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In response to environmental changes cells rapidly rearrange their gene expression pattern in order to adapt to the new conditions. Chromatin remodeling is critical for this process playing a major role in the induction of genes involved in stress responses. We demonstrated previously that TPK1, encoding one of the catalytic subunits of PKA from Saccharomyces cerevisiae, is upregulated under heat shock. Herein, we investigate the chromatin remodeling of the TPK1, TPK2 and TPK3 promoters under heat stress. The TPK1 promoter is the only one that presents three positioned nucleosomes. Upon heat stress or osmostress these nucleosomes are evicted in clear correlation with promoter activation and upregulation of TPK1 mRNA levels. We find that remodelers SWI/SNF, RSC, INO80 and ISW1 participate in chromatin remodeling of the TPK1 promoter under thermal stress conditions. RSC and INO80 are necessary for nucleosomes positioning and contribute to repression of the TPK1 promoter under normal conditions while SWI/SNF participates in the eviction of nucleosomes after heat stress. SWI/SNF complex is recruited to the TPK1 promoter upon heat shock in a Msn2/4-dependent manner. Finally, both Tpk1 and Tpk2 catalytic subunits are recruited to the TPK1 promoter with opposite association patterns. Tpk1 catalytic activity is necessary for nucleosome rearrangement on the TPK1 promoter while Tpk2 and Tpk3 inhibit the promoter activity and maintain a repressive chromatin conformation. This work enlightens the mechanism of regulation of TPK1 expression during heat-stress, contributing to the knowledge of specificity in fine-tuning the cAMP-PKA signaling circuit.

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BACKGROUND: Liver transplantation (LT) can be associated with early complications, such as allograft dysfunction and acute kidney injury, which contribute significantly to morbidity and mortality. High-mobility group box 1 protein (HMGB1) has been identified as mediator in ischemia-reperfusion injury. Nucleosomes are complexes formed by DNA and histone proteins, and histones contribute to organs failure and death during sepsis. METHODS: HMGB1 and nucleosome plasma levels were measured, by enzyme-linked immunosorbent assays, during LT and in the first 48 post-operative hours in 22 LT patients. The association between HMGB1 and nucleosome levels and the complications and survival within 6 months after LT were investigated. RESULTS: We observed peak HMGB1 and nucleosome levels after graft reperfusion. HMGB1 and nucleosome levels were associated with the occurrence of acute kidney injury, early allograft dysfunction, and early survival after LT. Nucleosome levels after graft reperfusion were associated with the occurrence of systemic inflammatory response syndrome. CONCLUSIONS: HMGB1 and nucleosome levels increased after liver reperfusion in human LT setting and were associated with early complications and survival. New studies are necessary to explore their role as early markers of hepatocellular injury in human LT and the risk of graft and organs dysfunction and death.

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[This corrects the article on p. 221 in vol. 6, PMID: 26029207.].

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Autoimmune dysfunctions are the "bête noire" in a range of debilitating nephropathies. Autoimmune-mediated damage to the kidneys can be triggered by autoantibodies directed against specific proteins or renal structures, for example, the phospholipase A2 receptor or the glomerular basement membrane, resulting in glomerular diseases such as primary membranous nephropathy or Goodpasture's disease. Moreover, secondary damage to the kidney can be part of the wide-reaching effects of systemic autoimmune diseases such as vasculitis or systemic lupus erythematosus (SLE) - the latter counts lupus nephritis among its most severe manifestations. Systemic autoimmune diseases are characterized by non-organ-specific autoantibodies, directed for example against neutrophil cytoplasmic antigens in systemic vasculitis and against double-stranded DNA and nucleosomes in SLE. A large variety of innovative and highly specific and sensitive autoantibody tests have been developed in the last years that are available to identify autoimmune kidney diseases at an early stage. Thus, serological in vitro diagnostics allow for appropriate interventional therapy in order to prevent disease progression often resulting in need of dialysis and transplantation.

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Actualmente se percibe una necesidad apremiante en la identificación y validación debiomarcadores que reflejen tempranamente el inicio de actividad lúpica o que se conviertanen predictores de la misma. La actividad clínica del lupus eritematoso sistémico (LES) esondulante a lo largo del tiempo y la actividad subyacente persistente lleva a daño tisular.Este daño es reflejo de cambios irreversibles en la función y estructura orgánica, por loque la prevención, más que el tratamiento, debería ser la meta de cualquier terapia enLES y así lograr disminuir la morbimortalidad y los costos directos e indirectos causadospor la enfermedad. Es necesario encontrar biomarcadores no invasivos de actividadlúpica que no solo permitan tomar de forma oportuna decisiones terapéuticas, sino quetambién se correlacionen con los desenlaces clínicos y sean útiles en los ensayos clínicos,permitiendo acortar el tiempo del desarrollo de estos estudios. Este artículo pretendebuscar la evidencia que se tiene con respecto a los nuevos biomarcadores existentes paraactividad de la enfermedad en LES y su utilidad actual y futura, enfatizando en la necesidadde buscar nuevas moléculas que permitan un diagnóstico más precoz de la actividad de laenfermedad.

There is a need for the identification and validation of biomarkers that reflect the early onset of lupus activity or may be predictors of this. The clinical activity of systemic lupus erythematosus (SLE) fluctuates over time and the underlying activity leads to persistent tissue damage. This damage is a reflection of irreversible changes in the function and organic structure, so prevention, rather than treatment, should be the goal of any therapy in SLE.This will reduce morbidity, mortality, direct and indirect costs caused by the disease. It is necessary to find biomarkers of lupus activity that not only allow making treatment decisions in the short term, but also to correlate with clinical outcomes. These could also be useful in clinical trials and may shorten the duration of these studies. This article aims to find evidence on new biomarkers for SLE disease activity, and their current and future use. Emphasis will be made on the need to find new molecules for an early diagnosis of disease activity.

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OBJETIVOS: Determinar a frequência de anticorpos contra componentes da cromatina no lúpus eritematoso sistêmico juvenil (LESJ) e correlacionar a presença desses autoanticorpos com manifestações clínicas e atividade da doença. MÉTODOS: Os anticorpos anticromatina (anti-CHR), antinucleossomo (anti-NCS) e anti-dsDNA foram medidos em 175 indivíduos, incluindo 37 pacientes com LESJ ativo e 41 com doença inativa, 47 com doenças autoimunes não lúpicas, e 50 crianças saudáveis. Um teste ELISA in house foi desenvolvido com nucleossomos purificados a partir de timo de bezerro para determinar os anticorpos IgG e IgG3 anti-NCS. Anti-CHR e anti-dsDNA foram detectados por kits comerciais de ELISA (INOVA). RESULTADOS: Anticorpos anti-NCS e anti-CHR exibiram não só uma alta especificidade para LESJ, mas também uma frequência semelhante em LESJ ativo e inativo. Os níveis séricos de anti-CHR e IgG/IgG3 anti-NCS não diferiram entre LESJ ativo e inativo. Houve correlação entre o SLEDAI e os anticorpos anti-dsDNA, mas não com os anticorpos contra outros componentes da cromatina. Houve associação de anticorpos anti-dsDNA, anti-CHR e IgG/IgG3 anti-NCS com proteinúria e baixos níveis séricos de C4. Foram observados anticorpos anti-NCS em 14% dos pacientes com LESJ na ausência de anticorpos anti-dsDNA. CONCLUSÕES: Nossos dados indicam que os anticorpos anti-NCS e anti-CHR são marcadores diagnósticos relevantes para LESJ e parecem estar correlacionados com a atividade da nefrite lúpica no LESJ. O anticorpo IgG3 anti-NCS não parece ser mais relevante como marcador de atividade da doença ou nefrite ativa no LESJ em comparação ao anticorpo IgG anti-NCS.

OBJECTIVES: To determine the frequency of antibodies to chromatin components in juvenile systemic lupus erythematosus (JSLE), and to correlate the presence of these autoantibodies with clinical manifestations and disease activity. METHODS: Anti-chromatin (anti-CHR), anti-nucleosome core particle (anti-NCS) and anti-dsDNA antibodies were measured in 175 individuals, including 37 patients with active JSLE and 41 with inactive disease, 47 non-lupus autoimmune disease patients (non-lupus AD), and 50 healthy children. An in-house ELISA was developed with purified nucleosome core particles from calf thymus to determine IgG and IgG3 anti-NCS antibodies. Anti-CHR and anti-dsDNA antibodies were detected by commercial ELISA kits (INOVA). RESULTS: Anti-NCS and anti-CHR antibodies exhibited high specificity for JSLE and similar frequency in active and inactive JSLE. Anti-CHR and IgG/IgG3 anti-NCS serum levels did not differ between active and inactive JSLE. SLEDAI correlated with anti-dsDNA antibodies but not with antibodies to other chromatin components. There was association of anti-dsDNA, anti-CHR and IgG/IgG3 anti-NCS antibodies with proteinuria and low C4 serum levels. Anti-NCS antibodies in the absence of anti-dsDNA were observed in 14% of the JSLE patients. CONCLUSIONS: Our data indicate that anti-NCS and anti-CHR antibodies are relevant diagnostic markers for JSLE and appear to be correlated with JSLE lupus nephritis activity. IgG3 isotype anti-NCS antibodies do not seem to be more relevant than IgG anti-NCS antibodies as markers of disease activity or active nephritis in JSLE.

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OBJETIVO: Avaliar a associação entre a presença de anticorpos antinucleossomo (anti-NCS) e a síndrome antifosfolipídica primária (SAFP) e o posterior desenvolvimento de lúpus eritematoso sistêmico (LES). MATERIAIS E MÉTODOS: Trinta e seis mulheres com o diagnóstico de SAFP foram avaliadas prospectivamente para manifestações de doenças reumáticas autoimunes e para a presença de anticorpos antifosfolípides, anticorpos antinucleares e anti-NCS/cromatina. RESULTADOS: Após um período médio de seguimento de 45,7 meses, anticorpos anti-NCS/cromatina foram detectados em apenas uma paciente (2,8%), que desenvolveu manifestações de LES tais como poliartrite, linfopenia, neurite óptica, lesões compatíveis com esclerose múltipla em substância branca cerebral e perfil de autoanticorpos altamente sugestivo de LES. CONCLUSÃO: A frequência de anticorpos anti-NCS/cromatina é baixa em pacientes com SAFP, e sua presença pode associar-se ao desenvolvimento de manifestações de LES.

OBJECTIVE: To study the association of anti-nucleosome (anti-NCS) antibodies in primary antiphospholipid syndrome (APS) and the development of systemic lupus erythematosus (SLE) during follow-up. MATERIALS AND METHODS: Thirty-six women with primary APS were evaluated prospectively for clinical features of systemic autoimmune diseases and for the presence of antiphospholipid antibodies, antinuclear antibodies and anti-NCS/chromatin antibodies. RESULTS: After a mean follow-up period of 45.7 months, anti-NCS/chromatin antibodies were detected in only one patient (2.8%), who developed features of SLE including polyarthritis, lymphopenia, optic neuritis, multiple sclerosis-like lesions, and an autoantibody profile suggestive of SLE. CONCLUSION: The frequency of anti-NCS/chromatin antibodies in primary APS patients is very low, and they may be associated with the development of SLE manifestations.

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