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Background: Recent studies analyzed the impact of Merkel cell polyomavirus (MCPyV) on the prognosis of Merkel cell carcinoma (MCC) patients. No data on specific morphological clinical differences of MCPyV+ or MCPyV- are currently available neither on the possible prognostic implication of different clinical presentation of MCC., Objectives: 1) to describe clinicopathological characteristics of MCC patients and the prevalence of MCPyV infection in an Italian cohort of patients; 2) to define possible differences in clinicopathological and prognostic features among MCPyV+ and MCPyV- MCCs., Methods: Retrospective, multicenter, cohort study conducted in two Italian tertiary referral centers. MCPyV presence was detected by immunohistochemistry (IHC) and PCR with two different primers amplifying VP1 (VP1-PCR) and LT viral region (LT-PCR). Clinicopathological features were compared between MCPyV+ and MCPyV- tumors and between red exophytic nodules and subcutaneous cyst-like MCCs., Results: 62 MCCs were included, presenting as red exophytic nodules (69.3%) or with a subcutaneous cyst-like appearance (19.3%); MCPyV was detected in 40.3% of cases by IHC, 56.4% by VP1-PCR and 79% by LT-PCR. No correlation was found between clinical morphology and viral status. Mortality rate was 40.8% for MCPyV- and 23.1% for MCPyV+ (p-value 0.239) and 69.8% for red nodules and 25% for cyst-like lesions (p-value 0.005). By multivariable analysis, age at diagnosis, ki67 and treatment with surgery/radiotherapy remained the only factors significantly affecting the OS., Conclusions: This study highlights the potential impact of clinical morphology of MCCs on prognosis. Subcutaneous cyst-like morphology may provide a survival benefit to the patients, regardless the presence of MCPyV., (© The Author(s) 2025. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aim: This review aims to explore the clinical applications, biological mechanisms, and potential benefits of concentrated growth factors (CGFs), autologous materials, and xenografts in bone regeneration, particularly in dental treatments such as alveolar ridge preservation, mandibular osteonecrosis, and peri-implantitis., Materials and Methods: A systematic literature search was conducted using databases like PubMed, Scopus, and Web of Science, with keywords such as "bone regeneration" and "CGF" from 2014 to 2024. Only English-language clinical studies involving human subjects were included. A total of 10 studies were selected for qualitative analysis. Data were processed through multiple stages, including title and abstract screening and full-text evaluation., Conclusion: The findings of the reviewed studies underscore the potential of the CGF in enhancing bone regeneration through stimulating cell proliferation, angiogenesis, and extracellular matrix mineralization. Autologous materials have also demonstrated promising results due to their biocompatibility and capacity for seamless integration with natural bone tissue. When combined with xenografts, these materials show synergistic effects in improving bone quantity and quality, which are crucial for dental implant success. Future research should focus on direct comparisons of different techniques, the optimization of protocols, and broader applications beyond dental medicine. The integration of CGFs and autologous materials into routine clinical practice represents a significant advancement in regenerative dental medicine, with the potential for improved patient outcomes and satisfaction.

Background : The aim of this systematic review was to evaluate the clinical efficacy, benefits, and limitations of piezosurgery in tooth extractions compared to conventional methods. Piezosurgery has emerged as a minimally invasive alternative, promoting better preservation of soft tissues and bone structures. Understanding its impact on postoperative outcomes such as pain, swelling, trismus, and bone healing is critical for its application in oral surgery; Materials and Methods: We restricted our search to English-language articles published between 1 January 2004 and 28 August 2024, in PubMed, Scopus, and Web of Science. The Boolean search keywords "piezosurgery AND tooth extraction" were used. Results: A total of 983 articles were identified, and after duplicates were removed, 766 studies were screened. Following the application of inclusion and exclusion criteria, seven articles were selected for qualitative analysis. Conclusions: The literature suggests that piezosurgery offers advantages, such as reduced postoperative pain, swelling, and trismus, despite longer surgical times compared to conventional methods. While piezosurgery shows promise for improved patient comfort and soft tissue preservation, further research is required to validate its long-term impact on bone healing and regeneration.

The infraocclusion (IO) of primary molars, often seen in retained deciduous teeth, is a common condition that presents significant challenges for pediatric oral health. It occurs when primary molars are positioned below the occlusal plane due to the absence of permanent successors, leading to complications such as misaligned teeth, impaired chewing, and long-term dental health issues., Objectives: This study examines IO prevalence, diagnosis, and treatment approaches., Methods: A systematic review following PRISMA guidelines was conducted, searching PubMed, Web of Science, and Scopus for articles from the last 15 years. Nine articles were included for qualitative analysis., Results: IO was associated with several complications, including root resorption, altered eruption of adjacent teeth, and space loss within the dental arch. Clinical and radiographic evaluations are key to early detection. Severe cases often require invasive treatments, such as tooth extraction and space maintenance, while mild cases could be monitored., Conclusions: IO is prevalent in pediatric dentistry and can lead to significant dental issues if untreated. Early detection and intervention are crucial for preventing complications like tooth misalignment and impacted premolars. Tailored treatment strategies based on severity, along with increased awareness among dental practitioners, are essential to improve long-term outcomes for affected children.

The investigation's goal was to obtain further knowledge about the connection between Herpes Zoster infection and dentistry therapy for the osteonecrosis of the jaws, combining the review with a case report relevant to the purpose. It is important to study this association because it is a possible additional factor to be considered in the causes of the osteonecrosis of the jaws. We limited our search to English-language papers published between 1 January 2004 and 7 June 2024 in PubMed, Scopus, and Web of Science that were relevant to our topic. In the search approach, the Boolean keywords "Herpes Zoster AND osteonecros*" were used. Results: This study analyzed 148 papers from Web of Science, PubMed, and Scopus, resulting in 95 articles after removing duplicates. Of these, 49 were removed because they were off topic, and 46 were confirmed. This study includes a qualitative analysis of the final 12 articles, removing 34 articles that were off topic. The literature highlights severe oral complications from Herpes Zoster reactivation, emphasizing the need for early diagnosis, comprehensive management, and multidisciplinary care. Treatment strategies include antiviral therapy, pain management, surgical debridement, and antibiotics. Immunocompromised individuals require vigilant monitoring and balanced immunosuppressive therapy. Further research is needed to enhance therapeutic approaches.

The objective of this review is to identify the microbiological alterations caused by various therapy modalities by critically analyzing the current findings. We limited our search to English-language papers published between 1 January 2004 and 7 May 2024 in PubMed, Scopus, and Web of Science that were relevant to our topic. In the search approach, the Boolean keywords "microbio*" AND "periodontitis" were used. A total of 5152 papers were obtained from the databases Web of Science (2205), PubMed (1793), and Scopus (1154). This resulted in 3266 articles after eliminating duplicates (1886), and 1411 entries were eliminated after their titles and abstracts were examined. The qualitative analysis of the 22 final articles is included in this study. Research on periodontal disease shows that periodontitis alters the oral microbiome and increases antibiotic resistance. Treatments like scaling and root planing (SRP), especially when combined with minocycline, improve clinical outcomes by reducing harmful bacteria. Comprehensive mechanical debridement with antibiotics, probiotics, EMD with bone grafts, and other adjunctive therapies enhances periodontal health. Personalized treatment strategies and advanced microbial analyses are crucial for effective periodontal management and antibiotic resistance control.

Poor school performance may increase the risk of crime and violence via effects on self-esteem, risky behaviours, peer networks, and perceived stakes in society. Despite very high rates of violence in Latin America, no longitudinal research has addressed this issue in the region. Two aspects of educational performance (grade repetition and school completion) were examined during adolescence in a population-based Brazilian birth cohort study ( n  = 3584). Violent and non-violent crime were measured at age 22 years in confidential self-reports; sociodemographic, family, and individual confounders were measured between birth and age 11 years, and potential mediators were measured at age 18 years. The prevalence of violent and non-violent crimes at 22 years was 8.2% and 3.3%, respectively, referring to acts in the previous twelve months. For youth repeating school grades three times or more, the odds of violent crime were 2.4 (95%CI: 1.6-3.6) times higher than for those who had not repeated any school grade. Youth completing school had a lower risk for both violent (OR = 0.5; 95%CI: 0.4-0.7) and non-violent crime (OR = 0.3; 95%CI: 0.2-0.5), compared to those who did not finish school by the expected age. The protective effect of completing school was independent of the number of grades previously repeated. In conclusion, repeating school grades was associated with increased risk for crime; however, successfully managing to complete school by the expected age was an important protective factor against crime, even after multiple grade repetitions., Supplementary Information: The online version contains supplementary material available at 10.1007/s40865-022-00214-x., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s) 2022.)

Functional rescue of NK-cells in solid tumors represents a central aim for new immunotherapeutic strategies. We have conducted a genomic, phenotypic and functional analysis of circulating NK-cells from patients with HCV-related liver cirrhosis and hepatocellular carcinoma. NK-cells were sorted from patients with HCC or liver cirrhosis and from healthy donors. Comparative mRNA gene expression profiling by whole-human-genome microarrays of sorted NK-cells was followed by phenotypic and functional characterization. To further identify possible mediators of NK-cell dysfunction, an in vitro model using media conditioned with patients' and controls' plasma was set up. Metabolic and cell motility defects were identified at the genomic level. Dysregulated gene expression profile has been translated into reduced cytokine production and degranulation despite a prevalent phenotype of terminally differentiated NK-cells. NKG2D-downregulation, high SMAD2 phosphorylation and other phenotypic and molecular alterations suggested TGF-β as possible mediator of this dysfunction. Blocking TGF-β could partially restore functional defects of NK-cells from healthy donors, exposed to TGF-β rich HCC patients' plasma, suggesting that TGF-β among other molecules may represent a suitable target for immunotherapeutic intervention aimed at NK-cell functional restoration. By an unbiased approach, we have identified energy metabolism and cell motility defects of circulating NK-cells as main mechanisms responsible for functional NK-cell impairment in patients with hepatocellular carcinoma. This opens the way to test different approaches to restore NK-cell response in these patients.

Background: More than 30 causative genes have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS). The next-generation sequencing (NGS) is a powerful and groundbreaking tool to identify disease-associated variants. Despite documented advantages of NGS, its diagnostic reliability needs to be addressed in order to use this technology for specific routine diagnosis., Material and Methods: Literature database was explored to identify studies comparing NGS and Sanger sequencing for the detection of variants causing ALS. We collected data about patients' characteristics, disease type and duration, NGS and Sanger properties., Results: More than 200 bibliographic references were identified, of which only 14 studies matching our inclusion criteria. Only 2 out of 14 studies compared results of NGS analysis with the Sanger sequencing. Twelve studies screened causative genes associated to ALS using NGS technologies and confirmed the identified variants with Sanger sequencing. Overall, data about more 2,000 patients were analysed. The number of genes that were investigated in each study ranged from 1 to 32, the most frequent being FUS, OPTN, SETX and VCP. NGS identified already known mutations in 21 genes, and new or rare variants in 27 genes., Conclusions: NGS seems to be a promising tool for the diagnosis of ALS in routine clinical practice. Its advantages are represented by an increased speed and a lowest sequencing cost, but patients' counselling could be problematic due to the discovery of frequent variants of unknown significance., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation.)

The mechanisms whereby autoreactive T cells escape peripheral tolerance establishing thus autoimmune diseases in humans remain an unresolved question. Here, we demonstrate that autoreactive polyfunctional CD8 + T cells recognizing self-antigens (i.e., vimentin, actin cytoplasmic 1, or non-muscle myosin heavy chain 9 epitopes) with high avidity, counter-regulate Tregs by killing them, in a consistent percentage of rheumatoid arthritis (RA) patients. Indeed, these CD8 + T cells express a phenotype and gene profile of effector (eff) cells and, upon antigen-specific activation, kill Tregs indirectly in an NKG2D-dependent bystander fashion in vitro. This data provides a mechanistic basis for the finding showing that AE-specific (CD107a + ) CD8 + T killer cells correlate, directly with the disease activity score, and inversely with the percentage of activated Tregs, in both steady state and follow-up studies in vivo. In addition, multiplex immunofluorescence imaging analyses of inflamed synovial tissues in vivo show that a remarkable number of CD8 + T cells express granzyme-B and selectively contact FOXP3 + Tregs, some of which are in an apoptotic state, validating hence the possibility that CD8 + Teff cells can counteract neighboring Tregs within inflamed tissues, by killing them. Alternatively, the disease activity score of a different subset of patients is correlated with the expansion of a peculiar subpopulation of autoreactive low avidity, partially-activated (pa)CD8 + T cells that, despite they conserve the conventional naïve (N) phenotype, produce high levels of tumor necrosis factor (TNF)-α and exhibit a gene expression signature of a progressive activation state. Tregs directly correlate with the expansion of this autoreactive (low avidity) paCD8 + TN cell subset in vivo, and efficiently control their differentiation rather their proliferation in vitro. Interestingly, autoreactive high avidity CD8 + Teff cells or low avidity paCD8 + TN cells are significantly expanded in RA patients who would become non-responders or patients who would become responders to TNF-α inhibitor therapy, respectively. These data provide evidence of a previously undescribed role of such mechanisms in the progression and therapy of RA., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The antitumor immune response may play a major role in the clinical outcome of hepatocellular carcinoma (HCC). We characterized the liver immune microenvironment by direct hybridization of RNA extracted from HCC and nontumorous tissues., Methods: RNA was extracted from frozen liver tissue samples of HCC (T; n = 30) and nontumorous tissues (NT; n = 33) obtained from 38 patients. Matched samples were available for 25 patients. The immune gene expression profile was analyzed with the nCounter GX Human Immunology v2 system (NanoString Technologies), which detects the expression levels of 579 immune response-related genes simultaneously., Results: Since the immune gene expression profile of T and NT tissues was significantly different, the prognostic relevance of the liver immune microenvironment was evaluated in the T and NT samples separately. Unsupervised clustering detected two main clusters of immune gene expression both in T and in NT liver samples. In both cases, the expression clusters identified groups of patients with a significantly different median time to HCC recurrence (TTR) but similar overall survival. Based on T tissue, two groups with median TTR of 19 and 127 months, respectively, were detected ( p < 0.005). Expression of genes related to T-cell activation was associated with longer TTR. The analysis of NT tissue discriminated subsets of patients with median TTR of 22 and 68 months ( p < 0.05). In contrast to T tissue, a predominant inflammatory immune environment was associated with shorter TTR., Conclusions: Immune gene expression profiles predictive of TTR could be identified both in HCC and in adjacent cirrhotic tissues. Longer TTR was associated with overexpression in T tissue and downregulation in NT tissue of the immune response and of inflammation-related genes.

Several clinical observations have demonstrated a link between heart rate and anxiety or panic disorders. In these patients, β-adrenergic receptor function was altered. This prompted us to investigate whether the β-adrenergic receptor agonist isoproterenol, at a dose that stimulates peripheral β-adrenergic system but has no effects at the central nervous system, can induce anxiety-like behavior in rats. Moreover, some possible messengers involved in the peripheral to brain communication were investigated. Our results showed that isoproterenol (5 mg kg(-1) i.p.) increased heart rate, evoked anxiety-like behavior, did not result in motor impairments and increased extracellular vesicle content in the blood. Plasma corticosterone level was unmodified as well as vesicular Hsp70 content. Vesicular miR-208 was also unmodified indicating a source of increased extracellular vesicles different from cardiomyocytes. We can hypothesize that peripheral extracellular vesicles might contribute to the β-adrenergic receptor-evoked anxiety-like behavior, acting as peripheral signals in modulating the mental state., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The effects of cocaine (150 nM, 300 nM, and 150 μM) on human glioblastoma cell cultures were studied on tunneling nanotube formation (1-h cocaine treatment) and extracellular vesicle release (1-, 3-, and 8-h cocaine treatment). Cocaine significantly increased the number of tunneling nanotubes only at the lowest concentration used. The release of extracellular vesicles (mainly exosomes) into the medium was stimulated by cocaine at each concentration used with a maximum effect at the highest concentration tested (150 μM). Moreover, cocaine (150 nM) significantly increased the number of vesicles with 61-80 nm diameter while at concentrations of 300 nM and 150 μM, and the smaller vesicles (30-40 nm diameter) were significantly increased with a reduction of the larger vesicles (41-60 nm diameter). A time dependence in the release of extracellular vesicles was observed. In view of the proposed role of these novel intercellular communication modes in the glial-neuronal plasticity, it seems possible that they can participate in the processes leading to cocaine addiction. The molecular target/s involved in these cocaine effects could be specific molecular components of plasma membrane lipid rafts and/or cocaine-induced modifications in cytoplasmic lipid composition.

The current view on the organization of the central nervous system (CNS) is basically anchored to the paradigm describing the brain as formed by networks of neurons interconnected by synapses. Synaptic contacts are a fundamental characteristic for describing CNS operations, but increasing evidence accumulated in the last 30 years pointed to a refinement of this view. A possible overcoming of the classical "neuroscience paradigm" will be here outlined, based on the following hypotheses: (1) the basic morpho-functional unit in the brain is a compartment of tissue (functional module) where different resident cells (not only neurons) work as an integrated unit; (2) in these complex networks, a spectrum of intercellular communication processes is exploited, that can be classified according to a dichotomous criterion: wiring transmission (occurring through physically delimited channels) and volume transmission (exploiting diffusion in the extracellular space); (3) the connections between cells can themselves be described as a network, leading to an information processing occurring at different levels from cell network down to molecular level; (4) recent evidence of the existence of specialized structures (microvesicles and tunneling nanotubes) for intercellular exchange of materials, could allow a further type of polymorphism of the CNS networks based on at least transient changes in cell phenotype. When compared to the classical paradigm, the proposed scheme of cellular organization could allow a strong increase of the degrees of freedom available to the whole system and then of its plasticity. Furthermore, long range coordination and correlation can be more easily accommodated within this framework.

Background: Carotid endarterectomy (CEA) is the gold standard for treating severe carotid artery stenosis, whereas carotid artery stenting (CAS) represents an endovascular alternative. The objective of this study was to assess the potential neural damage following open or endovascular carotid surgery measured by peripheral blood concentration of 3 biomarkers: S100β, matrix metalloproteinase-9 (MMP-9), and d-dimer., Methods: Data for this prospective investigation were obtained from the Carotid Markers study (January 2010-2011), which sought to measure the levels of specific biomarkers of neuronal damage and thrombosis on candidates to CEA or CAS presenting at the Department of Vascular Surgery of the Nuovo Ospedale S. Agostino Estense of Modena (Italy) at baseline and at 24 hr after surgery. Relevant medical comorbidities were noted., Results: A total of 113 consecutive patients were enrolled in the study, 41 in the endarterectomy group and 72 in the endovascular group. The baseline levels of the studied biomarkers did not show any statistically significant difference between the groups with the exception of MMP-9, which showed higher concentrations in the endovascular group (median 731 vs. 401, P = 0.0007), while 24 hr after surgery the endarterectomy group featured significantly higher peripheral blood concentrations of MMP-9, S100β, and d-dimer. Conversely, no significant difference was detected in the endovascular group except the d-dimer level., Conclusions: Neural damage biomarkers demonstrated a substantial difference between open and endovascular carotid surgery, which, if performed in selected patients, may become a less invasive alternative to CEA., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

The role of hyperhomocysteinemia (HHcy) as a cardiovascular risk factor remains a matter of debate, while it correlates with folates, it demonstrates inverse correlation with plasma homocysteine (Hcy) levels and vitamin B12 levels and reduces plasma Hcy levels following supplementation with multivitamins. The purpose of this study was to demonstrate that administering multivitamins at specific doses for 90 days restores normal plasma Hcy levels in women who are homozygous for the thermolabile variant of 5,10 methylenetetrahydrofolate reductase (MTHFR C677T). We enrolled 106 healthy females aged between 30 and 42 years, who were non-smokers, non-vegetarian, normotensive and who had no history of food abuse in the previous months. Only females were enrolled in order to rule out any bias due to the variation in Hcy plasma concentrations between males and females. Patient blood sampling was performed in order to determine plasma Hcy, serum folic acid and vitamin B12 levels. Furthermore, molecular characterization of the C677T polymorphism present in the MTHFR gene, was also performed. The results of this study demonstrated that supplementation with specific multivitamins restores normal plasma Hcy levels, regardless of the MTHFR genotype. Furthermore, it is unnecessary to adminster high doses of folate to reduce plasma Hcy levels, and administering high doses of folate may cause pro-inflammatory and pro-proliferative effects.

Conformational Protein Diseases (CPDs) comprise over forty clinically and pathologically diverse disorders in which specific altered proteins accumulate in cells or tissues of the body. The most studied are Alzheimerβ's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, inclusion body myopathy, and the systemic amyloidoses. They are characterised by three dimensional conformational alterations, which are often rich in β- structure. Proteins in this non-native conformation are highly stable, resistant to degradation, and have an enhanced tendency to aggregate with like protein molecules. The misfolded proteins can impart their anomalous properties to soluble, monomeric proteins with the same amino acid sequence by a process that has been likened to seeded crystallization. However, these potentially pathogenic proteins also have important physiological actions, which have not completely characterized. This opens up the question of what process transforms physiological actions into pathological actions and most intriguing, is why potentially dangerous proteins have been maintained during evolution and are present from yeasts to humans. In the present paper, we introduce the concept of mis-exaptation and of mis-tinkering since they may help in clarifying some of the double edged sword aspects of these proteins. Against this background an original interpretative paradigm for CPDs will be given in the frame of the previously proposed Red Queen Theory of Aging.

The effects of low and high concentrations of cocaine have been studied in vitro on the trafficking of plasma membrane A(2A) and D(2) immunoreactivities in previously characterized A(2A)-D(2) CHO cell lines. Receptor double immunofluorescence staining was performed with D(2) and A(2A) antibodies, planar lipid rafts immunolabeling with biotinylated cholera toxin subunit B and membrane invaginations with an anti-caveolin-1 antibody. A computer-assisted image analysis demonstrated a substantial and highly significant rise of membrane-associated D(2) immunoreactivity (IR) after 8 h of exposure to a low concentration of cocaine (150 nM). At this low concentration of cocaine, there was also an increase of membrane associated A(2A) immunoreactivity but smaller and less significant. However, this increase became considerably larger and highly significant at 150 microM at which concentration the rise of D(2) immunoreactivity had begun to disappear. It may be suggested that an allosteric action of cocaine at 150 nM on the D(2) receptors may primarily increase the insertion of D(2) monomers, homomers and also of a subpopulation of A(2A)-D(2) heteromers from the cytoplasm into the plasma membrane due to the conformational change induced by cocaine in the D(2) receptor. The planar lipid rafts and the caveolae are only affected by the higher concentrations of cocaine. It is proposed that changes in D(2) and A(2A)-D(2) trafficking induced by allosteric actions of cocaine at D(2) receptors may contribute to the alterations of D(2) signaling found in cocaine abusers.

A key event in Alzheimer's disease (AD) pathogenesis is the formation of insoluble peptides beta-amyloid aggregates and this process is favoured by a condition of hyperhomocysteinemia. To date, there is growing evidence that implicates glycosaminoglycans (GAGs) in the pathophysiology of amyloidosis but no data are available on the characterization of brain GAGs involved in the enhancing beta-amyloid fibrillogenesis in relationship to their structure and physico-chemical properties. Furthermore, few studies have been performed on the relationship between hyperhomocysteinemia and extracellular matrix (ECM) modifications. The aim of this study was to evaluate the amount and chemical structure of GAGs in rat striatal areas where beta-amyioid fibrillogenesis was induced, and in conditions of hyperhomocysteinemia. The intrastriatal injection of beta-amyloid produced a significant decrease (-40.8%) in the hyaluronic acid (HA) percentage and an increase (+14.5%) in the dermatan sulfate (DS) with a total charge density increasing of 14.9%. A significant decrease (-19.5%) in the HA percentage and an increase (+6.9%) in the DS % was also observed in striata obtained from the hyperhomocysteinemic animals. The total charge density increased by 6.8%. Quite the same trend was observed in rats after intrastriatal injection of beta-amyloid and in a condition of hyperhomocysteinemia. The observed increase of DS concentration and the correspondent decrease of the nonsulfated polymer HA after in vivo treatment with beta-amyloid and in a condition of hyperhocysteinemia support the hypothesis that an increase in local production of sulfated GAGs may reduce beta-amyloid neurotoxicity. However, the consequent modification of the ECM network might impair the extracellular diffusion pathways of different signal molecules and participate in the progression of AD.

A brief historical presentation of the hypothesis on receptor-receptor interactions as an important integrative mechanism taking place at plasma membrane level is given. Some concepts derived from this integrative mechanism especially the possible assemblage of receptors in receptor mosaics (high-order receptor oligomers) and their relevance for the molecular networks associated with the plasma membrane are discussed. In particular, the Rodbell's disaggregation theory for G-proteins is revisited in the frame of receptor mosaic model. The paper also presents some new indirect evidence on A2A;D2 receptor interactions obtained by means of Atomic Force Microscopy on immunogold preparations of A2A and D2 receptors in CHO cells. These findings support previous data obtained by means of computer-assisted confocal laser microscopy. The allosteric control of G-protein coupled receptors is examined in the light of the new views on allosterism and recent data on a homocysteine analogue capable of modulating D2 receptors are shown. Finally, the hypothesis is introduced on the existence of check-points along the amino acid pathways connecting allosteric and orthosteric binding sites of a receptor and their potential importance for drug development., (Copyright 2009 Elsevier Ltd. All rights reserved.)

The central nervous system (CNS) is a nested network at all levels of its organization. In particular, neuronal cellular networks (the neuronal circuits), interconnected to form neuronal systems, are formed by neurons, which operate thanks to their molecular networks. Proteins are the main components of the molecular networks and via protein-protein interactions can be assembled in multimeric complexes, which can work as micro-devices. On this basis, we have introduced the term "fractal logic" to describe networks of networks where at the various levels of the nested organization the same rules (logic) to perform operations are used. If this assumption is true, the description of the information handling at one of the nested levels sheds light on the way in which similar operations are carried out at other levels. This conceptual frame has been used to deduce from some features of neuronal networks the features of the molecular networks as far as modes for inter-node communication and their architecture. It should be noted that these features are such to allow a highly regulated cross-talk between signalling pathways, hence preserving selectivity and privacy. To investigate these aspects, the protein-protein interactions in beta2 Adrenergic Receptor (beta2AR) and Epidermal growth factor receptor (EGFR) signalling pathways have been analysed. The presence of disordered sequences in interacting domains can favour via the "fly-casting mechanism" protein-protein interactions, in addition it favours an induced-fitting rather than a lock-key type of interactions. Thus, by means of a computer assisted analysis the presence of disorder sequences in the main streams of the molecular networks that have beta2AR and EGFR as input proteins leading to MAP kinase activation has been evaluated.

Amyloid peptides (Abeta) are fragments of the Amyloid Precursor Protein (APP), an integral membrane protein. Abeta peptides are continuously generated by neurons and non-neuronal cells via sequential cleavage of APP by secretases. In particular, Abeta1-42 is the main component of the senile plaques associated with Alzheimer's disease (AD). Glial cells participate in the uptake of soluble extra-cellular Abeta and in the clearance of this material at localized sites where the Abeta are concentrated. It has been shown that clusterin (Apo J) and apolipoprotein E (ApoE) exert important additive effects in reducing Abeta deposition. In agreement with the fact that homocysteine (Hcy) potentiates Abeta peptide neurotoxicity, and Hcy brain levels increase with age, it has been demonstrated that high plasma levels of Hcy are a risk factor for AD. In the present paper, we used animals subjected to chronic intake of methionine (1 g/kg/day) in the drinking water, since this treatment can increase plasma Hcy levels by 30%. By means of this animal model, interactions between the Abeta beta-sheet rich fibrils and clusterin, have been evaluated in striata of animals after Abeta injection. Furthermore, it has been demonstrated that Abeta peptides are not only signals capable of activating astrocytes but also capable of reducing tyrosine-hydroxylase immunoreactivity in the basal ganglia probably leading to a reduction of volume transmission. These alterations in the neuroglial network morphology and function can, at least in part, explain the enhanced pain threshold observed in the Abeta intra-striatally injected animals.