Expander-based cryptography meets natural proofs

We introduce new forms of attack on expander-based cryptography, and in particular on Goldreich's pseudorandom generator and one-way function. Our attacks exploit low circuit complexity of the underlying expander's neighbor function and/or of the local predicate. Our two key conceptual contributions are: 1) We put forward the possibility that the choice of expander matters in expander-based cryptography. In particular, using expanders whose neighbour function has low circuit complexity might compromise the security of Goldreich's PRG and OWF in certain settings. 2) We show that the security of Goldreich's PRG and OWF is closely related to two other long-standing problems: Specifically, to the existence of unbalanced lossless expanders with low-complexity neighbor function, and to limitations on circuit lower bounds (i.e., natural proofs). In particular, our results further motivate the investigation of affine/local unbalanced lossless expanders and of average-case lower bounds against DNF-XOR circuits. We prove two types of technical results that support the above conceptual messages. First, we unconditionally break Goldreich's PRG when instantiated with a specific expander (whose existence we prove), for a class of predicates that match the parameters of the currently-best "hard" candidates, in the regime of quasi-polynomial stretch. Secondly, conditioned on the existence of expanders whose neighbor functions have extremely low circuit complexity, we present attacks on Goldreich's generator in the regime of polynomial stretch. As one corollary, conditioned on the existence of the foregoing expanders, we show that either the parameters of natural properties for several constant-depth circuit classes cannot be improved, even mildly; or Goldreich's generator is insecure in the regime of a large polynomial stretch, regardless of the predicate used

The importance of redox state in liver damage.

Oxidative stress is a major pathogenetic event occurring in several liver disorders ranging from metabolic to proliferative ones, and is a major cause of liver damage due to Ischemia/Reperfusion (I/R) during liver transplantation. The main sources of ROS are represented by mitochondria and cytocrome P450 enzymes in the hepatocyte, by Kupffer cells and by neutrophils. Cells are provided with efficient molecular strategies to strictly control the intracellular ROS level and to maintain the balance between oxidant and antioxidant molecules. A cellular oxidative stress condition is determined by an imbalance between the generation of ROS and the antioxidant defense capacity of the cell and can affect major cellular components including lipids, proteins and DNA. Proteins are very important signposts of cellular redox status and through their structure/function modulation, ROS can also influence gene expression profile by affecting intracellular signal transduction pathways. While several enzymatic (such as superoxide dismutase, catalase, glutathione peroxidase) and non enzymatic (such as 4-hydroxynonenal, decrease of glutathione, vitamin E, vitamin C, malondialdehyde) markers of chronic oxidative stress in liver are well known, early protein targets of oxidative injury are yet not well defined. Identification of these markers will enable early detection of liver diseases and will allow monitoring the degree of liver damage, the re1 Department of Biomedical Sciences and Technologies, University of Udine, P.le Kolbe 4, 33100 Udine, Italy. 2 Department of Biochemistry, Biophysics and Macromolecular Chemistry, University of Trieste, via Giorgieri 1, 34127 Trieste, Italy. 3 Centro Studi Fegato, AREA Science Park Bldg Q, Campus Basovizza, ss 14, km 163.5, 34012 Trieste, Italy. Address for correspondence

Hybrid Software Development Approaches in Practice: A European Perspective

Agile and traditional development approaches are used in combination in todays software development. To improve the understanding and to provide better guidance for selecting appropriate development approaches, it is important to analyze such combinations in practice. Results obtained from an online survey strongly confirm that hybrid development approaches are widely used in industry. Our results show that hybrid development approaches: (i) have become reality for nearly all companies; (ii) are applied to specific projects even in the presence of company-wide policies for process usage; (iii) are neither planned nor designed but emerge from the evolution of different work practices; and, (iv) are consistently used regardless of company size or industry secto

New perspectives in cancer biology from a study of canonical and non-canonical functions of base excision repair proteins with a focus on early steps

Alterations of DNA repair enzymes and consequential triggering of aberrant DNA damage response (DDR) pathways are thought to play a pivotal role in genomic instabilities associated with cancer development, and are further thought to be important predictive biomarkers for therapy using the synthetic lethality paradigm. However, novel unpredicted perspectives are emerging from the identification of several non-canonical roles of DNA repair enzymes, particularly in gene expression regulation, by different molecular mechanisms, such as (i) non-coding RNA regulation of tumour suppressors, (ii) epigenetic and transcriptional regulation of genes involved in genotoxic responses and (iii) paracrine effects of secreted DNA repair enzymes triggering the cell senescence phenotype. The base excision repair (BER) pathway, canonically involved in the repair of non-distorting DNA lesions generated by oxidative stress, ionising radiation, alkylation damage and spontaneous or enzymatic deamination of nucleotide bases, represents a paradigm for the multifaceted roles of complex DDR in human cells. This review will focus on what is known about the canonical and non-canonical functions of BER enzymes related to cancer development, highlighting novel opportunities to understand the biology of cancer and representing future perspectives for designing new anticancer strategies. We will specifically focus on APE1 as an example of a pleiotropic and multifunctional BER protein

Short peptide self-assembly in the Martini coarse grain forcefield family

Pivotal to the success of any computational experiment is the ability to make reliable predictions about the system under study and the time required to yield these results. Biomolecular interactions is one area of research that sits in every camp of resolution vs time required, from the quantum mechanical level through to in vivo studies. At an approximate mid-point there is coarse-grained molecular dynamics, for which the Martini forcefields have become the most widely used, fast enough to simulate the entire membrane of a mitochondrion though lacking atom-specific precision. While many forcefields have been parameterized to account for a specific system under study, the Martini forcefield has aimed at casting a wider net with more generalized bead types that have demonstrated suitability for broad use and reuse in applications from protein-graphene oxide co-assembly to polysaccharides interactions. In this account, the progressive (Martini versions 1 through 3) and peripheral (Sour Martini, constant pH, Martini Straight, Dry Martini, etc) developmental trajectory of the Martini forcefield will be analyzed in terms of self-assembling systems with a focus on short (2-3 amino acids) peptide self-assembly in aqueous environments. Particularly, this will focus on the effects of the Martini solvent model and compare how changes in bead definitions and mapping have effects on different systems. Considerable effort in the development of Martini has been taken to reduce the ”stickiness” of amino acids to better simulate proteins in bilayers. We have included in this account a short study of dipeptide self-assembly in water, using all mainstream Martini forcefields, to examine their ability to reproduce this behavior. The three most recently released versions of Martini and variations in their solvents are used to simulate in triplicate all 400 dipeptides of the 20 gene-encoded amino acids. The ability of the forcefields to model the self-assembly of the dipeptides in aqueoues environments is determined by measurement of the aggregation propensity and additional descriptors are used to gain further insight into the dipeptide aggregates

Enzymatically active apurinic/apyrimidinic endodeoxyribonuclease 1 is released by mammalian cells through exosomes

The apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1), the main AP-endonuclease of the DNA base excision repair pathway, is a key molecule of interest to researchers due to its unsuspected roles in different nonrepair activities, such as: I) adaptive cell response to genotoxic stress, ii) regulation of gene expression, and iii) processing of microRNAs, which make it an excellent drug target for cancer treatment. We and others recently demonstrated that APE1 can be secreted in the extracellular environment and that serum APE1 may represent a novel prognostic biomarker in hepatocellular and non-smallcell lung cancers. However, the mechanism by which APE1 is released extracellularly was not described before. Here, using three different approaches for exosomes isolation: Commercial kit, nickel-based isolation, and ultracentrifugation methods and various mammalian cell lines, we elucidated the mechanisms responsible for APE1 secretion. We demonstrated that APE1 p37 and p33 forms are actively secreted through extracellular vesicles (EVs), including exosomes from different mammalian cell lines. We then observed that APE1 p33 form is generated by proteasomal-mediated degradation and is enzymatically active in EVs. Finally, we revealed that the p33 form of APE1 accumulates in EVs upon genotoxic treatment by cisplatin and doxorubicin, compounds commonly found in chemotherapy pharmacological treatments. Taken together, these findings provide for the first time evidence that a functional Base Excision Repair protein is delivered through exosomes in response to genotoxic stresses, shedding new light into the complex noncanonical biological functions of APE1 and opening new intriguing perspectives on its role in cancer biology