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"Murphy, Matthew"
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MR elastography of the brain and its application in neurological diseases
Magnetic resonance elastography (MRE) is an imaging technique for noninvasively and quantitatively assessing tissue stiffness, akin to palpation. MRE is further able assess the mechanical properties of tissues that cannot be reached by hand including the brain. The technique is a three-step process beginning with the introduction of shear waves into the tissue of interest by applying an external vibration. Next, the resulting motion is imaged using a phase-contrast MR pulse sequence with motion encoding gradients that are synchronized to the vibration. Finally, the measured displacement images are mathematically inverted to compute a map of the estimated stiffness. In the brain, the technique has demonstrated strong test-retest repeatability with typical errors of 1% for measuring global stiffness, 2% for measuring stiffness in the lobes of the brain, and 3–7% for measuring stiffness in subcortical gray matter. In healthy volunteers, multiple studies have confirmed that stiffness decreases with age, while more recent studies have demonstrated a strong relationship between viscoelasticity and behavioral performance. Furthermore, several studies have demonstrated the sensitivity of brain stiffness to neurodegeneration, as stiffness has been shown to decrease in multiple sclerosis and in several forms of dementia. Moreover, the spatial pattern of stiffness changes varies among these different classes of dementia. Finally, MRE is a promising tool for the preoperative assessment of intracranial tumors, as it can measure both tumor consistency and adherence to surrounding tissues. These factors are important predictors of surgical difficulty. In brief, MRE demonstrates potential value in a number of neurological diseases. However, significant opportunity remains to further refine the technique and better understand the underlying physiology.
•Magnetic resonance elastography (MRE) noninvasively measures tissue stiffness.•MRE can reliably measure global and regional stiffness in the brain in vivo.•Brain stiffness is sensitive to physiological and pathological processes.•Intracranial MRE can be used for preoperative assessment of tumors.•Further work is needed to refine technique and better understand biological basis.
Journal Article
Leadership 2050 : critical challenges, key contexts, and emerging trends
What kind of leaders will the world need over the next thirty-five years? How will our knowledge of leadership, leadership development, and leadership education change? 'Leadership 2050' examines the issues, drivers, and contexts that will most likely influence leaders in the coming decades.
Book
Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine
Mesenchymal stem cells (MSCs) are partially defined by their ability to differentiate into tissues including bone, cartilage and adipose
in vitro
, but it is their trophic, paracrine and immunomodulatory functions that may have the greatest therapeutic impact
in vivo
. Unlike pharmaceutical treatments that deliver a single agent at a specific dose, MSCs are site regulated and secrete bioactive factors and signals at variable concentrations in response to local microenvironmental cues. Significant progress has been made in understanding the biochemical and metabolic mechanisms and feedback associated with MSC response. The anti-inflammatory and immunomodulatory capacity of MSC may be paramount in the restoration of localized or systemic conditions for normal healing and tissue regeneration. Allogeneic MSC treatments, categorized as a drug by regulatory agencies, have been widely pursued, but new studies demonstrate the efficacy of autologous MSC therapies, even for individuals affected by a disease state. Safety and regulatory concerns surrounding allogeneic cell preparations make autologous and minimally manipulated cell therapies an attractive option for many regenerative, anti-inflammatory and autoimmune applications.
Stem cells: Tailor-made regeneration
A review of ongoing research into mesenchymal stem cells (MSCs) highlights their promise as a tool for treating injury and disease. MSCs are found in perivascular reservoirs throughout the body where they exhibit many therapeutically useful characteristics. Arnold Caplan from Case Western Reserve University and colleagues examine basic and clinical research into MSCs from the past few decades. Several studies indicate that these cells directly help to repair bones, but also secrete various regulatory factors that modulate immune system function and stimulate other cells to grow, and their potential as a treatment for autoimmune and neurological disease is assessed. Although MSC therapies appear to be safe, determining the scope of their efficacy and identifying optimal MSC subpopulations for clinical use will require further research.
Journal Article
Non-Stationarity in the “Resting Brain’s” Modular Architecture
Task-free functional magnetic resonance imaging (TF-fMRI) has great potential for advancing the understanding and treatment of neurologic illness. However, as with all measures of neural activity, variability is a hallmark of intrinsic connectivity networks (ICNs) identified by TF-fMRI. This variability has hampered efforts to define a robust metric of connectivity suitable as a biomarker for neurologic illness. We hypothesized that some of this variability rather than representing noise in the measurement process, is related to a fundamental feature of connectivity within ICNs, which is their non-stationary nature. To test this hypothesis, we used a large (n = 892) population-based sample of older subjects to construct a well characterized atlas of 68 functional regions, which were categorized based on independent component analysis network of origin, anatomical locations, and a functional meta-analysis. These regions were then used to construct dynamic graphical representations of brain connectivity within a sliding time window for each subject. This allowed us to demonstrate the non-stationary nature of the brain's modular organization and assign each region to a \"meta-modular\" group. Using this grouping, we then compared dwell time in strong sub-network configurations of the default mode network (DMN) between 28 subjects with Alzheimer's dementia and 56 cognitively normal elderly subjects matched 1:2 on age, gender, and education. We found that differences in connectivity we and others have previously observed in Alzheimer's disease can be explained by differences in dwell time in DMN sub-network configurations, rather than steady state connectivity magnitude. DMN dwell time in specific modular configurations may also underlie the TF-fMRI findings that have been described in mild cognitive impairment and cognitively normal subjects who are at risk for Alzheimer's dementia.
Journal Article
HST Transmission Spectra of the Hot Neptune HD 219666 b: Detection of Water and the Challenge of Constraining Both Water and Methane
Although Neptunian-sized (2–5 R⊕) planets appear to be extremely common in the Galaxy, many mysteries remain about their overall nature. To date, only 11 Neptunian-sized planets have had their atmospheres spectroscopically characterized, and these observations hint at interesting diversity within this class of planets. Much of our understanding of these worlds and others derive from transmission spectroscopy with the Hubble Space Telescope’s Wide Field Camera 3 (HST/WFC3). One key outcome of HST/WFC3 observations has been the consistent detection of water but no methane in Neptunian atmospheres, though recent James Webb Space Telescope (JWST) observations are potentially starting to overturn this “missing methane” paradigm. In this work, we present the transmission spectrum of the hot Neptune HD 219666 b from 1.1 to 1.6 μm from two transit observations using HST/WFC3 G141. Our fiducial atmospheric retrieval detects water at ∼3σ in HD 219666 b’s atmosphere and prefers no contribution from methane, similar to these previous observations of other planets. Motivated by recent detections of methane in Neptunian atmospheres by JWST, we explore additional models and find that a methane-only scenario could adequately fit the data, though it is not preferred and likely unphysical. We discuss the impact of this methane detection challenge on our understanding of planetary atmospheres based on HST/WFC3 observations alone, and where JWST observations offer a solution.
Journal Article
An Analytic Characterization of the Limb Asymmetry—Transit Time Degeneracy
Atmospheres are not spatially homogeneous. This is particularly true for hot, tidally locked exoplanets with large day-to-night temperature variations, which can yield significant differences between the morning and evening terminators—known as limb asymmetry. Current transit observations with the James Webb Space Telescope (JWST) are precise enough to disentangle the separate contributions of these morning and evening limbs to the overall transmission spectrum in certain circumstances. However, the signature of limb asymmetry in a transit light curve is highly degenerate with uncertainty in the planet’s time of conjunction. This raises the question of how precisely transit times must be measured to enable accurate studies of limb asymmetry, in particular with JWST. Although this degeneracy has been discussed in the literature, a general description of it has not been presented. In this work, we show how this degeneracy results from apparent changes in the transit contact times when the planetary disk has asymmetric limb sizes. We derive a general formula relating the magnitude of limb asymmetry to the amount by which it would cause the apparent time of conjunction to vary, which can reach tens of seconds. Comparing our formula to simulated observations, we find that numerical fitting techniques add additional bias to the measured time, of generally less than a second, resulting from the occultation geometry. We also derive an analytical formula for this extra numerical bias. These formulae can be applied to planning new observations or interpreting literature measurements, and we show examples for commonly studied exoplanets.
Journal Article
Aged skeletal stem cells generate an inflammatory degenerative niche
Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts
1
. Here we show that intrinsic ageing of skeletal stem cells (SSCs)
2
in mice alters signalling in the bone marrow niche and skews the differentiation of bone and blood lineages, leading to fragile bones that regenerate poorly. Functionally, aged SSCs have a decreased bone- and cartilage-forming potential but produce more stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell RNA-sequencing studies link the functional loss to a diminished transcriptomic diversity of SSCs in aged mice, which thereby contributes to the transformation of the bone marrow niche. Exposure to a youthful circulation through heterochronic parabiosis or systemic reconstitution with young haematopoietic stem cells did not reverse the diminished osteochondrogenic activity of aged SSCs, or improve bone mass or skeletal healing parameters in aged mice. Conversely, the aged SSC lineage promoted osteoclastic activity and myeloid skewing by haematopoietic stem and progenitor cells, suggesting that the ageing of SSCs is a driver of haematopoietic ageing. Deficient bone regeneration in aged mice could only be returned to youthful levels by applying a combinatorial treatment of BMP2 and a CSF1 antagonist locally to fractures, which reactivated aged SSCs and simultaneously ablated the inflammatory, pro-osteoclastic milieu. Our findings provide mechanistic insights into the complex, multifactorial mechanisms that underlie skeletal ageing and offer prospects for rejuvenating the aged skeletal system.
An analysis of skeletal stem cells in mice reveals that bone ageing occurs at the level of local niches affecting skeletal and haematopoietic lineage output, which may influence systemic aspects of multi-organ physiological ageing.
Journal Article
Articular cartilage regeneration by activated skeletal stem cells
Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage
1
. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation
2
–
4
. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis
5
–
7
. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA.
Endogenous skeletal stem cells are recruited to form cartilage in mice when stimulated by microfracture surgery together with localized delivery of growth factors, pointing to a new approach for treating cartilage defects.
Journal Article
A high internal heat flux and large core in a warm Neptune exoplanet
Interactions between exoplanetary atmospheres and internal properties have long been proposed to be drivers of the inflation mechanisms of gaseous planets and apparent atmospheric chemical disequilibrium conditions
1
. However, transmission spectra of exoplanets have been limited in their ability to observationally confirm these theories owing to the limited wavelength coverage of the Hubble Space Telescope (HST) and inferences of single molecules, mostly H
2
O (ref.
2
). In this work, we present the panchromatic transmission spectrum of the approximately 750 K, low-density, Neptune-sized exoplanet WASP-107b using a combination of HST Wide Field Camera 3 (WFC3) and JWST Near-Infrared Camera (NIRCam) and Mid-Infrared Instrument (MIRI). From this spectrum, we detect spectroscopic features resulting from H
2
O (21
σ
), CH
4
(5
σ
), CO (7
σ
), CO
2
(29
σ
), SO
2
(9
σ
) and NH
3
(6
σ
). The presence of these molecules enables constraints on the atmospheric metal enrichment (M/H is 10–18× solar
3
), vertical mixing strength (log
10
K
z
z
= 8.4–9.0 cm
2
s
−1
) and internal temperature (>345 K). The high internal temperature is suggestive of tidally driven inflation
4
acting on a Neptune-like internal structure, which can naturally explain the large radius and low density of the planet. These findings suggest that eccentricity-driven tidal heating is a critical process governing atmospheric chemistry and interior-structure inferences for most of the cool (<1,000 K) super-Earth-to-Saturn-mass exoplanet population.
Analysis of the panchromatic transmission spectrum of the warm, low-density, Neptune-sized exoplanet WASP-107b from instruments aboard the HST and JWST suggests that tidal interaction with its host star led to changes in its atmospheric chemistry.
Journal Article