MMP-13, VEGF, and Disease Activity in a Cohort of Rheumatoid Arthritis Patients.

Identifying certain serum biomarkers associated with the degree of rheumatoid arthritis (RA) activity can provide us with a more accurate view of the evolution, prognosis, and future quality of life for these patients. Our aim was to analyze the presence and clinical use of matrix metalloproteinase-13 (MMP-13), along with vascular endothelial growth factor (VEGF) and well-known cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) for patients with RA. We also wanted to identify the possible correlations between MMP-13 and these serological markers, as well as their relationship with disease activity indices, quality of life, and ultrasonographic evaluation. For this purpose, we analyzed serum samples of 34 RA patients and 12 controls. In order to assess serum concentrations for MMP-13, VEGF, TNF-α, and IL-6, we used the enzyme-linked immunosorbent assay (ELISA) technique. Our results concluded that higher levels of MMP-13, VEGF, TNF-α, and IL-6 were present in the serum of RA patients compared to controls, with statistical significance. We furthermore identified moderately positive correlations between VEGF, MMP-13, and disease activity indices, as well as with the ultrasound findings. We also observed that VEGF had the best accuracy (97.80%), for differentiating patients with moderate disease activity. According to the data obtained in our study, that although MMP-13, TNF-α and C-reactive protein (CRP) have the same sensitivity (55.56%), MMP-13 has a better specificity (86.67%) in the diagnosis of patients with DAS28(4v) CRP values corresponding to moderate disease activity. Thus, MMP-13 can be used as a biomarker that can differentiate patients with moderate or low disease activity. VEGF and MMP-13 can be used as additional parameters, along with TNF-α and IL-6, that can provide the clinician a better picture of the inflammatory process, disease activity, and structural damage in patients with RA. Our data can certainly constitute a start point for future research and extended studies with multicenter involvement, to support the selection of individualized and accurate therapeutic management strategies for our patients.

An effective solution to boost generation from waves: Benefits of a hybrid energy storage system integration to wave energy converter in grid-connected systems.

Background: Wave energy represents one of the most promising renewable energies due to its great theoretical potential. Nevertheless, the electrical compliance of grid-connected systems is a great issue nowadays, due to the highly stochastic nature of wave energy. Methods: In this paper, a Hybrid Energy Storage System (HESS) consisting of a Li-ion battery and a flywheel is coupled to a Wave Energy Converter (WEC) that operates in grid connected mode. The study is performed using real yearly wave power profiles relating to three different sites located along the European coasts. The Simultaneous Perturbation Stochastic Approximation (SPSA) principle is implemented as real-time power management strategy for HESS in wave energy conversion systems. Results: Obtained results demonstrate how the proposed HESS and the implementation of the SPSA power management coupled to a WEC allow a reduction of more than 80% of power oscillations at the Point of Common Coupling (PCC), while proving the robustness of the developed management strategy over the investigated sites. Moreover, the average energy penalty due to the HESS integration results slightly higher than 5% and battery solicitation is reduced by more than 64% with respect to the flywheel solicitation, contributing to extend its lifetime. Conclusions: HESS integration in renewable generation systems maximizes the WEC production while smoothing the power at the PCC. Specifically, flywheel-battery HESS together with the implemented power management strategy could provide a great flexibility in the view of increasing power production from waves, strongly mitigating the variability of this source while enhancing grid safety and stability.

New insights into IL-17/IL-23 signaling in ankylosing spondylitis (Review).

Ankylosing spondylitis (AS) is a progressive common autoimmune inflammatory disease, part of the spondylarthritis group, characterized, besides clinical spinal and peripheral joint inflammation, by enthesitis and new bone formation, that can lead to severe functional impairment. Beyond intensive and continuous research on the pathogenic process extensively performed in recent years, their impact on therapeutic management remains open to future development. Better knowledge of AS pathogenesis have shown results progressively and studies are being performed to advance our current understanding of the disease. It is well known that tumor necrosis factor (TNF) exerts a central role, along with interleukin-17 (IL-17) and interleukin-23 (IL-23), demonstrated by several clinical studies. Similar to other rheumatic inflammatory conditions, SA is associated with an early process of systemic bone loss, both trabecular and cortical, consecutive osteopenia, osteoporosis, and high fracture risk. Current personalized therapeutic options benefit from new published data, to prevent future complications and to improve quality of life.

JAK/STAT pathway in pathology of rheumatoid arthritis (Review).

Rheumatoid arthritis (RA) is classified as an inflammatory, chronic autoimmune and disabling disease based on the intricate interplay between environmental and genetic factors. With a prevalence ranging from 0.3 to 1%, RA is the most prevalent inflammatory joint disease observed in adults. Disruption of immune tolerance becomes evident when abnormal stimulation of the innate and adaptive immune system occurs. This cascade of events causes persistent joint inflammation, proliferative synovitis and, ultimately, damage of the underlying cartilage as well as the subchondral bone, leading to permanent joint destruction, deformity and subsequent loss of function. With cytokines being the key to a multitude of biological processes, including inflammation, hematopoiesis and overall immune response, one must inevitably look at the main pathways through which a significant number of those molecules exert their function. Janus kinase/signal transducers and activators of transcription (JAK/STATs) represent one such pathway and, recently, JAK inhibitors (JAKinibs) have shown promise in the treatment of several inflammatory diseases, including RA. This narrative review focuses on the intricate signaling pathways involved as well as on the clinical aspects and safety profiles of JAKinibs approved for the treatment of RA.

Neuroinflammation in systemic lupus erythematosus - a review.

Neuroinflammation is a complex process that contributes to the pathogenesis of both immune mediated and neurodegenerative pathologies. Systemic lupus erythematosus (SLE) is the prototype of connective tissue diseases that can present the complete spectrum of neurological and psychiatric dysfunctions. The precise etiological diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) is rather difficult to be established and it is still controversial the exact timing of neuropsychiatric (NPS) events: either central nervous system (CNS) is the initial target of autoimmune abnormalities, either NPS symptoms are a part of multisystem involvement. Ischemic and inflammatory mechanisms have an important input on NPSLE pathogenesis. Neuroinflammation, consequent to blood-brain barrier (BBB) damage, local and systemic production of autoantibodies, determine neuronal injury and apoptosis, further responsible for diffuse cerebral events, mostly cognitive dysfunction and psychotic disorder. Moreover, SLE complications or therapy complications can interfere and contribute to complex clinical manifestations that can be present in SLE patients. Understanding the role of each pathogenic way can provide not only an early diagnosis, but a more accurate therapeutic approach of these patients.

Rationally designed, heterologous S. cerevisiae transcripts expose novel expression determinants.

Deducing generic causal relations between RNA transcript features and protein expression profiles from endogenous gene expression data remains a major unsolved problem in biology. The analysis of gene expression from heterologous genes contributes significantly to solving this problem, but has been heavily biased toward the study of the effect of 5' transcript regions and to prokaryotes. Here, we employ a synthetic biology driven approach that systematically differentiates the effect of different regions of the transcript on gene expression up to 240 nucleotides into the ORF. This enabled us to discover new causal effects between features in previously unexplored regions of transcripts, and gene expression in natural regimes. We rationally designed, constructed, and analyzed 383 gene variants of the viral HRSVgp04 gene ORF, with multiple synonymous mutations at key positions along the transcript in the eukaryote S. cerevisiae. Our results show that a few silent mutations at the 5'UTR can have a dramatic effect of up to 15 fold change on protein levels, and that even synonymous mutations in positions more than 120 nucleotides downstream from the ORF 5'end can modulate protein levels up to 160%-300%. We demonstrate that the correlation between protein levels and folding energy increases with the significance of the level of selection of the latter in endogenous genes, reinforcing the notion that selection for folding strength in different parts of the ORF is related to translation regulation. Our measured protein abundance correlates notably(correlation up to r = 0.62 (p=0.0013)) with mean relative codon decoding times, based on ribosomal densities (Ribo-Seq) in endogenous genes, supporting the conjecture that translation elongation and adaptation to the tRNA pool can modify protein levels in a causal/direct manner. This report provides an improved understanding of transcript evolution, design principles of gene expression regulation, and suggests simple rules for engineering synthetic gene expression in eukaryotes.

Mean of the typical decoding rates: a new translation efficiency index based on the analysis of ribosome profiling data.

Gene translation modeling and prediction is a fundamental problem that has numerous biomedical implementations. In this work we present a novel, user-friendly tool/index for calculating the mean of the typical decoding rates that enables predicting translation elongation efficiency of protein coding genes for different tissue types, developmental stages, and experimental conditions. The suggested translation efficiency index is based on the analysis of the organism's ribosome profiling data. This index could be used for example to predict changes in translation elongation efficiency of lowly expressed genes that usually have relatively low and/or biased ribosomal densities and protein levels measurements, or can be used for example for predicting translation efficiency of new genetically engineered genes. We demonstrate the usability of this index via the analysis of six organisms in different tissues and developmental stages. Distributable cross platform application and guideline are available for download at: http://www.cs.tau.ac.il/~tamirtul/MTDR/MTDR_Install.html.

The effect of tRNA levels on decoding times of mRNA codons.

The possible effect of transfer ribonucleic acid (tRNA) concentrations on codons decoding time is a fundamental biomedical research question; however, due to a large number of variables affecting this process and the non-direct relation between them, a conclusive answer to this question has eluded so far researchers in the field. In this study, we perform a novel analysis of the ribosome profiling data of four organisms which enables ranking the decoding times of different codons while filtering translational phenomena such as experimental biases, extreme ribosomal pauses and ribosome traffic jams. Based on this filtering, we show for the first time that there is a significant correlation between tRNA concentrations and the codons estimated decoding time both in prokaryotes and in eukaryotes in natural conditions (-0.38 to -0.66, all P values <0.006); in addition, we show that when considering tRNA concentrations, codons decoding times are not correlated with aminoacyl-tRNA levels. The reported results support the conjecture that translation efficiency is directly influenced by the tRNA levels in the cell. Thus, they should help to understand the evolution of synonymous aspects of coding sequences via the adaptation of their codons to the tRNA pool.

Ribosomal mutations affecting the translation of genes that use non-optimal codons.

Genes that are laterally acquired by a new host species often contain codons that are non-optimal to the tRNA repertoire of the new host, which may lead to insufficient translational levels. Inefficient translation can be overcome by different mechanisms, such as incremental amelioration of the coding sequence, compensatory mutations in the regulatory sequences leading to increased transcription or increase in gene copy number. However, there is also a possibility that ribosomal mutations can improve the expression of such genes. To test this hypothesis, we examined the effects of point mutations in the endogenous ribosomal proteins S12 and S5 in Escherichia coli, which are known to be involved in the decoding of the mRNA, on the efficiency of translation of exogenous genes that use non-optimal codons, in vivo. We show that an S12 mutant in E. coli is able to express exogenous genes, with non-optimal codons, to higher levels than the wild-type, and explore the mechanisms underlying this phenomenon in this mutant. Our results suggest that the transient emergence of mutants that allow efficient expression of exogenous genes with non-optimal codons could also increase the chances of fixation of laterally transferred genes.

Properties and determinants of codon decoding time distributions.

BACKGROUND: Codon decoding time is a fundamental property of mRNA translation believed to affect the abundance, function, and properties of proteins. Recently, a novel experimental technology--ribosome profiling--was developed to measure the density, and thus the speed, of ribosomes at codon resolution. Specifically, this method is based on next-generation sequencing, which theoretically can provide footprint counts that correspond to the probability of observing a ribosome in this position for each nucleotide in each transcript. RESULTS: In this study, we report for the first time various novel properties of the distribution of codon footprint counts in five organisms, based on large-scale analysis of ribosomal profiling data. We show that codons have distinctive footprint count distributions. These tend to be preserved along the inner part of the ORF, but differ at the 5' and 3' ends of the ORF, suggesting that the translation-elongation stage actually includes three biophysical sub-steps. In addition, we study various basic properties of the codon footprint count distributions and show that some of them correlate with the abundance of the tRNA molecule types recognizing them. CONCLUSIONS: Our approach emphasizes the advantages of analyzing ribosome profiling and similar types of data via a comparative genomic codon-distribution-centric view. Thus, our methods can be used in future studies related to translation and even transcription elongation.

Determinants of translation elongation speed and ribosomal profiling biases in mouse embryonic stem cells.

Ribosomal profiling is a promising approach with increasing popularity for studying translation. This approach enables monitoring the ribosomal density along genes at a resolution of single nucleotides.In this study, we focused on ribosomal density profiles of mouse embryonic stem cells. Our analysis suggests, for the first time, that even in mammals such as M. musculus the elongation speed is significantly and directly affected by determinants of the coding sequence such as: 1) the adaptation of codons to the tRNA pool; 2) the local mRNA folding of the coding sequence; 3) the local charge of amino acids encoded in the codon sequence. In addition, our analyses suggest that in general, the translation velocity of ribosomes is slower at the beginning of the coding sequence and tends to increase downstream.Finally, a comparison of these data to the expected biophysical behavior of translation suggests that it suffers from some unknown biases. Specifically, the ribosomal flux measured on the experimental data increases along the coding sequence; however, according to any biophysical model of ribosomal movement lacking internal initiation sites, the flux is expected to remain constant or decrease. Thus, developing experimental and/or statistical methods for understanding, detecting and dealing with such biases is of high importance.

Efficient manipulations of synonymous mutations for controlling translation rate: an analytical approach.

Gene translation is a central process in all living organism with important ramifications to almost every biomedical field. Previous systems evolutionary studies in the field have demonstrated that in many organisms coding sequence features undergo selection to optimize this process. In the current study, we report for the first time analytical proofs related to the various aspects of this process and its optimality. Among our results we show that coding sequences with mono- tonic increasing profiles of translation efficiency (i.e., with slower codons near the 5'UTR), mathematically optimize ribosomal allocation by minimizing the number of ribosomes needed for translating a codon per time unit. Thus, the genomic translation efficiency profile reported in previous studies for many organisms is optimal in this sense. In addition, we show that improving translation efficiency of a codon in a gene may result in a decrease in the translation rate of other genes, demonstrating that the relation between codon bias and protein translation rate is less trivial than was assumed before. Based on these observations we describe an efficient heuristic for designing coding sequences with specific translation efficiency and minimal ribosomal allocation for heterologous gene expression. We demonstrate how this heuristic can be used in biotechnology for engineering a heterologous gene before expressing it in a new host.