Looking at Alzheimer’s disease pathogenesis from the nuclear side

Alzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid‐β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is the amyloid precursor protein (APP), which is cleaved by secretases to produce several metabolites, including Aβ and APP intracellular domain (AICD). The greatest genetic risk factor associated with AD is represented by the Apolipoprotein E ε4 (APOE ε4) allele. Importantly, all of the above‐mentioned molecules that are strictly related to AD pathogenesis have also been described as playing roles in the cell nucleus. Accordingly, evidence suggests that nuclear functions are compromised in AD. Furthermore, modulation of transcription maintains cellular homeostasis, and alterations in transcriptomic profiles have been found in neurodegenerative diseases. This report reviews recent advancements in the AD players‐mediated gene expression. Aβ, tau, AICD, and APOE ε4 localize in the nucleus and regulate the transcription of several genes, part of which is involved in AD pathogenesis, thus suggesting that targeting nuclear functions might provide new therapeutic tools for the disease

Damage assessment of different FDM-processed materials adopting Infrared Thermography

The use of components obtained through the additive manufacturing (AM) technique has become increasingly widespread in recent years, playing a central role in industrial production, and in particular in some fields such as automotive, biomedical, aerospace and electronics. Among all AM techniques, FDM (Fused Deposition Modelling) represents the most used printing technique to produce polymeric and composite components, thanks to the flexible printing process, the low cost and the diversity of the materials adopted. The aim of the present work concerns the comparison between the mechanical properties of three plastic materials printed with the FDM technique (polylactic acid PLA, polyethylene terephthalate glycol-modified PETG and Acrylonitrile-butadiene-styrene ABS) using an Original Prusa i3 MK3S, by varying the raster angle between 0°, 45° and 90° degrees. Infrared Thermography has been adopted to monitor the temperature evolution during static tensile tests and to assess stress level that can initiate damage within the material. Failure analysis was performed to correlate the mechanical behaviour with the microstructural characteristics of the materials

Comparison of methods to determine accurate dose calibrator activity measurements

<p>Abstract</p> <p>Background</p> <p>In nuclear medicine, liquid radiopharmaceuticals for diagnostic or therapeutic purposes are administered to patients by using various types of syringes with different volumes. The activity of each "dose" must be carefully measured and documented prior to administration using an activity calibrator.</p> <p>Methods</p> <p>Calibrator response is a function of the measurement geometry and, in particular, it depends on the syringe type and filling volume. To minimize the uncertainty associated with the measured activity of the syringe, it is necessary to calculate a calibration curve depending on filling volume for each syringe type. This curve can be obtained by fitting experimentally determined volume correction factors.</p> <p>Results</p> <p>A theoretical evaluation of volume correction factors for syringes is reported for three different experimental methods. The aim is to determine the most accurate experimental method among those considered, by examining the expression of uncertainty for the correction factor. This theoretical analysis was then tested experimentally.</p> <p>Conclusion</p> <p>The agreement between the experimental data obtained in the constant activity method and gravimetric method at constant specific activity and the small associated uncertainties show the accuracy of these two procedures; while the volumetric method at constant specific activity could lead to a wrong evaluation of the correction factors.</p

Effects of the VIVIFRAIL Exercise Protocol on Circulatory and Intracellular Peripheral Mediators Bridging Mitochondrial Dynamics and Inflammation in Robust and Frail Older People

Physical exercise has been associated with healthier aging trajectories, potentially preventing or mitigating age-related declines. This occurs through a complex, yet poorly characterized network of multi-organ interactions involving mitochondrial, inflammatory, and cell death/survival pathways. Here, we comprehensively evaluated the 12-week VIVIFRAIL multicomponent exercise protocol in physically frail (n = 16, mean age 81.4 ± 5.6) and robust (n = 50, mean-age 73.6 ± 4.7) old individuals. Before (T0) and after (T1) the protocol, functional outcomes were assessed alongside a detailed exploratory analysis of mitochondrial, inflammatory, apoptotic, and neuro-muscular mediators concerning their plasmatic/serum concentrations, and/or mRNA expression from peripheral blood mononuclear cells (PBMCs). Besides significant functional improvements across both groups, our findings highlighted unique and overlapping modulations of key biological pathways. Both groups showed refined mitochondrial integrity/turnover (upregulated mt-ND1, downregulated TFAM, and ULK1), anti-inflammatory responses (upregulated IL10, and TGF-B, and downregulated IL6/IL10 mRNA ratio), as well as reduced cellular damage/apoptosis (reduced plasmatic ccf-nDNA, downregulated BAX, and upregulated BCL-2/BAX ratio). Plasmatic ccf-mtDNA was significantly reduced in robust subjects, while plasmatic IL6 and IL6/IL10 ratio were reduced in frail subjects uniquely. Spearman correlations between physical improvements and biological pathway variations also suggested different adaptation mechanisms influenced not only by chronological age but also by frailty status. In conclusion, this study confirms the benefits of physical activity in the older population and provides novel insights into specific biological mediators of the mitochondria-inflammation axis as key players in such effects. Moreover, our findings establish PBMCs as a valuable tool for monitoring the biological trajectories of aging and health-promoting lifestyle interventions

An association study of cyclase-associated protein 2 and frailty

Frailty is a geriatric syndrome that results from multisystem impairment caused by age-associated accumulation of deficits. The frailty index is used to define the level of frailty. Several studies have searched for molecular biomarkers associated with frailty, to meet the needs for personalized care. Cyclase-associated protein 2 (CAP2) is a multifunctional actin-binding protein involved in various physiological and pathological processes, that might reflect frailty's intrinsic complexity. This study aimed to investigate the association between frailty index and circulating CAP2 concentration in 467 community-dwelling older adults (median age: 79; range: 65-92 years) from Milan, Italy. The selected robust regression model showed that circulating CAP2 concentration was not associated with chronological age, as well as sex and education. However, circulating CAP2 concentration was significantly and inversely associated with the frailty index: a 0.1-unit increase in frailty index leads to similar to 0.5-point mean decrease in CAP2 concentration. Furthermore, mean CAP2 concentration was significantly lower in frail participants (i.e., frailty index &amp; GE;0.25) than in non-frail participants. This study shows the association between serum CAP2 concentration and frailty status for the first time, highlighting the potential of CAP2 as a biomarker for age-associated accumulation of deficits

Estimating SARS-CoV-2 transmission in educational settings: a retrospective cohort study

Background School closures and distance learning have been extensively adopted to counter the COVID-19 pandemic. However, the contribution of school transmission to the spread of SARS-CoV-2 remains poorly quantified. Methods We analyzed transmission patterns associated with 976 SARS-CoV-2 exposure events, involving 460 positive individuals, as identified in early 2021 through routine surveillance and an extensive screening conducted on students, school personnel, and their household members in a small Italian municipality. In addition to population screenings and contact-tracing operations, reactive closures of class and schools were implemented. Results From the analysis of 152 clear infection episodes and 584 exposure events identified by epidemiological investigations, we estimated that approximately 50%, 21%, and 29% of SARS-CoV-2 transmission was associated with household, school, and community contacts, respectively. We found substantial transmission heterogeneities, with 20% positive individuals causing 75% to 80% of ascertained infection episodes. A higher proportion of infected individuals causing onward transmission was found among students (46.2% vs. 25%, on average), who also caused a markedly higher number of secondary cases (mean: 1.03 vs. 0.35). By reconstructing likely transmission chains from the entire set of exposures identified during contact-tracing operations, we found that clusters originated from students or school personnel were associated with a larger average cluster size (3.32 vs. 1.15) and a larger average number of generations in the transmission chain (1.56 vs. 1.17). Conclusions Uncontrolled SARS-CoV-2 transmission at school could disrupt the regular conduct of teaching activities, likely seeding the transmission into other settings, and increasing the burden on contact-tracing operations

Estimating SARS-CoV-2 transmission in educational settings: a retrospective cohort study

Background School closures and distance learning have been extensively adopted to counter the COVID-19 pandemic. However, the contribution of school transmission to the spread of SARS-CoV-2 remains poorly quantified. Methods We analyzed transmission patterns associated with 976 SARS-CoV-2 exposure events, involving 460 positive individuals, as identified in early 2021 through routine surveillance and an extensive screening conducted on students, school personnel, and their household members in a small Italian municipality. In addition to population screenings and contact-tracing operations, reactive closures of class and schools were implemented. Results From the analysis of 152 clear infection episodes and 584 exposure events identified by epidemiological investigations, we estimated that approximately 50%, 21%, and 29% of SARS-CoV-2 transmission was associated with household, school, and community contacts, respectively. We found substantial transmission heterogeneities, with 20% positive individuals causing 75% to 80% of ascertained infection episodes. A higher proportion of infected individuals causing onward transmission was found among students (46.2% vs. 25%, on average), who also caused a markedly higher number of secondary cases (mean: 1.03 vs. 0.35). By reconstructing likely transmission chains from the entire set of exposures identified during contact-tracing operations, we found that clusters originated from students or school personnel were associated with a larger average cluster size (3.32 vs. 1.15) and a larger average number of generations in the transmission chain (1.56 vs. 1.17). Conclusions Uncontrolled SARS-CoV-2 transmission at school could disrupt the regular conduct of teaching activities, likely seeding the transmission into other settings, and increasing the burden on contact-tracing operations

Diaphragm ultrasound evaluation during weaning from mechanical ventilation in COVID-19 patients: a pragmatic, cross-section, multicenter study

Background Diaphragmatic dysfunction is a major factor responsible for weaning failure in patients that underwent prolonged invasive mechanical ventilation for acute severe respiratory failure from COVID-19. This study hypothesizes that ultrasound measured diaphragmatic thickening fraction (DTF) could provide corroborating information for weaning COVID-19 patients from mechanical ventilation. Methods This was an observational, pragmatic, cross-section, multicenter study in 6 Italian intensive care units. DTF was assessed in COVID-19 patients undergoing weaning from mechanical ventilation from 1st March 2020 to 30th June 2021. Primary aim was to evaluate whether DTF is a predictive factor for weaning failure. Results Fifty-seven patients were enrolled, 25 patients failed spontaneous breathing trial (44%). Median length of invasive ventilation was 14 days (IQR 7-22). Median DTF within 24 h since the start of weaning was 28% (IQR 22-39%), RASS score (- 2 vs - 2; p = 0.031); Kelly-Matthay score (2 vs 1; p = 0.002); inspiratory oxygen fraction (0.45 vs 0.40; p = 0.033). PaO2/FiO(2) ratio was lower (176 vs 241; p = 0.032) and length of intensive care stay was longer (27 vs 16.5 days; p = 0.025) in patients who failed weaning. The generalized linear regression model did not select any variables that could predict weaning failure. DTF was correlated with pH (RR 1.56 x 10(27); p = 0.002); Kelly-Matthay score (RR 353; p &lt; 0.001); RASS (RR 2.11; p = 0.003); PaO2/FiO(2) ratio (RR 1.03; p = 0.05); SAPS2 (RR 0.71; p = 0.005); hospital and ICU length of stay (RR 1.22 and 0.79, respectively; p &lt; 0.001 and p = 0.004). Conclusions DTF in COVID-19 patients was not predictive of weaning failure from mechanical ventilation, and larger studies are needed to evaluate it in clinical practice further. Registered: ClinicalTrial.gov (NCT05019313, 24 August 2021)