Is the acquired hypothyroidism a risk factor for developing psychiatric disorders?

Hypothyroidism is a prevalent thyroid condition in which the thyroid gland fails to secrete an adequate amount of thyroid hormone into the bloodstream. This condition may develop due to genetic or acquired factors. The most frequent cause of acquired hypothyroidism is chronic autoimmune thyroiditis, also known as Hashimoto's disease. Acquired hypothyroidism is diagnosed when patients present with overt hypothyroidism (also known as clinical hypothyroidism), as they exhibit increased TSH and decreased T3 and T4 serum levels. This article examines the prevalence of psychiatric disorders among patients diagnosed with acquired hypothyroidism with or without Levothyroxine treatment. We discuss the available evidence indicating that acquired hypothyroidism may be a risk factor for psychiatric disorders, and the effectiveness of thyroid treatment in relieving psychiatric symptoms. Additionally, we provide critical details on thyroid hormone cutoff values reported in the literature, their potential clinical importance, and their correlation with psychiatric symptoms. Finally, we examined the various mechanisms by which acquired hypothyroidism can lead to depression. The high rate of comorbidity between hypothyroidism and psychiatric disorders deserves special attention, indicating the importance of consistent monitoring and timely identification of psychiatric symptoms to prevent disease exacerbation and facilitate therapeutic management. On the other hand, several mechanisms underlie the strong association between depression and acquired hypothyroidism. Deeper research into these mechanisms will allow knowledge of the pathophysiology of depression in patients with acquired hypothyroidism and will provide clues to design more precise therapeutic strategies for these patients.

Extraction, Identification, and Quantification of Polyphenols from the Theobroma cacao L. Fruit: Yield vs. Environmental Friendliness.

The cacao fruit is a rich source of polyphenols, including flavonoids and phenolic acids, which possess significant health benefits. The accurate identification and quantification of these bioactive compounds extracted from different parts of the cacao fruit, such as pods, beans, nibs, and cacao shells, require specific treatment conditions and analytical techniques. This review presents a comprehensive comparison of extraction processes and analytical techniques used to identify and quantify polyphenols from various parts of the cacao fruit. Additionally, it highlights the environmental impact of these methods, exploring the challenges and opportunities in selecting and utilizing extraction, analytical, and impact assessment techniques, while considering polyphenols' yield. The review aims to provide a thorough overview of the current knowledge that can guide future decisions for those seeking to obtain polyphenols from different parts of the cacao fruit.

How a Long-Term Cover Crop Cultivation Impacts Soil Phosphorus Availability in a No-Tillage System?

The growth of cover crops can contribute to the increase in phosphorus content at depth by root decomposition. The aim of this work was to verify the effect of cover crops on soil phosphorus availability and use by successive plants, and the accumulation of soil P in a no-tillage system conducted for 14 years. This research was carried out during the 2016/2017 and 2017/2018 crop seasons, whose treatments have been installed and maintained since 2003. The experimental design was a randomized block design, and the plots consisted of spring crops: pearl millet, forage sorghum, sunn hemp, and additionally, a fallow/chiseling area. The evaluation of available P was determined by P fractionation. In general, in the two years of evaluation, the accumulation of P in the shoot dry matter was higher in sunn hemp growth, on average 25% higher than pearl millet in 2016 and 40% higher than sorghum in 2017. The highest contents of labile inorganic P were in the sorghum-soybean and fallow/chiseling-soybean successions, with values higher than 50 mg kg-1 of P in the 0-0.1 m soil layer. However, in the other layers analyzed, the cover crops obtained higher availability of labile inorganic P. The systems using cover crops recovered 100% of the P fertilized in soybean.

Peruvian fava beans for health and food innovation: physicochemical, morphological, nutritional, and techno-functional characterization.

Peruvian fava beans (PFB) are used in traditional cuisine as a nutrient-rich, flavorful, and textural ingredient; however, little is known about their industrial properties. This study evaluated the physicochemical, nutritional, and techno-functional characteristics of PFB varieties: Verde, Quelcao, and Peruanita. PFB exhibited distinct physical characteristics, quality parameters, and morphology. The color patterns of the seed coat and the hardness were the main parameters for distinguishing them. Nutritionally, all three samples exhibited high protein (23.88-24.88 g/100 g), with high proportion of essential amino acids, high dietary fiber (21.74-25.28 g/100 g), and mineral content. They also contain polyphenols (0.79-1.25 mg GAE/g) and flavonoids (0.91-1.06 mg CE/g) with antioxidant potential (16.60-21.01 and 4.68-5.17 µmol TE/g for ABTS and DPPH assays, respectively). Through XRD measurements, the semi-crystalline nature of samples was identified, belonging to the C-type crystalline form. Regarding techno-functionality, PFB flours displayed great foaming capacity, with Verde variety being the most stable. Emulsifying capacity was similar among samples, although Peruanita was more stable during heating. Upon heating with water, PFB flours reached peak viscosities between 175 and 272 cP, and final viscosities between 242 and 384 cP. Quelcao and Verde formed firmer gels after refrigeration. Based on these results, PFB would be useful to developing innovative, nutritious, and healthy products that meet market needs.

Correlation of PD-L1 expression with different clinico-pathological and immunohistochemical features of ovarian surface epithelial tumors.

BACKGROUND: Primary carcinoma of the ovary (OCs) are responsible for a significant number of deaths related to cancer, and have the highest rate of death related to cancers of the female reproductive organs. Programmed cell death 1 (PD1) protein, acts as an immune checkpoint, and has an important role in the down-regulation of the immune system by preventing the activation of T-cells, which will weaken the autoimmunity and increases self-tolerance. This study aimed at the evaluation of the immunohistochemical (IHC) expression of PD-L1 in various primary surface ovarian epithelial tumours and to test its correlation with different clinicopathological parameters together with the expression of a panel of P53, ER and PR. METHODS: A set of 102 cases of primary ovarian surface epithelial neoplasms (benign, borderline and malignant) were collected to construct Tissue Microarray (TMA) using 3 tissue cores from each case. IHC for PD-L1, p53, PR and ER was performed. The expression of PD-L1 was evaluated in relation to some clinicopathological parameters and to the expression patterns of other markers. RESULTS: Expression of PD-L1 was detected in about 51% (n = 36) of malignant tumours. The malignant group significantly showed PD-L1 positivity compared to borderline and benign groups. The malignant tumours significantly showed PD-L1 and total p53 positivity in comparison to borderline group. Also, malignant tumours significantly showed higher combined positivity of PD-L1 and either PR or ER compared to borderline and benign lesions. No significant correlation was appreciated between PD-L1 expression and with any of the studied clinicopathological parameters. CONCLUSIONS: This study showed a significant PD-L1 expression in malignant primary surface epithelial tumours. Construction of a panel of IHC markers, including PD-L1, could have a potential value to define patients those would benefit from the addition of immunotherapy to the treatment plan.

[20q11.2 microdeletion syndrome: a phenotypic spectrum expansion. Case report]. / Síndrome de microdeleción 20q11.2: ampliación del espectro fenotípico. Reporte de un caso.

Background: 20q11.2 microdeletion syndrome [ORPHA: 444051] is a rare disease, since 16 patients have been reported in literature worldwide. Prevalence ratio is < 1:1,000,000 individuals. Haploinsufficiency on GDF5, SAMHD1 and EPB41L1 genes is important due to phenotypic manifestations in patients. Clinical features can be grouped into craniofacial abnormalities, limb abnormalities, neurological and perinatal disorders. The aim of this report is to present a clinical case of 20q11.21-q11.23 microdeletion, to describe clinical manifestations found, to compare them with features reported in literature, and to contribute to the phenotypic spectrum expansion. Clinical case: 5-year-old female patient who presented hypotonia, psychomotor retardation, microcephaly, facial dysmorphia, pectus excavatum, thoracolumbar scoliosis, right hip subluxation, camptodactyly and clinodactyly. Karyotype test was normal and SNP microarray test reported deletion of chromosomal region 20q11.21-q11.23. Conclusions: It was presented a 20q11.2 microdeletion syndrome confirmed case that shares the features reported in literature, in addition to previously unreported features, such as blepharoptosis, pectus excavatum, scoliosis and hip dysplasia. Interdisciplinary management is important to improve the patient's condition (in her 3 spheres), in order to achieve her best possible health status.

Introducción: el síndrome de microdeleción 20q11.2 [ORPHA: 444051] es una enfermedad rara, pues se han reportado 16 casos a nivel mundial. Su prevalencia se estima en < 1:1,000,000 de nacidos vivos. Induce haploinsuficiencia en los genes GDF5, SAMHD1 y EPB41L1, los cuales son de importancia clínica por las manifestaciones fenotípicas. Se caracteriza por anomalías craneofaciales, anomalías de extremidades, alteraciones neurológicas y perinatales. El objetivo de este reporte es presentar un caso de microdeleción 20q11.21-q11.23, describir las manifestaciones clínicas encontradas, compararlo con lo reportado en la literatura y colaborar en la ampliación del espectro fenotípico. Caso clínico: paciente del sexo femenino de 5 años que presentó hipotonía, retraso psicomotor, microcefalia, dismorfias faciales, pectus excavatum, escoliosis toracolumbar, subluxación de cadera derecha, camptodactilia y clinodactilia. La prueba de cariotipo se reportó sin alteraciones y el ensayo de microarreglo de polimorfismos de un nucleótido (SNP) reportó deleción de la región cromosómica 20q11.21-q11.23. Conclusiones: se presentó un caso confirmado de síndrome de microdeleción 20q11.2 que comparte las características reportadas en la literatura, además de características no reportadas previamente, como ptosis palpebral, pectus excavatum, escoliosis y displasia del desarrollo de cadera. Es importante el manejo interdisciplinario para buscar mejoría en la condición de la paciente (en sus 3 esferas), a fin de alcanzar el mejor estado de salud posible.

SCI1, a flower regulator of cell proliferation, and its partners NtCDKG2 and NtRH35 interact with the splicing machinery.

Successful plant reproduction depends on the adequate development of flower organs controlled by cell proliferation and other processes. The SCI1 gene regulates cell proliferation and affects the final size of the female reproductive organ. To unravel the molecular mechanism exerted by SCI1 in cell proliferation control, we searched for its interaction partners through semi-in vivo pulldown experiments, uncovering a cyclin-dependent kinase, NtCDKG;2. Bimolecular fluorescence complementation (BiFC) and co-localization experiments showed that SCI1 interacts with NtCDKG;2 and its cognate NtCyclin L in nucleoli and splicing speckles. The screening of a yeast two-hybrid (Y2H) cDNA library using SCI1 as bait revealed a novel DEAD-box RNA helicase (NtRH35). The interaction between the NtCDKG;2-NtCyclin L complex, and NtRH35 was also shown. Subcellular localization experiments showed that SCI1, NtRH35, and the NtCDKG;2-NtCyclin L complex associate with each other within splicing speckles. The Y2H screening of NtCDKG;2 and NtRH35 identified the conserved spliceosome components U2a', NKAP, and CACTIN. This work presents SCI1 and its interactors NtCDKG;2-NtCyclin L complex, and NtRH35 as new spliceosome-associated proteins. Our findings reveal a network of interactions and suggest that SCI1 may regulate cell proliferation through the splicing process. This study provides new valuable insights into the intricate molecular pathways governing plant development.

PD-L1 expression in non-small cell lung carcinoma in Latin America: a systematic review and meta-analysis.

Background: Programmed cell death ligand 1 (PD-L1) expression in non-small cell lung carcinoma (NSCLC) is a crucial factor in predicting responses to immunotherapy. This systematic review and meta-analysis focuses on the prevalence of PD-L1 expression and clinicopathological features among Hispanic/Latino (H/L) populations. Methods: Embase, LILACS, Medline, and Virtual Health Library were searched for studies that evaluated the prevalence of PD-L1 in H/L patients. The protocol was submitted to PROSPERO with ID CRD42023488547. We employed the Joanna Briggs Institute Checklist for Systematic Reviews and Research Syntheses to assess the methodological quality and applicability of the included studies. Meta-analyses were done to determine the prevalence using a random effects model. Results: The meta-analysis, encompassing 21 articles with 16,486, revealed that 80.2% of patients had PD-L1 expression data available (n=13,222). The prevalence calculated of PD-L1 expression in Latino NSCLC patients was 55% [95% confidence interval (CI): 0.54-0.55], with 31% (95% CI: 0.27-0.36) showing a tumoral proportion score (TPS) of 1-49%, and 23% (95% CI: 0.16-0.30) registering a TPS ≥50%. Higher expression was observed in male gender, smoking, adenocarcinoma subtypes, poor tumor differentiation, and advanced stages. PD-L1 expression was most frequent in EGFR wild-type status (82.5%) with a odds ratio (OR) 1.54 (95% CI: 1.24-1.92) and PD-L1 expression was associated with ALK positive (OR =1.54; 95% CI: 1.24-1.92). Conclusions: This meta-analysis provides a comprehensive overview of PD-L1 expression in NSCLC in the H/L population. The findings underscore the significant prevalence of PD-L1 expression and emphasize the relevance of immunotherapy in this population. Understanding the clinicopathological features associated with PD-L1 expression can contribute to tailored treatment strategies for NSCLC in Latin America.

Nuclear Factor-Kappa-B Mediates the Advanced Glycation End Product-Induced Repression of Slc2a4 Gene Expression in 3T3-L1 Adipocytes.

Advanced glycated end products (AGEs) are cytotoxic compounds that are mainly increased in diabetes mellitus (DM), kidney failure, inflammation, and in response to the ingestion of AGE-rich diets. AGEs can also impair glycemic homeostasis by decreasing the expression of the Slc2a4 (solute carrier family 2 member 4) gene and its GLUT4 (solute carrier family 2, facilitated glucose transporter member 4) protein in muscle. However, the mechanisms underlying AGE's effect on adipocytes have not been demonstrated yet. This study investigated the effects of AGEs upon Slc2a4/GLUT4 expression in 3T3-L1 adipocytes, as well as the potential role of NFKB (nuclear factor NF-kappa-B) activity in the effects observed. Adipocytes were cultured in the presence of control albumin (CA) or advanced glycated albumin (GA) at concentrations of 0.4, 3.6, and 5.4 mg/mL for 24 h or 72 h. Slc2a4, Rela, and Nfkb1mRNAs were measured by RT-qPCR, GLUT4, IKKA/B, and p50/p65 NFKB subunits using Western blotting, and p50/p65 binding into the Slc2a4 promoter was analyzed by chromatin immunoprecipitation (ChIP) assay. GA at 0.4 mg/mL increased Slc2a4/GLUT4 expression after 24 h and 72 h (from 50% to 100%), but at 5.4 mg/mL, Slc2a4/GLUT4 expression decreased at 72 h (by 50%). Rela and Nfkb1 expression increased after 24 h at all concentrations, but this effect was not observed at 72 h. Furthermore, 5.4 mg/mL of GA increased the p50/p65 nuclear content and binding into Slc2a4 at 72 h. In summary, this study reveals AGE-induced and NFKB-mediated repression of Slc2a4/GLUT4 expression. This can compromise the adipocyte glucose utilization, contributing not only to the worsening of glycemic control in DM subjects but also the impairment of glycemic homeostasis in non-DM subjects under the high intake of AGE-rich foods.

Cashew nut (Anacardium occidentale L.) and cashew nut oil reduce cardiovascular risk factors in adults on weight-loss treatment: a randomized controlled three-arm trial (Brazilian Nuts Study).

Introduction: Cashew nut contains bioactive compounds that modulate satiety and food intake, but its effects on body fat during energy restriction remains unknown. This study aimed to assess the effects of cashew nut and cashew nut oil on body fat (primary outcome) as well as adiposity, cardiometabolic and liver function markers (secondary outcomes). Materials and methods: An eight-week (8-wk) randomized controlled-feeding study involved 68 adults with overweight/obesity (40 women, BMI: 33 ± 4 kg/m2). Participants were randomly assigned to one of the energy-restricted (-500 kcal/d) groups: control (CT, free-nuts), cashew nut (CN, 30 g/d), or cashew nut oil (OL, 30 mL/d). Body weight, body composition, and blood collection were assessed at the baseline and endpoint of the study. Results: After 8-wk, all groups reduced significantly body fat (CT: -3.1 ± 2.8 kg; CN: -3.3 ± 2.7 kg; OL: -1.8 ± 2.6 kg), body weight (CT: -4.2 ± 3.8 kg; CN: -3.9 ± 3.1 kg; OL: -3.4 ± 2.4 kg), waist (CT: -5.1 ± 4.6 cm; CN: -3.9 ± 3.9 cm; OL: -3.7 ± 5.3 cm) and hip circumferences (CT: -2.9 ± 3.0 cm; CN: -2.7 ± 3.1 cm; OL: -2.9 ± 2.3 cm). CN-group reduced liver enzymes (AST: -3.1 ± 5.3 U/L; ALT: -6.0 ± 9.9 U/L), while the OL-group reduced LDL-c (-11.5 ± 21.8 mg/dL) and atherogenic index (-0.2 ± 0.5). Both intervention groups decreased neck circumference (CN: -1.0 ± 1.2 cm; OL: -0.5 ± 1.2 cm) and apo B (CN: -6.6 ± 10.7 mg/dL; OL: -7.0 ± 15.3 mg/dL). Conclusion: After an 8-wk energy-restricted intervention, all groups reduced body fat (kg), weight, and some others adiposity indicators, with no different effect of cashew nut or cashew nut oil. However, participants in the intervention groups experienced additional reductions in atherogenic marker, liver function biomarkers, and cardiovascular risk factors (neck circumference and apo B levels), with these effects observed across the OL group, CN group, and both intervention groups, respectively.Clinical trial registration:https://ensaiosclinicos.gov.br/rg/RBR-8xzkyp2, identifier 8xzkyp2.

Resilience and quality of life in patients who underwent mechanical ventilation due to COVID-19, one year after discharge: a cross-sectional study.

BACKGROUND: Patients with COVID-19 often experience severe long-term sequelae. This study aimed to assess resilience and Quality of Life (QoL) of patients who underwent mechanical ventilation due to COVID-19, one year after discharge. METHODS: This cross-sectional study enrolled patients who received mechanical ventilation for severe COVID-19 and were assessed one-year post-discharge. Participants completed a structured questionnaire via telephone comprising the Connor-Davidson Resilience Scale (CD-RISC) and the Post-COVID-19 Functional Status scale (PCFS). To establish the association between QoL and resilience, Spearman correlations were calculated between the PCFS and the CD-RISC. Linear regression models were adjusted to evaluate which factors were associated with QoL, with the total score of PCFS as the dependent variable. RESULTS: A total of 225 patients were included in the analysis. The CD-RISC had a median score of 83 (IQR 74-91). The PCFS results showed that 61.3% (n = 138) of the patients were able to resume their daily activities without limitations. Among them, 37.3% (n = 84) were classified as Grade 0 and 24% (n = 54) as Grade 1. Mild and moderate functional limitations were found in 33.7% of the patients, with 24.8% (n = 56) classified as Grade 2 and 8.8% (n = 20) as Grade 3. Severe functional limitations (Grade 4) were observed in 4.8% (n = 11) of the patients. High CD-RISC scores were associated with lower levels of PCFS score (p < 0.001). CONCLUSIONS: In this cohort of critically ill patients who underwent mechanical ventilation due to COVID-19, 38% of patients experienced a significant decline in their QoL one year after hospital discharge. Finally, a high level of resilience was strongly associated with better QoL one year after discharge.

Stability of Buriti Oil Microencapsulated in Mixtures of Azuki and Lima Bean Flours with Maltodextrin.

Buriti oil (Mauritia flexuosa L.) is rich in carotenoids, mainly ß-carotene, and has great value for application as a food, pharmaceutical, or cosmetic ingredient, as well as a natural pigment. Microencapsulation is a promising technique to protect compounds sensitive to degradation such as ß-carotene. Materials composed of carbohydrates and proteins, such as azuki bean (Vigna angularis L.) and lima bean (Phaseolus lunatus L.) flours, are alternative matrices for microencapsulation, which additionally provide good amounts of nutrients. In combination with maltodextrin, the flours represent a protective barrier in stabilizing lipophilic compounds such as buriti oil for subsequent spray drying. In this work, the performance of mixtures of maltodextrin with whole azuki and lima bean flours was evaluated in the microencapsulation of buriti oil. The microcapsules showed good results for solubility (>80%), hygroscopicity (~7%), encapsulation efficiency (43.52 to 51.94%), and carotenoid retention (64.13 to 77.49%.) After 77 days of storage, the microcapsules produced maintained 87.79% and 90.16% of carotenoids, indicating that the powders have high potential for application as encapsulants in the food and pharmaceutical industries.

Sweet Cherry Plants Prioritize Their Response to Cope with Summer Drought, Overshadowing the Defense Response to Pseudomonas syringae pv. syringae.

Disease severity and drought due to climate change present significant challenges to orchard productivity. This study examines the effects of spring inoculation with Pseudomonas syringae pv. syringae (Pss) on sweet cherry plants, cvs. Bing and Santina with varying defense responses, assessing plant growth, physiological variables (water potential, gas exchange, and plant hydraulic conductance), and the levels of abscisic acid (ABA) and salicylic acid (SA) under two summer irrigation levels. Pss inoculation elicited a more pronounced response in 'Santina' compared to 'Bing' at 14 days post-inoculation (dpi), and those plants inoculated with Pss exhibited a slower leaf growth and reduced transpiration compared to control plants during 60 dpi. During differential irrigations, leaf area was reduced 14% and 44% in Pss inoculated plants of 'Bing' and 'Santina' respectively, under well-watered (WW) conditions, without changes in plant water status or gas exchange. Conversely, water-deficit (WD) conditions led to gas exchange limitations and a 43% decrease in plant biomass compared to that under WW conditions, with no differences between inoculation treatments. ABA levels were lower under WW than under WD at 90 dpi, while SA levels were significantly higher in Pss-inoculated plants under WW conditions. These findings underscore the influence on plant growth during summer in sweet cherry cultivars that showed a differential response to Pss inoculations and how the relationship between ABA and SA changes in plant drought level responses.

Molecular characterization of EcCLP1, a new putative cathepsin L protease from Echinococcus canadensis.

Echinococcus granulosus sensu lato is a platyhelminth parasite and the etiological cause of cystic echinococcosis (CE), a zoonotic and neglected disease that infects animals and humans worldwide. As a part of the biological arsenal of the parasite, cathepsin L proteases are a group of proteins that are believed to be essential for parasite penetration, immune evasion, and establishment in the tissues of the host. In this work, we have cloned and sequenced a new putative cathepsin L protease from Echinococcus canadensis (EcCLP1). The bioinformatic analysis suggests that EcCLP1 could be synthesized as a zymogen and activated after proteolytic cleavage. The multiple sequence alignment with other cathepsin proteases reveals important functional conserved features like a conserved active site, an N-linked glycosylation residue, a catalytic triad, an oxyanion hole, and three putative disulfide bonds. The phylogenetic analysis suggests that EcCLP1 could indeed be a cathepsin L cysteine protease from clade 1 as it grouped with cathepsins from other species in this clade. Modeling studies suggest that EcCLP1 has two domains forming a cleft where the active site is located and an occluding role for the propeptide. The transcriptomic analysis reveals different levels of cathepsin transcript expression along the different stages of the parasite life cycle. The whole-mount immunohistochemistry shows an interesting superficial punctate pattern of staining which suggests a secretory pattern of expression. The putative cathepsin L protease characterized here may represent an interesting tool for diagnostic purposes, vaccine design, or a new pharmacological target for antiparasitic intervention.

Title: Caractérisation moléculaire d'EcCLP1, une nouvelle protéase putative de type cathepsine L d'Echinococcus canadensis. Abstract: Echinococcus granulosus sensu lato est un Plathelminthe parasite et la cause étiologique de l'échinococcose kystique (EK), une maladie zoonotique et négligée qui infecte les animaux et les humains dans le monde entier. En tant que partie de l'arsenal biologique du parasite, les protéases de type cathepsine L sont un groupe de protéines considérées comme essentielles à la pénétration du parasite, l'évasion immunitaire et son établissement dans les tissus de l'hôte. Dans ce travail, nous avons cloné et séquencé une nouvelle protéase putative de type cathepsine L d'Echinococcus canadensis (EcCLP1). L'analyse bioinformatique suggère qu'EcCLP1 pourrait être synthétisée sous forme de zymogène et activée après clivage protéolytique. L'alignement de séquences multiples avec d'autres protéases de type cathepsine révèle d'importantes caractéristiques fonctionnelles conservées telles qu'un site actif conservé, un résidu de glycosylation lié à N, une triade catalytique, un trou oxyanion et trois liaisons disulfure putatives. L'analyse phylogénétique suggère qu'EcCLP1 pourrait en effet être une protéase de type cathepsine L du clade 1 car elle se regroupe avec les cathepsines d'autres espèces de ce clade. Les études de modélisation suggèrent qu'EcCLP1 possède deux domaines formant une fente où se trouve le site actif et un rôle d'occlusion pour le propeptide. L'analyse transcriptomique révèle différents niveaux d'expression du transcrit de la cathepsine au cours des différentes étapes du cycle de vie du parasite. L'immunohistochimie de montages entiers montre un intéressant motif de coloration ponctuée superficielle qui suggère un modèle d'expression sécrétoire. La protéase putative de type cathepsine L caractérisée ici peut représenter un outil intéressant à des fins de diagnostic, de conception de vaccins ou une nouvelle cible pharmacologique pour une intervention antiparasitaire.

Evaluation of Reproductive Histology Response of Adult Fasciola hepatica in Goats Vaccinated with Cathepsin L Phage-Exposed Mimotopes.

Fasciolosis, a globally re-emerging zoonotic disease, is mostly caused by the parasitic infection with Fasciola hepatica, often known as the liver fluke. This disease has a considerable impact on livestock productivity. This study aimed to evaluate the fluke burdens and faecal egg counts in goats that were administered phage clones of cathepsin L mimotopes and then infected with F. hepatica metacercariae. Additionally, the impact of vaccination on the histology of the reproductive system, specifically related to egg generation in adult parasites, was examined. A total of twenty-four goats, which were raised in sheds, were divided into four groups consisting of six animals each. These groups were randomly assigned. The goats were then subjected to two rounds of vaccination. Each vaccination involved the administration of 1 × 1013 phage particles containing specific mimotopes for cathepsin L2 (group 1: PPIRNGK), cathepsin L1 (group 2: DPWWLKQ), and cathepsin L1 (group 3: SGTFLFS). The immunisations were carried out on weeks 0 and 4, and the Quil A adjuvant was used in combination with the mimotopes. The control group was administered phosphate-buffered saline (PBS) (group 4). At week 6, all groups were orally infected with 200 metacercariae of F. hepatica. At week 22 following the initial immunisation, the subjects were euthanised, and adult F. hepatica specimens were retrieved from the bile ducts and liver tissue, and subsequently quantified. The specimens underwent whole-mount histology for the examination of the reproductive system, including the testis, ovary, vitellaria, Mehlis' gland, and uterus. The mean fluke burdens following the challenge were seen to decrease by 50.4%, 62.2%, and 75.3% (p < 0.05) in goats that received vaccinations containing cathepsin L2 PPIRNGK, cathepsin L1 DPWWLKQ, and cathepsin L1 SGTFLFS, respectively. Animals that received vaccination exhibited a significant reduction in the production of parasite eggs. The levels of IgG1 and IgG2 isotypes in vaccinated goats were significantly higher than in the control group, indicating that protection is associated with the induction of a mixed Th1/Th2 immune response. The administration of cathepsin L to goats exhibits a modest level of efficacy in inducing histological impairment in the reproductive organs of liver flukes, resulting in a reduction in egg output.

The EQ-5D-5L valuation study for Trinidad and Tobago.

PURPOSE: The 2016 EQ-5D-3L value set for Trinidad and Tobago (T&T) allows for the calculation of EQ-5D-5L values via the crosswalk algorithm. The 2016 value set was based on methods predating the EQ-VT protocol, now considered the gold standard for developing EQ-5D value sets. Furthermore, direct elicitation of EQ-5D-5L is preferred over crosswalked values. This study aimed to produce an EQ-5D-5L value set for T&T. METHODS: A representative sample (age, sex, geography) of adults each completed 10 composite Time Trade-Off (cTTO) tasks and 12 Discrete Choice Experiment (DCE) tasks in face-to-face interviews. The cTTO data were analyzed using a Tobit model that corrects for heteroskedasticity. DCE data were analyzed using a mixed logit model. The cTTO and DCE data were combined in hybrid models. RESULTS: One thousand and seventy-nine adults completed the valuation interviews. Among the modelling approaches that were explored, the hybrid heteroskedastic Tobit model produced all internally consistent, statistically significant coefficients, and performed best in terms of out-of-sample predictivity for single states. Compared to the existing EQ-5D-5L crosswalk set, the new value set had a higher number of negative values (236 or 7.6% versus 21 or 0.7%). The mean absolute difference was 0.157 and the correlation coefficient between the two sets was 0.879. CONCLUSION: This study provides a value set for the EQ-5D-5L for T&T using the EQ-VT protocol. We recommend this value set for QALY computations relating to T&T.

The EQ-5D-3L valuation study for Bermuda: using an on-line EQ-VT protocol.

BACKGROUND: In many countries, methods of economic evaluation and Health Technology Assessment are used to inform healthcare resource allocation decisions. These approaches often require EQ-5D health outcomes measures. This study aimed to create an EQ-5D-3L value set for Bermuda from which EQ-5D-5L Crosswalk values could be obtained. METHODS: Respondents in Bermuda were recruited locally. A team of Trinidad-based interviewers with prior EQ-5D-3L valuation experience conducted valuation interviews on-line using the EQ-VT protocol. Respondents completed composite time-trade off (cTTO) and discrete choice experiment (DCE) tasks. A hybrid model that included both the cTTO and DCE data was estimated. An EQ-5D-5L crosswalk value set was then created from the EQ-5D-3L index values. Coefficients in the resulting crosswalk model were compared with those of crosswalk and valuation studies from other countries. RESULTS: The valuation tasks were completed by a near-representative sample of 366 adult Bermuda citizens. Half of the respondents reported being in state 11111. The lowest EQ VAS and EQ-5D-3L index values were 20 and - 0.120 respectively. The hybrid model produced all logically consistent and statistically significant coefficients that in turn produced index values that were very similar to those obtained in a preliminary model (MAD of 0.027). DISCUSSION: The on-line EQ-VT valuation study was successfully conducted in Bermuda and the values therein can now be used for economic analysis in Bermuda. The Bermuda values differed considerably from those of the other countries against which they were compared. Challenges were encountered with recruitment for an on-line survey in a small population.

NPPC and AREG supplementation in IVM systems alter mRNA translation and decay programs-related gene expression in bovine COC.

During oocyte meiosis resumption, a coordinated program of transcript translation and decay machinery promotes a remodeling of mRNA stores, which determines the success of the acquisition of competence and early embryo development. We investigated levels of two genes related to mRNA translation (CPEB1 and CPEB4) and two related to mRNA degradation (CNOT7 and ZFP36L2) machinery and found ZFP36L2 downregulated in in vitro-matured bovine oocytes compared to in vivo counterparts. Thereafter, we tested the effects of a pre-IVM step with NPPC and a modified IVM with AREG on the modulation of members of mRNA translation and degradation pathways in cumulus cells and oocytes. Our data showed a massive upregulation of genes associated with translational and decay processes in cumulus cells, promoted by NPPC and AREG supplementation, up to 9h of IVM. The oocytes were less affected by NPPC and AREG, and even though ZFP36L2 transcript and protein levels were downregulated at 9 and 19h of IVM, only one (KDM4C) from the ten target genes evaluated was differently expressed in these treatments. These data suggest that cumulus cells are more prone to respond to NPPC and AREG supplementation in vitro, regarding translational and mRNA decay programs. Given the important nursing role of these cells, further studies could contribute to a better understanding of the impact of these modulators in maternal mRNA modulation and improve IVM outcomes.

The influence of PD-L1 expression levels on the efficacy of combination therapy in thymic epithelial tumors.

BACKGROUND: The significant expression of PD-L1 in thymic epithelial tumors (TETs) has been confirmed, and immunotherapy and its combination therapy have been effective in TETs. However, there is no present evidence that the expression levels of PD-L1 affects the efficacy of combination therapy. Our study aimed to shed light on this relationship. METHODS: Patients with thymic epithelial tumors (TETs) from multicenter hospitals were retrospectively identified. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) in 22 patients were included. We divided the patients the 22 patients with PD-L1 test into three levels (high expression, low expression and no expression) and analyzed the relationship between the levels of PD-L1 expression and the efficacy of combination therapy. RESULTS: Combination therapy showed an effective benefit in 22 patients with TETs, the median PFS (mPFS) was 16 months (95% CI: 8.5-23.5) and the median OS (mOS) was 38 months (95% CI: 21.5-54.5). Cox-regressive analysis found whether PD-L1 expression affected the PFS of patients (p = 0.017). Among the patients with PD-L1 expression, the levels of expression were correlated with curative effect (Kruskal-Wallis test, PFS: P = 0.012; OS: P = 0.01), and high expression group was along with better efficacy than low expression (Wilcoxon test, P = 0.01). Moreover, in 17 patients treated with immunotherapy combined with chemotherapy, the expression of PD-L1 was also associated with efficacy (Kruskal-Wallis test, p = 0.021). CONCLUSIONS: PD-L1 expression affects the PFS of patients. High expression of PD-L1 patients with TETs responded better to combination therapy, which could provide a therapeutic option in clinic. Besides, other targeted treatments should be considered.

MDSCs use a complex molecular network to suppress T-cell immunity in a pulmonary model of fungal infection.

Background: Paracoccidioidomycosis (PCM) is a systemic endemic fungal disease prevalent in Latin America. Previous studies revealed that host immunity against PCM is tightly regulated by several suppressive mechanisms mediated by tolerogenic plasmacytoid dendritic cells, the enzyme 2,3 indoleamine dioxygenase (IDO-1), regulatory T-cells (Tregs), and through the recruitment and activation of myeloid-derived suppressor cells (MDSCs). We have recently shown that Dectin-1, TLR2, and TLR4 signaling influence the IDO-1-mediated suppression caused by MDSCs. However, the contribution of these receptors in the production of important immunosuppressive molecules used by MDSCs has not yet been explored in pulmonary PCM. Methods: We evaluated the expression of PD-L1, IL-10, as well as nitrotyrosine by MDSCs after anti-Dectin-1, anti-TLR2, and anti-TLR4 antibody treatment followed by P. brasiliensis yeasts challenge in vitro. We also investigated the influence of PD-L1, IL-10, and nitrotyrosine in the suppressive activity of lung-infiltrating MDSCs of C57BL/6-WT, Dectin-1KO, TLR2KO, and TLR4KO mice after in vivo fungal infection. The suppressive activity of MDSCs was evaluated in cocultures of isolated MDSCs with activated T-cells. Results: A reduced expression of IL-10 and nitrotyrosine was observed after in vitro anti-Dectin-1 treatment of MDSCs challenged with fungal cells. This finding was further confirmed in vitro and in vivo by using Dectin-1KO mice. Furthermore, MDSCs derived from Dectin-1KO mice showed a significantly reduced immunosuppressive activity on the proliferation of CD4+ and CD8+ T lymphocytes. Blocking of TLR2 and TLR4 by mAbs and using MDSCs from TLR2KO and TLR4KO mice also reduced the production of suppressive molecules induced by fungal challenge. In vitro, MDSCs from TLR4KO mice presented a reduced suppressive capacity over the proliferation of CD4+ T-cells. Conclusion: We showed that the pathogen recognition receptors (PRRs) Dectin-1, TLR2, and TLR4 contribute to the suppressive activity of MDSCs by inducing the expression of several immunosuppressive molecules such as PD-L1, IL-10, and nitrotyrosine. This is the first demonstration of a complex network of PRRs signaling in the induction of several suppressive molecules by MDSCs and its contribution to the immunosuppressive mechanisms that control immunity and severity of pulmonary PCM.