Elucidation of the cellular functions of TrappC11

Transport protein particle complex component 11 (TRAPPC11) is a subunit of TRAPP III, a protein complex which is involved in membrane traffic, autophagy and maintenance of Golgi structure. The mechanisms by which it functions in these processes are not fully understood. Mutations in human TRAPPC11 have been linked to a wide spectrum of phenotypes including developmental delays, muscular dystrophies, intellectual disabilities, dystroglycanopathies and fatty liver. Here, we show that TRAPPC11 has a role upstream of autophagosome formation in macroautophagy. This contrasts with other TRAPP III proteins that function earlier (TRAPPC8) or later (TRAPPC12) than TRAPPC11 in the pathway. Upon TRAPPC11 depletion, LC3-positive membranes fail to become sealed autophagosomes and are not cleared during starvation conditions. ATG2B and its binding partner WIPI4/WDR45 are thought to be TRAPPC11 interactors, and TRAPPC11 depletion phenocopies the one of either ATG2 or WIPI4, which act in isolation membrane expansion. In the absence of TRAPPC11, recruitment of both these proteins to membranes is defective and fibroblasts from an individual with an altered carboxy-terminus of TRAPPC11 failed to recruit ATG2B-WIPI4, suggesting that this interaction is physiologically relevant. We propose a model whereby the TRAPP III complex coordinates growth and expansion of the isolation membrane through multiple interactions. TRAPPC11 can also function independent of the complex in the formation of lipid-linked oligosaccharides in N-glycosylation, so further research is needed to tease apart the roles of TRAPPC11 independently and within the complex. Collectively, all these dysregulated functions could potentially explain the spectrum of phenotypes seen in individuals having variants of TRAPPC11. The region around the highly-conserved Gly980 appears to be critical for membrane trafficking and N-linked glycosylation, causing the muscular weakness phenotype, whereas the extreme carboxy-terminus seems to be involved in autophagy, being linked to some of the same neurological phenotypes shared with TRAPPC12 variants

A N-D VIRTUAL NOTEBOOK ABOUT THE BASILICA OF S. AMBROGIO IN MILAN: INFORMATION MODELING FOR THE COMMUNICATION OF HISTORICAL PHASES SUBTRACTION PROCESS

This essay describes the combination of 3D solutions and software techniques with traditional studies and researches in order to achieve an integrated digital documentation between performed surveys, collected data, and historical research. The approach of this study is based on the comparison of survey data with historical research, and interpretations deduced from a data cross-check between the two mentioned sources. The case study is the Basilica of S. Ambrogio in Milan, one of the greatest monuments in the city, a pillar of the Christianity and of the History of Architecture. It is characterized by a complex stratification of phases of restoration and transformation. Rediscovering the great richness of the traditional architectural notebook, which collected surveys and data, this research aims to realize a virtual notebook, based on a 3D model that supports the dissemination of the collected information. It can potentially be understandable and accessible by anyone through the development of a mobile app. The 3D model was used to explore the different historical phases, starting from the recent layers to the oldest ones, through a virtual subtraction process, following the methods of Archaeology of Architecture. Its components can be imported into parametric software and recognized both in their morphological and typological aspects. It is based on the concept of LoD and ReverseLoD in order to fit the accuracy required by each step of the research

Unfolded p53 in the pathogenesis of Alzheimer's disease: is HIPK2 the link?

p53 transcriptional activity depends mainly on posttranslational modifications and protein/protein interaction. Another important mechanism that controls p53 function is its conformational stability since p53 is an intrinsically unstable protein. An altered conformational state of p53, independent from point mutations, has been reported in tissues from patients with Alzheimer's disease (AD), leading to an impaired and dysfunctional response to stressors. Recent evidence shows that one of the activators that induces p53 posttranslational modification and wild-type conformational stability is homeodomain interacting protein kinase 2 (HIPK2). Hence, conditions that induce HIPK2 deregulation would result in a dysfunctional response to stressors by affecting p53 activity. Discovering the mechanisms of HIPK2 activation/inhibition and the ways to manipulate HIPK2 activity are an interesting option to affect several biological pathways, including those underlying AD. Soluble beta-amyloid peptides have recently been involved in HIPK2 degradation, in turn regulating the p53 conformational state and vulnerability to a noxious stimulus, before triggering the amyloidogenic cascade. Here we discuss about these findings and the potential relevance of HIPK2 as a target for AD and highlight the existence of a novel amyloid-based mechanism in AD potentially leading to the survival of injured dysfunctional cells

Homeodomain Interacting Protein Kinase 2: A Target for Alzheimer's Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival

BACKGROUND: Homeodomain interacting protein kinase 2 (HIPK2) is an evolutionary conserved serine/threonine kinase whose activity is fundamental in maintaining wild-type p53 function, thereby controlling the destiny of cells when exposed to DNA damaging agents. We recently reported an altered conformational state of p53 in tissues from patients with Alzheimer's Disease (AD) that led to an impaired and dysfunctional response to stressors. METHODOLOGY/PRINCIPAL FINDINGS: Here we examined the molecular mechanisms underlying the impairment of p53 activity in two cellular models, HEK-293 cells overexpressing the amyloid precursor protein and fibroblasts from AD patients, starting from recent findings showing that p53 conformation may be regulated by HIPK2. We demonstrated that beta-amyloid 1-40 induces HIPK2 degradation and alters HIPK2 binding activity to DNA, in turn regulating the p53 conformational state and vulnerability to a noxious stimulus. Expression of HIPK2 was analysed by western blot experiments, whereas HIPK2 DNA binding was examined by chromatin immunoprecipitation analysis. In particular, we evaluated the recruitment of HIPK2 onto some target promoters, including hypoxia inducible factor-1alpha and metallothionein 2A. CONCLUSIONS/SIGNIFICANCE: These results support the existence of a novel amyloid-based pathogenetic mechanism in AD potentially leading to the survival of injured dysfunctional cells

Monocrystalline fibres for low thermal noise suspension in advanced gravitational wave detectors

Thermal noise in mirror suspension will be the most severe fundamental limit to the low-frequency sensitivity of future interferometric gravitational wave detectors. We propose a new type of materials to realize low thermal noise suspension in such detectors. Monocrystalline suspension fibres are good candidates both for cryogenic and for ambient temperature interferometers. Material characteristics and a production facility are described in this paper

The role of LAR RPTPs family Receptor Protein Tyrosine Phosphatases RPTP Sigma, RPTP Delta and RPTP Lar in mouse embryonic development

RPTP_Sigma, RPTP_Delta and RPTP_Lar are the three members of the LAR_RPTPs family. These members share similar structures and superposed expression patterns in different tissues. Although they are key players in different cellular functions their role in embryonic development is little known. We show that RPTP_Sigma, RPTP_Delta and RPTP_Lar are redundant in the heart and liver. Triple mutant (SDLKO) embryos show lethality starting with E12.5 and have defect in erythrocytes maturation translated by a delay in erythroblasts enucleation and persistent truncus arteriosus that leads to a failure in separation of aorta from pulmonary artery.RPTP_Sigma, RPTP_Delta et RPTP_Lar sont trois membres de la famille des LAR_RPTPs. Ces membres partagent un patron d'expression dans différents tissus et des structures similaires. Malgré le fait qu'ils sont des acteurs important de différentes fonctions cellulaires, leur rôle dans le développement embryonnaire reste mal compris. Nos résultats montrent que RPTP_Sigma, RPTP_Delta et RPTP_Lar agissent de façon redondante dans le cœur et le foie. Les embryons triple mutants (SDLKO) commencent à présenter une létalité à partir E12.5 et un défaut dans la maturation des érythrocytes se traduisant par un délai d'énucléation des érythroblastes. De plus, ces embryons montrent un truncus arteriosus persistant causant un défaut dans la séparation entre l'aorte et l'artère pulmonaire

A ESCOLHA DE SOFIA EM RELAÇÃO AS VÍTIMAS DA PANDEMIA DA COVID-19

A Escolha de Sofia em relação as vítimas da pandemia da COVID – 19. A Escolha de Sofia relacionada com as decisões tomadas pelos profissionais da saúde em relação as vítimas durante a pandemia da COVID – 19. Quais os critérios de escolha para saber quem receberia tratamento e atendimento primeiro? A escolha realizada pelos profissionais pode ser enquadrada como Escolha de Sofia? O presente trabalho de pesquisa tem como objetivo pesquisar e demonstrar como foram feitas as escolhas pelos profissionais da saúde na hora de realizar os atendimentos hospitalares durante a pandemia da COVID – 19 e como essa escolha está relacionada à Escolha de Sofia. Ao final concluiu-se que a decisão demanda extremo profissionalismo e controle emocional, podendo ser enquadrada em uma Escolha de Sofia, e, ainda que o cumprimento do protocolo desenvolvido foi eficaz. A prova disso são os mais de 37.199.182 pacientes recuperados pelo SUS. A pesquisa realizada aplicou o método de pesquisa dedutivo, dando ênfase à pesquisa teórica/descritiva, utilizou-se material bibliográfico consistente com os assuntos tratados