Synthesis of Prosthesis Architectures and Design of Prosthetic Devices for Upper Limb Amputees

This chapter presents a procedure for the Determination of the Optimal Prosthesis Architecture for upper limb amputees (DOPA). The presented approach can consistently manage both the clinical aspects and the technical issues involved in the design of electromechanically actuated prostheses. The procedure is composed on one hand of algorithms useful for analyzing the patients\u2019 requirements and on the other hand of algorithms that perform kinematic and kinetostatic simulations of several architectures of artificial arms attempting to fulfil important activities of daily living. The systematic evaluation of the prosthesis models\u2019 performance can methodically guide designers in the synthesis of the optimal prosthesis that best suits the patients\u2019 requirements

Large Language Models and Explainable Law: a Hybrid Methodology

The paper advocates for LLMs to enhance the accessibility, usage and explainability of rule-based legal systems, contributing to a democratic and stakeholder-oriented view of legal technology. A methodology is developed to explore the potential use of LLMs for translating the explanations produced by rule-based systems, from high-level programming languages to natural language, allowing all users a fast, clear, and accessible interaction with such technologies. The study continues by building upon these explanations to empower laypeople with the ability to execute complex juridical tasks on their own, using a Chain of Prompts for the autonomous legal comparison of different rule-based inferences, applied to the same factual case

State-of-the-Art of Hand Exoskeleton Systems

This paper deals with the analysis of the state-of-the-art of robotic hand exoskeletons (updated at May 2011), which is intended as the first step of a designing activity. A large number of hand exoskeletons (both products and prototypes) that feature some common characteristics and many special peculiarities are reported in the literature. Indeed, in spite of very similar functionalities, different hand exoskeletons can be extremely different for the characteristics of their mechanism architectures, control systems and working principles. The aim of this paper is to provide the reader with a complete and schematic picture of the state-of-the-art of hand exoskeletons. The focus is placed on the description of the main aspects that are involved in the exoskeleton design such as the system kinematics, the actuator systems, the transmission parts and the control schemes. Additionally, the critical issues provided by the literature analysis are discussed in order to enlighten the differences and the common features of different practical solutions. This paper may help to understand both the reasons why certain solutions are proposed for the different applications and the advantages and drawbacks of the different designs proposed in the literature. The motivation of this study is the need to design a new hand exoskeleton for rehabilitation purposes

Cancer and aging: a multidisciplinary medicinal chemistry approach on relevant biological targets such as proteasome, sirtuins and interleukin 6

It is well known that ageing and cancer have common origins due to internal and environmental stress and share some common hallmarks such as genomic instability, epigenetic alteration, aberrant telomeres, inflammation and immune injury. Moreover, ageing is involved in a number of events responsible for carcinogenesis and cancer development at the molecular, cellular, and tissue levels. Ageing could represent a “blockbuster” market because the target patient group includes potentially every person; at the same time, oncology has become the largest therapeutic area in the pharmaceutical industry in terms of the number of projects, clinical trials and research and development (R&D) spending, but cancer remains one of the leading causes of mortality worldwide. The overall aim of the work presented in this thesis was the rational design of new compounds able to modulate activity of relevant targets involved in cancer and aging-related pathologies, namely proteasome and immunoproteasome, sirtuins and interleukin 6. These three targets play different roles in human cells, but the modulation of its activity using small molecules could have beneficial effects on one or more aging-related diseases and cancer. We identified new moderately active and selective non-peptidic compounds able to inhibit the activity of both standard and immunoproteasome, as well as novel and selective scaffolds that would bind and inhibit SIRT6 selectively and can be used to sensitize tumor cells to commonly used anticancer agents such gemcitabine and olaparib. Moreover, our virtual screening approach led us also to the discovery of new putative modulators of SIRT3 with interesting in-vitro and cellular activity. Although the selectivity and potency of the identified chemical scaffolds are susceptible to be further improved, these compounds can be considered as highly promising leads for the development of future therapeutics

G-protein-coupled receptors, cholesterol and palmitoylation: facts about fats

G-protein-coupled receptors (GPCRs) are integral membrane proteins, hence it is not surprising that a number of their structural and functional features are modulated by both proteins and lipids. The impact of interacting proteins and lipids on the assembly and signalling of GPCRs has been extensively investigated over the last 20–30 years, and a further impetus has been given by the proposal that GPCRs and/or their immediate signalling partners (G proteins) can partition within plasma membrane domains, termed rafts and caveolae, enriched in glycosphingolipids and cholesterol. The high content of these specific lipids, in particular of cholesterol, in the vicinity of GPCR transmembranes can affect GPCR structure and/or function. In addition, most GPCRs are post-translationally modified with one or more palmitic acid(s), a 16-carbon saturated fatty acid, covalently bound to cysteine(s) localised in the carboxyl-terminal cytoplasmic tail. The insertion of palmitate into the cytoplasmic leaflet of the plasma membrane can create a fourth loop, thus profoundly affecting GPCR structure and hence the interactions with intracellular partner proteins. This review briefly highlights how lipids of the membrane and the receptor themselves can influence GPCR organisation and functioning

Wheat Grain Composition, Dough Rheology and Bread Quality as Affected by Nitrogen and Sulfur Fertilization and Seeding Density

Flour from old varieties are usually considered very weak flours, and thus difficult to use in breadmaking especially when processed as Italian \u201cTipo 2\u201d flour. Hence, the aim of our study was to understand if agronomic treatments can be used to improve flour processability and the quality of three old wheat varieties. An experimental strip-plot scheme was used: three old wheat varieties (Andriolo, Sieve, Verna), two seeding densities, three levels of nitrogen fertilization (N35, N80, and N135), and two levels of foliar sulfur fertilization. Analyzed parameters related to kernel composition, dough rheology and bread quality. Sulfur and nitrogen treatments significantly affected protein composition and dough alveograph strength, which increased by about 34% with nitrogen fertilization, and by about 14% with the sulfur treatment. However, only nitrogen fertilization affected bread characteristics. Crumb density significantly decreased from N35 to N135, while springiness and cohesiveness increased. On the other hand, sulfur did not improve breads. This highlight the importance of performing breadmaking tests in addition to the rheological determinations. The poor technological performance of old wheat flours can be improved with agronomical treatments designed to obtain higher-quality bread

A meta-model framework for grinding simulation

When considering the mechanics of grinding, several physical phenomena have to be modeled, each one having effect on the resulting grinding forces, wheel and workpiece geometry. Depending on the analyzed problem, some dependencies can be neglected to privilege some aspects instead of others. Nevertheless, all models essentially start considering wheel-workpiece engagement and the corresponding material removal (both wheel and workpiece side), deriving the forces by means of energy balances and/or shear mechanics. The meta-model proposed in this paper represents a general framework conceived for providing a time-domain simulation engine based on a dexel representation of wheel and workpiece, capable to “host” all the semi-empirical models existing in literature, where the overall grinding force is the result of the integration of the force contributions associated to the local removal along wheel-workpiece engagement arc. A cascade approach is adopted to solve for forces and displacements the DAEs set describing the dynamic interactions between wheel and workpiece, whereas all the algebraic relationships pertaining to the various specific models are solved in a pre-processing phase, yielding a set of response surfaces that are queried during time integration. Finally, the meta-model framework is instantiated for a model of traverse roll grinding with force-dependent wheel wear

Plasma heme oxygenase-1 is decreased in peripheral artery disease patients

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The Dually Acylated NH2-terminal Domain of Gi1α Is Sufficient to Target a Green Fluorescent Protein Reporter to Caveolin-enriched Plasma Membrane Domains: PALMITOYLATION OF CAVEOLIN-1 IS REQUIRED FOR THE RECOGNITION OF DUALLY ACYLATED G-PROTEIN α SUBUNITS IN VIVO

Here we investigate the molecular mechanisms that govern the targeting of G-protein α subunits to the plasma membrane. For this purpose, we used Gi1α as a model dually acylated G-protein. We fused full-length Gi1α or its extreme NH2-terminal domain (residues 1–32 or 1–122) to green fluorescent protein (GFP) and analyzed the subcellular localization of these fusion proteins. We show that the first 32 amino acids of Gi1α are sufficient to target GFP to caveolin-enriched domains of the plasma membrane in vivo, as demonstrated by co-fractionation and co-immunoprecipitation with caveolin-1. Interestingly, when dual acylation of this 32-amino acid domain was blocked by specific point mutations (G2A or C3S), the resulting GFP fusion proteins were localized to the cytoplasm and excluded from caveolin-rich regions. The myristoylated but nonpalmitoylated (C3S) chimera only partially partitioned into caveolin-containing fractions. However, both nonacylated GFP fusions (G2A and C3S) no longer co-immunoprecipitated with caveolin-1. Taken together, these results indicate that lipid modification of the NH2-terminal of Gi1α is essential for targeting to its correct destination and interaction with caveolin-1. Also, a caveolin-1 mutant lacking all three palmitoylation sites (C133S, C143S, and C156S) was unable to co-immunoprecipitate these dually acylated GFP-G-protein fusions. Thus, dual acylation of the NH2-terminal domain of Gi1α and palmitoylation of caveolin-1 are both required to stabilize and perhaps regulate this reciprocal interaction at the plasma membrane in vivo. Our results provide the first demonstration of a functional role for caveolin-1 palmitoylation in its interaction with signaling molecules