ABSTRACT
We present a determination of the Hubble constant from the joint, free-form analysis of eight strongly, quadruply lensing systems. In the concordance cosmology, we find $H_0{} = ...71.8^{+3.9}_{-3.3}\, \mathrm{km}\, \mathrm{s}^{-1}\, \mathrm{Mpc}^{-1}{}{}$ with a precision of $4.97{{\ \rm per\ cent}}$. This is in agreement with the latest measurements from supernovae Type Ia and Planck observations of the cosmic microwave background. Our precision is lower compared to these and other recent time-delay cosmography determinations, because our modelling strategies reflect the systematic uncertainties of lensing degeneracies. We furthermore are able to find reasonable lensed image reconstructions by constraining to either value of H0 from local and early Universe measurements. This leads us to conclude that current lensing constraints on H0 are not strong enough to break the ‘Hubble tension’ problem of cosmology.
Rapid progress is being made in understanding the roles of the cerebral meninges in the maintenance of normal brain function, in immune surveillance, and as a site of disease. Most basic research on ...the meninges and the neural brain is now done on mice, major attractions being the availability of reporter mice with fluorescent cells, and of a huge range of antibodies useful for immunocytochemistry and the characterization of isolated cells. In addition, two-photon microscopy through the unperforated calvaria allows intravital imaging of the undisturbed meninges with sub-micron resolution. The anatomy of the dorsal meninges of the mouse (and, indeed, of all mammals) differs considerably from that shown in many published diagrams: over cortical convexities, the outer layer, the dura, is usually thicker than the inner layer, the leptomeninx, and both layers are richly vascularized and innervated, and communicate with the lymphatic system. A membrane barrier separates them and, in disease, inflammation can be localized to one layer or the other, so experimentalists must be able to identify the compartment they are studying. Here, we present current knowledge of the functional anatomy of the meninges, particularly as it appears in intravital imaging, and review their role as a gateway between the brain, blood, and lymphatics, drawing on information that is scattered among works on different pathologies.
Outcome following traumatic brain injury (TBI) remains variable, and derangements in cerebral metabolism are a common finding in patients with poor outcome. This review compares our understanding of ...cerebral metabolism in health with derangements seen following TBI.
Ischemia is common within the first 24 h of injury and inconsistently detected by bedside monitoring. Metabolic derangements can also result from tissue hypoxia in the absence of ischemic reductions in blood flow due to microvascular ischemia and mitochondrial dysfunction. Glucose delivery across the injured brain is dependent on blood glucose and regional cerebral blood flow, and is an important contributor to derangements in glucose metabolism. Alternative energy substrates such as lactate, ketone bodies and succinate that may support mitochondrial function, and can be utilized when glucose availability is low, have been studied following TBI but require further investigation.
Mitochondrial dysfunction and the use of alternative energy substrates are potential therapeutic targets, but improved understanding of the causes, impact and significance of metabolic derangements in clinical TBI are needed. Maintaining adequate oxygen and glucose delivery across the injured brain may accelerate the recovery of mitochondrial function and cerebral energy metabolism and remain important management targets.
ABSTRACT
We introduce the star formation and supernova (SN) feedback model of the satin (Simulating AGNs Through ISM with Non-Equilibrium Effects) project to simulate the evolution of the star ...forming multiphase interstellar medium (ISM) of entire disc galaxies. This galaxy-wide implementation of a successful ISM feedback model tested in small box simulations naturally covers an order of magnitude in gas surface density, shear and radial motions. It is implemented in the adaptive mesh refinement code ramses at a peak resolution of 9 pc. New stars are represented by star cluster (sink) particles with individual SN delay times for massive stars. With SN feedback, cooling, and gravity, the galactic ISM develops a three-phase structure. The star formation rates naturally follow observed scaling relations for the local Milky Way gas surface density. SNe drive additional turbulence in the warm (300 < T < 104 K) gas and increase the kinetic energy of the cold gas, cooling out of the warm phase. The majority of the gas leaving the galactic ISM is warm and hot with mass loading factors of 3 ≤ η ≤ 10 up to h = 5 kpc away from the galaxy. While the hot gas is leaving the system, the warm and cold gas falls back onto the disc in a galactic fountain flow. The inclusion of other stellar feedback processes from massive stars seems to be needed to reduce the rate at which stars form at higher surface densities and to increase/decrease the amount of warm/cold gas.
Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly ...understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.
There is significant evidence that brain-infiltrating CD8+ T cells play a central role in the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 ...mice. However, the mechanisms through which they mediate their pathogenic activity during malaria infection remain poorly understood. Utilizing intravital two-photon microscopy combined with detailed ex vivo flow cytometric analysis, we show that brain-infiltrating T cells accumulate within the perivascular spaces of brains of mice infected with both ECM-inducing (P. berghei ANKA) and non-inducing (P. berghei NK65) infections. However, perivascular T cells displayed an arrested behavior specifically during P. berghei ANKA infection, despite the brain-accumulating CD8+ T cells exhibiting comparable activation phenotypes during both infections. We observed T cells forming long-term cognate interactions with CX3CR1-bearing antigen presenting cells within the brains during P. berghei ANKA infection, but abrogation of this interaction by targeted depletion of the APC cells failed to prevent ECM development. Pathogenic CD8+ T cells were found to colocalize with rare apoptotic cells expressing CD31, a marker of endothelial cells, within the brain during ECM. However, cellular apoptosis was a rare event and did not result in loss of cerebral vasculature or correspond with the extensive disruption to its integrity observed during ECM. In summary, our data show that the arrest of T cells in the perivascular compartments of the brain is a unique signature of ECM-inducing malaria infection and implies an important role for this event in the development of the ECM-syndrome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We ...investigated how neuroinflammation relates to the localization of tau and TDP-43 pathology, and to the heterogeneity of clinical disease. We used PET in vivo with (i) 11C-PK-11195, a marker of activated microglia and a proxy index of neuroinflammation; and (ii) 18F-AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and TDP-43-related disease, and which is used as a surrogate marker of non-amyloid-β protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant, 11 with the semantic variant and 10 with the non-fluent variant), 28 of whom underwent both 18F-AV-1451 and 11C-PK-11195 PET, and matched control subjects (14 for 18F-AV-1451 and 15 for 11C-PK-11195). We used a univariate region of interest analysis, a paired correlation analysis of the regional relationship between binding distributions of the two ligands, a principal component analysis of the spatial distributions of binding, and a multivariate analysis of the distribution of binding that explicitly controls for individual differences in ligand affinity for TDP-43 and different tau isoforms. We found significant group-wise differences in 11C-PK-11195 binding between each patient group and controls in frontotemporal regions, in both a regions-of-interest analysis and in the comparison of principal spatial components of binding. 18F-AV-1451 binding was increased in semantic variant primary progressive aphasia compared to controls in the temporal regions, and both semantic variant primary progressive aphasia and behavioural variant frontotemporal dementia differed from controls in the expression of principal spatial components of binding, across temporal and frontotemporal cortex, respectively. There was a strong positive correlation between 11C-PK-11195 and 18F-AV-1451 uptake in all disease groups, across widespread cortical regions. We confirmed this association with post-mortem quantification in 12 brains, demonstrating strong associations between the regional densities of microglia and neuropathology in FTLD-TDP (A), FTLD-TDP (C), and FTLD-Pick's. This was driven by amoeboid (activated) microglia, with no change in the density of ramified (sessile) microglia. The multivariate distribution of 11C-PK-11195 binding related better to clinical heterogeneity than did 18F-AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate classification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.
ABSTRACT
In the coming years, strong gravitational lens discoveries are expected to increase in frequency by two orders of magnitude. Lens-modelling techniques are being developed to prepare for the ...coming massive influx of new lens data, and blind tests of lens reconstruction with simulated data are needed for validation. In this paper, we present a systematic blind study of a sample of 15 simulated strong gravitational lenses from the EAGLE suite of hydrodynamic simulations. We model these lenses with a free-form technique and evaluate reconstructed mass distributions using criteria based on shape, orientation, and lensed image reconstruction. Especially useful is a lensing analogue of the Roche potential in binary star systems, which we call the lensing Roche potential. This we introduce in order to factor out the well-known problem of steepness or mass-sheet degeneracy. Einstein radii are on average well recovered with a relative error of ${\sim }5{{\ \rm per\ cent}}$ for quads and ${\sim }25{{\ \rm per\ cent}}$ for doubles; the position angle of ellipticity is on average also reproduced well up to ±10°, but the reconstructed mass maps tend to be too round and too shallow. It is also easy to reproduce the lensed images, but optimizing on this criterion does not guarantee better reconstruction of the mass distribution.
Semantic dementia, including the semantic variant of primary progressive aphasia (svPPA), is strongly associated with TAR-DNA binding protein 43 (TDP-43) type C pathology. It provides a useful model ...in which to test the specificity of in vivo binding of the putative tau ligand
FAV-1451, which is elevated in frontotemporal lobar degeneration tauopathies.
Seven patients (five with svPPA and two with 'right' semantic dementia) and 12 healthy controls underwent positron emission tomography brain imaging with
FAV-1451. Two independent preprocessing methods were used. For both methods, all patients had clearly elevated binding potential (BP
(non-displaceable binding potential)) in temporal lobes, lateralising according to their clinical syndrome and evident in raw images. Region of interest analyses confirmed that BP
was significantly increased in temporal regions, insula and fusiform gyrus, consistent with those areas known to be most affected in semantic dementia. Hierarchical cluster analysis, based on the distribution of
FAV-1451 binding potential, separated semantic dementia from controls with 86% sensitivity and 100% specificity.
FAV-1451 binds in vivo regions that are likely to contain TDP-43 and not significant tau pathology. While this suggests a non-tau target for
FAV-1451, the pathological regions in semantic dementia do not normally contain significant levels of recently proposed 'off target' binding sites for
FAV-1451, such as neuronal monoamine oxidase or neuromelanin. Postmortem and longitudinal data will be useful to assess the utility of
FAV-1451 to differentiate and track different types of frontotemporal lobar degeneration.
Optimal glycaemic targets in traumatic brain injury (TBI) remain unclear. We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing intensive with ...conventional glycaemic control in TBI requiring admission to an intensive care unit (ICU).
We systematically searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to November 2016. Outcomes of interest included ICU and in-hospital mortality, poor neurological outcome, the incidence of hypoglycaemia and infective complications. Data were analysed by pairwise random effects models with secondary analysis of differing levels of conventional glycaemic control.
Ten RCTs, involving 1066 TBI patients were included. Three studies were conducted exclusively in a TBI population, whereas in seven trials, the TBI population was a sub-cohort of a mixed neurocritical or general ICU population. Glycaemic targets with intensive control ranged from 4.4 to 6.7 mmol/L, while conventional targets aimed to keep glucose levels below thresholds of 8.4-12 mmol/L. Conventional versus intensive control showed no association with ICU or hospital mortality (relative risk (RR) (95% CI) 0.93 (0.68-1.27), P = 0.64 and 1.07 (0.84-1.36), P = 0.62, respectively). The risk of a poor neurological outcome was higher with conventional control (RR (95% CI) = 1.10 (1.001-1.24), P = 0.047). However, severe hypoglycaemia occurred less frequently with conventional control (RR (95% CI) = 0.22 (0.09-0.52), P = 0.001).
This meta-analysis of intensive glycaemic control shows no association with reduced mortality in TBI. Intensive glucose control showed a borderline significant reduction in the risk of poor neurological outcome, but markedly increased the risk of hypoglycaemia. These contradictory findings should motivate further research.
PDF
![[ 18 F]AV-1451 binding in v...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1468-330X_0022-3050/small "[ 18 F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia")
