Telomerase is the enzyme responsible for maintenance of the length of telomeres by addition of guanine-rich repetitive sequences. Telomerase activity is exhibited in gametes and stem and tumor cells. ...In human somatic cells, proliferation potential is strictly limited and senescence follows approximately 50-70 cell divisions. In most tumor cells, on the contrary, replication potential is unlimited. The key role in this process of the system of the telomere length maintenance with involvement of telomerase is still poorly studied. Undoubtedly, DNA polymerase is not capable of completely copying DNA at the very ends of chromosomes; therefore, approximately 50 nucleotides are lost during each cell cycle, which results in gradual telomere length shortening. Critically short telomeres cause senescence, following crisis and cell death. However, in tumor cells the system of telomere length maintenance is activated. Much work has been done regarding the complex telomere/telomerase as a unique target, highly specific in cancer cells. Telomeres have additional proteins that regulate the binding of telomerase. Telomerase, also associates with a number of proteins forming the sheltering complex having a central role in telomerase activity. This review focuses on the structure and function of the telomere/telomerase complex and its altered behavior leading to disease, mainly cancer. Although telomerase therapeutics are not approved yet for clinical use, we can assume that based on the promising in vitro and in vivo results and successful clinical trials, it can be predicted that telomerase therapeutics will be utilized soon in the combat against malignancies and degenerative diseases. The active search for modulators is justified, because the telomere/telomerase system is an extremely promising target offering possibilities to decrease or increase the viability of the cell for therapeutic purposes.
Monocytes/macrophages are activated in several autoimmune diseases, including systemic sclerosis (scleroderma; SSc), with increased expression of interferon (IFN)-regulatory genes and inflammatory ...cytokines, suggesting dysregulation of the innate immune response in autoimmunity. In this study, we investigated whether the lytic form of Epstein-Barr virus (EBV) infection (infectious EBV) is present in scleroderma monocytes and contributes to their activation in SSc.
Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) depleted of the CD19+ cell fraction, using CD14/CD16 negative-depletion. Circulating monocytes from SSc and healthy donors (HDs) were infected with EBV. Gene expression of innate immune mediators were evaluated in EBV-infected monocytes from SSc and HDs. Involvement of Toll-like receptor (TLR)8 in viral-mediated TLR8 response was investigated by comparing the TLR8 expression induced by infectious EBV to the expression stimulated by CL075/TLR8/agonist-ligand in the presence of TLR8 inhibitor in THP-1 cells.
Infectious EBV strongly induced TLR8 expression in infected SSc and HD monocytes in vitro. Markers of activated monocytes, such as IFN-regulated genes and chemokines, were upregulated in SSc- and HD-EBV-infected monocytes. Inhibiting TLR8 expression reduced virally induced TLR8 in THP-1 infected cells, demonstrating that innate immune activation by infectious EBV is partially dependent on TLR8. Viral mRNA and proteins were detected in freshly isolated SSc monocytes. Microarray analysis substantiated the evidence of an increased IFN signature and altered level of TLR8 expression in SSc monocytes carrying infectious EBV compared to HD monocytes.
This study provides the first evidence of infectious EBV in monocytes from patients with SSc and links EBV to the activation of TLR8 and IFN innate immune response in freshly isolated SSc monocytes. This study provides the first evidence of EBV replication activating the TLR8 molecular pathway in primary monocytes. Immunogenicity of infectious EBV suggests a novel mechanism mediating monocyte inflammation in SSc, by which EBV triggers the innate immune response in infected cells.
Systemic risk attribution in the EU Farina, G.; Giacometti, R.; De Giuli, M. E.
The Journal of the Operational Research Society,
07/2019, Letnik:
70, Številka:
7
Journal Article
Recenzirano
Systemic default risk is due to multiple private and/or public entities' simultaneous default. This risk has caused great concern in the recent past and its assessment is not a trivial subject. We ...have provided a model for systemic risk attribution in order to disentangle its different components. We have applied it to a selection of EU countries consistent with previous research. We have extracted a common EU factor and analysed the residual components related to an individual country's banking system, to the interaction between banking system and government, and to the country's and banking idiosyncratic components, as well.For this purpose, we have introduced a multivariate distribution for all the countries and the relative banks, also providing an integrated analysis. We have applied the multivariate Marshall-Olkin distribution, where the marginal probability of default for any country or bank depends on its default intensity. Risk attribution has been performed using weekly market data referred to sovereign and bank CDSs over the period 2009-2015. Our results have highlighted relevant differences between Northern and Southern EU countries, as far as risk decomposition is concerned. In Southern countries, risk is mainly concentrated in a country-banking system shock at each level. In Northern countries, the prevailing components of risk are the systemic EU shock at country level, and the idiosyncratic component at banking system level and individual bank level.
A Network Theory of Patentability Pedraza-Fariña, Laura G.; Whalen, Ryan
The University of Chicago law review,
01/2020, Letnik:
87, Številka:
1
Journal Article
Recenzirano
Patent law is built upon a fundamental premise: only significant inventions receive patent protection while minor improvements remain in the public domain. This premise is indispensable for ...maintaining an optimal balance between incentivizing new innovation and providing public access to existing innovation. Despite its importance, the doctrine that performs this gatekeeping role—nonobviousness—has long remained indeterminate and vague. Judicial opinions have struggled to articulate both what makes an invention significant (or nonobvious) and how to measure nonobviousness in specific cases. These difficulties are due in large part to the existence of two clashing theoretical frameworks, cognitive and economic, that have vied for prominence in justifying nonobviousness. Neither framework, however, has generated doctrinal tests that can be easily and consistently applied.
This Article draws on a novel approach—network theory—to answer both the conceptual question (what is a nonobvious invention?) and the measurement question (how do we determine nonobviousness in specific cases?). First, it shows that what is missing in current conceptual definitions of nonobviousness is an underlying theory of innovation. It then supplies this missing piece. Building upon insights from network science, we model innovation as a process of search and recombination of existing knowledge. Distant searches that combine disparate or weakly connected portions of social and information networks tend to produce high-impact, new ideas that open novel innovation trajectories. Distant searches also tend to be costly and risky. In contrast, local searches tend to result in incremental innovation that is more routine, less costly, and less risky. From a network theory perspective, then, the goal of nonobviousness should be to reward, and therefore to incentivize, those risky distant searches and recombinations that produce the most socially significant innovations. By emphasizing factors specific to the structure of innovation—namely, the risks and costs of the search and recombination process—a network approach complements and deepens current economic understandings of nonobviousness. Second, based on our network theory of innovation, we develop an empirical, algorithmic measure of patentability—what we term a patent's "network nonobviousness score" (NNOS). We harness data from US patent records to calculate the distance between the technical knowledge areas recombined in any given invention (or patent), allowing us to assign each patent a specific NNOS. We propose a doctrinal framework that incorporates an invention's NNOS to nonobviousness determinations both at the examination phase and during patent litigation.
Our use of network science to develop a legal algorithm is a methodological innovation in law, with implications for broader debates about computational law. We illustrate how differences in algorithm design can lead to different nonobviousness outcomes, and discuss how to mitigate the negative impact of black box algorithms.
Extensive farming systems are characterized by seasons with different diet quality along the year, as pasture availability is strictly depending on climatic conditions. A number of problems for ...cattle may occur in each season. Tannins are natural polyphenolic compounds that can be integrated in cows' diet to overcome these seasonal problems, but little is known about their effect on milk quality according to the season. This study was designed to assess the effects of 150 g/head × day of tannin extract supplementation on proximate composition, urea, colour, cheesemaking aptitude, antioxidant capacity, and fatty acid (FA) profile of cow milk, measured during the wet season (WS) and the dry season (DS) of Mediterranean climate. In WS, dietary tannins had marginal effect on milk quality. Conversely, in DS, the milk from cows eating tannins showed 10% lower urea and slight improvement in antioxidant capacity, measured with FRAP and TEAC assays. Also, tannin extract supplementation in DS reduced branched-chain FA concentration, C18:1 t10 to C18:1 t11 ratio and rumenic to linoleic acid ratio. Tannins effect on rumen metabolism was enhanced in the season in which green herbage was not available, probably because of the low protein content, and high acid detergent fibre and lignin contents in diet. Thus, the integration of tannin in the diet should be adapted to the season. This could have practical implications for a more conscious use of tannin-rich extracts, and other tannin sources such as agro-industrial by-products and forages.
Pathogens have been implicated in the initiation and/or promotion of systemic sclerosis (scleroderma, SSc); however, no evidence was found to substantiate the direct contribution to this disease in ...past years. Recently, significant advances have been made in understanding the role of the innate immune system in SSc pathogenesis, supporting the idea that pathogens might interact with host innate immune-regulatory responses in SSc. In light of these findings, we review the studies that identified the presence of pathogens in SSc, along with studies on pathogens implicated in driving the innate immune dysregulation in SSc. The goal of this review is to illustrate how these pathogens, specifically viruses, may play important role both as triggers of the innate immune system, and critical players in the development of SSc disease.
Casein-kinase CK2 is a Ser/Thr protein kinase that fosters cell survival and proliferation of malignant cells. The CK2 holoenzyme, formed by the association of two catalytic alpha/alpha’ (CK2α/CK2α’) ...and two regulatory beta subunits (CK2β), phosphorylates diverse intracellular proteins partaking in key cellular processes. A handful of such CK2 substrates have been identified as targets for the substrate-binding anticancer peptide CIGB-300. However, since CK2β also contains a CK2 phosphorylation consensus motif, this peptide may also directly impinge on CK2 enzymatic activity, thus globally modifying the CK2-dependent phosphoproteome. To address such a possibility, firstly, we evaluated the potential interaction of CIGB-300 with CK2 subunits, both in cell-free assays and cellular lysates, as well as its effect on CK2 enzymatic activity. Then, we performed a phosphoproteomic survey focusing on early inhibitory events triggered by CIGB-300 and identified those CK2 substrates significantly inhibited along with disturbed cellular processes. Altogether, we provided here the first evidence for a direct impairment of CK2 enzymatic activity by CIGB-300. Of note, both CK2-mediated inhibitory mechanisms of this anticancer peptide (i.e., substrate- and enzyme-binding mechanism) may run in parallel in tumor cells and help to explain the different anti-neoplastic effects exerted by CIGB-300 in preclinical cancer models.
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•The homogenization method applied to collect ricotta cheese samples affected the TS contents of the products.•The repeatability and the standard deviation of repeatability are ...indicators of agreement between repeated measures for TS contents.•Ultra-Turrax homogenization provides repeatable measurements when compared with others.•The use of a better homogenization method results in a better estimate of the data, reducing sources of uncertainty.
Ricotta cheese is an Italian dairy product obtained by heat-coagulation of the proteins in whey, resulting from cheese production. The homogenization method applied to collect ricotta cheese samples could affect the total solids (TS) contents of the products. The aim of this study was to determine the effects of 5 different homogenization methods of the samples collection applied for the accuracy in TS determination in ricotta cheese, including un-homogenized method (UNH), un-homogenized combined with the Ultra-Turrax (IKA-Werke GmbH & Co. KG) method (UNH-UTX), spoon-homogenized method (SPN), spoon-homogenized combined with Ultra-Turrax method (SPN-UTX), and Ultra-Turrax homogenized method (UTX). The repeatability and the standard deviation of repeatability are indicators of agreement between repeated measures for TS contents. Results reported that UNH ricotta cheese samples showed large variation in TS content with values ranging from 18.31% to 25.85% and a standard deviation of repeatability higher than 1%; SPN samples showed repeatability values higher than 0.35% and standard deviation of repeatability ranged until 1.36%, suggesting large variability even in this case; the Ultra-Turrax homogenization reported repeatability values lower than 0.1% and standard deviation of repeatability lower than 0.05%, indicating that this method provides repeatable measurements that may reduce the sources of uncertainty in TS determination.
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