Increased mitochondrial fragmentation in polycystic kidney disease acts as a modifier of disease progression.

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disorder, characterized by bilateral renal cyst formation. Multiple pathways are de-regulated in cystic epithelia offering good opportunities for therapy. Others and we have previously reported that metabolic reprogramming, including alterations of the TCA cycle, are prominent features of ADPKD. Several lines of evidence suggest that mitochondrial impairment might be responsible for the metabolic alterations. Here, we performed morphologic and morphometric evaluation of mitochondria by TEM in an orthologous mouse model of PKD caused by mutations in the Pkd1 gene (Ksp-Cre;Pkd1flox/- ). Furthermore, we measured mitochondrial respiration by COX and SDH enzymatic activity in situ. We found several alterations including reduced mitochondrial mass, altered structure and fragmentation of the mitochondrial network in cystic epithelia of Ksp-Cre;Pkd1flox/- mice. At the molecular level, we found reduced expression of the pro-fusion proteins OPA1 and MFN1 and up-regulation of the pro-fission protein DRP1. Importantly, administration of Mdivi-1, which interferes with DRP1 rescuing mitochondrial fragmentation, significantly reduced kidney/body weight, cyst formation, and improved renal function in Ksp-Cre;Pkd1flox/- mice. Our data indicate that impaired mitochondrial structure and function play a role in disease progression, and that their improvement can significantly modify the course of the disease

Defects of glucose metabolism in polycystic kidney disease: first studies and future perspectives

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Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder caused by loss-of-function mutations in PKD1 or PKD2. Increased glycolysis is a prominent feature of the disease, but how it impacts on other metabolic pathways is unknown. Here, we present an analysis of mouse Pkd1 mutant cells and kidneys to investigate the metabolic reprogramming of this pathology. We show that loss of Pkd1 leads to profound metabolic changes that affect glycolysis, mitochondrial metabolism, and fatty acid synthesis (FAS). We find that Pkd1-mutant cells preferentially use glutamine to fuel the TCA cycle and to sustain FAS. Interfering with either glutamine uptake or FAS retards cell growth and survival. We also find that glutamine is diverted to asparagine via asparagine synthetase (ASNS). Transcriptional profiling of PKD1-mutant human kidneys confirmed these alterations. We find that silencing of Asns is lethal in Pkd1-mutant cells when combined with glucose deprivation, suggesting therapeutic approaches for ADPKD

Toward Future Automatic Warehouses: An Autonomous Depalletizing System Based on Mobile Manipulation and 3D Perception

This paper presents a mobile manipulation platform designed for autonomous depalletizing tasks. The proposed solution integrates machine vision, control and mechanical components to increase flexibility and ease of deployment in industrial environments such as warehouses. A collaborative robot mounted on a mobile base is proposed, equipped with a simple manipulation tool and a 3D in-hand vision system that detects parcel boxes on a pallet, and that pulls them one by one on the mobile base for transportation. The robot setup allows to avoid the cumbersome implementation of pick-and-place operations, since it does not require lifting the boxes. The 3D vision system is used to provide an initial estimation of the pose of the boxes on the top layer of the pallet, and to accurately detect the separation between the boxes for manipulation. Force measurement provided by the robot together with admittance control are exploited to verify the correct execution of the manipulation task. The proposed system was implemented and tested in a simplified laboratory scenario and the results of experimental trials are reported

Characterisation of protease activity during SARS-CoV-2 infection identifies novel viral cleavage sites and cellular targets with therapeutic potential

SARS-CoV-2 is the causative agent behind the COVID-19 pandemic, and responsible for over 170 million infections, and over 3.7 million deaths worldwide. Efforts to test, treat and vaccinate against this pathogen all benefit from an improved understanding of the basic biology of SARS-CoV-2. Both viral and cellular proteases play a crucial role in SARS-CoV-2 replication, and inhibitors targeting proteases have already shown success at inhibiting SARS-CoV-2 in cell culture models. Here, we study proteolytic cleavage of viral and cellular proteins in two cell line models of SARS-CoV-2 replication using mass spectrometry to identify protein neo-N-termini generated through protease activity. We identify previously unknown cleavage sites in multiple viral proteins, including major antigenic proteins S and N, which are the main targets for vaccine and antibody testing efforts. We discovered significant increases in cellular cleavage events consistent with cleavage by SARS-CoV-2 main protease, and identify 14 potential high-confidence substrates of the main and papain-like proteases, validating a subset with in vitro assays. We showed that siRNA depletion of these cellular proteins inhibits SARS-CoV-2 replication, and that drugs targeting two of these proteins: the tyrosine kinase SRC and Ser/Thr kinase MYLK, showed a dose-dependent reduction in SARS-CoV-2 titres. Overall, our study provides a powerful resource to understand proteolysis in the context of viral infection, and to inform the development of targeted strategies to inhibit SARS-CoV-2 and treat COVID-19

Il suicidio giovanile in provincia di Varese dal 1980 al 1999.

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Il suicidio giovanile in provincia di Varese dal 1980 al 1999.

missin

Playing to play: a piano-based user interface for music education video-games

This paper presents and discusses a case-study where a video-game is the means through which the user is induced to learn to use a complex and not-intuitive control interface such as the keyboard of a piano. The interaction paradigm is based on the idea, common to the Tangible Interfaces, to employ everyday objects, or anyway not designed for video games, as control user interface. In this research, the case study is the video game called Musa, in which players are led into an imaginary world where music is magic and every action is carried out through it. Combined with an educational path, this is thought to make players able to learn and, in a successive moment, to abstract this knowledge from the game, just by playing. Musa was evaluated in an experimental setup with 51 kids between 6 and 11 years old. Results show that subjects are able to improve their knowledge of the piano keyboard after two sessions of game and no significant differences were found between children with pre-acquired knowledge of the keyboard and the others