Mitogen Activated Protein Kinase Phosphatase-1 Prevents the Development of Tactile Sensitivity In a Rodent Model of Neuropathic Pain

Neuropathic pain due to nerve injury is one of the most difficult types of pain to treat. Following peripheral nerve injury, neuronal and glial plastic changes contribute to central sensitization and perpetuation of mechanical hypersensitivity in rodents. The mitogen activated protein kinase (MAPK) family is pivotal in this spinal cord plasticity. MAPK phosphatases (MKPs) limit inflammatory processes by dephosphorylating MAPKs. For example, MKP-1 preferentially dephosphorylates p-p38. Since spinal p-p38 is pivotal for the development of chronic hypersensitivity in rodent models of pain, and p-p38 inhibitors have shown clinical potential in acute and chronic pain patients, we hypothesize that induction of spinal MKP-1 will prevent the development of peripheral nerve-injury-induced hypersensitivity and p-p38 overexpression. We cloned rat spinal cord MKP-1 and optimize MKP-1 cDNA in vitro using transfections to BV-2 cells. We observed that in vitro overexpression of MKP-1 blocked lipopolysaccharide-induced phosphorylation of p38 (and other MAPKs) as well as release of pro-algesic effectors (i.e., cytokines, chemokines, nitric oxide). Using this cDNA MKP-1 and a non-viral, in vivo nanoparticle transfection approach, we found that spinal cord overexpression of MKP-1 prevented development of peripheral nerve-injury-induced tactile hypersensitivity and reduced pro-inflammatory cytokines and chemokines and the phosphorylated form of p38

Antibody-Mediated Targeting of Iron Oxide Nanoparticles to the Folate Receptor Alpha Increases Tumor Cell Association In Vitro and In Vivo

Active molecular targeting has become an important aspect of nanoparticle development for oncology indications. Here, we describe molecular targeting of iron oxide nanoparticles (IONPs) to the folate receptor alpha (FOLRα) using an engineered antibody fragment (Ffab). Compared to control nanoparticles targeting the non-relevant botulinum toxin, the Ffab-IONP constructs selectively accumulated on FOLRα-overexpressing cancer cells in vitro, where they exhibited the capacity to internalize into intracellular vesicles. Similarly, Ffab-IONPs homed to FOLRα-positive tumors upon intraperitoneal administration in an orthotopic murine xenograft model of ovarian cancer, whereas negative control particles showed no detectable tumor accumulation. Interestingly, Ffab-IONPs built with custom 120 nm nanoparticles exhibited lower in vitro targeting efficiency when compared to those built with commercially sourced 180 nm nanoparticles. In vivo, however, the two Ffab-IONP platforms achieved equivalent tumor homing, although the smaller 120 nm IONPs were more prone to liver sequestration. Overall, the results show that Ffab-mediated targeting of IONPs yields specific, high-level accumulation within cancer cells, and this fact suggests that Ffab-IONPs could have future utility in ovarian cancer diagnostics and therapy

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Contribution à l'étude du couplage électromagnéto-mécanique de polymères chargés (analyse micro-onde)

Le but de ce travail est d étudier les propriétés électromagnétiques et de résistance mécanique de plusieurs plasto-ferrites (PFs) disponibles dans le commerce, en milieu ambiant. On effectue la sélection d un groupe de PFs et la mesure de leur permittivité = -j et de leur perméabilité = -j effectives complexes sous contrainte uniaxiale dans le domaine micro-onde (0.1 - 6 GHz) à la température ambiante. On analyse les spectres de et de . En confrontant les données expérimentales de avec plusieurs comportements de relaxation diélectrique, on trouve qu un seul mécanisme de relaxation ne permet pas de comprendre entierement la physique. On continue en montrant que le mécanisme de résonance de spin gyromagnétique est,le mécanisme d aimantation approprié. On combine la théorie du champ moyen de Bruggeman et le modèle de Landau-Lifshitz-Gilbert (B-LLG) pour reproduire les caractéristiques expérimentales de la perméabilité magnétique effective complexe. Ces conclusions sont discutées à la lumière de la polydispersion, en taille des grains de ferrites contenus dans les PFs. Les études de l aimantation statique à partir d un magnétomètre à échantillon vibrant (VSM) sont en accord avec ce modèle (B-LLG). De plus, l analyse montre aussi comment les PFs aimantés se comportent avec les ondes électromagnétiques, et on évalue l hystérésis de et de . Plus important, on montre que les mesures et sous contrainte peuvent être décrites par un Modèle du Réseau d Elasticité de Chaînes Gaussiennes (MRECG) dans la limite de faible contrainte. Puis, l évàlutionfréquentielle du spectre d absorption des plasto-ferrites et des composites copolyméres d Ethyléne-co-Acrylate de Butyle (EAB) chargés en noir de carbone soumis à une contrainte uniaxiale a montré un spectre d absorption présentant deux pics avec deux composantes larges et symétriques. Enfin, lors de l étude de vieillissement mécanique, le résultat principal est l observation d un vieillissement qui se produit en trois étapes avec des variations de en ln(t). Les résultats présentés ont d importantes applications dans des matériaux composites magnétoactif intellignts, par exemple la technologie de circuit flexible dans l industrie électronique (capteurs, systèmes actifs et systèmes micromécaniques), mise au point de peau et muscles artificiels pour des applications dans la robotique.The impetus of this work was to investigate tbe electromagnetic and tensile properties of several commercially available plasto-ferrites (PFs) at ambient conditions, The approach involved selection of a set of PFs, and measuring their complex effective permittivity = -j and permeability = -j under uniaxial stress at microwave frequencies (0.1 - 6 GHz) and room temperature. We analyze the and spectra for tensilely strained PFs. Comparing our experimental data against several dielectric relaxational behaviors. we find that the main physics cannot be understood with a single relaxation mechanism. We then go on to consider the magnetic permeahility spectra in the microwave range of frequencies and show that an appropriate magnetization mechanism is given by the gyroinagnetic spin resonance mechanism. We use a combination of Bruggeman mean field analysis and Landau-Lifshitz-Cilbert (SBG) modeling to reproduce the experimental bimodal line-shape characteristics of the effective complex magnetic permeability. Thesé flndings are discussed in light of the polydispersity in size of the ferrites gains contained in the PFs. Tbe vibrating sample magnetometry investigations of the static magnetization are found to be consistent with this modeling. In addition, the analysis shows also bow magnetized PFs respond to electromagnetic waves, and we evaluate the hysteretic behavior of and . More importantly we show that the and measurements under stress can be explained in terms of a Gaussian molecular network model in the limit of low stress (GMNM). Then, the evolution of the frequency-dependent absorption spectra for plasto-ferrites and carbon black-filled ethylene butylacrylate (EBA) copolymer composites subjected to a uniaxial tension show one absorption spectrum bas a doublepeaked structure with two broad and symmetrical components. Finally, aging phenomena, the key achievement is that we present observational evidence for a three-stage aging with e change as the ln(t). The present results have important applications in magnetoactive smart composite materials, e.g. flexible circuit technology in the electronics industry (sensors, actuators and micromechanical systems), functionahzed artiflcial skin and muscles for robotic applications.BREST-BU Droit-Sciences-Sports (290192103) / SudocSudocFranceF

Electromagnetomechanical coupling characteristics of plastoferrites

International audienc

Mitogen activated protein kinase phosphatase-1 prevents the development of tactile sensitivity in a rodent model of neuropathic pain

<p>Abstract</p> <p>Background</p> <p>Neuropathic pain due to nerve injury is one of the most difficult types of pain to treat. Following peripheral nerve injury, neuronal and glial plastic changes contribute to central sensitization and perpetuation of mechanical hypersensitivity in rodents. The mitogen activated protein kinase (MAPK) family is pivotal in this spinal cord plasticity. MAPK phosphatases (MKPs) limit inflammatory processes by dephosphorylating MAPKs. For example, MKP-1 preferentially dephosphorylates p-p38. Since spinal p-p38 is pivotal for the development of chronic hypersensitivity in rodent models of pain, and p-p38 inhibitors have shown clinical potential in acute and chronic pain patients, we hypothesize that induction of spinal MKP-1 will prevent the development of peripheral nerve-injury-induced hypersensitivity and p-p38 overexpression.</p> <p>Results</p> <p>We cloned rat spinal cord MKP-1 and optimize MKP-1 cDNA <it>in vitro</it> using transfections to BV-2 cells. We observed that in vitro overexpression of MKP-1 blocked lipopolysaccharide-induced phosphorylation of p38 (and other MAPKs) as well as release of pro-algesic effectors (i.e., cytokines, chemokines, nitric oxide). Using this cDNA MKP-1 and a non-viral, <it>in vivo</it> nanoparticle transfection approach, we found that spinal cord overexpression of MKP-1 prevented development of peripheral nerve-injury-induced tactile hypersensitivity and reduced pro-inflammatory cytokines and chemokines and the phosphorylated form of p38.</p> <p>Conclusions</p> <p>Our results indicate that MKP-1, the natural regulator of p-p38, mediates resolution of the spinal cord pro-inflammatory milieu induced by peripheral nerve injury, resulting in prevention of chronic mechanical hypersensitivity. We propose that MKP-1 is a potential therapeutic target for pain treatment or prevention.</p