Transcriptomic Analysis Reveals the Response Mechanisms of Bell Pepper (Capsicum annuum) to Phosphorus Deficiency.

Phosphorus (P) is an important nutritional element needed by plants. Roots obtain P as inorganic phosphate (Pi), mostly in H2PO-4 form. It is vital for plants to have a sufficient supply of Pi since it participates in important processes like photosynthesis, energy transfer, and protein activation, among others. The physicochemical properties and the organic material usually make Pi bioavailability in soil low, causing crops and undomesticated plants to experience variations in accessibility or even a persistent phosphate limitation. In this study, transcriptome data from pepper roots under low-Pi stress was analyzed in order to identify Pi starvation-responsive genes and their relationship with metabolic pathways and functions. Transcriptome data were obtained from pepper roots with Pi deficiency by RNASeq and analyzed with bioinformatic tools. A total of 97 differentially expressed genes (DEGs) were identified; Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment revealed that metabolic pathways, such as porphyrin and chlorophyll metabolism, were down-regulated, and galactose and fatty acid metabolism were up-regulated. The results indicate that bell pepper follows diverse processes related to low Pi tolerance regulation, such as the remobilization of internal Pi, alternative metabolic pathways to generate energy, and regulators of root development.

Metabolomic Characterization of Phoradendron brachystachyum Mistletoe and In-Silico and In-Vitro Investigation of Its Therapeutic Potential in Metabolic Disorders.

Plants of the Phoradendron genus have been traditionally used for their lipid- and glucose-lowering effects. However, the compounds responsible for these effects and the overall chemical profile of these plants have not been thoroughly investigated. We aimed to characterize the metabolome of leaves, stems, and aerial parts of the Phoradendron brachystachyum plant. We used mass spectrometry and colorimetric screening techniques (with various solvents) to identify and characterize the metabolites present. We also evaluated the antioxidant (FRAP, ORAC, TEAC, and DPPH assays) and inhibitory effects on pancreatic lipase and α-glucosidase enzymes of hydrophilic extracts. Furthermore, we compared the molecular fingerprints between the identified metabolites and FDA-approved drugs to gain insights into the metabolites that might be responsible for the observed effects on enzymes. Our findings revealed the presence of 59 putative metabolites, primarily flavonoids. However, we also hint at the presence of peptide and carbohydrate derivatives. The leaf extracts demonstrated the most promising metrics across all assays, exhibiting strong antioxidant and enzyme inhibitory effects as well as high levels of phenolic compounds, flavonoids, and tannins. Fingerprint analysis suggested potential peptide and carbohydrate metabolites as pancreatic lipase and α-glucosidase inhibitors. Overall, our study provides evidence on specific metabolites in Phoradendron brachystachyum that could be responsible for the therapeutic effects noted in obese and type 2 diabetes subjects.

Single-Cell Transcriptomic Analysis Links Nonmyelinating Schwann Cells to Proinflammatory Response in the Lung.

The lung is a barrier tissue with constant exposure to the inhaled environment. Therefore, innate immunity against particulates and pathogens is of critical importance to maintain tissue homeostasis. Although the lung harbors both myelinating and nonmyelinating Schwann cells (NMSCs), NMSCs represent the most abundant Schwann cell (SC) population in the lung. However, their contribution to lung physiology remains largely unknown. In this study, we used the human glial fibrillary acidic protein promoter driving tdTomato expression in mice to identify SCs in the peripheral nervous system and determine their location within the lung. Single-cell transcriptomic analysis revealed the existence of two NMSC populations (NMSC1 and NMSC2) that may participate in pathogen recognition. We demonstrated that these pulmonary SCs produce chemokines and cytokines upon LPS stimulation using in vitro conditions. Furthermore, we challenged mouse lungs with LPS and found that NMSC1 exhibits an enriched proinflammatory response among all SC subtypes. Collectively, these findings define the molecular profiles of lung SCs and suggest a potential role for NMSCs in lung inflammation.

Ultrasound and Microwave-Assisted Synthesis of Hexagonally Ordered Ce-Promoted Mesoporous Silica as Ni Supports for Ethanol Steam Reforming.

Solvothermal synthesis of mesoporous materials based on amphiphilic molecules as structure-directing agents can be enhanced using non-conventional technologies for stirring and thermal activation. Here, we disclose a green synthesis approach for the preparation of cerium-modified hexagonally ordered silica sieves. Ultrasound micromixing enabled us to obtain well-dispersed Ce in the self-assembled silica network and yielded ordered materials with high cerium content (Ce/Si molar ratio = 0.08). Microwave dielectric heating, applied by an innovative open-end coaxial antenna, was used to reduce the overall hydrothermal synthesis time and to improve the surface area and textural properties. These mesoporous materials were used as a Ni catalyst support (10 wt.% metal loading) for the ethanol steam reforming reaction. The new catalysts featured complete ethanol conversion, high H2 selectivity (65%) and better stability, compared to the same catalyst prepared with magnetic stirring and conventional heating. The Ce-promoted silica sieves offered a suitable support for the controlled growth of nanocarbon that does not result in catalyst deactivation or poisoning after 6 h on stream.

The Multitasker Protein: A Look at the Multiple Capabilities of NUMB.

NUMB, a plasma membrane-associated protein originally described in Drosophila, is involved in determining cell function and fate during early stages of development. It is secreted asymmetrically in dividing cells, with one daughter cell inheriting NUMB and the other inheriting its antagonist, NOTCH. NUMB has been proposed as a polarizing agent and has multiple functions, including endocytosis and serving as an adaptor in various cellular pathways such as NOTCH, Hedgehog, and the P53-MDM2 axis. Due to its role in maintaining cellular homeostasis, it has been suggested that NUMB may be involved in various human pathologies such as cancer and Alzheimer's disease. Further research on NUMB could aid in understanding disease mechanisms and advancing the field of personalized medicine and the development of new therapies.

Severe COVID-19 in patients with immune-mediated rheumatic diseases: a stratified analysis from the SORCOM multicenter registry.

OBJECTIVES: To evaluate risk factors for severe Coronavirus Disease 2019 (COVID-19) in patients with immune-mediated rheumatic diseases, stratified by systemic autoimmune conditions and chronic inflammatory arthritis. METHODS: An observational, cross-sectional multicenter study was performed. Patients from 10 Rheumatology departments in Madrid who presented with SARS-CoV-2 infection between Feb 2020 and May 2021 were included. The main outcome was COVID-19 severity (hospital admission or mortality). Risk factors for severity were estimated, adjusting for covariates (sociodemographic, clinical and treatments), using logistic regression analyses. RESULTS: 523 patients with COVID-19 were included, among whom 192 (35.6%) patients required hospital admission and 38 (7.3%) died. Male gender, older age and comorbidities such as diabetes mellitus, hypertension and obesity were associated with severe COVID-19. Corticosteroid doses over 10 mg/day, rituximab, sulfasalazine and mycophenolate use, were independently associated with worse outcomes. COVID-19 severity decreased over the different pandemic waves. Mortality was higher in the systemic autoimmune conditions (univariate analysis, p<0.001), although there were no differences in overall severity in the multivariate analysis. CONCLUSIONS: This study confirms and provides new insights regarding the harmful effects of corticosteroids, rituximab and other therapies (mycophenolate and sulfasalazine) in COVID-19. Methotrexate and anti-TNF therapy were not associated with worse outcomes.

Agronomic Behavior of Mexican Roselle Cultivars Produced under Protected Agricultural Conditions.

Growth dynamics and morphological traits are used to define the characteristics of roselle cultivars Hibiscus sabdariffa. The morpho-agronomic variability of plants was evaluated, as well as the concentration of macro and micronutrients in leaves of Mexican roselle cultivars in hydroponic and greenhouse conditions. The following roselle cultivars were studied: 'Cruza Negra', 'UAN16-2', 'Criolla Huajicori', 'UAN 6 Puga', 'UAN 25-1' and '4Q4'. The relative growth rate of the crops was fitted to a positive cubic, negative quadratic and positive linear model, whereas stem diameter, fitted to a linear model, had a negative quadratic response. The foliar surface of the cultivars '4Q4', 'Cruza Negra', 'UAN16-2' and 'Criolla Huajicori' was directly related to the size of the flower, the calyx and the corolla. Nitrogen and potassium are the elements that showed the highest concentration in the cultivars Criolla Huajicori and Cruza Negra, while in the other four cultivars the highest concentrations of minerals in the leaf were nitrogen and calcium. The leaves of cultivar 4Q4 provided the greatest amount of minerals, with 83,565 mg kg-1 dry basis. Criolla Huajicori was the cultivar that exhibited the tallest height, the most productive branches and the greatest calyx number per plant; however, Cruza Negra exhibited the highest yield by having the longest calyx.

IL-23 signaling is not an important driver of liver inflammation and fibrosis in murine non-alcoholic steatohepatitis models.

Non-alcoholic fatty liver disease (NAFLD), represents an unmet medical need that can progress to non-alcoholic steatohepatitis (NASH), which, without intervention, can result in the development of cirrhosis and hepatocellular carcinoma (HCC). Inflammation is a pathological hallmark of NASH, and targeting key inflammatory mediators of NASH may lead to potential therapeutics for the disease. Herein, we aimed to investigate the role of IL-23 signaling in NASH progression in murine models. We showed that recombinant IL-23 can promote IL-17 producing cell expansion in the liver and that these cells are predominately γδ T cells and Mucosal Associated Invariant T cells (MAITs). Reciprocally, we found that IL-23 signaling is necessary for the expansion of γδ T cells and MAIT cells in the western diet (WD) diet induced NASH model. However, we did not observe any significant differences in liver inflammation and fibrosis between wild type and Il23r-/- mice in the same NASH model. Furthermore, we found that Il23r deletion does not impact liver inflammation and fibrosis in the choline-deficient, L-amino acid-defined and high-fat diet (CDA-HFD) induced NASH model. Based on these findings, we therefore propose that IL-23 signaling is not necessary for NASH pathogenesis in preclinical models and targeting this pathway alone may not be an effective therapeutic approach to ameliorate the disease progression in NASH patients.

Biosíntesis inducida de fengicina y surfactina en una cepa de Bacillus amyloliquefaciens con actividad oomiceticida sobre zoosporas de Phytophthora capsica / Induced biosynthesis of fengycin and surfactin in a strain of Bacillus amyloliquefaciens with oomyceticidal activity on zoospores of Phytophthora capsici

Resumen La aplicación de metabolitos antimicrobianos biosintetizados por especies de Bacillus es una alternativa potencial para controlar Phytophthora capsici (P. capsici) en hortalizas y podría evitar el uso de productos químicos con acción oomiceticida. El objetivo de este estudio fue evaluar el impacto de la adición al medio de cultivo de distintos agentes (ácido glutámico, hierro, celulosa, quitina y células inactivas de Colletotrichum spp.) sobre la biosíntesis de lipopéptidos en Bacillus amyloliquefaciens KX953161.1 y examinar la capacidad oomiceticida de dichos compuestos in vitro sobre las zoosporas de P. capsici. Los lipopéptidos identificados y cuantificados por cromatografía en capa fina de alta resolución (HPTLC) en los extractos crudos fueron fengicina y surfactina. El cultivo bacteriano adicionado con células inactivas de Colletotrichum spp. demostró la mayor biosíntesis de lipopéptidos: 1.847,02 ±11,8 pg/mL de fengicina y 2.563,45 ± 18,4 pg/mL de surfactina. Los tratamientos con menor producción de estos lipopéptidos fueron aquellos a los que se añadió hierro (608,05 ± 22,6 pg/mL de fengicina y 903,74 ±22,1 pg/mL de surfactina) o celulosa (563,31 ±11,9 y 936,96 ±41,1 pg/mL, igual orden). El extracto con los lipopéptidos presentó una inhibición del 100% en la germinación de zoosporas de P. capsici, se observó enquistamiento, malformaciones en el tubo germinal y degradación celular. Se concluye que los lipopéptidos producidos por B. amyloliquefaciens KX953161.1 podrían contribuir al control de P. capsici, sin embargo, se requieren más estudios a fin de elucidar el modo de acción biológica de estos compuestos y optimizar el perfil de producción y el rendimiento.

Abstract A potential alternative to the use of chemical products with oomyceticidal action for the control of Phytophthora capsici in vegetables is the use of antimicrobial metabolites, biosynthesized in Bacillus species. The objective of this study was to induce the biosynthesis of lipopeptides in Bacillus amyloliquefaciens KX953161.1 by using glutamic acid, iron, cellulose, chitin, or inactive Colletotrichum spp. cells. The in vitro oomyceticidal effect of the bacterial lipopeptides on zoospores of Phytophthora capsici was evaluated. The lipopeptides identified and quantified in the crude extracts by high performance thin layer chromatography (HPTLC) were fengycin and surfactin. The bacterial culture with inactive fungal cells yielded the greatest biosynthesis of lipopeptides, at 1847.02± 11.8 and 2563.45± 18.4 pg/ml of fengycin and surfactin, respectively and the treatments that obtained lower production of these lipopepti-des, were those to which iron and cellulose were added with 608.05 ± 22.6 and 903.74± 22.1; 563.31± 11.9 and 936.96± 41.1 pg/ml for fengicin and surfactin, respectively. The lipopeptide extracted showed 100% germination inhibition on zoospores of P. capsici, revealing encystment, malformations in the germ tube and cellular degradation. Lipopeptides have the potential to control P. capsici; however, the biosynthesis of these lipopeptides requires further study to determine their biological mode of action and optimize lipopeptide performance and profile.

[Induced biosynthesis of fengycin and surfactin in a strain of Bacillus amyloliquefaciens with oomyceticidal activity on zoospores of Phytophthora capsici]. / Biosíntesis inducida de fengicina y surfactina en una cepa de Bacillus amyloliquefaciens con actividad oomiceticida sobre zoosporas de Phytophthora capsica.

A potential alternative to the use of chemical products with oomyceticidal action for the control of Phytophthora capsici in vegetables is the use of antimicrobial metabolites, biosynthesized in Bacillus species. The objective of this study was to induce the biosynthesis of lipopeptides in Bacillus amyloliquefaciens KX953161.1 by using glutamic acid, iron, cellulose, chitin, or inactive Colletotrichum spp. cells. The in vitro oomyceticidal effect of the bacterial lipopeptides on zoospores of Phytophthora capsici was evaluated. The lipopeptides identified and quantified in the crude extracts by high performance thin layer chromatography (HPTLC) were fengycin and surfactin. The bacterial culture with inactive fungal cells yielded the greatest biosynthesis of lipopeptides, at 1847.02± 11.8 and 2563.45± 18.4 µg/ml of fengycin and surfactin, respectively and the treatments that obtained lower production of these lipopeptides, were those to which iron and cellulose were added with 608.05 ± 22.6 and 903.74± 22.1; 563.31± 11.9 and 936.96± 41.1 µg/ml for fengicin and surfactin, respectively. The lipopeptide extracted showed 100% germination inhibition on zoospores of P. capsici, revealing encystment, malformations in the germ tube and cellular degradation. Lipopeptides have the potential to control P. capsici; however, the biosynthesis of these lipopeptides requires further study to determine their biological mode of action and optimize lipopeptide performance and profile.

Comparison of the Effect of Hydrostatic and Dynamic High Pressure Processing on the Enzymatic Activity and Physicochemical Quality Attributes of 'Ataulfo' Mango Nectar.

The effects of hydrostatic (HHP) and dynamic (HPH) high-pressure treatments on the activity of pectin methylesterase (PME) and polyphenol oxidase (PPO) as well as the physicochemical quality attributes of 'Ataulfo' mango nectar were assessed. HHP reduced PME relative activity by 28% at 100 MPa for 5 min but increased PPO activity almost five-fold. Contrarily, HPH did not affect PME activity, but PPO was effectively reduced to 10% of residual activity at 300 MPa and at three passes. Color parameters (CIEL*a*b*), °hue, and chroma were differently affected by each type of high-pressure processing technology. The viscosity and fluid behavior were not affected by HHP, however, HPH changed the apparent viscosity at low dynamic pressure levels (100 MPa with one and three passes). The viscosity decreased at high shear rates in nectar samples, showing a shear-thinning effect. The results highlight how different effects can be achieved with each high-pressure technology; thus, selecting the most appropriate system for processing and preserving liquid foods like fruit beverages is recommended.

Disease activity indexes might not capture the same disease aspects in males and females with ankylosing spondylitis: A real-world nationwide analysis.

Background: To evaluate gender differences in disease activity and health status (HS) in patients with radiographic axial spondyloarthritis (r-axSpA)/ankylosing spondylitis (AS). Methods: Ancillary analysis of the MIDAS study, an observational, non-interventional, cross-sectional and retrospective multicenter nationwide study to assess disease activity and its relationship with HS in clinical practice. Adult patients with AS diagnosis, fulfilling ASAS and modified New York criteria, treated for ≥3 months upon study inclusion according to clinical practice were included. The primary outcome was "disease control" assessed by the percentage of patients in remission and low disease activity (BASDAI and ASDAS-CRP scores). HS was evaluated using the ASAS health index (ASAS-HI). Patients' responses and characteristics were analyzed by gender. Results: We analyzed 313 patients with AS, 237 (75.7%) males and 76 (24.3%) females. A total of 202 (64.5%) patients had adequate disease control (BASDAI < 4); 69.2% of males [mean (SD) BASDAI 2.9 (2.1)] and 50.0% of females [mean (SD) BASDAI 3.8 (2.4); p = 0.01]. According to ASDAS-CRP, 57.5% of patients were adequately controlled (ASDAS-ID +ASDAS-LDA); 138 (58.2%) males and 42 (55.3%) females. The mean (SD) ASDAS-CRP was 1.9 (1.1); being 1.9 (1.0) in males and 2.0 (1.1) in females. Overall, the impact of AS on HS was low to moderate [mean (SD) ASAS-HI 5.8 (4.4)]; being 5.5 (4.4) for males and 6.8 (4.2) for females (p = 0.02). Conclusion: This study showed a higher proportion of females with AS and active disease using the BASDAI definition. When using the ASDAS-CRP definition these differences by gender were less pronounced. The impact of disease activity on HS appears to be higher in females than males.

Valorization of Fermented Shrimp Waste with Supercritical CO2 Conditions: Extraction of Astaxanthin and Effect of Simulated Gastrointestinal Digestion on Its Antioxidant Capacity.

Lactic acid fermentation increases the bioactive properties of shrimp waste. Astaxanthin is the principal carotenoid present in shrimp waste, which can be found esterified in the liquid fraction (liquor) after its lactic acid fermentation. Supercritical CO2 technology has been proposed as a green alternative to obtain astaxanthin from fermented shrimp waste. This study aimed to optimize astaxanthin extraction by supercritical CO2 technology from fermented liquor of shrimp waste and study bioaccessibility using simulated gastrointestinal digestion (GD) of the optimized extract. A Box-Behnken design with three variables (pressure, temperature, and flow rate) was used to optimize the supercritical CO2 extraction. The optimized CO2 extract was obtained at 300 bar, 60 °C, and 6 mL/min, and the estimated characteristics showed a predictive extraction yield of 11.17%, antioxidant capacity of 1.965 mmol of Trolox equivalent (TE)/g, and astaxanthin concentration of 0.6353 µg/g. The experiment with optimal conditions performed to validate the predicted values showed an extraction yield of 12.62%, an antioxidant capacity of 1.784 mmol TE/g, and an astaxanthin concentration of 0.52 µg/g. The astaxanthin concentration decreased, and the antioxidant capacity of the optimized extract increased during gastrointestinal digestion. In conclusion, our optimized supercritical CO2 process is suitable for obtaining astaxanthin from shrimp by-products after lactic acid fermentation.

Vegetable oils as green solvents for carotenoid extraction from pumpkin (Cucurbita argyrosperma Huber) byproducts: Optimization of extraction parameters.

Pumpkin pulp is the main waste generated by pumpkin seed growers. This agro-industrial waste is a valuable source of bioactive compounds, especially carotenoids (ß-carotene, α-carotene, and lutein), which exhibit a broad spectrum of health-promoting effects. In this study, vegetable oils (canola, corn, and soybean oil) were used as green solvent alternatives to conventional organic solvents for carotenoid extraction from dried pumpkin pulp (DPP) waste. The highest carotenoid extraction yield (CEY) was obtained with canola oil, at a 1:10 DPP/oil ratio. Response surface methodology (RSM) was used to optimize the extraction process parameters (temperature, time, and stirring rate) through a Box-Behnken design (BBD) maximizing CEY in canola oil. The extraction temperature and stirring rate were found to have a significant linear and quadratic effect, respectively, on CEY. Optimum conditions were achieved at 21.8 min, 250 rpm, and 60°C. Under these optimized conditions, the estimated value for CEY was 378.1 µg ß-carotene equivalents/g of DPP, corresponding to 61.6% of the total carotenoid content present in the DPP. In contrast, the observed experimental value was 373.2 µg ß-carotene equivalents/g of DPP (61.2%). The experimental value was very close to the estimated value, which verifies the model's adequacy and fit. This study shows an alternative method to extract carotenoids from DPP with canola oil, obtaining an oil naturally enriched with carotenoids that could be used as a potential functional ingredient in the development of food, cosmetics, and medicinal products. PRACTICAL APPLICATION: Pumpkin by-products are a potential carotenoid source. Vegetable oil can be used as an alternative solvent for carotenoid extraction from pumpkin residues to obtain an enriched carotenoid oil that can be used to formulate food products.

Checklist of Staphylinidae (Coleoptera) of El Salvador.

This paper is primarily a compilation of published data on the staphylinid beetle species reported for El Salvador. It is based on taxonomic and ecological literature, with inclusion of some new records from different entomological collections. Thirty eight genera and 96 species are reported in the list, including a first country record: Eulissus chalybaeus. Country-level distribution outside of El Salvador, locality references and topographic zones are included for each species. In the list, three endemic species are recorded: Seeversiella badia, S. minima and Stenus salvadorensis. It is remarkable that 14 genera (37%) and 52 species (54%) have only been reported at a country level in the literature, without a specific locality of collection, indicating the need for local inventories of this coleopteran family in the salvadoran territory.

Influence of prognosis factors on the prescription of targeted treatments in rheumatoid arthritis: A Delphi survey.

OBJECTIVES: To explore current evidence on the management of poor prognostic factors in rheumatoid arthritis (RA) and to investigate whether this evidence is taken into account by clinicians when deciding on treatment in daily clinical practice. METHODS: We performed a systematic literature review (SLR) to analyse the effects of currently available biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi) on the classically accepted poor prognostic factors of RA. All randomized controlled trials reporting subgroup analyses about effects on prognostic factors were identified and synthesized. In a second phase, a two-round Delphi survey was carried out to contrast the SLR results with the grade of agreement of a large group of rheumatologists about the effectiveness of each drug class on each prognostic factor. RESULTS: According to the Delphi results, the only prognostic factor that significantly influenced the selection of treatment was the presence of interstitial lung disease (ILD), being the preferred treatment in this scenario abatacept or rituximab. The rest of the poor prognostic factors (including high disease activity at baseline, disability as measured by the Health Assessment Questionnaire index, seropositivity, elevated acute-phase reactants, and evidence of erosions based on plain radiography or ultrasonography) did not seem to significantly influence rheumatologists when choosing a treatment. The results of the SLR results did not show solid evidence regarding the use of any specific therapy in the management of patients with specific poor factors, except in the case of RA-ILD, although the data in the literature in this regard are not free of bias. CONCLUSIONS: The only prognostic factor that seems to significantly influence the selection of treatment is the presence of RA-ILD.

Effectiveness and persistence of golimumab as a second biological drug in patients with spondyloarthritis: A retrospective study.

ABSTRACT: This observational, longitudinal retrospective, noncomparative study was designed to assess the persistence and effectiveness of golimumab as a second anti-tumor necrosis factor (TNF) drug in patients with spondyloarthritis requiring discontinuation from a first anti-TNF drug.Data were collected retrospectively for all patients with axial spondyloarthritis or psoriatic arthritis from 20 rheumatology clinics in Spain who started golimumab as a second anti-TNF drug between January 2013 and December 2015. Golimumab persistence was assessed with Kaplan-Meier survival analysis, and associated factors were assessed with Cox regression analysis.210 patients started golimumab as a second anti-TNF drug: 131 with axial spondyloarthritis and 79 with psoriatic arthritis. In axial spondyloarthritis patients, the mean (standard deviation) Bath Ankylosing Spondylitis Disease Activity Index score at baseline was 5.5 (2.1), decreasing to 3.9 (2.0) at month 3 and 3.5 (2.0) at year 1, and remaining stable thereafter. In psoriatic arthritis patients, mean (standard deviation) baseline Disease Activity Score was 4.0 (1.3), reducing to 2.5 (1.2) at month 3 and to 2.2 (1.3) at year 1. Corresponding improvements were recorded from baseline in C-reactive protein levels and erythrocyte sedimentation rates. The probability of persistence of treatment with golimumab was 80% at year 1, 70% at year 2 and 65% at years 3 and year 4, and was similar in those who had stopped the first anti-TNF due to loss of efficacy or other reasons. Cox regression analysis showed that the probability of survival with golimumab was higher in patients with higher erythrocyte sedimentation rate, in patients with axial spondyloarthritis than with psoriatic arthritis, and in those who had discontinued adalimumab as first anti-TNF. Seventy-two patients (34.3%) discontinued golimumab during follow-up, 50 of them due to lack of efficacy.In patients with spondyloarthritis requiring discontinuation from a first anti-TNF drug, treatment with golimumab was effective and showed a high probability of persistence up to 4 years of treatment.

A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment.

Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.