Detecting Selection Bias in Community Disseminations of Universal Family-Based Prevention Programs

The goals of the present study were to demonstrate a method for examining selection bias in large-scale implementations of community-based family skills programs, and to explore the nature of selection bias in one such implementation. We used evaluation data from a statewide dissemination of a popular substance abuse prevention program (N programs = 42; N youth = 294). The program’s evaluation measures were designed to match publicly available data on risk and protective factor scales collected in the state’s schools, which enabled us to construct a comparison sample of non-participants (N = 20,608). We then examined the risk status of adolescents in both groups to determine whether risk and protective factor scores were related to the probability of program participation. Participation was predicted by both demographics and risk and protective factor scores. Among families with younger adolescents, program attendance was associated with lower risk; among families with older adolescents, participation was associated with both higher risk (on parental management skills) and lower risk (on substance use). Selection effects must be identified and corrected for in order to calculate valid estimates of program benefits, but in community-based disseminations, the necessary supplemental comparison sample is difficult to obtain. The evaluation design and analytic approach described here can be used in program evaluations of real-world, “bottom-up” dissemination efforts to identify who attends a program, which in turn can help to inform recruitment strategies, to pinpoint possible selection influences on measured program outcomes, and to refine estimates of program costs and benefits.repeated auction; selectivity; prevention program; community-based implementation; program evaluation

System for the measurement of ultra-low stray light levels

An apparatus is described for measuring the effectiveness of stray light suppression light shields and baffle arrangements used in optical space experiments and large space telescopes. The light shield and baffle arrangement and a telescope model are contained in a vacuum chamber. A source of short, high-powered light energy illuminates portions of the light shield and baffle arrangement and reflects a portion of same to a photomultiplier tube by virtue of multipath scattering. The resulting signal is transferred to time-channel electronics timed by the firing of the high energy light source allowing time discrimination of the signal thereby enabling the light scattered and suppressed by the model to be distinguished from the walls and holders around the apparatus

Structure-based inhibitors of amyloid beta core suggest a common interface with tau.

Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline

Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity.

hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of β-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile β-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP

Exact Thermodynamics of the Double sinh-Gordon Theory in 1+1-Dimensions

We study the classical thermodynamics of a 1+1-dimensional double-well sinh-Gordon theory. Remarkably, the Schrodinger-like equation resulting from the transfer integral method is quasi-exactly solvable at several temperatures. This allows exact calculation of the partition function and some correlation functions above and below the short-range order (``kink'') transition, in striking agreement with high resolution Langevin simulations. Interesting connections with the Landau-Ginzburg and double sine-Gordon models are also established.Comment: 4 pages, 3 figures (embedded using epsf), uses RevTeX plus macro (included). Minor revision to match journal version, Phys. Rev. Lett. (in press

The RacGAP β2-Chimaerin Selectively Mediates Axonal Pruning in the Hippocampus

SummaryAxon pruning and synapse elimination promote neural connectivity and synaptic plasticity. Stereotyped pruning of axons that originate in the hippocampal dentate gyrus (DG) and extend along the infrapyramidal tract (IPT) occurs during postnatal murine development by neurite retraction and resembles axon repulsion. The chemorepellent Sema3F is required for IPT axon pruning, dendritic spine remodeling, and repulsion of DG axons. The signaling events that regulate IPT axon pruning are not known. We find that inhibition of the small G protein Rac1 by the Rac GTPase-activating protein (GAP) β2-Chimaerin (β2Chn) mediates Sema3F-dependent pruning. The Sema3F receptor neuropilin-2 selectively binds β2Chn, and ligand engagement activates this GAP to ultimately restrain Rac1-dependent effects on cytoskeletal reorganization. β2Chn is necessary for axon pruning both in vitro and in vivo, but it is dispensable for axon repulsion and spine remodeling. Therefore, a Npn2/β2Chn/Rac1 signaling axis distinguishes DG axon pruning from the effects of Sema3F on repulsion and dendritic spine remodeling

Noise-Induced Phase Space Transport in Two-Dimensional Hamiltonian Systems

First passage time experiments were used to explore the effects of low amplitude noise as a source of accelerated phase space diffusion in two-dimensional Hamiltonian systems, and these effects were then compared with the effects of periodic driving. The objective was to quantify and understand the manner in which ``sticky'' chaotic orbits that, in the absence of perturbations, are confined near regular islands for very long times, can become ``unstuck'' much more quickly when subjected to even very weak perturbations. For both noise and periodic driving, the typical escape time scales logarithmically with the amplitude of the perturbation. For white noise, the details seem unimportant: Additive and multiplicative noise typically have very similar effects, and the presence or absence of a friction related to the noise by a Fluctuation-Dissipation Theorem is also largely irrelevant. Allowing for colored noise can significantly decrease the efficacy of the perturbation, but only when the autocorrelation time becomes so large that there is little power at frequencies comparable to the natural frequencies of the unperturbed orbit. Similarly, periodic driving is relatively inefficient when the driving frequency is not comparable to these natural frequencies. This suggests strongly that noise-induced extrinsic diffusion, like modulational diffusion associated with periodic driving, is a resonance phenomenon. The logarithmic dependence of the escape time on amplitude reflects the fact that the time required for perturbed and unperturbed orbits to diverge a given distance scales logarithmically in the amplitude of the perturbation.Comment: 15 pages, including 13 Figures and 1 Table, uses Phys. Rev. macro

Chaos and the continuum limit in the gravitational N-body problem II. Nonintegrable potentials

This paper continues a numerical investigation of orbits evolved in `frozen,' time-independent N-body realisations of smooth time-independent density distributions corresponding to both integrable and nonintegrable potentials, allowing for N as large as 300,000. The principal focus is on distinguishing between, and quantifying, the effects of graininess on initial conditions corresponding, in the continuum limit, to regular and chaotic orbits. Ordinary Lyapunov exponents X do not provide a useful diagnostic for distinguishing between regular and chaotic behaviour. Frozen-N orbits corresponding in the continuum limit to both regular and chaotic characteristics have large positive X even though, for large N, the `regular' frozen-N orbits closely resemble regular characteristics in the smooth potential. Viewed macroscopically both `regular' and `chaotic' frozen-N orbits diverge as a power law in time from smooth orbits with the same initial condition. There is, however, an important difference between `regular' and `chaotic' frozen-N orbits: For regular orbits, the time scale associated with this divergence t_G ~ N^{1/2}t_D, with t_D a characteristic dynamical time; for chaotic orbits t_G ~ (ln N) t_D. At least for N>1000 or so, clear distinctions exist between phase mixing of initially localised orbit ensembles which, in the continuum limit, exhibit regular versus chaotic behaviour. For both regular and chaotic ensembles, finite-N effects are well mimicked, both qualitatively and quantitatively, by energy-conserving white noise with amplitude ~ 1/N. This suggests strongly that earlier investigations of the effects of low amplitude noise on phase space transport in smooth potentials are directly relevant to real physical systems.Comment: 20 pages, including 21 FIGURES, uses RevTeX macro

Chaos and Noise in Galactic Potentials

ABBREVIATED ABSTRACT: This paper summarises an investigation of the effects of weak friction and noise in time-independent, nonintegrable potentials which admit both regular and stochastic orbits. The aim is to understand the qualitative effects of internal and external irregularities associated, e.g., with discreteness effects or couplings to an external environment, which stars in any real galaxy must experience. The two principal conclusions are: (1) These irregularities can be important on time scales much shorter than the natural relaxation time scale t_R associated with the friction and noise. For stochastic orbits friction and noise induce an average exponential divergence from the unperturbed Hamiltonian trajectory at a rate set by the value of the local Lyapunov exponent. Even weak noise can make a pointwise interpretation of orbits suspect already on time scales much shorter than t_R. (2) The friction and noise can also have significant effects on the statistical properties of ensembles of stochastic orbits, these also occurring on time scales much shorter than t_R. Potential implications for galactic dynamics are discussed, including the problem of shadowing.Comment: 45 pages, uuencoded PostScript (figures included), LA-UR-94-282

Protein kinase Cδ expression in breast cancer as measured by real-time PCR, western blotting and ELISA

The protein kinase C (PKC) family of genes encode serine/threonine kinases that regulate proliferation, apoptosis, cell survival and migration. Multiple isoforms of PKC have been described, one of which is PKCδ. Currently, it is unclear whether PKCδ is involved in promoting or inhibiting cancer formation/progression. The aim of this study was therefore to investigate the expression of PKCδ in human breast cancer and relate its levels to multiple parameters of tumour progression. Protein kinase Cδ expression at the mRNA level was measured using real-time PCR (n=208) and at protein level by both immunoblotting (n=94) and ELISA (n=98). Following immunoblotting, two proteins were identified, migrating with molecular masses of 78 and 160 kDa. The 78 kDa protein is likely to be the mature form of PKCδ but the identity of the 160 kDa form is unknown. Levels of both these proteins correlated weakly but significantly with PKCδ concentrations determined by ELISA (for the 78 kDa form, r=0.444, P<0.005, n=91 and for the 160 kDa form, r=0.237, P=0.023, n=91) and with PKCδ mRNA levels (for the 78 kDa form, r=0.351, P=0.001, n=94 and for the 160 kDa form, r=0.216, P=0.037, n=94). Protein kinase Cδ mRNA expression was significantly higher in oestrogen receptor (ER)-positive compared with ER-negative tumours (P=0.007, Mann–Whitney U-test). Increasing concentrations of PKCδ mRNA were associated with reduced overall patient survival (P=0.004). Our results are consistent with a role for PKCδ in breast cancer progression