Thermodynamic bounds on the ultra- and infra-affinity of Hsp70 for its substrates

The 70 kDa Heat Shock Proteins Hsp70 have several essential functions in living systems, such as protecting cells against protein aggregation, assisting protein folding, remodeling protein complexes and driving the translocation into organelles. These functions require high affinity for non-specific amino-acid sequences that are ubiquitous in proteins. It has been recently shown that this high affinity, called ultra-affinity, depends on a process driven out of equilibrium by ATP hydrolysis. Here we establish the thermodynamic bounds for ultra-affinity, and further show that the same reaction scheme can in principle be used both to strengthen and to weaken affinities (leading in this case to infra-affinity). We show that cofactors are essential to achieve affinity beyond the equilibrium range. Finally, biological implications are discussed.Comment: 14 pages, 5 figure

Assessment of Source Code Obfuscation Techniques

Obfuscation techniques are a general category of software protections widely adopted to prevent malicious tampering of the code by making applications more difficult to understand and thus harder to modify. Obfuscation techniques are divided in code and data obfuscation, depending on the protected asset. While preliminary empirical studies have been conducted to determine the impact of code obfuscation, our work aims at assessing the effectiveness and efficiency in preventing attacks of a specific data obfuscation technique - VarMerge. We conducted an experiment with student participants performing two attack tasks on clear and obfuscated versions of two applications written in C. The experiment showed a significant effect of data obfuscation on both the time required to complete and the successful attack efficiency. An application with VarMerge reduces by six times the number of successful attacks per unit of time. This outcome provides a practical clue that can be used when applying software protections based on data obfuscation.Comment: Post-print, SCAM 201

The Impacts of Bibliometrics Measurement in the Scientific Community A Statistical Analysis of Multiple Case Studies

In recent years, statistical methods such as bibliometrics have increasingly intensified to analyse books, articles, and other publications. Bibliometric methods, as techniques to measure the information distribution models, are frequently used in the field of information science and social research. The main purpose of this article is to offer scholars a general framework for the comparison between positive and negative aspects of bibliometrics, on the methods and tools used. Therefore, both the strengths and the critical points will be highlighted, to obtain a complete and detailed overview of the entire argument. In the methodological part, a bibliometric analysis will be applied to various case studies, such as with the Generalized Error Distribution, analysing and commenting on the data, and using the Bibliometrix software. The results suggest that in the future there will be greater consolidation of bibliometrics, as the introduction of increasingly advanced technologies will create new tools and methods characterized by a high degree of automation and speed

Digitalizing Circular Economy through Blockchains: The Blockchain Circular Economy Index

The integration of circular economy (CE) models into everyday contexts generates huge amount of data involved in goods tracking and tokenization procedures. The sector of blockchain platforms is extremely varied, and the choice of the proper technology is not easy. It is important that the selection is conducted consistently with respect to the CE models. With this study, we present a performance index named Blockchain Circular Economy Index (BCEI). BCEI, obtained through Multicriteria Decision Analysis and Analytic Hierarchy Process, aims to measure the suitability of blockchain platforms to the needs highlighted by a CE scenario. The present study is contextualized by comparing six blockchain platforms, for each of which, the related BCEI is calculated. The results of the analysis show that transaction fee and energy consumption are the two most critical parameters. In addition, the results show the lack of a leading blockchain technology in CE models. Thus, there is a market space that can be exploited given the growing interest in digital and sustainable issues

Effective continuum models for the buckling of non-periodic architected sheets that display quasi-mechanism behaviors

In this work, we construct an effective continuum model for architected sheets that are composed of bulky tiles connected by slender elastic joints. Due to their mesostructure, these sheets feature quasi-mechanisms -- low-energy local kinematic modes that are strongly favored over other deformations. In sheets with non-uniform mesostructure, kinematic incompatibilities arise between neighboring regions, causing out-of-plane buckling. The effective continuum model is based on a geometric analysis of the sheets' unit cells and their energetically favorable modes of deformation. Its major feature is the construction of a strain energy that penalizes deviations from these preferred modes of deformation. The effect of non-periodicity is entirely described through the use of spatially varying geometric parameters in the model. Our simulations capture the out-of-plane buckling that occurs in non-periodic specimens and show good agreement with experiments. While we only consider one class of quasi-mechanisms, our modeling approach could be applied to a diverse set of shape-morphing systems that are of interest to the mechanics community

Concurrent inhibition of enzymatic activity and NF-Y-mediated transcription of Topoisomerase-IIα by bis-DemethoxyCurcumin in cancer cells

Topoisomerase-IIa (TOP2A) enzyme is essential for cell viability due to its fundamental role in DNA metabolism and in chromatin organization during interphase and mitosis. TOP2A expression is finely regulated at the transcriptional level through the binding of the CCAAT-transcription factor NF-Y to its promoter. Overexpression and/or amplification of TOP2A have been observed in many types of cancers. For this reason, TOP2A is the target of the most widely successful drugs in cancer chemotherapy, such as TOP2A poisons, which stabilize TOP2A-DNA cleavage complexes and create DSBs, leading to chromosome damage and cell death. We previously reported that the Curcumin-derivative bis-DemethoxyCurcumin (bDMC) is an anti-proliferative agent that inhibits cell growth by concomitant G1/S and G2/M arrest. Here we showed that bDMC irreversibly induces DSBs in cancer cells, but not in normal cells, by targeting TOP2A activity and expression. TOP2A ablation by siRNA corroborates its contribution to apoptosis induced by bDMC. Short-term exposure to bDMC induces retention of TOP2A-DNA intermediates, while longer exposure inhibits TOP2A transcription by affecting expression and sub-cellular localization of NF-Y subunits. ChIP analysis highlighted reduced recruitment of NF-Y to TOP2A regulatory regions, concomitantly to histone deacetylation and decreased gene transcription. Our findings suggest that the dual activity of bDMC on TOP2A represents a novel therapeutic strategy to induce persistent apoptosis in cancer cells and identify NF-Y regulation as a promising approach in anti-cancer therapy

NF-Y loss triggers p53 stabilization and apoptosis in HPV18-positive cells by affecting E6 transcription

The expression of the high risk HPV18 E6 and E7 oncogenic proteins induces the transformation of epithelial cells, through the disruption of p53 and Rb function. The binding of cellular transcription factors to cis-regulatory elements in the viral Upstream Regulatory Region (URR) stimulates E6/E7 transcription. Here, we demonstrate that the CCAAT-transcription factor NF-Y binds to a non-canonical motif within the URR and activates viral gene expression. In addition, NF-Y indirectly up-regulates HPV18 transcription through the transactivation of multiple cellular transcription factors. NFYA depletion inhibits the expression of E6 and E7 genes and re-establishes functional p53. The activation of p53 target genes in turn leads to apoptotic cell death. Finally, we show that NF-YA loss sensitizes HPV18-positive cells toward the DNA damaging agent Doxorubicin, via p53-mediated transcriptional response