Miracle-dz/UniFAR-FTUs huggingface dataset:
Fenofibrate Decreases Hepatic P-Glycoprotein in a Rat Model of Hereditary Hypertriglyceridemia

P-glycoprotein (P-gp) is a membrane-bound transporter encoded by Mdr1a/Abcb1a and Mdr1b/Abcb1b genes in rodents involved in the efflux of cytotoxic chemicals and metabolites from cells. Modulation of its activity influences P-gp-mediated drug delivery and drug-drug interaction (DDI). In the current study, we tested the effects of fenofibrate on P-gp mRNA and protein content in non-obese model of metabolic syndrome. Males hereditary hypertriglyceridemic rats (HHTg) were fed standard laboratory diet (STD) (Controls) supplemented with micronized fenofibrate in lower (25 mg/kg b. wt./day) or in higher (100 mg/kg b. wt./day) dose for 4 weeks. Liver was used for the subsequent mRNA and protein content analysis. Fenofibrate in lower dose decreased hepatic Mdr1a by 75% and Mdr1b by 85%, while fenofibrate in higher dose decreased Mdr1a by 90% and Mdr1b by 92%. P-gp protein content in the liver was decreased by 74% in rat treated with fenofibrate at lower dose and by 88% in rats using fenofibrate at higher dose. These findings demonstrate for the first time that fenofibrate decreases both mRNA and protein amount of P-gp and suggest that fenofibrate could affect bioavailability and interaction of drugs used to treat dyslipidemia-induced metabolic disorders.
Prognostic Value of CD44 and Its Isoforms in Advanced Cancer: A Systematic Meta-Analysis With Trial Sequential Analysis

Objective: Cancer stem cell marker CD44 and its variant isoforms (CD44v) may be correlated with tumor growth, metastasis, and chemo-radiotherapy resistance. However, the prognostic power of CD44 and CD44v in advanced cancer remains controversial. Therefore, the purpose of our study was to generalize the prognostic significance of these cancer stem cell markers in advanced cancer patients. Methods: Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated from multivariable analysis to assess the associations among CD44, CD44v6, and CD44v9 positivity and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), and recurrence-free survival (RFS). Trial sequential analysis (TSA) was also conducted. Results: We included 15 articles that reported on 1,201 patients with advanced cancer (CD44: nine studies with 796 cases, CD44v6: three studies with 143 cases, and CD44v9: three studies with 262 cases). CD44 expression was slightly linked to worse OS (HR = 2.03, P = 0.027), but there was no correlation between CD44 expression and DFS, RFS, or PFS. Stratified analysis showed that CD44 expression was not correlated with OS at ≥5 years or OS in patients receiving adjuvant therapy. CD44v6 expression was not associated with OS. CD44v9 expression was closely associated with poor 5-years CSS in patients treated with chemo/radiotherapy (HR = 3.62, P < 0.001). However, TSA suggested that additional trials were needed to confirm these conclusions. Conclusions: CD44 or CD44v9 might be novel therapeutic targets for improving the treatment of advanced cancer patients. Additional prospective clinical trials are strongly needed across different cancer types.
Repeated Administration of Norbinaltorphimine Produces Cumulative Kappa Opioid Receptor Inactivation

Kappa receptor activation by dynorphins contributes to the anxiogenic, dysphoric, and cognitive disrupting effects of repeated stress, suggesting that kappa receptor antagonists might have therapeutic utility in the treatment of stress disorders. Three classes of kappa antagonists have been distinguished: non-selective, selective-competitive (readily reversible), and non-competitive (receptor-inactivating); however, which would be the most effective medication has not been established. To assess the utility of receptor inactivating antagonists, we tested the effects of a range of doses in both male and female mice. As previously established, the antinociceptive effects of the kappa agonist U50,488 were blocked by a single injection of the long-acting antagonist norbinatorphimine (norBNI) (10 mg/kg i.p.) in male mice. Ten to 20-fold lower doses of norBNI were ineffective after a single administration, but daily administration of 1.0 or 0.5 mg/kg for 5 days completely blocked U50,488 antinociceptive effects. Daily administration of 0.1 mg/kg norBNI produced slowly accumulating inhibition and completely blocked the antinociceptive effect of U50,488 after 20–30 days. Estrogen reduces female sensitivity to kappa opioid effects, but 30 days of 0.1 mg/kg norBNI completely blocked U50,488 analgesia in ovariectomized mice. Receptor inactivation in both male and female mice treated for 30 days with 0.1 mg/kg norBNI persisted for at least 1-week. These results suggest that receptor-inactivating kappa antagonists are effective in both males and females when given at 100-fold lower doses than typically administered in preclinical studies. The enhanced safety of this low-dosing protocol has important clinical implications if receptor inactivating kappa antagonists advance in medication development.
Theft and Reception of Host Cell's Sialic Acid: Dynamics of Trypanosoma Cruzi Trans-sialidases and Mucin-Like Molecules on Chagas' Disease Immunomodulation

The last decades have produced a plethora of evidence on the role of glycans, from cell adhesion to signaling pathways. Much of that information pertains to their role on the immune system and their importance on the surface of many human pathogens. A clear example of this is the flagellated protozoan Trypanosoma cruzi, which displays on its surface a great variety of glycoconjugates, including O-glycosylated mucin-like glycoproteins, as well as multiple glycan-binding proteins belonging to the trans-sialidase (TS) family. Among the latter, different and concurrently expressed molecules may present or not TS activity, and are accordingly known as active (aTS) and inactive (iTS) members. Over the last thirty years, it has been well described that T. cruzi is unable to synthesize sialic acid (SIA) on its own, making use of aTS to steal the host's SIA. Although iTS did not show enzymatic activity, it retains a substrate specificity similar to aTS (α-2,3 SIA-containing glycotopes), displaying lectinic properties. It is accepted that aTS members act as virulence factors in mammals coursing the acute phase of the T. cruzi infection. However, recent findings have demonstrated that iTS may also play a pathogenic role during T. cruzi infection, since it modulates events related to adhesion and invasion of the parasite into the host cells. Since both aTS and iTS proteins share structural substrate specificity, it might be plausible to speculate that iTS proteins are able to assuage and/or attenuate biological phenomena depending on the catalytic activity displayed by aTS members. Since SIA-containing glycotopes modulate the host immune system, it should not come as any surprise that changes in the sialylation of parasite's mucin-like molecules, as well as host cell glycoconjugates might disrupt critical physiological events, such as the building of effective immune responses. This review aims to discuss the importance of mucin-like glycoproteins and both aTS and iTS for T. cruzi biology, as well as to present a snapshot of how disturbances in both parasite and host cell sialoglycophenotypes may facilitate the persistence of T. cruzi in the infected mammalian host.
Transcriptome Sequencing Identifies Novel Immune Response Genes Highly Related to the Severity of Human Adenovirus Type 55 Infection

Human adenovirus type 55 (HAdV-55) is considered a highly virulent pathogen causing severe and even deadly pneumonia in immunocompetent people. The mechanisms of HAdV-55-induced initiation and progression of severe pneumonia remain ambiguous. In the current study, we endeavored to identify novel immune response genes which are substantially involved in the pathogenesis of severe inflammation in HAdV-55-infected patients. HAdV-55-infected patients with upper respiratory tract symptoms (minor patients) and pneumonia (severe patients) were enrolled. Through transcriptome sequencing and quantitative real-time PCR, the peripheral blood mononuclear cells of the patients were analyzed. We found that the expression of eight genes, including Il18, Il36b, Il17rc, Tnfsf10, Tnfsf11, Tnfsf14, Tnfsf15, and Il1a, were closely correlated with the severity of HAdV-55 infection. Most of these genes belong to interleukin-1 family or tumor necrosis factor (TNF) superfamily, respectively. The changes in gene expression were confirmed by Western blot assay. Our data will be crucial for deepening the understanding of the pathogenic mechanisms of severe pneumonia in HAdV-55 infection.
Molecular Players in Hematologic Tumor Cell Trafficking

The trafficking of neoplastic cells represents a key process that contributes to progression of hematologic malignancies. Diapedesis of neoplastic cells across endothelium and perivascular cells is facilitated by adhesion molecules and chemokines, which act in concert to tightly regulate directional motility. Intravital microscopy provides spatio-temporal views of neoplastic cell trafficking, and is crucial for testing and developing therapies against hematologic cancers. Multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia (ALL) are hematologic malignancies characterized by continuous neoplastic cell trafficking during disease progression. A common feature of these neoplasias is the homing and infiltration of blood cancer cells into the bone marrow (BM), which favors growth and survival of the malignant cells. MM cells traffic between different BM niches and egress from BM at late disease stages. Besides the BM, CLL cells commonly home to lymph nodes (LNs) and spleen. Likewise, ALL cells also infiltrate extramedullary organs, such as the central nervous system, spleen, liver, and testicles. The α4β1 integrin and the chemokine receptor CXCR4 are key molecules for MM, ALL, and CLL cell trafficking into and out of the BM. In addition, the chemokine receptor CCR7 controls CLL cell homing to LNs, and CXCR4, CCR7, and CXCR3 contribute to ALL cell migration across endothelia and the blood brain barrier. Some of these receptors are used as diagnostic markers for relapse and survival in ALL patients, and their level of expression allows clinicians to choose the appropriate treatments. In CLL, elevated α4β1 expression is an established adverse prognostic marker, reinforcing its role in the disease expansion. Combining current chemotherapies with inhibitors of malignant cell trafficking could represent a useful therapy against these neoplasias. Moreover, immunotherapy using humanized antibodies, CAR-T cells, or immune check-point inhibitors together with agents targeting the migration of tumor cells could also restrict their survival. In this review, we provide a view of the molecular players that regulate the trafficking of neoplastic cells during development and progression of MM, CLL, and ALL, together with current therapies that target the malignant cells.
Discovering Language of the Stocks

Stock prediction has always been attractive area for researchers and investors since the financial gains can be substantial. However, stock prediction can be a challenging task since stocks are influenced by a multitude of factors whose influence vary rapidly through time. This paper proposes a novel approach (Word2Vec) for stock trend prediction combining NLP and Japanese candlesticks. First, we create a simple language of Japanese candlesticks from the source OHLC data. Then, sentences of words are used to train the NLP Word2Vec model where training data classification also takes into account trading commissions. Finally, the model is used to predict trading actions. The proposed approach was compared to three trading models Buy & Hold, MA and MACD according to the yield achieved. We first evaluated Word2Vec on three shares of Apple, Microsoft and Coca-Cola where it outperformed the comparative models. Next we evaluated Word2Vec on stocks from Russell Top 50 Index where our Word2Vec method was also very successful in test phase and only fall behind the Buy & Hold method in validation phase. Word2Vec achieved positive results in all scenarios while the average yields of MA and MACD were still lower compared to Word2Vec.
Analysis of linkages between an unplugged activity and the development of computational thinking

ABSTRACT Unplugged activities have been one approach to introduce computational thinking (CT) to students before any form of coding is involved. This paper reports on a study that examines the evaluation of the types of CT skills inculcated through an unplugged activity. Students in a grade 9 class were engaged in an unplugged activity on sorting before being asked to represent their understanding in the form of pseudo-English, flowchart or Python code. The assessment of CT skills comprises the aspects of decomposition, algorithmic design, generalization, abstraction and evaluation. Qualitative Comparative Analysis (QCA) was used to take a closer look at the unplugged CT activity and the subsequent artifact production. Such a QCA analysis can be used to inform a framework for designing instruction and tasks to target and teach certain types of CT knowledge in novice programmers, as well as for assessing an instruction package as to what CT knowledge is being covered.
Pythagorean fuzzy multiple criteria decision analysis based on Shapley fuzzy measures and partitioned normalized weighted Bonferroni mean operator

Pythagorean fuzzy sets are powerful techniques for modeling vagueness in practice. The aim of this article is to investigate an effective means to aggregate uncertain information and then employ it into settling multiple criteria decision making (MCDM) problems within the Pythagorean fuzzy circumstances. To capture the nature of the reality, some special cases should be comprehensively considered. First, though correlation commonly exist among criteria, a deep insight should also be provided into some realistic situations, in which not all the criteria are interrelated to others. Besides, it is more reasonable to take the importance of the input arguments into consideration. Effected by aforementioned point, this article explores a Pythagorean fuzzy partitioned normalized weighted Bonferroni mean (PFPNWBM) operator with the combination of partitioned Bonferroni mean (BM) and normalized weighted BM operators considering Shapley fuzzy measure. Subsequently, in the context of partially known weight information, models are established to identify the optimal Shapley fuzzy measure. Moreover, integrated the PFPNWBM operator with the optimal Shapley fuzzy measure identification model, a Pythagorean fuzzy MCDM approach is designed. Finally, an illustrative example and detailed analyses are performed to demonstrate its feasibility and reliability.
Seasonality Matters: A Multi-Season, Multi-State Dynamic Optimization in Fishery

Many biological and economic processes in fishery happen seasonally. Most of the extant literature tends to neglect this fact. This work is an initial attempt to treat seasonality in a systematic and proper way. We apply a periodic Bellman approach to obtain the optimal feedback policy of each season. Our approach has rich potentials. It could deal with seasonal patterns of uneven lengths: some may span years and some within the year. We find that, in some cases the equilibrium consists of one harvesting season followed by a moratorium period, indicating an optimal closure of the fishery that would be overlooked by a yearly model. Unlike a typical policy that enforces a moratorium to recover the stock, we find that many states first undergo harvesting all year round and later evolve into the seasonal moratorium. A rising group biomass could be the overshooting effect instead of a clear sign to increase harvest. We sometimes observe declining optimal harvest with increasing states (‘valley’), which may relate to the unit profit difference between seasons. Fishing pressure on the mature elicits even heavier harvest in the next season on the same group. A protective moratorium of the immature seems to hinder the value of the whole stock.
Measurements of intrahost viral diversity require an unbiased diversity metric

Abstract Viruses exist within hosts at large population sizes and are subject to high rates of mutation. As such, viral populations exhibit considerable sequence diversity. A variety of summary statistics have been developed which describe, in a single number, the extent of diversity in a viral population; such measurements allow the diversities of different populations to be compared, and the effect of evolutionary forces on a population to be assessed. Here we highlight statistical artefacts underlying some common measures of sequence diversity, whereby variation in the depth of genome sequencing may substantially affect the extent of diversity measured in a viral population, making comparisons of population diversity invalid. Specifically, naive estimation of sequence entropy provides a systematically biased metric, a lower read depth being expected to produce a lower estimate of diversity. The number of polymorphic loci per kilobase of genome is more unpredictably affected by read depth, giving potentially flawed results at lower sequencing depths. We show that the nucleotide diversity statistic π provides an unbiased estimate of diversity in the sense that the expected value of the statistic is equal to the correct value of the property being measured. Our results are of importance for studies interpreting genome sequence data; we describe how diversity may be assessed in viral populations in a fair and unbiased manner.
The Impact of Early Human Migration on Brown Adipose Tissue Evolution and Its Relevance to the Modern Obesity Pandemic

Abstract Genetic factors are believed to be primarily responsible for obesity; however, an understanding of how genes for obesity have become so prevalent in modern society has proved elusive. Several theories have attempted to explain the genetic basis for obesity, but none of these appear to factor in the interethnic variation in obesity. Emerging evidence is increasingly pointing to a link between reduced basal metabolism and ineffective brown adipose tissue (BAT) thermogenesis. In fact, BAT presence and function are strongly correlated with metabolic rates and directly influence obesity susceptibility. My colleagues and I recently theorized that ancestral exposure to cold necessitated the evolution of enhanced BAT thermogenesis, which, with today’s hypercaloric and sedentary lifestyle, becomes advantageous, because thermogenesis is energetically wasteful, raising basal metabolism and burning excess calories. The opposite may be true for the descendants of heat-adapted populations. This review further reconciles global evolutionary climatic exposures with obesity demographics to understand the genetic basis for the obesity pandemic, and new insights from the most recent studies are provided, including those assessing archaic human admixture. Key genetic variants influencing BAT thermogenesis are outlined that have also been linked with climatic exposure to cold and appear to support the theory that evolutionary factors relevant to climate may have shaped the modern obesity pandemic.
An extension of the Alma-Ata vision for primary health care in light of twenty-first century evidence and realities

This paper builds upon and extends the definition of primary health care in the 1978 Declaration of Alma-Ata. The definition proposes a stronger role for community-based delivery of services and community mobilization, participation and empowerment. It calls for a stronger integration with vertical, disease-specific programs. And, finally, it calls for a strong role for certain curative services (including basic and essential surgery) that many today would not consider as part of primary health care. There is growing evidence that communities can and should play a stronger role than has traditionally been the case, that community-level workers who are properly trained and supported can provide effective services outside of health facilities, and that primary health centers staffed with non-specialist physicians and even non-physician clinicians can perform many of the lower-level inpatient services now performed at first-level referral hospitals. An approach to primary health care that is appropriate to the local context and that merges local epidemiological priorities with the communities' perceived priorities will make it possible to engage communities as partners. Currently, essential and basic health care services are available to only one-half of the world’s population. The full development of primary health care as envisioned here will accelerate progress in achieving Health for All as envisioned at the International Conference on Primary Health Care in 1978.
Urban plums and toads: do fleshy fruits affect the post-metamorphic growth of amphibians?

Background The main aim of the study was to analyse the influence of fleshy fruits (plums) on the post-metamorphic growth and feeding behaviour of the green toad Bufotes viridis. We tested the following two hypotheses: (1) juveniles of the green toad are characterised by faster growth in conditions involving fallen plums Prunus cerasifera due to the associated presence of more varied food such as invertebrates; (2) green toads exhibit more active feeding behaviour in the presence of fleshy fruits. Methods A total of 120 fresh metamorphs of the green toad were randomly assigned to one of four groups: two experimental groups with fleshy plums and two other groups as controls (without fruits). Each group was kept in an enclosure to which wild invertebrates had free access. Each individual toad was measured for snout-vent length (mm) and body mass (g) every other day for 30 days. In order to determine whether fallen plums influence the feeding behaviour of toads, the number of active and hidden (under an artificial shelter) individuals was also noted. Results The results showed that green toads from both enclosures with plums were characterised by more rapid growth than individuals from the control treatments. Simultaneously, in the enclosure with fleshy fruits, greater species richness of wild invertebrates was observed. No differences in active feeding behaviour were noted between control groups and groups with plums. Discussion Fleshy fruits, upon falling, attract many types of invertebrates; thus they may represent good dietary supplements for fresh amphibian metamorphs. Therefore, the presence of fruit trees close to a breeding site might influences the post-metamorphic growth of amphibians, but not their feeding behaviour. The presence of insects associated with fallen fruit seems to favour the occurrence of amphibian populations, which is particularly important, since, due to political and social pressure, numbers of fruit trees are currently being reduced. To our knowledge, no previous study has investigated the potential influence of the presence of fruit trees on the growth and behaviour of anurans.