Brain function distinguishes female carriers and non-carriers of familial risk for autism

BACKGROUND: Autism spectrum disorder (ASD) is characterized by high population-level heritability and a three-to-one male-to-female ratio that occurs independent of sex linkage. Prior research in a mixed-sex pediatric sample identified neural signatures of familial risk elicited by passive viewing of point light motion displays, suggesting the possibility that both resilience and risk of autism might be associated with brain responses to biological motion. To confirm a relationship between these signatures and inherited risk of autism, we tested them in families enriched for genetic loading through undiagnosed ( carrier ) females. METHODS: Using functional magnetic resonance imaging, we examined brain responses to passive viewing of point light displays-depicting biological versus non-biological motion-in a sample of undiagnosed adult females enriched for inherited susceptibility to ASD on the basis of affectation in their respective family pedigrees. Brain responses in carrier females were compared to responses in age-, SRS-, and IQ-matched non-carrier-females-i.e., females unrelated to individuals with ASD. We conducted a hypothesis-driven analysis focused on previously published regions of interest as well as exploratory, brain-wide analyses designed to characterize more fully the rich responses to this paradigm. RESULTS: We observed robust responses to biological motion. Notwithstanding, the 12 regions implicated by prior research did not exhibit the hypothesized interaction between group (carriers vs. controls) and point light displays (biological vs. non-biological motion). Exploratory, brain-wide analyses identified this interaction in three novel regions. Post hoc analyses additionally revealed significant variations in the time course of brain activation in 20 regions spanning occipital and temporal cortex, indicating group differences in response to point light displays (irrespective of the nature of motion) for exploration in future studies. LIMITATIONS: We were unable to successfully eye-track all participants, which prevented us from being able to control for potential differences in eye gaze position. CONCLUSIONS: These methods confirmed pronounced neural signatures that differentiate brain responses to biological and scrambled motion. Our sample of undiagnosed females enriched for family genetic loading enabled discovery of numerous contrasts between carriers and non-carriers of risk of ASD that may index variations in visual attention and motion processing related to genetic susceptibility and inform our understanding of mechanisms incurred by inherited liability for ASD

The osmotic pressure of charged colloidal suspensions: A unified approach to linearized Poisson-Boltzmann theory

We study theoretically the osmotic pressure of a suspension of charged objects (e.g., colloids, polyelectrolytes, clay platelets, etc.) dialyzed against an electrolyte solution using the cell model and linear Poisson-Boltzmann (PB) theory. From the volume derivative of the grand potential functional of linear theory we obtain two novel expressions for the osmotic pressure in terms of the potential- or ion-profiles, neither of which coincides with the expression known from nonlinear PB theory, namely, the density of microions at the cell boundary. We show that the range of validity of linearization depends strongly on the linearization point and proof that expansion about the selfconsistently determined average potential is optimal in several respects. For instance, screening inside the suspension is automatically described by the actual ionic strength, resulting in the correct asymptotics at high colloid concentration. Together with the analytical solution of the linear PB equation for cell models of arbitrary dimension and electrolyte composition explicit and very general formulas for the osmotic pressure ensue. A comparison with nonlinear PB theory is provided. Our analysis also shows that whether or not linear theory predicts a phase separation depends crucially on the precise definition of the pressure, showing that an improper choice could predict an artificial phase separation in systems as important as DNA in physiological salt solution.Comment: 16 pages, 5 figures, REVTeX4 styl

Surfactant status and respiratory outcome in premature infants receiving late surfactant treatment.

BACKGROUND:Many premature infants with respiratory failure are deficient in surfactant, but the relationship to occurrence of bronchopulmonary dysplasia (BPD) is uncertain. METHODS:Tracheal aspirates were collected from 209 treated and control infants enrolled at 7-14 days in the Trial of Late Surfactant. The content of phospholipid, surfactant protein B, and total protein were determined in large aggregate (active) surfactant. RESULTS:At 24 h, surfactant treatment transiently increased surfactant protein B content (70%, p < 0.01), but did not affect recovered airway surfactant or total protein/phospholipid. The level of recovered surfactant during dosing was directly associated with content of surfactant protein B (r = 0.50, p < 0.00001) and inversely related to total protein (r = 0.39, p < 0.0001). For all infants, occurrence of BPD was associated with lower levels of recovered large aggregate surfactant, higher protein content, and lower SP-B levels. Tracheal aspirates with lower amounts of recovered surfactant had an increased proportion of small vesicle (inactive) surfactant. CONCLUSIONS:We conclude that many intubated premature infants are deficient in active surfactant, in part due to increased intra-alveolar metabolism, low SP-B content, and protein inhibition, and that the severity of this deficit is predictive of BPD. Late surfactant treatment at the frequency used did not provide a sustained increase in airway surfactant

The `Friction' of Vacuum, and other Fluctuation-Induced Forces

The static Casimir effect describes an attractive force between two conducting plates, due to quantum fluctuations of the electromagnetic (EM) field in the intervening space. {\it Thermal fluctuations} of correlated fluids (such as critical mixtures, super-fluids, liquid crystals, or electrolytes) are also modified by the boundaries, resulting in finite-size corrections at criticality, and additional forces that effect wetting and layering phenomena. Modified fluctuations of the EM field can also account for the `van der Waals' interaction between conducting spheres, and have analogs in the fluctuation--induced interactions between inclusions on a membrane. We employ a path integral formalism to study these phenomena for boundaries of arbitrary shape. This allows us to examine the many unexpected phenomena of the dynamic Casimir effect due to moving boundaries. With the inclusion of quantum fluctuations, the EM vacuum behaves essentially as a complex fluid, and modifies the motion of objects through it. In particular, from the mechanical response function of the EM vacuum, we extract a plethora of interesting results, the most notable being: (i) The effective mass of a plate depends on its shape, and becomes anisotropic. (ii) There is dissipation and damping of the motion, again dependent upon shape and direction of motion, due to emission of photons. (iii) There is a continuous spectrum of resonant cavity modes that can be excited by the motion of the (neutral) boundaries.Comment: RevTex, 2 ps figures included. The presentation is completely revised, and new sections are adde

The Angiotensin Converting Enzyme Insertion/Deletion polymorphism is not associated with an increased risk of death or bronchopulmonary dysplasia in ventilated very low birth weight infants

BACKGROUND: The ACE gene contains a polymorphism consisting of either the presence (insertion, I) or absence (deletion, D) of a 287 bp alu repeat in intron 16. The D allele is associated with increased ACE activity in both tissue and plasma. The DD genotype is associated with risk of developing ARDS and mortality. The frequency of the D allele is higher in patients with pulmonary fibrosis, sarcoidosis and berylliosis. The role of this polymorphism has not been studied in the development of BPD in the premature newborn. METHODS: ACE I/D genotype was determined in 245 (194 African-American, 47 Caucasian and 4 Hispanic) mechanically ventilated infants weighing less than 1250 grams at birth and compared to outcome (death and/or development of BPD). RESULTS: The incidence of the D allele in the study population was 0.58. Eighty-eight (35.9%) infants were homozygous DD, 107 (43.7%) were heterozygous ID and 50 (20.4%) were homozygous II. There were no significant differences between genotype groups with respect to ethnic origin, birth weight, gestation, or gender. There was no effect of the ACE I/D polymorphism on mortality or development of BPD (O(2 )on 28 days or 36 weeks PCA). Secondary outcomes (intraventricular hemorrhage and periventricular leukomalacia) similarly were not influenced by the ACE ID polymorphism. CONCLUSIONS: The ACE I/D polymorphism does not significantly influence the development of BPD in ventilated infants less than 1250 grams

Surfactant phosphatidylcholine half-life and pool size measurements in premature baboons developing bronchopulmonary dysplasia

Because minimal information is available about surfactant metabolism in bronchopulmonary dysplasia, we measured half-lives and pool sizes of surfactant phosphatidylcholine in very preterm baboons recovering from respiratory distress syndrome and developing bronchopulmonary dysplasia, using stable isotopes, radioactive isotopes, and direct pool size measurements. Eight ventilated premature baboons received (2)H-DPPC (dipalmitoyl phosphatidylcholine) on d 5 of life, and radioactive (14)C-DPPC with a treatment dose of surfactant on d 8. After 14 d, lung pool sizes of saturated phosphatidylcholine were measured. Half-life of (2)H-DPPC (d 5) in tracheal aspirates was 28 +/- 4 h (mean +/- SEM). Half-life of radioactive DPPC (d 8) was 35 +/- 4 h. Saturated phosphatidylcholine pool size measured with stable isotopes on d 5 was 129 +/- 14 micro mol/kg, and 123 +/- 11 micro mol/kg on d 14 at autopsy. Half-lives were comparable to those obtained at d 0 and d 6 in our previous baboon studies. We conclude that surfactant metabolism does not change during the early development of bronchopulmonary dysplasia, more specifically, the metabolism of exogenous surfactant on d 8 is similar to that on the day of birth. Surfactant pool size is low at birth, increases after surfactant therapy, and is kept constant during the first 2 wk of life by endogenous surfactant synthesis. Measurements with stable isotopes are comparable to measurements with radioactive tracers and measurements at autopsy

Some aspects of the Liouville equation in mathematical physics and statistical mechanics

This paper presents some mathematical aspects of Classical Liouville theorem and we have noted some mathematical theorems about its initial value problem. Furthermore, we have implied on the formal frame work of Stochastic Liouville equation (SLE)

Real-Space Mesh Techniques in Density Functional Theory

This review discusses progress in efficient solvers which have as their foundation a representation in real space, either through finite-difference or finite-element formulations. The relationship of real-space approaches to linear-scaling electrostatics and electronic structure methods is first discussed. Then the basic aspects of real-space representations are presented. Multigrid techniques for solving the discretized problems are covered; these numerical schemes allow for highly efficient solution of the grid-based equations. Applications to problems in electrostatics are discussed, in particular numerical solutions of Poisson and Poisson-Boltzmann equations. Next, methods for solving self-consistent eigenvalue problems in real space are presented; these techniques have been extensively applied to solutions of the Hartree-Fock and Kohn-Sham equations of electronic structure, and to eigenvalue problems arising in semiconductor and polymer physics. Finally, real-space methods have found recent application in computations of optical response and excited states in time-dependent density functional theory, and these computational developments are summarized. Multiscale solvers are competitive with the most efficient available plane-wave techniques in terms of the number of self-consistency steps required to reach the ground state, and they require less work in each self-consistency update on a uniform grid. Besides excellent efficiencies, the decided advantages of the real-space multiscale approach are 1) the near-locality of each function update, 2) the ability to handle global eigenfunction constraints and potential updates on coarse levels, and 3) the ability to incorporate adaptive local mesh refinements without loss of optimal multigrid efficiencies.Comment: 70 pages, 11 figures. To be published in Reviews of Modern Physic

Type IV collagen drives alveolar epithelial-endothelial association and the morphogenetic movements of septation

Background: Type IV collagen is the main component of the basement membrane that gives strength to the blood-gas barrier (BGB). In mammals, the formation of a mature BGB occurs primarily after birth during alveologenesis and requires the formation of septa from the walls of the saccule. In contrast, in avians, the formation of the BGB occurs rapidly and prior to hatching. Mutation in basement membrane components results in an abnormal alveolar phenotype; however, the specific role of type IV collagen in regulating alveologenesis remains unknown. Results: We have performed a microarray expression analysis in late chick lung development and found that COL4A1 and COL4A2 were among the most significantly upregulated genes during the formation of the avian BGB. Using mouse models, we discovered that mutations in murine Col4a1 and Col4a2 genes affected the balance between lung epithelial progenitors and differentiated cells. Mutations in Col4a1 derived from the vascular component were sufficient to cause defects in vascular development and the BGB. We also show that Col4a1 and Col4a2 mutants displayed disrupted myofibroblast proliferation, differentiation and migration. Lastly, we revealed that addition of type IV collagen protein induced myofibroblast proliferation and migration in monolayer culture and increased the formation of mesenchymal-epithelial septal-like structures in co-culture. Conclusions: Our study showed that type IV collagen and, therefore the basement membrane, play fundamental roles in coordinating alveolar morphogenesis. In addition to its role in the formation of epithelium and vasculature, type IV collagen appears to be key for alveolar myofibroblast development by inducing their proliferation, differentiation and migration throughout the developing septum