Mechanisms of matrix metalloproteinase-2 (mmp-2) transcriptional repression by progesterone in jar choriocarcinoma cells

<p>Abstract</p> <p>Background</p> <p>Although the MMP-2 promoter lacks a canonical progesterone response element (PRE), the hormone inhibits MMP-2 expression and is part of treatment protocols in gynecological invasive pathologies, including endometriosis and endometrial hyperplasia. This study aimed to explore the mechanism by which progesterone inhibits MMP-2 expression.</p> <p>Methods</p> <p>The effect of progesterone on MMP-2 expression in the JAR human choriocarcinoma cell line was analyzed by gelatin zymography. MMP-2 transcript expression was studied using Northern blot and semi-quantitative RT-PCR. Rat promoter deletion analysis, electrophoretic mobility shift and chromatin immuno-precipitation assays were performed in order to locate the DNA binding site and the transcription factors involved in MMP-2 regulation.</p> <p>Results</p> <p>Progesterone significantly decreased secretion of pro-MMP-2 and MMP-2 transcript expression level in a dose-dependent manner. Progesterone (1 microM) significantly decreased both human and rat MMP-2 promoter activity (80.1% +/- 0.3 and 81.3% +/- 0.23, respectively). Progesterone acts through the SP1 family transcription factors-binding site, located between -1433 and -1342 bp region from the transcriptional start site of the rat MMP-2 promoter, which are present in the orthologous human MMP-2 promoter. Progesterone receptor (PR), SP2, SP3 and SP4 proteins are constitutively bound to this consensus sequence.</p> <p>Conclusion</p> <p>Progesterone reducesPR and SP4 binding to the MMP-2 promoter, thereby suppressing transcription. Progesterone also promotes SP4 degradation. These novel mechanisms of MMP-2 regulation by progesterone provide the biological rationale for the use of progesterone in clinical settings associated with increased MMP-2 expression.</p

A sufficient condition for a number to be the order of a nonsingular derivation of a Lie algebra

A study of the set N_p of positive integers which occur as orders of nonsingular derivations of finite-dimensional non-nilpotent Lie algebras of characteristic p>0 was initiated by Shalev and continued by the present author. The main goal of this paper is to show the abundance of elements of N_p. Our main result shows that any divisor n of q-1, where q is a power of p, such that $n\ge (p-1)^{1/p} (q-1)^{1-1/(2p)}$, belongs to N_p. This extends its special case for p=2 which was proved in a previous paper by a different method.Comment: 10 pages. This version has been revised according to a referee's suggestions. The additions include a discussion of the (lower) density of the set N_p, and the results of more extensive machine computations. Note that the title has also changed. To appear in Israel J. Mat

The spatio-temporal distribution of lightning over Israel and the neighboring area and its relation to regional synoptic systems

The spatio-temporal distribution of lightning flashes over Israel and the neighboring area and its relation to the regional synoptic systems has been studied, based on data obtained from the Israel Lightning Location System (ILLS) operated by the Israel Electric Corporation (IEC). The system detects cloud-to-ground lightning discharges in a range of ~500 km around central Israel (32.5° N, 35° E). The study period was defined for annual activity from August through July, for 5 seasons in the period 2004–2010. &lt;br&gt;&lt;br&gt; The spatial distribution of lightning flash density indicates the highest concentration over the Mediterranean Sea, attributed to the contribution of moisture as well as sensible and latent heat fluxes from the sea surface. Other centers of high density appear along the coastal plain, orographic barriers, especially in northern Israel, and downwind from the metropolitan area of Tel Aviv, Israel. The intra-annual distribution shows an absence of lightning during the summer months (JJA) due to the persistent subsidence over the region. The vast majority of lightning activity occurs during 7 months, October to April. Although over 65 % of the rainfall in Israel is obtained during the winter months (DJF), only 35 % of lightning flashes occur in these months. October is the richest month, with 40 % of total annual flashes. This is attributed both to tropical intrusions, i.e., Red Sea Troughs (RST), which are characterized by intense static instability and convection, and to Cyprus Lows (CLs) arriving from the west. &lt;br&gt;&lt;br&gt; Based on daily study of the spatial distribution of lightning, three patterns have been defined; "land", "maritime" and "hybrid". CLs cause high flash density over the Mediterranean Sea, whereas some of the RST days are typified by flashes over land. The pattern defined "hybrid" is a combination of the other 2 patterns. On CL days, only the maritime pattern was noted, whereas in RST days all 3 patterns were found, including the maritime pattern. It is suggested that atmospheric processes associated with RST produce the land pattern. Hence, the occurrence of a maritime pattern in days identified as RST reflects an "apparent RST". The hybrid pattern was associated with an RST located east of Israel. This synoptic type produced the typical flash maximum over the land, but the upper-level trough together with the onshore winds it induced over the eastern coast of the Mediterranean resulted in lightning activity over the sea as well, similar to that of CLs. &lt;br&gt;&lt;br&gt; It is suggested that the spatial distribution patterns of lightning may better identify the synoptic system responsible, a CL, an "active RST" or an "apparent RST". The electrical activity thus serves as a "fingerprint" for the synoptic situation responsible for its generation

The Computational Power of Optimization in Online Learning

We consider the fundamental problem of prediction with expert advice where the experts are "optimizable": there is a black-box optimization oracle that can be used to compute, in constant time, the leading expert in retrospect at any point in time. In this setting, we give a novel online algorithm that attains vanishing regret with respect to $N$ experts in total $\widetilde{O}(\sqrt{N})$ computation time. We also give a lower bound showing that this running time cannot be improved (up to log factors) in the oracle model, thereby exhibiting a quadratic speedup as compared to the standard, oracle-free setting where the required time for vanishing regret is $\widetilde{\Theta}(N)$. These results demonstrate an exponential gap between the power of optimization in online learning and its power in statistical learning: in the latter, an optimization oracle---i.e., an efficient empirical risk minimizer---allows to learn a finite hypothesis class of size $N$ in time $O(\log{N})$. We also study the implications of our results to learning in repeated zero-sum games, in a setting where the players have access to oracles that compute, in constant time, their best-response to any mixed strategy of their opponent. We show that the runtime required for approximating the minimax value of the game in this setting is $\widetilde{\Theta}(\sqrt{N})$, yielding again a quadratic improvement upon the oracle-free setting, where $\widetilde{\Theta}(N)$ is known to be tight

Coarse-Graining and Self-Dissimilarity of Complex Networks

Can complex engineered and biological networks be coarse-grained into smaller and more understandable versions in which each node represents an entire pattern in the original network? To address this, we define coarse-graining units (CGU) as connectivity patterns which can serve as the nodes of a coarse-grained network, and present algorithms to detect them. We use this approach to systematically reverse-engineer electronic circuits, forming understandable high-level maps from incomprehensible transistor wiring: first, a coarse-grained version in which each node is a gate made of several transistors is established. Then, the coarse-grained network is itself coarse-grained, resulting in a high-level blueprint in which each node is a circuit-module made of multiple gates. We apply our approach also to a mammalian protein-signaling network, to find a simplified coarse-grained network with three main signaling channels that correspond to cross-interacting MAP-kinase cascades. We find that both biological and electronic networks are 'self-dissimilar', with different network motifs found at each level. The present approach can be used to simplify a wide variety of directed and nondirected, natural and designed networks.Comment: 11 pages, 11 figure

Primitive Words, Free Factors and Measure Preservation

Let F_k be the free group on k generators. A word w \in F_k is called primitive if it belongs to some basis of F_k. We investigate two criteria for primitivity, and consider more generally, subgroups of F_k which are free factors. The first criterion is graph-theoretic and uses Stallings core graphs: given subgroups of finite rank H \le J \le F_k we present a simple procedure to determine whether H is a free factor of J. This yields, in particular, a procedure to determine whether a given element in F_k is primitive. Again let w \in F_k and consider the word map w:G x G x ... x G \to G (from the direct product of k copies of G to G), where G is an arbitrary finite group. We call w measure preserving if given uniform measure on G x G x ... x G, w induces uniform measure on G (for every finite G). This is the second criterion we investigate: it is not hard to see that primitivity implies measure preservation and it was conjectured that the two properties are equivalent. Our combinatorial approach to primitivity allows us to make progress on this problem and in particular prove the conjecture for k=2. It was asked whether the primitive elements of F_k form a closed set in the profinite topology of free groups. Our results provide a positive answer for F_2.Comment: This is a unified version of two manuscripts: "On Primitive words I: A New Algorithm", and "On Primitive Words II: Measure Preservation". 42 pages, 14 figures. Some parts of the paper reorganized towards publication in the Israel J. of Mat

Invariant Distribution of Promoter Activities in Escherichia coli

Cells need to allocate their limited resources to express a wide range of genes. To understand how Escherichia coli partitions its transcriptional resources between its different promoters, we employ a robotic assay using a comprehensive reporter strain library for E. coli to measure promoter activity on a genomic scale at high-temporal resolution and accuracy. This allows continuous tracking of promoter activity as cells change their growth rate from exponential to stationary phase in different media. We find a heavy-tailed distribution of promoter activities, with promoter activities spanning several orders of magnitude. While the shape of the distribution is almost completely independent of the growth conditions, the identity of the promoters expressed at different levels does depend on them. Translation machinery genes, however, keep the same relative expression levels in the distribution across conditions, and their fractional promoter activity tracks growth rate tightly. We present a simple optimization model for resource allocation which suggests that the observed invariant distributions might maximize growth rate. These invariant features of the distribution of promoter activities may suggest design constraints that shape the allocation of transcriptional resources

Dyscalculia from a developmental and differential perspective

Developmental dyscalculia (DD) and its treatment are receiving increasing research attention. A PsychInfo search for peer-reviewed articles with dyscalculia as a title word reveals 31 papers published from 1991–2001, versus 74 papers published from 2002–2012. Still, these small counts reflect the paucity of research on DD compared to dyslexia, despite the prevalence of mathematical difficulties. In the UK, 22% of adults have mathematical difficulties sufficient to impose severe practical and occupational restrictions (Bynner and Parsons, 1997; National Center for Education Statistics, 2011). It is unlikely that all of these individuals with mathematical difficulties have DD, but criteria for defining and diagnosing dyscalculia remain ambiguous (Mazzocco and Myers, 2003). What is treated as DD in one study may be conceptualized as another form of mathematical impairment in another study. Furthermore, DD is frequently—but, we believe, mistakenly- considered a largely homogeneous disorder. Here we advocate a differential and developmental perspective on DD focused on identifying behavioral, cognitive, and neural sources of individual differences that contribute to our understanding of what DD is and what it is not

Robustness and Generalization

We derive generalization bounds for learning algorithms based on their robustness: the property that if a testing sample is "similar" to a training sample, then the testing error is close to the training error. This provides a novel approach, different from the complexity or stability arguments, to study generalization of learning algorithms. We further show that a weak notion of robustness is both sufficient and necessary for generalizability, which implies that robustness is a fundamental property for learning algorithms to work