Convective drying of yellow discarded onion (Angaco INTA): Modelling of moisture loss kinetics and effect on phenolic compounds

The Angaco INTA onion variety is the most cultivated and its production, mostly is destined for export. Due to their high-quality standards of these markets, many onions are discarded. The drying process seems to be a promising solution that not only give added value to this product, but also extend shelf life. In this work, the influence of convective drying process, at 60 and 70 °C, on the kinetic behavior, antioxidant activity, phenolic and flavonoid contents of discarded onion slices were investigated. Considering that, the Angaco INTA onion is a variety genetically developed to have shorter cultivation times in this region; the phenolic compounds content in this onion variety, the drying kinetics and its influence on this content have never been studied. In this study, the phenolic compounds contributions to dehydrated product quality was evaluated, observing that the convective drying increased the total soluble phenolic and flavonoid contents and antioxidant properties for both temperatures, being highest at 70 °C. The rehydration ratios were similar to the slices dried at 60 and 70 °C. Several models were used for describing the obtained drying curve equation of onion slices, being the Midilli’s model the one that presented the best fit. Ficks’s model of water diffusion fitted all experimental data with acceptable correlation coefficients. Considering the achieved findings, 70 °C is the optimum temperature to produce the dehydrated Angaco INTA onion.Fil: Roman, María Celia. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Ingeniería Química; ArgentinaFil: Fabani, Maria Paula. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Luna, Lorena Celina. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Ingeniería Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Feresin, Gabriela Egly. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mazza, German Delfor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas. Universidad Nacional del Comahue. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas; ArgentinaFil: Rodriguez, Rosa. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Ingeniería Química; Argentin

Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.

The IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and innate immune cells. We identified JNJ-54271074, a potent and highly-selective RORγt inverse agonist, which dose-dependently inhibited RORγt-driven transcription, decreased co-activator binding and promoted interaction with co-repressor protein. This compound selectively blocked Th17 differentiation, significantly reduced IL-17A production from memory T cells, and decreased IL-17A- and IL-22-producing human and murine γδ and NKT cells. In a murine collagen-induced arthritis model, JNJ-54271074 dose-dependently suppressed joint inflammation. Furthermore, JNJ-54271074 suppressed IL-17A production in human PBMC from rheumatoid arthritis patients. RORγt-deficient mice showed decreased IL-23-induced psoriasis-like skin inflammation and cytokine gene expression, consistent with dose-dependent inhibition in wild-type mice through oral dosing of JNJ-54271074. In a translational model of human psoriatic epidermal cells and skin-homing T cells, JNJ-54271074 selectively inhibited streptococcus extract-induced IL-17A and IL-17F. JNJ-54271074 is thus a potent, selective RORγt modulator with therapeutic potential in IL-23/IL-17 mediated autoimmune diseases

Mechanisms Establishing TLR4-Responsive Activation States of Inflammatory Response Genes

Precise control of the innate immune response is required for resistance to microbial infections and maintenance of normal tissue homeostasis. Because this response involves coordinate regulation of hundreds of genes, it provides a powerful biological system to elucidate the molecular strategies that underlie signal- and time-dependent transitions of gene expression. Comprehensive genome-wide analysis of the epigenetic and transcription status of the TLR4-induced transcriptional program in macrophages suggests that Toll-like receptor 4 (TLR4)-dependent activation of nearly all immediate/early- (I/E) and late-response genes results from a sequential process in which signal-independent factors initially establish basal levels of gene expression that are then amplified by signal-dependent transcription factors. Promoters of I/E genes are distinguished from those of late genes by encoding a distinct set of signal-dependent transcription factor elements, including TATA boxes, which lead to preferential binding of TBP and basal enrichment for RNA polymerase II immediately downstream of transcriptional start sites. Global nuclear run-on (GRO) sequencing and total RNA sequencing further indicates that TLR4 signaling markedly increases the overall rates of both transcriptional initiation and the efficiency of transcriptional elongation of nearly all I/E genes, while RNA splicing is largely unaffected. Collectively, these findings reveal broadly utilized mechanisms underlying temporally distinct patterns of TLR4-dependent gene activation required for homeostasis and effective immune responses

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Surveillance of Trypanosoma cruzi infection in Triatomine vectors, feral dogs and cats, and wild animals in and around El Paso county, Texas, and New Mexico.

The causative agent of Chagas disease, Trypanosoma cruzi, is transmitted by triatomine vectors. The insect is endemic in the Americas, including the United States, where epidemiological studies are limited, particularly in the Southwestern region. Here, we have determined the prevalence of T. cruzi in triatomines, feral cats and dogs, and wild animals, the infecting parasite genotypes and the mammalian host bloodmeal sources of the triatomines at four different geographical sites in the U.S.-Mexico border, including El Paso County, Texas, and nearby cities in New Mexico. Using qualitative polymerase chain reaction to detect T. cruzi infections, we found 66.4% (n = 225) of triatomines, 45.3% (n = 95) of feral dogs, 39.2% (n = 24) of feral cats, and 71.4% (n = 7) of wild animals positive for T. cruzi. Over 95% of T. cruzi genotypes or discrete typing units (DTUs) identified were TcI and some TcIV. Furthermore, Triatoma rubida was the triatomine species most frequently (98.2%) collected in all samples analyzed. These findings suggest a high prevalence of T. cruzi infections among triatomines, and feral and wild animals in the studied sites. Therefore, our results underscore the urgent need for implementation of a systematic epidemiological surveillance program for T. cruzi infections in insect vectors, and feral and wild animals, and Chagas disease in the human population in the southwestern region of the United States

Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.

The IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and innate immune cells. We identified JNJ-54271074, a potent and highly-selective RORγt inverse agonist, which dose-dependently inhibited RORγt-driven transcription, decreased co-activator binding and promoted interaction with co-repressor protein. This compound selectively blocked Th17 differentiation, significantly reduced IL-17A production from memory T cells, and decreased IL-17A- and IL-22-producing human and murine γδ and NKT cells. In a murine collagen-induced arthritis model, JNJ-54271074 dose-dependently suppressed joint inflammation. Furthermore, JNJ-54271074 suppressed IL-17A production in human PBMC from rheumatoid arthritis patients. RORγt-deficient mice showed decreased IL-23-induced psoriasis-like skin inflammation and cytokine gene expression, consistent with dose-dependent inhibition in wild-type mice through oral dosing of JNJ-54271074. In a translational model of human psoriatic epidermal cells and skin-homing T cells, JNJ-54271074 selectively inhibited streptococcus extract-induced IL-17A and IL-17F. JNJ-54271074 is thus a potent, selective RORγt modulator with therapeutic potential in IL-23/IL-17 mediated autoimmune diseases

RORγt and RORα signature genes in human Th17 cells

<div><p>RORγt and RORα are transcription factors of the RAR-related orphan nuclear receptor (ROR) family. They are expressed in Th17 cells and have been suggested to play a role in Th17 differentiation. Although RORγt signature genes have been characterized in mouse Th17 cells, detailed information on its transcriptional control in human Th17 cells is limited and even less is known about RORα signature genes which have not been reported in either human or mouse T cells. In this study, global gene expression of human CD4 T cells activated under Th17 skewing conditions was profiled by RNA sequencing. RORγt and RORα signature genes were identified in these Th17 cells treated with specific siRNAs to knock down RORγt or RORα expression. We have generated selective small molecule RORγt modulators and they were also utilized as pharmacological tools in RORγt signature gene identification. Our results showed that RORγt controlled the expression of a very selective number of genes in Th17 cells and most of them were regulated by RORα as well albeit a weaker influence. Key Th17 genes including IL-17A, IL-17F, IL-23R, CCL20 and CCR6 were shown to be regulated by both RORγt and RORα. Our results demonstrated an overlapping role of RORγt and RORα in human Th17 cell differentiation through regulation of a defined common set of Th17 genes. RORγt as a drug target for treatment of Th17 mediated autoimmune diseases such as psoriasis has been demonstrated recently in clinical trials. Our results suggest that RORα could be involved in same disease mechanisms and gene signatures identified in this report could be valuable biomarkers for tracking the pharmacodynamic effects of compounds that modulate RORγt or RORα activities in patients.</p></div

Expression of RORγt and RORα4 in human CD4 T cells during Th17 differentiation.

<p>Expression of RORγt isoform from the RORC gene (A) and RORα4 isoform from the RORA gene (B) was determined from detection of isoform specific exon sequences in RNA-Seq data analysis. Exons utilized by different isoforms of the RORC and RORA genes are shown in green, and the frequency of exon sequences in RNA-Seq data are shown in red in the histograms. DMSO treated human CD4 T cell samples from 2 donors at different time points of activation under Th17 differentiation conditions were used for isoform expression analysis.</p

Upstream regulators of the 24 genes down-regulated by RORγt siRNAs or inverse agonists in human Th17 cells were predicted from IPA analysis and the top 20 regulators are shown.

<p>These regulators were ranked by their P values which reflect the enrichment of the 24 genes regulated directly or indirectly by these upstream regulators. The activation status of upstream regulators was determined from the treatment effect on the involved genes and presented as activation z-scores, with positive value for activated status, and negative value for inhibited status.</p

Global gene expression profile with RNA-Seq identified genes differentially regulated by RORγt or RORα siRNA in human CD4 T cells during Th17 differentiation.

<p>RNA sequencing profile was performed on RNA samples extracted from human CD4 T cells treated with RORγt or RORα siRNA, or RORγt inverse agonists as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181868#pone.0181868.s001" target="_blank">S1 Table</a>. Genes down-regulated by RORγt (A) and RORα (B) siRNAs, or up-regulated by RORγt or RORα siRNAs (C) were identified in analysis of RNA-Seq data using the criteria described in Materials and Methods. Each column represents log2 ratios of selected genes in one of the 72 comparisons, including comparison of untreated Th17 cells with RORγt or RORα siRNA transfected cells or RORγt inverse agonist treated cells at two time points and T cells from 2 independent donors.</p