State Dependence of Stimulus-Induced Variability Tuning in Macaque MT

Behavioral states marked by varying levels of arousal and attention modulate some properties of cortical responses (e.g. average firing rates or pairwise correlations), yet it is not fully understood what drives these response changes and how they might affect downstream stimulus decoding. Here we show that changes in state modulate the tuning of response variance-to-mean ratios (Fano factors) in a fashion that is neither predicted by a Poisson spiking model nor changes in the mean firing rate, with a substantial effect on stimulus discriminability. We recorded motion-sensitive neurons in middle temporal cortex (MT) in two states: alert fixation and light, opioid anesthesia. Anesthesia tended to lower average spike counts, without decreasing trial-to-trial variability compared to the alert state. Under anesthesia, within-trial fluctuations in excitability were correlated over longer time scales compared to the alert state, creating supra-Poisson Fano factors. In contrast, alert-state MT neurons have higher mean firing rates and largely sub-Poisson variability that is stimulus-dependent and cannot be explained by firing rate differences alone. The absence of such stimulus-induced variability tuning in the anesthetized state suggests different sources of variability between states. A simple model explains state-dependent shifts in the distribution of observed Fano factors via a suppression in the variance of gain fluctuations in the alert state. A population model with stimulus-induced variability tuning and behaviorally constrained information-limiting correlations explores the potential enhancement in stimulus discriminability by the cortical population in the alert state.Comment: 36 pages, 18 figure

Inhibitory Regulation of Dendritic Activity in vivo

The spatiotemporal control of neuronal excitability is fundamental to the inhibitory process. We now have a wealth of information about the active dendritic properties of cortical neurons including axonally generated sodium action potentials as well as local sodium spikelets generated in the dendrites, calcium plateau spikes, and NMDA spikes. All of these events have been shown to be highly modified by the spatiotemporal pattern of nearby inhibitory input which can drastically change the output firing mode of the neuron. This means that particular populations of interneurons embedded in the neocortical microcircuitry can more precisely control pyramidal cell output than has previously been thought. Furthermore, the output of any given neuron tends to feed back onto inhibitory circuits making the resultant network activity further dependent on inhibition. Network activity is therefore ultimately governed by the subcellular microcircuitry of the cortex and it is impossible to ignore the subcompartmentalization of inhibitory influence at the neuronal level in order to understand its effects at the network level. In this article, we summarize the inhibitory circuits that have been shown so far to act on specific dendritic compartments in vivo

Shelf Seas Baroclinic Energy Loss: Pycnocline Mixing and Bottom Boundary Layer Dissipation

Observations of turbulent kinetic energy dissipation rate from a range of historical shelf seas data sets are viewed from the perspective of their forcing and dissipation mechanisms: barotropic to baroclinic tidal energy conversion, and pycnocline and bottom boundary layer (BBL) dissipation. The observations are placed in their geographical context using a high resolution numerical model (NEMO AMM60) in order to compute relevant maps of the forcing (conversion). We analyze, in total, 18 shear microstructure surveys undertaken over a 17 year period from 1996 to 2013 on the North West European shelf, consisting of 3,717 vertical profiles of shear microstructure: 2,013 from free falling profilers and 1,704 from underwater gliders. A robust positive relationship is found between model-derived barotropic to baroclinic conversion, and observed pycnocline integrated. A fitted power law relationship of approximately one-third is found, giving a simple new parameterization. We discuss reasons for this apparent power law and where the “missing” dissipation may be occurring. We conclude that internal wave related dissipation in the bottom boundary layer provides a robust explanation and is consistent with a commonly used fine-scale pycnocline dissipation parameterization

Storms modify baroclinic energy fluxes in a seasonally stratified shelf sea: inertial-tidal interaction

Observations made near the Celtic Sea shelf edge are used to investigate the interaction between wind-generated near-inertial oscillations and the semidiurnal internal tide. Linear, baroclinic energy fluxes within the near-inertial (f) and semidiurnal (M2) wave bands are calculated from measurements of velocity and density structure at two moorings located 40 km from the internal tidal generation zone. Over the 2 week deployment period, the semidiurnal tide drove 28–48 W m−1 of energy directly on-shelf. Little spring-neap variability could be detected. Horizontal near-inertial energy fluxes were an order of magnitude weaker, but nonlinear interaction between the vertical shear of inertial oscillations and the vertical velocity associated with the semidiurnal internal tide led to a 25–43% increase in positive on-shelf energy flux. The phase relationship between f and M2 determines whether this nonlinear interaction enhances or dampens the linear tidal component of the flux, and introduces a 2 day counter-clockwise beating to the energy transport. Two very clear contrasting regimes of (a) tidally and (b) inertially driven shear and energy flux are captured in the observations

NMDA spikes enhance action potential generation during sensory input

Recent evidence in vitro suggests that the tuft dendrites of pyramidal neurons are capable of evoking local NMDA receptor–dependent electrogenesis, so-called NMDA spikes. However, it has so far proved difficult to demonstrate their existence in vivo. Moreover, it is not clear whether NMDA spikes are relevant to the output of pyramidal neurons. We found that local NMDA spikes occurred in tuft dendrites of layer 2/3 pyramidal neurons both spontaneously and following sensory input, and had a large influence on the number of output action potentials. Using two-photon activation of an intracellular caged NMDA receptor antagonist (tc-MK801), we found that isolated NMDA spikes typically occurred in multiple branches simultaneously and that sensory stimulation substantially increased their probability. Our results demonstrate that NMDA receptors have a vital role in coupling the tuft region of the layer 2/3 pyramidal neuron to the cell body, enhancing the effectiveness of layer 1 input

Baroclinic energy flux at the continental shelf edge modified by wind-mixing

Temperature and current measurements from two moorings onshore of the Celtic Sea shelf break, a well-known hot spot for tidal energy conversion, show the impact of passing summer storms on the baroclinic wavefield. Wind-driven vertical mixing changed stratification to permit an increased on-shelf energy transport, and baroclinic energy in the semidiurnal band appeared at the moorings 1–4 days after the storm mixed the upper 50 m of the water column. The timing of the maximum in the baroclinic energy flux is consistent with the propagation of the semidiurnal internal tide from generation sites at the shelf break to the moorings 40 km away. Also, the ∼3 day duration of the peak in M2 baroclinic energy flux at the moorings corresponds to the restratification time scale following the first storm

Assessing the relationship between human well-being and ecosystem services: a review of frameworks

Focusing on the most impoverished populations, we critically review and synthesise key themes from dominant frameworks for assessing the relationship between well-being and ecosystem services in developing countries. This requires a differentiated approach to conceptualising well-being that appropriately reflects the perspectives of the poorest-those most directly dependent on ecosystem services, and their vulnerability to external and policy-driven environmental change. The frameworks analysed draw upon environmental sciences, economics, psychology, sociology, and anthropology, and were selected on the basis of their demonstrated or potential ability to illustrate the relationship between environmental change and human well-being, as well as their prevalence in real world applications. Thus, the synthesis offered here is informed by the various theoretical, methodological, and hermeneutical contributions from each field to the notion of well-being. The review highlights several key dimensions that should be considered by those interested in understanding and assessing the impact of environmental change on the well-being of the world's poorest people: the importance of interdisciplinary consideration of well-being, the need for frameworks that integrate subjective and objective aspects of well-being, and the central importance of context and relational aspects of well-being. The review is of particular interest to those engaged in the post-2015 development agenda

Efficacy and Safety of Ertugliflozin in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease Treated With Metformin and Sulfonylurea

Abstract Introduction: Ertugliflozin (ERTU), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is approved as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM). Aim: As a pre-specified sub-study of the Phase 3 VERTIS CV trial (NCT01986881), the efficacy and safety of ERTU were assessed in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) inadequately controlled with metformin and sulfonylurea (SU). Methods: Patients with T2DM, established ASCVD, and HbA1c 7.0–10.5% on stable metformin (≥1500 mg/day) and SU doses as defined per protocol were randomized to once-daily ERTU (5 mg or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ERTU on HbA1c compared with placebo and to evaluate safety and tolerability during 18-week follow-up. Key secondary endpoints included proportion of patients achieving HbA1c <7%, fasting plasma glucose (FPG), body weight, and systolic blood pressure. Changes from baseline at Week 18 for continuous efficacy endpoints were assessed using a constrained longitudinal data analysis model. Results: Of the 8246 patients enrolled in the VERTIS CV trial, 330 patients were eligible for this sub-study (ERTU 5 mg, n=100; ERTU 15 mg, n=113; placebo, n=117). Patients had a mean (SD) age of 63.2 (8.4) years, T2DM duration 11.4 (7.4) years, estimated glomerular filtration rate 83.5 (17.8) mL/min/1.73 m2, and HbA1c 8.3% (1.0) (67.4 [10.6] mmol/mol). At Week 18, ERTU 5 mg and 15 mg were each associated with a significantly greater least squares mean (95% CI) HbA1c reduction from baseline versus placebo; the placebo-adjusted differences for ERTU 5 mg and 15 mg were –0.7% (–0.9, –0.4) and –0.8% (–1.0, –0.5), respectively (P<0.001). A higher proportion of patients in each ERTU group achieved HbA1c <7% relative to placebo (P<0.001). ERTU significantly reduced FPG and body weight (P<0.001, for each dose versus placebo), but not systolic blood pressure. Adverse events were reported in 48.0%, 54.9%, and 47.0% of patients in the ERTU 5 mg, 15 mg, and placebo groups, respectively. Genital mycotic infections were experienced by significantly higher proportions of male patients who received ERTU 5 mg and 15 mg (4.2% and 4.8%, respectively) versus placebo (0.0%; P≤0.05) and by a numerically, but not significantly, higher proportion of female patients who received ERTU 15 mg (10.3%) compared with placebo (3.8%) (P=0.36). The incidences of symptomatic hypoglycemia were 11.0% (5 mg), 12.4% (15 mg), and 7.7% (placebo), and of severe hypoglycemia 2.0% (5 mg), 1.8% (15 mg), and 0.9% (placebo). Conclusion: Among patients with T2DM and ASCVD, ERTU (5 mg and 15 mg) added to metformin and SU for 18 weeks improved glycemic control (HbA1c and FPG) and reduced body weight, and was generally well tolerated with a safety profile consistent with the SGLT2 inhibitor class

Evolution of oceanic near surface stratification in response to an autumn storm

Understanding the processes that control the evolution of the ocean surface boundary layer (OSBL) is a prerequisite for obtaining accurate simulations of air-sea fluxes of heat and trace gases. Observations of the rate of dissipation of turbulent kinetic energy (ɛ), temperature, salinity, current structure and wave-field over a period of 9.5 days in the NE Atlantic during the Ocean Surface Mixing, Ocean Submesoscale Interaction Study (OSMOSIS), are presented. The focus of this study is a storm which passed over the observational area during this period. The profiles of ɛ in the OSBL are consistent with profiles from large eddy simulation (LES) of Langmuir turbulence. In the transition layer (TL), at the base of the OSBL, ɛ was found to vary periodically at the local inertial frequency. A simple bulk model of the OSBL and a parametrisation of shear driven turbulence in the TL are developed. The parametrisation of ɛ is based on assumptions about the momentum balance of the OSBL and shear across the TL. The predicted rate of deepening, heat budget and the inertial currents in the OSBL were in good agreement with the observations, as is the agreement between the observed value of ɛ and that predicted using the parametrisation. A previous study reported spikes of elevated dissipation related to enhanced wind-shear alignment at the base of the OSBL after this storm. The spikes in dissipation are not predicted by this new parametrisation, implying that they are not an important source of dissipation during the storm