Postnatal development of the primate cerebral cortex involves an initial proliferation and the subsequent attrition of cortical synapses. Although these maturational changes in synaptic density have ...been observed across the cortical mantle, little is known about the precise time course of developmental refinements in synaptic inputs to specific populations of cortical neurons. We examined the postnatal development of two markers of excitatory and inhibitory inputs to a subpopulation of layer III pyramidal neurons in areas 9 and 46 of rhesus monkey prefrontal cortex. These neurons are of particular interest because they play a major role in the flow of information both within and between cortical regions. Quantitative reconstructions of Golgi-impregnated mid-layer III pyramidal neurons revealed substantial developmental changes in the relative density of dendritic spines, the major site of excitatory inputs to these neurons. Relative spine density on both the apical and basilar dendritic trees increased by 50% during the first two postnatal months, remained at a plateau through 1.5 years of age, and then decreased over the peripubertal age range until stable adult levels were achieved. As a measure of the postnatal changes in inhibitory input to the axon initial segment of these pyramidal neurons, we determined the density of parvalbumin-immunoreactive axon terminals belonging to the chandelier class of local circuit neurons. The density of these distinctive axon terminals (cartridges) exhibited a temporal pattern of change that exactly paralleled the changes in dendritic spine density.
These results suggest that subpopulations of cortical neurons may be regulated by dynamic interactions between excitatory and inhibitory inputs during development and, in concert with other data, they emphasize the cellular specificity of postnatal refinements in cortical circuitry.
Abstract Blood and urine samples are collected when the Norwegian police apprehend a person suspected of driving under the influence of drugs other than alcohol. Impairment is judged from the ...findings in blood. In our routine samples, urine is analysed if morphine is detected in blood to differentiate between ingestion of heroin, morphine or codeine and also in cases where the amount of blood is too low to perform both screening and quantification analysis. In several cases, the collection of urine might be time consuming and challenging. The aim of this study was to investigate if drugs detected in blood were found in oral fluid and if interpretation of opiate findings in oral fluid is as conclusive as in urine. Blood, urine and oral fluid samples were collected from 100 drivers suspected of drugged driving. Oral fluid and blood were screened using LC–MS/MS methods and urine by immunological methods. Positive findings in blood and urine were confirmed with chromatographic methods. The analytical method for oral fluid included 25 of the most commonly abused drugs in Norway and some metabolites. The analysis showed a good correlation between the findings in urine and oral fluid for amphetamines, cocaine/benzoylecgonine, methadone, opiates, zopiclone and benzodiazepines including the 7-amino-benzodiazepines. Cocaine and the heroin marker 6-monoacetylmorphine (6-MAM) were more frequently detected in oral fluid than in urine. Drug concentrations above the cut-off values were found in both samples of oral fluid and urine in 15 of 22 cases positive for morphine, in 18 of 20 cases positive for codeine and in 19 of 26 cases positive for 6-MAM. The use of cannabis was confirmed by detecting THC in oral fluid and THC-COOH in urine. In 34 of 46 cases the use of cannabis was confirmed both in oral fluid and urine. The use of cannabis was confirmed by a positive finding in only urine in 11 cases and in only oral fluid in one case. All the drug groups detected in blood were also found in oral fluid. Since all relevant drugs detected in blood were possible to find in oral fluid and the interpretation of the opiate findings in oral fluid was more conclusive than in urine, oral fluid might replace urine in driving under the influence cases. The fast and easy sampling is time saving and less intrusive for the drivers.
BACKGROUND:A systemic pro-inflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection ...fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm.
METHODS:In 228 HFpEF patients from the multicenter PROMIS-HFpEF study, 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component (PC) analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted co-expression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without HF.
RESULTS:Comorbidity burden was associated with abnormal cardiac structure/function and with PCs/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e’ ratio, and tricuspid regurgitation (TR) velocity; and worse right ventricular function (tricuspid annular plane systolic excursion TAPSE and right ventricular. RV free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19-35%), E/e’ ratio (18-29%), TR velocity (27-41%), and tricuspid annular plane systolic excursion (13%) (P<0.05 for all) but not RV free wall strain. TNF-R1, UPAR, IGFBP-7 and GDF-15 were the top individual proteins that mediated the relationship between comorbidity burden and echocardiographic parameters. In the validation cohort, inflammation was upregulated in HFpEF cases versus controls, and the most prominent inflammation protein cluster identified in PROMIS-HFpEF was also present in HFpEF cases (but not controls) in the validation cohort.
CONCLUSIONS:Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and RV dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.
We perform a direct numerical simulation (DNS) of interacting Kelvin–Helmholtz instabilities (KHI) that arise at a stratified shear layer where KH billow cores are misaligned or exhibit varying ...phases along their axes. Significant evidence of these dynamics in early laboratory shear-flow studies by Thorpe (Geophys. Astrophys. Fluid Dyn., vol. 34, 1985, pp. 175–199) and Thorpe (J. Geophys. Res., vol. 92, 1987, pp. 5231–5248), in observations of KH billow misalignments in tropospheric clouds (Thorpe, Q. J. R. Meteorol. Soc., vol. 128, 2002, pp. 1529–1542) and in recent direct observations of such events in airglow and polar mesospheric cloud imaging in the upper mesosphere reveals that these dynamics are common. More importantly, the laboratory and mesospheric observations suggest that these dynamics lead to more rapid and more intense instabilities and turbulence than secondary convective instabilities in billow cores and secondary KHI in stratified braids between and around adjacent billows. To date, however, no simulations exploring the dynamics and energetics of interacting KH billows (apart from pairing) have been performed. Our DNS performed for Richardson number $Ri=0.10$ and Reynolds number $Re=5000$ demonstrates that KHI tubes and knots (i) comprise strong and complex vortex interactions accompanying misaligned KH billows, (ii) accelerate the transition to turbulence relative to secondary instabilities of individual KH billows, (iii) yield significantly stronger turbulence than secondary KHI in billow braids and secondary convective instabilities in KHI billow cores and (iv) expand the suite of secondary instabilities previously recognized to contribute to KHI dynamics and breakdown to turbulence in realistic geophysical environments.
Fritts et al. (J. Fluid Mech., vol. xx, 2022, xx) describe a direct numerical simulation of interacting Kelvin–Helmholtz instability (KHI) billows arising due to initial billow cores that exhibit ...variable phases along their axes. Such KHI exhibit strong ‘tube and knot’ dynamics identified in early laboratory studies by Thorpe (Geophys. Astrophys. Fluid Dyn., vol. 34, 1985, pp. 175–199). Thorpe (Q.J.R. Meteorol. Soc., vol. 128, 2002, pp. 1529–1542) noted that these dynamics may be prevalent in the atmosphere, and they were recently identified in atmospheric observations at high altitudes. Tube and knot dynamics were found by Fritts et al. (J. Fluid. Mech., 2022) to drive stronger and faster turbulence transitions than secondary instabilities of individual KH billows. Results presented here reveal that KHI tube and knot dynamics also yield energy dissipation rates $\sim$2–4 times larger as turbulence arises and that remain $\sim$2–3 times larger to later stages of the flow evolution, compared with those of secondary convective instabilities (CI) and secondary KHI accompanying KH billows without tube and knot influences. Elevated energy dissipation rates occur due to turbulence transitions by tube and knot dynamics arising on much larger scales than secondary CI and KHI where initial KH billows are misaligned. Tube and knot dynamics also excite large-scale Kelvin ‘twist waves’ that cause vortex tube and billow core fragmentation, more energetic cascades of similar interactions to smaller scales and account for the strongest energy dissipation events accompanying such KH billow evolutions.
RATIONALE:Hyperglycemia -induced reactive oxygen species are key mediators of cardiac dysfunction. JunD (Jund proto-oncogene subunit), a member of the AP-1 (activator protein-1) family of ...transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to redox state and inflammation in the diabetic heart remains to be elucidated.
OBJECTIVE:The present study investigates the role of JunD in hyperglycemia-induced and reactive oxygen species–driven myocardial dysfunction.
METHODS AND RESULTS:JunD mRNA and protein expression were reduced in the myocardium of mice with streptozotocin-induced diabetes mellitus as compared to controls. JunD downregulation was associated with oxidative stress and left ventricular dysfunction assessed by electron spin resonance spectroscopy as well as conventional and 2-dimensional speckle-tracking echocardiography. Furthermore, myocardial expression of free radical scavenger superoxide dismutase 1 and aldehyde dehydrogenase 2 was reduced, whereas the NOX2 (NADPH nicotinamide adenine dinucleotide phosphatase oxidase subunit 2) and NOX4 (NADPH nicotinamide adenine dinucleotide phosphatase oxidase subunit 4) were upregulated. The redox changes were associated with increased NF-κB (nuclear factor kappa B) binding activity and expression of inflammatory mediators. Interestingly, mice with cardiac-specific overexpression of JunD via the α MHC (α- myosin heavy chain) promoter (α MHC JunD) were protected against hyperglycemia-induced cardiac dysfunction. We also showed that JunD was epigenetically regulated by promoter hypermethylation, post-translational modification of histone marks, and translational repression by miRNA (microRNA)-673/menin. Reduced JunD mRNA and protein expression were confirmed in left ventricular specimens obtained from patients with type 2 diabetes mellitus as compared to nondiabetic subjects.
CONCLUSIONS:Here, we show that a complex epigenetic machinery involving DNA methylation, histone modifications, and microRNAs mediates hyperglycemia-induced JunD downregulation and myocardial dysfunction in experimental and human diabetes mellitus. Our results pave the way for tissue-specific therapeutic modulation of JunD to prevent diabetic cardiomyopathy.
Highlights ► Complex locomotor tasks are executed by activation impulses acting on motor modules. ► Consistent inter-subject strategies were found for motor modules. ► External work in cutting ...manoeuvres is related to timing of motor module activation.
We document the ability of the new-generation Oslo
chemistry-transport model, Oslo CTM3, to accurately simulate present-day
aerosol distributions. The model is then used with the new Community ...Emission
Data System (CEDS) historical emission inventory to provide updated time
series of anthropogenic aerosol concentrations and consequent direct
radiative forcing (RFari) from 1750 to 2014. Overall, Oslo CTM3 performs well compared with measurements of surface
concentrations and remotely sensed aerosol optical depth. Concentrations are
underestimated in Asia, but the higher emissions in CEDS than previous
inventories result in improvements compared to observations. The treatment
of black carbon (BC) scavenging in Oslo CTM3 gives better agreement with
observed vertical BC profiles relative to the predecessor Oslo CTM2. However,
Arctic wintertime BC concentrations remain underestimated, and a range of
sensitivity tests indicate that better physical understanding of processes
associated with atmospheric BC processing is required to simultaneously
reproduce both the observed features. Uncertainties in model input data,
resolution, and scavenging affect the distribution of all aerosols species,
especially at high latitudes and altitudes. However, we find no evidence of
consistently better model performance across all observables and regions in
the sensitivity tests than in the baseline configuration. Using CEDS, we estimate a net RFari in 2014 relative to 1750 of
−0.17 W m−2, significantly weaker than the IPCC AR5 2011–1750
estimate. Differences are attributable to several factors, including stronger
absorption by organic aerosol, updated parameterization of BC absorption, and
reduced sulfate cooling. The trend towards a weaker RFari over recent years
is more pronounced than in the IPCC AR5, illustrating the importance of
capturing recent regional emission changes.
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