Cytokines at the Interplay Between Asthma and Atherosclerosis?

Cardiovascular disease (CVD) is an important comorbidity in a number of chronic inflammatory diseases. However, evidence in highly prevalent respiratory disease such as asthma are still limited. Epidemiological and clinical data are not univocal in supporting the hypothesis that asthma and CVD are linked and the mechanisms of this relationship remain poorly defined. In this review, we explore the relationship between asthma and cardiovascular disease, with a specific focus on cytokine contribution to vascular dysfunction and atherosclerosis. This is important in the context of recent evidence linking broad inflammatory signaling to cardiovascular events. However inflammatory regulation in asthma is different to the one typically observed in atherosclerosis. We focus on the contribution of cytokine networks encompassing IL-4, IL-6, IL-9, IL-17A, IL-33 but also IFN-γ and TNF-α to vascular dysfunction in atherosclerosis. In doing so we highlight areas of unmet need and possible therapeutic implications

Exploiting Intrinsic Kinematic Null Space for Supernumerary Robotic Limbs Control

Supernumerary robotic limbs (SRLs) gained increasing interest in the last years for their applicability as healthcare and assistive technologies. These devices can either support or augment human sensorimotor capabilities, allowing users to complete tasks that are more complex than those feasible for their natural limbs. However, for a successful coordination between natural and artificial limbs, intuitiveness of interaction and perception of autonomy are key enabling features, especially for people suffering from motor disorders and impairments. The development of suitable human-robot interfaces is thus fundamental to foster the adoption of SRLs.With this work, we describe how to control an extra degree of freedom by taking advantage of what we defined the Intrinsic Kinematic Null Space, i.e. the redundancy of the human kinematic chain involved in the ongoing task. Obtained results demonstrated that the proposed control strategy is effective for performing complex tasks with a supernumerary robotic finger, and that practice improves users' control ability

Modulating Lipoprotein Transcellular Transport and Atherosclerotic Plaque Formation in ApoE-/-Mice via Nanoformulated Lipid-Methotrexate Conjugates

Macrophage inflammation and maturation into foam cells, following the engulfment of oxidized low-density lipoproteins (oxLDL), are major hallmarks in the onset and progression of atherosclerosis. Yet, chronic treatments with anti-inflammatory agents, such as methotrexate (MTX), failed to modulate disease progression, possibly for the limited drug bioavailability and plaque deposition. Here, MTX-lipid conjugates, based on 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), were integrated in the structure of spherical polymeric nanoparticles (MTX-SPNs) or intercalated in the lipid bilayer of liposomes (MTX-LIP). Although, both nanoparticles were colloidally stable with an average diameter of ∼200 nm, MTX-LIP exhibited a higher encapsulation efficiency (>70%) and slower release rate (∼50% at 10 h) compared to MTX-SPN. In primary bone marrow derived macrophages (BMDMs), MTX-LIP modulated the transcellular transport of oxLDL more efficiently than free MTX mostly by inducing a 2-fold overexpression of ABCA1 (regulating oxLDL efflux), while the effect on CD36 and SRA-1 (regulating oxLDL influx) was minimal. Furthermore, in BMDMs, MTX-LIP showed a stronger anti-inflammatory activity than free MTX, reducing the expression of IL-1β by 3-fold, IL-6 by 2-fold, and also moderately of TNF-α. In 28 days high-fat-diet-fed apoE-/- mice, MTX-LIP reduced the mean plaque area by 2-fold and the hematic amounts of RANTES by half as compared to free MTX. These results would suggest that the nanoenhanced delivery to vascular plaques of the anti-inflammatory DSPE-MTX conjugate could effectively modulate the disease progression by halting monocytes' maturation and recruitment already at the onset of atherosclerosis

The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition

RAB39B is a member of the RAB family of small GTPases that controls intracellular vesicular trafficking in a compartment-specific manner. Mutations in the RAB39B gene cause intellectual disability comorbid with autism spectrum disorder and epilepsy, but the impact of RAB39B loss of function on synaptic activity is largely unexplained. Here we show that protein interacting with C-kinase 1 (PICK1) is a downstream effector of GTP-bound RAB39B and that RAB39B-PICK1 controls trafficking from the endoplasmic reticulum to the Golgi and, hence, surface expression of GluA2, a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). The role of AMPARs in synaptic transmission varies depending on the combination of subunits (GluA1, GluA2 and GluA3) they incorporate. RAB39B downregulation in mouse hippocampal neurons skews AMPAR composition towards non GluA2-containing Ca(2+)-permeable forms and thereby alters synaptic activity, specifically in hippocampal neurons. We posit that the resulting alteration in synaptic function underlies cognitive dysfunction in RAB39B-related disorders

Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2

Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5. In vitro administration of RB5 disrupts the preferential interaction of ERK1 MAP kinase with importinα1/KPNA2 over ERK2, facilitates ERK1/2 nuclear translocation, and enhances global ERK activity. Importantly, RB5 treatment in vivo promotes neuroprotection in mouse models of Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) disease, and enhances ERK signaling in a human cellular model of HD. Additionally, RB5‐mediated potentiation of ERK nuclear signaling facilitates synaptic plasticity, enhances cognition in healthy rodents, and rescues cognitive impairments in AD and HD models. The reported molecular mechanism shared across multiple neurodegenerative disorders reveals a potential new therapeutic target approach based on the modulation of KPNA2‐ERK1/2 interactions

Enter the MATRIX model: a Multi-Agent model for Transition Risks with application to energy shocks

The global energy crisis that began in fall 2021 and the subsequent spike in energy prices constitute a significant challenge for the world economy that risks undermining the postCOVID-19 recovery. In this paper, we develop and calibrate a new Multi-Agent model for Transition Risks (MATRIX) to analyze the role of energy in the functioning of a complex adaptive system and the economic and distributional effects of energy shocks. The economic system is populated by heterogeneous agents, i.e., households, firms and banks, which take optimal decision rules and interact in decentralized markets characterized by limited information. After calibrating the model on US quarterly macroeconomic data, we assess the economic and distributional impacts of different types of energy shocks, namely: (i) an exogenous increase in the price of fossil fuels (e.g., oil or gas); (ii) a decrease in energy firms' productivity; (iii) a reduction in the available quantity of fossil fuels. We find that the energy shocks entail similar effects at the aggregate level in terms of higher inflation and lower real GDP. Nevertheless, the distribution of gains and losses across sectors and agents varies significantly depending on the type of shock. Our findings suggest that policymakers should carefully consider the nature of energy shocks and the resulting distributional effects to design effective measures in response to energy crises.(c) 2022 Elsevier B.V. All rights reserved

L-cysteine/cystathionine-β-synthase-induced relaxation in mouse aorta involves a L-serine/sphingosine-1-phosphate/NO pathway

Among the three enzymes involved in the transsulfuration pathway, only cystathionine β-synthase (CBS) converts L-cysteine into L-serine and H2 S. L-serine is also involved in the de novo sphingolipid biosynthesis through a condensation with palmitoyl-CoA by the action of serine palmitoyltransferase (SPT). Here, we have investigated if L-serine contributes to the vasorelaxant effect