Hebb and the art of spine remodeling

The notion that synaptic remodeling underlies certain forms of learning is one of the main tenets of Hebb's inspiring theories dating from the 1940s. Until recently, however, direct evidence for tight relationships between synaptic remodeling and behavior has been scarce. Fascinating data from recent studies on the remodeling of postsynaptic structures known as dendritic spines indicates that such relationships might be more complex than initially expected

Serially-regulated biological networks fully realize a constrained set of functions

We show that biological networks with serial regulation (each node regulated by at most one other node) are constrained to {\it direct functionality}, in which the sign of the effect of an environmental input on a target species depends only on the direct path from the input to the target, even when there is a feedback loop allowing for multiple interaction pathways. Using a stochastic model for a set of small transcriptional regulatory networks that have been studied experimentally, we further find that all networks can achieve all functions permitted by this constraint under reasonable settings of biochemical parameters. This underscores the functional versatility of the networks.Comment: 9 pages, 3 figure

Relation between stress heterogeneity and aftershock rate in the rate-and-state model

We estimate the rate of aftershocks triggered by a heterogeneous stress change, using the rate-and-state model of Dieterich [1994].We show that an exponential stress distribution Pt(au) ~exp(-tautau_0) gives an Omori law decay of aftershocks with time ~1/t^p, with an exponent p=1-A sigma_n/tau_0, where A is a parameter of the rate-and-state friction law, and \sigma_n the normal stress. Omori exponent p thus decreases if the stress "heterogeneity" tau_0 decreases. We also invert the stress distribution P(tau) from the seismicity rate R(t), assuming that the stress does not change with time. We apply this method to a synthetic stress map, using the (modified) scale invariant "k^2" slip model [Herrero and Bernard, 1994]. We generate synthetic aftershock catalogs from this stress change.The seismicity rate on the rupture area shows a huge increase at short times, even if the stress decreases on average. Aftershocks are clustered in the regions of low slip, but the spatial distribution is more diffuse than for a simple slip dislocation. Because the stress field is very heterogeneous, there are many patches of positive stress changes everywhere on the fault.This stochastic slip model gives a Gaussian stress distribution, but nevertheless produces an aftershock rate which is very close to Omori's law, with an effective p<=1, which increases slowly with time. We obtain a good estimation of the stress distribution for realistic catalogs, when we constrain the shape of the distribution. However, there are probably other factors which also affect the temporal decay of aftershocks with time. In particular, heterogeneity of A\sigma_n can also modify the parameters p and c of Omori's law. Finally, we show that stress shadows are very difficult to observe in a heterogeneous stress context.Comment: In press in JG

Biological interaction networks are conserved at the module level

<p>Abstract</p> <p>Background</p> <p>Orthologous genes are highly conserved between closely related species and biological systems often utilize the same genes across different organisms. However, while sequence similarity often implies functional similarity, interaction data is not well conserved even for proteins with high sequence similarity. Several recent studies comparing high throughput data including expression, protein-protein, protein-DNA, and genetic interactions between close species show conservation at a much lower rate than expected.</p> <p>Results</p> <p>In this work we collected comprehensive high-throughput interaction datasets for four model organisms (<it>S. cerevisiae, S. pombe, C. elegans</it>, and <it>D. melanogaster</it>) and carried out systematic analyses in order to explain the apparent lower conservation of interaction data when compared to the conservation of sequence data. We first showed that several previously proposed hypotheses only provide a limited explanation for such lower conservation rates. We combined all interaction evidences into an integrated network for each species and identified functional modules from these integrated networks. We then demonstrate that interactions that are part of functional modules are conserved at much higher rates than previous reports in the literature, while interactions that connect between distinct functional modules are conserved at lower rates.</p> <p>Conclusions</p> <p>We show that conservation is maintained between species, but mainly at the module level. Our results indicate that interactions within modules are much more likely to be conserved than interactions between proteins in different modules. This provides a network based explanation to the observed conservation rates that can also help explain why so many biological processes are well conserved despite the lower levels of conservation for the interactions of proteins participating in these processes.</p> <p>Accompanying website: <url>http://www.sb.cs.cmu.edu/CrossSP</url></p

Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors.

Genome-wide association studies have identified over 70 single-nucleotide polymorphisms (SNPs) associated with breast cancer. A subset of these SNPs are associated with quantitative expression of nearby genes, but the functional effects of the majority remain unknown. We hypothesized that some risk SNPs may regulate alternative splicing. Using RNA-sequencing data from breast tumors and germline genotypes from The Cancer Genome Atlas, we tested the association between each risk SNP genotype and exon-, exon-exon junction- or transcript-specific expression of nearby genes. Six SNPs were associated with differential transcript expression of seven nearby genes at FDR &lt; 0.05 (BABAM1, DCLRE1B/PHTF1, PEX14, RAD51L1, SRGAP2D and STXBP4). We next developed a Bayesian approach to evaluate, for each SNP, the overlap between the signal of association with breast cancer and the signal of association with alternative splicing. At one locus (SRGAP2D), this method eliminated the possibility that the breast cancer risk and the alternate splicing event were due to the same causal SNP. Lastly, at two loci, we identified the likely causal SNP for the alternative splicing event, and at one, functionally validated the effect of that SNP on alternative splicing using a minigene reporter assay. Our results suggest that the regulation of differential transcript isoform expression is the functional mechanism of some breast cancer risk SNPs and that we can use these associations to identify causal SNPs, target genes and the specific transcripts that may mediate breast cancer risk

Efficient LZ78 factorization of grammar compressed text

We present an efficient algorithm for computing the LZ78 factorization of a text, where the text is represented as a straight line program (SLP), which is a context free grammar in the Chomsky normal form that generates a single string. Given an SLP of size $n$ representing a text $S$ of length $N$, our algorithm computes the LZ78 factorization of $T$ in $O(n\sqrt{N}+m\log N)$ time and $O(n\sqrt{N}+m)$ space, where $m$ is the number of resulting LZ78 factors. We also show how to improve the algorithm so that the $n\sqrt{N}$ term in the time and space complexities becomes either $nL$, where $L$ is the length of the longest LZ78 factor, or $(N - \alpha)$ where $\alpha \geq 0$ is a quantity which depends on the amount of redundancy that the SLP captures with respect to substrings of $S$ of a certain length. Since $m = O(N/\log_\sigma N)$ where $\sigma$ is the alphabet size, the latter is asymptotically at least as fast as a linear time algorithm which runs on the uncompressed string when $\sigma$ is constant, and can be more efficient when the text is compressible, i.e. when $m$ and $n$ are small.Comment: SPIRE 201

Dynamic Fluctuation Phenomena in Double Membrane Films

Dynamics of double membrane films is investigated in the long-wavelength limit including the overdamped squeezing mode. We demonstrate that thermal fluctuations essentially modify the character of the mode due to its nonlinear coupling to the transversal shear hydrodynamic mode. The corresponding Green function acquires as a function of the frequency a cut along the imaginary semi-axis. Fluctuations lead to increasing the attenuation of the squeezing mode it becomes larger than the `bare' value.Comment: 7 pages, Revte

Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points

Synaptic integrity and function depend on myriad proteins - labile molecules with finite lifetimes that need to be continually replaced with freshly synthesized copies. Here we describe experiments designed to expose synaptic (and neuronal) properties and functions that are particularly sensitive to disruptions in protein supply, identify proteins lost early upon such disruptions, and uncover potential, yet currently underappreciated failure points. We report here that acute suppressions of protein synthesis are followed within hours by reductions in spontaneous network activity levels, impaired oxidative phosphorylation and mitochondrial function, and, importantly, destabilization and loss of both excitatory and inhibitory postsynaptic specializations. Conversely, gross impairments in presynaptic vesicle recycling occur over longer time scales (days), as does overt cell death. Proteomic analysis identified groups of potentially essential ‘early-lost’ proteins including regulators of synapse stability, proteins related to bioenergetics, fatty acid and lipid metabolism, and, unexpectedly, numerous proteins involved in Alzheimer’s disease pathology and amyloid beta processing. Collectively, these findings point to neuronal excitability, energy supply and synaptic stability as early-occurring failure points under conditions of compromised supply of newly synthesized protein copies