John R. Deane Jr. (1919--2013) was born with all the advantages a man needs to succeed in a career in the US Army, and he capitalized on his many opportunities in spectacular fashion. The son of one ...of George C. Marshall's closest assistants, Deane graduated from West Point with the first class of World War II and served in combat under the dynamic General Terry de la Mesa Allen Sr. After the war, he led a German espionage unit in operations against the Soviets, personally led the first foot patrol following the course of the Berlin Wall as it was being constructed, participated in the 1965 Dominican Republic intervention, and saw combat in Vietnam. In 1975, he received his fourth star and became commander of the US Army Materiel Development and Readiness Command.
InLessons in Leadership, this exceptional soldier not only discusses working with some of the army's most influential and colorful leaders -- including James M. Gavin, William E. DePuy, William Westmoreland, and Creighton Abrams Jr. -- but also the many junior officers who helped him develop the leadership skills for which he became well known. Throughout, he offers eyewitness accounts of key Cold War--era events as well as wise observations concerning the leadership and management challenges facing the Department of Defense. Ably edited and annotated by Jack C. Mason, Deane's illuminating memoir also features interviews with several of Deane's contemporaries, whose comments and recollections are interspersed to provide depth and context to the narrative.
Galaxies are believed to evolve through merging, which should lead to some hosting multiple supermassive black holes. There are four known triple black hole systems, with the closest black hole pair ...being 2.4 kiloparsecs apart (the third component in this system is at 3 kiloparsecs), which is far from the gravitational sphere of influence (about 100 parsecs for a black hole with mass one billion times that of the Sun). Previous searches for compact black hole systems concluded that they were rare, with the tightest binary system having a separation of 7 parsecs (ref. 10). Here we report observations of a triple black hole system at redshift z = 0.39, with the closest pair separated by about 140 parsecs and significantly more distant from Earth than any other known binary of comparable orbital separation. The effect of the tight pair is to introduce a rotationally symmetric helical modulation on the structure of the large-scale radio jets, which provides a useful way to search for other tight pairs without needing extremely high resolution observations. As we found this tight pair after searching only six galaxies, we conclude that tight pairs are more common than hitherto believed, which is an important observational constraint for low-frequency gravitational wave experiments.
The glymphatic pathway expedites clearance of waste, including soluble amyloid β (Aβ) from the brain. Transport through this pathway is controlled by the brain's arousal level because, during sleep ...or anesthesia, the brain's interstitial space volume expands (compared with wakefulness), resulting in faster waste removal. Humans, as well as animals, exhibit different body postures during sleep, which may also affect waste removal. Therefore, not only the level of consciousness, but also body posture, might affect CSF-interstitial fluid (ISF) exchange efficiency. We used dynamic-contrast-enhanced MRI and kinetic modeling to quantify CSF-ISF exchange rates in anesthetized rodents' brains in supine, prone, or lateral positions. To validate the MRI data and to assess specifically the influence of body posture on clearance of Aβ, we used fluorescence microscopy and radioactive tracers, respectively. The analysis showed that glymphatic transport was most efficient in the lateral position compared with the supine or prone positions. In the prone position, in which the rat's head was in the most upright position (mimicking posture during the awake state), transport was characterized by "retention" of the tracer, slower clearance, and more CSF efflux along larger caliber cervical vessels. The optical imaging and radiotracer studies confirmed that glymphatic transport and Aβ clearance were superior in the lateral and supine positions. We propose that the most popular sleep posture (lateral) has evolved to optimize waste removal during sleep and that posture must be considered in diagnostic imaging procedures developed in the future to assess CSF-ISF transport in humans.
The rodent brain removes waste better during sleep or anesthesia compared with the awake state. Animals exhibit different body posture during the awake and sleep states, which might affect the brain's waste removal efficiency. We investigated the influence of body posture on brainwide transport of inert tracers of anesthetized rodents. The major finding of our study was that waste, including Aβ, removal was most efficient in the lateral position (compared with the prone position), which mimics the natural resting/sleeping position of rodents. Although our finding awaits testing in humans, we speculate that the lateral position during sleep has advantage with regard to the removal of waste products including Aβ, because clinical studies have shown that sleep drives Aβ clearance from the brain.
The main receptors for amyloid-beta peptide (Abeta) transport across the blood-brain barrier (BBB) from brain to blood and blood to brain are low-density lipoprotein receptor related protein-1 (LRP1) ...and receptor for advanced glycation end products (RAGE), respectively. In normal human plasma a soluble form of LRP1 (sLRP1) is a major endogenous brain Abeta 'sinker' that sequesters some 70 to 90 % of plasma Abeta peptides. In Alzheimer's disease (AD), the levels of sLRP1 and its capacity to bind Abeta are reduced which increases free Abeta fraction in plasma. This in turn may increase brain Abeta burden through decreased Abeta efflux and/or increased Abeta influx across the BBB. In Abeta immunotherapy, anti-Abeta antibody sequestration of plasma Abeta enhances the peripheral Abeta 'sink action'. However, in contrast to endogenous sLRP1 which does not penetrate the BBB, some anti-Abeta antibodies may slowly enter the brain which reduces the effectiveness of their sink action and may contribute to neuroinflammation and intracerebral hemorrhage. Anti-Abeta antibody/Abeta immune complexes are rapidly cleared from brain to blood via FcRn (neonatal Fc receptor) across the BBB. In a mouse model of AD, restoring plasma sLRP1 with recombinant LRP-IV cluster reduces brain Abeta burden and improves functional changes in cerebral blood flow (CBF) and behavioral responses, without causing neuroinflammation and/or hemorrhage. The C-terminal sequence of Abeta is required for its direct interaction with sLRP and LRP-IV cluster which is completely blocked by the receptor-associated protein (RAP) that does not directly bind Abeta. Therapies to increase LRP1 expression or reduce RAGE activity at the BBB and/or restore the peripheral Abeta 'sink' action, hold potential to reduce brain Abeta and inflammation, and improve CBF and functional recovery in AD models, and by extension in AD patients.
Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, ...but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.
Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4. APOE4 is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological ...outcome after traumatic brain injury and haemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of Apoe leads to blood-brain barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.
ABSTRACT
We present MeerKAT 1.28 GHz total-intensity, polarization, and spectral-index images covering the giant (projected length l ≈ 1.57 Mpc) X-shaped radio source PKS 2014−55 with an ...unprecedented combination of brightness sensitivity and angular resolution. They show the clear ‘double boomerang’ morphology of hydrodynamical backflows from the straight main jets deflected by the large and oblique hot-gas halo of the host galaxy PGC 064440. The magnetic field orientation in PKS 2014−55 follows the flow lines from the jets through the secondary wings. The radio source is embedded in faint ($T_\mathrm{b} \approx 0.5 \mathrm{\, K}$) cocoons having the uniform brightness temperature and sharp outer edges characteristic of subsonic expansion into the ambient intragroup medium. The position angle of the much smaller (l ∼ 25 kpc) restarted central source is within 5° of the main jets, ruling out models that invoke jet re-orientation or two independent jets. Compression and turbulence in the backflows probably produce the irregular and low polarization bright region behind the apex of each boomerang as well as several features in the flow with bright heads and dark tails.
ABSTRACT
MIGHTEE is a galaxy evolution survey using simultaneous radio continuum, spectropolarimetry, and spectral line observations from the South African MeerKAT telescope. When complete, the ...survey will image ∼20 deg2 over the COSMOS, E-CDFS, ELAIS-S1, and XMM-Newton Large Scale Structure field (XMM-LSS) extragalactic deep fields with a central frequency of 1284 MHz. These were selected based on the extensive multiwavelength data sets from numerous existing and forthcoming observational campaigns. Here, we describe and validate the data processing strategy for the total intensity continuum aspect of MIGHTEE, using a single deep pointing in COSMOS (1.6 deg2) and a three-pointing mosaic in XMM-LSS (3.5 deg2). The processing includes the correction of direction-dependent effects, and results in thermal noise levels below 2 $\mathrm{\mu }$Jy beam−1 in both fields, limited in the central regions by classical confusion at ∼8 arcsec angular resolution, and meeting the survey specifications. We also produce images at ∼5 arcsec resolution that are ∼3 times shallower. The resulting image products form the basis of the Early Science continuum data release for MIGHTEE. From these images we extract catalogues containing 9896 and 20 274 radio components in COSMOS and XMM-LSS, respectively. We also process a close-packed mosaic of 14 additional pointings in COSMOS and use these in conjunction with the Early Science pointing to investigate methods for primary beam correction of broad-band radio images, an analysis that is of relevance to all full-band MeerKAT continuum observations, and wide-field interferometric imaging in general. A public release of the MIGHTEE Early Science continuum data products accompanies this article.
The neurophysiology underlying temporal perception significantly overlaps with areas of dysfunction identified in schizophrenia. Patients commonly exhibit distorted temporal perception, which likely ...contributes to functional impairments. Thus, study of temporal perception in animal models of the disease may help to understand both cognitive and neurobiological factors involved in functional impairments in patients. As maternal immune activation (MIA) has been shown to be a significant etiological risk factor in development of schizophrenia and other developmental psychiatric diseases, we tested interval timing in a rat model of MIA that has previously been shown to recapitulate several behavioural and neurophysiological impairments observed in the disease. Rats were tested on a temporal-bisection task, in which temporal duration stimuli were categorized as either "short" or "long" by responding to a corresponding lever. Data from this task were modeled to provide estimates of accuracy and sensitivity of temporal perception. Parameter estimates derived from the model fitting showed that MIA rats significantly overestimated the passage of time compared to controls. These results indicate that the MIA rat paradigm recapitulates timing distortions that are phenotypical of schizophrenia. These findings lend further support to the epidemiological validity of this MIA rat model, supporting its relevance for future research into the role of maternal immune activation in producing neurobiological and behavioural impairments in schizophrenia.
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