Understanding the mechanism of binding between Gab2 and the C terminal SH3 domain from Grb2

Gab2 is a large disordered protein that regulates several cellular signalling pathways and is overexpressed in different forms of cancer. Because of its disordered nature, a detailed characterization of the mechanisms of recognition between Gab2 and its physiological partners is particularly difficult. Here we provide a detailed kinetic characterization of the binding reaction between Gab2 and the C-terminal SH3 domain of the growth factor receptor-bound protein 2 (Grb2). We demonstrate that Gab2 folds upon binding following an induced fit type mechanism, whereby recognition is characterized by the formation of an intermediate, in which Gab2 is primarily disordered. In this scenario, folding of Gab2 into the bound conformation occurs only after binding. However, an alanine scanning of the proline residues of Gab2 suggests that the intermediate contains some degree of native-like structure, which might play a role for the recognition event to take place. The results, which represent a fundamental step forward in the understanding of this functional proteinprotein interaction, are discussed on the light of previous structural works on these proteins

New route to attosecond pulse characterization

LAUREA MAGISTRALELo studio delle dinamiche elettroniche che evolvono sulla scala temporale dei femtosecondi si basa su esperimenti di spettroscopia pump-probe ad attosecondi (1 as = 10$^{-18}$ s). In queste tecniche, il fascio di pompa è un impulso laser infrarosso (IR) a pochi periodi e molto intenso, che incide su un campione e innesca la dinamica elettronica. Il fascio di sonda è costituito da impulsi ultravioletti ad attosecondi, generati tramite il processo di generazione di armoniche di ordine molto elevato, un fenomeno che deriva dall'interazione tra impulsi laser IR molto intensi e atomi di gas nobile. L'attuale linea nel laboratorio AuDACE al Politecnico di Milano offre l'opportunità di investigare processi ultraveloci all'interno di campioni solidi. In particolare, l'esperimento ha luogo in un'innovativa linea a due fuochi sequenziali: variando il ritardo tra gli impulsi XUV e IR, è possibile registrare simultaneamente due mappe bi-dimensionali definite sui domini di energia e del ritardo tra impulsi. La prima misura avviene all'interno di uno spettrometro di elettroni e permette la ricostruzione degli impulsi e la calibrazione dell'asse del ritardo tra impulsi; la seconda è misurata da uno spettrometro di fotoni XUV e registra l'evoluzione delle variazioni di riflettività transiente, che descrive le proprietà del campione perturbate dal fascio di pompa e rivela la dinamica elettronica ultraveloce con risoluzione ad attosecondi. Quindi, la linea ad attosecondi in AuDACE da' la possibilità di raggiungere un obbiettivo duplice: la caratterizzazione degli impulsi IR e XUV e la seguente interpretazione dei fenomeni fisici ultraveloci con una risoluzione temporale estremamente spinta. In questo elaborato, un'analisi dettagliata di due aspetti fondamentali verrà affrontata: l’implementazione hardware necessaria per studiare dinamiche di portatori innescate da impulsi polarizzati circolarmente e una valutazione rigorosa di un nuovo algoritmo per la ricostruzione di impulsi, caratterizzato da una forte robustezza contro il rumore.The study of electron dynamics occurring on the sub-femtosecond time scale relies on attosecond (1 as = 10$^{-18}$ s) pump-probe spectroscopy experiments. In these techniques, the pump beam is an intense IR few-cycles laser pulse which impinges on the sample and triggers the electron dynamics. The probe beam consists of attosecond extreme-ultraviolet (XUV) pulses generated through the process named high-order harmonic generation (HHG), a phenomenon that stems from the interaction between a strong IR laser pulse and noble gas atoms. The current beamline in the AuDACE laboratory at Politecnico di Milano offers the opportunity to investigate sub-femtosecond processes inside solid samples. In particular, the experiments take place in an innovative sequential double-foci geometry: changing the delay between XUV and IR beams, it is possible to recover simultaneously two bi-dimensional maps defined over the energy and delay domains. The former is recorded inside an electron spectrometer and allows the pulse reconstruction and delay axis calibration; the latter is recorded by an XUV spectrometer and depicts the evolution of the transient reflectivity changes, encoding the pump-modified properties of the sample and revealing the underlying sub-femtosecond carrier dynamics with attosecond resolution. Therefore, the AuDACE attosecond beamline gives the possibility to achieve a two-fold goal: the temporal characterization of IR and XUV pulses and the sequent interpretation of ultrafast physical phenomena with super short temporal resolution. In this work, an in-depth analysis of two key aspects will be shown: the hardware implementation required to study carrier dynamics triggered by circularly polarized pulses and a rigorous assessment of a new pulse reconstruction algorithm, characterized by a high robustness against noise

Driver's visual attention to different categories of roadside advertising signs

Roadside advertising signs are a salient potential source of driver's distraction. Previous research has mainly investigated driver's visual attention to billboards, which represents only one category of advertising signs. In this study, driver's visual attention was assessed in a naturalistic driving setting for six categories of roadside advertising signs: vendor signs, billboards, movable display boards, single and multiple commercial directional signs, and gas price LED displays. Fixation rate, fixation duration, fixation distance and driving speed were assessed in a sample of 15 drivers along a 30-km route including a total of 154 advertising signs belonging to the six categories described above. The role of clearance from the road, elevation, height, width, surface, number and size of characters, total number of characters, side of the road (driving side, opposite side), context (rural, urban), were also considered. Overall 24% of the roadside advertising signs were fixated. Fixation rate was significantly influenced by sign category, clearance from the road and number of characters. Median value for fixation duration was 297 ms. Fixation duration was significantly influenced by speed, elevation from road level, number of medium size characters, and was higher in the rural context. Median value for fixation distance was 58.10 m, and was significantly influenced by advertising sign category, character count and speed

A ética utilitarista e a pesquisa empírica qualitativa no Direito

RESUMO O presente artigo, que adota metodologia indutiva, baseado em análise documental e bibliográfica, tem por finalidade realizar uma breve incursão na Ética Utilitarista de Jeremy Bentham e John Stuart Mill, que desenvolveram racionalidades distintas para uma mesma filosofia, ao atribuírem ao cálculo inerente ao princípio da utilidade aspectos quantitativos (Bentham) e qualitativos (Mill). O utilitarismo será abordado como teoria racional que teve origem no Iluminismo, movimento cultural europeu amplo da segunda metade do século XVIII, que se refletiu no pensamento filosófico, nas artes, na literatura, na teoria política e, igualmente, na ciência jurídica. Em decorrência da classificação do utilitarismo como uma teoria ética normativa teleológica hedonista e consequencialista, serão examinados, ainda que de maneira bastante sucinta, os conceitos de ética e moral, as subdivisões da ética (ética normativa e metaética) e seus desdobramentos. No tópico final destinado à pesquisa empírica quantitativa e qualitativa no Direito, trataremos de aspectos conceituais do termo “empírico” e das pesquisas quantitativas e qualitativas, com destaque à Jurimetria, ramo do saber que se ocupa basicamente da aplicação da estatística ao Direito, analisando, ao final, os Relatórios de natureza quantitativa e qualitativa elaborados pelo Conselho Nacional de Justiça. Concluiu-se que a pesquisa empírica, no âmbito do Direito, é sempre importante para proporcionar a avaliação das consequências concretas da aplicação das normas jurídicas no âmbito social e que os estudos baseados na jurimetria denotam maior relevância prática quando adota a perspectiva da análise qualitativa de dados, dado que permitem realizar maior aproximação da realidade

Treatment With Efmoroctocog Alfa (Elocta®) in Hemophilia: A Case Series

Hemophilia A is a rare X-linked disease that occurs as a result of a defect in the FVIII-encoding gene. The reduction or absence of plasma FVIII compromises the coagulation cascade, resulting in frequent bleeds, especially in joints or soft tissues. Currently, replacement therapy with coagulation factor concentrates is the gold standard for the treatment of FVIII deficiency.Herein, we report a case series of five hemophilia A patients treated with an extended half-life recombinant human coagulation factor, FVIII-Fc fusion protein (efmoroctocog alfa). The prophylactic regimen for each patient was individualized based on their pharmacokinetic profile.Compared to previous prophylactic treatments, most patients received a reduced weekly dose of concentrate, all underwent a reduced frequency of administration, the annualized bleeding rates (ABR) and hemophilia joint health scores (HJHS) were stable or improved. The half-life of efmoroctocog alfa and the 72-hour trough levels were higher than those observed in the A-LONG Phase III trial.In conclusion, all patients reported clinical improvements and general subjective wellbeing in the absence of significant safety concerns after switching to efmoroctocog alfa.

Reconstruction of the Axillary Region after Excision of Hidradenitis Suppurativa: A Systematic Review

Introduction Hidradenitis suppurativa (HS) is a chronic, debilitating, recurrent, auto-inflammatory disease of the pilosebaceous units of the skin. The axillary region is the most affected anatomical site and its reconstructive options include skin grafts, local random plasties, regional axial flaps, and regional perforator flaps. The main aim of this systematic review is to identify the best surgical technique for axillary reconstruction in the context of HS, in terms of efficacy and safety. Methods We adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) throughout the whole review protocol build-up. The literature search was performed using MEDLINE, Embase, and Cochrane library databases, updated to March 2021. Quality was assessed for each study, through the National Institutes of Health Quality Assessment Tool. Results A total of 23 studies were included in the final analysis. We reviewed a total of 394 axillary reconstructions in 313 patients affected by HS Hurley Stage II or III. Skin grafts were associated with the highest overall complication rate (37%), and highest rate of reconstruction failure (22%). Between thoraco-dorsal artery perforator flap, posterior arm flap, and parascapular flap, the latter showed fewer total complications, recurrences, and failures. Conclusion Regional axial flaps should be considered as the best surgical approach in the management of advanced HS. The parascapular flap emerges as the most effective and safest option for axillary reconstruction. Local random flaps might be considered only for selected minor excisions, due to the higher risk of recurrence. The use of skin grafts for axillary reconstruction is discouraged

Programa de Treinamento em Voz e Comunicação Melhora o Desempenho de Universitários em Apresentações Orais

Resumo Objetivo Investigar o efeito de um programa de treinamento em voz e comunicação para apresentações orais em estudantes de ensino superior. Método O programa de treinamento proposto foi baseado nas áreas das habilidades sociais, técnicas de projeção vocal e expressividade e a programação neurolinguística, sendo composto de dez sessões com duração média de duas horas cada. Trinta e oito estudantes participaram do treinamento com metodologias ativas de aprendizagem na própria universidade. Antes e após a intervenção, os participantes realizaram uma apresentação oral sobre um tópico da própria escolha, apresentada aos demais participantes e para uma banca formada por três juízes (dois fonoaudiólogos e um psicólogo), que avaliaram o desempenho nas apresentações orais. As apresentações foram gravadas para que cada indivíduo pudesse realizar a autoavaliação da sua comunicação. Os critérios de avaliação foram os aspectos linguísticos formais e não formais, verbais e não verbais, planejamento e elaboração da apresentação. Resultados todos os participantes obtiveram melhora de desempenho nas apresentações orais, quanto aos aspectos verbais, não verbais, capacidade de manter a audiência, controle emocional, planejamento, objetivo, conteúdo, abordagem, organização, recurso visual, forma de apresentar, linguagem e geral (apresentação geral). Conclusão o programa de treinamento apresentado é efetivo para melhorar o desempenho de universitários durante apresentações orais

Chronic graft-versus-host-disease-related polymyositis: a 17-months-old child with a rare and late complication of haematopoietic stem cell transplantation

Background: Chronic graft versus host disease (cGVHD) occurs in 20-30% of paediatric patients receiving haemopoietic stem cell transplantation (HSCT). Neuromuscular disorders such as polymyositis are considered a rare and distinctive but non-diagnostic manifestation of cGVHD and, in the absence of other characteristic signs and symptoms, biopsy is highly recommended to exclude other causes. Case report: We report a case of a 17-months-old child affected by hemophagocytic lymphohistiocytosis who underwent a matched unrelated donor haematopoietic stem cell transplantation (HSCT). She developed severe cGVHD-related polymyositis that was successfully treated with high-dose steroid therapy, rituximab and sirolimus. Conclusions: This is the first case of cGVHD-related-polymyositis described in a pediatric patient which was successfully treated with rituximab