Clinical impact of splicing in neurodevelopmental disorders.

Clinical exome sequencing is frequently used to identify gene-disrupting variants in individuals with neurodevelopmental disorders. While splice-disrupting variants are known to contribute to these disorders, clinical interpretation of cryptic splice variants outside of the canonical splice site has been challenging. Here, we discuss papers that improve such detection

Agencies Running from Agency Discretion

Discretion is the root source of administrative agency power and influence, but exercising discretion often requires agencies to undergo costly and time-consuming predecision assessment programs, such as under the Endangered Species Act (ESA) and National Environmental Policy Act (NEPA). Many federal agencies thus have argued strenuously, and counter-intuitively, that they do not have discretion over particular actions so as to avoid such predecision requirements. Interest group litigation challenging such agency moves has led to a new wave of jurisprudence exploring the dimensions of agency discretion. The emerging body of case law provides one of the most robust, focused judicial examinations of the nature and scope of agency discretion available in modern administrative law, but agency discretion aversion and the concerns it raises have gone largely unaddressed in legal scholarship. And yet the discretion aversion syndrome is primed only to expand as climate change implicates a broadening span of agency programs as having environmental impacts. This Article is the first to comprehensively describe and assess the discretion aversion trend and to extract what it has to say not only about agencies, courts, and statutes, but also about agency discretion in general. Part I describes the origins and features of the ESA and NEPA assessment programs leading to agency discretion aversion. Part II identifies the strategies agencies use to escape the ESA and NEPA assessment programs by disclaiming discretion. Part III probes institutional concerns for agencies, courts, and the statutes that arise from the discretion aversion syndrome, including agency gaming behavior, judicial conflicts regarding when nondiscretion exists, and compromised statutory purposes. Before turning to solutions, Part IV steps back to assess what questions the ESA and NEPA nondiscretion case law raises for the conceptualization of agency discretion writ large, identifying discretion’s “negative space” as the source of tension between agencies and courts. Part V then circles back to reexamine the ESA and NEPA nondiscretion doctrines, evaluating alternative measures to deflate agencies’ discretion aversion impulse while promoting the statutes’ purposes. We conclude that the most effective reform will be to eliminate discretion as the litmus test for the ESA and NEPA, replacing it with criteria more responsive to the statutes’ twin purposes of improving agency decisions and providing information to other political institutions and the public

Baryons Still Trace Dark Matter: Probing CMB Lensing Maps For Hidden Isocurvature

Compensated isocurvature perturbations (CIPs) are primordial fluctuations that balance baryon and dark-matter isocurvature to leave the total matter density unperturbed. The effects of CIPs on the cosmic microwave background (CMB) anisotropies are similar to those produced by weak lensing of the CMB: smoothing of the power spectrum and generation of non-Gaussian features. Here, an entirely new CIP contribution to the standard estimator for the lensing-potential power spectrum is derived. Planck measurements of the temperature and polarization power spectrum, as well as estimates of CMB lensing, are used to place limits on the variance of the CIP fluctuations on CMB scales, Δ2rms(RCMB). The resulting constraint of Δ2rms(RCMB)\u3c4.3×10−3 at 95% confidence level (CL) using this new technique improves on past work by a factor of ∼3. We find that for Planck data our constraints almost reach the sensitivity of the optimal CIP estimator. The method presented here is currently the most sensitive probe of the amplitude of a scale-invariant CIP power spectrum, ACIP, placing an upper limit of ACIP\u3c0.017 at 95% CL. Future measurements of the large-scale CMB lensing-potential power spectrum could probe CIP amplitudes as low as Δ2rms(RCMB)=8×10−5 at 95% CL (corresponding to ACIP=3.2×10−4)

Web Applet For Predicting Structure And Thermodynamics Of Complex Fluids

Based on a recently introduced analytical strategy [Hollingshead et al., J. Chem. Phys. 139, 161102 (2013)], we present a web applet that can quickly and semi-quantitatively estimate the equilibrium radial distribution function and related thermodynamic properties of a fluid from knowledge of its pair interaction. We describe the applet's features and present two (of many possible) examples of how it can be used to illustrate concepts of interest for introductory statistical mechanics courses: the transition from ideal gas-like behavior to correlated-liquid behavior with increasing density, and the tradeoff between dominant length scales with changing temperature in a system with ramp-shaped repulsions. The latter type of interaction qualitatively captures distinctive thermodynamic properties of liquid water, because its energetic bias toward locally open structures mimics that of water's hydrogen-bond network. (C) 2015 American Association of Physics Teachers.Chemical Engineerin

Methods for Surveying Stable Fly Populations

Stable flies are among the most important pests of livestock throughout much of the world. Their painful bites induce costly behavioral and physiological stress responses and reduce productivity. Stable flies are anthropogenic and their population dynamics vary depending on agricultural and animal husbandry practices. Standardized sampling methods are needed to better identify the factors controlling stable fly populations, test novel control technologies, and determine optimal management strategies. The current study reviewed methods used for a long-term study of stable fly population dynamics in the central Great Plains. An additional study compared the relative size of flies sampled from the general population with that of flies sampled emerging from substrates associated with livestock production. Flies developing in livestock associated substrates are significantly larger than those in the general population indicating that other types of developmental sites are contributing significant numbers of flies to the general population. Because efforts to identify those sites have yet to be successful, we speculate that they may be sites with low densities of developing stable flies, but covering large areas such as croplands and grasslands. The stable fly surveillance methods discussed can be used and further improved for monitoring stable fly populations for research and management programs

Methods for Surveying Stable Fly Populations

Stable flies are among the most important pests of livestock throughout much of the world. Their painful bites induce costly behavioral and physiological stress responses and reduce productivity. Stable flies are anthropogenic and their population dynamics vary depending on agricultural and animal husbandry practices. Standardized sampling methods are needed to better identify the factors controlling stable fly populations, test novel control technologies, and determine optimal management strategies. The current study reviewed methods used for a long-term study of stable fly population dynamics in the central Great Plains. An additional study compared the relative size of flies sampled from the general population with that of flies sampled emerging from substrates associated with livestock production. Flies developing in livestock associated substrates are significantly larger than those in the general population indicating that other types of developmental sites are contributing significant numbers of flies to the general population. Because efforts to identify those sites have yet to be successful, we speculate that they may be sites with low densities of developing stable flies, but covering large areas such as croplands and grasslands. The stable fly surveillance methods discussed can be used and further improved for monitoring stable fly populations for research and management programs

Pilot study of the safety and effect of adalimumab on pain, physical function, and musculoskeletal disease in mucopolysaccharidosis types I and II.

Mucopolysaccharidosis I and II are lysosomal storage disorders that, despite treatment with hematopoietic cell transplantation (HCT) and/or enzyme replacement therapy (ERT), continue to cause significant skeletal abnormalities leading to pain, stiffness, physical dysfunction, and short stature. Tumor necrosis factor - alpha (TNF-α) is elevated in individuals with MPS I and II and associated with pain and physical dysfunction. Therefore, we evaluated the safety and effects of the TNF-α inhibitor adalimumab in patients with MPS I and II in a 32-week, randomized, double blind, placebo-controlled, crossover study of adalimumab at a dose of 20 mg (weight 15-<30 kg) or 40 mg (weight ≥ 30 kg) administered subcutaneously every other week or saline placebo for 16 weeks. Participants were evaluated at baseline, week 16, and week 32 with the Children's Health Questionnaire - Parent Form 50 (CHQ-PF50), the Pediatric Pain Questionnaire (PPQ), range-of-motion (ROM) measurements, anthropometry, six-minute walk test (6MWT), hand dynamometer, and laboratory evaluations for safety. The primary outcome was safety and primary efficacy outcome was bodily pain (BP) measured by the CHQ-PF50. Two subjects, one with MPS I and one with MPS II, completed the study. Adalimumab was well tolerated and there were no serious adverse events. Standardized BP scores for age and gender were higher (i.e. less pain) at the end of the treatment versus placebo phase for both subjects. Subject #1 became unblinded during treatment due to skin erythema. Behavior measured by both CHQ-PF50 and parental report improved during treatment compared to placebo in both subjects. ROM improved by > 5° in seven of eight joints in Subject #1 and five of eight joints in Subject #2 (range 7.0° to 52.8°). There was no change in the PPQ, 6MWT, or hand dynamometer. Data from this small pilot study suggest that treatment with adalimumab is safe, tolerable, and may improve ROM, physical function, and possibly pain, in children with MPS I or II. However, additional clinical trials are needed before this therapy should be recommended as part of clinical care

Electron Transfer Reactivity of Type Zero Pseudomonas aeruginosa Azurin

Type zero copper is a hard-ligand analogue of the classical type 1 or blue site in copper proteins that function as electron transfer (ET) agents in photosynthesis and other biological processes. The EPR spectroscopic features of type zero Cu^(II) are very similar to those of blue copper, although lacking the deep blue color, due to the absence of thiolate ligation. We have measured the rates of intramolecular ET from the pulse radiolytically generated C3−C26 disulfide radical anion to the Cu^(II) in both type zero C112D/M121L and type 2 C112D Pseudomonas aeruginosa azurins in pH 7.0 aqueous solutions between 8 and 45 °C. We also have obtained rate/temperature (10−30 °C) profiles for ET reactions between these mutants and the wild-type azurin. Analysis of the rates and activation parameters for both intramolecular and intermolecular ET reactions indicates that the type zero copper reorganization energy falls in a range (0.9−1.1 eV) slightly above that for type 1 (0.7−0.8 eV), but substantially smaller than that for type 2 (>2 eV), consistent with XAS and EXAFS data that reveal minimal type zero site reorientation during redox cycling

Familial colloid cyst of the third ventricle

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Colloid cysts of the third ventricle are rare benign lesions. They can present as incidental finding on imaging or with symptoms of obstructive hydrocephalus. To date, 18 familial cases of colloid cyst have been reported. Due to the extreme rarity of these cysts, it has been suggested that there is a genetic component involved. This report presents a familial colloid cyst in non-twin brothers who both presented in their early twenties. In addition, both of them had congenital inguinal hernia. This may represent a potential association between familial colloid cysts and congenital inguinal hernia that could provide us with insight into the genetic mechanism involved

Modelling gravity on a hyper-cubic lattice

We present an elegant and simple dynamical model of symmetric, non-degenerate (n x n) matrices of fixed signature defined on a n-dimensional hyper-cubic lattice with nearest-neighbor interactions. We show how this model is related to General Relativity, and discuss multiple ways in which it can be useful for studying gravity, both classical and quantum. In particular, we show that the dynamics of the model when all matrices are close to the identity corresponds exactly to a finite-difference discretization of weak-field gravity in harmonic gauge. We also show that the action which defines the full dynamics of the model corresponds to the Einstein-Hilbert action to leading order in the lattice spacing, and use this observation to define a lattice analogue of the Ricci scalar and Einstein tensor. Finally, we perform a mean-field analysis of the statistical mechanics of this model.Comment: 5 page