Miracle-dz/UniFAR-FTUs huggingface dataset:
Global Pharmacogenomics: Distribution of CYP3A5 Polymorphisms and Phenotypes in the Brazilian Population

The influence of self-reported “race/color”, geographical origin and genetic ancestry on the distribution of three functional CYP3A5 polymorphisms, their imputed haplotypes and inferred phenotypes was examined in 909 healthy, adult Brazilians, self-identified as White, Brown or Black (“race/color” categories of the Brazilian census). The cohort was genotyped for CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343), CYP3A5 haplotypes were imputed and CYP3A5 metabolizer phenotypes were inferred according to the number of defective CYP3A5 alleles. Estimates of the individual proportions of Amerindian, African and European ancestry were available for the entire cohort. Multinomial log-linear regression models were applied to infer the statistical association between the distribution of CYP3A5 alleles, haplotypes and phenotypes (response variables), and self-reported Color, geographical region and ancestry (explanatory variables). We found that Color per se or in combination with geographical region associates significantly with the distribution of CYP3A5 variant alleles and CYP3A5 metabolizer phenotypes, whereas geographical region per se influences the frequency distribution of CYP3A5 variant alleles. The odds of having the default CYP3A5*3 allele and the poor metabolizer phenotype increases continuously with the increase of European ancestry and decrease of African ancestry. The opposite trend is observed in relation to CYP3A5*6, CYP3A5*7, the default CYP3A5*1 allele, and both the extensive and intermediate phenotypes. No significant effect of Amerindian ancestry on the distribution of CYP3A5 alleles or phenotypes was observed. In conclusion, this study strongly supports the notion that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies, and dealt with as a continuous variable, rather than proportioned in arbitrary categories that do not capture the diversity of the population. The relevance of this work extrapolates the Brazilian borders, and extends to other admixed peoples of the Americas, with ancestral roots in Europe, Africa and the American continent.
The Balance of Th1/Th2 and LAP+Tregs/Th17 Cells Is Crucial for Graft Survival in Allogeneic Corneal Transplantation

Purpose CD4+LAP+ T cells are newly discovered regulatory T cells (Tregs). The aim of this study is to investigate the balance of Th1/Th2 and LAP+Tregs/Th17 in mice after allogeneic corneal transplantation. Methods A total of 65 mice received orthotopic penetrating transplantation. According to the survival scores of the grafts, the mice were divided into the rejection group and the survival group 3 weeks after transplantation. Th1, Th2, Th17, and regulatory T cells in the ipsilateral drainage lymph nodes and spleens were measured with flow cytometry. The related cytokines in aqueous humor were also analyzed. Results The frequencies of Foxp3+Tregs, GARP+Tregs, and LAP+Tregs in the survival group were significantly higher than those in the rejection group. And the expression trend of CD4+LAP+ T cells and CD4+GARP+ T cells was consistent. The level of IFN-γ, TNF, IL-6, and IL-17A markedly increased in aqueous humor during corneal allograft rejection. The ratio of Th1/Th2 and Th17/LAP+Tregs significantly increased in the rejection group at the 3rd week after corneal transplantation. Conclusion LAP+Tregs might be regarded as substitute for Foxp3+Tregs. The balance of Th1/Th2 and LAP+Tregs/Th17 is crucial for corneal allograft survival.
Growth and annealing kinetics of α-sexithiophene and fullerene C60 mixed films

Thin films of α-sexithiophene (6T) and C60 mixtures deposited on nSiO substrates at 303 and 373 K were investigated in real time and in situ during the film growth using X-ray diffraction. The mixtures are observed to contain the well known 6T low-temperature crystal phase and the β phase, which usually coexist in pure 6T films. The addition of C60 modifies the structure to almost purely β-phase-dominated films if the substrate is at 303 K. In contrast, at 373 K the low-temperature crystal phase of 6T dominates the film growth of the mixtures. Post-growth annealing experiments up to 373 K on equimolar mixtures and pure 6T films were also performed and followed in real time with X-ray diffraction. Annealing of pure 6T films results in a strong increase of film ordering, whereas annealing of equimolar 6T:C60 mixed films does not induce any significant changes in the film structure. These results lend further support to theories about the important influence of C60 on the growth behaviour and structure formation process of 6T in mixtures of the two materials.
When to eat? The influence of circadian rhythms on metabolic health: are animal studies providing the evidence?

Abstract As obesity and metabolic diseases rise, there is need to investigate physiological and behavioural aspects associated with their development. Circadian rhythms have a profound influence on metabolic processes, as they prepare the body to optimise energy use and storage. Moreover, food-related signals confer temporal order to organs involved in metabolic regulation. Therefore food intake should be synchronised with the suprachiasmatic nucleus (SCN) to elaborate efficient responses to environmental challenges. Human studies suggest that a loss of synchrony between mealtime and the SCN promotes obesity and metabolic disturbances. Animal research using different paradigms has been performed to characterise the effects of timing of food intake on metabolic profiles. Therefore the purpose of the present review is to critically examine the evidence of animal studies, to provide a state of the art on metabolic findings and to assess whether the paradigms used in rodent models give the evidence to support a ‘best time’ for food intake. First we analyse and compare the current findings of studies where mealtime has been shifted out of phase from the light–dark cycle. Then, we analyse studies restricting meal times to different moments within the active period. So far animal studies correlate well with human studies, demonstrating that restricting food intake to the active phase limits metabolic disturbances produced by high-energy diets and that eating during the inactive/sleep phase leads to a worse metabolic outcome. Based on the latter we discuss the missing elements and possible mechanisms leading to the metabolic consequences, as these are still lacking.
A Review on Studies and Research on Various Aspects of Leaching

Leaching is one of the major unit operations used in mining sector. Leaching is extraction of the component from solids by using a solvent. The solvent preferably removes certain component. Leaching finds application in recovery of various valuable metals. Microbial leaching is gaining importance for recovery of metals from waste. It also plays important role in agriculture. It is always desirable to avoid the leaching of valuable components of soil through run offs. Various investigators have carried out research on various aspects of leaching. This review paper summarizes studies and research on various aspects of leaching.
ARPP-16 Is a Striatal-Enriched Inhibitor of Protein Phosphatase 2A Regulated by Microtubule-Associated Serine/Threonine Kinase 3 (Mast 3 Kinase)

ARPP-16 (cAMP-regulated phospho-protein of molecular weight 16 kDa) is one of several small acid-soluble proteins highly expressed in medium spiny neurons of striatum that are phosphorylated in response to dopamine acting via D1 receptor/protein kinase A (PKA) signaling. We show here that ARPP-16 is also phosphorylated in vitro and in vivo by microtubule-associated serine/threonine kinase 3 (MAST3 kinase), an enzyme of previously unknown function that is enriched in striatum. We find that ARPP-16 interacts directly with the scaffolding A subunit of the serine/threonine protein phosphatase, PP2A, and that phosphorylation of ARPP-16 at Ser46 by MAST3 kinase converts the protein into a selective inhibitor of B55α- and B56δ-containing heterotrimeric forms of PP2A. Ser46 of ARPP-16 is phosphorylated to a high basal stoichiometry in striatum, suggestive of basal inhibition of PP2A in striatal neurons. In support of this hypothesis, conditional knock-out of ARPP-16 in CaMKIIα::cre/floxed ARPP-16/19 mice results in dephosphorylation of a subset of PP2A substrates including phospho-Thr75-DARPP-32, phospho-T308-Akt, and phospho-T202/Y204-ERK. Conditional knock-out of ARPP-16/19 is associated with increased motivation measured on a progressive ratio schedule of food reinforcement, yet an attenuated locomotor response to acute cocaine. Our previous studies have shown that ARPP-16 is phosphorylated at Ser88 by PKA. Activation of PKA in striatal slices leads to phosphorylation of Ser88, and this is accompanied by marked dephosphorylation of Ser46. Together, these studies suggest that phospho-Ser46-ARPP-16 acts to basally control PP2A in striatal medium spiny neurons but that dopamine acting via PKA inactivates ARPP-16 leading to selective potentiation of PP2A signaling. SIGNIFICANCE STATEMENT We describe a novel mechanism of signal transduction enriched in medium spiny neurons of striatum that likely mediates effects of the neurotransmitter dopamine acting on these cells. We find that the protein ARPP-16, which is highly expressed in striatal medium spiny neurons, acts as a selective inhibitor of certain forms of the serine/threonine protein phosphatase, PP2A, when phosphorylated by the kinase, MAST3. Under basal conditions, ARPP-16 is phosphorylated by MAST3 to a very high stoichiometry. However, the actions of MAST3 are antagonized by dopamine and cAMP-regulated signaling leading to disinhibition of ARPP-16 and increased PP2A action.
Barriers to Diagnosis Access for Chagas Disease in Colombia

Chagas disease is the leading cause of nonischemic cardiomyopathy in Latin America. Timely access to diagnosis and trypanocidal treatment and preventive tools for millions of infected people continues to be a challenge. The purpose of this study was to identify potential barriers for the diagnosis of Chagas disease in Colombia from the perspective of healthcare providers. Using a simultaneous mixed-methods study design, we analyzed trends in access to screening and diagnosis for Chagas disease in Colombia and assessed the national barriers to access. The main barriers to access at the national level included a limited governmental public health infrastructure for the diagnosis of Chagas disease and limited physician awareness and knowledge of the disease. Data indicate that 1.5% of total expected cases based on national prevalence estimates were reported. Few public health laboratories have the capacity to perform complementary tests for the diagnosis of Chagas disease and almost 6 months elapse between the requests of the tests and the confirmation of the disease. This study shows that infected people must overcome a number of barriers to achieve diagnosis. Reducing barriers to early diagnosis of Chagas disease is an important goal in the fight against the disease.
Developing safe fall strategies for lower limb exoskeletons

One of the main challenges in the use of a powered lower limb exoskeleton (LLE) is to ensure that balance is maintained throughout the operation of the device. Since no control strategy has yet been implemented that prevents falls in the case of a loss of balance, head or other serious injuries may occur during independent use of LLEs in the event of a fall. These safety concerns limit LLEs in the community to supervised use only. Using the backward fall as a model, we used optimization techniques to develop safe fall control strategies in order to avoid head impact and mitigate the impact velocity of the hips. From available human biomechanics data, we first developed an optimization methodology to study falls of healthy people. The results showed similar kinematic and dynamic characteristics to findings of previous studies on real-life human falls. Second, we extended the optimization methodology to include characteristics of a hypothetical LLE and to generate optimal joint trajectories and optimal torque profiles for the fall duration. The results revealed that by applying the optimal fall strategy, the severity of a simulated fall was minimized compared to when the device fell with locked joints (i.e., how currently used exoskeletons fall): head impact was avoided and hip impact velocity was reduced by more than 50%.
Cytochrome P450 27A1 Deficiency and Regional Differences in Brain Sterol Metabolism Cause Preferential Cholestanol Accumulation in the Cerebellum*

Cytochrome P450 27A1 (CYP27A1 or sterol 27-hydroxylase) is a ubiquitous, multifunctional enzyme catalyzing regio- and stereospecific hydroxylation of different sterols. In humans, complete CYP27A1 deficiency leads to cerebrotendinous xanthomatosis or nodule formation in tendons and brain (preferentially in the cerebellum) rich in cholesterol and cholestanol, the 5α-saturated analog of cholesterol. In Cyp27a1−/− mice, xanthomas are not formed, despite a significant cholestanol increase in the brain and cerebellum. The mechanism behind cholestanol production has been clarified, yet little is known about its metabolism, except that CYP27A1 might metabolize cholestanol. It also is unclear why CYP27A1 deficiency results in preferential cholestanol accumulation in the cerebellum. We hypothesized that cholestanol might be metabolized by CYP46A1, the principal cholesterol 24-hydroxylase in the brain. We quantified sterols along with CYP27A1 and CYP46A1 in mouse models (Cyp27a1−/−, Cyp46a1−/−, Cyp27a1−/−Cyp46a1−/−, and two wild type strains) and human brain specimens. In vitro experiments with purified P450s were conducted as well. We demonstrate that CYP46A1 is involved in cholestanol removal from the brain and that several factors contribute to the preferential increase in cholestanol in the cerebellum arising from CYP27A1 deficiency. These factors include (i) low cerebellar abundance of CYP46A1 and high cerebellar abundance of CYP27A1, the lack of which probably selectively increases the cerebellar cholestanol production; (ii) spatial separation in the cerebellum of cholesterol/cholestanol-metabolizing P450s from a pool of metabolically available cholestanol; and (iii) weak cerebellar regulation of cholesterol biosynthesis. We identified a new physiological role of CYP46A1, an important brain enzyme and cytochrome P450 that could be activated pharmacologically.
Pharmacological Rac1 inhibitors with selective apoptotic activity in human acute leukemic cell lines

Rac1 GTPase has long been recognized as a critical regulatory protein in different cellular and molecular processes involved in cancer progression, including acute myeloid leukemia. Here we show the antitumoral activity of ZINC69391 and 1A-116, two chemically-related Rac1 pharmacological inhibitors, on a panel of four leukemic cell lines representing different levels of maturation. Importantly, we show that the main mechanism involved in the antitumoral effect triggered by the Rac1 inhibitors comprises the induction of the mitochondrial or intrinsic apoptotic pathway. Interestingly, Rac1 inhibition selectively induced apoptosis on patient-derived leukemia cells but not on normal mononuclear cells. These results show the potential therapeutic benefits of targeting Rac1 pathway in hematopoietic malignancies.
Epidemiological Pattern of Scabies and Its Social Determinant Factors in West of Iran

Objectives: Scabies has a different epidemiological distribution among different communities worldwide due to different social factors, management approaches and healthcare policies. The present study came to address outbreaks of scabies according to the social factors in west of Iran. Methods: In a cross-sectional study, using the census sampling method, all consecutive patients with the primary diagnosis of scabies based on clinical manifestations referred to healthcare center throughout the two great provinces of Hamadan and Kermanshah at western Iran between March 2006 and February 2010 were enrolled into the study. The baseline characteristics were collected from recorded files at the healthcare centers or by interviewing with the affected patients. Results: Among 3,625,966 subjects covered by the two studied provinces, 177 cases of scabies (170 cases in Kermanshah and 7 cases in Hamadan) were identified by medical staff at the healthcare centers according to clinical manifestations (85.3%) and laboratory microscopic assessments (14.7%). The highest and the lowest prevalence rates were specified to 2009 (58.2%) and 2008 (1.7%). Regarding gender distribution of disease, 53.1% of men and 46.9% of women suffered from scabies with no significant discrepancy. In respect to age distribution of disease, the highest rates of scabies were revealed in the ages ranged 17 to 30 years (31.6%), followed by younger than 17 years (30.5%). The prevalence of scabies was dependently associated with residency in rural areas, family history of scabies, lower educational level, household density, lower monthly income, low personal hygiene, the existence of livestock or rodents at home, seasonal conditions, and movement to contaminated areas. Conclusion: West region of Iran especially Kermanshah province faced with high prevalence and this high disease burden can be determined by some potential factors such as residency in rural areas, family history of scabies, lower educational level, household density, lower monthly income, low personal hygiene, the existence of livestock or rodents at home, seasonal conditions, and movement to contaminated areas.
Anopheles funestus (Diptera: Culicidae) in a Humid Savannah Area of Western Burkina Faso: Bionomics, Insecticide Resistance Status, and Role in Malaria Transmission

Abstract An entomological survey was carried out in three humid savannah sites of western Burkina Faso (Bama, Lena, and Soumousso) to 1) update the taxonomy of the Anopheles funestus Giles group, 2) examine the role of each species in malaria transmission, 3) characterize the insecticide resistance status of this malaria vector, and 4) determine the distribution of An. funestus chromosomal forms in these areas. Polymerase chain reaction identification of the members showed the occurrence of An. leesoni Evans in Lena and An. rivulorum-like in Soumousso in addition to An. funestus s.s. Malaria transmission was ensured mainly by An. funestus s.s. both in Soumousso and Lena and by An. gambiae s.s. Giles in Bama, the rice-growing area. The insecticide resistance status performed only on An. funestus indicated that this mosquito was susceptible to pyrethroids irrespective of the study area, but it was resistant to dieldrin. Furthermore, the occurrence of the two chromosomal forms of An. funestus, namely, Kiribina and Folonzo, seemed to follow ecological setups where Kiribina predominated in the irrigated area and Folonzo was more frequent in classic savannah. This study revealed that the problematic of An. funestus taxonomy was closer to that of An. gambiae requiring more structured studies to understand its genetic ecology.
Risk factors of adverse events in endoscopic retrograde cholangiopancreatography for patients aged ≥85 years

Little is known about the factors that contribute to the occurrence of adverse events in endoscopic retrograde cholangiopancreatography (ERCP) for people aged ≥85 years and safety for the super‐old. Therefore, we decided to identify these factors and to examine whether ERCP is safe in the super‐old.
Virtual Rheoscopic Fluids for Flow Visualization

Physics-based flow visualization techniques seek to mimic laboratory flow visualization methods with virtual analogues. In this work we describe the rendering of a virtual rheoscopic fluid to produce images with results strikingly similar to laboratory experiments with real-world rheoscopic fluids using products such as Kalliroscope. These fluid additives consist of microscopic, anisotropic particles which, when suspended in the flow, align with both the flow velocity and the local shear to produce high-quality depictions of complex flow structures. Our virtual rheoscopic fluid is produced by defining a closed-form formula for the orientation of shear layers in the flow and using this orientation to volume render the flow as a material with anisotropic reflectance and transparency. Examples are presented for natural convection, thermocapillary convection, and Taylor-Couette flow simulations. The latter agree well with photographs of experimental results of Taylor-Couette flows from the literature.
Colloidal nanocarriers for the enhanced cutaneous delivery of naftifine: characterization studies and in vitro and in vivo evaluations

In topical administration of antifungals, the drugs should pass the stratum corneum to reach lower layers of the skin in effective concentrations. Thus, the formulation of antifungal agents into a suitable delivery system is important for the topical treatment of fungal infections. Nanosized colloidal carriers have gained great interest during the recent years to serve as efficient promoters of drug penetration into the skin. Microemulsions are soft colloidal nanosized drug carriers, which are thermodynamically stable and isotropic systems. They have been extensively explored for the enhancement of skin delivery of drugs. This study was carried out to exploit the feasibility of colloidal carriers as to improve skin transport of naftifine, which is an allylamine antifungal drug. The microemulsions were formulated by construction of pseudoternary phase diagrams and composed of oleic acid (oil phase), Kolliphor® EL or Kolliphor® RH40 (surfactant), Transcutol® (cosurfactant), and water (aqueous phase). The plain and drug-loaded microemulsions were characterized in terms of isotropy, particle size and size distribution, pH value, refractive index, viscosity, and conductivity. The in vitro skin uptake of naftifine from microemulsions was studied using tape stripping technique in pig skin. The drug penetrated significantly into stratum corneum from microemulsions compared to its marketed cream (P<0.05). Moreover, the microemulsion formulations led to highly significant amount of naftifine deposition in deeper layers of skin than that of commercial formulation (P<0.001). Microemulsion–skin interaction was confirmed by attenuated total reflectance – Fourier transformed infrared spectroscopy data, in vitro. The results of the in vivo tape stripping experiment showed similar trends as the in vitro skin penetration study. Topical application of the microemulsion on human forearms in vivo enhanced significantly the distribution and the amount of naftifine penetrated into the stratum corneum as compared to the marketed formulation (P<0.05). The relative safety of the microemulsion formulations was demonstrated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability test. This study indicated that the nanosized colloidal carriers developed could be considered as an effective and safe topical delivery system for naftifine.