Mechanistic models of α\alpha-synuclein homeostasis for Parkinson's disease: A blueprint for therapeutic intervention

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, yet there is no disease-modifying therapy up to this date. The biological complexity underlying PD hampers the investigation of the principal contributors to its pathogenesis. In this context, mechanistic models grounded in molecular-level knowledge provide virtual labs to uncover the primary events triggering PD onset and progression and suggest promising therapeutic targets. Multiple modeling efforts in PD research have focused on the pathological role of $\alpha$-synuclein ($\alpha$syn), a presynaptic protein that emerges from the intricate molecular network as a crucial driver of neurodegeneration. Here, we collect the advances in mathematical modeling of $\alpha$syn homeostasis, focusing on aggregation and degradation pathways, and discussing potential modeling improvements and possible implications in PD therapeutic strategy design

Vulnerabilità in migrazione: sguardi critici su asilo e protezione internazionale in Italia

In the political and legal debate on migration and asylum there is a growing emphasis on situations of vulnerability, and the concept of ‘vulnerability’ plays an increasingly central role in migration policies. However, the issue is often addressed in reductive or instrumental ways. Through a selection of interdisciplinary contributions from the conference “Vulnerability in Migration” (Venice 2023) and the results from Italy in the H2020 research project VULNER – Vulnerabilities Under the Global Protection Regime, the volume provides tools for understanding the multiple dimensions at play, interrogating rights, policies, discourses, and social practices

Synthesis and spectroscopic/DFT structural characterization of coordination compounds of Nb(V) and Ti(IV) with bioactive carboxylic acids

The reactions are reported of NbX5(X = Cl, Br), TiCl4and Ti(OiPr)4with a selection of carboxylic acids exhibiting a known biological role, in a chlorinated solvent. The reactions of NbX5with acetylsalicylic acid (aspirin) proceeded with selective deacetylation of the organic reactant and formation of the salicylate complexes NbX4(C7H5O3) (1a, X = Cl; 1b, X = Br) in 60–65% yields. NbCl5reacted with diclofenac and ethacrynic acid (EA-CO2H) to give NbCl3[κ3O,O,N-O2CCH2(C6H4)NC6H3Cl2], 2 (80% yield), and NbCl4(O2C-EA), 3 (72% yield), respectively. Ti(OiPr)4reacted with ethacrynic acid giving Ti(OiPr)2(O2C-EA)2, 4, in 74% yield, as a mixture of two isomers. All the products were characterized by means of analytical and spectroscopic methods, moreover DFT studies were carried out to give insight into structural features

Lipoaspirate Shows In Vitro Potential for Wound Healing

Mesenchymal stem cells (MSCs) are a promising therapy in wound healing, although extensive time and manipulation are necessary for their use. In our previous study on cartilage regeneration, we demonstrated that lipoaspirate acts as a natural scaffold for MSCs and gives rise to their spontaneous outgrowth, together with a paracrine effect on resident cells that overcome the limitations connected to MSC use. In this study, we aimed to investigate in vitro whether the microfragmented adipose tissue (lipoaspirate), obtained with Lipogems® technology, could promote and accelerate wound healing. We showed the ability of resident cells to outgrow from the clusters of lipoaspirate encapsulated in a 3D collagen substrate as capability of repopulating a culture of human skin. Moreover, we demonstrated that the in vitro lipoaspirate paracrine effect on fibroblasts and keratinocytes proliferation, migration, and contraction rate is mediated by the release of trophic/reparative proteins. Finally, an analysis of the paracrine antibacterial effect of lipoaspirate proved its ability to secrete antibacterial factors and its ability to modulate their secretion in culture media based on a bacterial stimulus. The results suggest that lipoaspirate may be a promising approach in wound healing showing in vitro regenerative and antibacterial activities that could improve current therapeutic strategies

A general strategy to add diversity to ruthenium arene complexes with bioactive organic compounds: Via a coordinated (4-hydroxyphenyl)diphenylphosphine ligand

Esterification of (4-hydroxyphenyl)diphenylphosphine, coordinated to the [Ru(η6-p-cymene)Cl2] fragment, allows a series of bioactive carboxylic acids to be introduced directly into the organometallic molecule. Evaluation of the compounds on human ovarian cancer cells reveals synergistic enhancements in their antiproliferative activity relative to their bioactive organic and organometallic precursors

Mechanistic models of α-synuclein homeostasis for Parkinson's disease: A blueprint for therapeutic intervention

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, yet there is no disease-modifying therapy up to this date. The biological complexity underlying PD hampers the investigation of the principal contributors to its pathogenesis. In this context, mechanistic models grounded in molecular-level knowledge provide virtual labs to uncover the primary events triggering PD onset and progression and suggest promising therapeutic targets. Multiple modeling efforts in PD research have focused on the pathological role of α-synuclein (αsyn), a presynaptic protein that emerges from the intricate molecular network as a crucial driver of neurodegeneration. Here, we collect the advances in mathematical modeling of αsyn homeostasis, focusing on aggregation and degradation pathways, and discussing potential modeling improvements and possible implications in PD therapeutic strategy design

The Use of Statins as an Adjunctive Periodontal Disease Treatment: Systematic Review and Meta-Analysis

Background: the purpose of this systematic review was to assess the clinical and radiographic effect of subgingival-administered statins as an adjunct periodontal treatment in patients with periodontitis. Methods: Electronic literature searches in Medline/PubMed and the Cochrane Library were conducted to identify all relevant articles. Eligibility was based on inclusion criteria which included Randomized Controlled Trials (RCTs) published after 2010, where the periodontal variables were assessed before and after periodontal treatment in combination with a statin administration. The risk of bias was assessed with the ROBINS-2 tool. The outcome variables were probing depth, clinical attachment level, bleeding on probing, and bone fill in systematically healthy patients, patients with type 2 diabetes, and smokers. Results: Out of 119 potentially eligible articles, 18 randomized controlled trials were included with a total of 1171 participants. The data retrieved from the meta-analysis showed the positive effect that statins have as an adjunctive periodontal disease treatment. When comparing the different types of statins, the PD reduction in the Simvastatin group was significantly higher than the Atorvastatin group at 6 months and at 9 months, while no differences between statins were found for the rest of the outcomes. Over 66% of the articles presented an overall risk of bias with some concerns, making this a limitation of this present RCT. Conclusions: The adjunct administration of statins has proven to have a positive effect on the periodontium by improving both clinical and radiographic parameters by a considerable margin

The stable repression of mesenchymal program is required for hepatocyte identity: A novel role for hepatocyte nuclear factor 4α

The concept that cellular terminal differentiation is stably maintained once development is complete has been questioned by numerous observations showing that differentiated epithelium may undergo an epithelial-to-mesenchymal transition (EMT) program. EMT and the reverse process, mesenchymal-to-epithelial transition (MET), are typical events of development, tissue repair, and tumor progression. In this study, we aimed to clarify the molecular mechanisms underlying these phenotypic conversions in hepatocytes. Hepatocyte nuclear factor 4α (HNF4α) was overexpressed in different hepatocyte cell lines and the resulting gene expression profile was determined by real-time quantitative polymerase chain reaction. HNF4α recruitment on promoters of both mesenchymal and EMT regulator genes was determined by way of electrophoretic mobility shift assay and chromatin immunoprecipitation. The effect of HNF4α depletion was assessed in silenced cells and in the context of the whole liver of HNF4 knockout animals. Our results identified key EMT regulators and mesenchymal genes as new targets of HNF4α. HNF4α, in cooperation with its target HNF1α, directly inhibits transcription of the EMT master regulatory genes Snail, Slug, and HMGA2 and of several mesenchymal markers. HNF4α-mediated repression of EMT genes induces MET in hepatomas, and its silencing triggers the mesenchymal program in differentiated hepatocytes both in cell culture and in the whole liver. Conclusion: The pivotal role of HNF4α in the induction and maintenance of hepatocyte differentiation should also be ascribed to its capacity to continuously repress the mesenchymal program; thus, both HNF4α activator and repressor functions are necessary for the identity of hepatocytes. Copyright © 2011 American Association for the Study of Liver Diseases

Identifying the factors that influence surgeon's compliance with excisional margins of non-melanoma skin cancer

The rising incidence of Non Melanoma Skin Cancers (NMSC) leads to a high number of surgical procedures worldwide. The strict compliance with international guidelines with regard to excisional margins may help decrease the number of re-excision procedures and reduce the risk of NMSC recurrence. The aim of this study was to investigate the prevalence of excisional margins as recommended by the European Academy of Dermatology and Venereology (EADV) and the European Dermatology Forum (EDF) guidelines, and the factors (demographic or clinical) that influence surgeons' compliance with these guidelines.This was a prevalence study looking at surgical excisions of NMSCs performed over a period of 2 years (2011-2012). A sample size of 1669 patients was considered. Definition of excisional margins recommended by the international guidelines (EADV and EDF) were used as point of reference for the analysis. Tumor and histologic specimen size were calculated ex vivo by 5 different pathologists. The size of skin specimens was measured with a major axis and a minor axis. The same was done for the tumor present on the skin specimens. The differences between the major and minor axes of surgical specimen and tumor were calculated. These differences were subsequently divided by two, hypothesizing that the lesion had the same distance from the margins of the surgical specimen. The differences obtained were named "Delta", the formulas applied being the following: Delta major = (major axis specimen-major axis tumor)/2; Delta minor = (minor axis specimen -minor axis tumor)/2.Results show a significant statistical difference, associated with factors such as: Age of the patient, anatomical localization of the tumor, histological diagnosis, and surgeons' experience.The identification of these factors sheds light on clinicians' practice and decision-making regarding excisional margins. Hopefully a higher level of adherence to the guidelines can be achieved in the future