzed. Results: Recovering optimal levels of vitD improved endothelial function, measured by an increase in the endothelium-dependent vasodilator response to acetylcholine. It also increased the activity of TASK-1 potassium channels. However, vitD supplementation did not reduce pulmonary pressure and did not ameliorate pulmonary vascular remodeling and right ventricle hypertrophy. Conclusions: Altogether, these data suggest that in animals with PAH and severe deficit of vitD, restoring vitD levels to an optimal range partially improves some pathophysiological features of PAH.
HA and HS Changes in Endothelial Inflammatory Activation

Cardiovascular diseases are a group of disorders caused by the presence of a combination of risk factors, such as tobacco use, unhealthy diet and obesity, physical inactivity, etc., which cause the modification of the composition of the vessel’s matrix and lead to the alteration of blood flow, matched with an inflammation condition. Nevertheless, it is not clear if the inflammation is a permissive condition or a consequent one. In order to investigate the effect of inflammation on the onset of vascular disease, we treated endothelial cells with the cytokine TNF-α that is increased in obese patients and is reported to induce cardiometabolic diseases. The inflammation induced a large change in the extracellular matrix, increasing the pericellular hyaluronan and altering the heparan sulfate Syndecans sets, which seems to be related to layer permeability but does not influence cell proliferation or migration nor induce blood cell recruitment or activation.
Predicting One-Year Deaths and Major Adverse Vascular Events with the Controlling Nutritional Status Score in Elderly Patients with Non–ST-Elevated Myocardial Infarction Undergoing Percutaneous Coronary Intervention

The prognostic value of malnutrition in elderly patients with non-ST-elevated myocardial infarction (NSTEMI) is not fully understood. Nutritional characteristics were evaluated by novel Controlling Nutritional status (CONUT), the prognostic nutritional index (PNI) and the geriatric nutritional risk index (GNRI) scores. The impact of these scores on major outcomes in 253 NSTEMI patients over 60 years and older were assessed. Compared to those with good nutritional status; malnourished patients had more major adverse cardiac and cerebrovascular events (MACCEs) at 1-year follow up. Multivariable cox regression analysis revealed that CONUT (hazard ratio = 1.372; p < 0.01) was independent predictor of MACCEs, whereas PNI (p = 0.44) and GNRI (p = 0.52) were not. The discriminating power of the CONUT (AUC: 0.79) was adequate and significantly superior to both the PNI (AUC: 0.68) and the GNRI (AUC: 0.60), with a p-value for both < 0.01. Patients with elevated CONUT exhibited the highest event rate for all-cause mortality and MACCEs in survival analysis (p < 0.01). We conclude that malnutrition is strongly associated with adverse outcomes in older patients with NSTEMI. In fact, the CONUT score adequately predicts one-year MACCEs among elderly NSTEMI patients who achieve complete revascularization after coronary intervention.
Evaluation of Floxuridine Oligonucleotide Conjugates Carrying Potential Enhancers of Cellular Uptake

Conjugation of small molecules such as lipids or receptor ligands to anti-cancer drugs has been used to improve their pharmacological properties. In this work, we studied the biological effects of several small-molecule enhancers into a short oligonucleotide made of five floxuridine units. Specifically, we studied adding cholesterol, palmitic acid, polyethyleneglycol (PEG 1000), folic acid and triantennary N-acetylgalactosamine (GalNAc) as potential enhancers of cellular uptake. As expected, all these molecules increased the internalization efficiency with different degrees depending on the cell line. The conjugates showed antiproliferative activity due to their metabolic activation by nuclease degradation generating floxuridine monophosphate. The cytotoxicity and apoptosis assays showed an increase in the anti-cancer activity of the conjugates related to the floxuridine oligomer, but this effect did not correlate with the internalization results. Palmitic and folic acid conjugates provide the highest antiproliferative activity without having the highest internalization results. On the contrary, cholesterol oligomers that were the best-internalized oligomers had poor antiproliferative activity, even worse than the unmodified floxuridine oligomer. Especially relevant is the effect induced by palmitic and folic acid derivatives generating the most active drugs. These results are of special interest for delivering other therapeutic oligonucleotides.
Electrocardiographic Versus Echocardiographic Left Ventricular Hypertrophy in Severe Aortic Stenosis

Although ECG used to be a traditional method to detect left ventricular hypertrophy (LVH), its importance has decreased over the years and echocardiography has emerged as a routine technique to diagnose LVH. Intriguingly, an independent negative prognostic effect of the “electrical” LVH (i.e., by ECG voltage criteria) beyond echocardiographic LVH was demonstrated both in hypertension and aortic stenosis (AS), the most prevalent heart valve disorder. Our aim was to estimate associations of the ECG-LVH voltage criteria with echocardiographic LVH and indices of AS severity. We retrospectively manually analyzed ECG tracings of 50 patients hospitalized in our center for severe isolated aortic stenosis, including 32 subjects with echocardiographic LVH. The sensitivity of single traditional ECG-LVH criteria in detecting echocardiographic LVH was 9–34% and their respective specificity averaged 78–100%. The ability to predict echocardiographic LVH was higher for S-waves than R-waves (mean area under the receiver operating curve (AUC): 0.62–0.70 vs. 0.58–0.65). Among combinations of R- and S-waves, the discriminating ability was highest for the Cornell voltage (AUC: 0.71) compared to the Sokolow–Lyon, Romhilt and Gubner–Ungerleider voltage (AUC: 0.62–0.68). By multiple regression, peak aortic pressure gradient was positively related to the Sokolow–Lyon (β = 1.7 ± 0.5, p = 0.002) and Romhilt voltage (β = 1.3 ± 0.5, p = 0.01), but not Cornell (0.5 ± 0.3, p = 0.2) or Gubner-Ungerleider voltage (β = 0.0 ± 0.5, p > 0.9), regardless of LV mass index. In conclusion, echocardiographic LVH and stenosis severity appear to have distinct associations with traditional ECG-LVH criteria in AS. A moderate diagnostic superiority of the Cornell voltage criterion with regard to anatomic LVH might result from its unique ability to include depolarization vectors in both the frontal and horizontal plane with consequent lesser sensitivity to the confounding effect of obesity.
Human Milk Concentrations of Minerals, Essential and Toxic Trace Elements and Association with Selective Medical, Social, Demographic and Environmental Factors

This study aims to quantify concentrations of minerals and trace elements in human milk (HM) and infant formula (IF) and evaluate associations with medical, social, environmental, and demographic variables. A prospective, case series study of 170 nursing mothers was made. HM samples were obtained from full-term (colostrum, intermediate and mature HM) and preterm (mature HM) mothers. Variables of interest were assessed by a questionnaire. For comparison, IF samples (n = 30) were analyzed in a cross-sectional study. Concentrations of 35 minerals, essential and toxic trace elements were quantified, 5 for the first time: thallium in HM and IF; strontium in preterm HM; and gallium, lithium and uranium in IF. In preterm and full-term HM, levels of selenium (p < 0.001) were significantly lower than recommended and were associated with low birth weight (p < 0.002). Cesium and strontium concentrations were significantly higher than recommended (p < 0.001). Associations were observed between arsenic and residence in an urban area (p = 0.013), and between lead and smoking (p = 0.024) and well-water consumption (p = 0.046). In IF, aluminum, vanadium, and uranium levels were higher than in HM (p < 0.001); uranium, quantified for the first time, was 100 times higher in all types of IF than in HM. Our results indicate that concentrations of most trace elements were within internationally accepted ranges for HM and IF. However, preterm infants are at increased risk of nutritional deficiencies and toxicity. IF manufacturers should reduce the content of toxic trace elements.
Genetic Diversity, Linkage Disequilibrium and Population Structure of Bulgarian Bread Wheat Assessed by Genome-Wide Distributed SNP Markers: From Old Germplasm to Semi-Dwarf Cultivars

Genetic diversity and population structure are key resources for breeding purposes and genetic studies of important agronomic traits in crops. In this study, we described SNP-based genetic diversity, linkage disequilibrium and population structure in a panel of 179 bread wheat advanced cultivars and old accessions from Bulgaria, using an optimized wheat 25K Infinium iSelect array. Out of 19,019 polymorphic SNPs, 17,968 had a known chromosome position on the A (41%), B (42%) and D (11%) genome, and 6% were not assigned to any chromosome. Homoeologous group 4, in particular chromosome 4D, was the least polymorphic. In the total population, the Nei’s gene diversity was within the range 0.1–0.5, and the polymorphism information content ranged from 0.1 to 0.4. Significant differences between the old and modern collections were revealed with respect to the linkage disequilibrium (LD): the average values for LD (r2), the percentage of the locus pairs in LD and the LD decay were 0.64, 16% and 3.3 for the old germplasm, and 0.43, 30% and 4.1 for the modern releases, respectively. Structure and k-means clustering algorithm divided the panel into three groups. The old accessions formed a distinct subpopulation. The cluster analysis further distinguished the modern releases according to the geographic region and genealogy. Gene exchange was evidenced mainly between the subpopulations of contemporary cultivars. The achieved understanding of the genetic diversity and structure of the Bulgarian wheat population and distinctiveness of the old germplasm could be of interest for breeders developing cultivars with improved characteristics. The obtained knowledge about SNP informativeness and the LD estimation are worthwhile for selecting markers and for considering the composition of a population in association mapping studies of traits of interest.
Brain Structure and Functional Connectivity Correlate with Psychosocial Development in Contemplative Practitioners and Controls

Jane Loevinger’s theory of adult development, termed ego development (1966) and more recently maturity development, provides a useful framework for understanding the development of the self throughout the lifespan. However, few studies have investigated its neural correlates. In the present study, we use structural and functional magnetic resonance imaging (MRI) to investigate the neural correlates of maturity development in contemplative practitioners and controls. Since traits possessed by individuals with higher levels of maturity development are similar to those attributed to individuals at advanced stages of contemplative practice, we chose to investigate levels of maturity development in meditation practitioners as well as matched controls. We used the Maturity Assessment Profile (MAP) to measure maturity development in a mixed sample of participants composed of 14 long-term meditators, 16 long-term yoga practitioners, and 16 demographically matched controls. We investigated the relationship between contemplative practice and maturity development with behavioral, seed-based resting state functional connectivity, and cortical thickness analyses. The results of this study indicate that contemplative practitioners possess higher maturity development compared to a matched control group, and in addition, maturity development correlates with cortical thickness in the posterior cingulate. Furthermore, we identify a brain network implicated in theory of mind, narrative, and self-referential processing, comprising the posterior cingulate cortex, dorsomedial prefrontal cortex, temporoparietal junction, and inferior frontal cortex, as a primary neural correlate.
Bioprocessing of Marine Chitinous Wastes for the Production of Bioactive Prodigiosin

Recently, microbial prodigiosin (PG) has received much attention due to its numerous beneficial applications. The aim of this study was to establish the bioprocessing of marine chitinous wastes (MCWs) for the cost-effective preparation of PG. Of the MCWs, demineralized shrimp shell powders (de-SSP) were found to be a potential source of carbon/nitrogen (C/N) for PG production by bacterial fermentation using Serratia marcescens strains. Further, PG scale-up production was investigated in a 15 L bioreactor system, and the highest yield (6200 mg/L) was achieved during fermentation using 5 L of a novel-designed culture broth that included 1.60% C/N sources (a de-SSP/casein ratio of 7/3), 0.02% K2SO4, and 0.05% K2HPO4, with an initial pH of 6–7. Fermentation was conducted in the dark at 27.5 °C for 8.0 h. This study was the first to report on the utilization of shrimp wastes for cost-effective, large-scale (5 L/pilot) PG production with high productivity (6200 mg/L) in a short cultivation time. The combination of 0.02% K2SO4 and 0.05% K2HPO4 was also found to be a novel salt composition that significantly enhanced PG yield. The red compound was purified and confirmed as PG after analyzing its HPLC profile, mass, and UV/vis spectra. The purified PG was then tested for its bioactivities and showed effective anticancer activities, moderated antioxidant activities, and novel anti-NO effects.
Pleiotropic Effects of Isoflavones in Inflammation and Chronic Degenerative Diseases

Isoflavones are phytoestrogens of plant origin, mostly found in the members of the Fabaceae family, that exert beneficial effects in various degenerative disorders. Having high similarity to 17-β-estradiol, isoflavones can bind estrogen receptors, scavenge reactive oxygen species, activate various cellular signal transduction pathways and modulate growth and transcription factors, activities of enzymes, cytokines, and genes regulating cell proliferation and apoptosis. Due to their pleiotropic activities isoflavones might be considered as a natural alternative for the treatment of estrogen decrease-related conditions during menopause. This review will focus on the effects of isoflavones on inflammation and chronic degenerative diseases including cancer, metabolic, cardiovascular, neurodegenerative diseases, rheumatoid arthritis and adverse postmenopausal symptoms.
Neurotrophins as Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis

Neurotrophins constitute a family of growth factors initially characterized as predominant mediators of nervous system development, neuronal survival, regeneration and plasticity. Their biological activity is promoted by the binding of two different types of receptors, leading to the generation of multiple and variegated signaling cascades in the target cells. Increasing evidence indicates that neurotrophins are also emerging as crucial regulators of metabolic processes in both neuronal and non-neuronal cells. In this context, it has been reported that neurotrophins affect redox balance, autophagy, glucose homeostasis and energy expenditure. Additionally, the trophic support provided by these secreted factors may involve the regulation of cholesterol metabolism. In this review, we examine the neurotrophins’ signaling pathways and their effects on metabolism by critically discussing the most up-to-date information. In particular, we gather experimental evidence demonstrating the impact of these growth factors on cholesterol metabolism.
Effect of Metal Lathe Waste Addition on the Mechanical and Thermal Properties of Concrete

The amount of steel chips generated by lathes and CNC machines is 1200 million tons per year, and they are difficult to recycle. The effect of adding steel chips without pre-cleaning (covered with production lubricants and cooling oils) on the properties of concrete was investigated. Steel waste was added as a replacement for fine aggregate in the amounts of 5%, 10% and 15% of the cement weight, which correspond with 1.1%, 2.2% and 3.3% mass of all ingredients and 0.33%, 0.66% and 0.99% volume of concrete mix, respectively. The slump cone, air content, pH value, density, compressive strength, tensile strength, tensile splitting strength, elastic modulus, Poisson’s ratio and thermal parameters were tested. It was observed that with the addition of lathe waste, the density decreased, but mechanical properties increased. With the addition of 5%, 10% and 15% metal chips, compressive strength increased by 13.9%, 20.8% and 36.3% respectively compared to plain concrete; flexural strength by 7.1%, 12.7% and 18.2%; and tensile splitting strength by 4.2%, 33.2% and 38.4%. Moreover, it was determined that with addition of steel chips, thermal diffusivity was reduced and specific heat capacity increased. With the addition of 15% metal chips, thermal diffusivity was 25.2% lower than in the reference sample, while specific heat was 23.0% higher. No effect was observed on thermal conductivity.
How Neural Crest Transcription Factors Contribute to Melanoma Heterogeneity, Cellular Plasticity, and Treatment Resistance

Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.
Influence of the Passive Stabilization of the Trunk and Upper Limb on Selected Parameters of the Hand Motor Coordination, Grip Strength and Muscle Tension, in Post-Stroke Patients

Objective: Assessment of the influence of a stable trunk and the affected upper limb (dominant or non-dominant) on the parameters of the wrist and hand motor coordination, grip strength and muscle tension in patients in the subacute post-stroke stage compared to healthy subjects. Design: An observational study. Setting: Stroke Rehabilitation Department. Subjects: Thirty-four subjects after ischemic cerebral stroke and control group-32 subjects without neurological deficits, age and body mass/ height matched were included. Main measures: The tone of the multifidus, transverse abdominal and supraspinatus muscles were assessed by Luna EMG device. A HandTutor device were used to measure motor coordination parameters (e.g., range of movement, frequency of movement), and a manual dynamometer for measuring the strength of a hand grip. Subjects were examined in two positions: sitting without back support (non-stabilized) and lying with stabilization of the trunk and the upper limb. Results: Passive stabilization of the trunk and the upper extremity caused a significant improvement in motor coordination of the fingers (p ˂ 0.001) and the wrist (p < 0.001) in patients after stroke. Improved motor coordination of the upper extremity was associated with an increased tone of the supraspinatus muscle. Conclusions: Passive stabilization of the trunk and the upper limb improved the hand and wrist coordination in patients following a stroke. Placing patients in a supine position with the stability of the affected upper limb during rehabilitation exercises may help them to access latent movement patterns lost due to neurological impairment after a stroke.