Clemastine/tamoxifen hybrids as easily accessible antileishmanial drug leads.

A library of hybrid molecules is developed based on the common chemical features shared by clemastine and tamoxifen both of which are well known for their antileishmanial activities. In the initial screening against Leishmania major and L. amazonensis promastigotes, as well as cytotoxicity assays using HepG2 cells, several hybrids showed submicromolar activity against the parasite and no toxicity against human cells. The compounds with an EC50 < 2 µM against promastigotes of both species and a selectivity index >10 were further characterized against intracellular amastigotes as well as promastigotes of species that cause both visceral and cutaneous leishmaniasis, such as L. infantum and L. braziliensis, respectively. These sequential screenings revealed the high pan-activity of this class of molecules against these species, with several compounds displaying an EC50 ≤ 2 µM against both promastigotes and intracellular amastigotes. Two of them were identified as the potential templates for lead optimization of this series having shown the highest activities against all species in both stages of parasite. The present findings can serve as a good starting point in the search for novel antileishmanial compounds that are easy to access and highly active.

Articulating the "stem cell niche" paradigm through the lens of non-model aquatic invertebrates.

Stem cells (SCs) in vertebrates typically reside in "stem cell niches" (SCNs), morphologically restricted tissue microenvironments that are important for SC survival and proliferation. SCNs are broadly defined by properties including physical location, but in contrast to vertebrates and other "model" organisms, aquatic invertebrate SCs do not have clearly documented niche outlines or properties. Life strategies such as regeneration or asexual reproduction may have conditioned the niche architectural variability in aquatic or marine animal groups. By both establishing the invertebrates SCNs as independent types, yet allowing inclusiveness among them, the comparative analysis will allow the future functional characterization of SCNs.

Translation and validation of the evidence-based practice attitude scale (EBPAS-15) to Brazilian Portuguese: Examining providers' perspective about evidence-based parent intervention.

Background: Few existing evidence-based parent interventions (EBPIs) for prevention and treatment of child and youth mental health disorders are implemented in low-middle-income countries. This study aimed to translate and confirm the factor structure of the Evidence-Based Practice Attitude Scale (EBPAS-15) survey in Brazilian Portuguese with the goal of examining providers' perspective about EBPIs. Methods: We translated and back translated the EBPAS-15 from English to Brazilian Portuguese. Participants were recruited via snowball sampling and data were collected using an online survey from July of 2018 through January of 2020. A confirmatory factor analysis was conducted to determine if the scale retained its original structure. Open-ended questions about providers' perspectives of their own clinical practice were coded using the Theoretical Domains Framework (TDF). Analyses included data from 362 clinicians (318 women, 41 men) from 20 of the 27 states of Brazil. Participants on average were 26.7 years old, held specialist degrees in the field of psychology, actively worked as therapists, and practiced in private clinics. Results: The translation of the EBPAS to Brazilian Portuguese retained the same four-factor structure as the English version except for dropping one item from the Divergence domain. When asked about the challenges in their practices, providers generally referred to parents as clients with little skills to discipline their children and lacking knowledge about child development. Discussion: The Brazilian version of the EBPAS-15 is promising, but future research should consider using quantitative data alongside qualitative information to better understand providers' attitudes about evidence-based interventions to inform implementation efforts. Trial registration: N/A.

Identification of Copy Number Variation by Array-CGH in Portuguese Children and Adolescents Diagnosed with Autism Spectrum Disorders.

BACKGROUND: Autism spectrum disorders (ASD) affect many children with an estimated prevalence of 1%. Array-comparative genomic hybridization (CGH) offers significant sensitivity for the identification of submicroscopic chromosomal abnormalities and it is one of the most used techniques in daily practice. The main objective of this study was to describe the usefulness of array-CGH in the etiologic diagnosis of ASD. METHODS: Two-hundred fifty-three patients admitted to a neurogenetic outpatient clinic and diagnosed with ASD were selected for array-CGH (4 × 180K microarrays). Public databases were used for classification in accordance with the American College of Medical Genetics Standards and Guidelines. RESULTS: About 3.56% (9/253) of copy number variations (CNVs) were classified as pathogenic. When likely pathogenic CNVs were considered, the rate increased to 11.46% (29/253). Some CNVs apparently not correlated to the ASD were also found. Considering a phenotype-genotype correlation, the patients were divided in two groups. One group according to previous literature includes all the CNVs related to ASDs (23 CNVs present in 22 children) and another with those apparently not related to ASD (10 CNVs present in 7 children). In 18 patients, a next-generation sequencing (NGS) panel were performed. From these, one pathogenic and 16 uncertain significance variants were identified. CONCLUSION: The results of our study are in accordance with the literature, highlighting the relevance of array-CGH in the genetic of diagnosis of ASD population, namely when associated with other features. Our study also reinforces the need for complementarity between array-CGH and NGS panels or whole exome sequencing in the etiological diagnosis of ASD.

Hexapartite Entanglement in an above-Threshold Optical Parametric Oscillator.

We demonstrate, theoretically and experimentally, the generation of hexapartite modal entanglement by the optical parametric oscillator (OPO) operating above the oscillation threshold. We show that the OPO generates a rich structure of entanglement among sets of six optical sideband modes interacting through the nonlinear crystal. The class of quantum states thus produced can be controlled by a single parameter, the power of the external laser that pumps the system. Our platform allows for the generation of massive entanglement among many optical modes with well defined but vastly different frequencies, potentially bridging nodes of a multicolor quantum network.

Assessing epidemiology of leprosy and socio-economic distribution of cases.

Leprosy still represents a serious health problem in a number of countries, including Brazil. Although leprosy has been associated with poverty for a long time, it is still difficult to accurately define this relationship. Here, we evaluated in an endemic municipality the progress from 1995 to 2015 of epidemiological indicators to establish if there were any strong associations between social indicators and the occurrence of leprosy. An ecological study was conducted using the SINAN database (Brazilian leprosy-national notifiable diseases information system) in combination with georeferencing of leprosy cases. The georeferencing used the ArcGis programme and occurrence of cases was evaluated in relation to the Health Vulnerability Index (HVI), an indicator that categorises socio-economic and sanitation factors. The data identified a marked decrease in the overall prevalence of leprosy, a reduction in the new case-detection rate and a reduction in the number of cases with grade 2 disabilities (albeit with transient peaks in 2007 and 2015). Logistic regression analysis showed association of detection rates with elevated HVI. Thus, while the epidemiological indicators point to the elimination of leprosy, there is evidence of hidden cases and an association between higher rates of leprosy detection and greater social vulnerability remain.

Role of inosine triphosphate pyrophosphatase gene variant on fever incidence during zidovudine antiretroviral therapy.

Zidovudine, the antiretroviral drug used to treat HIV infection, commonly causes adverse effects, such as systemic fever and gastrointestinal alterations. In the present study, the potential role of inosine triphosphate pyrophosphatase (ITPA) gene variant on the incidence of adverse events during antiretroviral therapy (ART) of HIV with zidovudine was discussed. Individuals from Northeastern Brazil (N = 204) receiving treatment for HIV-1 infection were recruited. Zidovudine-related adverse effects developed during the treatment were registered. The rs1127354 polymorphism in the ITPA gene was genotyped using real-time PCR to assess whether this single nucleotide polymorphism was associated with the occurrence of zidovudine-related adverse effects. We observed a significant association between the ITPA variant genotype and the reported systemic fever (odds ratio = 7.17, 95% confidence interval = 1.19-43.15; P = 0.032). Zidovudine use could indirectly lead to an increase in the levels of inosine monophosphate in an antimetabolite-like manner, which is converted to inosine triphosphate (ITP). The rs1127354 variant caused a decrease in ITPA activity, thereby leading to ITP accumulation. This in turn resulted in cytotoxicity, which was manifested by neutropenia and fever. Therefore, we hypothesized a pharmacogenetic model involving the ITPA variant genotype in multifactorial components that act together to determine the onset of zidovudine-related adverse effects.

Chromosome variations and diversity of Epidendrum ibaguense Lindl. (Orchidaceae) on the Tepequém's Tepuy, Roraima, Brazil.

Studies addressing chromosome variations have elucidated many points regarding the taxonomy of the Orchidaceae. Epidendrum L. besides being one the largest orchid genera, present remarkable morphological, and inter- and intraspecific chromosome variations. Thus, based on a previous report on flower color variation in individuals of E. ibaguense (magenta, pink, white, and red), our aim was to determine its chromosome number and test whether this trait is associated with flower color variation in natural populations on the Tepequém's Tepuy, Roraima. Root apices were pre-treated with 8-hydroxyquinoline at 4°C for 24 h and subsequently submitted to conventional cytogenetic procedures. Slides with the best spreading and contraction of chromosomes were photographed under light microscopy. Chromosome number was determined by counting at least 10 mitotic metaphase cells per individual. The types of interphase nuclei were determined for 30 nuclei per individual. E. ibaguense presented intra- and interpopulation variation in chromosome number, with 2n = 58, 72, and 76. The chromosome number 2n = 58 was most commonly found in individuals with magenta, pink, and white flowers, while the remaining two chromosome numbers occurred mostly in red-flowered individuals. The types of interphase nuclei were associated with the chromosome number. Individuals with 2n = 58 presented a predominance of semi-reticulated nuclei, while in those with 2n = 72 and 76 the nuclei were predominantly non-reticulated. The dominance of disploidy in E. ibaguense suggests that this cytotype provides this species with a territorial advantage and a higher reproductive success, possibly contradicting the polyploid hypothesis. Our results suggest that chromosome number may not represent a reproductive barrier in genus Epidendrum.

Discovery and characterization of new microsatellite loci in Dipteryx alata Vogel (Fabaceae) using next-generation sequencing data.

The use of next-generation sequencing (NGS) technologies provides a great volume of genome sequence data even for non-model species. The development of microsatellite markers using these data is a relatively quick and easy process. Dipteryx alata Vogel (Fabaceae) is an arboreal species from the Cerrado biome and is considered an important plant genetic resource. Here, we report the development of microsatellite markers for D. alata using NGS data. DNA samples from four individuals were sequenced using the Illumina MiSeq platform and high-quality reads were assembled into contigs of the D. alata genome sequence. Microsatellite regions were identified using the IMEX webserver and primer pairs were designed using the Primer3 software. The amplification settings for each locus were optimized. Fluorescent-labeled primers were developed and used to genotype individuals derived from three natural populations of D. alata. Fifty-four microsatellite regions were identified, from which 27 were elected to primer design. Among the amplified loci, 11 were polymorphic, with the number of alleles ranging from 2 to 10. The expected heterozygosity under Hardy-Weinberg Equilibrium (HWE) per locus varied from 0.191 to 0.807. Genotype and allele frequencies for all loci agreed with those expected under HWE and linkage disequilibrium was not significant for all pairs of loci. The probabilities of exclusion of paternity and of combined identity were equal to 0.993 and 5.65 x 10-8, respectively. The markers developed in this study are useful to several types of population genetic studies with D. alata and, eventually, for closely related species.

Synergic effect of oral contraceptives, GSTP1 polymorphisms, and high-risk HPV infection in development of cervical lesions.

Human papillomavirus (HPV) infection is considered a risk factor for cervical cancer. Even if the high-risk HPV (HR-HPV) infection is necessary, environmental co-factors and genetic susceptibility also play an important role in cervical cancer development. In this study, a possible association of rs1695 GSTP1 polymorphisms, HR-HPV infection, and oral contraceptive use with cancer lesion development in women was investigated. The study population comprised 441 Brazilian women from the Northeast region including 98 HPV-infected women with high-grade squamous intraepithelial lesions, 77 HPV-infected women with low-grade squamous intraepithelial lesions, and 266 HPV-negative women with no lesion, used as a control. Our data did not show a significant association between the GSTP1 polymorphism A/G (rs1695) and any HPV-related cervical abnormalities. However, considering the use of oral contraceptives, the GSTP1 rs1695 polymorphism was associated with higher susceptibility to the development of cervical lesions in HR-HPV-infected women. Our study suggests a synergic effect of oral contraceptive use, GSTP1 polymorphisms, and HR-HPV infection in the development of cervical lesions. Together, these risk factors may induce neoplastic transformation of the cervical squamous epithelium, setting conditions for secondary genetic events leading to cervical cancer.

[Post-appendectomy intra-abdominal abscesses: six years' experience in a Pediatric Surgery Department]. / Abscesos intraabdominales postapendicectomía: seis años de experiencia de un Servicio de Cirugía Pediátrica.

OBJECTIVES: Post-appendectomy intra-abdominal abscesses are estimated to complicate up to 4.2% of acute non-perforated appendicitis and between 6.7% and 28% acute perforated appendicitis. This study was performed with the aim to review and characterize post-appendectomy intra-abdominal abscesses in our Pediatric Surgery department; to calculate their incidence and to evaluate the efficacy of the treatment modality. MATERIAL AND METHODS: A retrospective analysis of all patients, under 18 years and with the diagnosis of intra-abdominal abscess post-appendectomy, between January 2010 and December 2015 was performed, taking in account initial surgical approach, type of acute appendicitis, length of hospital stay and the treatment applied. Data were collected by reviewing clinical files. RESULTS: In a total of 1,340 appendectomies performed, there were 24 intra-abdominal abscesses identified (1.79%). Eight were feminine and sixteen masculine, and mean age was 11.9 years. In 52% of cases the diagnosis was made in the initial admission. Twelve have been submitted to laparoscopic appendectomy and the other 12 to open appendectomy. Of the 24 patients, only 4 needed a surgical re-intervention, which leaves medical treatment an 83.3% success rate. CONCLUSIONS: TThe incidence of intra-abdominal abscesses post-appendectomy, in the studied population, is what was expected and inferior to what's described in the literature. In our sample, conservative management for intra-abdominal abscesses post-appendectomy was successful in most of the cases, only 4 needing further surgical intervention.

OBJETIVOS: Se estima que la frecuencia en la que aparecen los abscesos intraabdominales postapendicectomía es de un 4,2% en las apendicitis agudas no perforadas y entre un 6,7 y 28% en las apendicitis agudas perforadas. Este estudio fue realizado con el objetivo de revisar los casos de abscesos intraabdominales en el postoperatorio de apendicectomía por apendicitis aguda en nuestro Servicio de Cirugía Pediátrica, calcular su incidencia y evaluar la eficacia del tratamiento implementado. MATERIAL Y METODO: Análisis retrospectivo de los pacientes, menores de 18 años y con diagnóstico de absceso intraabdominal postapendicectomía, entre enero de 2010 y diciembre de 2015, teniendo en cuenta el abordaje quirúrgico inicial, el tipo de apendicitis aguda, la duración del internamiento y el tipo de tratamiento efectuado. RESULTADOS: En un total de 1.340 apendicectomías realizadas se identificaron 24 abscesos intraabdominales (1,79%): ocho del sexo femenino y dieciséis del sexo masculino, con una media de edad de 11,9 años. En el 52% de los casos el diagnóstico fue realizado durante el ingreso inicial. Doce pacientes fueron sometidos a apendicectomía laparoscópica y 12 por laparotomía. De los 24 pacientes solamente 4 necesitaron de nuevo una intervención quirúrgica. Por lo tanto, el porcentaje de éxito del tratamiento médico fue de un 83,3%. CONCLUSIONES: La incidencia de abscesos intraabdominales postapendicectomía en la población estudiada está dentro de lo esperado e incluso es inferior a los valores mencionados en la literatura. En nuestra muestra con el tratamiento médico de los abscesos intraabdominales tuvimos muy buenos resultados en la mayoría de los casos, necesitando solo en 4 recurrir al tratamiento quirúrgico.

Zero-Area Single-Photon Pulses.

Broadband single photons are usually considered not to couple efficiently to atomic gases because of the large mismatch in bandwidth. Contrary to this intuitive picture, here we demonstrate that the interaction of ultrashort single photons with a dense resonant atomic sample deeply modifies the temporal shape of their wave packet mode without degrading their nonclassical character, and effectively generates zero-area single-photon pulses. This is a clear signature of strong transient coupling between single broadband (THz-level) light quanta and atoms, with intriguing fundamental implications and possible new applications to the storage of quantum information.

HLA-G genetic variants and hepatocellular carcinoma: a meta-analysis.

Human leukocyte antigen (HLA)-G is a key tolerogenic molecule mainly expressed in the placenta and is crucial for implantation of the embryo and immunological tolerance of the fetus during pregnancy. However, under pathological conditions, such as cancer or viral infections, HLA-G can be expressed in other tissues. The gene coding for HLA-G (HLA-G, chromosome 6p21.3) presents numerous polymorphisms, some of them influencing its expression. One of the most studied, is the 14 bp ins/del (rs371194629) situated at the 3'-UTR of the gene. The insertion is thought to stabilize HLA-G mRNA. Different studies have analyzed the role of rs371194629 in hepatic injury, with either hepatotropic virus infection (i.e., HBV or HCV) or hepatocellular carcinoma (also induced by viral infection). Results from these studies are heterogeneous, differing with ethnicity and population age, and the role of rs371194629 is unclear. For these reasons, we decided to perform a meta-analysis of these results, concluding that the 14-bp ins/del polymorphism does not significantly contribute to hepatic injury.

[Bilateral submandibulectomy for the treatment of drooling in pediatric age: 10 years of experience]. / Submandibulectomía bilateral para tratamiento de sialorrea en edad pediátrica.

INTRODUCTION: Sialorrhea is a medical problem and can become a social issue, common in children with neurological disabilities. The bilateral submandibulectomy is one of the available treatment options for managing this pathology. AIM OF THE STUDY: The aim of this study is to evaluate the effectiveness of bilateral submandibulectomy in the management of sialorrhea in children with neurological disabilities through the parents' satisfaction grade. PATIENTS AND METHODS: We retrospectively analyzed 91 bilateral submandibulectomies for a period of time of 10 years (2004-2015). Data were taken from surgical records and patients files and were informatically processed. The severity grade before and after surgery was evaluated in line with the modified Teacher scale. Parental satisfaction was evaluated by applying a scale graded into five classes, according to the degree of sialorrhea severity in postoperative period. RESULTS: During the reporting period, 91 children underwent bilateral submandibulectomy in our center. Of these, 7 cases were excluded for lack of data. The average age of the children was 8,9 [± 3,5] years; 58,3% were male. The degree of preoperative sialorrhea severity was, in 52,4% of cases, level 4 (severe drooling), and in 28,6%, level 5 (very severe). The grade of parental satisfaction in postoperative period was ranked, in 73,8% of cases, between 81-100%. CONCLUSIONS: For children with drooling, a bilateral submandibulectomy emerges as an effective and efficient treatment, leaving parents with an extremely high satisfaction grade.

INTRODUCCION: La sialorrea es un problema médico y social, común en los niños con enfermedad neurológica. La submandibulectomía surge como una opción terapéutica posible y eficaz para esta patología. OBJETIVO: Evaluar la eficacia de la submandibulectomía bilateral, a través del grado de satisfacción de los padres de niños con sialorrea, sometidos a este procedimiento. MATERIAL Y METODOS: Análisis retrospectivo de 91 casos de niños sometidos a submandibulectomía bilateral durante 10 años (2004 a 2015). Los datos fueron obtenidos de los registros clínicos de cada paciente y tratados informáticamente. El grado de severidad en el pre y postoperatorio fue evaluado según la escala de Teacher modificada. La satisfacción de los padres fue evaluada a través de la aplicación de una escala que se divide en 5 clases, conforme el grado de severidad de sialorrea en el postoperatorio. RESULTADOS: Durante el periodo analizado, fueron sometidos a submandibulectomía bilateral 91 niños. De estos, fueron excluidos 7 casos por ausencia de datos. La edad media de los niños fue de 8,9 [± 3,5] años, siendo 58,3% del sexo masculino. El grado de severidad de sialorrea preoperatoria fue, en 52,4% de los casos, de nivel 4 (sialorrea grave) y, en 28,6%, de nivel 5 (muy grave). El grado de satisfacción de los padres fue alto o muy alto en el 94% de los casos. CONCLUSION: Para los niños con sialorrhea, la submandibulectomía surge como un tratamiento eficaz, que deja a los padres muy satisfechos y permite una mejor integración de los niños en la sociedad.

Polymorphisms in Host Immunity-Modulating Genes and Risk of Invasive Aspergillosis: Results from the AspBIOmics Consortium.

Recent studies suggest that immune-modulating single-nucleotide polymorphisms (SNPs) influence the risk of developing cancer-related infections. Here, we evaluated whether 36 SNPs within 14 immune-related genes are associated with the risk of invasive aspergillosis (IA) and whether genotyping of these variants might improve disease risk prediction. We conducted a case-control association study of 781 immunocompromised patients, 149 of whom were diagnosed with IA. Association analysis showed that the IL4Rrs2107356 and IL8rs2227307 SNPs (using dbSNP numbering) were associated with an increased risk of IA (IL4Rrs2107356 odds ratio [OR], 1.92; 95% confidence interval [CI], 1.20 to 3.09; IL8rs2227307 OR, 1.73; 95% CI, 1.06 to 2.81), whereas the IL12Brs3212227 and IFNγrs2069705 variants were significantly associated with a decreased risk of developing the infection (IL12Brs3212227 OR, 0.60; 95% CI, 0.38 to 0.96; IFNγrs2069705 OR, 0.63; 95% CI, 0.41 to 0.97). An allogeneic hematopoietic stem cell transplantation (allo-HSCT)-stratified analysis revealed that the effect observed for the IL4Rrs2107356 and IFNγrs2069705 SNPs was stronger in allo-HSCT (IL4Rrs2107356 OR, 5.63; 95% CI, 1.20 to 3.09; IFNγrs2069705 OR, 0.24; 95% CI, 0.10 to 0.59) than in non-HSCT patients, suggesting that the presence of these SNPs renders patients more vulnerable to infection, especially under severe and prolonged immunosuppressive conditions. Importantly, in vitro studies revealed that carriers of the IFNγrs2069705C allele showed a significantly increased macrophage-mediated neutralization of fungal conidia (P = 0.0003) and, under stimulation conditions, produced higher levels of gamma interferon (IFNγ) mRNA (P = 0.049) and IFNγ and tumor necrosis factor alpha (TNF-α) cytokines (P value for 96 h of treatment with lipopolysaccharide [PLPS-96 h], 0.057; P value for 96 h of treatment with phytohemagglutinin [PPHA-96 h], 0.036; PLPS+PHA-96 h = 0.030; PPHA-72 h = 0.045; PLPS+PHA-72 h = 0.018; PLPS-96 h = 0.058; PLPS+PHA-96 h = 0.0058). Finally, we also observed that the addition of SNPs significantly associated with IA to a model including clinical variables led to a substantial improvement in the discriminatory ability to predict disease (area under the concentration-time curve [AUC] of 0.659 versus AUC of 0.564; P-2 log likehood ratio test = 5.2 · 10(-4) and P50.000 permutation test = 9.34 · 10(-5)). These findings suggest that the IFNγrs2069705 SNP influences the risk of IA and that predictive models built with IFNγ, IL8, IL12p70, and VEGFA variants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.

Comprehensive analysis of polymorphisms in the HLA-G 5' upstream regulatory and 3' untranslated regions in Brazilian patients with systemic lupus erythematosus.

This study aims to comprehensively analyze human leucocyte antigen (HLA)-G polymorphisms association with susceptibility to systemic lupus erythematosus (SLE) development and clinical manifestations. The HLA-G 5' upstream regulatory region (URR), 3' untranslated region (UTR) and a cytosine deletion at exon 3 (ΔC, HLA-G*0105N allele) were analyzed in 114 SLE patients and 128 healthy controls from North East Brazil. The +3003T>C (rs1707) C allele and the HG010101c extended HLA-G allele were significantly more frequent in SLE patients than healthy controls (+3003C allele frequency: 12% in SLE patients vs 6% in controls; odds ratio (OR), 2.10, 95% confidence interval (CI), 1.06-4.28, P = 0.026; HG010101c frequency: 11.8% in SLE patients and 6.3% in controls; OR, 2.14, 95% CI, 1.01-4.51, P = 0.046) and were associated with susceptibility for disease development. Other polymorphisms were associated with different clinical manifestations. Although HLA-G role in SLE disease is far from being elucidated yet, our association study results along with a systematic review and meta-analysis suggest that HLA-G might be able to slightly modulate the complex SLE phenotype (pooled OR, 1.14, 95% CI, 1.02-1.27, P = 0.021).

Development of microsatellite markers for Hancornia speciosa Gomes (Apocynaceae).

Herein, we describe 34 microsatellite loci developed using an enrichment genomic library for the tree species Hancornia speciosa Gomes (Apocynaceae). Thirty-five individuals were genotyped using 34 primers to analyze the polymorphisms at each locus. The number of alleles per locus ranged from 4 to 20. The average number of alleles was 8.11, and the expected heterozygosity ranged from 0.62 to 0.94. These microsatellite primers will be useful in population genetics studies for this species.

A rapid screening of ancestry for genetic association studies in an admixed population from Pernambuco, Brazil.

Genetic association studies determine how genes influence traits. However, non-detected population substructure may bias the analysis, resulting in spurious results. One method to detect substructure is to genotype ancestry informative markers (AIMs) besides the candidate variants, quantifying how much ancestral populations contribute to the samples' genetic background. The present study aimed to use a minimum quantity of markers, while retaining full potential to estimate ancestries. We tested the feasibility of a subset of the 12 most informative markers from a previously established study to estimate influence from three ancestral populations: European, African and Amerindian. The results showed that in a sample with a diverse ethnicity (N = 822) derived from 1000 Genomes database, the 12 AIMs had the same capacity to estimate ancestries when compared to the original set of 128 AIMs, since estimates from the two panels were closely correlated. Thus, these 12 SNPs were used to estimate ancestry in a new sample (N = 192) from an admixed population in Recife, Northeast Brazil. The ancestry estimates from Recife subjects were in accordance with previous studies, showing that Northeastern Brazilian populations show great influence from European ancestry (59.7%), followed by African (23.0%) and Amerindian (17.3%) ancestries. Ethnicity self-classification according to skin-color was confirmed to be a poor indicator of population substructure in Brazilians, since ancestry estimates overlapped between classifications. Thus, our streamlined panel of 12 markers may substitute panels with more markers, while retaining the capacity to control for population substructure and admixture, thereby reducing sample processing time.

Association of the HLA-B*52 allele with non-progression to AIDS in Brazilian HIV-1-infected individuals.

Several human leukocyte antigen (HLA) class I alleles are associated with the susceptibility to human immunodeficiency virus-1 (HIV-1) infection and/or AIDS progression. Of these, the HLA-B alleles are considered the strongest genetic determinant of disease outcome. We evaluated the influence of the HLA-B alleles on AIDS progression among HIV-1-positive individuals from Rio de Janeiro, Brazil, who were categorized as rapid progressors (RPs), typical progressors (TPs) or long-term non-progressors (LTNPs). In this study, significant differences in HLA-B allele frequencies were observed among the three progression groups for the B*48, B*49 and B*52 alleles. After controlling for other factors associated with AIDS progression, the presence of the B*52 allele was shown to be a significant protective factor (hazard ratio (HR) 0.49 (95% confidence interval (CI) 0.27-0.90) P<0.03). Although no direct association was observed between the presence of the B*27 or B*57 allele and the LTNP profile compared with the TP or RP groups, the adjusted model confirmed that these alleles are protective factors against AIDS progression (HR 0.62 (95% CI 0.38-0.99) P<0.05), as previously described. These data corroborate the existence of significant differences in HLA-B allele frequencies among the distinct AIDS progression profiles and further elucidate the role of HLA alleles in the outcome of HIV infections in diverse populations.

Gene therapy approach to FAP: in vivo influence of T119M in TTR deposition in a transgenic V30M mouse model.

Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by extracellular deposition of amyloid fibrils composed by mutated transthyretin (TTR) mainly in the peripheral nervous system. At present, liver transplantation is still the standard treatment to halt the progression of clinical symptoms in FAP, but new therapeutic strategies are emerging, including the use of TTR stabilizers. Here we propose to establish a new gene therapy approach using adeno-associated virus (AAV) vectors to deliver the trans-suppressor TTR T119M variant to the liver of transgenic TTR V30M mice at different ages. This TTR variant is known for its ability to stabilize the tetrameric protein. Analysis of the gastrointestinal tract of AAV-treated animals revealed a significant reduction in deposition of TTR non-fibrillar aggregates in as much as 34% in stomach and 30% in colon, as well as decreased levels of biomarkers associated with TTR deposition, namely the endoplasmic reticulum stress marker BiP and the extracellular matrix protein MMP-9. Moreover, we showed with different studies that our approach leads to an increase in tetrameric and more stable forms of TTR, in favor of destabilized monomers. Altogether our data suggest the possibility to use this gene therapy approach in a prophylactic manner to prevent FAP pathology.