Sectional curvature of standard static space-times

Ankara : The Department of Mathematics and the Graduate School of Engineering and Science of Bilkent University, 2013.Thesis (Master's) -- Bilkent University, 2013.Includes bibliographical references leaves 45-47.Curvature related geometric properties of warped product manifolds are given. The casual structure of Lorentzian warped products is reviewed. In particular, two well-known examples of warped product space-times models, i.e, generalized Robertson-Walker and standard static space-times are studied. The sectional curvature of a standard static space-time is established and some conditions are obtained to have nonnegative sectional curvature so that applications of singularity theorems to a standard static space-time can be considered.Yavuz, Bengi RukenM.S

Mechanism of activation and the rewired network: New drug design concepts

Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism. We suggest that the decision whether to target an inactive (or active) conformation should largely rest on the protein mechanism of activation. We next discuss the recent identification of double (multiple) same-allele driver mutations and their impact on cell proliferation and suggest that like single driver mutations, double drivers also mimic the mechanism of activation. We further suggest that the structural perturbations of double (multiple) in cis mutations may reveal new surfaces/pockets for drug design. Finally, we underscore the preeminent role of the cellular network which is deregulated in cancer. Our structure-based review and outlook updates the traditional Mechanism of Action, informs decisions, and calls attention to the intrinsic activation mechanism of the target protein and the rewired tumor-specific network, ushering innovative considerations in precision medicine

Neurodevelopmental disorders and cancer networks share pathways, but differ in mechanisms, signaling strength, and outcome

Abstract Epidemiological studies suggest that individuals with neurodevelopmental disorders (NDDs) are more prone to develop certain types of cancer. Notably, however, the case statistics can be impacted by late discovery of cancer in individuals afflicted with NDDs, such as intellectual disorders, autism, and schizophrenia, which may bias the numbers. As to NDD-associated mutations, in most cases, they are germline while cancer mutations are sporadic, emerging during life. However, somatic mosaicism can spur NDDs, and cancer-related mutations can be germline. NDDs and cancer share proteins, pathways, and mutations. Here we ask (i) exactly which features they share, and (ii) how, despite their commonalities, they differ in clinical outcomes. To tackle these questions, we employed a statistical framework followed by network analysis. Our thorough exploration of the mutations, reconstructed disease-specific networks, pathways, and transcriptome levels and profiles of autism spectrum disorder (ASD) and cancers, point to signaling strength as the key factor: strong signaling promotes cell proliferation in cancer, and weaker (moderate) signaling impacts differentiation in ASD. Thus, we suggest that signaling strength, not activating mutations, can decide clinical outcome