Towards precision medicine for hypertension: a review of genomic, epigenomic, and microbiomic effects on blood pressure in experimental rat models and humans

Compelling evidence for the inherited nature of essential hypertension has led to extensive research in rats and humans. Rats have served as the primary model for research on the genetics of hypertension resulting in identification of genomic regions that are causally associated with hypertension. In more recent times, genome-wide studies in humans have also begun to improve our understanding of the inheritance of polygenic forms of hypertension. Based on the chronological progression of research into the genetics of hypertension as the "structural backbone," this review catalogs and discusses the rat and human genetic elements mapped and implicated in blood pressure regulation. Furthermore, the knowledge gained from these genetic studies that provide evidence to suggest that much of the genetic influence on hypertension residing within noncoding elements of our DNA and operating through pervasive epistasis or gene-gene interactions is highlighted. Lastly, perspectives on current thinking that the more complex "triad" of the genome, epigenome, and the microbiome operating to influence the inheritance of hypertension, is documented. Overall, the collective knowledge gained from rats and humans is disappointing in the sense that major hypertension-causing genes as targets for clinical management of essential hypertension may not be a clinical reality. On the other hand, the realization that the polygenic nature of hypertension prevents any single locus from being a relevant clinical target for all humans directs future studies on the genetics of hypertension towards an individualized genomic approach

Holographic Construction of Excited CFT States

We present a systematic construction of bulk solutions that are dual to CFT excited states. The bulk solution is constructed perturbatively in bulk fields. The linearised solution is universal and depends only on the conformal dimension of the primary operator that is associated with the state via the operator-state correspondence, while higher order terms depend on detailed properties of the operator, such as its OPE with itself and generally involve many bulk fields. We illustrate the discussion with the holographic construction of the universal part of the solution for states of two dimensional CFTs, either on $R \times S^1$ or on $R^{1,1}$. We compute the 1-point function both in the CFT and in the bulk, finding exact agreement. We comment on the relation with other reconstruction approaches.Comment: 26 pages, 4 figures, v2: comments adde

Ricci Flow Gravity

A theory of gravitation is proposed, modeled after the notion of a Ricci flow. In addition to the metric an independent volume enters as a fundamental geometric structure. Einstein gravity is included as a limiting case. Despite being a scalar-tensor theory the coupling to matter is different from Jordan-Brans-Dicke gravity. In particular there is no adjustable coupling constant. For the solar system the effects of Ricci flow gravity cannot be distinguished from Einstein gravity and therefore it passes all classical tests. However for cosmology significant deviations from standard Einstein cosmology will appear.Comment: 15 pages. V2: improved presentation, in particular Jordan vs. Brans-Dicke and on viability. Added section on physical interpretation. V3: more references. Reworked to agree with published versio

On direct measurement of the W production charge asymmetry at the LHC

The prospects for making a direct measurement of the W production charge asymmetry at the LHC are discussed. A modification to the method used at the Tevatron is proposed for measurements at the LHC. The expected sensitivity for such a measurement to parton distribution functions is compared to that for a measurement of the lepton charge asymmetry. The direct measurement approach is found to be less useful for placing constraints on parton distribution functions at the LHC than a measurement of the lepton charge asymmetry.Comment: 18 pages, 10 figures, v2: references and keywords updated v3: Additional paragraph discussing inclusion of W asymmetry in global fits adde

NLO QCD corrections in Herwig++ with MC@NLO

We present the calculations necessary to obtain next-to-leading order QCD precision with the Herwig++ event generator using the MC@NLO approach, and implement them for all the processes that were previously available from Fortran HERWIG with MC@NLO. We show a range of results comparing the two implementations. With these calculations and recent developments in the automatic generation of NLO matrix elements, it will be possible to obtain NLO precision with Herwig++ for a much wider range of processesComment: 26 pages, 28 figure

MINLO: Multi-scale improved NLO

In the present work we consider the assignment of the factorization and renormalization scales in hadron collider processes with associated jet production, at next-to-leading order (NLO) in perturbation theory. We propose a simple, definite prescription to this end, including Sudakov form factors to consistently account for the distinct kinematic scales occuring in such collisions. The scheme yields results that are accurate at NLO and, for a large class of observables, it resums to all orders the large logarithms that arise from kinematic configurations involving disparate scales. In practical terms the method is most simply understood as an NLO extension of the matrix element reweighting procedure employed in tree level matrix element-parton shower merging algorithms. By way of a proof-of-concept, we apply the method to Higgs and Z boson production in association with up to two jets.Comment: 27 pages, 17 figure

Exceptional sperm cooperation in the wood mouse

Spermatozoa from a single male will compete for fertilization of ova with spermatozoa from another male when present in the female reproductive tract at the same time. Close genetic relatedness predisposes individuals towards altruism, and as haploid germ cells of an ejaculate will have genotypic similarity of 50%, it is predicted that spermatozoa may display cooperation and altruism to gain an advantage when inter-male sperm competition is intense. We report here the probable altruistic behaviour of spermatozoa in an eutherian mammal. Spermatozoa of the common wood mouse, Apodemus sylvaticus, displayed a unique morphological transformation resulting in cooperation in distinctive aggregations or 'trains' of hundreds or thousands of cells, which significantly increased sperm progressive motility. Eventual dispersal of sperm trains was associated with most of the spermatozoa undergoing a premature acrosome reaction. Cells undergoing an acrosome reaction in aggregations remote from the egg are altruistic in that they help sperm transport to the egg but compromise their own fertilizing ability

The DAFNEplus programme for sustained type 1 diabetes self management: Intervention development using the Behaviour Change Wheel

AIMS: Self-management programmes for type 1 diabetes, such as the UK's Dose Adjustment for Normal Eating (DAFNE), improve short-term clinical outcomes but difficulties maintaining behavioural changes attenuate long-term impact. This study used the Behaviour Change Wheel (BCW) framework to revise the DAFNE intervention to support sustained behaviour change. METHODS: A four-step method was based on the BCW intervention development approach: 1) Identifying self-management behaviours and barriers/enablers to maintaining them via stakeholder consultation and evidence synthesis, and mapping barriers/enablers to the Capability, Opportunity, Motivation-Behaviour (COM-B) model. 2) Specifying behaviour change techniques (BCTs) in the existing DAFNE intervention using the Behaviour Change Techniques Taxonomy (BCTTv1). 3) Identifying additional BCTs to target the barriers/enablers using the BCW and BCTTv1. 4) Parallel stakeholder consultation to generate recommendations for intervention revision. Revised materials were co-designed by stakeholders (diabetologists, psychologists, specialist nurses and dietitians). RESULTS: Thirty-four barriers and five enablers to sustaining self-management post-DAFNE, were identified. The existing DAFNE intervention contained 24 BCTs, which partially addressed the enablers. Twenty-seven BCTs were added, including 'Habit formation', 'Credible source' and 'Conserving mental resources'. Fifteen stakeholder-agreed recommendations for content and delivery were incorporated into the final DAFNEplus intervention, comprising three co-designed components: (1) face-to-face group learning course, (2) individual structured follow-up sessions, (3) technological support, including blood glucose data management. CONCLUSIONS: This method provided a systematic approach to specifying and revising a behaviour change intervention incorporating stakeholder input. The revised DAFNEplus intervention aims to support the maintenance of behavioural changes by targeting barriers and enablers to sustaining self-management behaviours

The Adolescent Depression Rating Scale (ADRS): a validation study

BACKGROUND: To examine the psychometric properties of the Adolescent Depression Rating Scale (ADRS), a new measure was specifically designed to evaluate adolescent depression. METHODS: The 11-item clinician-report and 44-item self-report versions of the ADRS were developed from a qualitative phase involving interviews of experts and adolescents. These two instruments were then administered to 402 French speaking adolescents with and without depressive disorders. Item distribution, internal consistency, convergent validity, discriminant validity and factorial structure were assessed. RESULTS: After reduction procedures, a 10-item clinician version and a 10-item self-report version were obtained. The ADRS demonstrated good internal consistency (alpha Cronbach coefficient >.70). It also discriminated better between adolescents with and without depression than the Hamilton Depressive Rating Scale and the Beck Depression Inventory (BDI-13). CONCLUSION: The ADRS is a useful, short, clinician-report and self-report scale to evaluate adolescent depression. Further studies to replicate our findings and evaluate ADRS sensitivity to effects of treatment and psychometric properties in populations of adolescents with several psychiatric disorders are warranted