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Abstract Background Individuals with type 2 diabetes (T2D) face an increased mortality risk, not fully captured by canonical risk factors. Biological age estimation through DNA methylation (DNAm), i.e. the epigenetic clocks, is emerging as a possible tool to improve risk stratification for multiple outcomes. However, whether these tools predict mortality independently of canonical risk factors in subjects with T2D is unknown. Methods Among a cohort of 568 T2D patients followed for 16.8 years, we selected a subgroup of 50 subjects, 27 survived and 23 deceased at present, passing the quality check and balanced for all risk factors after propensity score matching. We analyzed DNAm from peripheral blood leukocytes using the Infinium Human MethylationEPIC BeadChip (Illumina) to evaluate biological aging through previously validated epigenetic clocks and assess the DNAm-estimated levels of selected inflammatory proteins and blood cell counts. We tested the associations of these estimates with mortality using two-stage residual-outcome regression analysis, creating a reference model on data from the group of survived patients. Results Deceased subjects had higher median epigenetic age expressed with DNAmPhenoAge algorithm (57.49 [54.72; 60.58] years. vs. 53.40 [49.73; 56.75] years; p = 0.012), and accelerated DunedinPoAm pace of aging (1.05 [1.02; 1.11] vs. 1.02 [0.98; 1.06]; p = 0.012). DNAm PhenoAge (HR 1.16, 95% CI 1.05–1.28; p = 0.004) and DunedinPoAm (HR 3.65, 95% CI 1.43–9.35; p = 0.007) showed an association with mortality independently of canonical risk factors. The epigenetic predictors of 3 chronic inflammation-related proteins, i.e. CXCL10, CXCL11 and enRAGE, C-reactive protein methylation risk score and DNAm-based estimates of exhausted CD8 + T cell counts were higher in deceased subjects when compared to survived. Conclusions These findings suggest that biological aging, as estimated through existing epigenetic tools, is associated with mortality risk in individuals with T2D, independently of common risk factors and that increased DNAm-surrogates of inflammatory protein levels characterize deceased T2D patients. Replication in larger cohorts is needed to assess the potential of this approach to refine mortality risk in T2D.

Abstract Parkinson’s disease is increasingly prevalent. It progresses from the pre-motor stage (characterised by non-motor symptoms like REM sleep behaviour disorder), to the disabling motor stage. We need objective biomarkers for early/pre-motor disease stages to be able to intervene and slow the underlying neurodegenerative process. Here, we validate a targeted multiplexed mass spectrometry assay for blood samples from recently diagnosed motor Parkinson’s patients (n = 99), pre-motor individuals with isolated REM sleep behaviour disorder (two cohorts: n = 18 and n = 54 longitudinally), and healthy controls (n = 36). Our machine-learning model accurately identifies all Parkinson patients and classifies 79% of the pre-motor individuals up to 7 years before motor onset by analysing the expression of eight proteins—Granulin precursor, Mannan-binding-lectin-serine-peptidase-2, Endoplasmatic-reticulum-chaperone-BiP, Prostaglaindin-H2-D-isomaerase, Interceullular-adhesion-molecule-1, Complement C3, Dickkopf-WNT-signalling pathway-inhibitor-3, and Plasma-protease-C1-inhibitor. Many of these biomarkers correlate with symptom severity. This specific blood panel indicates molecular events in early stages and could help identify at-risk participants for clinical trials aimed at slowing/preventing motor Parkinson’s disease.

Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible evidence. Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on n = 7039 blood and saliva samples from individuals older than 40, including n = 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105 +), and 25 samples from supercentenarians (aged 110 +). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (age  90). We present a chromatin state analysis of age effects in centenarians. The centenarian clocks are expected to be useful for validating claims surrounding exceptional old age.

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Abstract A relevant question concerning inter-areal communication in the cortex is whether these interactions are synergistic. Synergy refers to the complementary effect of multiple brain signals conveying more information than the sum of each isolated signal. Redundancy, on the other hand, refers to the common information shared between brain signals. Here, we dissociated cortical interactions encoding complementary information (synergy) from those sharing common information (redundancy) during prediction error (PE) processing. We analyzed auditory and frontal electrocorticography (ECoG) signals in five common awake marmosets performing two distinct auditory oddball tasks and investigated to what extent event-related potentials (ERP) and broadband (BB) dynamics encoded synergistic and redundant information about PE processing. The information conveyed by ERPs and BB signals was synergistic even at lower stages of the hierarchy in the auditory cortex and between auditory and frontal regions. Using a brain-constrained neural network, we simulated the synergy and redundancy observed in the experimental results and demonstrated that the emergence of synergy between auditory and frontal regions requires the presence of strong, long-distance, feedback, and feedforward connections. These results indicate that distributed representations of PE signals across the cortical hierarchy can be highly synergistic.

Abstract Recent literature shows that loss of replicative ability and acquisition of a proinflammatory secretory phenotype in senescent cells is coupled with the build-in of nucleic acids in the cytoplasm. Its implication in human age-related diseases is under scrutiny. In human endothelial cells (ECs), we assessed the accumulation of intracellular nucleic acids during in vitro replicative senescence and after exposure to high glucose concentrations, which mimic an in vivo condition of hyperglycemia. We showed that exposure to high glucose induces senescent-like features in ECs, including telomere shortening and proinflammatory cytokine release, coupled with the accrual in the cytoplasm of telomeres, double-stranded DNA and RNA (dsDNA, dsRNA), as well as RNA:DNA hybrid molecules. Senescent ECs showed an activation of the dsRNA sensors RIG-I and MDA5 and of the DNA sensor TLR9, which was not paralleled by the involvement of the canonical (cGAS) and non-canonical (IFI16) activation of the STING pathway. Under high glucose conditions, only a sustained activation of TLR9 was observed. Notably, senescent cells exhibit increased proinflammatory cytokine (IL-1β, IL-6, IL-8) production without a detectable secretion of type I interferon (IFN), a phenomenon that can be explained, at least in part, by the accumulation of methyl-adenosine containing RNAs. At variance, exposure to exogenous nucleic acids enhances both IL-6 and IFN-β1 expression in senescent cells. This study highlights the accrual of cytoplasmic nucleic acids as a marker of senescence-related endothelial dysfunction, that may play a role in dysmetabolic age-related diseases.

Down syndrome (DS) is a segmental progeroid genetic disorder associated with multi-systemic precocious aging phenotypes, which are particularly evident in the immune and nervous systems. Accordingly, people with DS show an increased biological age as measured by epigenetic clocks. The Ts65Dn trisomic mouse, which harbors extra-numerary copies of chromosome 21 (Hsa21)-syntenic regions, was shown to recapitulate several progeroid features of DS, but no biomarkers of age have been applied to it so far. In this pilot study, we used a mouse-specific epigenetic clock to measure the epigenetic age of hippocampi from Ts65Dn and euploid mice at 20 weeks. Ts65Dn mice showed an increased epigenetic age in comparison with controls, and the observed changes in DNA methylation partially recapitulated those observed in hippocampi from people with DS. Collectively, our results support the use of the Ts65Dn model to decipher the molecular mechanisms underlying the progeroid DS phenotypes.

Introduction: DNA methylation clocks presents advantageous characteristics with respect to the ambitious goal of identifying very early markers of disease, based on the concept that accelerated ageing is a reliable predictor in this sense.Methods: Such tools, being epigenomic based, are expected to be conditioned by sex and tissue specificities, and this work is about quantifying this dependency as well as that from the regression model and the size of the training set.Results: Our quantitative results indicate that elastic-net penalization is the best performing strategy, and better so when—unsurprisingly—the data set is bigger; sex does not appear to condition clocks performances and tissue specific clocks appear to perform better than generic blood clocks. Finally, when considering all trained clocks, we identified a subset of genes that, to the best of our knowledge, have not been presented yet and might deserve further investigation: CPT1A, MMP15, SHROOM3, SLIT3, and SYNGR.Conclusion: These factual starting points can be useful for the future medical translation of clocks and in particular in the debate between multi-tissue clocks, generally trained on a large majority of blood samples, and tissue-specific clocks.

Abstract The neurobiological nature of semantic knowledge, i.e., the encoding and storage of conceptual information in the human brain, remains a poorly understood and hotly debated subject. Clinical data on semantic deficits and neuroimaging evidence from healthy individuals have suggested multiple cortical regions to be involved in the processing of meaning. These include semantic hubs (most notably, anterior temporal lobe, ATL) that take part in semantic processing in general as well as sensorimotor areas that process specific aspects/categories according to their modality. Biologically inspired neurocomputational models can help elucidate the exact roles of these regions in the functioning of the semantic system and, importantly, in its breakdown in neurological deficits. We used a neuroanatomically constrained computational model of frontotemporal cortices implicated in word acquisition and processing, and adapted it to simulate and explain the effects of semantic dementia (SD) on word processing abilities. SD is a devastating, yet insufficiently understood progressive neurodegenerative disease, characterised by semantic knowledge deterioration that is hypothesised to be specifically related to neural damage in the ATL. The behaviour of our brain-based model is in full accordance with clinical data—namely, word comprehension performance decreases as SD lesions in ATL progress, whereas word repetition abilities remain less affected. Furthermore, our model makes predictions about lesion- and category-specific effects of SD: our simulation results indicate that word processing should be more impaired for object- than for action-related words, and that degradation of white matter should produce more severe consequences than the same proportion of grey matter decay. In sum, the present results provide a neuromechanistic explanatory account of cortical-level language impairments observed during the onset and progress of semantic dementia.

En el ámbito museístico es frecuente encontrarse con limitaciones logísticas que dificultan la documentación de las obras de arte. El patrimonio pictórico presenta además otras criticidades debidas a la imposibilidad de modificar la iluminación: basada en criterios de conservación y comunicación, haciendo resaltar las características materiales, cromáticas y de ejecución. Esto conduce a situaciones inadecuadas para el levantamientos por imágenes fotográficas, ya complicadas en sí por las complejas propiedades ópticas de los materiales. La técnica que aquí se presenta fue desarrollada para la documentación de la Anunciación (1430-32) de Fra Giovanni Angelico (Museo de la Basílica S. Maria delle Grazie, San Giovanni Valdarno, Arezzo) y permite eliminar y atenuar fenómenos indeseables debidos a las condiciones específicas del contexto museístico. Se mostrará una estrategia capaz de eliminar las sombras nitidas, así como los fenómenos de claroscuro, de las texturas asociadas al modelo digital de la pintura y su marco, garantizando su fidelidad visual.

In the field of the Cultural Heritage (CH), image-based 2D and 3D digital acquisition is today the most common technique used to create digital replicas of existing artifacts. This is carried out for many reasons, such as the following: research, analysis, preservation, conservation, communication, and valorization. These activities usually require complementary specialized equipment, tailored to specific purposes in order to achieve the desired results. This equipment is not easy-to-find on the market, it is not always affordable for museums operators; it is sometimes expensive, and it usually needs tricky customizations. However, the development in recent years of more generalized, versatile, and affordable instruments and technologies has led to new approaches, leveraging a new generation of low-cost, adaptable equipment. This paper presents custom-made equipment following this new path, designed to provide optimized results through calibrated tools alongside the software to make it work. The essay focuses specifically on the self-production of instruments for the digital reproduction of ancient drawings, manuscripts, paintings, and other museum artifacts and their transformative impact on digitization techniques. The outcomes of self and custom-built equipment specifically produced for the contexts described in this paper highlight their potential to foster interdisciplinary collaboration, facilitate scholarly research, enhance conservation efforts, and promote cultural exchange. The final goal is to propose inexpensive equipment that is easy to use (even by not specifically trained operators) and that provides remarkable quality.

Healthcare workers (HCWs) are a high-risk group for hepatitis B virus (HBV) infection. Notably, about 5–10% of the general population does not respond to the HBV vaccination. In this study, we aimed to investigate DNA methylation (DNAm) in order to estimate the biological age of B cells from HCW of both sexes, either responder (R) or non-responder (NR), to HBV vaccination. We used genome-wide DNA methylation data to calculate a set of biomarkers in B cells collected from 41 Rs and 30 NRs between 22 and 62 years old. Unresponsiveness to HBV vaccination was associated with accelerated epigenetic aging (DNAmAge, AltumAge, DunedinPoAm) and was accompanied by epigenetic drift. Female non-responders had higher estimates of telomere length and lower CRP inflammation risk score when compared to responders. Overall, epigenetic differences between responders and non-responders were more evident in females than males. In this study we demonstrated that several methylation DNAm-based clocks and biomarkers are associated with an increased risk of non-response to HBV vaccination, particularly in females. Based on these results, we propose that accelerated epigenetic age could contribute to vaccine unresponsiveness. These insights may help improve the evaluation of the effectiveness of vaccination strategies, especially among HCWs and vulnerable patients.

This paper introduces a discussion on the visualization tools for digital replicas of objects belonging to the domains of historic architecture, archaeology, and art museum institutions. Covering a range of artifacts, from ancient drawings to manuscripts, to paintings, to objects in museums’ collections, the discussion spans from levels of iconicity related to 3D models to their presentation and visualization media. Authors introduce some established experiences, inferred from real case studies showcased during real exhibitions, to show how digital artifacts can replicate existing objects for specific purposes, with high levels of iconicity. The paper traces approaches in 3D model visualization, utilizing technologies such as Real-Time Rendering (RTR) and Virtual Reality frameworks. After a methodical acquisition of artworks to be replicated, the digital models are targeted to various stakeholders with interests in historical and artistic research, curation of museum exhibition, art restoration, or simple tourism visits. The way through which the artwork can be visualized, presenting different features each time, depends on their needs, from guided navigation of 3D models on laptop screens accompanied by explanatory texts, to free visualization through gestures on interactive high-definition touch screens. By employing high-resolution replicas mapped with gigapixel textures, even the minutest details can be observed. This approach virtually places the artwork in the hands of the users, allowing them to appreciate its characteristics at a very high level of iconicity, also enhancing the narrative potential of digital replicas in museum exhibitions.DOI: https://doi.org/10.20365/disegnarecon.32.2024.1

This work investigates the tribological behavior of a machined S355JR structural steel in dry sliding conditions for the development of an innovative seismic dissipation system. Flat-ended pins and disks were made of the same structural steel to simulate the conformal contact of different device parts. Pins were machined by turning, while disks were milled and turned to obtain a nominal average surface Ra roughness ranging from 0.8 µm to 6.3 µm. The influence of the surface roughness on the coefficient of friction (COF), specific wear rate (SWR), and time to steady-state (TSS) was investigated. Tribological tests were conducted reciprocating motion in dry sliding conditions to simulate the operating conditions of the device, with 1 Hz and 2 Hz reciprocating frequencies and an applied normal load of 50 N. The Rsk and Rku roughness parameters helped to better understand the tribological response of milled and turned disks, having an influence on the TSS and SWR.

Since 2021, the Centro Internazionale di Studi di Architettura Andrea Palladio (CISAAP) in Vicenza and the Department of Architecture at the University of Bologna collaborated for a didactical joint initiative involving students from the Photogrammetry for Architecture course. The main goal was to develop a new teaching approach for architectural education exploiting photogrammetry as a digital tool for joining the Architectural Heritage (AH) documentation with the architecture analysis and design interpretation. Beginning from the new technological advances (semi-automatic workflows and smartphone cameras use), a ‘learning-by-doing’ didactical method and situated real work problems, a whole systematic process, based on the concept of a digital copy of an architectural artifact as mean to collect and to aggregate knowledge, was developed and inferred to the student. Starting from the designed teaching path, in which the perspectives of the historian, the surveyor, and the designer are blended to get a holistic vision of the architecture, 29 fireplaces by Andrea Palladio were chosen as emblematic case studies. These microarchitectures let students understand the complexities of historic objects and of their digitalization to produce 3D models as outcomes of an acquisition pipeline useful to train them for a future professional career.

The Annunciation by Guido di Pietro from Mugello, known as Beato Angelico, is a wide tempera painting with some fine gold foil placed on a wooden support, today hosted at the Museum of the Basilica of Santa Maria delle Grazie, in San Giovanni Valdarno. On the occasion of the exhibition “Masaccio e Angelico. Dialogo sulla verità nella pittura”, the museum asked to the Department of Architecture at the University of Bologna to develop a digital high-resolution surrogate to favour deep investigations, to plan restoration and to simply tell the stories behind the artwork. Two tasks were accomplished: to let visitors discover the secrets in the painting and to let scholars study the artwork, to better understand the masterpiece. This paper introduces the outcomes of the research developed to digitize the Annunciation, following a dedicated pipeline developed to improve the fruition of its digital replica, originated from different input sources, and surrogating the user experience on the real object. This work presents a method for the 3D reconstruction of the surfaces based on different techniques for elements with different depth resolutions (i.e., the painting and the wooden frame) which combine photogrammetry and photometric stereo exploiting both procedures and pushing forward the boundaries of Gigapixel Imaging and photogrammetric-based 3D model representation.

Abstract Isolated REM Sleep Behavior Disorder (iRBD) is the strongest prodromal marker for α-synucleinopathies. Overt α-synucleinopathies and aging share several mechanisms, but this relationship has been poorly investigated in prodromal phases. Using DNA methylation-based epigenetic clocks, we measured biological aging in videopolysomnography confirmed iRBD patients, videopolysomnography-negative and population-based controls. We found that iRBDs tended to be epigenetically older than controls, suggesting that accelerated aging characterizes prodromal neurodegeneration.

• Purpose: Partial wrist denervation can be performed by isolated posterior interosseous nerve (PIN) or combined PIN plus (+) anterior interosseous nerve (AIN) neurectomy procedures. • The purpose of the current systematic review is to investigate any differences in clinical outcomes and failures in patients undergoing AIN + PIN vs isolated PIN neurectomy. • Methods: A review of the English Literature was performed on Medline, WOS and Scopus according to PRISMA protocol combining ‘wrist denervation’, ‘PIN neurectomy’, ‘AIN neurectomy’, anterior interosseous nerve neurectomy’ and ‘posterior interosseous nerve neurectomy’. Studies were assessed with a modified Coleman Methodology Score (CMS). The primary outcome for meta-analysis was ‘Failures’, including all patients who have required a second surgery or those who are left with pain (defined as ‘bad’). • Results: Overall, 10 studies totalling 347 wrists were included in this systematic review, with a ‘moderate’ CMS. The isolated PIN neurectomy technique showed a 15.1% pooled failure rate at a median follow-up of 22 months, while the combined AIN+PIN denervation had a pooled failure rate of 23.6% at a follow-up with a median of 29 months. The combined analysis of both procedures did not show significantly better results in favour of either technique, with a general failure rate of 21.6% (P = 0.0501). • Conclusion: Partial denervation for chronic wrist pain is a salvage procedure that leads to an overall success of 78.4% for pain relief, with no substantial complications. Apparently, performing the neurectomy also of the AIN does not offer greater advantages compared to the isolated PIN neurectomy.

Subcutaneous adipocytes are crucial for mammary gland epithelial development during pregnancy. Our and others’ previous data have suggested that adipo-epithelial transdifferentiation could play a key role in the mammary gland alveolar development. In this study, we tested whether adipo-epithelial transdifferentiation occurs in vitro. Data show that, under appropriate co-culture conditions with mammary epithelial organoids (MEOs), mature adipocytes lose their phenotype and acquire an epithelial one. Interestingly, even in the absence of MEOs, extracellular matrix and diffusible growth factors are able to promote adipo-epithelial transdifferentiation. Gene and protein expression studies indicate that transdifferentiating adipocytes exhibit some characteristics of milk-secreting alveolar glands, including significantly higher expression of milk proteins such as whey acidic protein and β-casein. Similar data were also obtained in cultured human multipotent adipose-derived stem cell adipocytes. A miRNA sequencing experiment on the supernatant highlighted mir200c, which has a well-established role in the mesenchymal–epithelial transition, as a potential player in this phenomenon. Collectively, our data show that adipo-epithelial transdifferentiation can be reproduced in in vitro models where this phenomenon can be investigated at the molecular level.

Technologies and applications developed to assist and promote museum activities and cultural exhibitions have evolved significantly during the last decade, as has been proven by many works published in the scientific literature. This paper addresses a study developed with the specific purpose of understanding the possible knowledge-transfer outcomes of a digitization process meant to replicate original drawings by Leonardo da Vinci in the digital domain, allowing museums’ visitors to explore them as if they were manipulating the original artworks through custom interactive artifacts. A report is presented here to evaluate and investigate the didactic effectiveness of the fruition devices set up during a real exhibition, with a focus on the application dedicated to the drawing Study for the Adoration of the Magi, part of five artworks by Leonardo selected for exhibition during the reported event. The results encourage the adoption of this kind of technology for disseminating information at different levels, especially when knowledge contents are successfully explicated through proper didactic mediators.

Processes such as Building Information Modeling and, more generally, those involving the digitization of the built environment whose BIM is one of the possible expressions, are becoming increasingly pervasive in many different practices, from the design activities to the building site and management. Professional skills and working experience have now to be fostered by specific training on new methodologies concerning virtual replicas of existing domains, to explore the possibilities offered by digital interactions with Smart Heritage artifacts. This paper delves into the outcomes from the BIM Master Program held at the University of Pisa since 2016, presenting the results of the application of novel teaching techniques and topics related to the digitization of the built historic environment for the design preservation of Cultural Heritage monuments or sites.

Abstract Transcriptomics in Parkinson’s disease (PD) offers new insights into the molecular mechanism of PD pathogenesis. Several pathways, such as inflammation and protein degradation, have been identified by differential gene expression analysis. Our aim was to identify gene expression differences underlying the disease etiology and the discovery of pre-symptomatic risk biomarkers for PD from a multicenter study in the context of the PROPAG-AGEING project. We performed RNA sequencing from 47 patients with de novo PD, 10 centenarians, and 65 healthy controls. Using identified differentially expressed genes, functional annotations were assigned using gene ontology to unveil significant enriched biological processes. The expression of 16 selected genes was validated using OpenArray® assays and samples from independent cohorts of 201 patients with advanced PD, 340 healthy siblings of PD patients, and 177 healthy controls. Differential gene expression analysis identified higher FCGBP expression in patients with de novo PD compared with healthy controls and compared with centenarians. Furthermore, FCGBP showed no differences in terms of population origin or aging process. The increased FCGBP expression was validated in patients with advanced PD and their siblings. Thus, we provided evidence for an upregulation of FCGBP mRNA levels not only in patients with PD but also in individuals at putative higher risk of PD, suggesting that it could be important in gut–brain PD interaction, mediating the connection between microbiota and intestinal inflammatory processes, as well as neuroinflammation and neurodegeneration.

In a controlled laboratory experiment we investigate whether time pressure influences voting decisions, and in particular the degree of strategic (insincere) voting. We find that participants under time constraints are more sincere when using the widely-employed Plurality Voting method. That is, time pressure might reduce strategic voting and hence misrepresentation of preferences. However, there are no effects for Approval Voting, in line with arguments that this method provides no incentives for strategic voting.

Serum phosphate concentration is regulated by renal phosphate reabsorption and mediated by sodium–phosphate cotransporters. Germline mutations in genes encoding these cotransporters have been associated with clinical phenotypes, variably characterized by hyperphosphaturia, hypophosphatemia, recurrent kidney stones, skeletal demineralization, and early onset osteoporosis. We reported a 33-year-old male patient presenting a history of recurrent nephrolithiasis and early onset osteopenia in the lumbar spine and femur. He was tested, through next generation sequencing (NGS), by using a customized multigenic panel containing 33 genes, whose mutations are known to be responsible for the development of congenital parathyroid diseases. Two further genes, SLC34A1 and SLC34A3, encoding two sodium–phosphate cotransporters, were additionally tested. A novel germline heterozygous mutation was identified in the SLC34A1 gene, c.1627G>T (p.Gly543Cys), currently not reported in databases of human gene mutations and scientific literature. SLC34A1 germline heterozygous mutations have been associated with the autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis type 1 (NPHLOP1). Consistently, alongside the clinical features of NPHLOP1, our patient experienced recurrent nephrolithiasis and lumbar and femoral osteopenia at a young age. Genetic screening for the p.Gly453Cys variant and the clinical characterization of his first-degree relatives associated the presence of the variant in one younger brother, presenting renal colic and microlithiasis, suggesting p.Gly453Cys is possibly associated with renal altered function in the NPHLOP1 phenotype.

Dissimilar friction stir welding joints are widely employed in the industrial field due to the excellent microstructural and mechanical properties of the resulting joints. Nevertheless, to further enhance the weld properties, the addition of reinforcement particles on the joint-line during the process has been proven effective for increasing its mechanical performance. In the present investigation, the microstructure and the impact behaviour of FSWed joints between AA2024-T351 and AA7075-T651 aluminium plates were investigated, considering the effect of different process parameters selected through a full factorial 2k design of experiments: both the rotational and translational speed of the tool, as well as the addition of Al2O3-SiC microparticles, were considered as input parameters. Unnotched 10 x 5 x 55 mm impact specimens were tested through an instrumented 50 J Charpy pendulum: total impact energy, the two complementary initiation and propagation energies as well as the peak force were correlated to the adopted process parameters. From the performed analyses, it was found that joints with reinforcing particles are prone to form wormhole defects across the stir zone that not only affect the microstructural development, but also the impact behaviour since they require less energy at break in comparison with joints fabricated without particles addition.

Abstract Parkinson’s disease (PD) is the neurological disorder showing the greatest rise in prevalence from 1990 to 2016. Despite clinical definition criteria and a tremendous effort to develop objective biomarkers, precise diagnosis of PD is still unavailable at early stage. In recent years, an increasing number of studies have used omic methods to unveil the molecular basis of PD, providing a detailed characterization of potentially pathological alterations in various biological specimens. Metabolomics could provide useful insights to deepen our knowledge of PD aetiopathogenesis, to identify signatures that distinguish groups of patients and uncover responsive biomarkers of PD that may be significant in early detection and in tracking the disease progression and drug treatment efficacy. The present work is the first large metabolomic study based on nuclear magnetic resonance (NMR) with an independent validation cohort aiming at the serum characterization of de novo drug-naive PD patients. Here, NMR is applied to sera from large training and independent validation cohorts of German subjects. Multivariate and univariate approaches are used to infer metabolic differences that characterize the metabolite and the lipoprotein profiles of newly diagnosed de novo drug-naive PD patients also in relation to the biological sex of the subjects in the study, evidencing a more pronounced fingerprint of the pathology in male patients. The presence of a validation cohort allowed us to confirm altered levels of acetone and cholesterol in male PD patients. By comparing the metabolites and lipoproteins levels among de novo drug-naive PD patients, age- and sex-matched healthy controls, and a group of advanced PD patients, we detected several descriptors of stronger oxidative stress.

Abstract Advanced age represents one of the major risk factors for Parkinson’s Disease. Recent biomedical studies posit a role for microRNAs, also known to be remodelled during ageing. However, the relationship between microRNA remodelling and ageing in Parkinson’s Disease, has not been fully elucidated. Therefore, the aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson’s Disease within the ageing framework. We employed Next Generation Sequencing to profile serum microRNAs from samples informative for Parkinson’s Disease (recently diagnosed, drug-naïve) and healthy ageing (centenarians) plus healthy controls, age-matched with Parkinson’s Disease patients. Potential microRNA candidates markers, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson’s Disease patients, and healthy siblings of Parkinson’s Disease patients at higher genetic risk for developing the disease. While we did not find evidences of microRNAs co-regulated in Parkinson’s Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early Parkinson’s Disease patients. Moreover, interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson’s Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early Parkinson’s Disease, robustly confirmed across a variety of analytical and experimental analyses. These promising results ask for further research to unveil the functional details of the involvement of hsa-mir144-3p in Parkinson’s Disease.

In the current paper, a predefined thermomechanical procedure has been applied to the two-way shape memory effect (TWSME) in a NiTi alloy to study the effect of two different applied load conditions on the induced martensitic state. The microstructure of the strips was studied using optical microscopy (OM), scanning electron microscopy (SEM) fitted with an EDS microprobe, and microhardness tests at the end of both the training and thermal cycles. Inducing internal stresses along specified directions during training cycles results in the formation of oriented martensitic variants rather than expected twinned martensitic variants upon cooling. It was found that the microstructure is made up of interlocking martensitic lathes, including the fine martensite colony next to the coarse martensite lathes. Furthermore, the results of the average hardness tests for bending at one point and three points were 241 and 247 HV0.2, respectively. It was shown that only the cubic austenitic phase (B2) and the martensitic monoclinic phase (B19′) experience transformation. The results reveal that homogeneous bending in three locations leads to achieving the best difference between high- and low-temperature curvatures after training.

Abstract A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had

Quercetin (QUER) is a natural polyphenolic compound endowed with beneficial properties for human health, with anti-aging effects. However, although this flavonoid is commercially available as a nutraceutical, target molecules/pathways underlying its pro-longevity potential have yet to be fully clarified. Here, we investigated QUER activity in yeast chronological aging, the established model for simulating the aging of postmitotic quiescent mammalian cells. We found that QUER supplementation at the onset of chronological aging, namely at the diauxic shift, significantly increases chronological lifespan (CLS). Consistent with the antioxidant properties of QUER, this extension takes place in concert with a decrease in oxidative stress. In addition, QUER triggers substantial changes in carbon metabolism. Specifically, it promotes an enhancement of a pro-longevity anabolic metabolism toward gluconeogenesis due to improved catabolism of C2 by-products of yeast fermentation and glycerol. The former is attributable to the Sir2-dependent activity of phosphoenolpyruvate carboxykinase and the latter to the L-glycerol 3-phosphate pathway. Such a combined increased supply of gluconeogenesis leads to an increase in the reserve carbohydrate trehalose, ensuring CLS extension. Moreover, QUER supplementation to chronologically aging cells in water alone amplifies their long-lived phenotype. This is associated with intracellular glycerol catabolism and trehalose increase, further indicating a QUER-specific influence on carbon metabolism that results in CLS extension.

The aim of the present study was to provide a comprehensive characterization of whole genome DNA methylation patterns in replicative and ionizing irradiation- or doxorubicin-induced premature senescence, exhaustively exploring epigenetic modifications in three different human cell types: in somatic diploid skin fibroblasts and in bone marrow- and adipose-derived mesenchymal stem cells. With CpG-wise differential analysis, three epigenetic signatures were identified: (a) cell type- and treatment-specific signature; (b) cell type-specific senescence-related signature; and (c) cell type-transversal replicative senescence-related signature. Cluster analysis revealed that only replicative senescent cells created a distinct group reflecting notable alterations in the DNA methylation patterns accompanying this cellular state. Replicative senescence-associated epigenetic changes seemed to be of such an extent that they surpassed interpersonal dissimilarities. Enrichment in pathways linked to the nervous system and involved in the neurological functions was shown after pathway analysis of genes involved in the cell type-transversal replicative senescence-related signature. Although DNA methylation clock analysis provided no statistically significant evidence on epigenetic age acceleration related to senescence, a persistent trend of increased biological age in replicative senescent cultures of all three cell types was observed. Overall, this work indicates the heterogeneity of senescent cells depending on the tissue of origin and the type of senescence inducer that could be putatively translated to a distinct impact on tissue homeostasis.

Control of ribosome biogenesis is a critical aspect of the regulation of cell metabolism. As ribosomal genes (rDNA) are organized in repeated clusters on chromosomes 13, 14, 15, 21, and 22, trisomy of chromosome 21 confers an excess of rDNA copies to persons with Down syndrome (DS). Previous studies showed an alteration of ribosome biogenesis in children with DS, but the epigenetic regulation of rDNA genes has not been investigated in adults with DS so far. In this study, we used a targeted deep-sequencing approach to measure DNA methylation (DNAm) of rDNA units in whole blood from 69 adults with DS and 95 euploid controls. We further evaluated the expression of the precursor of ribosomal RNAs (RNA45S) in peripheral blood mononuclear cells (PBMCs) from the same subjects. We found that the rDNA promoter tends to be hypermethylated in DS concerning the control group. The analysis of epihaplotypes (the combination of methylated and unmethylated CpG sites along the same DNA molecule) showed a significantly lower intra-individual diversity in the DS group, which at the same time was characterized by a higher interindividual variability. Finally, we showed that RNA45S expression is lower in adults with DS. Collectively, our results suggest a rearrangement of the epigenetic profile of rDNA in DS, possibly to compensate for the extranumerary rDNA copies. Future studies should assess whether the regulation of ribosome biogenesis can contribute to the pathogenesis of DS and explain the clinical heterogeneity characteristic of the syndrome.

Abstract Background The cline of human genetic diversity observable across Europe is recapitulated at a micro-geographic scale by variation within the Italian population. Besides resulting from extensive gene flow, this might be ascribable also to local adaptations to diverse ecological contexts evolved by people who anciently spread along the Italian Peninsula. Dissecting the evolutionary history of the ancestors of present-day Italians may thus improve the understanding of demographic and biological processes that contributed to shape the gene pool of European populations. However, previous SNP array-based studies failed to investigate the full spectrum of Italian variation, generally neglecting low-frequency genetic variants and examining a limited set of small effect size alleles, which may represent important determinants of population structure and complex adaptive traits. To overcome these issues, we analyzed 38 high-coverage whole-genome sequences representative of population clusters at the opposite ends of the cline of Italian variation, along with a large panel of modern and ancient Euro-Mediterranean genomes. Results We provided evidence for the early divergence of Italian groups dating back to the Late Glacial and for Neolithic and distinct Bronze Age migrations having further differentiated their gene pools. We inferred adaptive evolution at insulin-related loci in people from Italian regions with a temperate climate, while possible adaptations to pathogens and ultraviolet radiation were observed in Mediterranean Italians. Some of these adaptive events may also have secondarily modulated population disease or longevity predisposition. Conclusions We disentangled the contribution of multiple migratory and adaptive events in shaping the heterogeneous Italian genomic background, which exemplify population dynamics and gene-environment interactions that played significant roles also in the formation of the Continental and Southern European genomic landscapes.

Background: Sevoflurane is a polyfluorinated compound extensively used as an inhalation anesthetic in patients undergoing surgery. If administered outside the operating room, sevoflurane is dangerous and potentially lethal, and toxicologists may be asked to investigate its presence in biological matrices for forensic purposes. The aim of the present study is to develop and validate a method for the detection and the quantification of sevoflurane in biological fluids and organs through gas chromatography coupled to flame ionization detection (GC–FID). Methods: The method was optimized based on the maximization of the signal-to-noise ratio. The GC–FID instrument was equipped with a Zebron capillary column ZB-624 (30 m, 0.32 mm ID, 1.80 µm film thickness). Results: The method was validated over a concentration range of 1.0–304.0 µg/mL (blood and urine) and µg/g (brain, lungs). The lower limit of quantitation was 1.0 µg/mL or µg/g. Both the intra- and interassay imprecision and inaccuracy were ≤15% at all quality control concentrations in all the matrices. The method was successfully applied to measure the sevoflurane concentrations for 20 negative controls and for a real forensic case. Conclusions: The present method is suitable for the identification and quantification of sevoflurane in fluids and organs and can be a reliable tool in forensic casework.

Bone marrow mesenchymal stromal cells (BMSCs) are multipotent cells able to self-renew and differentiate, depending on the microenvironment, into adipocytes and osteoblasts. These cells have a limited number of replications and enter replicative senescence during in vitro expansion. The role of DNA methylation (DNAm) assumes importance in cell function and commitment; however, its exact contribution to BMSC differentiation and replicative senescence is still unclear. We performed a genome-wide DNAm analysis on BMSCs cultured in vitro at early passages and induced to differentiate into adipocytes and osteoblasts, and on replicative senescent BMSCs and HUVECs, to identify DNAm patterns of senescence and differentiation. We also compared BMSCs and HUVECs in replicative senescence and found that, in both cellular systems, genome-wide hypomethylation was accompanied by a higher-than-expected overlap of differentially methylated positions (DMPs) and concordance in terms of direction of the change. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on lineage-independent senescence-associated DMPs revealed 16 common pathways, including Insulin resistance, Molecule adhesion, and Wnt/β-catenin signaling. In both adipogenesis and osteogenesis, we observed a general demethylation of CpG sites compared with undifferentiated BMSCs with a higher number of DMPs in osteogenesis. KEGG analysis resulted in 30 pathways enriched in osteoblasts and only 2 in adipocytes when compared to undifferentiated cells. When comparing differentiated BMSCs with senescent ones, osteogenesis exhibited a greater overlap with senescence in terms of number of DMPs and direction of methylation change compared to adipogenesis. In conclusion, this study may be useful for future research on general mechanisms that occur in replicative senescence and furthermore to identify trajectories of BMSC differentiation and common aspects of differentiated and senescent cells.