A Zero-Parameter Extension of General Relativity with Varying Cosmological Constant

We provide a new extension of general relativity (GR) which has the remarkable property of being more constrained than GR plus a cosmological constant, having one less free parameter. This is implemented by allowing the cosmological constant to have a consistent space-time variation, through coding its dynamics in the torsion tensor. We demonstrate this mechanism by adding a `quasi-topological' term to the Einstein action, which naturally realizes a dynamical torsion with an automatic satisfaction of the Bianchi identities. Moreover, variation of the action with respect to this dynamical $\Lambda$ fixes it in terms of other variables, thus providing a scenario with less freedom than general relativity with a cosmological constant. Once matter is introduced, at least in the homogeneous and isotropic reduction, $\Lambda$ is uniquely determined by the field content of the model. We make an explicit construction using the Palatini formulation of GR and describe the striking properties of this new theory. We also highlight some possible extensions to the theory. A companion paper [1] explores the Friedmann--Robertson--Walker reduction for cosmology, and future work will study Solar System tests of the theory.Comment: Companion paper to arXiv:1905.10382. Minor updates to match published versio

The cosmology of minimal varying Lambda theories

Inserting a varying Lambda in Einstein's field equations can be made consistent with the Bianchi identities by allowing for torsion, without the need to add scalar field degrees of freedom. In the minimal such theory, Lambda is totally free and undetermined by the field equations in the absence of matter. Inclusion of matter ties Lambda algebraically to it, at least when homogeneity and isotropy are assumed, i.e. when there is no Weyl curvature. We show that Lambda is proportional to the matter density, with a proportionality constant depending on the equation of state. Unfortunately, the proportionality constant becomes infinite for pure radiation, ruling out the minimal theory prima facie despite of its novel internal consistency. It is possible to generalize the theory still without the addition of kinetic terms, leading to a new algebraically-enforced proportionality between Lambda and the matter density. Lambda and radiation may now coexist in a form consistent with Big Bang Nucleosynthesis, though this places strict constraints on the single free parameter of the theory, $\theta$. In the matter epoch Lambda behaves just like a dark matter component. Its density is proportional to the baryonic and/or dark matter, and its presence and gravitational effects would need to be included in accounting for the necessary dark matter in our Universe. This is a companion paper to Ref. [1] where the underlying gravitational theory is developed in detail.Comment: Companion paper to arXiv:1905.10380. Minor updates to match published versio

Accuracy of pulse interval timing in ambulatory blood pressure measurement

Blood pressure (BP) monitors rely on pulse detection. Some blood pressure monitors use pulse timings to analyse pulse interval variability for arrhythmia screening, but this assumes that the pulse interval timings detected from BP cuffs are accurate compared with RR intervals derived from ECG. In this study we compared the accuracy of pulse intervals detected using an ambulatory blood pressure monitor (ABPM) with single lead ECG. Twenty participants wore an ABPM for three hours and a data logger which synchronously measured cuff pressure and ECG. RR intervals were compared with corresponding intervals derived from the cuff pressure tracings using three different pulse landmarks. Linear mixed effects models were used to assess differences between ECG and cuff pressure timings and to investigate the effect of potential covariates. In addition, the maximum number of successive oscillometric beats detectable in a measurement was assessed. From 243 BP measurements, the foot landmark of the oscillometric pulse was found to be associated with fewest covariates and had a random error of 9.5 ms. 99% of the cuff pressure recordings had more than 10 successive detectable oscillometric beats. RR intervals can be accurately estimated using an ABPM

Opportunistic detection of atrial fibrillation using blood pressure monitors: a systematic review

Background: Atrial Fibrillation (AF) affects around 2% of the population and early detection is beneficial, allowing patients to begin potentially life-saving anticoagulant therapies. Blood pressure (BP) monitors may offer an opportunity to screen for AF. Aim: To identify and appraise studies which report the diagnostic accuracy of automated BP monitors used for opportunistic AF detection. Methods: A systematic search was performed of the Medline, Medline-in-process and Embase literature databases. Papers were eligible if they described primary studies of the evaluation of a BP device for AF detection, were published in a peer reviewed journal and reported values for the sensitivity and specificity. Included studies were appraised using the QUADAS-2 tool to assess their risk of bias and applicability to opportunistic AF detection. Values for the sensitivity and specificity of AF detection were extracted from each paper and compared. Results and Conclusion: We identified seven papers evaluating six devices from two manufacturers. Only one study scored low risk in all of the QUADAS-2 domains. All studies reported specificity greater than 85% and six reported sensitivity greater than 90%. The studies showed that blood pressure devices with embedded algorithms for detecting arrhythmias show promise as screening tools for AF, comparing favourably with manual pulse palpation. But the studies used different methodologies and many were subject to potential bias. More studies are needed to more precisely define the sensitivity and specificity of opportunistic screening for AF during blood pressure measurement before its clinical utility in the population of interest can be assessed fully

Comparison of higher-order mode suppression and Q-switched laser performance in thulium-doped large mode area and photonic crystal fibers

We report the influence of higher order modes (HOMs) in large mode fibers operation in Q-switched oscillator configurations at similar to 2 mu m wavelength. S-2 measurements confirm guiding of LP11 and LP02 fiber modes in a large mode area (LMA) step-index fiber, whereas a prototype photonic crystal fiber (PCF) provides nearly single-mode performance with a small portion of light in the LP11 mode. The difference in HOM content leads to a significant difference in Q-switched oscillator performance. In the step-index fiber, the percentage of cladding light increases by 20% to \u3e 40% with increasing pulse energy to similar to 250 mu J. We accredit this degradation to saturation of the gain in the fundamental mode leading to more light generated in the HOMs, which is eventually converted into cladding light. No such degradation is seen in PCF laser system for \u3e 400 mu J energies

Targeting of Rac GTPases blocks the spread of intact human breast cancer

High expression of Rac small GTPases in invasive breast ductal carcinoma is associated with poor prognosis, but its therapeutic value in human cancers is not clear. The aim of the current study was to determine the response of human primary breast cancers to Rac-based drug treatments ex vivo. Three-dimensional organotypic cultures were used to assess candidate therapeutic avenues in invasive breast cancers. Uniquely, in these primary cultures, the tumour is not disaggregated, with both epithelial and mesenchymal components maintained within a three-dimensional matrix of type I collagen. EHT 1864, a small molecule inhibitor of Rac GTPases, prevents spread of breast cancers in this setting, and also reduces proliferation at the invading edge. Rac1+ epithelial cells in breast tumours also contain high levels of the phosphorylated form of the transcription factor STAT3. The small molecule Stattic inhibits activation of STAT3 and induces effects similar to those seen with EHT 1864. Pan-Rac inhibition of proliferation precedes down-regulation of STAT3 activity, defining it as the last step in Rac activation during human breast cancer invasion. Our data highlights the potential use of Rac and STAT3 inhibition in treatment of invasive human breast cancer and the benefit of studying novel cancer treatments using three-dimensional primary tumour tissue explant cultures

Approaches towards expression profiling the response to treatment

Over the past 8 years there has been a wealth of breast cancer gene expression studies. The majority of these studies have focused upon characterising a tumour at presentation, before treatment, rather than looking at the effects of treatment on the tumour. More recently, a number of groups have moved from predicting prognosis based upon long-term follow-up to alternative approaches of using expression profiling to measure the effect of treatment on breast tumours and potentially predict response to therapy using either post-treatment samples or both pre-treatment and post-treatment samples. Whilst this provides great potential to further our understanding of the mode of action of treatments and to more accurately select which patients will benefit from a particular treatment, serious issues of experimental design must be considered

Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns

ABSTRACT: BACKGROUND: Aberrant CpG island promoter DNA hypermethylation is frequently observed in cancer and is believed to contribute to tumor progression by silencing the expression of tumor suppressor genes. Previously, we observed that promoter hypermethylation in breast cancer reflects cell lineage rather than tumor progression and occurs at genes that are already repressed in a lineage-specific manner. To investigate the generality of our observation we analyzed the methylation profiles of 1,154 cancers from 7 different tissue types. RESULTS: We find that 1,009 genes are prone to hypermethylation in these 7 types of cancer. Nearly half of these genes varied in their susceptibility to hypermethylation between different cancer types. We show that the expression status of hypermethylation prone genes in the originator tissue determines their propensity to become hypermethylated in cancer; specifically, genes that are normally repressed in a tissue are prone to hypermethylation in cancers derived from that tissue. We also show that the promoter regions of hypermethylation-prone genes are depleted of repetitive elements and that DNA sequence around the same promoters is evolutionarily conserved. We propose that these two characteristics reflect tissue-specific gene promoter architecture regulating the expression of these hypermethylation prone genes in normal tissues. CONCLUSIONS: As aberrantly hypermethylated genes are already repressed in pre-cancerous tissue, we suggest that their hypermethylation does not directly contribute to cancer development via silencing. Instead aberrant hypermethylation reflects developmental history and the perturbation of epigenetic mechanisms maintaining these repressed promoters in a hypomethylated state in normal cells.Publisher PDFPeer reviewe

The embryonic transcription cofactor LBH is a direct target of the Wnt signaling pathway in epithelial development and in aggressive basal subtype breast cancers

Limb-bud and heart (LBH) is a novel key transcriptional regulator of vertebrate development. However, the molecular mechanisms upstream of LBH and its role in adult development are unknown. Here we show that in epithelial development, LBH expression is tightly controlled by Wnt signaling. LBH is transcriptionally induced by the canonical Wnt pathway, as evident by the presence of conserved functional T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) binding sites in the LBH locus and rapid β-catenin-dependent upregulation of endogenous LBH by Wnt3a. In contrast, LBH induction by Wnt/β-catenin signaling is inhibited by Wnt7a, which in limb development signals through a noncanonical pathway involving Lmx1b. Furthermore, we show that LBH is aberrantly overexpressed in mammary tumors of mouse mammary tumor virus (MMTV)-Wnt1-transgenic mice and in aggressive basal subtype human breast cancers that display Wnt/β-catenin hyperactivation. Deregulation of LBH in human basal breast cancer appears to be Wnt/β-catenin dependent, as DKK1 and Wnt7a inhibit LBH expression in breast tumor cells. Overexpression studies indicate that LBH suppresses mammary epithelial cell differentiation, an effect that could contribute to Wnt-induced tumorigenesis. Taken together, our findings link LBH for the first time to the Wnt signaling pathway in both development and cancer and highlight LBH as a potential new marker for therapeutically challenging basal-like breast cancers