Lessons from a BACE1 inhibitor trial: off-site but not off base

Alzheimer's disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-β peptide (Aβ). The rate-limiting step in the production of Aβ is the processing of Aβ precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Aβ within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of β-galactoside α-2,6-sialyltransferase I (STGal6 I). In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future

Analytical comparison of three stiffened panel concepts

Three stiffened panel concepts are evaluated to find optimized designs for integral stiffeners in the barrels of Reusable Launch Vehicle fuel tanks. The three panel concepts considered are a T-stiffened panel, a panel with one blade stiffener centered between each pair of T-stiffeners, and a panel with two blade stiffeners equally spaced between each pair of T-stiffeners. The panels are optimized using PASCO for a range of compressive loads, and the computed areal weight for each panel is used to compare the concepts and predict tank weights. The areal weight of the T-stiffened panel with one blade is up to seven-percent lower than the other panel concepts. Two tank construction methods are compared for a representative tank design with three barrels. In the first method, 45-degree circumferential sections of a barrel are each designed to carry the same maximum load in the barrel. In the second method, each barrel section is designed for the maximum load in that section. Representative tanks designed with the first method are over 250 lb heavier than tanks designed using the second method. Optimized panel designs and areal weights are also computed for variation of the nominal panel length and skin thickness

Mapping Children's Discussions of Evidence in Science to Assess Collaboration and Argumentation

The research reported in this paper concerns the development of children's skills of interpreting and evaluating evidence in science. Previous studies have shown that school teaching often places limited emphasis on the development of these skills, which are necessary for children to engage in scientific debate and decision-making. The research, undertaken in the UK, involved four collaborative decision-making activities to stimulate group discussion, each was carried out with five groups of four children (10-11 years old). The research shows how the children evaluated evidence for possible choices and judged whether their evidence was sufficient to support a particular conclusion or the rejection of alternative conclusions. A mapping technique was developed to analyse the discussions and identify different "levels" of argumentation. The authors conclude that suitable collaborative activities that focus on the discussion of evidence can be developed to exercise children's ability to argue effectively in making decisions

Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5′-untranslated region: Implications in Alzheimer’s disease

In addition to the devastating symptoms of dementia, Alzheimer’s disease (AD) is characterized by accumulation of the processing products of the amyloid-β (Aβ) peptide precursor protein (APP). APP’s non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~ 20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3′-untranslated region (UTR) sequence. By contrast, we report a novel activity of miR-346: specifically, that it targets the APP mRNA 5′-UTR to upregulate APP translation and Aβ production. This upregulation is reduced but not eliminated by knockdown of argonaute 2. The target site for miR-346 overlaps with active sites for an iron-responsive element (IRE) and an interleukin-1 (IL-1) acute box element. IREs interact with iron response protein1 (IRP1), an iron-dependent translational repressor. In primary human brain cultures, miR-346 activity required chelation of Fe. In addition, miR-346 levels are altered in late-Braak stage AD. Thus, miR-346 plays a role in upregulation of APP in the CNS and participates in maintaining APP regulation of Fe, which is disrupted in late stages of AD. Further work will be necessary to integrate other metals, and IL-1 into the Fe-miR-346 activity network. We, thus, propose a “FeAR” (Fe, APP, RNA) nexus in the APP 5′-UTR that includes an overlapping miR-346-binding site and the APP IRE. When a “healthy FeAR” exists, activities of miR-346 and IRP/Fe interact to maintain APP homeostasis. Disruption of an element that targets the FeAR nexus would lead to pathogenic disruption of APP translation and protein production

Acute and chronic effects of foam rolling vs eccentric exercise on ROM and force output of the plantar flexors

Foam rolling and eccentric exercise interventions have been demonstrated to improve range of motion (ROM). However, these two modalities have not been directly compared. Twenty-three academy soccer players (age: 18 ± 1; height: 1.74 ± 0.08 m; body mass: 69.3 ± 7.5 kg) were randomly allocated to either a foam rolling (FR) or eccentric exercise intervention designed to improve dorsiflexion ROM. Participants performed the intervention daily for a duration of four weeks. Measurements of dorsiflexion ROM, isometric plantar flexion torque and drop jump reactive strength index were taken at baseline (pre-intervention) and at three subsequent time-points (30-min post, 24-hours post and 4-weeks post). A significant time x group interaction effect was observed for dorsiflexion (P = 0.036), but not for torque or reactive strength index. For dorsiflexion, there was a significant increase in both acute (30-min; P < 0.001) and chronic (4-week; P < 0.001) ROM for the eccentric group, whilst FR exhibited only an acute improvement (P < 0.001). Eccentric training would appear a more efficacious modality than foam rolling for improving dorsiflexion ROM in elite academy soccer players

ASCA Observation of an X-Ray-Luminous Active Nucleus in Markarian 231

We have obtained a moderately long (100 kilosecond) ASCA observation of the Seyfert 1 galaxy Markarian 231, the most luminous of the local ultraluminous infrared galaxy (ULIRG) population. In the best-fitting model we do not see the X-ray source directly; the spectrum consists of a scattered power-law component and a reflection component, both of which have been absorbed by a column N_H \approx 3 X 10^(22)/cm^2. About 3/4 of the observed hard X-rays arise from the scattered component, reducing the equivalent width of the iron K alpha line. The implied ratio of 1-10 keV X-ray luminosity to bolometric luminosity, L_x/L_bol \sim 2%, is typical of Sy 1 galaxies and radio-quiet QSOs of comparable bolometric luminosities, and indicates that the bolometric luminosity is dominated by the AGN. Our estimate of the X-ray luminosity also moves Mrk 231 in line with the correlations found for AGN with extremely strong Fe II emission. A second source separated by about 2 arcminutes is also clearly detected, and contributes about 25% of the total flux.Comment: 11 pages, 3 figures; to appear in ApJ Letter

Non-Einstein geometries in Chiral Gravity

We analyze the asymptotic solutions of Chiral Gravity (Topologically Massive Gravity at \mu l = 1 with Brown-Henneaux boundary conditions) focusing on non-Einstein metrics. A class of such solutions admits curvature singularities in the interior which are reflected as singularities or infinite bulk energy of the corresponding linear solutions. A non-linear solution is found exactly. The back-reaction induces a repulsion of geodesics and a shielding of the singularity by an event horizon but also introduces closed timelike curves.Comment: 11 pages, 3 figures. v2: references and comments on linear stability (Sect.2) adde

Topologically Massive Gravity and Ricci-Cotton Flow

We consider Topologically Massive Gravity (TMG), which is three dimensional general relativity with a cosmological constant and a gravitational Chern-Simons term. When the cosmological constant is negative the theory has two potential vacuum solutions: Anti-de Sitter space and Warped Anti-de Sitter space. The theory also contains a massive graviton state which renders these solutions unstable for certain values of the parameters and boundary conditions. We study the decay of these solutions due to the condensation of the massive graviton mode using Ricci-Cotton flow, which is the appropriate generalization of Ricci flow to TMG. When the Chern-Simons coupling is small the AdS solution flows to warped AdS by the condensation of the massive graviton mode. When the coupling is large the situation is reversed, and warped AdS flows to AdS. Minisuperspace models are constructed where these flows are studied explicitly

The Universal Phase Space of AdS3 Gravity

We describe what can be called the "universal" phase space of AdS3 gravity, in which the moduli spaces of globally hyperbolic AdS spacetimes with compact spatial sections, as well as the moduli spaces of multi-black-hole spacetimes are realized as submanifolds. The universal phase space is parametrized by two copies of the Universal Teichm\"uller space T(1) and is obtained from the correspondence between maximal surfaces in AdS3 and quasisymmetric homeomorphisms of the unit circle. We also relate our parametrization to the Chern-Simons formulation of 2+1 gravity and, infinitesimally, to the holographic (Fefferman-Graham) description. In particular, we obtain a relation between the generators of quasiconformal deformations in each T(1) sector and the chiral Brown-Henneaux vector fields. We also relate the charges arising in the holographic description (such as the mass and angular momentum of an AdS3 spacetime) to the periods of the quadratic differentials arising via the Bers embedding of T(1)xT(1). Our construction also yields a symplectic map from T*T(1) to T(1)xT(1) generalizing the well-known Mess map in the compact spatial surface setting.Comment: 41 pages, 2 figures, revised version accepted for publication in Commun.Math.Phy

Using laboratory-based surveillance data for prevention: an algorithm for detecting Salmonella outbreaks.

By applying cumulative sums (CUSUM), a quality control method commonly used in manufacturing, we constructed a process for detecting unusual clusters among reported laboratory isolates of disease-causing organisms. We developed a computer algorithm based on minimal adjustments to the CUSUM method, which cumulates sums of the differences between frequencies of isolates and their expected means; we used the algorithm to identify outbreaks of Salmonella Enteritidis isolates reported in 1993. By comparing these detected outbreaks with known reported outbreaks, we estimated the sensitivity, specificity, and false-positive rate of the method. Sensitivity by state in which the outbreak was reported was 0%(0/1) to 100%. Specificity was 64% to 100%, and the false-positive rate was 0 to 1