Inverting family GH156 sialidases define an unusual catalytic motif for glycosidase action

Sialic acids are a family of related sugars that play essential roles in many biological events intimately linked to cellular recognition in both health and disease. Sialidases are therefore orchestrators of cellular biology and important therapeutic targets for viral infection. Here, we sought to define if uncharacterized sialidases would provide distinct paradigms in sialic acid biochemistry. We show that a recently discovered sialidase family, whose first member EnvSia156 was isolated from hot spring metagenomes, defines an unusual structural fold and active centre constellation, not previously described in sialidases. Consistent with an inverting mechanism, EnvSia156 reveals a His/Asp active center in which the His acts as a Bronsted acid and Asp as a Bronsted base in a single-displacement mechanism. A pre-dominantly hydrophobic aglycone site facilitates accommodation of a variety of 2-linked sialosides; a versatility that offers the potential for glycan hydrolysis across a range of biological and technological platforms

Identification of hepta-histidine as a candidate drug for Huntington’s disease by in silico-in vitro- in vivo-integrated screens of chemical libraries

We identified drug seeds for treating Huntington’s disease (HD) by combining in vitro single molecule fluorescence spectroscopy, in silico molecular docking simulations, and in vivo fly and mouse HD models to screen for inhibitors of abnormal interactions between mutant Htt and physiological Ku70, an essential DNA damage repair protein in neurons whose function is known to be impaired by mutant Htt. From 19,468 and 3,010,321 chemicals in actual and virtual libraries, fifty-six chemicals were selected from combined in vitro-in silico screens; six of these were further confirmed to have an in vivo effect on lifespan in a fly HD model, and two chemicals exerted an in vivo effect on the lifespan, body weight and motor function in a mouse HD model. Two oligopeptides, hepta-histidine (7H) and Angiotensin III, rescued the morphological abnormalities of primary neurons differentiated from iPS cells of human HD patients. For these selected drug seeds, we proposed a possible common structure. Unexpectedly, the selected chemicals enhanced rather than inhibited Htt aggregation, as indicated by dynamic light scattering analysis. Taken together, these integrated screens revealed a new pathway for the molecular targeted therapy of HD

Academic misconduct among Portuguese Economics and Business undergraduate students - a comparative analysis with other major students

The main purpose of this study is to understand the demographic, personal and situational determining factors leading to academic misconduct among undergraduate students by comparatively analyzing the differences among Economics and Business students and other major students. Two thousand four hundred ninety-two undergraduate students from different Portuguese Public Universities answered a questionnaire regarding their propensity to commit academic fraud, 640 of whom were Economics and Business students. Results concluded that Economics and Business students can be distinguished from others regarding the likelihood of copying from the other Major students. Younger students admit more readily to the possibility of cheating than older students. Results indicate a greater probability of acceptance of dishonest practices outside the area of Economics and Management and a greater probability of condemnation of improper practices by students of Economics and Management. This indicates that students of Economics and Management are aware that their behavior is incorrect and unacceptable; peer-pressure and the learning process itself constitute the main justifications provided by Economics and Business students for their fraudulent actions. Implications for this practice are discussed