Infecção por SARS-CoV-2: Manifestações Imunomediadas / SARS-CoV-2 Infection: Immunomediated Manifestations

A associação entre infecção por SARS-CoV-2 e estados inflamatórios e autoimunes é motivo de grande interesse no cenário clínico atual. O vírus apresenta definidas características pró-inflamatórias. Inerente à doença em si, o SARS-CoV-2 ativa macrófagos e induz síntese exacerbada de interleucina (IL)-6, IL-1, fator de necrose tumoral, quimiocinas e fator tecidual. A conhecida "tempestade de citocinas" se associa a um mau prognóstico pulmonar, dano multiorgânico e tendência trombótica. Em paralelo, a presença viral, por mimetismo molecular ou por inibição de células T reguladoras, parece exacerbar respostas linfocíticas e, eventualmente, deflagrar doenças autoimunes. A presente revisão aborda os mecanismos de resposta inata deflagrados pelo SARS-CoV-2 e as doenças autoimunes mais provavelmente associadas à exposição viral.

The association between SARS-CoV-2 infection and inflammatory and autoimmune states is of great interest in the current clinical scenario. The virus has definite pro-inflammatory characteristics. Inherent to the disease itself, SARS-CoV-2 activates macrophages and induces exacerbated synthesis of interleukin (IL)-6, IL-1, tumor necrosis factor, chemokines, and tissue factor. The well-known "cytokine storm" is associated with a poor lung prognosis, multi-organ damage, and thrombotic tendency. In parallel, the viral presence, by molecular mimicry or by inhibiting regulatory T cells, appears to exacerbate lymphocytic responses and eventually trigger autoimmune diseases. The present review addresses the innate response mechanisms triggered by SARS-CoV-2 and the autoimmune diseases most likely associated with viral exposure.

Resonant Charge Transfer of Hydrogen Rydberg Atoms Incident on a Cu(100) Projected Band-Gap Surface.

The charge transfer (ionization) of hydrogen Rydberg atoms (n=25-34) incident on a Cu(100) surface is investigated. Unlike fully metallic surfaces, where the Rydberg electron energy is degenerate with the conduction band of the metal, the Cu(100) surface has a projected band gap at these energies, and only discrete image states are available through which charge transfer can take place. Resonant enhancement of charge transfer is observed for Rydberg states whose energy matches one of the image states, and the integrated surface ionization signals (signal versus applied field) show clear periodicity as a function of n as the energies come in and out of resonance with the image states. The surface ionization dynamics show a velocity dependence; decreased velocity of the incident H atom leads to a greater mean distance of ionization and a lower field required to extract the ion. The surface ionization profiles for "on resonance" n values show a changing shape as the velocity is changed, reflecting the finite field range over which resonance occurs.

Altered Th17/Treg balance and dysregulated IL-1ß response influence susceptibility/resistance to experimental autoimmune arthritis.

This study was aimed at gaining an insight into immune mechanisms of differential susceptibility to autoimmunity of individuals sharing the same major histocompatibility complex by studying arthritis-susceptible Lewis (LEW) and arthritis-resistant Wistar Kyoto (WKY) rats (both RT.1(l)) using the adjuvant arthritis (AA) model of rheumatoid arthritis (RA). Lymph node cells (LNC) and synovium-infiltrating cells (SIC) of LEW and WKY rat subjected to an arthritogenic challenge were tested. The frequency of T helper 17 (Th17) and T regulatory (Treg) cells was determined by flow cytometry, whereas serum and spleen adherent cell (SAC)-derived supernatant were analyzed for specific cytokines and chemokines. We observed that WKY rats are not deficient in generating a Th17 response to the arthritogenic challenge in LNC (periphery); however, the Th17/Treg ratio is markedly reduced in the joint (target organ) of WKY versus LEW rats because of reduced Th17 levels therein in WKY rats. These results suggest differential and selective decrease in Th17 cell migration into the joints of WKY rats. Interestingly, serum levels of chemokines RANTES and MCP-1 were reduced in WKY rats. Furthermore, WKY rats showed reduced serum IL-1ß level in vivo but no defect in IL-1ß production by SAC in vitro, suggesting an effective in vivo regulation of IL-1ß response. We also unraveled the role of interferon-γ (IFNγ), which we have previously reported to be increased in WKY versus LEW rats, in regulation of IL-1ß. Thus, reduced Th17/Treg ratio in the target organ (joints) and decreased systemic IL-1ß might contribute to the AA-resistance of WKY rats; whereas the converse factors render LEW more vulnerable to AA.

Resultados agronômicos e qualitativos da nova cultivar de trigo 'BRS Marcante' / Agronomic and qualitative results of the new wheat cultivar 'BRS Marcante'

A cultivar de trigo 'BRS Marcante' foi desenvolvida pela Embrapa, envolvendo um híbrido F1 do cruzamento entre as linhagens PF 980533 e PF 970227 com a cultivar 'BRS Guamirim', realizado em telado, na Embrapa Trigo, no inverno de 2003. As gerações segregantes foram conduzidas pelo método genealógico e a linhagem resultante, nomeada de PF 080310. A cultivar caracteriza-se pela sua ampla capacidade de adaptação às condições de cultivo do sul do Brasil, pelo bom potencial de rendimento de grãos e qualidade industrial da classe Pão.

The wheat cultivar 'BRS Marcante' was developed by Embrapa, as a result a cross between F1 hybrid between lines PF 980533 and PF 970227 with 'BRS Guamirim' and carried out in a green-house of Embrapa Wheat, on 2003 winter season. The segregate generations were conducted by genealogic method and the genotype resulted was named PF 080310. It has wide adaptation ability to south Brazilian conditions, high grain yield potential and belongs to Bread Class.

Translational initiation regulated by ATM in dendritic cells development.

Ataxia telangiectasia mutated (ATM) protein has been implicated in multiple pathways such as DNA repair, cell cycle checkpoint, cell growth, development, and stem cell renewal. In this study, we demonstrate evidence that ATM is involved in granulocyte macrophage colony-stimulating factor (GM-CSF)-induced dendritic cell (DC) development from bone marrow (BM) cells. Inactivation of ATM protein results in decreased BM proliferation, leading to reduced DC development and their activity for T cell activation. Expression of Jak2, STAT5, and mTOR is suppressed in both wild-type and ATM-null BM prior to GM-CSF stimulation. Activation of those proteins is delayed and prolonged hypophosphorylation of 4EBP1 is observed in ATM-null BM when treated with GM-CSF, although Erk and p38 are similarly expressed and activated in both wild-type and ATM-null BM cell types. Akt is also suppressed in wild-type BM, and transduction of constitutively active Akt or STAT5 in ATM-null BM restores DC development. Together, these results illustrate that ATM deficiency causes impaired initiation of protein translation in BM, leading to immature development of DC.

Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.

OBJECTIVE: To evaluate a trial of immunotherapy as an aid to diagnosis in suspected autoimmune epilepsy. METHOD: We reviewed the charts of 110 patients seen at our autoimmune neurology clinic with seizures as a chief complaint. Twenty-nine patients met the following inclusion criteria: (1) autoimmune epilepsy suspected based on the presence of ≥ 1 neural autoantibody (n = 23), personal or family history or physical stigmata of autoimmunity, and frequent or medically intractable seizures; and (2) initiated a 6- to 12-week trial of IV methylprednisolone (IVMP), IV immune globulin (IVIg), or both. Patients were defined as responders if there was a 50% or greater reduction in seizure frequency. RESULTS: Eighteen patients (62%) responded, of whom 10 (34%) became seizure-free; 52% improved with the first agent. Of those receiving a second agent after not responding to the first, 43% improved. A favorable response correlated with shorter interval between symptom onset and treatment initiation (median 9.5 vs 22 months; p = 0.048). Responders included 14/16 (87.5%) patients with antibodies to plasma membrane antigens, 2/6 (33%) patients seropositive for glutamic acid decarboxylase 65 antibodies, and 2/6 (33%) patients without detectable antibodies. Of 13 responders followed for more than 6 months after initiating long-term oral immunosuppression, response was sustained in 11 (85%). CONCLUSIONS: These retrospective findings justify consideration of a trial of immunotherapy in patients with suspected autoimmune epilepsy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with suspected autoimmune epilepsy, IVMP, IVIg, or both improve seizure control.

Precisão experimental de ensaios de trigo analisados pelo método de Papadakis / Experimental precision in wheat cultivars trials using the Papadakis method

O objetivo deste trabalho foi verificar se o uso da análise dos resultados dos ensaios de valor de cultivo e uso (VCU) de trigo pelo método de Papadakis modifica os pressupostos do modelo matemático e as medidas de precisão experimental. Para isso, foram usados os dados de produtividade de grãos de trigo de 48 ensaios de VCU, conduzidos sob delineamento de blocos ao acaso, entre 2008 e 2011. Para cada ensaio, sem e com o uso do método de Papadakis, foram realizados a verificação dos pressupostos, a análise de variância, os testes de hipóteses e calculadas as estatísticas para a identificação da precisão experimental. Esses pressupostos não foram violados para os dois métodos de análise (sem e com Papadakis). Com o uso do método de Papadakis (parcelas vizinhas), aumenta o índice de diferenciação de Fasoulas, 29,7 contra 15,5 sem o uso do método e a acurácia seletiva, 0,95 contra 0,90 sem o uso do método. Ensaios com três repetições, analisados com o método de Papadakis, possibilitam a identificação de cultivares de trigo com superioridade na produtividade de grãos com 90% de precisão. Para manter a precisão de 90% na análise sem o uso de Papadakis, seriam necessárias seis repetições.

The aim of this research was to verify whether the use of wheat yield trials results analysis, using the Papadakis method, modifies the assumptions of the mathematical model and indicators of experimental precision. Wheat productivity data, 2008 to 2011 years, obtained from 48 cultivar yield trials under randomized block design were considered. In each trial, either with or without the use of the Papadakis method, the assumptions, analysis of variance and hypothesis tests were verified as well as the calculations to identify the experimental precision. The assumptions were not violated by both methods (with or without de Papadakis method). With the Papadakis method (neighboring plots) the differentiation of the Fasoulas index increased, 29.7 compared to 15.5 without the use of the method, and the selective accuracy, 0.95 against 0.90 without the method. Trials using three replications when analysed by the Papadakis method allowed to identify superior bean varieties with 90% precision. In order to maintain the same precision (90%), six replications would be necessary without the Papadakis method.

X-ray strain tensor imaging: FEM simulation and experiments with a micro-CT.

In tissue elasticity imaging, measuring the strain tensor components is necessary to solve the inverse problem. However, it is impractical to measure all the tensor components in ultrasound or MRI elastography because of their anisotropic spatial resolution. The objective of this study is to compute 3D strain tensor maps from the 3D CT images of a tissue-mimicking phantom. We took 3D micro-CT images of the phantom twice with applying two different mechanical compressions to it. Applying the 3D image correlation technique to the CT images under different compression, we computed 3D displacement vectors and strain tensors at every pixel. To evaluate the accuracy of the strain tensor maps, we made a 3D FEM model of the phantom, and we computed strain tensor maps through FEM simulation. Experimentally obtained strain tensor maps showed similar patterns to the FEM-simulated ones in visual inspection. The correlation between the strain tensor maps obtained from the experiment and the FEM simulation ranges from 0.03 to 0.93. Even though the strain tensor maps suffer from high level noise, we expect the x-ray strain tensor imaging may find some biomedical applications such as malignant tissue characterization and stress analysis inside the tissues.

Uso do germoplasma da Embrapa nos programas de melhoramento de trigo no Brasil / Use of Embrapa's germplasm in Brazilian wheat breeding programs

O programa de melhoramento genético de trigo da Embrapa tem papel importante na história da triticultura brasileira, tendo dado origem a mais de 100 novas cultivares para as diferentes regiões do Brasil, ao longo dos quase 40 anos de existência. Entretanto, não se pode atribuir sua importância somente ao número de cultivares criadas, mas também ao impacto de seu germoplasma nos programas de melhoramento genético de outras instituições. O trabalho teve como objetivo quantificar a importância do germoplasma da Embrapa nos programas de melhoramento genético de trigo no Brasil. Foram analisadas as genealogias de todas as cultivares de trigo indicadas para cultivo no País, no período de 2005 a 2012, por obtentor vegetal. No período estudado, a média de participação do germoplasma da Embrapa nas cultivares de outros obtentores é de 58,7%, com destaque para a Biotrigo Genética, a CCGL TEC e OR Melhoramento de Sementes Ltda, respectivamente, com média de uso de 100,0%, 97,5% e 87,7%.

The wheat breeding program of Embrapa has an important role in the history of this cereal in Brazil, releasing more than one hundred new cultivars to different regions of the country in almost forty years of existence. However, is not possible assign its importance only to the number of cultivars, but also the impact of their germplasm in other brazilian wheat breeding programs. The objective of this study was to quantify the importance of Embrapa's germplasm in the brazilian wheat breeding programs. Were analyzed the genealogies of all wheat cultivars indicated for growth since 2005 and 2012, by institution. During the study period, the average participation of Embrapa's germplasm on cultivars of other institutions was 58.7%, with emphasis to Biotrigo Genética, CCGL TEC and OR Melhoramento de Sementes Ltda, respectively, in which use was 100%, 97.5% and 87.7%.

Electrophysiological characterization of sodium-activated potassium channels in NG108-15 and NSC-34 motor neuron-like cells.

AIMS: The electrical properties of Na(+) -activated K(+) current (I(K(Na)) ) and its contribution to spike firing has not been characterized in motor neurons. METHODS: We evaluated how activation of voltage-gated K(+) current (I(K) ) at the cellular level could be coupled to Na(+) influx through voltage-gated Na(+) current (I(N) (a) ) in two motor neuron-like cells (NG108-15 and NSC-34 cells). RESULTS: Increasing stimulation frequency altered the amplitudes of both I(Na) and I(K) simultaneously. With changes in stimulation frequency, the kinetics of both I(Na) inactivation and I(K) activation were well correlated at the same cell. Addition of tetrodotoxin or ranolazine reduced the amplitudes of both I(Na) and I(K) simultaneously. Tefluthrin (Tef) increased the amplitudes of both I(Na) and I(K) throughout the voltages ranging from -30 to + 10 mV. In cell-attached recordings, single-channel conductance from a linear current-voltage relation was 94 ± 3 pS (n = 7). Tef (10 µm) enhanced channel activity with no change in single-channel conductance. Tef increased spike firing accompanied by enhanced facilitation of spike-frequency adaptation. Riluzole (10 µm) reversed Tef-stimulated activity of K(Na) channels. In motor neuron-like NSC-34 cells, increasing stimulation frequency altered the kinetics of both I(Na) and I(K) . Modelling studies of motor neurons were simulated to demonstrate that the magnitude of I(K(Na)) modulates AP firing. CONCLUSIONS: There is a direct association of Na(+) and K(Na) channels which can provide the rapid activation of K(Na) channels required to regulate AP firing occurring in motor neurons.

DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway.

The DNA damage response (DDR) cascade and ROS (reactive oxygen species) signaling are both involved in the induction of cell death after DNA damage, but a mechanistic link between these two pathways has not been clearly elucidated. This study demonstrates that ROS induction after treatment of cells with neocarzinostatin (NCS), an ionizing radiation mimetic, is at least partly mediated by increasing histone H2AX. Increased levels of ROS and cell death induced by H2AX overexpression alone or DNA damage leading to H2AX accumulation are reduced by treating cells with the antioxidant N-Acetyl-L-Cysteine (NAC), the NADP(H) oxidase (Nox) inhibitor DPI, expression of Rac1N17, and knockdown of Nox1, but not Nox4, indicating that induction of ROS by H2AX is mediated through Nox1 and Rac1 GTPase. H2AX increases Nox1 activity partly by reducing the interaction between a Nox1 activator NOXA1 and its inhibitor 14-3-3zeta. These results point to a novel role of histone H2AX that regulates Nox1-mediated ROS generation after DNA damage.

Charge transfer of Rydberg H atoms at a metal surface.

The charge transfer of Rydberg hydrogen atoms at a metal surface is investigated for the first time. The surface ionization of Stark states with various electron density distributions with respect to the surface is examined. Unlike the nonhydrogenic species studied previously, genuine control over the orientation of the electronic wave function in the surface-ionization process is demonstrated. A comparison of the results for a range of collisional velocities for the most redshifted Stark state with principal quantum numbers n=20-36 with the classical over-the-barrier approach shows a good agreement for the onset of the ion signal, but the shallow rise in signal is not accounted for. An excellent fit of the experimental results can be achieved using a simple semiempirical model.

Abbreviated report of the NIH/NINDS workshop on sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy and is not rare. The NIH and National Institute of Neurological Disorders and Stroke sponsored a 3-day multidisciplinary workshop to advance research into SUDEP and its prevention. Parallel sessions were held: one with a focus on the science of SUDEP, and the other with a focus on issues related to the education of health care practitioners and people with epilepsy. This report summarizes the discussions and recommendations of the workshop, including lessons learned from investigations of sudden infant death syndrome (SIDS), sudden cardiac death, autonomic and respiratory physiology, medical devices, genetics, and animal models. Recommendations include educating all people with epilepsy about SUDEP as part of their general education on the potential harm of seizures, except in extenuating circumstances. Increasing awareness of SUDEP may facilitate improved seizure control, possibly decreasing SUDEP incidence. There have been significant advances in our understanding of the clinical and physiologic features of SIDS, sudden cardiac death, and SUDEP in both people and animals. Research should continue to focus on the cardiac, autonomic, respiratory, and genetic factors that likely contribute to the risk of SUDEP. Multicenter collaborative research should be encouraged, especially investigations with direct implications for the prevention of SUDEP. An ongoing SUDEP Coalition has been established to facilitate this effort. With the expansion of clinical, genetic, and basic science research, there is reasonable hope of advancing our understanding of SUDEP and ultimately our ability to prevent it.

Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis.

DNA damage signaling pathways are initiated in response to chemical reagents and radiation damage, as well as in response to hypoxia. It is implicated that structural maintenance of chromosomes 1 (SMC1) is not only a component of the cohesion complex but also facilitates the activation of DNA damage checkpoint proteins. Here, we studied the mechanism of DNA damage checkpoint activated by ATR-SMC1 pathway when cells are treated with desferrioxamine (DFO), a hypoxia-mimetic reagent. We show that DFO treatment induces phosphorylation of SMC1 at Ser966, NBS1 at Ser343, Chk1 at Ser317, Chk2 at Thr68, and p53 at Ser15. Among these sites, phosphorylation of SMC1, NBS1, and Chk1 by DFO are mediated by ATR as it is greatly reduced in both ATR-deficient human fibroblasts and HCT116 human colon cancer cells in which ATR is heterozygously mutated, whereas these proteins are phosphorylated in cells deficient for ATM and DNA-PKcs. DFO-induced apoptosis is decreased in ATR-mutant HCT116 cells, although p53 is normally activated in those cells. Expression of SMC1 S966A in which Ser966 is substituted to Ala attenuates apoptosis and phosphorylation of Chk1 at Ser317 after DFO treatment, although levels of HIF1α are not significantly changed. These results suggest that DFO induces apoptosis through the ATR-SMC1 arm of the pathway.

Propofol inhibits lipopolysaccharide-induced lung epithelial cell injury by reducing hypoxia-inducible factor-1alpha expression.

BACKGROUND: Lipopolysaccharide (LPS) may activate hypoxia-inducible factor (HIF)-1α, which up-regulates cytokine expression and the lethality of LPS-induced shock. We investigated the effect of propofol on HIF-1α expression and acute lung injury in LPS-treated mice. METHODS: A series of both positive and negative control experiments were performed. We injected BALB/C mice with propofol or vehicle i.p. immediately and 12 h after an LPS challenge. After 24 h, we examined the lung wet/dry weight ratio, neutrophil infiltration, and HIF-1α mRNA expression and inflammatory cytokines in the lung tissue. Survival was determined for 48 h after LPS injection. In vitro, we determined the responses of A549 cells, with and without HIF-1α silenced, to treatment with LPS alone and LPS plus propofol. RESULTS: Propofol prolonged survival and attenuated acute lung injury and decreased the expression of HIF-1α, interleukin (IL)-6, keratinocyte-derived chemokine, and tumour necrosis factor-alpha (TNF-α) in the lungs of endotoxaemic mice. In HIF-1α knockdown-A549 cells, LPS-induced TNF-α, IL-6, and the pro-apoptotic gene, BNIP3 expression and apoptosis were reduced. Propofol, but not an inhibitor of nuclear factor κB, reduced HIF-1α expression in LPS-stimulated A549 cells. Propofol also down-regulated, in A549 cells, the expression of IL-6, IL-8, and TNF-α, Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), and apoptosis. CONCLUSIONS: Propofol reduces apoptosis in LPS-stimulated lung epithelial cells by decreasing HIF-1α, BNIP3, and cytokine production. Using propofol to inhibit HIF-1α expression may protect against the acute lung injury caused by LPS-induced sepsis.

Resultados agronômicos e qualitativos da nova cultivar de trigo 'BRS 296' / Agronomic and qualitative results of the new wheat cultivar 'BRS 296'

A cultivar de trigo 'BRS 296', desenvolvida pela Embrapa, foi registrada para cultivo em 2009. Originou-se do cruzamento entre o genitor feminino PF 93232 e o genitor masculino COOK*4/VPM1, realizado em telado, na Embrapa Trigo, no verão de 1992/1993. As gerações segregantes foram conduzidas pelo método genealógico até a fixação da linhagem, nomeada de PF 990283. Caracteriza-se pela sua excelente sanidade foliar e de espiga e pela estabilidade de produção. Preliminarmente, está enquadrada na classe comercial Pão e seu cultivo é recomendado para todas as regiões tritícolas do Brasil.

The wheat cultivar BRS 296, developed by Embrapa, was released to production in 2009. It was originated of cross between PF 93232 and COOK*4/VPM1, carried out in green-house, in the summer of 1992/1993. The segregate generations were conducted by genealogic method until homozigose of genotype, named PF 990283. It has excellent leave and spike sanity and production stability. Preliminarily, it was classified as Bread Wheat and is recommended to all wheat regions of Brazil.

Ictal SPECT statistical parametric mapping in temporal lobe epilepsy surgery.

OBJECTIVE: Although subtraction ictal SPECT coregistered to MRI (SISCOM) is clinically useful in epilepsy surgery evaluation, it does not determine whether the ictal-interictal subtraction difference is statistically different from the expected random variation between 2 SPECT studies. We developed a statistical parametric mapping and MRI voxel-based method of analyzing ictal-interictal SPECT difference data (statistical ictal SPECT coregistered to MRI [STATISCOM]) and compared it with SISCOM. METHODS: Two serial SPECT studies were performed in 11 healthy volunteers without epilepsy (control subjects) to measure random variation between serial studies from individuals. STATISCOM and SISCOM images from 87 consecutive patients who had ictal SPECT studies and subsequent temporal lobectomy were assessed by reviewers blinded to clinical data and outcome. RESULTS: Interobserver agreement between blinded reviewers was higher for STATISCOM images than for SISCOM images (kappa = 0.81 vs kappa = 0.36). STATISCOM identified a hyperperfusion focus in 84% of patients, SISCOM in 66% (p < 0.05). STATISCOM correctly localized the temporal lobe epilepsy (TLE) subtypes (mesial vs lateral neocortical) in 68% of patients compared with 24% by SISCOM (p = 0.02); subgroup analysis of patients without lesions (as determined by MRI) showed superiority of STATISCOM (80% vs 47%; p = 0.04). Moreover, the probability of seizure-free outcome was higher when STATISCOM correctly localized the TLE subtype than when it was indeterminate (81% vs 53%; p = 0.03). CONCLUSION: Statistical ictal SPECT coregistered to MRI (STATISCOM) was superior to subtraction ictal SPECT coregistered to MRI for seizure localization before temporal lobe epilepsy (TLE) surgery. STATISCOM localization to the correct TLE subtype was prognostically important for postsurgical seizure freedom.