IkappaBalpha regulates the transcription factor NF-kappaB through the formation of stable IkappaBalpha/NF-kappaB complexes. Prior to induction, IkappaBalpha retains NF-kappaB in the cytoplasm until the NF-kappaB activation signal is received. After activation, NF-kappaB is removed from gene promoters through association with nuclear IkappaBalpha, restoring the preinduction state. The 2.3 A crystal structure of IkappaBalpha in complex with the NF-kappaB p50/p65 heterodimer reveals mechanisms of these inhibitory activities. The presence of IkappaBalpha allows large en bloc movement of the NF-kappaB p65 subunit amino-terminal domain. This conformational change induces allosteric inhibition of NF-kappaB DNA binding. Amino acid residues immediately preceding the nuclear localization signals of both NF-kappaB p50 and p65 subunits are tethered to the IkappaBalpha amino-terminal ankyrin repeats, impeding NF-kappaB from nuclear import machinery recognition.

The NF-kappaB p50/p65 heterodimer is the classical member of the Rel family of transcription factors which regulate diverse cellular functions such as immune response, cell growth, and development. Other mammalian Rel family members, including the proteins p52, proto-oncoprotein c-Rel, and RelB, all have amino-terminal Rel-homology regions (RHRs). The RHR is responsible for the dimerization, DNA binding and cytosolic localization of these proteins by virtue of complex formation with inhibitor kappaB proteins. Signal-induced removal of kappaB inhibitors allows translocation of dimers to the cell nucleus and transcriptional regulation of kappaB DNA-containing genes. NF-kappaB specifically recognizes kappaB DNA elements with a consensus sequence of 5'-GGGRNYYYCC-3' (R is an unspecified purine; Y is an unspecified pyrimidine; and N is any nucleotide). Here we report the crystal structure at 2.9 A resolution of the p50/p65 heterodimer bound to the kappaB DNA of the intronic enhancer of the immunoglobulin light-chain gene. Our structure reveals a 5-base-pair 5' subsite for p50, and a 4-base-pair 3' subsite for p65. This structure indicates why the p50/p65 heterodimer interface is stronger than that of either homodimer. A comparison of this structure with those of other Rel dimers reveals that both subunits adopt variable conformations in a DNA-sequence-dependent manner. Our results explain the different behaviour of the p50/p65 heterodimer with heterologous promoters.

A small-world network has been suggested to be an efficient solution for achieving both modular and global processing—a property highly desirable for brain computations. Here, we investigated functional networks of cortical neurons using correlation analysis to identify functional connectivity. To reconstruct the interaction network, we applied the Ising model based on the principle of maximum entropy. This allowed us to assess the interactions by measuring pairwise correlations and to assess the strength of coupling from the degree of synchrony. Visual responses were recorded in visual cortex of anesthetized cats, simultaneously from up to 24 neurons. First, pairwise correlations captured most of the patterns in the population's activity and, therefore, provided a reliable basis for the reconstruction of the interaction networks. Second, and most importantly, the resulting networks had small-world properties; the average path lengths were as short as in simulated random networks, but the clustering coefficients were larger. Neurons differed considerably with respect to the number and strength of interactions, suggesting the existence of “hubs” in the network. Notably, there was no evidence for scale-free properties. These results suggest that cortical networks are optimized for the coexistence of local and global computations: feature detection and feature integration or binding.

Summary The signaling module that specifies nuclear factor-κB (NF-κB) activation is a three-component system: NF-κB, inhibitor of NFκB (IκB), and IκB kinase complex (IKK). IKK receives upstream signals from the surface or inside the cell and converts itself into a catalytically active form leading to the destruction of IκB in the inhibited IκB: NF-κB complex, leaving active NF-κB free to regulate target genes. Hidden within this simple module are family members that all can undergo various modifications resulting in expansion of functional spectrum. Three-dimensional structures representing all three components are now available. These structures have allowed us to interpret cellular observations in molecular terms and at the same time helped us to bring forward new concepts focused towards understanding the specificity in the NF-κB activation pathway.

Conformational change in human IKK2 permits dimers to form higher-order oligomers that support interaction between kinase domains and promote activation through trans auto-phosphorylation.

We report the crystal structure of a murine IB␤⅐NF-B p65 homodimer complex. Crystallographic models were determined for two triclinic crystalline systems and refined against data at 2.5 and 2.1 Å. The overall complex structure is similar to that of the IB␣⅐NF-B p50/p65 heterodimer complex. One NF-B p65 subunit nuclear localization signal clearly contacts IB␤, whereas a homologous segment from the second subunit of the homodimer is mostly solvent-exposed. The unique 47-amino acid insertion between ankyrin repeats three and four of IB␤ is mostly disordered in the structure. Primary sequence analysis and differences in the mode of binding at the IB␤ sixth ankyrin repeat and NF-B p65 homodimer suggest a model for nuclear IB␤⅐NF-B⅐DNA ternary complex formation. These unique structural features of IB␤ may contribute to its ability to mediate persistent NF-B activation.

Based on the invariance principle of differential equations, a simple adaptive-feedback scheme is proposed to strictly synchronize almost all chaotic systems. Unlike the usual linear feedback, the variable feedback strength is automatically adapted to completely synchronize two almost arbitrary identical chaotic systems, so this scheme is analytical, and simple to implement in practice.Moreover it is quite robust against the effect of noise. Since it was shown in [1] that for some chaotic systems the synchronization is possible, synchronization of (unidirectionally) coupled chaotic systems and its potential applications in engineering have been a field of great interest over a decade, see [2][3][4] and references cited therein. Due to the different applications, various specific synchronization schemes have been proposed in the literature, see [3] and references cited therein. However, just as what stated in [5], despite the large amount of effort many key issues remain open. One of the central questions is: Given two arbitrary identical chaotic systems, how can one design a physically available coupling scheme that is strictly guaranteed to produce stable identical synchronization motion (i.e., high-quality synchronization)? In most of the rigorous results based on the Lyapunov stability or the linear stability, the proposed scheme is very specific, but also the added controller is sometimes too big to be physically practical. One practical scheme is the linear feedback. However, in such technique it is very difficult to find the suitable feedback constant, and thus numerical calculation has to be used, e.g., the calculation of the conditional Lyapunov exponents. Due to numerical calculation, such scheme is not regular since it can be applied only to particular models.More unfortunately, it has been reported that the negativity of the conditional Lyapunov exponents is not a sufficient condition for complete chaotic synchronization, see [6]. Therefore the synchronization based on these numerical schemes can not be strict (i.e., high-qualitative), and is generally not robust against the effect of noise.Especially, in these schemes a very weak noise or a small parameter mismatch can trigger the desynchronization problem due to a sequence of bifurcations [7].Actually, this open problem, although significant for complete chaos synchronization, is very difficult and cannot admit the optimization solution [3]. For example, in [5] a rigorous criteria is presented to guarantee linearly stable synchronization motion, but the criteria is so complicated that the specific numerical calculation is necessary for particular examples in practice. The similar problem was ever addressed in [8].In this letter, we give a novel answer to the above open problem. We prove rigorously by using the invariance principle of differential equations [9] that a simple feedback coupling with the updated feedback strength, i.e., an adaptive-feedback scheme, can strictly synchronize two almost arbitrary identical chaotic systems.Let a chaotic (dr...

Purpose Secondary lymphedema is a frequent complication of breast cancer associated with surgery, chemotherapy, or radiation following breast cancer treatment. The potential contribution of genetic susceptibility to risk of developing secondary lymphedema following surgical trauma, radiation, and other tissue insults has not been studied. Experimental Design To determine if women with breast cancer and secondary lymphedema had mutations in candidate lymphedema genes, we undertook a case - control study of 188 women diagnosed with breast cancer recruited from the University of Pittsburgh Breast Cancer Program (http://www.upmccancercenter.com/breast/index.cfm) between 2000–2010. Candidate lymphedema genes, GJC2 (encoding connexin 47 [Cx47]), FOXC2, HGF, MET, and FLT4 (encoding VEGFR3), were sequenced for mutation. Bioinformatics analysis and in vitro functional assays were used to confirm significance of novel mutations. Results Cx47 mutations were identified in individuals having secondary lymphedema following breast cancer treatment but not in breast cancer controls or normal women without breast cancer. These novel mutations are dysfunctional as assessed through in vitro assays and bioinformatics analysis, and provide evidence that altered gap junction function leads to lymphedema. Conclusions Our findings challenge the view that secondary lymphedema is solely due to mechanical trauma and support the hypothesis that genetic susceptibility is an important risk factor for secondary lymphedema. A priori recognition of genetic risk 1) raises the potential for early detection and intervention for a high risk group, and 2) allows the possibility of altering surgical approach and/or chemo- and radiation therapy, or direct medical treatment of secondary lymphedema with novel connexin modifying drugs. Translational Relevance Secondary lymphedema is a frequent and serious chronic complication of breast cancer treatment. Our finding of four independent mutations in Cx47, including one shared mutation previously reported in primary lymphedema, not only supports these mutations as a genetic risk to the development of secondary lymphedema but raises the likelihood that other genes may contribute to such a genetic risk to secondary lymphedema as well.