Similar millennial climate variability on the Iberian margin during two early Pleistocene glacials and MIS 3

Although millennial-scale climate variability (<10 ka) has been well studied during the last glacial cycles, little is known about this important aspect of climate in the early Pleistocene, prior to the Middle Pleistocene Transition. Here we present an early Pleistocene climate record at centennial resolution for two representative glacials (marine isotope stages (MIS) 37–41 from approximately 1235 to 1320 ka) during the “41 ka world” at Integrated Ocean Drilling Program Site U1385 (the “Shackleton Site”) on the southwest Iberian margin. Millennial-scale climate variability was suppressed during interglacial periods (MIS 37, MIS 39, and MIS 41) and activated during glacial inceptions when benthic δ^18O exceeded 3.2‰. Millennial variability during glacials MIS 38 and MIS 40 closely resembled Dansgaard-Oeschger events from the last glacial (MIS 3) in amplitude, shape, and pacing. The phasing of oxygen and carbon isotope variability is consistent with an active oceanic thermal bipolar see-saw between the Northern and Southern Hemispheres during most of the prominent stadials. Surface cooling was associated with systematic decreases in benthic carbon isotopes, indicating concomitant changes in the meridional overturning circulation. A comparison to other North Atlantic records of ice rafting during the early Pleistocene suggests that freshwater forcing, a s proposed for the late Pleistocene, was involved in triggering or amplifying perturbations of the North Atlantic circulation that elicited a bipolar see-saw response. Our findings support similarities in the operation of the climate system occurring on millennial time scales before and after the Middle Pleistocene Transition despite the increases in global ice volume and duration of the glacial cycles.This work was made possible by a DAAD scholarship and NERC Grant NE/K005804/1.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/2015PA00286

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

© 2016 the American Physiological Society. Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediate-conductance calcium-activated K+ channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as bronchoconstriction in obstructive airway disease

An abnormality in glucocorticoid receptor expression differentiates steroid responders from nonresponders in keloid disease

Background: Glucocorticoids (GCs) are first-line treatment for keloid disease (KD) but are limited by high incidence of resistance, recurrence and undesirable sideeffects. Identifying patient responsiveness early could guide therapy. Methods: Nineteen patients with KD were recruited at week 0 (before treatment) and received intralesional steroids. At weeks 0, 2 and 4, noninvasive imaging and biopsies were performed. Responsiveness was determined by clinical response and a significant reduction in vascular perfusion following steroid treatment, using full-field laser perfusion imaging (FLPI). Responsiveness was also evaluated using (i) spectrophotometric intracutaneous analysis to quantify changes in collagen and melanin and (ii) histology to identify changes in epidermal thickness and glycosaminoglycan (GAG) expression. Biopsies were used to quantify changes in glucocorticoid receptor (GR) expression using quantitative reverse transcriptase polymerase chain reaction, immunoblotting and immunohistochemistry. Results: At week 2, the FLPI was used to separate patients into steroid responsive (n = 12) and nonresponsive groups (n = 7). All patients demonstrated a signifccant decrease in GAG at week 2 (P < 0 05). At week 4, responsive patients exhibited significant reduction in melanin, GAG, epidermal thickness (all P < 0 05) and a continued reduction in perfusion (P < 0 001) compared with nonresponders. Steroid-responsive patients had increased GR expression at baseline and showed autoregulation of GR compared with nonresponders, who showed no change in GR transcription or protein. Conclusions: This is the first demonstration that keloid response to steroids can be measured objectively using noninvasive imaging. FLPI is a potentially reliable tool to stratify KD responsiveness. Altered GR expression may be the mechanism gating therapeutic response

Effects of tidal-forcing variations on tidal properties along a narrow convergent estuary

A 1D analytical framework is implemented in a narrow convergent estuary that is 78 km in length (the Guadiana, Southern Iberia) to evaluate the tidal dynamics along the channel, including the effects of neap-spring amplitude variations at the mouth. The close match between the observations (damping from the mouth to ∼ 30 km, shoaling upstream) and outputs from semi-closed channel solutions indicates that the M2 tide is reflected at the estuary head. The model is used to determine the contribution of reflection to the dynamics of the propagating wave. This contribution is mainly confined to the upper one third of the estuary. The relatively constant mean wave height along the channel (< 10% variations) partly results from reflection effects that also modify significantly the wave celerity and the phase difference between tidal velocity and elevation (contradicting the definition of an “ideal” estuary). Furthermore, from the mouth to ∼ 50 km, the variable friction experienced by the incident wave at neap and spring tides produces wave shoaling and damping, respectively. As a result, the wave celerity is largest at neap tide along this lower reach, although the mean water level is highest in spring. Overall, the presented analytical framework is useful for describing the main tidal properties along estuaries considering various forcings (amplitude, period) at the estuary mouth and the proposed method could be applicable to other estuaries with small tidal amplitude to depth ratio and negligible river discharge.info:eu-repo/semantics/publishedVersio

Tightness for a stochastic Allen--Cahn equation

We study an Allen-Cahn equation perturbed by a multiplicative stochastic noise which is white in time and correlated in space. Formally this equation approximates a stochastically forced mean curvature flow. We derive uniform energy bounds and prove tightness of of solutions in the sharp interface limit, and show convergence to phase-indicator functions.Comment: 27 pages, final Version to appear in "Stochastic Partial Differential Equations: Analysis and Computations". In Version 4, Proposition 6.3 is new. It replaces and simplifies the old propositions 6.4-6.

Parametrizations of density matrices

This article gives a brief overview of some recent progress in the characterization and parametrization of density matrices of finite dimensional systems. We discuss in some detail the Bloch-vector and Jarlskog parametrizations and mention briefly the coset parametrization. As applications of the Bloch parametrization we discuss the trace invariants for the case of time dependent Hamiltonians and in some detail the dynamics of three-level systems. Furthermore, the Bloch vector of two-qubit systems as well as the use of the polarization operator basis is indicated. As the main application of the Jarlskog parametrization we construct density matrices for composite systems. In addition, some recent related articles are mentioned without further discussion.Comment: 31 pages. v2: 32 pages, Abstract and Introduction rewritten and Conclusion section added, references adde

Complex nature of SNP genotype effects on gene expression in primary human leucocytes.

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.BACKGROUND: Genome wide association studies have been hugely successful in identifying disease risk variants, yet most variants do not lead to coding changes and how variants influence biological function is usually unknown. METHODS: We correlated gene expression and genetic variation in untouched primary leucocytes (n = 110) from individuals with celiac disease - a common condition with multiple risk variants identified. We compared our observations with an EBV-transformed HapMap B cell line dataset (n = 90), and performed a meta-analysis to increase power to detect non-tissue specific effects. RESULTS: In celiac peripheral blood, 2,315 SNP variants influenced gene expression at 765 different transcripts (< 250 kb from SNP, at FDR = 0.05, cis expression quantitative trait loci, eQTLs). 135 of the detected SNP-probe effects (reflecting 51 unique probes) were also detected in a HapMap B cell line published dataset, all with effects in the same allelic direction. Overall gene expression differences within the two datasets predominantly explain the limited overlap in observed cis-eQTLs. Celiac associated risk variants from two regions, containing genes IL18RAP and CCR3, showed significant cis genotype-expression correlations in the peripheral blood but not in the B cell line datasets. We identified 14 genes where a SNP affected the expression of different probes within the same gene, but in opposite allelic directions. By incorporating genetic variation in co-expression analyses, functional relationships between genes can be more significantly detected. CONCLUSION: In conclusion, the complex nature of genotypic effects in human populations makes the use of a relevant tissue, large datasets, and analysis of different exons essential to enable the identification of the function for many genetic risk variants in common diseases.Coeliac UKNetherlands Organization for Scientific ResearchCeliac Disease Consortium (an innovative cluster approved by the Netherlands Genomics Initiative and partly funded by the Dutch government)Netherlands Genomics InitiativeWellcome Trus

Prediction of lethal and synthetically lethal knock-outs in regulatory networks

The complex interactions involved in regulation of a cell's function are captured by its interaction graph. More often than not, detailed knowledge about enhancing or suppressive regulatory influences and cooperative effects is lacking and merely the presence or absence of directed interactions is known. Here we investigate to which extent such reduced information allows to forecast the effect of a knock-out or a combination of knock-outs. Specifically we ask in how far the lethality of eliminating nodes may be predicted by their network centrality, such as degree and betweenness, without knowing the function of the system. The function is taken as the ability to reproduce a fixed point under a discrete Boolean dynamics. We investigate two types of stochastically generated networks: fully random networks and structures grown with a mechanism of node duplication and subsequent divergence of interactions. On all networks we find that the out-degree is a good predictor of the lethality of a single node knock-out. For knock-outs of node pairs, the fraction of successors shared between the two knocked-out nodes (out-overlap) is a good predictor of synthetic lethality. Out-degree and out-overlap are locally defined and computationally simple centrality measures that provide a predictive power close to the optimal predictor.Comment: published version, 10 pages, 6 figures, 2 tables; supplement at http://www.bioinf.uni-leipzig.de/publications/supplements/11-01

N=4 Superconformal Algebra and the Entropy of HyperKahler Manifolds

We study the elliptic genera of hyperKahler manifolds using the representation theory of N=4 superconformal algebra. We consider the decomposition of the elliptic genera in terms of N=4 irreducible characters, and derive the rate of increase of the multiplicities of half-BPS representations making use of Rademacher expansion. Exponential increase of the multiplicity suggests that we can associate the notion of an entropy to the geometry of hyperKahler manifolds. In the case of symmetric products of K3 surfaces our entropy agrees with the black hole entropy of D5-D1 system.Comment: 25 pages, 1 figur

The Second Transmembrane Domain of P2X7 Contributes to Dilated Pore Formation

Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors. © 2013 Sun et al