Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution.

The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation and cancer. While coding variation in HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 individuals and 1,131,414 single cells from three tissues. To mitigate technical confounding, we developed scHLApers, a pipeline to accurately quantify single-cell HLA expression using personalized reference genomes. We identified cell-type-specific cis-eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B and T cells. For example, a T cell HLA-DQA1 eQTL ( rs3104371 ) is strongest in cytotoxic cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.

Identification of a regulatory pathway governing TRAF1 via an arthritis-associated non-coding variant.

TRAF1/C5 was among the first loci shown to confer risk for inflammatory arthritis in the absence of an associated coding variant, but its genetic mechanism remains undefined. Using Immunochip data from 3,939 patients with juvenile idiopathic arthritis (JIA) and 14,412 control individuals, we identified 132 plausible common non-coding variants, reduced serially by single-nucleotide polymorphism sequencing (SNP-seq), electrophoretic mobility shift, and luciferase studies to the single variant rs7034653 in the third intron of TRAF1. Genetically manipulated experimental cells and primary monocytes from genotyped donors establish that the risk G allele reduces binding of Fos-related antigen 2 (FRA2), encoded by FOSL2, resulting in reduced TRAF1 expression and enhanced tumor necrosis factor (TNF) production. Conditioning on this JIA variant eliminated attributable risk for rheumatoid arthritis, implicating a mechanism shared across the arthritis spectrum. These findings reveal that rs7034653, FRA2, and TRAF1 mediate a pathway through which a non-coding functional variant drives risk of inflammatory arthritis in children and adults.

Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution.

The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation, and cancer. While coding variation in HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here, we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 individuals and 1,131,414 single cells from three tissues, using personalized reference genomes to mitigate technical confounding. We identified cell-type-specific cis-eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B, and T cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.

How Ancestry Influences the Chances of Finding Unrelated Donors: An Investigation in Admixed Brazilians.

A match of HLA loci between patients and donors is critical for successful hematopoietic stem cell transplantation. However, the extreme polymorphism of HLA loci - an outcome of millions of years of natural selection - reduces the chances that two individuals will carry identical combinations of multilocus HLA genotypes. Further, HLA variability is not homogeneously distributed throughout the world: African populations on average have greater variability than non-Africans, reducing the chances that two unrelated African individuals are HLA identical. Here, we explore how self-identification (often equated with "ethnicity" or "race") and genetic ancestry are related to the chances of finding HLA compatible donors in a large sample from Brazil, a highly admixed country. We query REDOME, Brazil's Bone Marrow Registry, and investigate how different criteria for identifying ancestry influence the chances of finding a match. We find that individuals who self-identify as "Black" and "Mixed" on average have lower chances of finding matches than those who self-identify as "White" (up to 57% reduction). We next show that an individual's African genetic ancestry, estimated using molecular markers and quantified as the proportion of an individual's genome that traces its ancestry to Africa, is strongly associated with reduced chances of finding a match (up to 60% reduction). Finally, we document that the strongest reduction in chances of finding a match is associated with having an MHC region of exclusively African ancestry (up to 75% reduction). We apply our findings to a specific condition, for which there is a clinical indication for transplantation: sickle-cell disease. We show that the increased African ancestry in patients with this disease leads to reduced chances of finding a match, when compared to the remainder of the sample, without the condition. Our results underscore the influence of ancestry on chances of finding compatible HLA matches, and indicate that efforts guided to increasing the African component of registries are necessary.

Neutron radiation effects on an electronic system on module.

The NUMEN (NUclear Matrix Elements for Neutrinoless double beta decay) project was recently proposed with the aim to investigate the nuclear response to Double Charge Exchange reactions for all the isotopes explored by present and future studies of 0νßß decay. The expected level of radiation in the NUMEN experiment imposes severe limitations on the average lifetime of the electronic devices. During the experiments, it is expected that the electronic devices will be exposed to about 105 neutrons/cm2/s according to FLUKA simulations. This paper investigates the reliability of a System On Module (SOM) under neutron radiation. The tests were performed using thermal, epithermal, and fast neutrons produced by the Instituto de Pesquisas Energéticas e Nucleares 4.5 MW Nuclear Research Reactor. The results show that the National Instruments SOM is robust to neutron radiation for the proposed applications in the NUMEN project.

HLApers: HLA Typing and Quantification of Expression with Personalized Index.

The plethora of RNA-seq data which have been generated in the recent years constitutes an attractive resource to investigate HLA variation and its relationship with normal and disease phenotypes, such as cancer. However, next generation sequencing (NGS) brings new challenges to HLA analysis because of the mapping bias introduced by aligning short reads originated from polymorphic genes to a single reference genome. Here we describe HLApers, a pipeline which adapts widely used tools for analysis of standard RNA-seq data to infer HLA genotypes and estimate expression. By generating reliable expression estimates for each HLA allele that an individual carries, HLApers allows a better understanding of the relationship between HLA alleles and phenotypes manifested by an individual.

Idiopathic Spinal Cord Herniation­Case Report

Idiopathic spinal cord herniation is a rare cause of progressivemyelopathy, especially in the absence of a history of spinal or surgical trauma. The radiological diagnosis ismade through a myelography or an MRI exam. The spinal cord is pushed anteriorly, buffering the dural defect and leading inmost cases to Brown-Séquard syndrome. The present study describes the case of a male patient with a clinical picture of progressive thoracicmyelopathy. In the clinical and radiological investigation, an idiopathic spinal cord herniation on the chest level was identified. During the surgery, the spinal cord was reduced to the natural site, taking its usual elliptical shape, and the dural defect was repaired with a dural substitute. The numbness of the patient improved, and the shocks in the lower limbs disappeared. A postoperative MRI confirmed the surgical reduction of the herniation and the restoration of the anterior cerebrospinal fluid (CSF) column to the spinal cord. The authors describe the clinical, radiological, intraoperative, and postoperative evolution.

Comparison of DGGE and immunohistochemistry in the detection of TP53 variants in a Brazilian sample of sporadic breast tumors.

The presence of TP53 gene mutations in breast cancer has been associated with worse prognosis. These mutations interfere with the ability of the p53 protein, a transcription factor, to regulate the expression of target genes. Unlike the wild-type protein, which is rapidly degraded in cells, mutated forms have increased half-life and accumulate in tumor cells. Immunohistochemistry (IHC) is widely used in Brazil in the determination of breast cancer patients' prognosis. However, this technique is not able to detect many altered forms of the p53 protein (false-negative results) and readily detects the accumulation of wild-type p53 (false-positive results) that is associated with non-tumoral processes. For these reasons, we have set out to compare the efficiency of IHC with a molecular technique that detects gene variations at the DNA level in the evaluation of Brazilian patients with sporadic breast cancer. We have used denaturing gradient gel electrophoresis (DGGE) to study the TP53 status in 45 tumors, finding 26 allelic variants, most of them located in exon 4. Comparing the two techniques, IHC showed a false-negative rate of 64% and a false-positive rate of 50%. These results confirm the inability of IHC to correctly detect TP53 status, reason because it should not be routinely used to establish prognosis of breast cancer patients in Brazilian Pathology Laboratories. We recommend the utilization of a screening method, such as DGGE, followed by sequencing of altered exonic fragments to correctly detect TP53 gene variants and establish the prognosis of breast cancer patients.

A influência das técnicas de mobilização com impulso na postura estática / The infl uence of mobilization techniques with impulse in static posture

O corpo humano mantém o seu padrão postural estático atravésde mecanismos autorreguladores do sistema nervoso reagindo acondições que lhe são impostas, sejam de origem interna ou externa.As técnicas de mobilização com impulso (TMI) aplicadas sobre acoluna vertebral promovem um ganho de mobilidade em áreasrestritas do sistema musculoesquelético, o que contribui para umrealinhamento postural. Este estudo teve como objetivo investigaro grau de signifi cância e relevância antes e após a aplicação das TMInos segmentos vertebrais cervicais, torácicos e lombares de 28 indivíduosassintomáticos, variando entre 20 a 48 anos. Foi mensuradaa variação no plano sagital dos ângulos torácicos e lombares com acifolordometria e a variação no plano transversal da pressão plantarcom a baropodometria eletrônica dos 28 indivíduos. Os resultadossugerem que ocorreram alterações das medianas do ângulo torácico(p = 0,005) e da pressão plantar (p = 0,028), antes e após a aplicaçãodas TMI, fazendo com que os indivíduos adotassem um novopadrão estático...

Th e human body maintains its standard static postural throughself-regulatory mechanisms of the nervous system reacting toconditions that are imposed to it, either from internal or externalorigin. Th e mobilization with impulse technique (MIT) applied onthe spinal column promotes a mobility gain in restricted areas ofthe musculoskeletal system helping to a postural realignment. Th eaim of this study was to investigate the signifi cance and importancelevel before and after MIT procedures in the cervical, thoracic andlumbar segments in 28 asymptomatic subjects, 20-48 years old. Itwas measured the variation in the sagittal alignment of the thoracicand lumbar angles with the kyphosis-lordosis measurement deviceand the variation in the transversal plan of the plantar pressure withthe electronic baropodometry of 28 individuals. Th e results suggestthat alterations on the median thoracic angle (p = 0,005) and on theplantar pressure (p = 0,028) occurred, before and after the applicationof MIT, and the individuals had to adopt a new static posture...