Global parameter search reveals design principles of the mammalian circadian clock

Background: Virtually all living organisms have evolved a circadian (~24 hour) clock that controls physiological and behavioural processes with exquisite precision throughout the day/night cycle. The suprachiasmatic nucleus (SCN), which generates these ~24 h rhythms in mammals, consists of several thousand neurons. Each neuron contains a gene-regulatory network generating molecular oscillations, and the individual neuron oscillations are synchronised by intercellular coupling, presumably via neurotransmitters. Although this basic mechanism is currently accepted and has been recapitulated in mathematical models, several fundamental questions about the design principles of the SCN remain little understood. For example, a remarkable property of the SCN is that the phase of the SCN rhythm resets rapidly after a 'jet lag' type experiment, i.e. when the light/ dark (LD) cycle is abruptly advanced or delayed by several hours. Results: Here, we describe an extensive parameter optimization of a previously constructed simplified model of the SCN in order to further understand its design principles. By examining the top 50 solutions from the parameter optimization, we show that the neurotransmitters' role in generating the molecular circadian rhythms is extremely important. In addition, we show that when a neurotransmitter drives the rhythm of a system of coupled damped oscillators, it exhibits very robust synchronization and is much more easily entrained to light/dark cycles. We were also able to recreate in our simulations the fast rhythm resetting seen after a 'jet lag' type experiment. Conclusion: Our work shows that a careful exploration of parameter space for even an extremely simplified model of the mammalian clock can reveal unexpected behaviours and non-trivial predictions. Our results suggest that the neurotransmitter feedback loop plays a crucial role in the robustness and phase resetting properties of the mammalian clock, even at the single neuron level

Output from VIP cells of the mammalian central clock regulates daily physiological rhythms

The suprachiasmatic nucleus (SCN) circadian clock is critical for optimising daily cycles in mammalian physiology and behaviour. The roles of the various SCN cell types in communicating timing information to downstream physiological systems remain incompletely understood, however. In particular, while vasoactive intestinal polypeptide (VIP) signalling is essential for SCN function and whole animal circadian rhythmicity, the specific contributions of VIP cell output to physiological control remains uncertain. Here we reveal a key role for SCN VIP cells in central clock output. Using multielectrode recording and optogenetic manipulations, we show that VIP neurons provide coordinated daily waves of GABAergic input to target cells across the paraventricular hypothalamus and ventral thalamus, supressing their activity during the mid to late day. Using chemogenetic manipulation, we further demonstrate specific roles for this circuitry in the daily control of heart rate and corticosterone secretion, collectively establishing SCN VIP cells as influential regulators of physiological timing

Synthetic light-cone catalogues of modern redshift and weak lensing surveys waith abacussummit

The joint analysis of different cosmological probes, such as galaxy clustering and weak lensing, can potentially yield invaluable insights into the nature of the primordial Universe, dark energy, and dark matter. However, the development of high-fidelity theoretical models is a necessary stepping stone. Here, we present public high-resolution weak lensing maps on the light-cone, generated using the N-body simulation suite abacussummit, and accompanying weak lensing mock catalogues, tuned to the Early Data Release small-scale clustering measurements of the Dark Energy Spectroscopic Instrument. Available in this release are maps of the cosmic shear, deflection angle, and convergence fields at source redshifts ranging from z = 0.15 to 2.45 as well as cosmic microwave background convergence maps for each of the 25 base-resolution simulations (and Npart = 69123) as well as for the two huge simulations (and Npart = 86403) at the fiducial abacussummit cosmology. The pixel resolution of each map is 0.21 arcmin, corresponding to a healpix Nside of 16 384. The sky coverage of the base simulations is an octant until z ≈ 0.8 (decreasing to about 1800 deg2 at z ≈ 2.4), whereas the huge simulations offer full-sky coverage until z ≈ 2.2. Mock lensing source catalogues are sampled matching the ensemble properties of the Kilo-Degree Survey, Dark Energy Survey, and Hyper Suprime-Cam data sets. The mock catalogues are validated against theoretical predictions for various clustering and lensing statistics, such as correlation multipoles, galaxy-shear, and shear-shear, showing excellent agreement. All products can be downloaded via a Globus endpoint (see Data Availability section)

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Implementing Routine HIV Testing: The Role of State Law

In September 2006, the Centers for Disease Control and Prevention (CDC) recommended routine HIV testing for all Americans aged 13–64, which would eliminate requirements for written consent and pretest counseling as previously required. However, this approach may conflict with state requirements concerning pretest counseling and informed consent for HIV testing. Our survey of state HIV testing laws demonstrates that the majority of states have HIV testing requirements that are inconsistent with the CDC's recommendations. Moreover, states that have recently amended their laws have not eased the requirements for pretest counseling and informed consent. The reasons for the persistence of these legal requirements must be understood to effect policy changes to increase HIV testing