111 research outputs found
US Real Estate Investment Performance: 1983-2012
This study provides an overview of real estate investment performance over a 1983-2012 time period. The results show that although equity REITs outperformed all other assets on average annual return, on a risk-adjusted basis both private retail and apartment real estate outperformed all other assets. The study also found a recent trend in increased correlation between common stocks and REITs
Mechanisms Of Intrinsic Epileptogenesis In Human Gelastic Seizures With Hypothalamic Hamartoma
Human hypothalamic hamartoma (HH) is a rare developmental malformation often characterized by gelastic seizures, which are refractory to medical therapy. Ictal EEG recordings from the HH have demonstrated that the epileptic source of gelastic seizures lies within the HH lesion itself. Recent advances in surgical techniques targeting HH have led to dramatic improvements in seizure control, which further supports the hypothesis that gelastic seizures originate within the HH. However, the basic cellular and molecular mechanisms of epileptogenesis in this subcortical lesion are poorly understood. Since 2003, Barrow Neurological Institute has maintained a multidisciplinary clinical program to evaluate and treat patients with HH. This program has provided a unique opportunity to investigate the basic mechanisms of epileptogenesis using surgically resected HH tissue. The first report on the electrophysiological properties of HH neurons was published in 2005. Since then, ongoing research has provided additional insights into the mechanisms by which HH generate seizure activity. In this review, we summarize this progress and propose a cellular model that suggests that GABA-mediated excitation contributes to epileptogenesis in HH lesions
Gap Junctions Contribute To Ictal/Interictal Genesis In Human Hypothalamic Hamartomas
Human hypothalamic hamartoma (HH) is a rare subcortical lesion associated with treatment-resistant epilepsy. Cellular mechanisms responsible for epileptogenesis are unknown. We hypothesized that neuronal gap junctions contribute to epileptogenesis through synchronous activity within the neuron networks in HH tissue. We studied surgically resected HH tissue with Western-blot analysis, immunohistochemistry, electron microscopy, biocytin microinjection of recorded HH neurons, and microelectrode patch clamp recordings with and without pharmacological blockade of gap junctions. Normal human hypothalamus tissue was used as a control. Western blots showed increased expression of both connexin-36 (Cx36) and connexin-43 (Cx43) in HH tissue compared with normal human mammillary body tissue. Immunohistochemistry demonstrated that Cx36 and Cx43 are expressed in HH tissue, but Cx36 was mainly expressed within neuron clusters while Cx43 was mainly expressed outside of neuron clusters. Gap-junction profiles were observed between small HH neurons with electron microscopy. Biocytin injection into single recorded small HH neurons showed labeling of adjacent neurons, which was not observed in the presence of a neuronal gap-junction blocker, mefloquine. Microelectrode field recordings from freshly resected HH slices demonstrated spontaneous ictal/interictal-like discharges in most slices. Bath-application of gap-junction blockers significantly reduced ictal/interictal-like discharges in a concentration-dependent manner, while not affecting the action-potential firing of small gamma-aminobutyric acid (GABA) neurons observed with whole-cell patch-clamp recordings from the same patient\u27s HH tissue. These results suggest that neuronal gap junctions between small GABAergic HH neurons participate in the genesis of epileptic-like discharges. Blockade of gap junctions may be a new therapeutic strategy for controlling seizure activity in HH patients
Helicobacter pylori-induced inhibition of vascular endothelial cell functions: a role for VacA-dependent nitric oxide reduction
Epidemiological and clinical studies provide compelling support for a causal relationship between Helicobacter pylori infection and endothelial dysfunction, leading to vascular diseases. However, clear biochemical evidence for this association is limited. In the present study, we have conducted a comprehensive investigation of endothelial injury in bovine aortic endothelial cells (BAECs) induced by H. pylori-conditioned medium (HPCM) prepared from H. pylori 60190 [vacuolating cytotoxin A (Vac(+))]. BAECs were treated with either unconditioned media, HPCM (0-25% vol/vol), or Escherichia coli-conditioned media for 24 h, and cell functions were monitored. Vac(+) HPCM significantly decreased BAEC proliferation, tube formation, and migration (by up to 44%, 65%, and 28%, respectively). Posttreatment, we also observed sporadic zonnula occludens-1 immunolocalization along the cell-cell border, and increased BAEC permeability to FD40 Dextran, indicating barrier reduction. These effects were blocked by 5-nitro-2-(3-phenylpropylamino)benzoic acid (VacA inhibitor) and were not observed with conditioned media prepared from either VacA-deleted H. pylori or E. coli. The cellular mechanism mediating these events was also considered. Vac(+) HPCM (but not Vac(-)) reduced nitric oxide (NO) by \u3e50%, whereas S-nitroso-N-acetylpenicillamine, an NO donor, recovered all Vac(+) HPCM-dependent effects on cell functions. We further demonstrated that laminar shear stress, an endothelial NO synthase/NO stimulus in vivo, could also recover the Vac(+) HPCM-induced decreases in BAEC functions. This study shows, for the first time, a significant proatherogenic effect of H. pylori-secreted factors on a range of vascular endothelial dysfunction markers. Specifically, the VacA-dependent reduction in endothelial NO is indicated in these events. The atheroprotective impact of laminar shear stress in this context is also evident
Network-Targeted Approach and Postoperative Resting-State Functional Magnetic Resonance Imaging Are Associated with Seizure Outcome
Objective
Postoperative restingâstate functional magnetic resonance imaging (MRI) in children with intractable epilepsy has not been quantified in relation to seizure outcome. Therefore, its value as a biomarker for epileptogenic pathology is not well understood.
Methods
In a sample of children with intractable epilepsy who underwent prospective restingâstate seizure onset zone (SOZ)âtargeted epilepsy surgery, postoperative restingâstate functional MRI (rsâfMRI) was performed 6 to 12 months later. Graded normalization of the postoperative restingâstate SOZ was compared to seizure outcomes, patient, surgery, and anatomical MRI characteristics.
Results
A total of 64 cases were evaluated. Networkâtargeted surgery, followed by postoperative rsâfMRI normalization was significantly (p < 0.001) correlated with seizure reduction, with a Spearman rank correlation coefficient of 0.83. Of 39 cases with postoperative rsâfMRI SOZ normalization, 38 (97%) became completely seizure free. In contrast, of the 25 cases without complete rsâfMRI SOZ normalization, only 3 (5%) became seizure free. The accuracy of rsâfMRI as a biomarker predicting seizure freedom is 94%, with 96% sensitivity and 93% specificity.
Interpretation
Among seizure localization techniques in pediatric epilepsy, networkâtargeted surgery, followed by postoperative rsâfMRI normalization, has high correlation with seizure freedom. This study shows that rsâfMRI SOZ can be used as a biomarker of the epileptogenic zone, and postoperative rsâfMRI normalization is a biomarker for SOZ quiescence
Recommendation of short tandem repeat profiling for authenticating human cell lines, stem cells, and tissues
Cell misidentification and cross-contamination have plagued biomedical research for as long as cells have been employed as research tools. Examples of misidentified cell lines continue to surface to this day. Efforts to eradicate the problem by raising awareness of the issue and by asking scientists voluntarily to take appropriate actions have not been successful. Unambiguous cell authentication is an essential step in the scientific process and should be an inherent consideration during peer review of papers submitted for publication or during review of grants submitted for funding. In order to facilitate proper identity testing, accurate, reliable, inexpensive, and standardized methods for authentication of cells and cell lines must be made available. To this end, an international team of scientists is, at this time, preparing a consensus standard on the authentication of human cells using short tandem repeat (STR) profiling. This standard, which will be submitted for review and approval as an American National Standard by the American National Standards Institute, will provide investigators guidance on the use of STR profiling for authenticating human cell lines. Such guidance will include methodological detail on the preparation of the DNA sample, the appropriate numbers and types of loci to be evaluated, and the interpretation and quality control of the results. Associated with the standard itself will be the establishment and maintenance of a public STR profile database under the auspices of the National Center for Biotechnology Information. The consensus standard is anticipated to be adopted by granting agencies and scientific journals as appropriate methodology for authenticating human cell lines, stem cells, and tissues
BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (the BIO-FLARE study): protocol for a non-randomised longitudinal cohort study
Background
Our knowledge of immune-mediated inflammatory disease (IMID) aetiology and pathogenesis has improved greatly over recent years, however, very little is known of the factors that trigger disease relapses (flares), converting diseases from inactive to active states. Focussing on rheumatoid arthritis (RA), the challenge that we will address is why IMIDs remit and relapse. Extrapolating from pathogenetic factors involved in disease initiation, new episodes of inflammation could be triggered by recurrent systemic immune dysregulation or locally by factors within the joint, either of which could be endorsed by overarching epigenetic factors or changes in systemic or localised metabolism.
Methods
The BIO-FLARE study is a non-randomised longitudinal cohort study that aims to enrol 150 patients with RA in remission on a stable dose of non-biologic disease-modifying anti-rheumatic drugs (DMARDs), who consent to discontinue treatment. Participants stop their DMARDs at time 0 and are offered an optional ultrasound-guided synovial biopsy. They are studied intensively, with blood sampling and clinical evaluation at weeks 0, 2, 5, 8, 12 and 24. It is anticipated that 50% of participants will have a disease flare, whilst 50% remain in drug-free remission for the study duration (24âweeks). Flaring participants undergo an ultrasound-guided synovial biopsy before reinstatement of previous treatment. Blood samples will be used to investigate immune cell subsets, their activation status and their cytokine profile, autoantibody profiles and epigenetic profiles. Synovial biopsies will be examined to profile cell lineages and subtypes present at flare. Blood, urine and synovium will be examined to determine metabolic profiles. Taking into account all generated data, multivariate statistical techniques will be employed to develop a model to predict impending flare in RA, highlighting therapeutic pathways and informative biomarkers. Despite initial recruitment to time and target, the SARS-CoV-2 pandemic has impacted significantly, and a decision was taken to close recruitment at 118 participants with complete data.
Discussion
This study aims to investigate the pathogenesis of flare in rheumatoid arthritis, which is a significant knowledge gap in our understanding, addressing a major unmet patient need
Detection of Cosmic Structures using the Bispectrum Phase. II. First Results from Application to Cosmic Reionization Using the Hydrogen Epoch of Reionization Array
Characterizing the epoch of reionization (EoR) at via the
redshifted 21 cm line of neutral Hydrogen (HI) is critical to modern
astrophysics and cosmology, and thus a key science goal of many current and
planned low-frequency radio telescopes. The primary challenge to detecting this
signal is the overwhelmingly bright foreground emission at these frequencies,
placing stringent requirements on the knowledge of the instruments and
inaccuracies in analyses. Results from these experiments have largely been
limited not by thermal sensitivity but by systematics, particularly caused by
the inability to calibrate the instrument to high accuracy. The interferometric
bispectrum phase is immune to antenna-based calibration and errors therein, and
presents an independent alternative to detect the EoR HI fluctuations while
largely avoiding calibration systematics. Here, we provide a demonstration of
this technique on a subset of data from the Hydrogen Epoch of Reionization
Array (HERA) to place approximate constraints on the brightness temperature of
the intergalactic medium (IGM). From this limited data, at we infer
"" upper limits on the IGM brightness temperature to be
"pseudo" mK at "pseudo" Mpc (data-limited)
and "pseudo" mK at "pseudo" Mpc
(noise-limited). The "pseudo" units denote only an approximate and not an exact
correspondence to the actual distance scales and brightness temperatures. By
propagating models in parallel to the data analysis, we confirm that the
dynamic range required to separate the cosmic HI signal from the foregrounds is
similar to that in standard approaches, and the power spectrum of the
bispectrum phase is still data-limited (at dynamic range)
indicating scope for further improvement in sensitivity as the array build-out
continues.Comment: 22 pages, 12 figures (including sub-figures). Published in PhRvD.
Abstract may be slightly abridged compared to the actual manuscript due to
length limitations on arXi
What does an interferometer really measure? Including instrument and data characteristics in the reconstruction of the 21cm power spectrum
Combining the visibilities measured by an interferometer to form a
cosmological power spectrum is a complicated process in which the window
functions play a crucial role. In a delay-based analysis, the mapping between
instrumental space, made of per-baseline delay spectra, and cosmological space
is not a one-to-one relation. Instead, neighbouring modes contribute to the
power measured at one point, with their respective contributions encoded in the
window functions. To better understand the power spectrum measured by an
interferometer, we assess the impact of instrument characteristics and analysis
choices on the estimator by deriving its exact window functions, outside of the
delay approximation. Focusing on HERA as a case study, we find that
observations made with long baselines tend to correspond to enhanced low-k
tails of the window functions, which facilitate foreground leakage outside the
wedge, whilst the choice of bandwidth and frequency taper can help narrow them
down. With the help of simple test cases and more realistic visibility
simulations, we show that, apart from tracing mode mixing, the window functions
can accurately reconstruct the power spectrum estimator of simulated
visibilities. We note that the window functions depend strongly on the
chromaticity of the beam, and less on its spatial structure - a Gaussian
approximation, ignoring side lobes, is sufficient. Finally, we investigate the
potential of asymmetric window functions, down-weighting the contribution of
low-k power to avoid foreground leakage. The window functions presented in this
work correspond to the latest HERA upper limits for the full Phase I data. They
allow an accurate reconstruction of the power spectrum measured by the
instrument and can be used in future analyses to confront theoretical models
and data directly in cylindrical space.Comment: 18 pages, 18 figures, submitted to MNRAS. Comments welcome
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