Regulatory activity revealed by dynamic correlations in gene expression noise

Gene regulatory interactions are context dependent, active in some cellular states but not in others. Stochastic fluctuations, or 'noise', in gene expression propagate through active, but not inactive, regulatory links^(1,2). Thus, correlations in gene expression noise could provide a noninvasive means to probe the activity states of regulatory links. However, global, 'extrinsic', noise sources generate correlations even without direct regulatory links. Here we show that single-cell time-lapse microscopy, by revealing time lags due to regulation, can discriminate between active regulatory connections and extrinsic noise. We demonstrate this principle mathematically, using stochastic modeling, and experimentally, using simple synthetic gene circuits. We then use this approach to analyze dynamic noise correlations in the galactose metabolism genes of Escherichia coli. We find that the CRP-GalS-GalE feed-forward loop is inactive in standard conditions but can become active in a GalR mutant. These results show how noise can help analyze the context dependence of regulatory interactions in endogenous gene circuits

Performance of two transferred modules in the Lagunera Region: Water relations

Water policy / Performance / Privatization / Irrigation systems / Operations / Maintenance / Irrigation efficiency / Water users' associations / Water rights / Water allocation / Water supply / Water distribution

Down Syndrome: Age-Dependence of PiB Binding in Postmortem Frontal Cortex Across the Lifespan

Beta-amyloid (Aβ) deposition in brain accumulates as a function of age in people with Down syndrome (DS) with subsequent development into Alzheimer disease neuropathology, typically by 40 years of age. In vivo imaging using the Pittsburgh Compound B (PiB) ligand has facilitated studies linking Aβ, cognition, and dementia in DS. However, there are no studies of PiB binding across the lifespan in DS. The current study describes in vitro 3H-PiB binding in the frontal cortex of autopsy cases with DS compared to non-DS controls. Tissue from 64 cases included controls (N=25) and DS (N=39). In DS, 3H-PiB binding was significantly associated with age. After age 40 years in DS, 3H-PiB binding rose dramatically along with increasing individual variability. 3H-PiB binding correlated with the amount of Aβ42. Using fixed frontal tissue and fluorescent 6-CN-PiB, neuritic and cored plaques along with extensive cerebral amyloid angiopathy (CAA) showed 6-CN-PiB binding. These results suggest that cortical PiB binding as shown by positron emission tomography imaging reflects plaques and CAA in DS brain

Spinons in a Crossed-Chains Model of a 2D Spin Liquid

Using Random Phase Approximation, we show that a crossed-chains model of a spin-1/2 Heisenberg spins, with frustrated interchain couplings, has a non-dimerized spin-liquid ground state in 2D, with deconfined spinons as the elementary excitations. The results are confirmed by a bosonization study, which shows that the system is an example of a `sliding Luttinger liquid'. In an external field, the system develops an incommensurate field-induced long range order with a finite transition temperature.Comment: 4 pages, 3 figures; added references; scaling analysis, preserving spin rotational invariance, is extended to finite temperatur

Hadronic light-by-light corrections to the muon g-2: the pion-pole contribution

The correction to the muon anomalous magnetic moment from the pion-pole contribution to the hadronic light-by-light scattering is considered using a description of the pi0 - gamma* - gamma* transition form factor based on the large-Nc and short-distance properties of QCD. The resulting two-loop integrals are treated by first performing the angular integration analytically, using the method of Gegenbauer polynomials, followed by a numerical evaluation of the remaining two-dimensional integration over the moduli of the Euclidean loop momenta. The value obtained, a_{mu}(LbyL;pi0) = +5.8 (1.0) x 10^{-10}, disagrees with other recent calculations. In the case of the vector meson dominance form factor, the result obtained by following the same procedure reads a_{mu}(LbyL;pi0)_{VMD} = +5.6 x 10^{-10}, and differs only by its overall sign from the value obtained by previous authors. Inclusion of the eta and eta-prime poles gives a total value a_{mu}(LbyL;PS) = +8.3 (1.2) x 10^{-10} for the three pseudoscalar states. This result substantially reduces the difference between the experimental value of a_{mu} and its theoretical counterpart in the standard model.Comment: 27 pages, Latex, 3 figures. v2: version to be published in Phys. Rev. D, Note added and references updated (don't worry, sign has not changed

Organizational Agility through Project Portfolio Management

In dynamic environments, organizational agility is essential for survival; organizations must be able to adapt to change in order to succeed. In project-based organizations, a dynamic project portfolio management (PPM) capability can enhance organizational agility. PPM is an important organizational capability that enables organizations to manage and balance the portfolio holistically, to align projects with strategy, and to ensure adequate resourcing for projects in order to maximize the benefits from project investments. A dynamic PPM capability enables organizations to be agile and flexible by facilitating adjustments to the project portfolio and reallocating resources in response to the changes in the environment. In order for the PPM capability to remain relevant, it must evolve to reflect changes in the environment. Examples of aspects of PPM that enhance organizational agility are outlined in this paper to provide guidance for practitioners

Therapy refractory hypertension in adults: aortic coarctation has to be ruled out

In patients with unexplained hypertension, especially in combination with a cardiac murmur, the presence of an aortic coarctation should always be ruled out given the high morbidity and mortality. However, particularly patients with an isolated coarctation often remain asymptomatic for years and the defect may be unnoticed even until the fifth or sixth decade of life. In the present article, we describe two patients with late detected coarctation to illustrate the clinical consequences, diagnostic clues for earlier detection and current therapeutic options to achieve optimal treatment. The key sign of an aortic coarctation, a difference in arterial blood pressure measured between the upper and lower extremities, should always be examined, followed by echocardiography. We conclude that even in case of a late detected severe coarctation, surgical or percutaneous repair has proven to be feasible and substantially effective, improving quality of life and lowering the risk of further hypertension-associated problems

Alzheimer\u27s Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer\u27s disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer\u27s disease patients\u27 brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics

A functionalized single-walled carbon nanotube-induced autophagic cell death in human lung cells through Akt–TSC2-mTOR signaling

Nanoparticles are now emerging as a novel class of autophagy activators. Functionalized single-walled carbon nanotubes (f-SWCNTs) are valuable nanomaterials in many industries. This article is designed to assess the autophagic response for f-SWCNTs exposure in vitro and in vivo. A few types of f-SWCNTs were screened in human lung adenocarcinoma A549 cells for the autophagic response and related pathways in vitro. Formation of autophagosomes and LC3-II upregulation were confirmed on the basis of electron microscopy and LC3 western blotting for COOH-CNT, but not for PABS-CNT and PEG-CNT. MTT assay showed marked increase in cell viability, when COOH-CNT was added to cells in the presence of autophagy inhibitor 3MA, ATG6 or TSC2 siRNA. Consistent with the involvement of the Akt–TSC1/2–mTOR pathway, the phosphorylation levels of mTOR, mTOR's substrate S6 and Akt were shown significantly decreased in A549 cells on treatment with COOH-CNT using western blotting. What's more, autophagy inhibitor 3MA significantly reduced the lung edema in vivo. In a word, COOH-CNT induced autophagic cell death in A549 cells through the AKT–TSC2–mTOR pathway and caused acute lung injury in vivo. Inhibition of autophagy significantly reduced COOH-CNT-induced autophagic cell death and ameliorated acute lung injury in mice, suggesting a potential remedy to address the growing concerns on the safety of nanomaterials

Protective Effects of Walnut Extract Against Amyloid Beta Peptide-Induced Cell Death and Oxidative Stress in PC12 Cells

Amyloid beta-protein (Aβ) is the major component of senile plaques and cerebrovascular amyloid deposits in individuals with Alzheimer’s disease. Aβ is known to increase free radical production in neuronal cells, leading to oxidative stress and cell death. Recently, considerable attention has been focused on dietary antioxidants that are able to scavenge reactive oxygen species (ROS), thereby offering protection against oxidative stress. Walnuts are rich in components that have anti-oxidant and anti-inflammatory properties. The inhibition of in vitro fibrillization of synthetic Aβ, and solubilization of preformed fibrillar Aβ by walnut extract was previously reported. The present study was designed to investigate whether walnut extract can protect against Aβ-induced oxidative damage and cytotoxicity. The effect of walnut extract on Aβ-induced cellular damage, ROS generation and apoptosis in PC12 pheochromocytoma cells was studied. Walnut extract reduced Aβ-mediated cell death assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) reduction, and release of lactate dehydrogenase (membrane damage), DNA damage (apoptosis) and generation of ROS in a concentration-dependent manner. These results suggest that walnut extract can counteract Aβ-induced oxidative stress and associated cell death