Ambient cosmology and spacetime singularities

We present a new approach to the issues of spacetime singularities and cosmic censorship in general relativity. This is based on the idea that standard 4-dimensional spacetime is the conformal infinity of an ambient metric for the 5-dimensional Einstein equations with fluid sources. We then find that the existence of spacetime singularities in four dimensions is constrained by asymptotic properties of the ambient 5-metric, while the non-degeneracy of the latter crucially depends on cosmic censorship holding on the boundary.

The Basement of the Deccan Traps and Its Madagascar Connection: Constraints from Xenoliths

Paleogeographic reconstructions of India and Madagascar before their late Cretaceous rifting juxtapose the Antongil Block of Madagascar against the Deccan Traps of India, indicating that the Western Dharwar Craton extends below the Deccan lavas. Some recent studies have suggested that the South Maharashtra Shear Zone along the northern Konkan coast of India limits the northern extent of the Western Dharwar Craton, implying that the craton does not extend below the Deccan Traps, raising a question mark on paleogeographic reconstructions of India and Madagascar. The continuity of the Western Dharwar Craton north of the South Maharashtra Shear Zone below the Deccan Traps—or its lack thereof—is critical for validating tectonic models correlating Madagascar with India. In this study, zircons in tonalitic basement xenoliths hosted in Deccan Trap dykes were dated in situ, using the U-Pb isotope system. The data furnish U-Pb ages that define three populations at 2527 ± 6, 2456 ± 6, and 2379 ± 9 Ma. The 2527 ± 6 Ma ages correspond to the igneous crystallization of the tonalites, whereas the 2456 ± 6 and 2379 ± 9 Ma ages date metamorphic overprints. The results help to establish for the first time that the basement is a part of the Neoarchean granitoid suite of the Western Dharwar Craton, which extends northward up to at least Talvade in central and Kihim beach in the western Deccan. By implication, the South Maharashtra Shear Zone cannot be the northern limit of the Western Dharwar Craton. The granitoids are correlated with the Neoarchean felsic intrusions (2.57–2.49) of the Masaola suite in the Antongil Block of Madagascar, supporting the existence of a Neoarchean Greater Dharwar Craton comprising the Western Dharwar Craton and the Antongil-Masora Block.

Freshman Friendship and University Connection

The purpose of this study is to understand better the support systems available to freshmen students at the University of Connecticut and how those support systems impact their connection to the university. The study involves two questionnaires, one distributed at the beginning of their first semester and a second follow-up questionnaire at the end of that same semester. Two main research questions are the focus of this study. The first question is whether freshmen who make friends on campus feel more connected than freshmen who report having fewer friends. The second question concerns whether freshmen who feel more connected to the university report stronger feelings of support than freshmen who do not feel connected to the university. This study has found that support at the university level needs to be more focused on individual students because freshmen who make friends at the university report experiencing greater levels of support. Parents, faculty, and counselors need to reexamine the way in which they provide support in order to reach those students who are not connecting with friends. The First Year Experience Program could better serve freshmen students by focusing on the relationship between students, instructor, and mentor to build friendships within the FYE class, which will foster friendships and support.

The connection between E2F and ATM in p53-dependent apoptosis

Programmed cell death is an anticancer mechanism utilized by p53 that when disrupted can accelerate tumor development in response to oncogenic stress. Defects in the RB tumor suppressor cause aberrant cell proliferation as well as apoptosis. The combinatorial loss of the p53 and RB pathways is observed in a large percentage of human tumors. The E2F family of transcription factors primarily mediates the phenotype of Rb loss, since RB is a negative regulator of E2F. Contrary to early expectations, it has now been shown that the ARF (alternative reading frame) tumor suppressor is not required for p53-dependent apoptosis in response to deregulation of the RB/E2F pathway. In this study, we demonstrate that ATM, known as a DNA double-strand break (DSB) sensor, is responsible for ARF-independent apoptosis and p53 activation induced by deregulated E2F1. Moreover, NBS1, a component of the MRN DNA repair complex, is also required for E2F1-induced apoptosis and apparently works in the same pathway as ATM. We further found that endogenous E2F1 and E2F3 both play a role in apoptosis and ATM activation in response to inhibition of RB by the adenoviral E1A oncoprotein. We demonstrate that, unlike deregulated E2F3 and Myc, ATM activation by deregulated E2F1 does not involve the induction of DNA damage, autophosphorylation of ATM on Ser 1981, a marker of ATM activation by DSB, but does depend on the presence of NBS1, suggesting that E2F1 activates ATM in a different manner from E2F3 and Myc. Results from domain mapping studies show that the DNA binding, dimerization, and marked box domains of E2F1 are required to activate ATM and stimulate apoptosis but the transactivation domain is not. This implies that E2F1's DNA binding and interaction with other proteins through the marked box domain are necessary to induce ATM activation leading to apoptosis but transcriptional activation by E2F1 is dispensable. Together these data suggest a model in which E2F1 activates ATM to phosphorylate p53 through a novel mechanism that is independent of DNA damage and transcriptional activation by E2F1.^

DETERMINING THE GENOTYPE-PHENOTYPE CONNECTION IN SYNTHETIC INDUCIBLE GENE EXPRESSION SYSTEMS

Introduction Gene expression is an important process whereby the genotype controls an individual cell’s phenotype. However, even genetically identical cells display a variety of phenotypes, which may be attributed to differences in their environment. Yet, even after controlling for these two factors, individual phenotypes still diverge due to noisy gene expression. Synthetic gene expression systems allow investigators to isolate, control, and measure the effects of noise on cell phenotypes. I used mathematical and computational methods to design, study, and predict the behavior of synthetic gene expression systems in S. cerevisiae, which were affected by noise. Methods I created probabilistic biochemical reaction models from known behaviors of the tetR and rtTA genes, gene products, and their gene architectures. I then simplified these models to account for essential behaviors of gene expression systems. Finally, I used these models to predict behaviors of modified gene expression systems, which were experimentally verified. Results Cell growth, which is often ignored when formulating chemical kinetics models, was essential for understanding gene expression behavior. Models incorporating growth effects were used to explain unexpected reductions in gene expression noise, design a set of gene expression systems with “linear” dose-responses, and quantify the speed with which cells explored their fitness landscapes due to noisy gene expression. Conclusions Models incorporating noisy gene expression and cell division were necessary to design, understand, and predict the behaviors of synthetic gene expression systems. The methods and models developed here will allow investigators to more efficiently design new gene expression systems, and infer gene expression properties of TetR based systems.

THE NEW ROLE OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9: A CONNECTION OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9, APOLIPOPROTEIN B, and AUTOPHAGY

Plasma low-density lipoprotein (LDL) levels are positively correlated with the incidence of coronary artery disease. In the circulation, the plasma LDL clearance is mainly achieved by the uptake via LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a newly discovered gene, playing an important role in LDL metabolism. Gain-of-function mutations of PCSK9 lead to hypercholesterolemia and loss-of-function mutations of PCSK9 are associated with decrease of LDL cholesterol. The effects of PCSK9 on cholesterol levels are the consequence of a strong interaction between the catalytic domain of PCSK9 and epidermal growth factor-like repeat A (EGF-A) domain of LDLR on the cell surface of hepatocytes. This PCSK9/LDLR complex enters the cell via endocytosis, where both PCSK9 and LDLR are removed via the lysosome pathway, resulting in decreased levels of LDLR and accumulation of LDL in the plasma. However, whether this is the exclusive function of PCSK9 on LDL metabolism was challenged by us; we observed PCSK9 interacted with apolipoprotein B (apoB) and increased apoB production, irrespective of the LDLR. ApoB is the primary structure protein of LDL particle and it also serves as the ligand for the LDL receptor. There is ample evidence showing that the levels of apoB are a better indicator for heart disease than either total cholesterol or LDL cholesterol levels. We used a second-generation adenoviral vector to overexpress PCSK9 (Ad-PCSK9) in wild-type C57BL/6 and LDLR deficient mice (Ldlr-/- and Ldlr-/-Apobec1-/-). Our study revealed that overexpression of PCSK9 promoted the production and secretion of apoB in the form of very-low density lipoprotein (VLDL), which is the precursor of LDL, in the 3 mouse models studied (C57BL/6J, Ldlr-/-, and Ldlr-/-Apobec1-/-). The increased apoB production in mice was regulated at post-transcriptional levels, since there was no difference in apoB mRNA levels between mice treated with Ad-PCSK9 and control vector Ad-Null. By using pulse-chase experiment on primary hepatocytes, we showed that overexpression of PCSK9 increased the secretion of apoB, independent of LDLR. In the circulation, we showed that PCSK9 was associated with LDL particles. By using 3 different protein–protein interaction assays of co-immunoprecipitation, mammalian two-hybrid system, and in situ proximity ligation assay, we demonstrated a direct protein–protein interaction between PCSK9 and apoB. The impact of this interaction inhibited the physiological removal process of apoB via autophagosome/lysosome pathway in an LDLR-independent fashion, resulting in increased production and secretion of apoB-containing lipoproteins. The significance of this process was shown in the Pcsk9 knockout mice in the background of Ldlr-/-Apobec1-/- mice (triple knockout mice); in the absence of Pcsk9 (triple knockout mice) the levels of cholesterol, triacylglycerol, and apoB decreased significantly in comparison to that of Ldlr-/-Apobec1-/- mice. Taken together, our study demonstrated a direct intracellular interaction of PCSK9 with apoB, resulting in the inhibition of apoB degradation via the autophagosome/lysosome pathway independent of LDLR. This discovery provides a new concept of the importance of PCSK9 and suggests new approaches for the therapeutic intervention of hyperlipidemia.

Richard Seaford. Cosmology and the Polis. The social Construction of Space and Time in the Tragedies of Aeschylus, Cambridge University Press, Cambridge, 2012, xiii + 366 pp.

Fil: Fernández Deagustini, María del Pilar. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Instituto de Investigaciones en Humanidades y Ciencias Sociales (UNLP-CONICET); Argentina.

Richard Seaford. Cosmology and the Polis. The social Construction of Space and Time in the Tragedies of Aeschylus, Cambridge University Press, Cambridge, 2012, xiii + 366 pp.

Fil: Fernández Deagustini, María del Pilar. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Instituto de Investigaciones en Humanidades y Ciencias Sociales (UNLP-CONICET); Argentina.

The flexibility matrix o timber composite beams with a discrete connection system

This work presents a method for the analysis of timber composite beams which considers the slip in the connection system, based on assembling the flexibility matrix of the whole structure. This method is based on one proposed by Tommola and Jutila (2001). This paper extends the method to the case of a gap between two pieces with an arbitrary location at the first connector, which notably broadens its practical application. The addition of the gap makes it possible to model a cracked zone in concrete topping, as well as the case in which forming produces the gap. The consideration of induced stresses due to changes in temperature and moisture content is also described, while the concept of equivalent eccentricity is generalized. This method has important advantages in connection with the current European Standard EN 1995-1-1: 2004, as it is able to deal with any type of load, variable section, discrete and non-regular connection systems, a gap between the two pieces, and variations in temperature and moisture content. Although it could be applied to any structural system, it is specially suited for the case of simple supported and continuous beams. Working examples are presented at the end, showing that the arrangement of the connection notably modifies shear force distribution. A first interpretation of the results is made on the basis of the strut and tie theory. The examples prove that the use of EC-5 is unsafe when, as a rule of thumb, the strut or compression field between the support and the first connector is at an angle with the axis of the beam of less than 60º.