Antibacterial-Nanocomposite Bone Filler Based on Silver Nanoparticles and Polysaccharides

Injectable bone fillers represent an attractive strategy for the treatment of bone defects. These injectable materials should be biocompatible, capable of supporting cell growth and possibly able to exert antibacterial effects. In this work, nanocomposite microbeads based on alginate, chitlac, hydroxyapatite and silver nanoparticles were prepared and characterized. The dried microbeads displayed a rapid swelling in contact with simulated body fluid and maintained their integrity for more than 30\ua0days. The evaluation of silver leakage from the microbeads showed that the antibacterial metal is slowly released in saline solution, with less than 6% of silver released after 1\ua0week. Antibacterial tests proved that the microbeads displayed bactericidal effects toward S. aureus, P. aeruginosa and S. epidermidis and were also able to damage pre-formed bacterial biofilms. On the other hand, the microbeads did not exert any cytotoxic effect towards osteoblast-like cells. After characterization of the bioactive microbeads, a possible means to embed them in a fluid medium was explored in order to obtain an injectable paste. Upon suspension of the particles in alginate solution or alginate/hyaluronic acid mixtures, a homogenous and time-stable paste was obtained. Mechanical tests enabled to quantify the extrusion forces from surgical syringes, pointing out the proper injectability of the material. This novel antibacterial bone-filler appears as a promising material for the treatment of bone defects, in particular when possible infections could compromise the bone-healing process

Genomic landscape of rat strain and substrain variation

Background: Since the completion of the rat reference genome in 2003, whole-genome sequencing data from more than 40 rat strains have become available. These data represent the broad range of strains that are used in rat research including commonly used substrains. Currently, this wealth of information cannot be used to its full extent, because the variety of different variant calling algorithms employed by different groups impairs comparison between strains. In addition, all rat whole genome sequencing studies to date used an outdated reference genome for analysis (RGSC3.4 released in 2004). Results: Here we present a comprehensive, multi-sample and uniformly called set of genetic variants in 40 rat strains, including 19 substrains. We reanalyzed all primary data using a recent version of the rat reference assembly (RGSC5.0 released in 2012) and identified over 12 million genomic variants (SNVs, indels and structural variants) among the 40 strains. 28,318 SNVs are specific to individual substrains, which may be explained by introgression from other unsequenced strains and ongoing evolution by genetic drift. Substrain SNVs may have a larger predicted functional impact compared to older shared SNVs. Conclusions: In summary we present a comprehensive catalog of uniformly analyzed genetic variants among 40 widely used rat inbred strains based on the RGSC5.0 assembly. This represents a valuable resource, which will facilitate rat functional genomic research. In line with previous observations, our genome-wide analyses do not show evidence for contribution of multiple ancestral founder rat subspecies to the currently used rat inbred strains, as is the case for mouse. In addition, we find that the degree of substrain variation is highly variable between strains, which is of importance for the correct interpretation of experimental data from different labs

Translational control of cardiac fibrosis

Background Fibrosis is a common pathology in many cardiac disorders and is driven by the activation of resident fibroblasts. The global post-transcriptional mechanisms underlying fibroblast-to-myofibroblast conversion in the heart have not been explored. Methods Genome-wide changes of RNA transcription and translation during human cardiac fibroblast activation were monitored with RNA sequencing and ribosome profiling. We then used miRNA-and RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes. To reveal post-transcriptional mechanisms in the human fibrotic heart, we then integrated our findings with cardiac ribosome occupancy levels of 30 dilated cardiomyopathy patients. Results We generated nucleotide-resolution translatome data during the TGFβ1-driven cellular transition of human cardiac fibroblasts to myofibroblasts. This identified dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early-responder genes. Remarkably, about one-third of all changes in gene expression in activated fibroblasts are subject to translational regulation and dynamic variation in ribosome occupancy affects protein abundance independent of RNA levels. Targets of RNA-binding proteins were strongly enriched in post-transcriptionally regulated genes, suggesting genes such as MBNL2 can act as translational activators or repressors. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggested an extensive post-transcriptional regulatory network underlying cardiac fibrosis. Key network hubs include RNA-binding proteins such as PUM2 and QKI that work in concert to regulate the translation of target transcripts in human diseased hearts. Conclusions We reveal widespread translational effects of TGFβ1 and define novel post-transcriptional events that control the fibroblast-to-myofibroblast transition. Regulatory networks that affect ribosome occupancy in fibroblasts are paralleled in human heart disease. Our findings show the central importance of translational control in fibrosis and highlight novel pathogenic mechanisms in heart failure

Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel mechanism

Primary carnitine deficiency (PCD) is an autosomal recessive monogenic disorder caused by mutations in SLC22A5. This gene encodes for OCTN2, which transports the essential metabolite carnitine into the cell. PCD patients suffer from muscular weakness and dilated cardiomyopathy. Two OCTN2-defective human induced pluripotent stem cell lines were generated, carrying a full OCTN2 knockout and a homozygous OCTN2 (N32S) loss-of-function mutation. OCTN2-defective genotypes showed lower force development and resting length in engineered heart tissue format compared with isogenic control. Force was sensitive to fatty acid-based media and associated with lipid accumulation, mitochondrial alteration, higher glucose uptake, and metabolic remodeling, replicating findings in animal models. The concordant results of OCTN2 (N32S) and -knockout emphasizes the relevance of OCTN2 for these findings. Importantly, genome-wide analysis and pharmacological inhibitor experiments identified ferroptosis, an iron- and lipid-dependent cell death pathway associated with fibroblast activation as a novel PCD cardiomyopathy disease mechanism

Titin-truncating variants affect heart function in disease cohorts and the general population

Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ~1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease

Rattus norvegicus BN/SHR liver and heart left ventricle ribosomal RNA depleted directional RNA sequencing

Abstract Objective The spontaneously hypertensive rat strain is a frequently used disease model. In a previous study, we measured translational efficiency from this strain and BN-Lx animals. Here, we describe long RNA sequencing reads from ribosomal RNA depleted samples from the same animals. This data can be used to investigate splicing-related events. Results RNA was extracted from rat liver and heart left ventricle from BN-Lx and SHR/Ola rats in biological replicates. Ribosomal RNA was removed and the samples subjected to directional high-throughput RNA-sequencing. Read and alignment statistics indicate high quality of the data. The raw sequencing reads are freely available on the NCBI short read archive and can be used for further research on tissue and strain differences, or analysed together with other published high-throughput data from the same animals

The pro-regenerative effects of hyperil6 in drug induced liver injury are unexpectedly due to competitive inhibition of il11 signaling

10.7554/elife.68843eLife10e6884

Rough and Porous Micropebbles of CeCu₂Si₂ for Energy Storage Applications

Supercapacitors have attracted considerable attention due to their advantages, including being lightweight and having rapid charge–discharge, a good rate capability, and high cyclic stability. Electrodes are one of the most important factors influencing the performance of supercapacitors. Herein, a three-dimensional network of rough and porous micropebbles of CeCu2Si2 has been prepared using a one-step procedure and tested for the first time as a supercapacitor electrode. The synthesized material was extensively characterized in a three-electrode configuration using different electrochemical techniques, such as cyclic voltammetry (CV), galvanostatic charge and discharge (GCD) tests, and electrochemical impedance spectroscopy (EIS). CeCu2Si2 shows rather high mass-capacitance values: 278 F/g at 1 A/g and 295 F/g at 10 mV/s. Moreover, the material exhibits remarkable long-term stability: 98% of the initial capacitance was retained after 20,000 cycles at 10 A/g and the Coulombic efficiency remains equal to 100% at the end of the cycles

Cardiorespiratory fitness, energy intake and cardiovascular risk in a sample of Paralympic athletes with locomotor impairment

Purpose: To evaluate the possible relationship between oxygen uptake peak (VO2peak), energy and macronutrient intakes (E&MI) and cardiovascular and inflammatory risks (CVR and InR) in a population of Paralympic athletes (PA) with a locomotor impairment (PA-LI). Methods: A retrospective chart review of the health and fitness evaluations preceding London 2012 Paralympic Games1 was performed in 46 male PA-LI. They were divided in 2 groups depending on their health conditions: 29 PA with spinal cord injury (PA-SCI, mean age: 37±8.9 years old), and 17 PA with other health conditions, e.g., lower limb amputation and poliomyelitis (PA-OHC, mean age: 35±9.1 years old). They underwent anthropometry assessment (standard and skinfold measurements); laboratory blood tests, including C reactive protein (CRP) and uric acid to estimate InR; nutritional 24-hour recall to assess energy and macronutrient intakes (E&MI); arm cranking ergometer incremental maximal exercise tests to measure VO2peak. CVR was estimated through 3 indices: fatty liver index2 (FLI), lipid accumulation product3 (LAP) and visceral adiposity index4 (VAI). FLI was calculated from body mass index (BMI), waist circumference (WC), gamma-GT and triglycerides (TG); LAP from WC and TG; VAI from BMI, WC, TG and high-density lipoprotein cholesterol. Mann-Whitney test and Spearman correlations were performed to compare the groups and to evaluate the relationship between variables, respectively. Results: In spite of no differences in E&MI, body composition and CVR indices, PA-SCI vs PA-OHC showed lower VO2peak (30±10.6 vs 37±7.9 ml/kg/min, p<0.01) and higher CRP (1.37, IQR: 0.53-1.79 vs 0.33, IQR: 0.26-0.96 mg/l, p <0.01). VO2peak/kg correlated negatively with uric acid levels (r: -0.563, p<0.0001), CRP levels (r: -0.425, p<0.01), FLI (r: -0.564, p<0.0001), LAP (r: -0.513, p=0.0001) and VAI (r: -0.558, p<0.001). Conclusion: In PA-LI VO2peak is inversely related to markers and indices of InR and CVR, suggesting a protective role of the cardiorespiratory fitness on health. Physical exercise5 and sport6 are highly recommended to improve VO2peak