Site-selective protein modification via disulfide rebridging for fast tetrazine/trans-cyclooctene bioconjugation

An inverse electron demand Diels–Alder reaction between tetrazine and trans-cyclooctene (TCO) holds great promise for protein modification and manipulation. Herein, we report the design and synthesis of a tetrazine-based disulfide rebridging reagent, which allows the site-selective installation of a tetrazine group into disulfide-containing peptides and proteins such as the hormone somatostatin (SST) and the antigen binding fragment (Fab) of human immunoglobulin G (IgG). The fast and efficient conjugation of the tetrazine modified proteins with three different TCO-containing substrates to form a set of bioconjugates in a site-selective manner was successfully demonstrated for the first time. Homogeneous, well-defined bioconjugates were obtained underlining the great potential of our method for fast bioconjugation in emerging protein therapeutics. The formed bioconjugates were stable against glutathione and in serum, and they maintained their secondary structure. With this work, we broaden the scope of tetrazine chemistry for site-selective protein modification to prepare well-defined SST and Fab conjugates with preserved structures and good stability under biologically relevant conditions

Cosmological Evolution of Supergiant Star-Forming Clouds

In an exploration of the birthplaces of globular clusters, we present a careful examination of the formation of self-gravitating gas clouds within assembling dark matter haloes in a hierarchical cosmological model. Our high-resolution smoothed particle hydrodynamical simulations are designed to determine whether or not hypothesized supergiant molecular clouds (SGMCs) form and, if they do, to determine their physical properties and mass spectra. It was suggested in earlier work that clouds with a median mass of several 10^8 M_sun are expected to assemble during the formation of a galaxy, and that globular clusters form within these SGMCs. Our simulations show that clouds with the predicted properties are indeed produced as smaller clouds collide and agglomerate within the merging dark matter haloes of our cosmological model. We find that the mass spectrum of these clouds obeys the same power-law form observed for globular clusters, molecular clouds, and their internal clumps in galaxies, and predicted for the supergiant clouds in which globular clusters may form. We follow the evolution and physical properties of gas clouds within small dark matter haloes up to z = 1, after which prolific star formation is expected to occur. Finally, we discuss how our results may lead to more physically motivated "rules" for star formation in cosmological simulations of galaxy formation.Comment: Accepted to The Astrophysical Journal; 17 pages, 8 figure

Angular Momentum Profiles of Warm Dark Matter Halos

We compare the specific angular momentum profiles of virialized dark halos in cold dark matter (CDM) and warm dark matter (WDM) models using high-resolution dissipationless simulations. The simulations were initialized using the same set of modes, except on small scales, where the power was suppressed in WDM below the filtering length. Remarkably, WDM as well as CDM halos are well-described by the two-parameter angular momentum profile of Bullock et al. (2001), even though the halo masses are below the filtering scale of the WDM. Although the best-fit shape parameters change quantitatively for individual halos in the two simulations, we find no systematic variation in profile shapes as a function of the dark matter type. The scatter in shape parameters is significantly smaller for the WDM halos, suggesting that substructure and/or merging history plays a role producing scatter about the mean angular momentum distribution, but that the average angular momentum profiles of halos originate from larger-scale phenomena or a mechanism associated with the virialization process. The known mismatch between the angular momentum distributions of dark halos and disk galaxies is therefore present in WDM as well as CDM models. Our WDM halos tend to have a less coherent (more misaligned) angular momentum structure and smaller spin parameters than do their CDM counterparts, although we caution that this result is based on a small number of halos.Comment: 5 pages, 1 figure, Submitted to ApJ

Star Formation, Supernovae Feedback and the Angular Momentum Problem in Numerical CDM Cosmogony: Half Way There?

We present a smoothed particle hydrodynamic (SPH) simulation that reproduces a galaxy that is a moderate facsimile of those observed. The primary failing point of previous simulations of disk formation, namely excessive transport of angular momentum from gas to dark matter, is ameliorated by the inclusion of a supernova feedback algorithm that allows energy to persist in the model ISM for a period corresponding to the lifetime of stellar associations. The inclusion of feedback leads to a disk at a redshift $z=0.52$, with a specific angular momentum content within 10% of the value required to fit observations. An exponential fit to the disk baryon surface density gives a scale length within 17% of the theoretical value. Runs without feedback, with or without star formation, exhibit the drastic angular momentum transport observed elsewhere.Comment: 4 pages, 3 figures, accepted for publication in ApJ Letter

Mg II Absorption Systems in SDSS QSO Spectra

We present the results of a MgII absorption-line survey using QSO spectra from the SDSS EDR. Over 1,300 doublets with rest equivalent widths greater than 0.3\AA and redshifts $0.366 \le z \le 2.269$ were identified and measured. We find that the $\lambda2796$ rest equivalent width ($W_0^{\lambda2796}$) distribution is described very well by an exponential function $\partial N/\partial W_0^{\lambda2796} = \frac{N^*}{W^*} e^{-\frac{W_0}{W^*}}$, with $N^*=1.187\pm0.052$ and $W^*=0.702\pm0.017$\AA. Previously reported power law fits drastically over-predict the number of strong lines. Extrapolating our exponential fit under-predicts the number of $W_0 \le 0.3$\AA systems, indicating a transition in $dN/dW_0$ near $W_0 \simeq 0.3$\AA. A combination of two exponentials reproduces the observed distribution well, suggesting that MgII absorbers are the superposition of at least two physically distinct populations of absorbing clouds. We also derive a new redshift parameterization for the number density of $W_0^{\lambda2796} \ge 0.3$\AA lines: $N^*=1.001\pm0.132(1+z)^{0.226\pm0.170}$ and $W^*=0.443\pm0.032(1+z)^{0.634\pm 0.097}$\AA. We find that the distribution steepens with decreasing redshift, with $W^*$ decreasing from $0.80\pm0.04$\AA at $z=1.6$ to $0.59\pm0.02$\AA at $z=0.7$. The incidence of moderately strong MgII $\lambda2796$ lines does not show evidence for evolution with redshift. However, lines stronger than $\approx 2$\AA show a decrease relative to the no-evolution prediction with decreasing redshift for $z \lesssim 1$. The evolution is stronger for increasingly stronger lines. Since $W_0$ in saturated absorption lines is an indicator of the velocity spread of the absorbing clouds, we interpret this as an evolution in the kinematic properties of galaxies from moderate to low z.Comment: 50 pages, 26 figures, accepted for publication in Ap

Pitfalls of lateral external fixation for supracondylar humeral fractures in children

Introduction: Closed reduction and percutaneous pinning is a standard treatment for dislocated supracondylar humeral fractures in children. However, the management of these fractures remains challenging. The aim of this study was to evaluate lateral external fixation as a treatment alternative for these fractures. Materials and methods: All supracondylar fractures treated with lateral external fixation between 2005 and 2007 were evaluated retrospectively. Long-term outcome was assessed with regards to carrying angle, malalignment, and motion. Results: Twenty-eight patients with Gartland type III fractures and one with a Y-type fracture were included in the study (mean age 6.5years). Cosmetic results were excellent in 88%, good in 8%, and fair in one patient. Functional results were excellent in 83%, good in 10%, and fair in 7%. However, 3 patients (10%) showed complete radial palsy postoperatively. In all of these patients, high insertion of the proximal pin (2.9-3.6cm above the fracture) was noted. On revision, one superficial lesion and one total transection of the nerve at the level of the proximal pin was detected. One patient showed no macroscopic damage. The transected nerve was reconstructed using an autograft, and all patients completely recovered within 2-6months. Conclusion: Lateral external fixation is an alternative method for the treatment of displaced or unstable supracondylar fractures in children, facilitating reduction and improving fracture stability. However, iatrogenic radial nerve injury is a risk, and we therefore strongly recommend inserting the proximal pin under direct vision within 2cm from the fracture line using a drill sleev

Neuroimaging in Parkinson's disease dementia: Connecting the dots

Dementia is a common and devastating symptom of Parkinson’s disease but the anatomical substrate remains unclear. Some evidence points towards hippocampal involvement but neuroimaging abnormalities have been reported throughout the brain and are largely inconsistent across studies. Here, we test whether these disparate neuroimaging findings for Parkinson’s disease dementia localize to a common brain network. We used a literature search to identify studies reporting neuroimaging correlates of Parkinson’s dementia (11 studies, 385 patients). We restricted our search to studies of brain atrophy and hypometabolism that compared Parkinson’s patients with dementia to those without cognitive involvement. We used a standard coordinate-based activation likelihood estimation meta-analysis to assess for consistency in the neuroimaging findings. We then used a new approach, coordinate-based network mapping, to test whether neuroimaging findings localized to a common brain network. This approach uses resting-state functional connectivity from a large cohort of normative subjects (n = 1000) to identify the network of regions connected to a reported neuroimaging coordinate. Activation likelihood estimation meta-analysis failed to identify any brain regions consistently associated with Parkinson’s dementia, showing major heterogeneity across studies. In contrast, coordinate-based network mapping found that these heterogeneous neuroimaging findings localized to a specific brain network centred on the hippocampus. Next, we tested whether this network showed symptom specificity and stage specificity by performing two further analyses. We tested symptom specificity by examining studies of Parkinson’s hallucinations (9 studies, 402 patients) that are frequently co-morbid with Parkinson’s dementia. We tested for stage specificity by using studies of mild cognitive impairment in Parkinson’s disease (15 studies, 844 patients). Coordinate-based network mapping revealed that correlates of visual hallucinations fell within a network centred on bilateral lateral geniculate nucleus and correlates of mild cognitive impairment in Parkinson’s disease fell within a network centred on posterior default mode network. In both cases, the identified networks were distinct from the hippocampal network of Parkinson’s dementia. Our results link heterogeneous neuroimaging findings in Parkinson’s dementia to a common network centred on the hippocampus. This finding was symptom and stage-specific, with implications for understanding Parkinson’s dementia and heterogeneity of neuroimaging findings in general

The Upper Asymptotic Giant Branch of the Elliptical Galaxy Maffei 1, and Comparisons with M32 and NGC 5128

Deep near-infrared images obtained with adaptive optics systems on the Gemini North and Canada-France-Hawaii telescopes are used to investigate the bright stellar content and central regions of the nearby elliptical galaxy Maffei 1. Stars evolving on the upper asymptotic giant branch (AGB) are resolved in a field 3 arcmin from the center of the galaxy. The locus of bright giants on the (K, H-K) color-magnitude diagram is consistent with a population of stars like those in Baade's Window reddened by E(H-K) = 0.28 +/- 0.05 mag. This corresponds to A_V = 4.5 +/- 0.8 mag, and is consistent with previous estimates of the line of sight extinction computed from the integrated properties of Maffei 1. The AGB-tip occurs at K = 20.0, which correponds to M_K = -8.7; hence, the AGB-tip brightness in Maffei 1 is comparable to that in M32, NGC 5128, and the bulges of M31 and the Milky-Way. The near-infrared luminosity functions (LFs) of bright AGB stars in Maffei 1, M32, and NGC 5128 are also in excellent agreement, both in terms of overall shape and the relative density of infrared-bright stars with respect to the fainter stars that dominate the light at visible and red wavelengths. It is concluded that the brightest AGB stars in Maffei 1, NGC 5128, M32, and the bulge of M31 trace an old, metal-rich population, rather than an intermediate age population. It is also demonstrated that Maffei 1 contains a distinct red nucleus, and this is likely the optical signature of low-level nuclear activity and/or a distinct central stellar population. Finally, there is an absence of globular clusters brighter than the peak of the globular cluster LF in the central 700 x 700 parsecs of Maffei 1.Comment: 22 pages of text and 9 postscript figures; to appear in the Astronomical Journa

Tidal disruption of dark matter halos around proto-globular clusters

Tidal disruption of dark matter halos around proto-globular clusters in a halo of a small galaxy is studied in the context of the hierarchical clustering scenario by using semi-cosmological N-body/SPH simulations assuming the standard cold dark matter model ($\Omega_0 = 1$). Our analysis on formation and evolution of the galaxy and its substructures archives until $z = 2.0$. In such a high-redshift universe, the Einstein-de Sitter universe is still a good approximation for a recently favored $\Lambda$-dominated universe, and then our results does not depend on the choice of cosmology. In order to resolve small gravitationally-bound clumps around galaxies and consider radiative cooling below $T = 10^4 K$, we adopt a fine mass resolution (m_{\rm SPH} = 1.12 \times 10^3 \Msun). Because of the cooling, each clump immediately forms a `core-halo' structure which consists of a baryonic core and a dark matter halo. The tidal force from the host galaxy mainly strips the dark matter halo from clumps and, as a result, theses clumps get dominated by baryons. Once a clump is captured by the host halo, its mass drastically decreases each pericenter passage. At $z = 2$, more than half of the clumps become baryon dominated systems (baryon mass/total mass $> 0.5$). Our results support the tidal evolution scenario of the formation of globular clusters and baryon dominated dwarf galaxies in the context of the cold dark matter universe.Comment: 9page, 13 figures. Accepted for publication in ApJ. A high-resolution PDF of the paper can be obtained from http://th.nao.ac.jp/~takayuki/ApJ05