Molecular basis for passive immunotherapy of Alzheimer's disease

Amyloid aggregates of the amyloid-{beta} (A{beta}) peptide are implicated in the pathology of Alzheimer's disease. Anti-A{beta} monoclonal antibodies (mAbs) have been shown to reduce amyloid plaques in vitro and in animal studies. Consequently, passive immunization is being considered for treating Alzheimer's, and anti-A{beta} mAbs are now in phase II trials. We report the isolation of two mAbs (PFA1 and PFA2) that recognize A{beta} monomers, protofibrils, and fibrils and the structures of their antigen binding fragments (Fabs) in complex with the A{beta}(1–8) peptide DAEFRHDS. The immunodominant EFRHD sequence forms salt bridges, hydrogen bonds, and hydrophobic contacts, including interactions with a striking WWDDD motif of the antigen binding fragments. We also show that a similar sequence (AKFRHD) derived from the human protein GRIP1 is able to cross-react with both PFA1 and PFA2 and, when cocrystallized with PFA1, binds in an identical conformation to A{beta}(1–8). Because such cross-reactivity has implications for potential side effects of immunotherapy, our structures provide a template for designing derivative mAbs that target A{beta} with improved specificity and higher affinity

CHY representations for gauge theory and gravity amplitudes with up to three massive particles

We show that a wide class of tree-level scattering amplitudes involving scalars, gauge bosons, and gravitons, up to three of which may be massive, can be expressed in terms of a Cachazo-He-Yuan representation as a sum over solutions of the scattering equations. These amplitudes, when expressed in terms of the appropriate kinematic invariants, are independent of the masses and therefore identical to the corresponding massless amplitudes.Comment: 20 pages, 1 figure; v2: minor typos corrected, published versio

Non-O ABO blood group genotypes differ in their associations with Plasmodium falciparum rosetting and severe malaria

Blood group O is associated with protection against severe malaria and reduced size and stability of P. falciparum-host red blood cell (RBC) rosettes compared to non-O blood groups. Whether the non-O blood groups encoded by the specific ABO genotypes AO, BO, AA, BB and AB differ in their associations with severe malaria and rosetting is unknown. The A and B antigens are host RBC receptors for rosetting, hence we hypothesized that the higher levels of A and/or B antigen on RBCs from AA, BB and AB genotypes compared to AO/BO genotypes could lead to larger rosettes, increased microvascular obstruction and higher risk of malaria pathology. We used a case-control study of Kenyan children and in vitro adhesion assays to test the hypothesis that “double dose” non-O genotypes (AA, BB, AB) are associated with increased risk of severe malaria and larger rosettes than “single dose” heterozygotes (AO, BO). In the case-control study, compared to OO, the double dose genotypes consistently had higher odds ratios (OR) for severe malaria than single dose genotypes, with AB (OR 1.93) and AO (OR 1.27) showing most marked difference (p = 0.02, Wald test). In vitro experiments with blood group A-preferring P. falciparum parasites showed that significantly larger rosettes were formed with AA and AB host RBCs compared to OO, whereas AO and BO genotypes rosettes were indistinguishable from OO. Overall, the data show that ABO genotype influences P. falciparum rosetting and support the hypothesis that double dose non-O genotypes confer a greater risk of severe malaria than AO/BO heterozygosity

My IoT Puzzle: Debugging IF-THEN Rules Through the Jigsaw Metaphor

End users can nowadays define applications in the format of IF-THEN rules to personalize their IoT devices and online services. Along with the possibility to compose such applications, however, comes the need to debug them, e.g., to avoid unpredictable and dangerous behaviors. In this context, different questions are still unexplored: which visual languages are more appropriate for debugging IF-THEN rules? Which information do end users need to understand, identify, and correct errors? To answer these questions, we first conducted a literature analysis by reviewing previous works on end-user debugging, with the aim of extracting design guidelines. Then, we developed My IoT Puzzle, a tool to compose and debug IF-THEN rules based on the Jigsaw metaphor. My IoT Puzzle interactively assists users in the debugging process with different real-time feedback, and it allows the resolution of conflicts by providing textual and graphical explanations. An exploratory study with 6 participants preliminary confirms the effectiveness of our approach, showing that the usage of the Jigsaw metaphor, along with real-time feedback and explanations, helps users understand and fix conflicts among IF-THEN rules

Suffering in long-term cancer survivors: An evaluation of the PRISM-R2 in a population-based cohort

The Pictorial Representation of Illness and Self Measure-Revised 2 (PRISM-R2) has been developed as generic measure to assess suffering. The aim of this study was to evaluate the ability of this instrument to identify long-term cancer survivors with high levels of suffering who may need additional support. 1299 cancer survivors completed the PRISM-R2, the Short Form Health Survey (SF-36), and the Quality of Life-Cancer Survivors questionnaire (QoL-CS). The PRISM-R2 distinguishes between the Self-Illness Separation (SIS) and Illness Perception Measure (IPM), both measuring aspects of suffering. 112 (9%) cancer survivors reported high suffering according to IPM. This group had a higher cancer stage at diagnosis, more cancer recurrences, more comorbidities, and were lower educated compared to people reporting less suffering. The PRISM-R2 could explain substantial amounts of variance (10-14%) in the psychological aspects of the SF-36 and QoL-CS. The IPM also discriminated statistically and clinically significant between high- and low-health status. The PRISM-R2 proved to be able to discriminate between individuals with good and deteriorated levels of QoL. Further evaluation of its validity and screening potential is recommended

Botulinum toxin in gastric submucosa reduces stimulated HCl production in rats

BACKGROUND: Botulinum toxin blocks acetylcholine release from nerve endings and acts as a long term, reversible inhibitor of muscle contraction as well as of salivary, sweat gland, adrenal and prostatic secretions. The aim of the present study is to investigate whether gastric submucosal injection of botulinum toxin type A reduces stimulated gastric production of HCl. METHODS: Sixty-four rats were randomized in two groups and laparotomized. One group was treated with botulinum toxin-A 10 U by multiple submucosal gastric injections, while the second group was injected with saline. Two weeks later, acid secretion was stimulated by pyloric ligation and acid output was measured. Body weight, food and water intake were also recorded daily. RESULTS: HCl production after pyloric ligation was found to be significantly lower in botulinum toxin-treated rats (657 ± 90.25 micromol HCl vs. 1247 ± 152. P = 0.0017). Botulinum toxin-treated rats also showed significantly lower food intake and weight gain. CONCLUSIONS: Botulinum toxin type A reduces stimulated gastric acidity. This is likely due either to inhibition of the cholinergic stimulation of gastric parietal cells, or to an action on the myenteric nervous plexuses. Reduction of growth and food intake may reflect both impaired digestion and decreased gastric motility

Comparison of embedded and added motor imagery training in patients after stroke: Study protocol of a randomised controlled pilot trial using a mixed methods approach

Copyright @ 2009 Schuster et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Two different approaches have been adopted when applying motor imagery (MI) to stroke patients. MI can be conducted either added to conventional physiotherapy or integrated within therapy sessions. The proposed study aims to compare the efficacy of embedded MI to an added MI intervention. Evidence from pilot studies reported in the literature suggests that both approaches can improve performance of a complex motor skill involving whole body movements, however, it remains to be demonstrated, which is the more effective one.Methods/Design: A single blinded, randomised controlled trial (RCT) with a pre-post intervention design will be carried out. The study design includes two experimental groups and a control group (CG). Both experimental groups (EG1, EG2) will receive physical practice of a clinical relevant motor task ('Going down, laying on the floor, and getting up again') over a two week intervention period: EG1 with embedded MI training, EG2 with MI training added after physiotherapy. The CG will receive standard physiotherapy intervention and an additional control intervention not related to MI.The primary study outcome is the time difference to perform the task from pre to post-intervention. Secondary outcomes include level of help needed, stages of motor task completion, degree of motor impairment, balance ability, fear of falling measure, motivation score, and motor imagery ability score. Four data collection points are proposed: twice during baseline phase, once following the intervention period, and once after a two week follow up. A nested qualitative part should add an important insight into patients' experience and attitudes towards MI. Semi-structured interviews of six to ten patients, who participate in the RCT, will be conducted to investigate patients' previous experience with MI and their expectations towards the MI intervention in the study. Patients will be interviewed prior and after the intervention period.Discussion: Results will determine whether embedded MI is superior to added MI. Findings of the semi-structured interviews will help to integrate patient's expectations of MI interventions in the design of research studies to improve practical applicability using MI as an adjunct therapy technique

Search for CP violation in D0 and D+ decays

A high statistics sample of photoproduced charm particles from the FOCUS (E831) experiment at Fermilab has been used to search for CP violation in the Cabibbo suppressed decay modes D+ to K-K+pi+, D0 to K-K+ and D0 to pi-pi+. We have measured the following CP asymmetry parameters: A_CP(K-K+pi+) = +0.006 +/- 0.011 +/- 0.005, A_CP(K-K+) = -0.001 +/- 0.022 +/- 0.015 and A_CP(pi-pi+) = +0.048 +/- 0.039 +/- 0.025 where the first error is statistical and the second error is systematic. These asymmetries are consistent with zero with smaller errors than previous measurements.Comment: 12 pages, 4 figure

A Study of D0 --> K0(S) K0(S) X Decay Channels

Using data from the FOCUS experiment (FNAL-E831), we report on the decay of $D^0$ mesons into final states containing more than one $K^0_S$. We present evidence for two Cabibbo favored decay modes, $D^0\to K^0_SK^0_S K^- \pi^+$ and $D^0\to K^0_SK^0_S K^+ \pi^-$, and measure their combined branching fraction relative to $D^0\to \bar{K} ^0\pi^+\pi^-$ to be $\frac{\Gamma(D^0\to K^0_SK^0_SK^{\pm}\pi^{\mp})}{\Gamma(D^0\to \bar{K} ^0\pi^+\pi^-)}$ = 0.0106 $\pm$ 0.0019 $\pm$ 0.0010. Further, we report new measurements of $\frac{\Gamma(D^0\to K^0_SK^0_SK^0_S)}{\Gamma(D^0\to \bar{K} ^0\pi^+\pi^-)}$ = 0.0179 $\pm$ 0.0027 $\pm$ 0.0026, $\frac{\Gamma(D^0\to K^0\bar{K} ^0)}{\Gamma(D^0\to \bar{K} ^0\pi^+\pi^-)}$ = 0.0144 $\pm$ 0.0032 $\pm$ 0.0016, and $\frac{\Gamma(D^0\to K^0_SK^0_S\pi^+\pi^-)}{\Gamma(D^0\to \bar{K} ^0\pi^+\pi^-)}$ = 0.0208 $\pm$ 0.0035 $\pm$ 0.0021 where the first error is statistical and the second is systematic.Comment: 11 pages, 3 figures, typos correcte

Motor neuronopathy with dropped hands and downbeat nystagmus: A distinctive disorder? A case report

BACKGROUND: Eye movements are clinically normal in most patients with motor neuron disorders until late in the disease course. Rare patients are reported to show slow vertical saccades, impaired smooth pursuit, and gaze-evoked nystagmus. We report clinical and oculomotor findings in three patients with motor neuronopathy and downbeat nystagmus, a classic sign of vestibulocerebellar disease. CASE PRESENTATION: All patients had clinical and electrodiagnostic features of anterior horn cell disease. Involvement of finger and wrist extensors predominated, causing finger and wrist drop. Bulbar or respiratory dysfunction did not occur. All three had clinically evident downbeat nystagmus worse on lateral and downgaze, confirmed on eye movement recordings using the magnetic search coil technique in two patients. Additional oculomotor findings included alternating skew deviation and intermittent horizontal saccadic oscillations, in one patient each. One patient had mild cerebellar atrophy, while the other two had no cerebellar or brainstem abnormality on neuroimaging. The disorder is slowly progressive, with survival up to 30 years from the time of onset. CONCLUSION: The combination of motor neuronopathy, characterized by early and prominent wrist and finger extensor weakness, and downbeat nystagmus with or without other cerebellar eye movement abnormalities may represent a novel motor neuron syndrome