Extended Palatini action for general relativity and the natural emergence of the cosmological constant

In the Palatini action of general relativity the connection and the metric are treated as independent dynamical variables. Instead of assuming a relation between these quantities, the desired relation between them is derived through the Euler-Lagrange equations of the Palatini action. In this manuscript we construct an extended Palatini action, where we do not assume any a priori relationship between the connection, the covariant metric tensor, and the contravariant metric tensor. Instead we treat these three quantities as independent dynamical variables. We show that this action reproduces the standard Einstein field equations depending on a single metric tensor. We further show that in this formulation the cosmological constant has an additional theoretical significance. Normally the cosmological constant is added to the Einstein field equations for the purpose of having general relativity be consistent with cosmological observations. In the formulation presented here, the nonvanishing cosmological constant also ensures the self-consistency of the theory.Comment: in the revised version the original scalar matter action is replaced with a general matter actio

Scalars, Vectors and Tensors from Metric-Affine Gravity

The metric-affine gravity provides a useful framework for analyzing gravitational dynamics since it treats metric tensor and affine connection as fundamentally independent variables. In this work, we show that, a metric-affine gravity theory composed of the invariants formed from non-metricity, torsion and curvature tensors can be decomposed into a theory of scalar, vector and tensor fields. These fields are natural candidates for the ones needed by various cosmological and other phenomena. Indeed, we show that the model accommodates TeVeS gravity (relativistic modified gravity theory), vector inflation, and aether-like models. Detailed analyses of these and other phenomena can lead to a standard metric-affine gravity model encoding scalars, vectors and tensors.Comment: 13 p

Birational aspects of the Geometry of Varieties of Sum of Powers

Varieties of Sums of Powers describe the additive decompositions of an homogeneous polynomial into powers of linear forms. Despite their long history, going back to Sylvester and Hilbert, few of them are known for special degrees and number of variables. In this paper we aim to understand a general birational behaviour of VSP, if any. To do this we birationally embed these varieties into Grassmannians and prove the rationality, unirationality or rational connectedness of many of those in arbitrary degrees and number of variables.Comment: 16 pages, corrected wrong attributio

USE OF NEXT-GENERATION SEQUENCING TO STUDY CODING AND NON-CODING RNA IN COLORECTAL CANCER

The identification of novel mRNA and small RNA signatures of prognostic and diagnostic value in colorectal cancer (CRC) is primary focus of the thesis. The overall aim of the body this work is a deeper understanding of the molecular causes in the pathology of CRC and the identification of biomarkers, specifically mRNAs and other small non-coding RNAs with prognostic values in the clinical setting. These findings would in turn lead to an optimization of the therapeutic targets and ultimately to better clinical management of patients diagnosed with CRC. Next-generation sequencing (NGS) is based on deep sequencing, which produces billions of short sequences at a time. NGS benefits biomedical research in several ways by interrogating whole or partially targeted genomes, transcriptomes and epigenomes, including non-coding RNAs (ncRNAs) and microRNAs (miRs). NGS is able to rapidly generate large amounts of sequence data at substantially lower cost and time respect Sanger Sequencing. I have been involved in the development and application of various novel techniques for the construction of sample libraries for NGS analysis. I have also worked with various methods of analysis of next-generation sequencing data of cancer samples. In addition to NGS, I have also worked with numerous genomics technologies including, microarrays (both commercial and custom), NanoString, Real-Time PCR, protein arrays, and other genomics technologies to investigate not only colorectal cancer, but several other types of cancer including, but not limited to leukemia/lymphoma, breast cancer, head/neck cancer, osteosarcoma, and lung cancer. MicroRNAs are non-coding RNA regulators of protein output by way of coding RNA disruption. MicroRNAs have been shown to be differentially expressed in many solid cancers, and they can be considered biomarkers for predictive signatures in cancer. The effects of microRNAs are exerted on cell pathology and physiology controlling translation of tens or even hundreds of different coding messengers and a unique messenger can be controlled by more than one microRNA. In turn, one, or more, microRNAs, can disrupt entire physiological pathways. Predictive markers are important in oncology as tumors of the same tissue of origin vary widely in their response to most available systemic therapies. Of all human cancers, colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world at more than 500,000 new cases diagnosed per year. Currently, the Tumor-Node-Metastasis (TNM) is currently the most effective and reliable predictor of CRC outcomes. However, recently new genetic alterations have been uncovered which could potentially be used to estimate prognosis in CRC, with several of them potentially representing predictive markers towards appropriate treatment regimens. Unfortunately, most of these biomarkers have failed validation in the clinical setting, with some notable exceptions being loss-of-function mutations in KRAS, BRAF, SMAD4 and TP53. In addition, there are genetic alterations such as chromosomal instability (CIN), loss of heterozygosity (LOH), micro-satellite instability (MSI), that affect mismatch repair (MMR) genes, including hMLH1, hMSH2, hMSH6, and PMS2. The overall predictive values of CIN and MSI remain controversial and the role of influence from mutations in other key genes involved in carcinogenesis still largely unclear. Short RNAs were sequenced from paired colon adenocarcinoma and normal samples. The RNA sequences were aligned on the human genome by using multiple independent algorithms. All short RNA sequences were de novo merged into more than 250,000 distinct RNA contigs covering the human genome. These de novo short RNA contigs, or shortigs, were then matched to human genome annotation. Using this unbiased genome wide approach, all short RNAs were profiled in colon adenocarcinoma. Alongside known miRNA, snoRNAs, piRNA, over 60 RNAs were differentially expressed from non annotated shortigs, and represented candidates for novel cancer non-coding genes. RNA expression plots were obtained for each shortig, revealing RNA processing of precursor miRNAs or even of entire miRNA clusters. A number of discrepancies with miRBase annotations were detected. The dynamic range and specificity of next generation sequencing allowed an unprecedented insight into miRNA and other non-coding RNA expression in colorectal cancer

Evidence for a gene influencing heart rate on chromosome 5p13-14 in a meta-analysis of genome-wide scans from the NHLBI Family Blood Pressure Program

BACKGROUND: Elevated resting heart rate has been shown in multiple studies to be a strong predictor of cardiovascular disease. Previous family studies have shown a significant heritable component to heart rate with several groups conducting genomic linkage scans to identify quantitative trait loci. METHODS: We performed a genome-wide linkage scan to identify quantitative trait loci influencing resting heart rate among 3,282 Caucasians and 3,989 African-Americans in three independent networks comprising the Family Blood Pressure Program (FBPP) using 368 microsatellite markers. Mean heart rate measurements were used in a regression model including covariates for age, body mass index, pack-years, currently drinking alcohol (yes/no), hypertension status and medication usage to create a standardized residual for each gender/ethnic group within each study network. This residual was used in a nonparametric variance component model to generate a LOD score and a corresponding P value for each ethnic group within each study network. P values from each ethnic group and study network were merged using an adjusted Fisher's combining P values method and the resulting P values were converted to LOD scores. The entire analysis was redone after individuals currently taking beta-blocker medication were removed. RESULTS: We identified significant evidence of linkage (LOD = 4.62) to chromosome 10 near 142.78 cM in the Caucasian group of HyperGEN. Between race and network groups we identified a LOD score of 1.86 on chromosome 5 (between 39.99 and 45.34 cM) in African-Americans in the GENOA network and the same region produced a LOD score of 1.12 among Caucasians within a different network (HyperGEN). Combining all network and race groups we identified a LOD score of 1.92 (P = 0.0013) on chromosome 5p13-14. We assessed heterogeneity for this locus between networks and ethnic groups and found significant evidence for low heterogeneity (P ≤ 0.05). CONCLUSION: We found replication (LOD > 1) between ethnic groups and between study networks with low heterogeneity on chromosome 5p13-14 suggesting that a gene in this region influences resting heart rate

The reality conditions for the new canonical variables of General Relativity

We examine the constraints and the reality conditions that have to be imposed in the canonical theory of 4--d gravity formulated in terms of Ashtekar variables. We find that the polynomial reality conditions are consistent with the constraints, and make the theory equivalent to Einstein's, as long as the inverse metric is not degenerate; when it is degenerate, reality conditions cannot be consistently imposed in general, and the theory describes complex general relativity.Comment: 11

Universality of affine formulation in General Relativity theory

Affine variational principle for General Relativity, proposed in 1978 by one of us (J.K.), is a good remedy for the non-universal properties of the standard, metric formulation, arising when the matter Lagrangian depends upon the metric derivatives. Affine version of the theory cures the standard drawback of the metric version, where the leading (second order) term of the field equations depends upon matter fields and its causal structure violates the light cone structure of the metric. Choosing the affine connection (and not the metric one) as the gravitational configuration, simplifies considerably the canonical structure of the theory and is more suitable for purposes of its quantization along the lines of Ashtekar and Lewandowski (see http://www.arxiv.org/gr-qc/0404018). We show how the affine formulation provides a simple method to handle boundary integrals in general relativity theory.Comment: 38 pages, no figures, LaTeX+BibTex, corrected (restructured contents, one example removed, no additional results, typos fixed) versio

Central blood pressure is an independent predictor of future hypertension in young to middle-aged stage 1 hypertensives.

The aim of the present study was to evaluate the association of central blood pressure (BP) with organ damage and risk of future hypertension in a cohort of young to middle-aged patients.We studied 305 subjects screened for stage 1 hypertension to determine which subjects developed hypertension needing therapy according to current guidelines. Central BP was obtained from radial artery tonometry. Organ damage was the presence of left ventricular hypertrophy and/or microalbuminuria.In a multiple logistic regression including ambulatory 24-h BP, central mean BP was associated with presence of end-organ damage (p = 0.003). In the subjects divided according to whether their central mean BP was above or below the median, subjects with high central mean BP presented an earlier impairment of arterial distensibility and developed sustained hypertension more frequently compared with those with low central mean BP (p0.001). In logistic analyses, central mean BP was an independent predictor of future hypertension (p0.001) and remained associated with outcome when 24-h BP was included in the same model (p = 0.006).In young to middle-aged subjects in the early stage of hypertension, central mean BP is a useful adjunct to brachial BPs to better define the individual risk profile

Ambulatory heart rate is underestimated when measured by an ambulatory blood pressure device

Objective: To test the validity of ambulatory heart rate (HR) assessment with a cuff ambulatory blood pressure (ABP) monitor. Design: Cross-instrument comparison of HR measured intermittently by a cuff ABP monitor (SpaceLabs, Redmond, Washington, USA), with HR derived from continuous electrocardiogram (ECG) recordings (1) in a controlled laboratory experiment and (2) during long-term recording in a true naturalistic setting. Participants: Six normotensive subjects participated in the laboratory study. A total of 109 male white-collar workers underwent ambulatory monitoring, of which 30 were mildly hypertensive. Methods: Four different laboratory conditions (postures: lying, sitting, standing, walking), repeated twice, were used to assess the short-term effects of cuff inflation on the HR. To test the actual ambulatory validity, participants simultaneously wore a continuous HR recorder and the ABP monitor from early morning to late evening on 2 workdays and one non-workday. Diary and vertical accelerometery information was used to obtain periods of fixed posture and (physical) activity across which HR from both devices was compared. Results: Laboratory results showed that the ABP device reliably detected HR during blood pressure measurement, but that this HR was systematically lower than the HR directly before and after the blood pressure measurement. The ambulatory study confirmed this systematic underestimation of the ongoing HR, but additionally showed that its amount increased when subjects went from sitting to standing to light physical activity (2.9; 4.3 and 9.1 bpm (beats/min), respectively). In spite of this activity-dependent underestimation of HR, the correlation of continuous ECG and intermittent ABP-derived HR was high (median r = 0.81). Also, underestimation was not different for normotensives and mild hypertensives. Conclusions: A direct effect of cuff inflation leads to the underestimation of ongoing HR during cuff-based ABP measurement. Additional underestimation of HR occurs during periods with physical activity, probably due to behavioural freezing during blood pressure measurements. HR underestimation was not affected by hypertensive state. When its limitations are taken into account, ABP-derived ambulatory HR can be considered a reliable and valid measure. © 2001 Lippincott Williams & Wilkins

Conformal Transformations in Metric-Affine Gravity and Ghosts

Conformal transformations play a widespread role in gravity theories in regard to their cosmological and other implications. In the pure metric theory of gravity, conformal transformations change the frame to a new one wherein one obtains a conformal-invariant scalar-tensor theory such that the scalar field, deriving from the conformal factor, is a ghost. In this work, conformal transformations and ghosts will be analyzed in the framework of the metric-affine theory of gravity. Within this framework, metric and connection are independent variables, and hence, transform independently under conformal transformations. It will be shown that, if affine connection is invariant under conformal transformations then the scalar field under concern is a non-ghost, non-dynamical field. It is an auxiliary field at the classical level, and might develop a kinetic term at the quantum level. Alternatively, if connection transforms additively with a structure similar to yet more general than that of the Levi-Civita connection, the resulting action describes the gravitational dynamics correctly, and more importantly, the scalar field becomes a dynamical non-ghost field. The equations of motion, for generic geometrical and matter-sector variables, do not reduce connection to the Levi-Civita connection, and hence, independence of connection from metric is maintained. Therefore, metric-affine gravity provides an arena in which ghosts arising from conformal factor are avoided thanks to the independence of connection from the metric.Comment: 12 p