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

A geometrical origin for the covariant entropy bound

Causal diamond-shaped subsets of space-time are naturally associated with operator algebras in quantum field theory, and they are also related to the Bousso covariant entropy bound. In this work we argue that the net of these causal sets to which are assigned the local operator algebras of quantum theories should be taken to be non orthomodular if there is some lowest scale for the description of space-time as a manifold. This geometry can be related to a reduction in the degrees of freedom of the holographic type under certain natural conditions for the local algebras. A non orthomodular net of causal sets that implements the cutoff in a covariant manner is constructed. It gives an explanation, in a simple example, of the non positive expansion condition for light-sheet selection in the covariant entropy bound. It also suggests a different covariant formulation of entropy bound.Comment: 20 pages, 8 figures, final versio

Geometric entropy, area, and strong subadditivity

The trace over the degrees of freedom located in a subset of the space transforms the vacuum state into a density matrix with non zero entropy. This geometric entropy is believed to be deeply related to the entropy of black holes. Indeed, previous calculations in the context of quantum field theory, where the result is actually ultraviolet divergent, have shown that the geometric entropy is proportional to the area for a very special type of subsets. In this work we show that the area law follows in general from simple considerations based on quantum mechanics and relativity. An essential ingredient of our approach is the strong subadditive property of the quantum mechanical entropy.Comment: Published versio

Effective Field Theories and Inflation

We investigate the possible influence of very-high-energy physics on inflationary predictions focussing on whether effective field theories can allow effects which are parametrically larger than order H^2/M^2, where M is the scale of heavy physics and H is the Hubble scale at horizon exit. By investigating supersymmetric hybrid inflation models, we show that decoupling does not preclude heavy-physics having effects for the CMB with observable size even if H^2/M^2 << O(1%), although their presence can only be inferred from observations given some a priori assumptions about the inflationary mechanism. Our analysis differs from the results of hep-th/0210233, in which other kinds of heavy-physics effects were found which could alter inflationary predictions for CMB fluctuations, inasmuch as the heavy-physics can be integrated out here to produce an effective field theory description of low-energy physics. We argue, as in hep-th/0210233, that the potential presence of heavy-physics effects in the CMB does not alter the predictions of inflation for generic models, but does make the search for deviations from standard predictions worthwhile.Comment: 19 pages, LaTeX, no figures, uses JHEP

International Construction Measurement Standards: Global Consistency in Presenting Construction Costs

This publication presents an international cost classification system for infrastructure projects. It aims to provide global consistency in classifying, defining, measuring, analysing and presenting the cost of infrastructure projects

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo

Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis

This document is the Accepted Manuscript version of the following article: Riessland et al., 'Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis', The American Journal of Human Genetics, Vol. 100 (2): 297-315, first published online 26 January 2017. The final, published version is available online at doi: http://dx.doi.org/10.1016/j.ajhg.2017.01.005 © 2017 American Society of Human Genetics.Homozygous SMN1 loss causes spinal muscular atrophy (SMA), the most common lethal genetic childhood motor neuron disease. SMN1 encodes SMN, a ubiquitous housekeeping protein, which makes the primarily motor neuron-specific phenotype rather unexpected. SMA-affected individuals harbor low SMN expression from one to six SMN2 copies, which is insufficient to functionally compensate for SMN1 loss. However, rarely individuals with homozygous absence of SMN1 and only three to four SMN2 copies are fully asymptomatic, suggesting protection through genetic modifier(s). Previously, we identified plastin 3 (PLS3) overexpression as an SMA protective modifier in humans and showed that SMN deficit impairs endocytosis, which is rescued by elevated PLS3 levels. Here, we identify reduction of the neuronal calcium sensor Neurocalcin delta (NCALD) as a protective SMA modifier in five asymptomatic SMN1-deleted individuals carrying only four SMN2 copies. We demonstrate that NCALD is a Ca(2+)-dependent negative regulator of endocytosis, as NCALD knockdown improves endocytosis in SMA models and ameliorates pharmacologically induced endocytosis defects in zebrafish. Importantly, NCALD knockdown effectively ameliorates SMA-associated pathological defects across species, including worm, zebrafish, and mouse. In conclusion, our study identifies a previously unknown protective SMA modifier in humans, demonstrates modifier impact in three different SMA animal models, and suggests a potential combinatorial therapeutic strategy to efficiently treat SMA. Since both protective modifiers restore endocytosis, our results confirm that endocytosis is a major cellular mechanism perturbed in SMA and emphasize the power of protective modifiers for understanding disease mechanism and developing therapies.Peer reviewedFinal Accepted Versio

Breast cancer polygenic risk score and contralateral breast cancer risk

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18–1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02–1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547–0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies