257 research outputs found
Quantitative detection of grey and white matter amyloid pathology using a combination of K114 and CRANAD-3 fluorescence
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that exacts a huge toll on the patient, the healthcare system and society in general. Abundance and morphology of protein aggregates such as amyloid ÎČ plaques and tau tangles, along with cortical atrophy and gliosis are used as measures to assess the changes in the brain induced by the disease. Not all of these parameters have a direct correlation with cognitive decline. Studies have shown that only particular protein conformers can be the main drivers of disease progression, and conventional approaches are unable to distinguish different conformations of disease-relevant proteins. METHODS AND RESULTS: Using the fluorescent amyloid probes K114 and CRANAD-3 and spectral confocal microscopy, we examined formalin-fixed paraffin-embedded brain samples from different control and AD cases. Based on the emission spectra of the probes used in this study, we found that certain spectral signatures can be correlated with different aggregates formed by different proteins. The combination of spectral imaging and advanced image analysis tools allowed us to detect variability of protein deposits across the samples. CONCLUSION: Our proposed method offers a quicker and easier neuropathological assessment of tissue samples, as well as introducing an additional parameter by which protein aggregates can be discriminated
Nonbacterial Thrombotic Mitral Valve Endocarditis Presenting as Embolic Stroke in a Young Patient with Lupus and Anti-phospholipid Syndrome
A 37-year-old man on systemic immunosuppression for clinically and biochemically quiescent lupus nephritis, presented with left hemiparesis. Brain MRI was concerning for right sided embolic stroke. Workup was negative for atrial fibrillation, deep venous thrombosis, and heart failure. Transesophageal echocardiogram was remarkable for fixed mitral valve leaflet echodensities. In the absence of bacteremia and systemic signs of infection, and with a history of lupus, small vegetations on atrial and ventricular sides of mitral valve leaflets are suggestive of nonbacterial thrombotic endocarditis. Nonbacterial thrombotic vegetations are composed of fibrin deposits on otherwise-healthy valves. Mainstay of treatment is therapeutic anticoagulation with clinical and echocardiographic surveillance for moderate-severe mitral regurgitation
Mechanistic underpinning of an insideâout concept for autoimmunity in multiple sclerosis
The neuroinflammatory disease multiple sclerosis is driven by autoimmune pathology in the central nervous system. However, the trigger of the autoimmune pathogenic process is unknown. MS models in immunologically naĂŻve, specificâpathogenâfree bred rodents support an exogenous trigger, such as an infection. The validity of this outsideâin pathogenic concept for MS has been frequently challenged by the difficulty to translate pathogenic concepts developed in these models into effective therapies for the MS patient. Studies in wellâvalidated nonâhuman primate multiple sclerosis models where, just like in humans, the autoimmune pathogenic process develops from an experienced immune system trained by prior infections, rather support an endogenous trigger. Data reviewed here corroborate the validity of this insideâout pathogenic concept for multiple sclerosis. They also provide a plausible sequence of events reminiscent of Wilkinâs primary lesion theory: (i) that autoimmunity is a physiological response of the immune system against excess antigen turnover in diseased tissue (the primary lesion) and (ii) that individuals developing autoimmune disease are (genetically predisposed) high responders against critical antigens. Data obtained in multiple sclerosis brains reveal the presence in normally appearing white matter of myelinated axons where myelin sheaths have locally dissociated from their enwrapped axon (i.e., blistering). The ensuing disintegration of axonâmyelin units potentially causes the excess systemic release of postâtranslationally modified myelin. Data obtained in a unique primate multiple sclerosis model revealed a core pathogenic role of T cells present in the normal repertoire, which hyperâreact to postâtranslationally modified (citrullinated) myelinâoligodendrocyte glycoprotein and evoke clinical and pathological aspects of multiple sclerosis
EC 11481-2303 - A Peculiar Subdwarf OB Star Revisited
EC 11481-2303 is a peculiar, hot, high-gravity pre-white dwarf. Previous
optical spectroscopy revealed that it is a sdOB star with an effective
temperature (Teff) of 41790 K, a surface gravity log(g)= 5.84, and He/H = 0.014
by number. We present an on-going spectral analysis by means of non-LTE
model-atmosphere techniques based on high-resolution, high-S/N optical
(VLT-UVES) and ultraviolet (FUSE, IUE) observations. We are able to reproduce
the optical and UV observations simultaneously with a chemically homogeneous
NLTE model atmosphere with a significantly higher effective temperature and
lower He abundance (Teff = 55000 K, log (g) = 5.8, and He / H = 0.0025 by
number). While C, N, and O appear less than 0.15 times solar, the iron-group
abundance is strongly enhanced by at least a factor of ten.Comment: 8 pages, 11 figure
A Transiting Planet of a Sun-like Star
A planet transits an 11th magnitude, G1V star in the constellation Corona
Borealis. We designate the planet XO-1b, and the star, XO-1, also known as GSC
02041-01657. XO-1 lacks a trigonometric distance; we estimate it to be 200+-20
pc. Of the ten stars currently known to host extrasolar transiting planets, the
star XO-1 is the most similar to the Sun in its physical characteristics: its
radius is 1.0+-0.08 R_Sun, its mass is 1.0+-0.03 M_Sun, V sini < 3 km/s, and
its metallicity [Fe/H] is 0.015+-0.04. The orbital period of the planet XO-1b
is 3.941534+-0.000027 days, one of the longer ones known. The planetary mass is
0.90+-0.07 M_Jupiter, which is marginally larger than that of other transiting
planets with periods between 3 and 4 days. Both the planetary radius and the
inclination are functions of the spectroscopically determined stellar radius.
If the stellar radius is 1.0+-0.08 R_Sun, then the planetary radius is
1.30+-0.11 R_Jupiter and the inclination of the orbit is 87.7+-1.2 degrees. We
have demonstrated a productive international collaboration between professional
and amateur astronomers that was important to distinguishing this planet from
many other similar candidates.Comment: 31 pages, 9 figures, accepted for part 1 of Ap
A T-type channel-calmodulin complex triggers αCaMKII activation
Abstract Calmodulin (CaM) is an important signaling molecule that regulates a vast array of cellular functions by activating second messengers involved in cell function and plasticity. Low voltage-activated calcium channels of the Cav3 family have the important role of mediating low threshold calcium influx, but were not believed to interact with CaM. We find a constitutive association between CaM and the Cav3.1 channel at rest that is lost through an activity-dependent and Cav3.1 calcium-dependent CaM dissociation. Moreover, Cav3 calcium influx is sufficient to activate αCaMKII in the cytoplasm in a manner that depends on an intact Cav3.1 C-terminus needed to support the CaM interaction. Our findings thus establish that T-type channel calcium influx invokes a novel dynamic interaction between CaM and Cav3.1 channels to trigger a signaling cascade that leads to αCaMKII activation
XO-2b: Transiting Hot Jupiter in a Metal-rich Common Proper Motion Binary
We report on a V=11.2 early K dwarf, XO-2 (GSC 03413-00005), that hosts a
Rp=0.98+0.03/-0.01 Rjup, Mp=0.57+/-0.06 Mjup transiting extrasolar planet,
XO-2b, with an orbital period of 2.615857+/-0.000005 days. XO-2 has high
metallicity, [Fe/H]=0.45+/-0.02, high proper motion, mu_tot=157 mas/yr, and has
a common proper motion stellar companion with 31" separation. The two stars are
nearly identical twins, with very similar spectra and apparent magnitudes. Due
to the high metallicity, these early K dwarf stars have a mass and radius close
to solar, Ms=0.98+/-0.02 Msolar and Rs=0.97+0.02/-0.01 Rsolar. The high proper
motion of XO-2 results from an eccentric orbit (Galactic pericenter, Rper<4
kpc) well confined to the Galactic disk (Zmax~100 pc). In addition, the phase
space position of XO-2 is near the Hercules dynamical stream, which points to
an origin of XO-2 in the metal-rich, inner Thin Disk and subsequent dynamical
scattering into the solar neighborhood. We describe an efficient Markov Chain
Monte Carlo algorithm for calculating the Bayesian posterior probability of the
system parameters from a transit light curve.Comment: 14 pages, 10 Figures, Accepted in ApJ. Negligible changes to XO-2
system properties. Removed Chi^2 light curve analysis section, and simplified
MCMC light curve analysis discussio
Hot subdwarfs from the ESO Supernova Ia Progenitor Survey: II. Atmospheric parameters of subdwarf O stars
We address the origin and evolutionary status of hot subdwarf stars by
studying the optical spectral properties of 58 subdwarf O (sdO) stars.
Combining them with the results of our previously studied subdwarf B (sdB)
stars, we aim at investigating possible evolutionary links. We analyze
high-resolution ESO VLT UVES spectra from the ESO Supernova Ia Progenitor
Survey (SPY). Effective temperatures, gravities, and helium abundances are
determined simultaneously by fitting the profiles of H and He lines using
dedicated synthetic spectra in NLTE. Evidence for cool companions to 8 sdOs as
well as a binary consisting of two sdO stars is found. A correlation between He
abundances and the presence of carbon and/or nitrogen lines emerges: below
solar He abundance, no sdO shows C or N lines. In contrast, C and/or N lines
are present in ALL sdOs with super- solar He abundance. We thus use the solar
He abundance to divide our sample into He-deficient and He-enriched sdOs. While
He-deficient sdOs are scattered in a wide range of the Teff-log(g)-diagram,
most of the He-enriched sdOs cluster in a narrow region at Teff = 40,000 ...
50,000K and log(g)=5.5 ... 6.0. An evolu- tionary link between sdBs and sdOs
appears plausible only for the He-deficient sdOs indicating that they are the
likely successors to sdBs. The properties of He-enriched sdOs cannot be
explained with canonical single star evolutionary models. Alternative scenarios
(late hot flasher) as well as for binary evolution (white dwarf merger;
post-RGB evolution) are tested. While we regard the post-RGB scenario as
inappropriate, the white dwarf merger and the late hot flasher scenarios remain
viable to explain the origin of He-enriched sdOs.Comment: 14 pages, 10 figures, Astronomy & Astrophysics accepte
A lifetimeâs adventure in extracellular K+ regulation: the Scottish connection
In a career that has spanned 45 years and shows no signs of slowing down, Dr Bruce Ransom has devoted considerable time and energy to studying regulation of interstitial K+. When Bruce commenced his studies in 1969 virtually nothing was known of the functions of glial cells, but Bruceâs research contributed to the physiological assignation of function to mammalian astrocytes, namely interstitial K+ buffering. The experiments that I describe in this review concern the response of the membrane potential (Em) of in vivo cat cortical astrocytes to changes in [K+]o, an experimental manoeuvre that was achieved in two different ways. The first involved recording the Em of an astrocyte while the initial aCSF was switched to one with different K+, whereas in the second series of experiments the cortex was stimulated and the response of the astrocyte Em to the K+ released from neighbouring neurons was recorded. The astrocytes responded in a qualitatively predictable manner, but quantitatively the changes were not as predicted by the Nernst equation. Elevations in interstitial K+ are not sustained and K+ returns to baseline rapidly due to the buffering capacity of astrocytes, a phenomenon studied by Bruce, and his son Chris, published 27 years after Bruceâs initial publications. Thus, a lifetime spent investigating K+ buffering has seen enormous advances in glial research, from the time cells were identified as âpresumedâ glial cells or âsilent cellsâ, to the present day, where glial cells are recognised as contributing to every important physiological brain function
Reverse Translation for Assessment of Confidence in Animal Models of Multiple Sclerosis for Drug Discovery
The poor predictive quality of currently used animal models in preclinical research is an important cause of the high attrition of promising drug candidates for human autoimmune disease in clinical trials. Examples from own work in a primate multiple sclerosis (MS) model illustrate that important lessons can be learned from a critical reassessment of failed drugs in the animal model, which can help improve the animal model and better understand the targeted disease
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