Screening the Pathogen Box for Identification of New Chemical Agents with Anti-Fasciola hepatica Activity

Fascioliasis is an infectious parasitic disease distributed globally and caused by the liver fluke Fasciola hepatica or F. gigantica. This neglected tropical disease affects both animals and humans, and it represents a latent public health problem due to the significant economic losses related to its effects on animal husbandry. For decades, triclabendazole has been the unique anti-Fasciola drug that can effectively treat this disease. However, triclabendazole resistance in fascioliasis has more recently been reported around the world, and thus, the discovery of novel drugs is an urgent need. The aim of this study was to investigate the fasciocidal properties of 400 compounds contained in the Pathogen Box. The first stage of the screening was carried out by measuring the fasciocidal activity on metacercariae at a concentration of 33 mu M each compound (the standard dose). Subsequently, the activities of the most active compounds (n = 33) at their 50% inhibitory concentration (IC50) values against metacercariae were assayed, and the results showed that 13 compounds had IC(50)s of 50%. Four hit compounds were selected on the basis of their predicted nontoxic properties, and the IC50 values obtained for adult worms were <10 mu M; thus, these compounds represented the best fasciocidal compounds tested here. A cytotoxicity assay on four types of cell lines demonstrated that three compounds were nontoxic at their most active concentration. In conclusion, three hit compounds identified in this proof-of-concept study are potential candidates in the discovery of new fasciocidal drugs. Further studies are warranted

The OASIS-Sustainable Nanomanufacturing Framework (OASIS-SNF): a new simplified approach to implement sustainable production in nanomanufacturing pilot lines and evaluate its sustainable manufacturing performance

The pilot production ecosystem deployed by the EU-project OASIS consists of 12 pilot lines (PLs) for the manufacture of nanomaterials, nano-intermediates and nano-enabled products, intended for the final production of lightweight multifunctional products, based on aluminium and polymer composites, for construction, energy, automotive and aeronautics. OASIS intends to deploy this nanomanufacturing ecosystem under a common umbrella of sustainable production, to ensure a future competitive, quality, safe and environmentally friendly production of nanoproducts, in compliance with the applicable regulation. This paper introduces the new OASIS-Sustainable Nanomanufaturing Framework (OASIS-SNF) and some first results obtained during the initial stages of deployment in the PLs (diagnostic and planning stages). The adoption of the OASIS-SNF among the OASIS PLs is intended to enable them to sustainable manufacturing their nanoproducts, properly manage their sustainability priorities, and continually improve their sustainability performance (management and results).The project OASIS received funding from the European Union’s Horizon 2020 research and innovation programme, under grant agreement Nº 814581. This paper reflects only the authors’ views, and the Commission is not responsible for any use that may be made of the information contained therein

Quality of Life in Chronic Pancreatitis is Determined by Constant Pain, Disability/Unemployment, Current Smoking, and Associated Co-Morbidities

OBJECTIVES: Chronic pancreatitis (CP) has a profound independent effect on quality of life (QOL). Our aim was to identify factors that impact the QOL in CP patients. METHODS: We used data on 1,024 CP patients enrolled in the three NAPS2 studies. Information on demographics, risk factors, co-morbidities, disease phenotype, and treatments was obtained from responses to structured questionnaires. Physical and mental component summary (PCS and MCS, respectively) scores generated using responses to the Short Form-12 (SF-12) survey were used to assess QOL at enrollment. Multivariable linear regression models determined independent predictors of QOL. RESULTS: Mean PCS and MCS scores were 36.7+/-11.7 and 42.4+/-12.2, respectively. Significant (P \u3c 0.05) negative impact on PCS scores in multivariable analyses was noted owing to constant mild-moderate pain with episodes of severe pain or constant severe pain (10 points), constant mild-moderate pain (5.2), pain-related disability/unemployment (5.1), current smoking (2.9 points), and medical co-morbidities. Significant (P \u3c 0.05) negative impact on MCS scores was related to constant pain irrespective of severity (6.8-6.9 points), current smoking (3.9 points), and pain-related disability/unemployment (2.4 points). In women, disability/unemployment resulted in an additional 3.7 point reduction in MCS score. Final multivariable models explained 27% and 18% of the variance in PCS and MCS scores, respectively. Etiology, disease duration, pancreatic morphology, diabetes, exocrine insufficiency, and prior endotherapy/pancreatic surgery had no significant independent effect on QOL. CONCLUSIONS: Constant pain, pain-related disability/unemployment, current smoking, and concurrent co-morbidities significantly affect the QOL in CP. Further research is needed to identify factors impacting QOL not explained by our analyses

Serum levels of cytokines in water buffaloes experimentally infected with Fasciola gigantica

Fasciola gigantica infection in water buffaloes causes significant economic losses especially 27 in developing countries. Although modulation of the host immune response by cytokine 28 neutralization or vaccination is a promising approach to control infection with this parasite, our 29 understanding of cytokine's dynamic during F. gigantica infection is limited. To address this, 30 we quantified the levels of serum cytokines produced in water buffaloes following experimental 31 infection with F. gigantica. Five buffaloes were infected via oral gavage with 500 viable F. 32 gigantica metacercariae and blood samples were collected from buffaloes one week before 33 infection and for 13 consecutive weeks thereafter. The levels of 10 cytokines in serum samples 34 were simultaneously determined using ELISA. F. gigantica failed to elicit the production of 35 various pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-2, IL-6, IL-12, and 36 IFN-γ. On the other hand, evidence of a Th2 type response was detected, but only early in the 37 course of parasite colonization and included modest increase in the levels of IL-10 and IL-13. 38 The results also revealed suppression of the immune responses as a feature of chronic F. 39 gigantica infection in buffaloes. Taken together, F. gigantica seems to elicit a modest Th2 40 response at early stage of infection in order to downregulate harmful Th1- and Th17-type 41 inflammatory responses in experimentally infected buffaloes. The full extent of anti-F. 42 gigantica immune response and its relation to pathogenesis requires further study

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all &gt;0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Expression profiles of genes involved in TLRs and NLRs signaling pathways of water buffaloes infected with Fasciola gigantica

Infection of ruminants and humans with Fasciola gigantica is attracting increasing attention due to its economic impact and public health significance. However, little is known of innate immune responses during F. gigantica infection. Here, we investigated the expression profiles of genes involved in Toll-like receptors (TLRs) and NOD-like receptors (NLRs) signaling pathways in buffaloes infected with 500 F. gigantica metacercariae. Serum, liver and peripheral blood mononuclear cell (PBMC) samples were collected from infected and control buffaloes at 3, 10, 28, and 70 days post infection (dpi). Then, the levels of 12 cytokines in serum samples were evaluated by ELISA. Also, the levels of expression of 42 genes, related to TLRs and NLRs signaling, in liver and PBMCs were determined using custom RT2 Profiler PCR Arrays. At 3 dpi, modest activation of TLR4 and TLR8 and the adaptor protein (TICAM1) was detected. At 10 dpi, NF-κB1 and Interferon Regulatory Factor signaling pathways were upregulated along with activation of TLR1, TLR2, TLR6, TLR10, TRAF6, IRF3, TBK1, CASP1, CD80, and IFNA1 in the liver, and inflammatory response with activated TLR4, TLR9, TICAM1, NF- κB1, NLRP3, CD86, IL-1B, IL-6, and IL-8 in PBMCs. At 28 dpi, there was increase in the levels of cytokines along with induction of NLRP1 and NLRP3 inflammasomes-dependent immune responses in the liver and PBMCs. At 70 dpi, F. gigantica activated TLRs and NLRs, and their downstream interacting molecules. The activation of TLR7/9 signaling (perhaps due to increased B-cell maturation and activation) and upregulation of NLRP3 gene were also detected. These findings indicate that F. gigantica alters the expression of TLRs and NLRs genes to evade host immune defenses. Elucidation of the roles of the downstream effectors interacting with these genes may aid in the development of new interventions to control disease caused by F. gigantica infection

Mineral nutrition of vegetable crops: XXV - Mineral nutrition of new zealand spinach plant (Tetragonia expansa Murr.)

The present work was carried out in order to study: a - the effect of omission and presence of the macronutrients and boron on the growth of the plants; b - deficiency symptoms of macronutrients, as well of boron; c - the effect of the deficiency of each nutrient on the chemical composition of the plants. Young spinach plants were grown in pots containing pure quartz sand. Several times a day the plants were irrigated by percolation with nutrient solutions. The treatments were: complete solution and deficient solution, in which each one of the macronutrients was omitted as well boron. Soon as the malnutrition symptoms appered, the plants were harvested and analysed chemically. - symptoms of malnutrition are easily observed for N, K, Ca and B. - symptoms of malnutrition for P, S and Mg are not easily identified. - the nutrient content, in dry matter, in deficient leaves and healthy leaves is:O trabalho teve como objetivo estudar alguns aspectos da nutrição mineral do espinafre (Tetragonia expansa Murr.) no que concerne: 1 - Efeitos da omissão dos macronutrientes e do boro, na obtenção de um quadro sintomatológico; 2 - Efeitos das carências na produção de matéria seca e composição química da planta. Mudas com trinta dias de idade foram transplantadas para soluções nutritivas carentes nos macronutrientes e/ou em boro. A coleta das plantas foi realizada quando os sintomas de deficiência se tornaram evidentes. No material seco procedeu-se a análise química. Os dados mostram que: 1 - os sintomas visuais de deficiência de N, K, Ca e B apresentam-se bem definidos; sendo que os de P, Mg e S são de difícil caracterização ; 2 - os teores dos nutrientes em plantas sadias e deficientes são

Metodología para establecer un sistema de gestión documental en un organización

In the present context, in which the different institutions and organizations develop, demands the application of certain systems, methods, procedures and other instruments that respond to those expectatives in the area of the information management and documentation