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Our structural and biochemical data therefore provide an important framework for the mechanistic understanding of nucleoside transporters of the NHS family.Allosteric proteins with multiple subunits and ligand binding sites are central in regulating biological signals. cAMP receptor protein from Mycobacterium tuberculosis (CRPMTB) is a global regulator of transcription composed of two identical subunits, each one harboring structurally conserved cAMP and DNA binding sites. EGFR inhibitor The mechanisms by which these four binding sites are allosterically coupled in CRPMTB remain unclear. Here, we investigate the binding mechanism between CRPMTB and cAMP, and the linkage between cAMP and DNA interactions. Using calorimetric and fluorescent-based assays, we find that cAMP binding is entropically driven and displays negative cooperativity. Fluorescence anisotropy experiments show that apo CRPMTB forms high-order CRPMTB-DNA oligomers through interactions with non-specific DNA sequences or preformed CRPMTB-DNA complexes. Additionally, we find that cAMP prevents and reverses the formation of CRPMTB-DNA oligomers, reduces the affinity of CRPMTB for non-specific DNA sequences, stabilizes 1-to-1 CRPMTB-DNA, but does not increase the affinity for DNA like in the canonical Escherichia coli CRP homolog (CRPEcoli). DNA binding assays as a function of cAMP concentration indicates that one cAMP molecule per homodimer dissociates high-order CRPMTB-DNA oligomers into 1-to-1 complexes. These cAMP-mediated allosteric effects are lost in the double mutant L47P/E178K from the attenuated M. bovis BCG strain (CRPBCG). The functional behavior, thermodynamic stability and dimerization constant of CRPBCG are not observed in the single mutants L47P or E178K, indicating long-range interactions between these two sites. Altogether, we provide a previously undescribed archetype of cAMP-mediated allosteric transcription regulation that differs from CRPEcoli, illustrating that structural homology does not imply allosteric homology.Olfactory receptors (ORs), the largest family of G protein-coupled receptors, are expressed in the nasal epithelium where they mediate the sense of smell. However, ORs are also found in other non-nasal tissues, but the role of these ectopic ORs in cell signaling, proliferation and survival is not well understood. Here, using an inducible expression system in the prostate cancer cell line LNCaP, we investigated two ectopic ORs, OR51E1 and OR51E2, which have been shown to be upregulated in prostate cancer. We found that, consistent with previous studies, OR51E1 stimulated adenylyl cyclase in response to treatment by short- to medium-chain organic acids (C3-C9), but not by acetate. OR51E2 responded to acetate and propionate, but not to the longer chain organic acids. Stimulation of LNCaP cells with butyrate inhibited their growth, and the knockdown of the endogenous OR51E1 negated this cytostatic effect. Most significantly, overexpression of OR51E1 or OR51E2 suppressed LNCaP cell proliferation. Overexpression of another ectopic olfactory receptor OR2AT4, β2-adrenergic receptor or treatment of cells with forskolin did not suppress cell proliferation, indicating that a rise in cAMP is not sufficient to induce cytostasis. Overexpression of OR51E1 caused an upregulation of cytostatic and cell death markers including p27, p21 and p53, strongly increased annexin V staining and stimulated ERK1/2. Overexpression and/or activation of OR51E1 did not affect HEK293 cell proliferation, indicating that cytotoxicity of OR51E1/2 is specific for LNCaP cells. Together, our results further our understanding of prostate cancer etiology and suggest that ectopic ORs may be useful therapeutic targets.We review studies on tissue transplantation experiments for various species one piece of the donor tissue is excised and transplanted into a slit in the host tissue, then observe the behavior of this grafted tissue. Although we have known the results of some transplantation experiments, there are many more possible experiments with unknown results. We develop a penalty function-based method that uses the known experimental results to infer the unknown experimental results. Similar experiments without similar results get penalized and correspond to smaller probability. This method can provide the most probable results of a group of experiments or the probability of a specific result for each experiment. This method is also generalized to other situations. Besides, we solve a problem how to design experiments so that such a method can be applied most efficiently.Transposable elements (TEs) are essential components of the eukaryotic genomes. While mostly deleterious, evidence is mounting that TEs provide the host with beneficial adaptations. How 'selfish' or 'parasitic' DNA persists until it helps species evolution is emerging as a major evolutionary puzzle, especially in asexual taxa where the lack of sex strongly impede the spread of TEs. Since occasional but unchecked TE proliferations would ultimately drive host lineages toward extinction, asexual genomes are typically predicted to be free of TEs, which contrasts with their persistence in asexual taxa. We designed innovative 'Eco-genomic' models that account for both host demography and within-host molecular mechanisms of transposition and silencing to analyze their impact on TE dynamics in asexual genome populations. We unraveled that the spread of TEs can be limited to a stable level by density-dependent purifying selection when TE copies are over-dispersed among lineages and the host demographic turn-over is fast. We also showed that TE silencing can protect host populations in two ways; by preventing TEs with weak effects to accumulate or by favoring the elimination of TEs with large effects. Our predictions may explain TE persistence in known asexual taxa that typically show fast demography and where TE copy number variation between lineages is expected. Such TE persistence in asexual taxa potentially has important implications for their evolvability and the preservation of sexual reproduction.Systems biology aims to understand how holistic systems theory can be used to explain the observable living system characteristics, and mathematical modeling tools have been successful in understanding the intricate relationships underlying cellular functions. Lately, researchers have been interested in understanding molecular mechanisms underlying obesity, which is a major health concern worldwide and has been linked to several diseases. Various mechanisms such as peroxisome proliferator-activated receptors (PPARs) are known to modulate obesity-induced inflammation and its consequences. In this study, we have modeled the PPAR pathway using a Bayesian model and inferred the sub-pathways that are potentially responsible for the activation of the output processes that are associated with high fat diet (HFD)-induced obesity. We examined a previously published dataset from a study that compared gene expression profiles of 40 mice maintained on HFD against 40 mice fed with chow diet (CD). Our simulations have highlighted that GPCR and FATCD36 sub-pathways were aberrantly active in HFD mice and are therefore favorable targets for anti-obesity strategies.
Here's my website: https://www.selleckchem.com/EGFR(HER).html