Probing Chemical Complexity of Amyloid Plaques in Alzheimer's Disease Mice using Hyperspectral Raman Imaging

One of the distinctive pathological features of Alzheimer's disease (AD) is the deposition of amyloid plaques within the brain of affected individuals. These plaques have traditionally been investigated using labeling techniques such as immunohistochemical imaging. However, the use of labeling can disrupt the structural integrity of the molecules being analyzed. Hence, it is imperative to employ label-free imaging methods for noninvasive examination of amyloid deposits in their native form, thereby providing more relevant information pertaining to AD. This study presents compelling evidence that label-free and nondestructive confocal Raman imaging is a highly effective approach for the identification and chemical characterization of amyloid plaques within cortical regions of an arcAβ mouse model of AD. Furthermore, this investigation elucidates how the spatial correlation of Raman signals can be exploited to identify robust Raman marker bands and discern proteins and lipids from amyloid plaques. Finally, this study uncovers the existence of distinct types of amyloid plaques in the arcAβ mouse brain, exhibiting significant disparities in terms of not only shape and size but also molecular composition

Kinematic Effects of Tidal Interaction on Galaxy Rotation Curves

We use self-consistent N-body models, in conjunction with models of test particles moving in galaxy potentials, to explore the initial effects of interactions on the rotation curves of spiral galaxies. Using nearly self-consistent disk/bulge/halo galaxy models (Kuijken & Dubinski 1995), we simulate the first pass of galaxies on nearly parabolic orbits; we vary orbit inclinations, galaxy halo masses and impact parameters. For each simulation, we mimic observed rotation curves of the model galaxies. Transient interaction-induced features of the curves include distinctly rising or falling profiles at large radii and pronounced bumps in the central regions. Remarkably similar features occur in our statistical sample of optical emission-line rotation curves of spiral galaxies in tight pairs and n-tuples.Comment: 9 pages, 2 figures, accepted for publication in ApJ Letter

High-Latitude HI in the Low Surface Brightness Galaxy UGC7321

From the analysis of sensitive HI 21-cm line observations, we find evidence for vertically extended HI emission (|z|<~2.4 kpc) in the edge-on, low surface brightness spiral galaxy UGC7321. Three-dimensional modelling suggests that the HI disk of UGC7321 is both warped and flared, but that neither effect can fully reproduce the spatial distribution and kinematics of the highest z-height gas. We are able to model the high-latitude emission as an additional HI component in the form of a ``thick disk'' or ``halo'' with a FWHM~3.3 kpc. We find tentative evidence that the vertically extended gas declines in rotational velocity as a function of z, although we are unable to completely rule out models with constant V(z). In spite of the low star formation rate of UGC7321, energy from supernovae may be sufficient to sustain this high-latitude gas. However, alternative origins for this material, such as slow, sustained infall, cannot yet be excluded.Comment: to appear in the August 20 Astrophysical Journal; 17 pages; version with full resolution figures available at http://cfa-www.harvard.edu/~lmatthew

Extinctions at 7um and 15um from the ISOGAL survey

The extinction laws at 7um and 15um are derived for more than 120 sightlines in the inner Galactic plane based on the ISOGAL survey data and the near-infrared data from DENIS and 2MASS. The tracers are the ISOGAL point sources with [7]-[15]<0.4 which are RGB tip stars or early AGB stars with moderate mass loss. They have well-defined intrinsic color indices (J-Ks)_0, (Ks-[7])_0 and (Ks-[15])_0. By a linear fitting of the observed color indices Ks-[7] and Ks-[15] to the observed J-Ks, we obtain the ratio between the E(Ks-[7]) and E(Ks-[15]) color excesses and E(J-Ks). We infer the selective extinctions at 7 and 15um in terms of the near-infrared extinction in the Ks band. The distribution of the derived extinctions around 7 micron (A_7) is well represented by a Gaussian function, with the peak at about 0.47A_Ks and ranging from 0.33 to 0.55A_Ks (using the near-infrared extinctions of Rieke & Lebovsky 1985). There is some evidence that A_7/A_Ks may vary significantly depending on the line of sight. The derived selective extinction at 15um suffers uncertainty mainly from the dispersion in the intrinsic color index (Ks-[15])_0 which is affected by dust emission from mass-losing AGB stars. The peak value of A_15 is around 0.40A_Ks.Comment: 21 pages, 6 figures, accepted for publication in Astronomy and Astrophysic

Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson's disease in vivo

BACKGROUND Abnormal alpha-synuclein and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim at visualizing alpha-synuclein inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo . METHODS Fluorescently labelled pyrimidoindole-derivative THK-565 was characterized by using recombinant fibrils and brains from 10-11 months old M83 mice, which subsequently underwent in vivo concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging. The in vivo results were verified against structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 Tesla and scanning transmission X-ray microscopy (STXM) of perfused brains. Brain slice immunofluorescence and Prussian blue staining were further performed to validate the detection of alpha-synuclein inclusions and iron deposition in the brain, respectively. RESULTS THK-565 showed increased fluorescence upon binding to recombinant alpha-synuclein fibrils and alpha-synuclein inclusions in post-mortem brain slices from patients with Parkinson's disease and M83 mice. i.v. administration of THK-565 in M83 mice showed higher cerebral retention at 20 and 40 minutes post-injection by wide-field fluorescence compared to non-transgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe $^{3+}$ form, as evinced by the STXM results. CONCLUSION We demonstrated in vivo mapping of alpha-synuclein by means of non-invasive epifluorescence and vMSOT imaging assisted with a targeted THK-565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo

The Disk and Dark Halo Mass of the Barred Galaxy NGC 4123. II. Fluid-Dynamical Models

We report a dynamical determination of the separate contributions of disk and dark halo masses to the rotation curve of a spiral galaxy. We use fluid-dynamical models of gas flow in the barred galaxy NGC 4123 to constrain the dynamical properties of the galaxy: disk M/L, bar pattern speed, and the central density and scale radius of the dark halo. We derive a realistic barred potential directly from the light distribution. For each model we assume a value of the stellar M/L and a bar pattern speed Omega_p and add a dark halo to fit the rotation curve. We then compute the gas flow velocities with a 2-D gas dynamical code, and compare the model flow patterns to a 2-D velocity field derived from Fabry-Perot observations. The strong shocks and non-circular motions in the observed gas flow require a high stellar M/L and a fast-rotating bar. Models with I-band disk M/L of 2.0 -- 2.5 h_75, or 80 -- 100% of the maximum disk value, are highly favored. The corotation radius of the bar must be <= 1.5 times the bar semi-major axis. These results contradict some recent claimed ``universal'' galaxy disk/halo relations, since NGC 4123 is of modest size (rotation curve maximum 145 km/sec, and V_flat = 130 km/sec) yet is quite disk-dominated. The dark halo of NGC 4123 is less concentrated than favored by current models of dark halos based on cosmological simulations. Since some 30% of bright disk galaxies are strongly barred and have dust lanes indicating shock morphology similar to that of NGC 4123, it is likely that they also have high stellar M/L and low density halos. We suggest that luminous matter dominates inside the optical radius R_25 of high surface brightness disk galaxies.Comment: accepted by ApJ, 20 pages, 11 figures (2 color), uses emulateapj.sty, onecolfloat.st

Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein

PURPOSE: There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils. METHODS: SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aβ)$_{42}$, K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies. RESULTS: We optimized the protocol for the immobilization of Aβ$_{42}$, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson's disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aβ in arcAβ mice, and AT-8/AT-100-positivity in pR5 mice. CONCLUSION: SPR measurements of small molecules binding to Aβ$_{42}$, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies

Gas flow models in the Milky Way embedded bars

The gas distribution and dynamics in the inner Galaxy present many unknowns as the origin of the asymmetry of the longitude-velocity (lv) diagram of the Central Molecular Zone (CMZ). On the other hand, there are recent evidences in the stellar component of the presence of a nuclear bar that could be slightly lopsided. Our goal is to characterize the nuclear bar observed in 2MASS maps and to study the gas dynamics in the inner Milky Way taking into account this secondary bar. We have derived a realistic mass distribution by fitting 2MASS star counts maps with three components (disk, bulge and nuclear bar) and we have simulated the gas dynamics, in the deduced gravitational potential, using a sticky-particles code. Our simulations of the gas dynamics reproduce successfully the main characteristics of the Milky Way for a bulge orientation of 20-35 deg with respect to the Sun-Galactic Center (GC) line and a pattern speed of 30-40 km/s/kpc. In our models the Galactic Molecular Ring (GMR) is not an actual ring but the inner parts of the spiral arms, while the 3-kpc arm and its far side counterpart are lateral arms that contour the bar. Our simulations reproduce, for the first time, the parallelogram shape of the lv-diagram of the CMZ as the gas response to the nuclear bar. This bar should be oriented by an angle of ~60-75 deg with respect to the Sun-GC line and its mass amounts to (2-5.5)10e9 Msun. We show that the observed asymmetry of the CMZ cannot be due to lopsidedness of the nuclear bar as suggested by the 2MASS maps. We do not find clear evidences of lopsidedness in the stellar potential. We propose that the observed asymmetry of the central gas layer can be due to the infalling of gas into the CMZ in the l=1.3-complexComment: 28 pages, 6 tables, 14 figures. To appear in Astronomy and Astrophysic

The Milky Way Bulge: Observed properties and a comparison to external galaxies

The Milky Way bulge offers a unique opportunity to investigate in detail the role that different processes such as dynamical instabilities, hierarchical merging, and dissipational collapse may have played in the history of the Galaxy formation and evolution based on its resolved stellar population properties. Large observation programmes and surveys of the bulge are providing for the first time a look into the global view of the Milky Way bulge that can be compared with the bulges of other galaxies, and be used as a template for detailed comparison with models. The Milky Way has been shown to have a box/peanut (B/P) bulge and recent evidence seems to suggest the presence of an additional spheroidal component. In this review we summarise the global chemical abundances, kinematics and structural properties that allow us to disentangle these multiple components and provide constraints to understand their origin. The investigation of both detailed and global properties of the bulge now provide us with the opportunity to characterise the bulge as observed in models, and to place the mixed component bulge scenario in the general context of external galaxies. When writing this review, we considered the perspectives of researchers working with the Milky Way and researchers working with external galaxies. It is an attempt to approach both communities for a fruitful exchange of ideas.Comment: Review article to appear in "Galactic Bulges", Editors: Laurikainen E., Peletier R., Gadotti D., Springer Publishing. 36 pages, 10 figure

Modelling the inner disc of the Milky Way with manifolds. I - A first step

We study the bar-driven dynamics in the inner part of the Milky Way by using invariant manifolds. This theory has been successfully applied to describe the morphology and kinematics of rings and spirals in external galaxies, and now, for the first time, we apply it to the Milky Way. We compute the orbits confined by the invariant manifolds of the unstable periodic orbits located at the ends of the bar. We discuss whether the COBE/DIRBE bar and the Long bar compose a single bar or two independent bars and perform a number of comparisons which, taken together, argue strongly in favour of the former. More specifically, we favour the possibility that the so-called COBE/DIRBE bar is the boxy/peanut bulge of a bar whose outer thin parts are the so-called Long bar. This possibility is in good agreement both with observations of external galaxies, with orbital structure theory and with simulations. We then analyse in detail the morphology and kinematics given by five representative Galactic potentials. Two have a Ferrers bar, two have a quadrupole bar and the last one a composite bar. We first consider only the COBE/DIRBE bar and then extend it to include the effect of the Long bar. We find that the large-scale structure given by the manifolds describes an inner ring, whose size is similar to the near and far 3-kpc arm, and an outer ring, whose properties resemble those of the Galactic Molecular Ring. We also analyse the kinematics of these two structures, under the different galactic potentials, and find they reproduce the main over-densities found in the galactic longitude-velocity CO diagram. Finally, we consider for what model parameters, the global morphology of the manifolds may reproduce the two outer spiral arms. We conclude that this would necessitate either more massive and more rapidly rotating bars, or including in the potential an extra component describing the spiral arms.Comment: 18 pages, 11 figures, accepted in MNRA