Rare genetic variants of NLRP12 in Admixed Latino-American Children with SARS-CoV-2-related Multisystem Inflammatory Syndrome.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare, potentially fatal complication of SARS-CoV-2 infection. Genetic defects in inflammation-related pathways have been linked to MIS-C, but additional research is needed, especially in diverse ethnic groups. The present study aimed to identify genetic variants underlying MIS-C in Brazilian patients. Whole-exome sequencing was performed, focusing on genes involved in the host immune response to SARS-CoV-2. Functional assays assessed the impact of selected variants on NF-κB signaling. Nine rare, potentially deleterious variants were found in eight of 21 patients, located in IL17RC, IFNA10, or NLRP12 genes. Unlike the wild-type NLRP12 protein, which inhibits NF-κB activation in HEK 293T cells, the mutant NLRP12 proteins have significantly reduced inhibitory properties. In conclusion, our results indicate that rare autosomal variants in immune-related genes may underlie MIS-C, highlighting the potential role of NLRP12 in its predisposition. These findings provide new insights for the appropriate management of MIS-C.

Interleukin-17 signaling influences CD8+ T cell immunity and tumor progression according to the IL-17 receptor subunit expression pattern in cancer cells.

IL-17 immune responses in cancer are controversial, with both tumor-promoting and tumor-repressing effects observed. To clarify the role of IL-17 signaling in cancer progression, we used syngeneic tumor models from different tissue origins. We found that deficiencies in host IL-17RA or IL-17A/F expression had varying effects on the in vivo growth of different solid tumors including melanoma, sarcoma, lymphoma, and leukemia. In each tumor type, the absence of IL-17 led to changes in the expression of mediators associated with inflammation and metastasis in the tumor microenvironment. Furthermore, IL-17 signaling deficiencies in the hosts resulted in decreased anti-tumor CD8+ T cell immunity and caused tumor-specific changes in several lymphoid cell populations. Our findings were associated with distinct patterns of IL-17A/F cytokine and receptor subunit expression in the injected tumor cell lines. These patterns affected tumor cell responsiveness to IL-17 and downstream intracellular signaling, leading to divergent effects on cancer progression. Additionally, we identified IL-17RC as a critical determinant of the IL-17-mediated response in tumor cells and a potential biomarker for IL-17 signaling effects in tumor progression. Our study offers insight into the molecular mechanisms underlying IL-17 activities in cancer and lays the groundwork for developing personalized immunotherapies.

In-feed nutritional additive probiotic Saccharomyces boulardii RC009 can substitute for prophylactic antibiotics and improve the production and health of weaning pigs.

Background and Aims: Non-therapeutic antibiotic use is associated with the current decrease in antibiotic therapeutic efficiency and the emergence of a wide range of resistant strains, which constitutes a public health risk. This study aimed to evaluate the use of Saccharomyces cerevisiae var. boulardii RC009 as a nutritional feed additive to substitute the prophylactic use of antibiotics and improve the productive performance and health of post-weaning piglets. Materials and Methods: Four regular nutritional phases were prepared. Post-weaning pigs (21-70 days old) received one of two dietary treatments: T1-basal diet (BD-control group) with in-feed antibiotics as a prophylactic medication (one pulse of Tiamulin in P3 and one pulse of Amoxicillin in P4); and T2-BD without in-feed antibiotics but with Saccharomyces boulardii RC009 (1 × 1012 colony forming unit/T feed). The feed conversion ratio (FCR), total weight gain (TWG-kg), and daily weight gain (DWG-kg) were determined. A post-weaning growth index (GI) was calculated and animals (160 days old) from each treatment were analyzed at the abattoir after sacrifice for carcass weight and respiratory tract lesions. Results: Pigs consuming probiotics had higher TWG and DWG than the control group. The group of animals with low body weight obtained the same results. Saccharomyces boulardii administration decreased diarrhea, and FCR reduction was related to a GI improvement. A significant increase in carcass weight and muscle thickness reduction was observed in animals received the probiotic post-weaning. Conclusion: Saccharomyces boulardii RC009, a probiotic additive, was found to improve the production parameters of pigs post-weaning and enhance their health status, indicating that it may be a promising alternative to prophylactic antibiotics.

Performance of Medium-Rise Buildings with Reinforced Concrete Shear Walls Designed for High Seismic Hazard.

This work has evaluated the collapse fragility of a typical Chilean building for residential use, structured based on shear-resistant RC walls and inverted beams arranged along its entire perimeter, using the incremental dynamic analysis (IDA) for the evaluation of its structural behavior, using for this the 2018 version of the SeismoStruct software. This method evaluates the global collapse capacity of the building from the graphical representation of its maximum inelastic response, obtained through a non-linear time-history analysis, against the scaled intensity of a set of seismic records obtained in the subduction zone, thus creating the IDA curves of the building. The processing of the seismic records is included within the applied methodology to make them compatible with the elastic spectrum of the Chilean design, achieving an adequate seismic input in the two main structural directions. In addition, an alternative IDA method based on the elongated period is applied to calculate the seismic intensity. The results of the IDA curve obtained with this procedure and the standard IDA analysis are analyzed and compared. The results show that the method relates very well to the structure's demand and capacity and confirms the non-monotonous behavior exposed by other authors. Regarding the alternative IDA procedure, the results indicate that the method is inadequate, failing to improve the results obtained by the standard method.

Carbonation Behavior of Mortar Made from Treated Recycled Aggregates: Influence of Diammonium Phosphate.

This research aims to improve the quality of recycled concrete fine aggregates (RFA) by using diammonium hydrogen phosphate (DAP). We aimed to understand the effect of DAP treatment on durability performance due to the carbonation action of mortars with the partial and total substitution of treated RFA. The results showed a maximum reduction in the RFA water absorption of up to 33% using a minimum DAP concentration due to a pore refinement as a consequence of the formation of calcium phosphates such as hydroxyapatite (HAP). The carbonation phenomenon did not have a significant effect on the durability of mortars with DAP-treated RFA, as we did not find a decrease in the compressive strength; the carbonation depth of the mortars with 100% treated RFA decreased up to 90% and 63% for a w/c of 0.45 and 0.50, in comparison with mortars with 0% treated RFA. An inversely proportional relationship was found between the accelerate carbonation and the compressive strength, showing that higher percentages of treated RFAs in the mortar promoted an increase in compressive strength and a decrease in the carbonation rate, which is behavior associated with a lower permeability of the cement matrix as one of the consequences of the microstructural densification by DAP treatment.

Information Theory Based Evaluation of the RC4 Stream Cipher Outputs.

This paper presents a criterion, based on information theory, to measure the amount of average information provided by the sequences of outputs of the RC4 on the internal state. The test statistic used is the sum of the maximum plausible estimates of the entropies H(jt|zt), corresponding to the probability distributions P(jt|zt) of the sequences of random variables (jt)t∈T and (zt)t∈T, independent, but not identically distributed, where zt are the known values of the outputs, while jt is one of the unknown elements of the internal state of the RC4. It is experimentally demonstrated that the test statistic allows for determining the most vulnerable RC4 outputs, and it is proposed to be used as a vulnerability metric for each RC4 output sequence concerning the iterative probabilistic attack.

Myorelaxation, respiratory depression and electrocardiographic changes caused by the administration of extract of açai (Euterpe oleracea Mart.) stone in rats.

The biological and pharmacological properties of natural polyphenols of the extract of Euterpe oleracea stone (EEOS) are associated with the central nervous system (CNS). To investigate the sedative and myorelaxant activity of EEOS in vivo, this study aimed to present the myorelaxant and sedative effects of EEOS in Wistar rats using spontaneous locomotor activity and motor electrophysiology. A total of 108 animals were used in the following experiments: a) behavioral tests (n = 27); b) electromyographic recordings of skeletal muscle (n = 27); c) respiratory muscle activity recordings (n = 27); d) cardiac muscle activity recordings (n = 27). The behavioral characteristics were measured according to the latency time of onset, the transient loss of posture reflex and maximum muscle relaxation. Electrodes were implanted in the gastrocnemius muscle and in the tenth intercostal space for electromyographic (EMG) signal capture to record muscle contraction, and in the D2 lead for electrocardiogram acquisition. After using the 300 mg/kg dose of EEOS intraperitoneally, a myorelaxant activity exhibited a lower frequency of contractility with an amplitude pattern of low and short duration at gastrocnemius muscle and intercostal muscle, which clearly describes a myorelaxant activity and changes in cardiac activity. The present report is so far the first study to demonstrate the myorelaxant activity of this extract, indicating an alternative route for açai stone valorization and its application in pharmaceutical fields.

Docking, Interaction Fingerprint, and Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) of Sigma1 Receptor Ligands, Analogs of the Neuroprotective Agent RC-33.

The human Sigma1 receptor (S1R), which has been identified as a target with an important role in neuropsychological disorders, was first crystallized 3 years ago. Since S1R structure has no relation with another previous crystallized structures, the presence of the new crystal is an important hallmark for the design of agonists and antagonists against this important target. Some years ago, our group identified RC-33, a potent and selective S1R agonist, endowed with neuroprotective properties. In this work, drawing on new structural information, we studied the interactions of RC-33 and its analogs with the S1R binding site by using computational methods such as docking, interaction fingerprints, and receptor-guided alignment three dimensional quantitative structure-activity relationship (3D-QSAR). We found that RC-33 and its analogs adopted similar orientations within S1R binding site, with high similitude with orientations of the crystallized ligands; such information was used for identifying the residues involved in chemical interactions with ligands. Furthermore, the structure-activity relationship of the studied ligands was adequately described considering classical QSAR tests. All relevant aspects of the interactions between the studied compounds and S1R were covered here, through descriptions of orientations, binding interactions, and features that influence differential affinities. In this sense, the present results could be useful in the future design of novel S1R modulators.

Gastrin-releasing peptide and its receptor increase arthritis fibroblast-like synoviocytes invasiveness through activating the PI3K/AKT pathway.

Rheumatoid arthritis (RA) is an autoimmune disease that leads to joint destruction. The fibroblast-like synoviocytes (FLS) has a central role on the disease pathophysiology. The present study aimed to examine the role of gastrin-releasing peptide (GRP) and its receptor (GRPR) on invasive behavior of mice fibroblast-like synoviocytes (FLS), as well as to evaluate GRP-induced signaling on PI3K/AKT pathway. The expression of GRPR in FLS was investigated by immunocytochemistry, western blot (WB) and qRT-PCR. The proliferation and invasion were assessed by SRB and matrigel-transwell assay after treatment with GRP and/or RC-3095 (GRPR antagonist), and/or Ly294002 (inhibitor of PI3K/AKT pathway). Finally, AKT phosphorylation was assessed by WB. GRPR protein was detected in FLS and the exposure to GRP increased FLS invasion by nearly two-fold, compared with untreated cells (p<0.05), while RC-3095 reversed that effect (p<0.001). GRP also increased phosphorylated AKT expression in FLS. When Ly294002 was added with GRP, it prevented the GRP-induced increased cell invasiveness (p<0.001). These data suggest that GRPR expression in FLS and that exogenous GRP are able to activate FLS invasion. This effect occurs at least in part through the AKT activation. Therefore, understanding of the GRP/GRPR pathway could be relevant in the development of FLS-targeted therapy for RA.

Structural Behavior of SFRC Beams strengthened with GFRP Laminates: An Experimental and Analytical Investigation

ABSTRACT This paper presents the experimental results of a reinforced concrete beams (RC) strengthened with internal steel fibers (SF) and external glass fiber reinforced polymer laminates (GFRP). The research work studied the load carrying capacity, deformation, crack width and ductility of the reinforced concrete beams strengthened with different steel fiber ratios and steel fiber reinforced concrete beams strengthened with three different glass fiber reinforced polymer laminates of two different thickness. The experimental results clearly shows that incorporating steel fibers in to the reinforced concrete beams reduced the crack width and distribute the crack evenly and also increases the bonding between tension face of the beam with glass fiber reinforced polymer laminates. The results also shows that glass fiber reinforced polymer laminates strengthened steel fiber reinforced concrete beams increases the flexural strength and ductility as compared with unstrengthened counterpart. In addition to this experimental work, theoretical calculations were done to find the ultimate load carrying capacity of the beam tested, and also compared with the experimental results.

Modulation of mitochondrial functions by the indirect antioxidant sulforaphane: a seemingly contradictory dual role and an integrative hypothesis.

The chemotherapeutic isothiocyanate sulforaphane (SFN) was early linked to anticarcinogenic and antiproliferative activities. Soon after, this compound, derived from cruciferous vegetables, became an excellent and useful trial for anti-cancer research in experimental models including growth tumor, metastasis, and angiogenesis. Many subsequent reports showed modifications in mitochondrial signaling, functionality, and integrity induced by SFN. When cytoprotective effects were found in toxic and ischemic insult models, seemingly contradictory behaviors of SFN were discovered: SFN was inducing deleterious changes in cancer cell mitochondria that eventually would carry the cell to death via apoptosis and also was protecting noncancer cell mitochondria against oxidative challenge, which prevented cell death. In both cases, SFN exhibited effects on mitochondrial redox balance and phase II enzyme expression, mitochondrial membrane potential, expression of the family of B cell lymphoma 2 homologs, regulation of proapoptotic proteins released from mitochondria, activation/inactivation of caspases, mitochondrial respiratory complex activities, oxygen consumption and bioenergetics, mitochondrial permeability transition pore opening, and modulation of some kinase pathways. With the ultimate findings related to the induction of mitochondrial biogenesis by SFN, it could be considered that SFN has effects on mitochondrial dynamics that explain some divergent points. In this review, we list the reports involving effects on mitochondrial modulation by SFN in anti-cancer models as well as in cytoprotective models against oxidative damage. We also attempt to integrate the data into a mechanism explaining the various effects of SFN on mitochondrial function in only one concept, taking into account mitochondrial biogenesis and dynamics and making a comparison with the theory of reactive oxygen species threshold of cell death. Our interest is to achieve a complete view of cancer and protective therapies based on SFN that can be extended to other chemotherapeutic compounds with similar characteristics. The work needed to test this hypothesis is quite extensive.

Association between obesity and postoperative atrial fibrillation in patients undergoing cardiac operations: a systematic review and meta-analysis.

In a systematic review and random-effects meta-analysis, we evaluated whether obesity is associated with postoperative atrial fibrillation (POAF) in patients undergoing cardiac operations. We selected 18 observational studies until December 2011 that excluded patients with preoperative AF (n=36,147). Obese patients had a modest higher risk of POAF compared with nonobese (odds ratio, 1.12; 95% confidence interval, 1.04 to 1.21; p=0.002). The association between obesity and POAF did not vary substantially by type of cardiac operation, study design, or year of publication. POAF was significantly associated with a higher risk of stroke, respiratory failure, and operative death.

Mitochondrial dysfunction in the hippocampus of rats caused by chronic oxidative stress.

The aim of this study was to analyze the effects of chronic oxidative stress on mitochondrial function and its relationship to progressive neurodegeneration in the hippocampus of rats chronically exposed to ozone. Animals were exposed to 0.25 ppm ozone for 7, 15, 30, or 60 days. Each group was tested for (1) protein oxidation and, manganese superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx) and succinate dehydrogenase (SDH) activity using spectrophotometric techniques, (2) oxygen consumption, (3) cytochrome c, inducible nitric oxide synthase (iNOS), peroxisome proliferator-activated receptor γ Co-activator 1α (PGC-1α), B-cell lymphoma (Bcl-2), and Bax expression using Western blotting, (4) histology using hematoxylin and eosin staining, and (5) mitochondrial structure using electron microscopy. Our results showed increased levels of carbonyl protein and Mn-SOD activity after 30 days of ozone exposure and decreased GPx activity. The SDH activity decreased from 7 to 60 days of exposure. The oxygen consumption decreased at 60 days. Western blotting showed an increase in cytochrome c at 60 days of ozone exposure and an increase in iNOS up to 60 days of ozone exposure. The expression of PGC-1α was decreased after 15, 30, and 60 days compared to the earlier time Bcl-2 was increased at 60 days compared to earlier time points, and Bax was increased after 30 and 60 days of exposure compared to earlier time points. We observed cellular damage, and mitochondrial swelling with a loss of mitochondrial cristae after 60 days of exposure. These changes suggest that low doses of ozone caused mitochondrial abnormalities that may lead to cell damage.