Development of L-proline-based Chiral Ionic Liquids for asymmetric Michael Reaction

co-financed by the ERDF under the PT2020 Partnership agreement (POCI-01-0145-FEDER–007265) The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by the Infrastructure Project N◦ 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC).Different Chiral Ionic Liquids (CIL) based on L-proline have been developed. Simple and efficient synthetic methodologies are used, allowing preparation in good yields for twelve novel CILs using L-proline as a cation or anion combined with suitable counter-ions. A detailed physical and chemical characterization of the CILs was performed to evaluate the influence of counter-ions on the final properties. The most promissory CILs were tested as efficient chiral catalysts in IL media for asymmetric Michael addition reactions of ketones and aldehydes to nitro-olefins. Similar or even better conversions and enantioselectivities (ee up to 95%) compared to the original L-proline were achieved. Additionally, a good product extraction performance using supercritical CO2 processes was obtained.publishersversionpublishe

A study on the immunological basis of the dissociation between type I-hypersensitivity skin reactions to Blomia tropicalis antigens and serum anti-B. tropicalis IgE antibodies

<p>Abstract</p> <p>Background</p> <p>Two conditions are used as markers of atopy: the presence of circulating anti-allergen IgE antibodies and the presence of positive skin prick test (SPT) reactions to allergenic extracts. The correlation between these conditions is not absolute. This study aimed at investigating immunological parameters that may mediate this lack of correlation. Individuals whose sera contained anti-<it>B. tropicalis </it>extract IgE antibodies (α<it>-Bt</it>E IgE) were divided into two groups, according to the presence or absence of skin reactivity to <it>B. tropicalis </it>extract (<it>Bt</it>E). The following parameters were investigated: total IgE levels; α<it>-Bt</it>E IgE levels; an arbitrary α<it>-Bt</it>E IgE/total IgE ratio; the proportion of carbohydrate-reactive α<it>-Bt</it>E IgE; the proportion of α<it>-Bt</it>E IgE that reacted with <it>Ascaris lumbricoides </it>extract (<it>Al</it>E); the production of IL-10 by <it>Bt</it>E- and <it>Al</it>E-stimulated peripheral blood cells (PBMC).</p> <p>Results</p> <p>Total IgE levels were similar in the two groups, but α<it>-Bt</it>E IgE was significantly higher in the SPT-positive group (SPT<b>+</b>). A large overlap of α<it>-Bt</it>E IgE levels was found in individuals of both groups, indicating that these levels alone cannot account for the differences in SPT outcome. Individuals of the two groups did not differ, statistically, in the proportion of α-<it>Bt</it>E IgE that reacted with carbohydrate and in the production of IL-10 by <it>Bt</it>E- and <it>Al</it>E-stimulated PBMC. Both groups had part of α-<it>Bt</it>E IgE activity absorbed out by <it>Al</it>E, indicating the existence of cross-reactive IgE antibodies. However, the α-<it>Bt</it>E IgE from the SPT-negative individuals (SPT-) was more absorbed with <it>AlE </it>than the α-<it>Bt</it>E IgE from the SPT+ individuals. This finding may be ascribed to avidity differences of the α-<it>Bt</it>E IgE that is present in the two groups of individuals, and could occur if at least part of the α-<it>Bt</it>E IgE from the SPT- individuals were elicited by <it>A. lumbricoides </it>infection.</p> <p>Conclusion</p> <p>The present results suggest that a low ratio of specific IgE to total IgE levels (in a minority of individuals), and differences in α-<it>Bt</it>E IgE avidities (which would have high affinities for <it>A. lumbricoides </it>antigens in SPT- than in SPT<b>+ </b>individuals) may play a role in the down-modulation of type-I hypersensitivity reaction against aeroallergens described in helminth-infected individuals.</p

Dissociation between skin test reactivity and anti-aeroallergen IgE: Determinants among urban Brazilian children.

BACKGROUND: The dissociation between specific IgE and skin prick test reactivity to aeroallergens, a common finding in populations living in low and middle-income countries, has important implications for the diagnosis and treatment of allergic diseases. Few studies have investigated the determinants of this dissociation. In the present study, we explored potential factors explaining this dissociation in children living in an urban area of Northeast Brazil, focusing in particular on factors associated with poor hygiene. METHODS: Of 1445 children from low income communities, investigated for risk factors of allergies, we studied 481 with specific IgE antibodies to any of Blomia tropicalis, Dermatophagoides pteronyssinus, Periplaneta americana and Blatella germanica allergens. Data on demographic, environmental and social exposures were collected by questionnaire; serum IgG and stool examinations were done to detect current or past infections with viral, bacterial, protozoan and intestinal helminth pathogens. We measured atopy by skin prick testing (SPT) and specific IgE (sIgE) to aerollergens in serum (by ImmunoCAP). SIgE reactivity to B. tropicalis extract depleted of carbohydrates was measured by an in-house ELISA. Total IgE was measured by in house capture ELISA. SNPs were typed using Illumina Omni 2.5. RESULTS: Negative skin prick tests in the presence of specific IgE antibodies were frequent. Factors independently associated with a reduced frequency of positive skin prick tests were large number of siblings, the presence of IgG to herpes simplex virus, Ascaris lumbricoides and Trichuris trichiura infections, living in neighborhoods with infrequent garbage collection, presence of rodents and cats in the household and sIgE reactivity to glycosylated B. tropicalis allergens. Also, SNP on IGHE (rs61737468) was negatively associated with SPT reactivity. CONCLUSIONS: A variety of factors were found to be associated with decreased frequency of SPT such as unhygienic living conditions, infections, total IgE, IgE response to glycosylated allergens and genetic polymorphisms, indicating that multiple mechanisms may be involved. Our data, showing that exposures to an unhygienic environment and childhood infections modulate immediate allergen skin test reactivity, provide support for the "hygiene hypothesis"

Stroke frequency, associated factors, and clinical features in primary systemic vasculitis: a multicentric observational study

Objectives: The cerebral vessels may be affected in primary systemic vasculitis (PSV), but little is known about cerebrovascular events (CVEs) in this population. This study aimed to determine the frequency of CVEs at the time of diagnosis of PSV, to identify factors associated with CVEs in PSV, and to explore features and outcomes of stroke in patients with PSV. Methods: Data from adults newly diagnosed with PSV within the Diagnostic and Classification Criteria in VASculitis (DCVAS) study were analysed. Demographics, risk factors for vascular disease, and clinical features were compared between patients with PSV with and without CVE. Stroke subtypes and cumulative incidence of recurrent CVE during a prospective 6-month follow-up were also assessed. Results: The analysis included 4828 PSV patients, and a CVE was reported in 169 (3.50%, 95% CI 3.00–4.06): 102 (2.13% 95% CI 1.73–2.56) with stroke and 81 (1.68% 95% CI 1.33–2.08) with transient ischemic attack (TIA). The frequency of CVE was highest in Behçet’s disease (9.5%, 95% CI 5.79–14.37), polyarteritis nodosa (6.2%, 95% CI 3.25–10.61), and Takayasu’s arteritis (6.0%, 95% CI 4.30–8.19), and lowest in microscopic polyangiitis (2.2%, 95% CI 1.09–3.86), granulomatosis with polyangiitis (2.0%, 95% CI 1.20–3.01), cryoglobulinaemic vasculitis (1.9%, 95% CI 0.05–9.89), and IgA-vasculitis (Henoch-Schönlein) (0.4%, 95% CI 0.01–2.05). PSV patients had a 11.9% cumulative incidence of recurrent CVE during a 6-month follow-up period. Conclusion: CVEs affect a significant proportion of patients at time of PSV diagnosis, and the frequency varies widely among different vasculitis, being higher in Behçet’s. Overall, CVE in PSV is not explained by traditional vascular risk factors and has a high risk of CVE recurrence

Stroke frequency, associated factors, and clinical features in primary systemic vasculitis: A multicentric observational study

Objectives: The cerebral vessels may be affected in primary systemic vasculitis (PSV), but little is known about cerebrovascular events (CVEs) in this population. This study aimed to determine the frequency of CVEs at the time of diagnosis of PSV, to identify factors associated with CVEs in PSV, and to explore features and outcomes of stroke in patients with PSV. Methods: Data from adults newly diagnosed with PSV within the Diagnostic and Classification Criteria in VASculitis (DCVAS) study were analysed. Demographics, risk factors for vascular disease, and clinical features were compared between patients with PSV with and without CVE. Stroke subtypes and cumulative incidence of recurrent CVE during a prospective 6-month follow-up were also assessed. Results: The analysis included 4828 PSV patients, and a CVE was reported in 169 (3.50%, 95% CI 3.00–4.06): 102 (2.13% 95% CI 1.73–2.56) with stroke and 81 (1.68% 95% CI 1.33–2.08) with transient ischemic attack (TIA). The frequency of CVE was highest in Behçet’s disease (9.5%, 95% CI 5.79–14.37), polyarteritis nodosa (6.2%, 95% CI 3.25–10.61), and Takayasu’s arteritis (6.0%, 95% CI 4.30–8.19), and lowest in microscopic polyangiitis (2.2%, 95% CI 1.09–3.86), granulomatosis with polyangiitis (2.0%, 95% CI 1.20–3.01), cryoglobulinaemic vasculitis (1.9%, 95% CI 0.05–9.89), and IgA-vasculitis (Henoch-Schönlein) (0.4%, 95% CI 0.01–2.05). PSV patients had a 11.9% cumulative incidence of recurrent CVE during a 6-month follow-up period. Conclusion: CVEs affect a significant proportion of patients at time of PSV diagnosis, and the frequency varies widely among different vasculitis, being higher in Behçet’s. Overall, CVE in PSV is not explained by traditional vascular risk factors and has a high risk of CVE recurrence

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Práticas e ações do formador de professores que ensinam Matemática na orquestração de discussões coletivas

Neste artigo busca-se investigar as ações e práticas de uma formadora de professores quando orquestrava discussões coletivas em um processo formativo destinado a professores que ensinam Matemática nos Anos Iniciais do Ensino Fundamental, no que refere ao ensino da álgebra. A metodologia é qualitativa-interpretativa e os dados foram recolhidos a partir de vídeos dos momentos de discussões coletivas. A análise dos dados permitiu levantar as ações desenvolvidas pela formadora que foram categorizadas em cinco práticas, o que levou à elaboração de um quadro de referência, associando características específicas das ações do formador a práticas gerais de orquestração de discussões coletivas. O quadro de referência que emerge, ao evidenciar a complexidade do papel do formador traduzido no conjunto de práticas de distinta natureza, pode contribuir tanto para o design e condução de processos formativos, como para a construção de conhecimentos e habilidades necessárias ao formador de professores, objetivando a criação de oportunidades de aprendizagem profissional de professores.info:eu-repo/semantics/publishedVersio

Prática profissional de professores dos anos iniciais e o pensamento algébrico: contribuições a partir de uma formação continuada

Neste artigo analisamos como dois professores dos anos iniciais do ensino fundamental planejaram e conduziram uma aula considerando aspectos do pensamento algébrico a partir de uma abordagem de ensino exploratório, tendo em conta sua participação em uma formação continuada. O estudo enquadra-se em uma perspectiva qualitativa-interpretativa de pesquisa, em que a recolha de dados foi proveniente do planejamento dos professores, de registros em áudio das aulas, com sua subsequente transcrição, e registro fotográfico das tarefas matemáticas realizadas pelos alunos. Os resultados mostram que como consequência da formação realizada, as ações de planejamento e condução das aulas dos professores consideraram as fases do ensino exploratório, bem como aspectos do pensamento algébrico.info:eu-repo/semantics/publishedVersio