Guanylate cyclase activity in permeabilized <em>Dictyostelium discoideum</em> cells

Dictyostelium discoideum cells respond to chemoattractants by transient activation of guanylate cyclase. Cyclic GMP is a second messenger that transduces the chemotactic signal. We used an electropermeabilized cell system to investigate the regulation of guanylate cyclase. Enzyme activity in permeabilized cells was dependent on the presence of a nonhydrolysable GTP analogue (e.g., GTPγS), which could not be replaced by GTP, GDP, or GMP. After the initiation of the guanylate cyclase reaction in permeabilized cells only a short burst of activity is observed, because the enzyme is inactivated with a t1.2 of about 15 s. We show that inactivation is not due to lack of substrate, resealing of the pores in the cell membrane, product inhibition by cGMP, or intrinsic instability of the enzyme. Physiological concentrations of Ca2+ ions inhibited the enzyme (half‐maximal effect at 0.3 μM), whereas InsP3 had no effect. Once inactivated, the enzyme could only be reactivated after homogenization of the permeabilized cells and removal of the soluble cell fraction. This suggests that a soluble factor is involved in an autonomous process that inactivates guanylate cyclase and is triggered only after the enzyme is activated. The initial rate of guanylate cyclase activity in permeabilized cells is similar to that in intact, chemotactically activated cells. Moreover, the rate of inactivation of the enzyme in permeabilized cells and that due to adaptation in vivo are about equal. This suggests that the activation and inactivation of guanylate cyclase observed in this permeabilized cell system is related to that of chemotactic activation and adaptation in intact cells

On Vanishing Theorems For Vector Bundle Valued p-Forms And Their Applications

Let $F: [0, \infty) \to [0, \infty)$ be a strictly increasing $C^2$ function with $F(0)=0$. We unify the concepts of $F$-harmonic maps, minimal hypersurfaces, maximal spacelike hypersurfaces, and Yang-Mills Fields, and introduce $F$-Yang-Mills fields, $F$-degree, $F$-lower degree, and generalized Yang-Mills-Born-Infeld fields (with the plus sign or with the minus sign) on manifolds. When $F(t)=t, \frac 1p(2t)^{\frac p2}, \sqrt{1+2t} -1,$ and $1-\sqrt{1-2t},$ the $F$-Yang-Mills field becomes an ordinary Yang-Mills field, $p$-Yang-Mills field, a generalized Yang-Mills-Born-Infeld field with the plus sign, and a generalized Yang-Mills-Born-Infeld field with the minus sign on a manifold respectively. We also introduce the $E_{F,g}-$energy functional (resp. $F$-Yang-Mills functional) and derive the first variational formula of the $E_{F,g}-$energy functional (resp. $F$-Yang-Mills functional) with applications. In a more general frame, we use a unified method to study the stress-energy tensors that arise from calculating the rate of change of various functionals when the metric of the domain or base manifold is changed. These stress-energy tensors, linked to $F$-conservation laws yield monotonicity formulae. A "macroscopic" version of these monotonicity inequalities enables us to derive some Liouville type results and vanishing theorems for $p-$forms with values in vector bundles, and to investigate constant Dirichlet boundary value problems for 1-forms. In particular, we obtain Liouville theorems for $F-$harmonic maps (e.g. $p$-harmonic maps), and $F-$Yang-Mills fields (e.g. generalized Yang-Mills-Born-Infeld fields on manifolds). We also obtain generalized Chern type results for constant mean curvature type equations for $p-$forms on $\Bbb{R}^m$ and on manifolds $M$ with the global doubling property by a different approach. The case $p=0$ and $M=\mathbb{R}^m$ is due to Chern.Comment: 1. This is a revised version with several new sections and an appendix that will appear in Communications in Mathematical Physics. 2. A "microscopic" approach to some of these monotonicity formulae leads to celebrated blow-up techniques and regularity theory in geometric measure theory. 3. Our unique solution of the Dirichlet problems generalizes the work of Karcher and Wood on harmonic map

The Strong Energy Condition and the S-Brane Singularity Problem

Recently it has been argued that, because tachyonic matter satisfies the Strong Energy Condition [SEC], there is little hope of avoiding the singularities which plague S-Brane spacetimes. Meanwhile, however, Townsend and Wohlfarth have suggested an ingenious way of circumventing the SEC in such situations, and other suggestions for actually violating it in the S-Brane context have recently been proposed. Of course, the natural context for discussions of [effective or actual] violations of the SEC is the theory of asymptotically deSitter spacetimes, which tend to be less singular than ordinary FRW spacetimes. However, while violating or circumventing the SEC is necessary if singularities are to be avoided, it is not at all clear that it is sufficient. That is, we can ask: would an asymptotically deSitter S-brane spacetime be non-singular? We show that this is difficult to achieve; this result is in the spirit of the recently proved "S-brane singularity theorem". Essentially our results suggest that circumventing or violating the SEC may not suffice to solve the S-Brane singularity problem, though we do propose two ways of avoiding this conclusion.Comment: 13 pages, minor corrections and improvements, references adde

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice

Differential microRNA expression in cultured palatal fibroblasts from infants with cleft palate and controls

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