IDO Mediates TLR9-Driven Protection from Experimental Autoimmune Diabetes

Abstract Originally predicated on the recognition of an increasing prevalence of allergy, the hygiene hypothesis was later found to accommodate the contrasting epidemiologic trends in developed countries for infectious vs autoimmune diseases. Experimentally, reduced exposure to infections will increase the risk of disease in several models of experimental autoimmunity. Although TLRs were initially considered as stimulatory molecules capable of activating early defense mechanisms against invading pathogens, emerging data suggest that they can also exert a regulatory function. In the present study, we evaluated whether TLR3 and TLR9, recognizing microbial dsDNA and CpG-containing DNA sequences, respectively, play a role in the protection from experimental autoimmune diabetes induced in C57BL/6 mice by streptozotocin. In wild-type animals, the disease was accompanied by up-regulation of IDO in pancreatic lymph nodes and would be greatly exacerbated by in vivo administration of an IDO inhibitor. Conversely, administration of a CpG-containing oligodeoxynucleotide greatly attenuated the disease in an IDO-dependent fashion. TLR9-, but not TLR3-deficient mice developed a more robust disease, an event accompanied by lack of IDO induction in pancreatic lymph nodes. Thus, our data suggest that the TLR9-IDO axis may represent a valuable target in the prevention/therapy of type 1 diabetes

Trichinella spp. in ostrich meat: a public health risk?

In the present work the biological behaviour of T. spiralis and T. pseudospiralis in ostriches is reported. Oral infections were performed in eight ostriches with two infective doses (10,000 and 80,000 larvae) for each species of Trichinella. On day 0, 30 and 60 p.i. blood samples were collected to assay the serum changes concerning specific muscle enzyme activities and total proteins. The immunological study, to determine specific IgG in sera, was conducted employing a monoclonal blocking ELISA. From the carcasses of sacrificed animals, samples of various muscle tissues were examined by the digestion method and by standard histopathologic procedures. The study showed a low susceptibility of the ostriches to T. pseudospiralis; preferential sites of larval distribution were muscle tissues of the legs. T. spiralis could be found in muscle tissues only when a high number of larvae were inoculated. Immunological reactivity was found only in animals infected with higher doses of T. pseudospiralis

Experimental trichinellosis in fallow-deer (Dama dama L.).

Herbivora can play a very important role in spreading trichinellosis, as showed by the massive epidemics in man, caused by the consumption of horse meat in the last years. In this context, the present study has been undertaken to verify, through an experimental infection, the susceptibility, together with other biological parameters, of fallow-deer to Trichinella infection. The four animals, 8-9 months of age and 18-25 Kg body weight, were orally infected with low doses of Trichinella britovi and T. pseudospiralis (2,000 larvae/animal). After day 30 p.i., the animals were necropsied and, using artificial digestion methods, larval burden of Trichinella in muscle tissues was determined. Histopathological, serological (IgG monoclonal blocking ELISA) and biochemical data were assessed during the experiment. The results showed the susceptibility of fallow-deer to T. britovi and T. pseudospiralis infection; under the same inoculum size, the number of larvae/g was higher in group infected with T. britovi. The animals showed a higher immunological response to T. pseudospiralis infection. The results are discussed

Plantas nativas del centro oeste argentino con aptitud ornamental: experiencias en Mendoza

En el oeste árido argentino crece una gran cantidad de especies nativas con potencial valor ornamental. Estas plantas están adaptadas a un clima con fuerte déficit hídrico anual, gran alternancia de temperaturas, tanto diarias como anuales, y baja humedad relativa a lo largo del año. La introducción de estas especies a cultivo, su domesticación y obtención de variedades comerciales, permitirá su empleo en proyectos de xeripaisajismo, responsables y coherentes con su entorno natural, que ayudarán a preservar recursos (plantas nativas y agua) cada vez más afectados por causas naturales o por acción antrópica. En Mendoza, desde la Facultad de Ciencias Agrarias, Universidad Nacional de Cuyo, y el INTA se trabaja en la introducción de especies nativas y la evaluación de su potencial ornamental desde hace 15 años. En los últimos años se incorporó la evaluación por sus propiedades aromáticas. Se presentan los resultados obtenidos acompañados por la descripción de cada una de las especies estudiadas. Se evaluaron especies pertenecientes a cuatro géneros de la familia Asteráceas (Solidago, Hysterionica, Verbesina, Grindelia); una de Verbenáceas (Glandularia); dos de Malváceas (Sphaeralcea, Lecanophora); uno de Solanáceas (Schizanthus).A large number of native species with ornamental potential grow in the arid west of Argentina. These plants are adapted to a climate characterized by extreme annual water deficit, large variations in daily and annual temperatures, and low relative humidity throughout the year. The domestication, cultivation and commercial varieties of these species will allow xeriscape landscaping projects to be designed in accordance with the natural environment. This will help conserve resources (native plant and water) that have been becoming increasingly limited by natural or human-made causes. For the last 15 years in Mendoza, the Faculty of Agrarian Sciences and INTA have worked on the identification and evaluation of native species for their ornamental potential. This work has more recently included the evaluation of their aromatic properties. A brief description of the species studied is presented along with a summary of the results obtained from these efforts. These studies have addressed genera of the Asteraceae (Solidago, Hysterionica, Verbesina, Grindelia) genus of Verbenaceae (Glandularia), genera of Malvaceae (Sphaeralcea, Lecanophora); genus of Solanaceae (Schizanthus).EEA MendozaFil: Cuesta, Graciela. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria La Consulta; ArgentinaFil: Fioretti, Sonia. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias; ArgentinaFil: Lorello, Ines Maria. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria La Consulta; ArgentinaFil: Lorello, Ines Maria. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias; ArgentinaFil: Pereyra Pizarro, Alicia. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Mendoza; ArgentinaFil: Gutierrez, Maria Teresa. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias; ArgentinaFil: Cabral, Juan Martin. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias; ArgentinaFil: Pisi, Gabriel Enrique. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Mendoza. Agencia De Extensión Rural Luján de Cuyo; ArgentinaFil: Baglio, Carla. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Mendoza. Agencia De Extensión Rural Luján de Cuyo; ArgentinaFil: Di Cenzi, Cecilia. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias; Argentin

SET-PP2A Complex as a New Therapeutic Target in KMT2A (MLL) Rearranged AML

KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. In this study we uncover the essential role and underlying mechanisms of SET, the endogenous inhibitor of Ser/Thr phosphatase PP2A, in KMT2A-R-leukemia. Investigation of SET expression in acute myeloid leukemia (AML) samples demonstrated that SET is overexpressed, and elevated expression of SET is correlated with poor prognosis and with the expression of MEIS and HOXA genes in AML patients. Silencing SET specifically abolished the clonogenic ability of KMT2A-R leukemic cells and the transcription of KMT2A targets genes HOXA9 and HOXA10. Subsequent mechanistic investigations showed that SET interacts with both KMT2A wild type and fusion proteins, and it is recruited to the HOXA10 promoter. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest and increased sensitivity to chemotherapy in KMT2A-R-leukemic models. Phospho-proteomic analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3β, AURB and PLK1 and led to suppression of MYC, supporting the hypothesis of a feedback loop among PP2A, AURB, PLK1, MYC, and SET. Our findings illustrate that SET is a novel player in KMT2A-R leukemia and they provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia

SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML

KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. In this study we uncover the essential role and underlying mechanisms of SET, the endogenous inhibitor of Ser/Thr phosphatase PP2A, in KMT2A-R-leukemia. Investigation of SET expression in acute myeloid leukemia (AML) samples demonstrated that SET is overexpressed, and elevated expression of SET is correlated with poor prognosis and with the expression of MEIS and HOXA genes in AML patients. Silencing SET specifically abolished the clonogenic ability of KMT2A-R leukemic cells and the transcription of KMT2A targets genes HOXA9 and HOXA10. Subsequent mechanistic investigations showed that SET interacts with both KMT2A wild type and fusion proteins, and it is recruited to the HOXA10 promoter. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest and increased sensitivity to chemotherapy in KMT2A-R-leukemic models. Phospho-proteomic analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3β, AURB and PLK1 and led to suppression of MYC, supporting the hypothesis of a feedback loop among PP2A, AURB, PLK1, MYC, and SET. Our findings illustrate that SET is a novel player in KMT2A-R leukemia and they provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia

Toxoplasma gondii in small ruminants in Northern Italy – prevalence and risk factors

[b]Objective[/b]. The aim of the survey was to evaluate [i]Toxoplasma gondii[/i] seroprevalence in small ruminants and possible risk factors associated with the infection. [b]Materials and methods[/b]. Sera from 474 goats and 502 sheep reared on 42 farms in northern Italy were collected and tested for IgG antibodies to [i]T. gondii[/i] by IFAT (indirect immunofluorescence antibody test). To identify risk factors, a binary logistic regression analysis of the variables was performed. An audit form about farm management was used. [b]Results[/b]. Antibodies to [i]T. gondii [/i]were found in 96.6% of goat farms and in 87.5% of sheep farms; 41.7% goats and 59.3% sheep resulted positive. Seroprevalence was significantly higher in sheep than in goats. Seroprevalence values were similar in goats from eastern and western areas, whereas goats from the southern area were at lower risk of infection. Saanen goats presented the lowest seroprevalence (30.7 %), whereas cross-breed exhibited the highest rate (48.7%). Goats from farms housing both sheep and goats had an infection risk 1.39 times higher than goats from farms that did not house sheep. Animals bred on intensive farms showed lower prevalence (22.1%) in comparison with those from extensive (45.6%) or semi-intensive farms (60%). Sampling area was one of the strongest predictors of [i]T. gondii [/i]infection in sheep flocks. Transhumant flocks showed a higher risk of infection by [i]T. gondii[/i] compared with semi-intensive farms (66.8% vs. 38.4%). [b]Conclusions[/b]. The highest [i]T. gondii[/i] seroprevalence values were registered in transhumant flocks of sheep and in family businesses rearing goats. As these traditional activities represent an important resource for the conservation of the territory and its economy, management practices for a better control of the disease should be improved

The Online Observation Quality System for the ASTRI Mini-Array

The ASTRI Mini-Array is an international collaboration led by the Italian National Institute for Astrophysics (INAF), aiming to construct and operate an array of nine Imaging Atmospheric Cherenkov Telescopes (IACTs) to study gamma-ray sources at very high energy (TeV) and to perform stellar intensity interferometry observations. This contribution describes the design and the technologies used by the ASTRI team to implement the Online Observation Quality System (OOQS). The main objective of the OOQS is to perform data quality analyses in real-time during Cherenkov and intensity interferometry observations to provide feedback to both the Central Control System and the Operator. The OOQS performs the analysis of key data quality parameters and can generate alarms to other sub-systems for a fast reaction to solve critical conditions. The results from the data quality analyses are saved into the Quality Archive for further investigations. The Operator can visualise the OOQS results through the Operator Human Machine Interface as soon as they are produced. The main challenge addressed by the OOQS design is to perform online data quality checks on the data streams produced by nine telescopes, acquired by the Array Data Acquisition System and forwarded to the OOQS. In the current OOQS design, the Redis in-memory database manages the data throughput generated by the telescopes, and the Slurm workload scheduler executes in parallel the high number of data quality analyses.Comment: 8 pages, 3 figures, Proceedings of the 37th International Cosmic Ray Conference (ICRC 2021), Berlin, German

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score > 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p < 0.001), RR = 2.19 for ICU admission (p < 0.001), and RR = 2.43 for death (p < 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon