471 research outputs found

    Feed-Forward Propagation of Temporal and Rate Information between Cortical Populations during Coherent Activation in Engineered In Vitro Networks.

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    Transient propagation of information across neuronal assembles is thought to underlie many cognitive processes. However, the nature of the neural code that is embedded within these transmissions remains uncertain. Much of our understanding of how information is transmitted among these assemblies has been derived from computational models. While these models have been instrumental in understanding these processes they often make simplifying assumptions about the biophysical properties of neurons that may influence the nature and properties expressed. To address this issue we created an in vitro analog of a feed-forward network composed of two small populations (also referred to as assemblies or layers) of living dissociated rat cortical neurons. The populations were separated by, and communicated through, a microelectromechanical systems (MEMS) device containing a strip of microscale tunnels. Delayed culturing of one population in the first layer followed by the second a few days later induced the unidirectional growth of axons through the microtunnels resulting in a primarily feed-forward communication between these two small neural populations. In this study we systematically manipulated the number of tunnels that connected each layer and hence, the number of axons providing communication between those populations. We then assess the effect of reducing the number of tunnels has upon the properties of between-layer communication capacity and fidelity of neural transmission among spike trains transmitted across and within layers. We show evidence based on Victor-Purpura's and van Rossum's spike train similarity metrics supporting the presence of both rate and temporal information embedded within these transmissions whose fidelity increased during communication both between and within layers when the number of tunnels are increased. We also provide evidence reinforcing the role of synchronized activity upon transmission fidelity during the spontaneous synchronized network burst events that propagated between layers and highlight the potential applications of these MEMs devices as a tool for further investigation of structure and functional dynamics among neural populations

    Repeating Spatial-Temporal Motifs of CA3 Activity Dependent on Engineered Inputs from Dentate Gyrus Neurons in Live Hippocampal Networks.

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    Anatomical and behavioral studies, and in vivo and slice electrophysiology of the hippocampus suggest specific functions of the dentate gyrus (DG) and the CA3 subregions, but the underlying activity dynamics and repeatability of information processing remains poorly understood. To approach this problem, we engineered separate living networks of the DG and CA3 neurons that develop connections through 51 tunnels for axonal communication. Growing these networks on top of an electrode array enabled us to determine whether the subregion dynamics were separable and repeatable. We found spontaneous development of polarized propagation of 80% of the activity in the native direction from DG to CA3 and different spike and burst dynamics for these subregions. Spatial-temporal differences emerged when the relationships of target CA3 activity were categorized with to the number and timing of inputs from the apposing network. Compared to times of CA3 activity when there was no recorded tunnel input, DG input led to CA3 activity bursts that were 7× more frequent, increased in amplitude and extended in temporal envelope. Logistic regression indicated that a high number of tunnel inputs predict CA3 activity with 90% sensitivity and 70% specificity. Compared to no tunnel input, patterns of >80% tunnel inputs from DG specified different patterns of first-to-fire neurons in the CA3 target well. Clustering dendrograms revealed repeating motifs of three or more patterns at up to 17 sites in CA3 that were importantly associated with specific spatial-temporal patterns of tunnel activity. The number of these motifs recorded in 3 min was significantly higher than shuffled spike activity and not seen above chance in control networks in which CA3 was apposed to CA3 or DG to DG. Together, these results demonstrate spontaneous input-dependent repeatable coding of distributed activity in CA3 networks driven by engineered inputs from DG networks. These functional configurations at measured times of activation (motifs) emerge from anatomically accurate feed-forward connections from DG through tunnels to CA3

    Sparse and Specific Coding during Information Transmission between Co-cultured Dentate Gyrus and CA3 Hippocampal Networks

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    To better understand encoding and decoding of stimulus information in two specific hippocampal sub-regions, we isolated and co-cultured rat primary dentate gyrus (DG) and CA3 neurons within a two-chamber device with axonal connectivity via micro-tunnels. We tested the hypothesis that, in these engineered networks, decoding performance of stimulus site information would be more accurate when stimuli and information flow occur in anatomically correct feed-forward DG to CA3 vs. CA3 back to DG. In particular, we characterized the neural code of these sub-regions by measuring sparseness and uniqueness of the responses evoked by specific paired-pulse stimuli. We used the evoked responses in CA3 to decode the stimulation sites in DG (and vice-versa) by means of learning algorithms for classification (support vector machine, SVM). The device was placed over an 8 × 8 grid of extracellular electrodes (micro-electrode array, MEA) in order to provide a platform for monitoring development, self-organization, and improved access to stimulation and recording at multiple sites. The micro-tunnels were designed with dimensions 3 × 10 × 400 μm allowing axonal growth but not migration of cell bodies and long enough to exclude traversal by dendrites. Paired-pulse stimulation (inter-pulse interval 50 ms) was applied at 22 different sites and repeated 25 times in each chamber for each sub-region to evoke time-locked activity. DG-DG and CA3-CA3 networks were used as controls. Stimulation in DG drove signals through the axons in the tunnels to activate a relatively small set of specific electrodes in CA3 (sparse code). CA3-CA3 and DG-DG controls were less sparse in coding than CA3 in DG-CA3 networks. Using all target electrodes with the three highest spike rates (14%), the evoked responses in CA3 specified each stimulation site in DG with optimum uniqueness of 64%. Finally, by SVM learning, these evoked responses in CA3 correctly decoded the stimulation sites in DG for 43% of the trials, significantly higher than the reverse, i.e., how well-recording in DG could predict the stimulation site in CA3. In conclusion, our co-cultured model for the in vivo DG-CA3 hippocampal network showed sparse and specific responses in CA3, selectively evoked by each stimulation site in DG

    Chemical Substructure in the Milky Way Halo: A New Population of Old Stars

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    We report the results of a coherent study of a new class of halo stars defined on the basis of the chemical compositions of three metal-poor objects ([Fe/H] -2) that exhibit unusually low abundances of α-element (Mg, Si, Ca) and neutron-capture (Sr, Y, Ba) material. Our analyses confirm and expand on earlier reports of atypical α- and neutron-capture abundances in BD +80°245, G4-36, and CS 22966-043. We also find that the latter two stars exhibit unusual relative abundance enhancements within the iron peak (Cr, Mn, Ni, Zn), along with what may be large abundances of Ga, an element not previously reported as being observed in any metal-poor star. These results provide further evidence that chemical enrichment and star formation histories varied from region to region within the Milky Way halo. Comparing the chemical abundances of the newly identified stellar population to supernova model yields, we derive supernova ratios of Type Ia versus Type II events in the range of 0.6 (NIa/NII)New Pop 1.3. For the Sun, we derive 0.18 ± 0.01 < (NIa/NII)☉ < 0.25 ± 0.06, supernova ratios in good agreement with values found in the literature. Given the relatively low metallicity and relatively high NIa/NII ratios of the low-α stars studied here, these objects may have been born from material produced in the yields of the earliest Type Ia supernova events. We also report the results of a preliminary attempt to employ the observed chemical abundances of low-metallicity stars in the identification, and possible cosmic evolution, of Type Ia supernova progenitors, and we discuss the limitations of current model yields

    Individual, Environmental, and Meteorological Predictors of Daily Personal Ultraviolet Radiation Exposure Measurements in a United States Cohort Study

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    Background Individual exposure to ultraviolet radiation (UVR) is challenging to measure, particularly for diseases with substantial latency periods between first exposure and diagnosis of outcome, such as cancer. To guide the choice of surrogates for long-term UVR exposure in epidemiologic studies, we assessed how well stable sun-related individual characteristics and environmental/meteorological factors predicted daily personal UVR exposure measurements. Methods We evaluated 123 United States Radiologic Technologists subjects who wore personal UVR dosimeters for 8 hours daily for up to 7 days (N = 837 days). Potential predictors of personal UVR derived from a self-administered questionnaire, and public databases that provided daily estimates of ambient UVR and weather conditions. Factors potentially related to personal UVR exposure were tested individually and in a model including all significant variables. Results The strongest predictors of daily personal UVR exposure in the full model were ambient UVR, latitude, daily rainfall, and skin reaction to prolonged sunlight (R2 = 0.30). In a model containing only environmental and meteorological variables, ambient UVR, latitude, and daily rainfall were the strongest predictors of daily personal UVR exposure (R2 = 0.25). Conclusions In the absence of feasible measures of individual longitudinal sun exposure history, stable personal characteristics, ambient UVR, and weather parameters may help estimate long-term personal UVR exposure

    Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories:Findings From the CANVAS Program

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    Rationale & Objective: Canagliflozin reduces the risk for cardiovascular and kidney outcomes in type 2 diabetes. This study aimed to assess the relative and absolute effects of canagliflozin on clinical outcomes across different KDIGO (Kidney Disease: Improving Global Outcomes) risk categories based on estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio. Study Design: Post hoc analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. Settings & Participants: The CANVAS Program randomly assigned 10,142 participants with type 2 diabetes at high cardiovascular risk and with eGFR ≥ 30 mL/min/1.73 m2 to treatment with canagliflozin or placebo. Intervention(s): Canagliflozin or matching placebo. Outcomes: The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with a set of other cardiovascular and kidney prespecified outcomes. Results: Of 10,142 participants, 10,031 (98.9%) had available baseline eGFR and urinary albumin-creatinine ratio data. The proportion of participants in low-, moderate-, high-, and very high–risk KDIGO categories was 58.6%, 25.8%, 10.6%, and 5.0%, respectively. The relative effect of canagliflozin on the primary outcome (HR, 0.86; 95% CI, 0.75-0.97) was consistent across KDIGO risk categories (P trend = 0.2), with similar results for other cardiovascular and kidney outcomes. Absolute reductions in the primary outcome were greater within higher KDIGO risk categories (P trend = 0.03) with a similar pattern of effect for the composite of cardiovascular death or hospitalization for heart failure (P trend = 0.06) and for chronic eGFR slope (P trend = 0.04). Limitations: Predominantly a low kidney risk population, relatively few participants in higher KDIGO risk categories, and exclusion of individuals with eGFR < 30 mL/min/1.73 m2. Conclusions: Although the relative effects of canagliflozin are similar across KDIGO risk categories, absolute risk reductions are likely greater for individuals at higher KDIGO risk. The KDIGO classification system may be able to identify individuals who might derive greater benefits for end-organ protection from treatment with canagliflozin. Funding: This post hoc analysis was not specifically funded. The original CANVAS Program trials were funded by Janssen Research & Development, LLC and were conducted as a collaboration between the funder, an academic steering committee, and an academic research organization, George Clinical. Trial Registration: The original trials of the CANVAS Program were registered at ClinicalTrials.gov with study numbers NCT01032629 and NCT01989754


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    We develop and apply a fully covariant 1+3 electromagnetic analogy for gravity. The free gravitational field is covariantly characterized by the Weyl gravito-electric and gravito-magnetic spatial tensor fields, whose dynamical equations are the Bianchi identities. Using a covariant generalization of spatial vector algebra and calculus to spatial tensor fields, we exhibit the covariant analogy between the tensor Bianchi equations and the vector Maxwell equations. We identify gravitational source terms, couplings and potentials with and without electromagnetic analogues. The nonlinear vacuum Bianchi equations are shown to be invariant under covariant spatial duality rotation of the gravito-electric and gravito-magnetic tensor fields. We construct the super-energy density and super-Poynting vector of the gravitational field as natural U(1) group invariants, and derive their super-energy conservation equation. A covariant approach to gravito-electric/magnetic monopoles is also presented.Comment: 14 pages. Version to appear in Class. Quant. Gra

    Canagliflozin Reduces Kidney-Related Adverse Events in Type 2 Diabetes and CKD:Findings From the Randomized CREDENCE Trial

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    RATIONALE AND OBJECTIVE: Canagliflozin reduced the risk of kidney failure and related outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in the CREDENCE trial. This analysis of CREDENCE trial data examines the effect of canagliflozin on the incidence of kidney-related adverse events (AEs). STUDY DESIGN: A randomized, double-blind, placebo-controlled, multicenter, international trial. SETTING AND PARTICIPANTS: 4,401 trial participants with T2DM, CKD, and urinary albumin:creatinine ratio >300-5000mg/g. INTERVENTIONS: Participants were randomly assigned to receive canagliflozin 100mg/day or placebo. OUTCOMES: Rates of kidney-related AEs were analyzed using an on-treatment approach, overall and by screening estimated glomerular filtration rate (eGFR) strata (30-<45, 45-<60, and 60-<90 mL/min/1.73m2). RESULTS: Canagliflozin was associated with a reduction in the overall incidence rate of kidney-related AEs (60.2 vs 84.0 per 1,000 patient-years; hazard ratio [HR]: 0.71 [95% confidence interval (CI): 0.61, 0.82]; P<0.001), with consistent results for serious kidney-related AEs (HR: 0.72 [95% CI: 0.51, 1.00]; P=0.05) and acute kidney injury (AKI; HR: 0.85 [95% CI: 0.64, 1.13]; P=0.3). The rates of kidney-related AEs were lower with canagliflozin relative to placebo across the 3 eGFR strata (HRs of 0.73, 0.60, and 0.81 for eGFR 30-<45, 45-<60, and 60-<90 mL/min/1.73m2, respectively; P-interaction=0.3), with similar results for AKI (P-interaction=0.9). Full recovery of kidney function within 30 days after an AKI event occurred more frequently with canagliflozin versus placebo (53.1% vs 35.4%; odds ratio: 2.2 [95% CI: 1.0, 4.7]; P=0.04). LIMITATIONS: Kidney-related AEs including AKI were investigator-reported and collected without central adjudication. Biomarkers of AKI and structural tubular damage were not measured and creatinine data after an AKI event were not available for all participants. CONCLUSION: Canagliflozin compared to placebo was associated with a reduced incidence of serious and non-serious kidney-related AEs in patients with T2DM and CKD. These results highlight the safety of canagliflozin with regard to adverse kidney disease events

    The Early Optical Afterglow of GRB 030418 and Progenitor Mass Loss

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    The ROTSE-IIIa telescope and the SSO 40 inch (1.0 m) telescope, both located at Siding Spring Observatory, imaged the early-time afterglow of GRB 030418. In this report, we present observations of the early afterglow, first detected by the ROTSE-IIIa telescope 211 s after the start of the burst and only 76 s after the end of the gamma-ray activity. We detect optical emission that rises for ∼600 s, slowly varies around R = 17.3 mag for ∼1400 s, and then fades as a power law of index α = -1.36. Additionally, the ROTSE-IIIb telescope, located at McDonald Observatory, imaged the early-time afterglow of GRB 030723. The behavior of this light curve was qualitatively similar to that of GRB 030418, but 2 mag dimmer. These two afterglows are dissimilar to other afterglows such as GRB 990123 and GRB 021211. We investigate whether or not the early afterglow can be attributed to a synchrotron break in a cooling synchrotron spectrum as it passes through the optical band, but we find that this model is unable to accurately describe the early light curve. We present a simple model for gamma-ray burst emission emerging from a wind medium surrounding a massive progenitor star. This model provides an effective description of the data and suggests that the rise of the afterglow can be ascribed to extinction in the local circumburst environment. In this interpretation, these events provide further evidence of the connection between gamma-ray bursts and the collapse of massive stars.This work has been supported by NASA grants NAG5- 5281 and F006794, NSF grants AST 01-19685 and 01-05221, the Australian Research Council, the University of New South Wales, and the University of Michigan. Work performed at LANL is supported by NASA SR&T through Department of Energy (DOE) contract W-7405-ENG-36 and through internal LDRD funding