Enrichment of Zα domains at cytoplasmic stress granules is due to their innate ability to bind to nucleic acids.

Zα domains recognize the left-handed helical Z conformation of double-stranded nucleic acids. They are found in proteins involved in the nucleic acid sensory pathway of the vertebrate innate immune system and host evasion by viral pathogens. Previously, it has been demonstrated that ADAR1 (encoded by ADAR in humans) and DAI (also known as ZBP1) localize to cytoplasmic stress granules (SGs), and this localization is mediated by their Zα domains. To investigate the mechanism, we determined the interactions and localization pattern for the N-terminal region of human DAI (ZαßDAI), which harbours two Zα domains, and for a ZαßDAI mutant deficient in nucleic acid binding. Electrophoretic mobility shift assays demonstrated the ability of ZαßDAI to bind to hyperedited nucleic acids, which are enriched in SGs. Furthermore, using immunofluorescence and immunoprecipitation coupled with mass spectrometry, we identified several interacting partners of the ZαßDAI-RNA complex in vivo under conditions of arsenite-induced stress. These interactions are lost upon loss of nucleic acid-binding ability or upon RNase treatment. Thus, we posit that the mechanism for the translocation of Zα domain-containing proteins to SGs is mainly mediated by the nucleic acid-binding ability of their Zα domains. This article has an associated First Person interview with Bharath Srinivasan, joint first author of the paper.

Speech therapy aspects in patients' palliative care / Aspectos fonoaudiológicos de pacientes em cuidados paliativos

ABSTRACT Purpose: to describe the speech therapy aspects of patients treated by the palliative care team in a hospital. Methods: an observational and cross-sectional study, performed from medical records of patients treated under Palliative Care Program, in a hospital, from July to September 2018. Information from the anamnesis and speech-language assessments, which were analyzed by frequency measures, were collected. Results: the sample was composed by 41 medical records, including 25 males and 16 females, with an average age of 61.2 years and hospitalization average time of 20.7 days. Oral feeding was present in 73% of the sample. It was observed that 24% of the patients had impaired expressive language, 56% had reduced maximum phonation times and 34% showed altered mobility phonoarticulatory organs. For swallowing, 22% showed difficulty in some consistency. A nutritional feeding was verified in 74% of the sample and the remaining was making use of comfort feeding. In relation to assistance, 46% of the sample was under management, 7% in therapy, and the remaining did not have follow-up indication. Conclusion: relevant alterations to orofacial motricity, voice, language and swallowing were found in patients under palliative care.

RESUMO Objetivo: caracterizar aspectos fonoaudiológicos de pacientes atendidos pela equipe de cuidados paliativos em complexo hospitalar. Métodos: estudo transversal, observacional, realizado a partir de dados de prontuários de pacientes internados pelo Programa de Cuidados Paliativos de um hospital, no período entre julho e setembro de 2018. Foram coletadas informações da anamnese e avaliações fonoaudiológicas, as quais foram analisadas por medidas de frequência para as variáveis categóricas e medidas de tendência central e dispersão para as variáveis contínuas. Resultados: a amostra foi composta por 41 prontuários, referentes a 25 homens e 16 mulheres, com média de idade de 61,2 anos e tempo médio de internação de 20,7 dias. A alimentação oral esteve presente em 73% da amostra. Observou-se que 24% dos pacientes apresentavam linguagem expressiva prejudicada, 56% apresentaram tempos máximos de fonação reduzidos e 34% mobilidade de órgãos fonoarticulatórios alterada. Quanto à deglutição, 22% apresentaram dificuldade em alguma consistência. Dieta para nutrição foi verificada em 74% da amostra e o restante fazia uso de dieta para conforto. Sobre a assistência, 46% da amostra estava em gerenciamento, 7% em terapia, demais sem acompanhamento. Conclusão: foram encontradas alterações pertinentes à motricidade orofacial, voz, linguagem e deglutição em pacientes em cuidados paliativos.

Parameters for Applying the Brainstem Auditory Evoked Potential with Speech Stimulus: Systematic Review

Abstract Introduction Studies using the Brainstem Auditory Evoked Potential with speech stimulus are increasing in Brazil, and there are divergences between the methodologies used for testing. Objectives To analyze the parameters used in the study of the Brainstem Auditory Evoked Potentials with speech stimulus. Data Synthesis The survey was performed using electronic databases. The search strategy was as follows: "Evoked potentials, auditory" OR "Brain stem" OR "Evoked potentials, auditory, brain stem" AND "Speech." The survey was performed from June to July of 2016. The criteria used for including articles in this study were: being written in Portuguese, English or Spanish; presenting the description of the testing parameters and the description of the sample. In the databases selected, 2,384 articles were found, and 43 articles met all of the inclusion criteria. The predominance of the following parameters was observed to achieve the potential during study: stimulation with the syllable /da/; monaural presentation with greater use of the right ear; intensity of 80 dB SPL; vertical placement of electrodes; use of in-ear headphones; patient seated, distracted in awake state; alternating polarity; use of speech synthesizer software for the elaboration of stimuli; presentation rate of 10.9/s; and sampling rate of 20 kHz. Conclusions The theme addressed in this systematic review is relatively recent. However, the results are significant enough to encourage the use of the procedure in clinical practice and advise clinicians about the most used procedures in each parameter.

Parameters for Applying the Brainstem Auditory Evoked Potential with Speech Stimulus: Systematic Review.

Introduction Studies using the Brainstem Auditory Evoked Potential with speech stimulus are increasing in Brazil, and there are divergences between the methodologies used for testing. Objectives To analyze the parameters used in the study of the Brainstem Auditory Evoked Potentials with speech stimulus. Data Synthesis The survey was performed using electronic databases. The search strategy was as follows: "Evoked potentials, auditory" OR "Brain stem" OR "Evoked potentials, auditory, brain stem" AND "Speech." The survey was performed from June to July of 2016. The criteria used for including articles in this study were: being written in Portuguese, English or Spanish; presenting the description of the testing parameters and the description of the sample. In the databases selected, 2,384 articles were found, and 43 articles met all of the inclusion criteria. The predominance of the following parameters was observed to achieve the potential during study: stimulation with the syllable /da/; monaural presentation with greater use of the right ear; intensity of 80 dB SPL; vertical placement of electrodes; use of in-ear headphones; patient seated, distracted in awake state; alternating polarity; use of speech synthesizer software for the elaboration of stimuli; presentation rate of 10.9/s; and sampling rate of 20 kHz. Conclusions The theme addressed in this systematic review is relatively recent. However, the results are significant enough to encourage the use of the procedure in clinical practice and advise clinicians about the most used procedures in each parameter.

The Structure of the Cyprinid herpesvirus 3 ORF112-Zα·Z-DNA Complex Reveals a Mechanism of Nucleic Acids Recognition Conserved with E3L, a Poxvirus Inhibitor of Interferon Response.

In vertebrate species, the innate immune system down-regulates protein translation in response to viral infection through the action of the double-stranded RNA (dsRNA)-activated protein kinase (PKR). In some teleost species another protein kinase, Z-DNA-dependent protein kinase (PKZ), plays a similar role but instead of dsRNA binding domains, PKZ has Zα domains. These domains recognize the left-handed conformer of dsDNA and dsRNA known as Z-DNA/Z-RNA. Cyprinid herpesvirus 3 infects common and koi carp, which have PKZ, and encodes the ORF112 protein that itself bears a Zα domain, a putative competitive inhibitor of PKZ. Here we present the crystal structure of ORF112-Zα in complex with an 18-bp CpG DNA repeat, at 1.5 Å. We demonstrate that the bound DNA is in the left-handed conformation and identify key interactions for the specificity of ORF112. Localization of ORF112 protein in stress granules induced in Cyprinid herpesvirus 3-infected fish cells suggests a functional behavior similar to that of Zα domains of the interferon-regulated, nucleic acid surveillance proteins ADAR1 and DAI.

The role of iNKT cells in the immunopathology of systemic lupus erythematosus.

An increasing body of evidence suggests that CD1d-restricted invariant natural killer T (iNKT) cells play an important immunoregulatory role in a variety of autoimmune diseases in both humans and mouse models. Their role in systemic lupus erythematosus (SLE), however, is not fully determined, as SLE mouse models have yielded conflicting results demonstrating both a protective function and a pathogenic role. The reduced frequency of iNKT cells in peripheral blood of lupus patients supports the idea of a protective role for these cells in the immunopathology of SLE. Therapeutic approaches using glycolipids provide a promising tool to correct numerical iNKT cell deficiencies and to modulate their function. This review highlights the potential role of iNKT cells in lupus immunopathology and summarizes recent studies concerning iNKT cells in SLE patients, lupus-prone murine models and glycolipid therapy.

A defect in Marco expression contributes to systemic lupus erythematosus development via failure to clear apoptotic cells.

Systemic lupus erythematosus is a multisystem autoimmune disease characterized by the production of numerous antinuclear autoantibodies and inflammatory mediators. The BXSB mouse strain is an excellent model of the disease. Previous work has determined a number of important disease susceptibility intervals that have been isolated in separate congenic strains. Here, we have combined expression data from those strains with functional analyses to demonstrate that reduced expression of the innate scavenger receptor Marco (macrophage receptor with collagenous structure) is a primary event in BXSB mice, that reduced mRNA expression is mirrored at the protein level, and that this results in a significant alteration in function. We have confirmed a role for Marco in the clearance of apoptotic cells and a generalized defect in both endocytosis and phagocytosis. The failure to clear apoptotic cells has previously been linked to the development of systemic lupus erythematosus. However, the use of congenic mice with limited phenotypes in this study has enabled us to propose that in the case of Marco at least, disease results from the production of anti-dsDNA Abs.

BXSB/long-lived is a recombinant inbred strain containing powerful disease suppressor loci.

The BXSB strain of recombinant inbred mice develops a spontaneous pathology that closely resembles the human disease systemic lupus erythematosus. Six non-MHC loci, Yaa, Bxs1-4, and Bxs6, have been linked to the development of aspects of the disease while a further locus, Bxs5, may be a BXSB-derived disease suppressor. Disease development is delayed in a substrain of BXSB, BXSB/MpJScr-long-lived (BXSB/ll). We compared the genetic derivation of BXSB/ll mice to the original strain, BXSB/MpJ, using microsatellite markers and single nucleotide polymorphisms across the genome. These differences were clustered and included two regions known to be important in the disease-susceptibility of these mice, Bxs5 and 6, as well as regions on chromosomes 5, 6, 9, 11, 12, and 13. We compared BXSB/ll to >20 strains including the BXSB parental SB/Le and C57BL/6 strains. This revealed that BXSB/ll is a separate recombinant inbred line derived from SB/Le and C57BL/6, but distinctly different from BXSB, that most likely arose due to residual heterozygosity in the BXSB stock. Despite the continued presence of the powerful disease-susceptibility locus Bxs3, BXSB/ll mice do not develop disease. We propose that the disappearance of the disease phenotype in the BXSB/ll mice is due to the inheritance of one or more suppressor loci in the differentially inherited intervals between the BXSB/ll and BXSB strains.

The Bxs6 locus of BXSB mice is sufficient for high-level expression of gp70 and the production of gp70 immune complexes.

High levels of the retroviral envelope protein gp70 and gp70 immune complexes have been linked to a single locus on chromosome 13 (Bxs6) in the BXSB model, to which linkage of nephritis was also seen. Congenic lines containing the BXSB Bxs6 interval on a non-autoimmune C57BL/10 background were bred in the presence or absence of the BXSB Y chromosome autoimmune accelerator gene (Yaa), which accelerates disease in male mice. In these mice, we have shown that Bxs6 is sufficient to cause high-level expression of gp70 and the production of gp70 autoantibodies, independently of Yaa, with gp70 immune complex levels enhanced by Yaa. In the presence of Yaa, Bxs6 also causes mild nephritis, and interestingly the sporadic production of high levels of anti-DNA Abs in some mice. Fine mapping using rare recombinant mice suggested that Bxs6 lies between 59.7 and 74.8 megabases (Mb), although the interval of 0.6 Mb between 73.6 and 78.6 Mb on chromosome 13 cannot be excluded in this study.