PCSK9 (PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9)AND GLUCOSE METABOLISM: WHICH CONNECTION?

PCSK9 (proprotein convertase subtilisin/kexin type 9) and glucose metabolism: which connection? Background: PCSK9 (proprotein convertase subtilisin/kexin type 9), is a protein, mainly synthesized and secreted by the liver, which binds to specific target proteins and escorts them towards lysosomes for degradation. The best defined activity of PCSK9 is its ability to modulate the hepatic uptake of LDL cholesterol (LDL-C), by enhancing the intracellular degradation of the LDL receptor (LDLR). In humans, several mutations in PCSK9 gene were described, both \u201cgain-of-function\u201d mutations associated to hypercholesterolemia and \u201closs of function\u201d mutations linked to low LDL-C levels [1]. These findings suggest PCSK9 inhibitors as a promising class of drugs for the treatment of patients with severe hypercholesterolemia or at very high cardiovascular risk. However, some gaps regarding the potential role of PCSK9 in targeting the LDLR in organs other than the liver are still open. Indeed, the LDLR is abundantly expressed in pancreatic \u3b2-cells, where it plays a key role in the uptake of plasma LDL particles [2]. Therefore, further investigations are needed to better clarify the physiological role of PCSK9, also in light of its pharmacological targeting. Methods: WT, PCSK9 KO, LDLR KO, PCSK9/LDLR DKO, albumin (Alb)Cre+/PCSK9LoxP/LoxP (liver selective PCSK9 KO mice) and AlbCre-/PCSK9LoxP/LoxP mice were fed a HFD (High Fat Diet \u2013 45% Kcal fat) or SFD (Standard Fat Diet \u2013 10% Kcal fat) for 12 or 20 weeks. GTT, ITT, insulin and C-peptide plasma levels, pancreas morphology and cholesterol accumulation in pancreatic islets were studied in the different animal models. Results: Glucose clearance was significantly impaired in PCSK9 KO mice fed a SFD or a HFD for 20 weeks compared to WT animals, with both diet. On the contrary, insulin sensitivity was not affected as both animals showed a similar decrease in plasma glucose levels following insulin injection (ITT). Plasma insulin and C-peptide levels were reduced in PCSK9 KO mice compared to WT and accordingly fasting and refeeding experiments showed increased plasma glucose but reduced insulin levels in PCSK9 KO compared to controls. A detailed analysis of pancreas morphology of PCSK9 KO mice vs WT littermates revealed larger islets with increased accumulation of cholesteryl esters, paralleled by increased insulin intracellular levels. This phenotype was completely reverted in PCSK9/LDLR DKO mice implying the LDLR as the PCSK9 target responsible for the phenotype observed. Further studies in AlbCre+/PCSK9LoxP/LoxP, which lack detectable circulating PCSK9, also showed a complete recovery of the phenotype, thus indicating that circulating, liver-derived PCSK9 does not impact \u3b2-cells function and insulin secretion. Conclusion:The PCSK9/LDLR axis affects \u3b2-cells function and control insulin secretion. Our data indicate that this effect is independent of circulating PCSK9, and is probably related to local effects of PCSK9 suggesting the possibility that anti-PCSK9 antibodies or liver specific therapies, such as siRNAs, might have a limited impact on LDLR expression in pancreas and \u3b2-cells dysfunction

Correlated Nanoscopic Josephson Junctions

We discuss correlated lattice models with a time-dependent potential across a barrier and show how to implement a Josephson-junction-like behavior. The pairing occurs by a correlation effect enhanced by the symmetry of the system. In order to produce the effect we need a mild distortion which causes avoided crossings in the many-body spectrum. The Josephson-like response involves a quasi-adiabatic evolution in the time-dependent field. Besides, we observe an inverse-Josephson (Shapiro) current by applying an AC bias; a supercurrent in the absence of electromotive force can also be excited. The qualitative arguments are supported by explicit exact solutions in prototype 5-atom clusters with on-site repulsion. These basic units are then combined in ring-shaped systems, where one of the units sits at a higher potential and works as a barrier. In this case the solution is found by mapping the low-energy Hamiltonian into an effective anisotropic Heisenberg chain. Once again, we present evidence for a superconducting flux quantization, i.e. a Josephson-junction-like behavior suggesting the build-up of an effective order parameter already in few-electron systems. Some general implications for the quantum theory of transport are also briefly discussed, stressing the nontrivial occurrence of asymptotic current oscillations for long times in the presence of bound states.Comment: 12 pages, 2 figures, to appear in J. Phys. - Cond. Ma

HyBIS: Windows Guest Protection through Advanced Memory Introspection

Effectively protecting the Windows OS is a challenging task, since most implementation details are not publicly known. Windows has always been the main target of malwares that have exploited numerous bugs and vulnerabilities. Recent trusted boot and additional integrity checks have rendered the Windows OS less vulnerable to kernel-level rootkits. Nevertheless, guest Windows Virtual Machines are becoming an increasingly interesting attack target. In this work we introduce and analyze a novel Hypervisor-Based Introspection System (HyBIS) we developed for protecting Windows OSes from malware and rootkits. The HyBIS architecture is motivated and detailed, while targeted experimental results show its effectiveness. Comparison with related work highlights main HyBIS advantages such as: effective semantic introspection, support for 64-bit architectures and for latest Windows (8.x and 10), advanced malware disabling capabilities. We believe the research effort reported here will pave the way to further advances in the security of Windows OSes

Urban Voids After the Pandemic. A New Chance for Greenway

Our proposal deals with the meaning of urban voids in the post-COVID-19 period to suggest new understandings of how urban green corridors can positively affect design for healthier and more sustainable cities. According to Secchi (1986), planning through the void involves a profound revision of the way we think about the city, reversing the points of interest, proposing as polarities the spaces that do not usually emerge. The void thus becomes an opportunity, a chance to improve the structure of our urban landscape (Lopez-Pineiro, 2020). A city is a powerful place, always in motion and transformation. It has an artificial spirit full of surprises and vague limits. It is the scene of remarkable transformations that in their wildness are partially ungovernable by the designers themselves. The desire to control them leaves a series of abandoned and unfinished spaces, “holes” that live from their discontinuity with the surroundings (Labriola, 2021). During a period of crisis, like the one that we are still living with COVID-19 (Fabris et al, 2020), it is common to re-think our cities to create better places for the community. After the long period of forced distance that we lived, an evolution of public space is recommended. During the pandemic, the emptiness of our cities permitted Nature to re-appropriate its spaces. Following this trend and thinking about a new kind of public space where Nature and its inside processes are the protagonists, it is possible to intervene in our cities. The porosity of the urban fabric in towns without humans, blocked at home by the never-ending lockdowns, became a new green corridor that revealed the presence of wildlife (both fauna and flora) as part of a forgotten urban layer that turned visible again. The preservation of this new asset should be possible. The spaces to allow this change can be the abandoned and empty areas present in the contemporary city’s sick body that we can finally heal. The so-called wastelands, voids, or terrain vague, have a significant value independent from the environment in which they are inserted, showing a relationship with the contemporary city extraneous to its rhythms. For this reason, they are the perfect place for experimentation in terms of greenways, a possible starting point to re-think how green can be part of the urban texture and how to conceive public and open spaces after the nowadays crisis. The paper considers the Metropolitan City of Milan as a remarkable case study to understand the pivotal role played by urban voids in the formation of greenways and their capacity of reshaping the environmental, aesthetic and healthy dimensions of urban landscapes

A study of the pair distribution function of self-organized Ge quantum dots

We explore the use of the pair distribution function to study the self-organization process of Gequantum dots on both nanopatterned and nonpatterned oxidized Si(001) surfaces.Dots formation and ordering upon annealing of a Ge thin film are analyzed. The method we use is not limited to this case study. We show how it can be applied to determine short and long range self-ordering of nanostructures. We support our results by applying a software routine to simulate patterns of dots to finally spot the relevant physical aspects of Ge islands self-assembly

WeDRAW: using multisensory serious games to explore concepts in primary mathematics

WeDRAW aims to mediate learning of primary school mathematical concepts, such as geometry and arithmetic, through the design, development and evaluation of multisensory serious games, using a combination of sensory interactive technologies. Working closely with schools, using participatory design techniques, the WeDRAW system will be embedded into the school curricula, and configurable by teachers. Besides application to typically developing children, a major goal is to examine this multisensory approach with visually impaired and dyslexic children

Transformations of public spaces - sustainable and ethical approach to architectural and urban design using mixed cultural background

Transformations of public spaces are an integral part of city life. These processes although addressing site specific problems are universal for the urban centres across European countries struggling with desurbanisation, social exclusion, massive tourism, climate change and pollution

Clinical Management of Long-Term Survivors after Classical Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma

Compared to other patients suffering from hematological malignancies, classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) patients have a long life expectancy when in complete remission at the end of first, or sometimes second, line treatments [...]