Obesity represents one of the most important public health challenges of the 21st century and is characterized by a multifactorial etiology in which environmental, behavioral, metabolic, and genetic ...factors work together. Despite the rapid increase in prevalence of obesity in the last decades, especially in children, it remains a preventable disease. To battle obesity a multisector approach promoting healthier lifestyle in terms of physical activity and nutrition is needed. Specifically, biologically active dietary compounds, as polyphenols, are able to modulate the expression of genes involved in the development and progression of obesity and its comorbidities as demonstrated by multiple studies using different obesity models. However, human studies focusing on the transcriptomic modulation by polyphenols in obese patients are still limited and do not often recapitulate the results obtained in preclinical setting likely due to the underestimation of some variables such as bioavailability, dose and form (native vs. metabolized) of polyphenols used. The aim of this review is to summarize the state-of-art of nutrigenomic in vitro, in vivo and ex vivo studies as well as clinical trials based on dietary polyphenols to fight obesity. We also critical discuss the variables to be considered to fill the gap between preclinical and clinical settings.
An increasing number of rare mutations linked to autism spectrum disorders have been reported in genes encoding for proteins involved in synapse formation and maintenance, such as the post-synaptic ...cell adhesion proteins neuroligins. Most of the autism-linked mutations in the neuroligin genes map on the extracellular protein domain. The autism-linked substitution R451C in Neuroligin3 (NLGN3) induces a local misfolding of the extracellular domain, causing defective trafficking and retention of the mutant protein in the endoplasmic reticulum (ER). The activation of the unfolded protein response (UPR), due to misfolded proteins accumulating in the ER, has been implicated in pathological and physiological conditions of the nervous system. It was previously shown that the over-expression of R451C NLGN3 in a cellular system leads to the activation of the UPR. Here, we have investigated whether this protective cellular response is detectable in the knock-in mouse model of autism endogenously expressing R451C NLGN3. Our data showed up-regulation of UPR markers uniquely in the cerebellum of the R451C mice compared to WT littermates, at both embryonic and adult stages, but not in other brain regions. Miniature excitatory currents in the Purkinje cells of the R451C mice showed higher frequency than in the WT, which was rescued inhibiting the PERK branch of UPR.
Taken together, our data indicate that the R451C mutation in neuroligin3 elicits UPR in vivo, which appears to trigger alterations of synaptic function in the cerebellum of a mouse model expressing the R451C autism-linked mutation.
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•In vivo, R451C NLGN3 is partially retained in the ER.•UPR is uniquely detected in the cerebellum of the R451C NLGN3 knock-in mouse•Higher frequency of mEPSCs are found in the Purkinje cells of the R451C mouse•Inhibiting UPR rescues the excitatory functional phenotype in the Purkinje cells•UPR modulates glutamate release in the cerebellum of the R451C NLGN3 mouse model
Increasing evidence demonstrates a phenotypic plasticity of endothelial cells (ECs). Endothelial-to-mesenchymal transition (EndMT) contributes to the development of tissue fibrosis. However, the ...pathogenic factors and signalling pathways regulating this process in ischaemia/reperfusion (I/R) injury are still poorly understood.
We investigated the possible role of complement in the induction of this endothelial dysfunction in a swine model of renal I/R injury by using recombinant C1 inhibitor in vivo.
Here, we showed that I/R injury reduced the density of renal peritubular capillaries and induced tissue fibrosis with generation of CD31(+)/α-SMA(+) and CD31(+)/FPS-1(+) cells indicating EndMT. When we inhibited complement, the process of EndMT became rare, with preserved density of peritubular capillaries and significant reduction in renal fibrosis. When we activated ECs by anaphylatoxins in vitro, C3a and C5a led to altered endothelial phenotype with increased expression of fibroblast markers and decrease expression of specific endothelial markers. The activation of Akt pathway was pivotal for the C3a and C5a-induced EndMT in vitro. In accordance, inhibition of complement in vivo led to the abrogation of Akt signalling, with hampered EndMT and tissue fibrosis.
Our data demonstrate a critical role for complement in the acute induction of EndMT via the Akt pathway. Therapeutic inhibition of these systems may be essential to prevent vascular damage and tissue fibrosis in transplanted kidney.
A programmable multichannel antialiasing filter for the CUORE experiment Arnaboldi, C.; Cariello, M.; Di Domizio, S. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
05/2010, Letnik:
617, Številka:
1
Journal Article
Recenzirano
The first prototype of antialiasing filter for the CUORE experiment is a board that accommodates 12 independent channels. Each channel is an active six-pole Bessel–Thomson low-pass filter (LPF) with ...a roll-off of 120
dB/decade. In order to adapt the bandwidth to every detector, the filtering frequency can be selected independently for every channel by a remote control between four possible values (8, 12, 16 or 20
Hz). The board is equipped with an ARM microcontroller which communicates with the on-board peripherals via I2C synchronous serial bus and with the remote control via CAN-bus. Important features are the low-cost, the compact realization and the capability to perform diagnostic routine remotely.
Rapamycin, an immunosuppressive drug used to prevent rejection after kidney transplantation, influences phosphate homeostasis, induces insulin resistance and has been shown to prolong lifespan in ...animal models. Because Klotho is an aging‐suppressor gene controlling phosphate metabolism and insulin sensitivity, we investigated the influence of rapamycin on Klotho expression. A total of 100 kidney transplant recipients, 50 chronically treated with rapamycin and 50 with calcineurin inhibitors, were enrolled; 20 healthy subjects were employed as control. In the rapamycin group, serum phosphate was lower than in the CNI group with an increase in phosphate excretion and a reduction in its reabsorption. In addition, rapamycin increased insulin resistance as shown by HOMA index. Rapamycin treatment of an immortalized proximal tubular cell line induced the expression of Klotho, the phosphorylation of AKT in Ser473, downstream target of mTORC2 and the expression of RICTOR, mTORC2 main component. AKT inhibition reduced the rapamycin‐induced expression of Klotho. In vivo rapamycin treatment induced higher degree of RICTOR and AKT Ser473 expression directly correlating with long‐term rapamycin exposure, FEPO4 and HOMA index. In conclusion, our data would suggest that rapamycin may influence phosphate homeostasis and insulin resistance modulating Klotho expression through mTORC2 activation.
Rapamycin influences phosphate homeostasis and insulin resistance modulating klotho expression in epithelial tubular cells and this event is mediated by mTORC2 through AKT phosphorylation.
► We measured the elongation of a loaded Kevlar-49 fiber at 4.2K. ► We kept a fiber under a constant tension for 8months. ► We obtained an upper limit of 0.028% in the relative elongation. ► The ...results shows that Kevlar-49 can be used in cryogenic applications.
We have measured the rate of elongation of a loaded Kevlar-49 fiber as a function of time at 4.2K. The result puts a worst case upper limit of 0.028% in the elongation rate ΔL/L for a 0.5mm diameter fiber kept under a constant tension of 2.7kg for 8months. A value that is probably closer to reality is actually 0.004%. This result proves that Kevlar-49 can be safely used in cryogenic applications in which high mechanical stability under stress is required.
Abstract
Background
The current Risk Score for Life-Threatening Ventricular Tachyarrhythmias (LTVT) in LMNA cardiomyopathy does not consider the frequent association between cardiac and neuromuscular ...phenotypes as a part of a multisystemic disease. In particular, the prognostic value of tendon retractions (TR) has been recently described.
Objectives
We aimed to assess the prognostic role of TR in a cohort of probands with LMNA cardiomyopathy undergoing multidisciplinary workup at a referral center.
Methods
We included 28 probands with LMNA cardiomyopathy undergoing regular, prospective follow-up at a national referral center for laminopathies. All patients underwent extensive baseline characterization, including complete neuromuscular examination and systematic assessment of TR. Indications to implantable cardioverter defibrillators (ICD) for the primary prevention of sudden cardiac death were guideline-based. Patients were clustered in tertiles according to their baseline LMNA-Risk Score. The primary endpoint was the 5-year occurrence of LTVT, namely arrhythmic cardiac death, VF, sustained VT, or appropriate ICD shocks.
Results
Of the 28 probands with LMNA cardiomyopathy (mean age 33±15 years, 50% males, mean LVEF 55±14 %), neurological assessment identified 14 patients (50%) with TR, including 8 cases with no other signs of neuromuscular involvement. At baseline assessment, the median LMNA-Risk Score was 10% (IQR 6-20%). By 5-year follow-up, 9 patients (32%) met the primary endpoint, including three patients in the lowest tertiles of risk (median LMNA-Risk Score 23, range 6-15%). While other variables showed no remarkable differences between groups, the prevalence of TR was 78% among cases experiencing LTVT and 37% otherwise. The presence of either baseline LMNA-Risk score at the highest tertile (>17%) or TR was 100% predictive of 5-year LTVT (9/9 vs. 7/19, p=0.003). Results did not change after reassessment by the end of follow-up (15±5 years).
Conclusions
Our preliminary data suggest that the inclusion of TR in risk stratification may result in a better patient selection for primary prevention ICD implant in LMNA cardiomyopathy.
Cardiometabolic risk factors increase the risk of atherosclerotic cardiovascular disease (ASCVD), but whether these metabolic anomalies affect the anti-atherogenic function of reverse cholesterol ...transport (RCT) is not yet clearly known. The present study aimed to delineate if the function and maturation of high density lipoprotein (HDL) particles cross-sectionally associate with surrogate markers of ASCVD in a population comprising of different degree of cardiometabolic risk.
We enrolled 131 subjects and characterized cardiometabolic risk based on the IDF criteria's for metabolic syndrome (MS). In this population, cholesterol efflux capacity (CEC), Lecithin–cholesterol acyltransferase (LCAT) and ApoA-1 glycation was associated with waist circumference, abdominal visceral fat (VFA) and abdominal subcutaneous fat. In multivariate analyses, VFA was identified as a critical contributor for low CEC and LCAT. When stratified into groups based on the presence of cardiometabolic risk factors, we found a prominent reduction in CEC and LCAT as a function of the progressive increase of cardiometabolic risk from 0–2, 0–3 to 0–4/5, whereas an increase in Pre-β-HDL and ApoA-1 glycation was observed between the lowest and highest risk groups.
These findings confirm the connection between MS and its predisposing conditions to an impairment of atheroprotective efflux-promoting function of HDLs. Furthermore, we have identified the bona fide pathogenically contribution of abdominal obesity to profound alterations of key metrics of RCT.
•Abdominal obesity is associated with impairment of HDL function.•Enhanced glycation of ApoA1 and abdominal visceral fat relates with low plasma LCAT.•Cardio-metabolic risk clustering disturbs RCT before manifestation of the MS.
Front-end electronic system for large area photomultipliers readout Bottino, B.; Caminata, A.; Cariello, M. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
08/2019, Letnik:
936
Journal Article
Recenzirano
We developed a front-end electronic system for large area photomultipliers. Connection to the PMT can be made by a single cable, useful to minimize cabling in a underwater detector. The cabling is ...done in the rear part of the crate to permit easy access to the electronic boards. A front-end board houses 8 channels each one is composed by a preamplifier and a leading edge discriminator. Up to 8 front-end boards can be housed in a crate, giving a modularity of 64 channels. A controller board is needed to setup and monitor the front-end parameters. This board implements also scalers and time to digital converters with time over threshold capability. A standard gigabit ethernet line is used for communication with the outside world. Details on the design and specification of the system is reported together some preliminary measurements done with the prototypes now under test in laboratory.
•Underwater detectors with large number of channels need dedicated data acquisition system.•Compact and modular systems are mandatory to build up the system.•FPGA are always used to have the maximum flexibility in implementing user logic.
Increased Fibroblast Growth Factor-21 (FGF-21) circulating levels have been described in obesity. In this observational study, we analysed a group of subjects with metabolic disorders to unravel the ...putative link between visceral adiposity and FGF-21 serum levels.
Total and intact serum FGF-21 concentration was measured with an ELISA assay respectively in 51 and 46 subjects, comparing FGF-21 levels in dysmetabolic conditions. We also tested Spearman's correlations between FGF-21 serum levels and biochemical and clinical metabolic parameters.
FGF-21 was not significantly increased in high-risk conditions such as visceral obesity, Metabolic Syndrome, diabetes, smoking, and atherosclerosis. Waist Circumference (WC), but not BMI, positively correlated with total FGF-21 levels (r=0.31, p <0.05), while HDL-cholesterol (r=-0.29, p <0.05) and 25-OH Vitamin D (r=-0.32, p <0.05) showed a significant negative correlation with total FGF-21. ROC analysis of FGF-21 in prediction of increased WC, showed that patients with total FGF-21 level over cut-off value of 161.47 pg/mL presented with impaired FPG. Conversely, serum levels of the intact form of FGF-21 did not correlate with WC and other metabolic biomarkers.
Our newly calculated cut-off for total FGF-21 according to visceral adiposity identified subjects with fasting hyperglycemia. However, waist circumference correlates with total FGF-21 serum levels but does not correlate with intact FGF-21, suggesting that functional FGF-21 does not necessarily relate with obesity and metabolic features.
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