Properties of graphene-related materials controlling the thermal conductivity of their polymer nanocomposites

Different types of graphene-related materials (GRM) are industrially available and have been exploited for thermal conductivity enhancement in polymers. These include materials with very different features, in terms of thickness, lateral size and composition, especially concerning the oxygen to carbon ratio and the possible presence of surface functionalization. Due to the variability of GRM properties, the differences in polymer nanocomposites preparation methods and the microstructures obtained, a large scatter of thermal conductivity performance is found in literature. However, detailed correlations between GRM-based nanocomposites features, including nanoplatelets thickness and size, defectiveness, composition and dispersion, with their thermal conductivity remain mostly undefined. In the present paper, the thermal conductivity of GRM-based polymer nanocomposites, prepared by melt polymerization of cyclic polybutylene terephtalate oligomers and exploiting 13 different GRM grades, was investigated. The selected GRM, covering a wide range of specific surface area, size and defectiveness, secure a sound basis for the understanding of the effect of GRM properties on the thermal conductivity of their relevant polymer nanocomposites. Indeed, the obtained thermal conductivity appeares to depend on the interplay between the above GRM feature. In particular, the combination of low GRM defectiveness and high filler percolation density was found to maximize the thermal conductivity of nanocomposites

An Efficient Time-Varying Filter for Detrending and Bandwidth Limiting the Heart Rate Variability Tachogram without Resampling: MATLAB Open-Source Code and Internet Web-Based Implementation

The heart rate variability (HRV) signal derived from the ECG is a beat-to-beat record of RR intervals and is, as a time series, irregularly sampled. It is common engineering practice to resample this record, typically at 4 Hz, onto a regular time axis for analysis in advance of time domain filtering and spectral analysis based on the DFT. However, it is recognised that resampling introduces noise and frequency bias. The present work describes the implementation of a time-varying filter using a smoothing priors approach based on a Gaussian process model, which does not require data to be regular in time. Its output is directly compatible with the Lomb-Scargle algorithm for power density estimation. A web-based demonstration is available over the Internet for exemplar data. The MATLAB (MathWorks Inc.) code can be downloaded as open source

20S proteasome mediated degradation of DHFR: implications in neurodegenerative disorders

The 20S proteasome is responsible for the degradation of protein substrates implicated in the onset and progression of neurodegenerative disorders, such as a-synuclein and tau protein. Here we show that the 20S proteasome isolated from bovine brain directly hydrolyzes, in vitro, the dihydrofolate reductase (DHFR), demonstrated to be involved in the pathogenesis of neurodegenerative diseases. Furthermore, the DHFR susceptibility to proteolysis is enhanced by oxidative conditions induced by peroxynitrite, mimicking the oxidative environment typical of these disorders. The results obtained suggest that the folate metabolism may be impaired by an increased degradation of DHFR, mediated by the 20S proteasome

Crosstalk between the ubiquitin-proteasome system and autophagy in a human cellular model of Alzheimer's disease

Alzheimer's disease is the most common progressive neurodegenerative disorder characterized by the abnormal deposition of amyloid plaques, likely as a consequence of an incorrect processing of the amyloid-β precursor protein (AβPP). Dysfunctions in both the ubiquitin-proteasome system and autophagy have also been observed. Recently, an extensive cross-talk between these two degradation pathways has emerged, but the exact implicated processes are yet to be clarified. In this work, we gained insight into such interplay by analyzing human SH-SY5Y neuroblastoma cells stably transfected either with wild-type AβPP gene or 717 valine-to-glycine AβPP-mutated gene. The over-expression of the AβPP mutant isoform correlates with an increase in oxidative stress and a remodeled pattern of protein degradation, with both marked inhibition of proteasome activities and impairment in the autophagic flux. To compensate for this altered scenario, cells try to promote the autophagy activation in a HDAC6-dependent manner. The treatment with amyloid-β(42) oligomers further compromises proteasome activity and also contributes to the inhibition of cathepsin-mediated proteolysis, finally favoring the neuronal degeneration and suggesting the existence of an Aβ(42) threshold level beyond which proteasome-dependent proteolysis becomes definitely dysfunctional

Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS

Ambulatory heart rate range predicts mode-specific mortality and hospitalisation in chronic heart failure

Objective: We aimed to define the prognostic value of the heart rate range during a 24 h period in patients with chronic heart failure (CHF). Methods: Prospective observational cohort study of 791 patients with CHF associated with left ventricular systolic dysfunction. Mode-specific mortality and hospitalisation were linked with ambulatory heart rate range (AHRR; calculated as maximum minus minimum heart rate using 24 h Holter monitor data, including paced and non-sinus complexes) in univariate and multivariate analyses. Findings were then corroborated in a validation cohort of 408 patients with CHF with preserved or reduced left ventricular ejection fraction. Results: After a mean 4.1 years of follow-up, increasing AHRR was associated with reduced risk of all-cause, sudden, non-cardiovascular and progressive heart failure death in univariate analyses. After accounting for characteristics that differed between groups above and below median AHRR using multivariate analysis, AHRR remained strongly associated with all-cause mortality (HR 0.991/bpm increase in AHRR (95% CI 0.999 to 0.982); p=0.046). AHRR was not associated with the risk of any non-elective hospitalisation, but was associated with heart-failure-related hospitalisation. AHRR was modestly associated with the SD of normal-to-normal beats (R2=0.2; p<0.001) and with peak exercise-test heart rate (R2=0.33; p<0.001). Analysis of the validation cohort revealed AHRR to be associated with all-cause and mode-specific death as described in the derivation cohort. Conclusions: AHRR is a novel and readily available prognosticator in patients with CHF, which may reflect autonomic tone and exercise capacity