Go East! I mercati adriatici come bacino di collaborazione e opportunit\ue0 di internazionalizzazione per le PMI del Nord Est

e Piccole e Medie Imprese (PMI) che approcciano i mercati internazionali risultano condizionate da almeno due fattori inibitori: la cosiddetta \u201cliability of foreigness\u201d \u2013 con cui si intende la scarsa conoscenza degli usi, costumi, delle leggi e delle istituzioni che caratterizzano un determinato mercato \u2013 e la \u201cliability of smallness\u201d. Quest\u2019ultima \u2013 anche intesa come \u201cvincolo dimensionale\u201d e pertanto riferita alla limitata disponibilit\ue0 di risorse e competenze a supporto dei processi di internazionalizzazione \u2013 rappresenta a detta di molti uno dei principali fattori che limitano il processo di espansione internazionale della piccola impresa

Novel Insights into RAD52’s Structure, Function, and Druggability for Synthetic Lethality and Innovative Anticancer Therapies

Simple Summary Human RAD52 is a non-essential DNA/RNA-binding protein thought to be involved in many DNA repair mechanisms. Initially regarded as having a major role only in error-prone backup DNA repair mechanisms, RAD52 has recently gained attention because its inhibition induces synthetic lethality in cancer cells with an inactivated homologous recombination pathway (for error-free double-strand-break repair). RAD52 is thus a potential target to overcome resistance and unwanted side effects. Unfortunately, researchers still lack detailed structural and mechanistic information on RAD52 and have identified only a limited number of inhibitors, none of which are in the preclinical phase. This review summarizes the current knowledge on RAD52, highlighting the potential of its inhibition. This review also discusses the critical gaps in knowledge and sets out future directions for effective campaigns to discover RAD52 inhibitors. In recent years, the RAD52 protein has been highlighted as a mediator of many DNA repair mechanisms. While RAD52 was initially considered to be a non-essential auxiliary factor, its inhibition has more recently been demonstrated to be synthetically lethal in cancer cells bearing mutations and inactivation of specific intracellular pathways, such as homologous recombination. RAD52 is now recognized as a novel and critical pharmacological target. In this review, we comprehensively describe the available structural and functional information on RAD52. The review highlights the pathways in which RAD52 is involved and the approaches to RAD52 inhibition. We discuss the multifaceted role of this protein, which has a complex, dynamic, and functional 3D superstructural arrangement. This complexity reinforces the need to further investigate and characterize RAD52 to solve a challenging mechanistic puzzle and pave the way for a robust drug discovery campaign

Differential inflammation-mediated function of prokineticin 2 in the synovial fibroblasts of patients with rheumatoid arthritis compared with osteoarthritis

Prokineticin 2 (PK2) is a secreted protein involved in several pathological and physiological processes, including the regulation of inflammation, sickness behaviors, and circadian rhythms. Recently, it was reported that PK2 is associated with the pathogenesis of collagen-induced arthritis in mice. However, the role of PK2 in the pathogenesis of rheumatoid arthritis (RA) or osteoarthritis (OA) remains unknown. In this study, we collected synovial tissue, plasma, synovial fluid, and synovial fibroblasts (SF) from RA and OA patients to analyze the function of PK2 using immunohistochemistry, enzyme-linked immunosorbent assays, and tissue superfusion studies. PK2 and its receptors prokineticin receptor (PKR) 1 and 2 were expressed in RA and OA synovial tissues. PKR1 expression was downregulated in RA synovial tissue compared with OA synovial tissue. The PK2 concentration was higher in RA synovial fluid than in OA synovial fluid but similar between RA and OA plasma. PK2 suppressed the production of IL-6 from TNFα-prestimulated OA-SF, and this effect was attenuated in TNFα-prestimulated RA-SF. This phenomenon was accompanied by the upregulation of PKR1 in OA-SF. This study provides a new model to explain some aspects underlying the chronicity of inflammation in RA

The antagonism of the prokineticin system counteracts bortezomib induced side effects: Focus on mood alterations

The development of neuropathy and of mood alterations is frequent after chemotherapy. These complications, independent from the antitumoral mechanism, are interconnected due to an overlapping in their processing pathways and a common neuroinflammatory condition. This study aims to verify whether in mice the treatment with the proteasome inhibitor bortezomib (BTZ), at a protocol capable of inducing painful neuropathy, is associated with anxiety, depression and supraspinal neuroinflammation. We also verify if the therapeutic treatment with the antagonist of the prokineticin (PK) system PC1, which is known to contrast pain and neuroinflammation, can prevent mood alterations. Mice were treated with BTZ (0.4 mg/kg three times/week for 4 weeks); mechanical allodynia and locomotor activity were evaluated over time while anxiety (dark light and marble burying test), depression (sucrose preference and swimming test) and supraspinal neuroinflammation were checked at the end of the protocol. BTZ treated neuropathic mice develop anxiety and depression. The presence of mood alterations is related to the presence of neuroinflammation and PK system activation in prefrontal cortex, hippocampus and hypothalamus with high levels of PK2 and PKR2 receptor, IL‐6 and TNF‐α, TLR4 and an upregulation of glial markers. PC1 treatment, counteracting pain, prevented the development of supraspinal inflammation and depression‐like behavior in BTZ mice

Concentration for One and Two Species One-Dimensional Reaction-Diffusion Systems

We look for similarity transformations which yield mappings between different one-dimensional reaction-diffusion processes. In this way results obtained for special systems can be generalized to equivalent reaction-diffusion models. The coagulation (A + A -> A) or the annihilation (A + A -> 0) models can be mapped onto systems in which both processes are allowed. With the help of the coagulation-decoagulation model results for some death-decoagulation and annihilation-creation systems are given. We also find a reaction-diffusion system which is equivalent to the two species annihilation model (A + B ->0). Besides we present numerical results of Monte Carlo simulations. An accurate description of the effects of the reaction rates on the concentration in one-species diffusion-annihilation model is made. The asymptotic behavior of the concentration in the two species annihilation system (A + B -> 0) with symmetric initial conditions is studied.Comment: 20 pages latex, uuencoded figures at the en

Complete Exact Solution of Diffusion-Limited Coalescence, A + A -> A

Some models of diffusion-limited reaction processes in one dimension lend themselves to exact analysis. The known approaches yield exact expressions for a limited number of quantities of interest, such as the particle concentration, or the distribution of distances between nearest particles. However, a full characterization of a particle system is only provided by the infinite hierarchy of multiple-point density correlation functions. We derive an exact description of the full hierarchy of correlation functions for the diffusion-limited irreversible coalescence process A + A -> A.Comment: 4 pages, 2 figures (postscript). Typeset with Revte

Outbreak of Leptospira borgpetersenii serogroup Sejroe infection in kennel: the role of dogs as sentinel in specific environments

Kennels may represent high-risk environments for the diffusion of Leptospira infection in dogs and consequently a threat to public health. This study describes an outbreak of Leptospira infection in a kennel in Italy in 2020, both with clinically ill and asymptomatic dogs. Fifty-nine dogs, including three ill dogs, were tested for Leptospira spp. infection by the microscopic agglutination test (MAT) and real-time qPCR. Multi-locus sequence typing (MLST) analysis was used to genotype the identified leptospires. Thirty of the fifty-nine (50.9%) dogs had MAT titer and/or molecular positivity indicative of Leptospira infection. Twenty-two of the fifty-nine (37.3%) dogs exhibited seropositivity against at least one serovar belonging to the Sejroe serogroup, and MLST analysis identified L. borgpetersenii serogroup Sejroe (Leptospira ST155) as responsible for the outbreak. Up to now, Sejroe serogroup infection was sporadically reported in dogs. The extension of the MAT antigen panel to several serovars belonging to the serogroup Sejroe could be useful in the diagnosis of canine leptospirosis. Dogs may serve as sentinel of leptospires in specific environments, and surveillance of Leptospira infection in kennels is strongly recommended even when the correct vaccine prophylaxis is administered, because the vaccines currently available are not able to protect from all of the serogroups

On the universality of a class of annihilation-coagulation models

A class of $d$-dimensional reaction-diffusion models interpolating continuously between the diffusion-coagulation and the diffusion-annihilation models is introduced. Exact relations among the observables of different models are established. For the one-dimensional case, it is shown how correlations in the initial state can lead to non-universal amplitudes for time-dependent particles density.Comment: 18 pages with no figures. Latex file using REVTE

Identification of RAD51-BRCA2 Inhibitors Using N-Acylhydrazone-Based Dynamic Combinatorial Chemistry

RAD51 is an ATP-dependent recombinase, recruited by BRCA2 to mediate DNA double-strand breaks repair through homologous recombination and represents an attractive cancer drug target. Herein, we applied for the first-time protein-templated dynamic combinatorial chemistry on RAD51 as a hit identification strategy. Upon design of N-acylhydrazone-based dynamic combinatorial libraries, RAD51 showed a clear templating effect, amplifying 19 N-acylhydrazones. Screening against the RAD51-BRCA2 protein-protein interaction via ELISA assay afforded 10 inhibitors in the micromolar range. Further 19F NMR experiments revealed that 7 could bind RAD51 and be displaced by BRC4, suggesting an interaction in the same binding pocket of BRCA2. These results proved not only that ptDCC could be successfully applied on full-length oligomeric RAD51, but also that it could address the need of alternative strategies toward the identification of small-molecule PPI inhibitors