A Molecular Analysis of the Aminopeptidase P-Related Domain of PID-5 from Caenorhabditis elegans

A novel protein, PID-5, has been shown to be a requirement for germline immortality and has recently been implicated in RNA-induced epigenetic silencing in the Caenorhabditis elegans embryo. Importantly, it has been shown to contain both an eTudor and aminopeptidase P-related domain. However, the silencing mechanism has not yet been fully characterised. In this study, bioinformatic tools were used to compare pre-existing aminopeptidase P molecular structures to the AlphaFold2-predicted aminopeptidase P-related domain of PID-5 (PID-5 APP-RD). Structural homology, metal composition, inhibitor-bonding interactions, and the potential for dimerisation were critically assessed through computational techniques, including structural superimposition and protein-ligand docking. Results from this research suggest that the metallopeptidase-like domain shares high structural homology with known aminopeptidase P enzymes and possesses the canonical ‘pita-bread fold’. However, the absence of conserved metal-coordinating residues indicates that only a single Zn2+ may be bound at the active site. The PID-5 APP-RD may form transient interactions with a known aminopeptidase P inhibitor and may therefore recognise substrates in a comparable way to the known structures. However, loss of key catalytic residues suggests the domain will be inactive. Further evidence suggests that heterodimerisation with C. elegans aminopeptidase P is feasible and therefore PID-5 is predicted to regulate proteolytic cleavage in the silencing pathway. PID-5 may interact with PID-2 to bring aminopeptidase P activity to the Z-granule, where it could influence WAGO-4 activity to ensure the balanced production of 22G-RNA signals for transgenerational silencing. Targeted experiments into APPs implicated in malaria and cancer are required in order to build upon the biological and therapeutic significance of this research

dS/CFT correspondence on a brane

We study branes moving in an AdS Schwarzschild black hole background. When the brane tension exceeds a critical value, the induced metric on the brane is of FRW type and asymptotically de Sitter. We discuss the relevance of such configurations to dS/CFT correspondence. When the black hole mass reaches a critical value that depends on the brane tension, the brane interpolates in the infinite past and future between a dS space and a finite space of zero Hubble constant. This corresponds to a cosmological evolution without a Big Bang or a Big Crunch. Moreover, the central charge of the CFT dual to the dS brane enters the Cardy-Verlinde formula that gives the entropy of the thermal CFT dual to the bulk AdS black hole.Comment: 15 pages, 1 figure, v2 references adde

Cosmic D-Strings and Vortons in Supergravity

Recent developments in string inspired models of inflation suggest that D-strings are formed at the end of inflation. Within the supergravity model of D-strings there are 2(n-1) chiral fermion zero modes for a D-string of winding n. Using the bounds on the relic vorton density, we show that D-strings with winding number n>1 are more strongly constrained than cosmic strings arising in cosmological phase transitions. The D-string tension of such vortons, if they survive until the present, has to satisfy 8\pi G_N \mu \lesssim p 10^{-26} where p is the intercommutation probability. Similarly, D-strings coupled with spectator fermions carry currents and also need to respect the above bound. D-strings with n=1 do not carry currents and evade the bound. We discuss the coupling of D-strings to supersymmetry breaking. When a single U(1) gauge group is present, we show that there is an incompatibility between spontaneous supersymmetry breaking and cosmic D-strings. We propose an alternative mechanism for supersymmetry breaking, which includes an additional U(1), and might alleviate the problem. We conjecture what effect this would have on the fermion zero modes.Comment: 11 page

Calcium Intake From Diet and Supplements and the Risk of Coronary Artery Calcification and its Progression Among Older Adults: 10‐Year Follow‐up of the Multi‐Ethnic Study of Atherosclerosis (MESA)

BACKGROUND: Recent randomized data suggest that calcium supplements may be associated with increased risk of cardiovascular disease (CVD) events. Using a longitudinal cohort study, we assessed the association between calcium intake, from both foods and supplements, and atherosclerosis, as measured by coronary artery calcification (CAC). METHODS AND RESULTS: We studied 5448 adults free of clinically diagnosed CVD (52% female; aged 45-84 years) from the Multi-Ethnic Study of Atherosclerosis. Baseline total calcium intake was assessed from diet (using a food frequency questionnaire) and calcium supplements (by a medication inventory) and categorized into quintiles. Baseline CAC was measured by computed tomography, and CAC measurements were repeated in 2742 participants ≈10 years later. At baseline, mean calcium intakes across quintiles were 313.3, 540.3, 783.0, 1168.9, and 2157.4 mg/day. Women had higher calcium intakes than men. After adjustment for potential confounders, among 1567 participants without baseline CAC, the relative risk (RR) of developing incident CAC over 10 years, by quintile 1 to 5 of calcium intake, were 1 (reference), 0.95 (0.79-1.14), 1.02 (0.85-1.23), 0.86 (0.69-1.05), and 0.73 (0.57-0.93). After accounting for total calcium intake, calcium supplement use was associated with increased risk for incident CAC (RR=1.22 [1.07-1.39]). No relation was found between baseline calcium intake and 10-year changes in log-transformed CAC among those participants with baseline CAC >0. CONCLUSIONS: High total calcium intake was associated with a decreased risk of incident atherosclerosis over long-term follow-up, particularly if achieved without supplement use. However, calcium supplement use may increase the risk for incident CAC

Hypertension and Smoking Are Associated With Reduced Regional Left Ventricular Function in Asymptomatic Individuals The Multi-Ethnic Study of Atherosclerosis

ObjectivesThis study sought to test the hypothesis that reduced regional left ventricular (LV) function is associated with traditional risk factors including hypertension, hypercholesterolemia, and smoking in asymptomatic individuals.BackgroundCoronary artery disease is the main etiology of congestive heart failure in the U.S. and Europe. However, the relationship between risk factors for coronary artery disease and decreased myocardial function has not been studied systematically in asymptomatic individuals.MethodsThe Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study designed to investigate the nature of atherosclerosis in asymptomatic individuals. A total of 1,184 participants (45 to 84 years old) underwent tagged cardiac magnetic resonance imaging. Regional LV function was quantified by analyzing peak systolic circumferential strain (Ecc) in regions corresponding to the left anterior descending (LAD), circumflex (LCX), and right coronary (RCA) territories. The association between risk factors and strains was studied using multiple linear regression.ResultsHigher diastolic blood pressure (DBP) was associated with lower Ecc (p ≤ 0.002). The Ecc’s in the LAD territory of participants with DBP <80, 80 to 84, 85 to 89, and ≥90 mm Hg were −15.6%, −14.8%, −14.2%, and −13.7%, respectively (p < 0.001). Similar results were documented in other territories and after multivariable analysis. Smokers had lower Ecc in the LAD and RCA regions compared with nonsmokers. Furthermore, dose response relationship between cigarette consumption measured in pack-years and regional LV dysfunction by Ecc was noted (p ≤ 0.01 in LAD and RCA territories). Finally, combined diastolic hypertension and smoking was associated with a greater reduction of regional LV function.ConclusionsHigher diastolic blood pressure and smoking are associated with decreased regional LV function in asymptomatic individuals

Hamiltonian Study of Improved U(1U(1 Lattice Gauge Theory in Three Dimensions

A comprehensive analysis of the Symanzik improved anisotropic three-dimensional U(1) lattice gauge theory in the Hamiltonian limit is made. Monte Carlo techniques are used to obtain numerical results for the static potential, ratio of the renormalized and bare anisotropies, the string tension, lowest glueball masses and the mass ratio. Evidence that rotational symmetry is established more accurately for the Symanzik improved anisotropic action is presented. The discretization errors in the static potential and the renormalization of the bare anisotropy are found to be only a few percent compared to errors of about 20-25% for the unimproved gauge action. Evidence of scaling in the string tension, antisymmetric mass gap and the mass ratio is observed in the weak coupling region and the behaviour is tested against analytic and numerical results obtained in various other Hamiltonian studies of the theory. We find that more accurate determination of the scaling coefficients of the string tension and the antisymmetric mass gap has been achieved, and the agreement with various other Hamiltonian studies of the theory is excellent. The improved action is found to give faster convergence to the continuum limit. Very clear evidence is obtained that in the continuum limit the glueball ratio $M_{S}/M_{A}$ approaches exactly 2, as expected in a theory of free, massive bosons.Comment: 13 pages, 15 figures, submitted to Phys. Rev.

Of Bounces, Branes and Bounds

Some recent studies have considered a Randall-Sundrum-like brane world evolving in the background of an anti-de Sitter Reissner-Nordstrom black hole. For this scenario, it has been shown that, when the bulk charge is non-vanishing, a singularity-free ``bounce'' universe will always be obtained. However, for the physically relevant case of a de Sitter brane world, we have recently argued that, from a holographic (c-theorem) perspective, such brane worlds may not be physically viable. In the current paper, we reconsider the validity of such models by appealing to the so-called ``causal entropy bound''. In this framework, a paradoxical outcome is obtained: these brane worlds are indeed holographically viable, provided that the bulk charge is not too small. We go on to argue that this new finding is likely the more reliable one.Comment: 15 pages, Revtex; references added and very minor change

Prospects in computational molecular medicine: a millennial mega-project on peptide folding

During the second half of the 20th century, Molecular Computations have reached to a level that can revolutionize chemistry. The next target will be structural biology, which will be followed soon by Molecular Medicine. The present paper outlines where we are at, in this field, at the end of the 20th century, and in what direction the development may take in the new millennium. In view of the gigantic nature of the problem, it is suggested that a suitably designed cooperative Millennial Mega-project might accelerate our schedule. (C) 2000 Elsevier Science B.V. All rights reserved

Challenges and Obstacles for a Bouncing Universe in Brane Models

A Brane evolving in the background of a charged AdS black-hole displays in general a bouncing behaviour with a smooth transition from a contracting to an expanding phase. We examine in detail the conditions and consequences of this behaviour in various cases. For a cosmological-constant-dominated Brane, we obtain a singularity-free, inflationary era which is shown to be compatible only with an intermediate-scale fundamental Planck mass. For a radiation-dominated Brane, the bouncing behaviour can occur only for background-charge values exceeding those allowed for non-extremal black holes. For a matter-dominated Brane, the black-hole mass affects the proper volume or the expansion rate of the Brane. We also consider the Brane evolving in an asymmetric background of two distinct charged AdS black hole spacetimes being bounded by the Brane and find that, in the case of an empty critical Brane, bouncing behaviour occurs only if the black-hole mass difference is smaller than a certain value. The effects of a Brane curvature term on the bounce at early and late times are also investigated.Comment: 23 pages, Latex file, comments and references added, version to appear in Phys. Rev.