MODIFIED THEORIES OF GRAVITY

The recent observational data in cosmology seem to indicate that the universe is currently expanding in an accelerated way. This unexpected conclusion can be explained assuming the presence of a non-vanishing yet extremely fine tuned cosmological constant, or invoking the existence of an exotic source of energy, dark energy, which is not observed in laboratory experiments yet seems to dominate the energy budget of the Universe. On the other hand, it may be that these observations are just signalling the fact that Einstein's General Relativity is not the correct description of gravity when we consider distances of the order of the present horizon of the universe. In order to study if the latter explanation is correct, we have to formulate new theories of the gravitational interaction, and see if they admit cosmological solutions which fit the observational data in a satisfactory way. A necessary condition for the viability of a theory of ``modified gravity'' is that it has to reproduce to high precision the results of General Relativity in experimental setups where the latter is well tested. Quite in general, modifying General Relativity introduces new degrees of freedom, which are responsible for the different large distance behavior. For a modified gravity theory to be phenomenologically viable, it is necessary that the extra degrees of freedom are efficiently screened on terrestrial and astrophysical scales. One of the known mechanisms which can screen the extra degrees of freedom is known as the Vainshtein mechanism, which involves derivative self-interaction terms for these degrees of freedom. In this thesis, we consider a class of nonlinear massive gravity theories known as dGRT Massive Gravity. These theories are candidates as viable models to modify gravity at very large distances, and, apart from the mass, they contain two free parameters. We investigate the effectiveness of the Vainshtein screening mechanism in this class of theories. There are two branches of static and spherically symmetric solutions, and we consider only the branch in which the Vainshtein mechanism can occur. We truncate the analysis to scales below the gravitational Compton wavelength, and consider the weak f\mbox{}ield limit for the gravitational potentials, while keeping all non-linearities of the mode which is involved in the screening. We determine analytically the number and properties of local solutions which exist asymptotically on large scales, and of local (inner) solutions which exist on small scales. We analyze in detail in which cases the solutions match in an intermediate region. Asymptotically flat solutions connect only to inner configurations displaying the Vainshtein mechanism, while non asymptotically flat solutions can connect both with inner solutions which display the Vainshtein mechanism, or with solutions which display a self-shielding behaviour of the gravitational field. We show furthermore that there are some regions in the parameter space where global solutions do not exist, and characterise precisely in which regions of the phase space the Vainshtein mechanism takes place

Whole-Exome and Transcriptome Sequencing Expands the Genotype of Majewski Osteodysplastic Primordial Dwarfism Type II

Microcephalic Osteodysplastic Primordial Dwarfism type II (MOPDII) represents the most common form of primordial dwarfism. MOPD clinical features include severe prenatal and postnatal growth retardation, postnatal severe microcephaly, hypotonia, and an increased risk for cerebrovascular disease and insulin resistance. Autosomal recessive biallelic loss-of-function genomic variants in the centrosomal pericentrin (PCNT) gene on chromosome 21q22 cause MOPDII. Over the past decade, exome sequencing (ES) and massive RNA sequencing have been effectively employed for both the discovery of novel disease genes and to expand the genotypes of well-known diseases. In this paper we report the results both the RNA sequencing and ES of three patients affected by MOPDII with the aim of exploring whether differentially expressed genes and previously uncharacterized gene variants, in addition to PCNT pathogenic variants, could be associated with the complex phenotype of this disease. We discovered a downregulation of key factors involved in growth, such as IGF1R, IGF2R, and RAF1, in all three investigated patients. Moreover, ES identified a shortlist of genes associated with deleterious, rare variants in MOPDII patients. Our results suggest that Next Generation Sequencing (NGS) technologies can be successfully applied for the molecular characterization of the complex genotypic background of MOPDII

Hairy black holes in theories with massive gravitons

This is a brief survey of the known black hole solutions in the theories of ghost-free bigravity and massive gravity. Various black holes exist in these theories, in particular those supporting a massive graviton hair. However, it seems that solutions which could be astrophysically relevant are the same as in General Relativity, or very close to them. Therefore, the no-hair conjecture essentially applies, and so it would be hard to detect the graviton mass by observing black holes.Comment: References added. 20 pages, 3 figures, based on the talk given at the 7-th Aegean Summer School "Beyond Einstein's theory of gravity", September 201

Galileon Higgs vortices

Vortex solutions are topologically stable field configurations that can play an important role in condensed matter, field theory, and cosmology. We investigate vortex configuration in a 2+1 dimensional Abelian Higgs theory supplemented by higher order derivative self-interactions, related with Galileons. Our vortex solutions have features that make them qualitatively different from well-known Abrikosov-Nielsen-Olesen configurations, since the derivative interactions turn on gauge invariant field profiles that break axial symmetry. By promoting the system to a 3+1 dimensional string configuration, we study its gravitational backreaction. Our results are all derived within a specific, analytically manageable system, and might offer indications for understanding Galileonic interactions and screening mechanisms around configurations that are not spherically symmetric, but only at most cylindrically symmetric.Comment: 26 pages, 8 figure

DRAR-CPI: a server for identifying drug repositioning potential and adverse drug reactions via the chemical–protein interactome

Identifying new indications for existing drugs (drug repositioning) is an efficient way of maximizing their potential. Adverse drug reaction (ADR) is one of the leading causes of death among hospitalized patients. As both new indications and ADRs are caused by unexpected chemical–protein interactions on off-targets, it is reasonable to predict these interactions by mining the chemical–protein interactome (CPI). Making such predictions has recently been facilitated by a web server named DRAR-CPI. This server has a representative collection of drug molecules and targetable human proteins built up from our work in drug repositioning and ADR. When a user submits a molecule, the server will give the positive or negative association scores between the user’s molecule and our library drugs based on their interaction profiles towards the targets. Users can thus predict the indications or ADRs of their molecule based on the association scores towards our library drugs. We have matched our predictions of drug–drug associations with those predicted via gene-expression profiles, achieving a matching rate as high as 74%. We have also successfully predicted the connections between anti-psychotics and anti-infectives, indicating the underlying relevance of anti-psychotics in the potential treatment of infections, vice versa. This server is freely available at http://cpi.bio-x.cn/drar/

Characterization of genome-wide p53-binding sites upon stress response

The tumor suppressor p53 is a sequence-specific transcription factor, which regulates the expression of target genes involved in different stress responses. To understand p53's essential transcriptional functions, unbiased analysis of its DNA-binding repertoire is pivotal. In a genome-wide tiling ChIP-on-chip approach, we have identified and characterized 1546 binding sites of p53 upon Actinomycin D treatment. Among those binding sites were known as well as novel p53 target sites, which included regulatory regions of potentially novel transcripts. Using this collection of genome-wide binding sites, a new high-confidence algorithm was developed, p53scan, to identify the p53 consensus-binding motif. Strikingly, this motif was present in the majority of all bound sequences with 83% of all binding sites containing the motif. In the surrounding sequences of the binding sites, several motifs for potential regulatory cobinders were identified. Finally, we show that the majority of the genome-wide p53 target sites can also be bound by overexpressed p63 and p73 in vivo, suggesting that they can possibly play an important role at p53 binding sites. This emphasizes the possible interplay of p53 and its family members in the context of target gene binding. Our study greatly expands the known, experimentally validated p53 binding site repertoire and serves as a valuable knowledgebase for future research

p53 activates the PANK1/miRNA-107 gene leading to downregulation of CDK6 and p130 cell cycle proteins

The tumor suppressor p53 is a central regulator of cell-cycle arrest and apoptosis by acting as a transcription factor to regulate numerous genes. We identified all human p53-regulated mRNAs by microarray analyses and searched for protein-coding genes which contain intronic miRNAs. Among others, this analysis yielded the panthothenate kinase 1 (PANK1) gene and its intronic miRNA-107. We showed that miRNA-107 and PANK1 are coregulated by p53 in different cell systems. The PANK1 protein, which catalyzes the rate-limiting step of coenzyme A biosynthesis, is also upregulated by p53. We observed that p53 directly activates PANK1 and miRNA-107 transcription through a binding site in the PANK1 promoter. Furthermore, p53 is recruited to the PANK1 promoter after DNA damage. In order to get more insight into miRNA-107 function we investigated its potential target genes. Cell-cycle regulators are significantly enriched among predicted miRNA-107 targets. We found miRNA-107-dependent regulation of two important regulators of G1/S progression, CDK6 and the RB-related 2 gene RBL2 (p130). CDK6 and p130 proteins are downregulated upon miRNA-107 expression. Our results uncover a novel miRNA-dependent signaling pathway which leads to downregulation of cell cycle proteins in the absence of transcriptional repression

Evidence for a Fourteenth mtDNA-Encoded Protein in the Female-Transmitted mtDNA of Marine Mussels (Bivalvia: Mytilidae)

BACKGROUND: A novel feature for animal mitochondrial genomes has been recently established: i.e., the presence of additional, lineage-specific, mtDNA-encoded proteins with functional significance. This feature has been observed in freshwater mussels with doubly uniparental inheritance of mtDNA (DUI). The latter unique system of mtDNA transmission, which also exists in some marine mussels and marine clams, is characterized by one mt genome inherited from the female parent (F mtDNA) and one mt genome inherited from the male parent (M mtDNA). In freshwater mussels, the novel mtDNA-encoded proteins have been shown to be mt genome-specific (i.e., one novel protein for F genomes and one novel protein for M genomes). It has been hypothesized that these novel, F- and M-specific, mtDNA-encoded proteins (and/or other F- and/or M-specific mtDNA sequences) could be responsible for the different modes of mtDNA transmission in bivalves but this remains to be demonstrated. METHODOLOGY/PRINCIPAL FINDINGS: We investigated all complete (or nearly complete) female- and male-transmitted marine mussel mtDNAs previously sequenced for the presence of ORFs that could have functional importance in these bivalves. Our results confirm the presence of a novel F genome-specific mt ORF, of significant length (>100aa) and located in the control region, that most likely has functional significance in marine mussels. The identification of this ORF in five Mytilus species suggests that it has been maintained in the mytilid lineage (subfamily Mytilinae) for ∼13 million years. Furthermore, this ORF likely has a homologue in the F mt genome of Musculista senhousia, a DUI-containing mytilid species in the subfamily Crenellinae. We present evidence supporting the functionality of this F-specific ORF at the transcriptional, amino acid and nucleotide levels. CONCLUSIONS/SIGNIFICANCE: Our results offer support for the hypothesis that "novel F genome-specific mitochondrial genes" are involved in key biological functions in bivalve species with DUI

Modulation of gene expression in U251 glioblastoma cells by binding of mutant p53 R273H to intronic and intergenic sequences

Missense point mutations in the TP53 gene are frequent genetic alterations in human tumor tissue and cell lines derived thereof. Mutant p53 (mutp53) proteins have lost sequence-specific DNA binding, but have retained the ability to interact in a structure-selective manner with non-B DNA and to act as regulators of transcription. To identify functional binding sites of mutp53, we established a small library of genomic sequences bound by p53R273H in U251 human glioblastoma cells using chromatin immunoprecipitation (ChIP). Mutp53 binding to isolated DNA fragments confirmed the specificity of the ChIP. The mutp53 bound DNA sequences are rich in repetitive DNA elements, which are dispersed over non-coding DNA regions. Stable down-regulation of mutp53 expression strongly suggested that mutp53 binding to genomic DNA is functional. We identified the PPARGC1A and FRMD5 genes as p53R273H targets regulated by binding to intronic and intra-genic sequences. We propose a model that attributes the oncogenic functions of mutp53 to its ability to interact with intronic and intergenic non-B DNA sequences and modulate gene transcription via re-organization of chromatin