Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling

Despite the prevalence and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), genetic etiology remains elusive. Clinical evidence points in part to reduced function of the striatum, but which specific genes are differentially expressed and how they sculpt striatal physiology to predispose ADHD are not well understood. As an exploratory tool, a polygenic mouse model of ADHD was recently developed through selective breeding for high home cage activity. Relative to the Control line, the High-Active line displays hyperactivity and motor impulsivity which are ameliorated with amphetamine. This study compared gene expression in the striatum between Control and High-Active mice to develop a coherent hypothesis for how genes might affect striatal physiology and predispose ADHD-like symptoms. To this end, striatal transcriptomes of High-Active and Control mice were analyzed after mice were treated with saline or amphetamines. The pseudogene Gm6180 for n-cofilin (Cfl1) displayed 20-fold higher expression in High-Active mice corresponding with reduced Cfl1 expression suggesting synaptic actin dysregulation. Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice. Multiple genes were altered in High-Active mice in a manner predicted to downregulate the canonical Wnt pathway. A smaller and different set of genes including glyoxalase (Glo1) were differentially regulated in High-Active as compared to Control in response to amphetamine. Together, results suggest genes involved in excitatory synapse regulation and maintenance are downregulated in ADHD-like mice. Consistent with the molecular prediction, stereological analysis of the striatum from a separate set of mice processed for imunohistochemical detection of synaptophysin revealed approximately a 46% reduction in synaptophysin immunoreactivity in High-Active relative to Control. Results provide a new set of molecular targets related to synapse maintenance for the next generation of ADHD medicines

Achieving Acetylcholine Receptor Clustering in Tissue-Engineered Skeletal Muscle Constructs In vitro through a Materials-Directed Agrin Delivery Approach

Volumetric muscle loss (VML) can result from trauma, infection, congenital anomalies, or surgery, and produce permanent functional and cosmetic deficits. There are no effective treatment options for VML injuries, and recent advances toward development of muscle constructs lack the ability to achieve innervation necessary for long-term function. We sought to develop a proof-of-concept biomaterial construct that could achieve acetylcholine receptor (AChR) clustering on muscle-derived cells (MDCs) in vitro. The approach consisted of the presentation of neural (Z+) agrin from the surface of microspheres embedded with a fibrin hydrogel to muscle cells (C2C12 cell line or primary rat MDCs). AChR clustering was spatially restricted to areas of cell (C2C12)-microsphere contact when the microspheres were delivered in suspension or when they were incorporated into a thin (2D) fibrin hydrogel. AChR clusters were observed from 16 to 72 h after treatment when Z+ agrin was adsorbed to the microspheres, and for greater than 120 h when agrin was covalently coupled to the microspheres. Little to no AChR clustering was observed when agrin-coated microspheres were delivered from specially designed 3D fibrin constructs. However, cyclic stretch in combination with agrin-presenting microspheres led to dramatic enhancement of AChR clustering in cells cultured on these 3D fibrin constructs, suggesting a synergistic effect between mechanical strain and agrin stimulation of AChR clustering in vitro. These studies highlight a strategy for maintaining a physiological phenotype characterized by motor endplates of muscle cells used in tissue engineering strategies for muscle regeneration. As such, these observations may provide an important first step toward improving function of tissue-engineered constructs for treatment of VML injuries

First results from 2+1 dynamical quark flavors on an anisotropic lattice: light-hadron spectroscopy and setting the strange-quark mass

We present the first light-hadron spectroscopy on a set of $N_f=2+1$ dynamical, anisotropic lattices. A convenient set of coordinates that parameterize the two-dimensional plane of light and strange-quark masses is introduced. These coordinates are used to extrapolate data obtained at the simulated values of the quark masses to the physical light and strange-quark point. A measurement of the Sommer scale on these ensembles is made, and the performance of the hybrid Monte Carlo algorithm used for generating the ensembles is estimated.Comment: 24 pages. Hadron Spectrum Collaboratio

In vitro and in vivo Assessment of Keratose as a Novel Excipient of Paclitaxel Coated Balloons

Purpose: Drug coated balloons (DCB) are continually improving due to advances in coating techniques and more effective excipients. Paclitaxel, the current drug choice of DCB, is a microtubule-stabilizing chemotherapeutic agent that inhibits smooth muscle cell proliferation. Excipients work to promote coating stability and facilitate paclitaxel transfer and retention at the target lesion, although current excipients lack sustained, long-term paclitaxel retention. Keratose, a naturally derived protein, has exhibited unique properties allowing for tuned release of various therapeutic agents. However, little is known regarding its ability to support delivery of anti-proliferative agents such as paclitaxel. The goal of this project was to thus demonstrate the feasibility of keratose as a DCB-coating excipient to promote the release and delivery of paclitaxel.Methods: Keratose was combined with paclitaxel in vitro and the release kinetics of paclitaxel and keratose were evaluated through high performance liquid chromatograph-mass spectroscopy (HPLC-MS) and spectrophotometry, respectively. A custom coating method was developed to deposit keratose and paclitaxel on commercially available angioplasty balloons via an air spraying method. Coatings were then visualized under scanning electron microscopy and drug load quantified by HPLC-MS. Acute arterial transfer of paclitaxel at 1 h was assessed using a novel ex vivo model and further evaluated in vivo in a porcine ilio-femoral injury model.Results: Keratose demonstrated tunable release of paclitaxel as a function of keratose concentration in vitro. DCB coated via air spraying yielded consistent drug loading of 4.0 ± 0.70 μg/mm2. Under scanning electron microscopy, the keratose-paclitaxel DCB showed uniform coverage with a consistent, textured appearance. The acute drug transfer of the keratose-paclitaxel DCB was 43.60 ± 14.8 ng/mg at 1 h ex vivo. These measurements were further confirmed in vivo as the acute 1 h arterial paclitaxel levels were 56.60 ± 66.4 ng/mg.Conclusion: The keratose-paclitaxel coated DCB exhibited paclitaxel uptake and achieved acute therapeutic arterial tissue levels, confirming the feasibility of keratose as a novel excipient for DCB

Weak Lensing from Space III: Cosmological Parameters

Weak gravitational lensing provides a unique method to directly map the dark matter in the universe and measure cosmological parameters. Current weak lensing surveys are limited by the atmospheric seeing from the ground and by the small field of view of existing space telescopes. We study how a future wide-field space telescope can measure the lensing power spectrum and skewness, and set constraints on cosmological parameters. The lensing sensitivity was calculated using detailed image simulations and instrumental specifications studied in earlier papers in this series. For instance, the planned SuperNova/Acceleration Probe (SNAP) mission will be able to measure the matter density parameter Omega_m and the dark energy equation of state parameter w with precisions comparable and nearly orthogonal to those derived with SNAP from supernovae. The constraints degrade by a factor of about 2 if redshift tomography is not used, but are little affected if the skewness only is dropped. We also study how the constraints on these parameters depend upon the survey geometry and define an optimal observing strategy.Comment: 12 pages, 11 figures. Accepted versio

Renormalized couplings and scaling correction amplitudes in the N-vector spin models on the sc and the bcc lattices

For the classical N-vector model, with arbitrary N, we have computed through order \beta^{17} the high temperature expansions of the second field derivative of the susceptibility \chi_4(N,\beta) on the simple cubic and on the body centered cubic lattices. (The N-vector model is also known as the O(N) symmetric classical spin Heisenberg model or, in quantum field theory, as the lattice O(N) nonlinear sigma model.) By analyzing the expansion of \chi_4(N,\beta) on the two lattices, and by carefully allowing for the corrections to scaling, we obtain updated estimates of the critical parameters and more accurate tests of the hyperscaling relation d\nu(N) +\gamma(N) -2\Delta_4(N)=0 for a range of values of the spin dimensionality N, including N=0 [the self-avoiding walk model], N=1 [the Ising spin 1/2 model], N=2 [the XY model], N=3 [the classical Heisenberg model]. Using the recently extended series for the susceptibility and for the second correlation moment, we also compute the dimensionless renormalized four point coupling constants and some universal ratios of scaling correction amplitudes in fair agreement with recent renormalization group estimates.Comment: 23 pages, latex, no figure

Updated tests of scaling and universality for the spin-spin correlations in the 2D and 3D spin-S Ising models using high-temperature expansions

We have extended, from order 12 through order 25, the high-temperature series expansions (in zero magnetic field) for the spin-spin correlations of the spin-S Ising models on the square, simple-cubic and body-centered-cubic lattices. On the basis of this large set of data, we confirm accurately the validity of the scaling and universality hypotheses by resuming several tests which involve the correlation function, its moments and the exponential or the second-moment correlation-lengths.Comment: 21 pages, 8 figure

Comparing serial X-ray crystallography and microcrystal electron diffraction (MicroED) as methods for routine structure determination from small macromolecular crystals.

Innovative new crystallographic methods are facilitating structural studies from ever smaller crystals of biological macromolecules. In particular, serial X-ray crystallography and microcrystal electron diffraction (MicroED) have emerged as useful methods for obtaining structural information from crystals on the nanometre to micrometre scale. Despite the utility of these methods, their implementation can often be difficult, as they present many challenges that are not encountered in traditional macromolecular crystallography experiments. Here, XFEL serial crystallography experiments and MicroED experiments using batch-grown microcrystals of the enzyme cyclophilin A are described. The results provide a roadmap for researchers hoping to design macromolecular microcrystallography experiments, and they highlight the strengths and weaknesses of the two methods. Specifically, we focus on how the different physical conditions imposed by the sample-preparation and delivery methods required for each type of experiment affect the crystal structure of the enzyme

A forgotten figure in Siouan and Caddoan linguistics: Samuel Stehman Haldeman.

The Siouan family comprises some twenty languages, historically spoken across a broad swath of the central North American plains and woodlands, as well as in parts of the southeastern United States. In spite of its geographical extent and diversity, and the size and importance of several Siouan-speaking tribes, this family has received relatively little attention in the linguistic literature and many of the individual Siouan languages are severely understudied. This volume aims to make work on Siouan languages more broadly available and to encourage deeper investigation of the myriad typological, theoretical, descriptive, and pedagogical issues they raise. The 17 chapters in this volume present a broad range of current Siouan research, focusing on various Siouan languages, from a variety of linguistic perspectives: historical-genetic, philological, applied, descriptive, formal/generative, and comparative/typological. The editors' preface summarizes characteristic features of the Siouan family, including head-final and "verb-centered" syntax, a complex system of verbal affixes including applicatives and subject-possessives, head-internal relative clauses, gendered speech markers, stop-systems including ejectives, and a preference for certain prosodic and phonotactic patterns. The volume is dedicated to the memory of Professor Robert L. Rankin, a towering figure in Siouan linguistics throughout his long career, who passed away in February of 2014