New chemical modalities for leishmaniasis drug discovery

Leishmaniasis is one of the major parasitic diseases among neglected tropical diseases with a high rate of morbidity and mortality. Human migration and climate change have spread the disease from limited endemic areas all over the world, also reaching regions in Southern Europe, and causing significant health and economic burden. The currently available treatments are far from ideal due to host toxicity, elevated cost, and increasing rates of drug resistance. Safer and more effective drugs are thus urgently required. Nevertheless, the identification of new chemical entities for leishmaniasis has proven to be incredibly hard and exacerbated by the scarcity of well-validated targets. Trypanothione reductase (TR) represents one robustly validated target in Leishmania that fulfils most of the requirements for a good drug target. However, due to the large and featureless active site, TR is considered extremely challenging and almost undruggable by small molecules. This scenario advocates the development of new chemical entities by unlocking new modalities for leishmaniasis drug discovery. The classical toolbox for drug discovery has enormously expanded in the last decade, and medicinal chemists can now strategize across a variety of new chemical modalities and a vast chemical space, to efficiently modulate challenging targets and provide effective treatments. Beyond others, Targeted p Protein Degradation (TPD) is an emerging strategy that uses small molecules to hijack endogenous proteolysis systems to degrade disease-relevant proteins and thus reduce their abundance in the cell. Based on these considerations, this thesis aimed to develop new strategies for leishmaniasis drug discovery while embracing novel chemical modalities and navigating the chemical space by chasing unprecedented chemotypes. This has been achieved by four complementary projects. We believe that these next-generation chemical modalities for leishmaniasis will play an important role in what was previously thought to be a drug discovery landscape dominated by small molecules.

The Clinical Impact Of Cerebellar Grey Matter Pathology In Multiple Sclerosis.

The cerebellum is an important site for cortical demyelination in multiple sclerosis, but the functional significance of this finding is not fully understood. To evaluate the clinical and cognitive impact of cerebellar grey-matter pathology in multiple sclerosis patients. Forty-two relapsing-remitting multiple sclerosis patients and 30 controls underwent clinical assessment including the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale (EDSS) and cerebellar functional system (FS) score, and cognitive evaluation, including the Paced Auditory Serial Addition Test (PASAT) and the Symbol-Digit Modalities Test (SDMT). Magnetic resonance imaging was performed with a 3T scanner and variables of interest were: brain white-matter and cortical lesion load, cerebellar intracortical and leukocortical lesion volumes, and brain cortical and cerebellar white-matter and grey-matter volumes. After multivariate analysis high burden of cerebellar intracortical lesions was the only predictor for the EDSS (p<0.001), cerebellar FS (p = 0.002), arm function (p = 0.049), and for leg function (p<0.001). Patients with high burden of cerebellar leukocortical lesions had lower PASAT scores (p = 0.013), while patients with greater volumes of cerebellar intracortical lesions had worse SDMT scores (p = 0.015). Cerebellar grey-matter pathology is widely present and contributes to clinical dysfunction in relapsing-remitting multiple sclerosis patients, independently of brain grey-matter damage.

[recommendations For Physical Exercise Practice During Pregnancy: A Critical Review].

Physical exercise is recommended for all healthy pregnant women. Regular practice of exercises during pregnancy can provide many physical and psychological benefits, with no evidence of adverse outcomes for the fetus or the newborn when exercise is performed at mild to moderate intensity. However, few pregnant women engage in this practice and many still have fears and doubts about the safety of exercise. The objective of the present study was to inform the professionals who provide care for Brazilian pregnant women about the current recommendations regarding physical exercise during pregnancy based on the best scientific evidence available. In view of the perception that few systematic models are available about this topic and after performing several studies in this specific area, we assembled practical information of interest to both the professionals and the pregnant women. We also provide recommendations about the indications, contraindications, modalities (aerobics, resistance training, stretching and pelvic floor training), frequency, intensity and duration indicated for each gestational trimester. The review addresses physical exercise recommendation both for low risk pregnant women and for special populations, such as athletes and obese, hypertensive and diabetic subjects. The advantages of an active and healthy lifestyle should be always reinforced during and after gestation since pregnancy is an appropriate period to introduce new habits because pregnant women are usually more motivated to adhere to recommendations. Thus, routine exams, frequent returns and supervision are recommended in order to provide new guidelines that will have long-term beneficial effects for both mother and child.

Adaptação do handebol para a prática em cadeira de rodas

Universidade Estadual de Campinas . Faculdade de Educação Física

Realidade da olimpíada colegial do estado de São Paulo (OCESP) em relação ao discurso presente na educação física acerca da competição escolar : estudo da região leste de Campinas

Universidade Estadual de Campinas . Faculdade de Educação Física

Lesões esportivas em atletas com deficiencia visual

Universidade Estadual de Campinas . Faculdade de Educação Física

Analise comparativa das caracteristicas cinematicas da coluna durante a marcha e a corrida

Universidade Estadual de Campinas . Faculdade de Educação Física

Ginastica artistica feminina e historia oral : a formação desportiva de ginastas brasileiras participantes de jogos olimpicos (1980-2004)

Universidade Estadual de Campinas . Faculdade de Educação Física

Procedimentos pedagogicos para o ensino das lutas : contextos e possibilidades

Universidade Estadual de Campinas . Faculdade de Educação Física

Estudo comparativo das respostas autonomicas cardiovasculares entre corredores de provas de fundo, halterofilistas e sedentarios

Universidade Estadual de Campinas . Faculdade de Educação Física

Analise das capacidades de resistencia, força e velocidade na periodização de modalidades intermitentes

Universidade Estadual de Campinas . Faculdade de Educação Física

A ginastica em Campinas : suas formas de expressão da decada de 20 a decada de 70

Universidade Estadual de Campinas. Faculdade de Educação Física

As artes marciais chinesas para pessoas com deficiência : contextos, dilemas e possibilidades = Chinese martial arts for people with disabilities : contexts, dilemmas and possibilities

Universidade Estadual de Campinas . Faculdade de Educação Física

O Taekwondo como modalidade paradesportiva

Universidade Estadual de Campinas . Faculdade de Educação Física

Desenvolvimento de ferramentas de análise de desempenho de atletas em 3 diferentes modalidades : Handebol, Provas Combinadas e Salto com Vara

Universidade Estadual de Campinas. Faculdade de Educação Física