Varying constants, Gravitation and Cosmology

Fundamental constants are a cornerstone of our physical laws. Any constant varying in space and/or time would reflect the existence of an almost massless field that couples to matter. This will induce a violation of the universality of free fall. It is thus of utmost importance for our understanding of gravity and of the domain of validity of general relativity to test for their constancy. We thus detail the relations between the constants, the tests of the local position invariance and of the universality of free fall. We then review the main experimental and observational constraints that have been obtained from atomic clocks, the Oklo phenomenon, Solar system observations, meteorites dating, quasar absorption spectra, stellar physics, pulsar timing, the cosmic microwave background and big bang nucleosynthesis. At each step we describe the basics of each system, its dependence with respect to the constants, the known systematic effects and the most recent constraints that have been obtained. We then describe the main theoretical frameworks in which the low-energy constants may actually be varying and we focus on the unification mechanisms and the relations between the variation of different constants. To finish, we discuss the more speculative possibility of understanding their numerical values and the apparent fine-tuning that they confront us with.Comment: 145 pages, 10 figures, Review for Living Reviews in Relativit

Cdc14 phosphatase promotes segregation of telomeres through repression of RNA polymerase II transcription

Kinases and phosphatases regulate messenger RNA synthesis through post-translational modification of the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II (ref. 1). In yeast, the phosphatase Cdc14 is required for mitotic exit2,3 and for segregation of repetitive regions4. Cdc14 is also a subunit of the silencing complex RENT (refs 5, 6), but no roles in transcriptional repression have been described. Here we report that inactivation of Cdc14 causes silencing defects at the intergenic spacer sequences of ribosomal genes during interphase and at Y′ repeats in subtelomeric regions during mitosis. We show that the role of Cdc14 in silencing is independent of the RENT deacetylase subunit Sir2. Instead, Cdc14 acts directly on RNA polymerase II by targeting CTD phosphorylation at Ser 2 and Ser 5. We also find that the role of Cdc14 as a CTD phosphatase is conserved in humans. Finally, telomere segregation defects in cdc14 mutants4 correlate with the presence of subtelomeric Y′ elements and can be rescued by transcriptional inhibition of RNA polymerase II

Orthostatic hypotension and health outcomes: an umbrella review of observational studies

Purpose: Orthostatic Hypotension (OH) is associated with older age and many negative clinical outcomes in geriatric practice. We aimed to capture the breadth of outcomes that have been associated with the presence of OH and systematically assess the quality, strength and credibility of these associations using an umbrella review with integrated meta-analyses. Methods: We systematically searched several major databases from their commencements through to 16th May 2019 for meta-analyses of observational studies of OH and any health-related outcome. We used these metrics to categorize the strength of evidence of significant outcomes (p<0.05) from class I (convincing) to class IV (weak), according to pre-established criteria. Results: From 975 abstracts, 7 meta-analyses of 12 outcomes were included. For each outcome, the median number of studies was 4, the median number of participants was 46,493, with a median of 3,630 incident cases. There was suggestive (class III) evidence that OH was associated with significantly higher risk of coronary heart disease (HR=1.32, 95%CI: 1.12-1.56), stroke (HR=1.22, 95%CI: 1.08-1.38), congestive heart failure (HR=1.30, 95%CI: 1.09-1.55), all-cause mortality (RR=1.50, 95%CI: 1.24-1.81), falls (OR=1.84, 95%CI: 1.39-2.44), and dementia (HR=1.22, 95%CI: 1.11-1.35). Conclusion: The current evidence base indicates that OH is significantly associated with a range of adverse cardiovascular, cognitive, and mortality outcomes in older people, although the strength of this evidence remains only suggestive. Further research in larger samples and with lower risk of bias is required to build a fuller picture of the impact of OH on health