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 β 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

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

Mechanistic underpinning of an inside–out 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 naïve, specific‐pathogen‐free bred rodents support an exogenous trigger, such as an infection. The validity of this outside–in 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 well‐validated non‐human 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 inside–out pathogenic concept for multiple sclerosis. They also provide a plausible sequence of events reminiscent of Wilkin’s 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 axon–myelin units potentially causes the excess systemic release of post‐translationally 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 hyper‐react to post‐translationally modified (citrullinated) myelin–oligodendrocyte glycoprotein and evoke clinical and pathological aspects of multiple sclerosis

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 lifetime’s 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 Bruce’s 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 Bruce’s initial publications. Thus, a lifetime spent investigating K+ buffering has seen enormous advances in glial research, from the time cells were identified as ‘presumed’ glial cells or ‘silent cells’, 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