Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo

Current challenges facing the assessment of the allergenic capacity of food allergens in animal models

Food allergy is a major health problem of increasing concern. The insufficiency of protein sources for human nutrition in a world with a growing population is also a significant problem. The introduction of new protein sources into the diet, such as newly developed innovative foods or foods produced using new technologies and production processes, insects, algae, duckweed, or agricultural products from third countries, creates the opportunity for development of new food allergies, and this in turn has driven the need to develop test methods capable of characterizing the allergenic potential of novel food proteins. There is no doubt that robust and reliable animal models for the identification and characterization of food allergens would be valuable tools for safety assessment. However, although various animal models have been proposed for this purpose, to date, none have been formally validated as predictive and none are currently suitable to test the allergenic potential of new foods. Here, the design of various animal models are reviewed, including among others considerations of species and strain, diet, route of administration, dose and formulation of the test protein, relevant controls and endpoints measured

Public Attitudes Towards Moral Enhancement. Evidence that Means Matter Morally

To gain insight into the reasons that the public may have for endorsing or eschewing pharmacological moral enhancement for themselves or for others, we used empirical tools to explore public attitudes towards these issues. Participants (N = 293) from the United States were recruited via Amazon’s Mechanical Turk and were randomly assigned to read one of several contrastive vignettes in which a 13-year-old child is described as bullying another student in school and then is offered an empathy-enhancing program. The empathy-enhancing program is described as either involving taking a pill or playing a video game on a daily basis for four weeks. In addition, participants were asked to imagine either their own child bullying another student at school, or their own child being bullied by another student. This resulted in a 2 × 2 between-subjects design. In an escalating series of morally challenging questions, we asked participants to rate their overall support for the program; whether they would support requiring participation; whether they would support requiring participation of children who are at higher risk to become bullies in the future; whether they would support requiring participation of all children or even the entire population; and whether they would be willing to participate in the program themselves. We found that people were significantly more troubled by pharmacological as opposed to non-pharmacological moral enhancement interventions. The results indicate that members of the public for the greater part oppose pharmacological moral bioenhancement, yet are open to non-biomedical means to attain moral enhancement. [248 words]

The Impact in Older Women of Ovarian FMR1 Genotypes and Sub-Genotypes on Ovarian Reserve

We recently associated ovarian FMR1genotypes and sub-genotypes with distinct ovarian aging patterns. How they impact older females is, however, unknown. We, therefore, investigated 217 consecutive first in vitro fertilization (IVF) cycles in women >40 assessing oocyte yields, stratified for better (anti-Müllerian hormone, AMH >1.05 ng/mL) or poorer (AMH≤1.05 ng/mL) functional reserve (FOR)). Mean age was 42.4±2.0 years, mean AMH 0.76±0.92 ng/mL and mean oocyte yield 5.3±5.4. Overall, and in women with better FOR, FMR1 did not affect oocyte yields. With poorer FOR (AMH≤1.05 ng/mL) women with het-norm/high, however, demonstrated higher oocyte yields (5.0±3.8) than those with het-norm/low sub-genotype 3.1±2.5; P = 0.03), confirmed after log conversion. Known associated with low FOR at young age, het-norm/high, thus, appears to preserve FOR into older age, and both het sub-genotypes appear to expand female reproductive lifespan into opposite directions

Physician Attitudes towards Pharmacological Cognitive Enhancement: Safety Concerns Are Paramount

The ethical dimensions of pharmacological cognitive enhancement have been widely discussed in academic circles and the popular media, but missing from the conversation have been the perspectives of physicians - key decision makers in the adoption of new technologies into medical practice. We queried primary care physicians in major urban centers in Canada and the United States with the aim of understanding their attitudes towards cognitive enhancement. Our primary hypothesis was that physicians would be more comfortable prescribing cognitive enhancers to older patients than to young adults. Physicians were presented with a hypothetical pharmaceutical cognitive enhancer that had been approved by the regulatory authorities for use in healthy adults, and was characterized as being safe, effective, and without significant adverse side effects. Respondents overwhelmingly reported increasing comfort with prescribing cognitive enhancers as the patient age increased from 25 to 65. When asked about their comfort with prescribing extant drugs that might be considered enhancements (sildenafil, modafinil, and methylphenidate) or our hypothetical cognitive enhancer to a normal, healthy 40 year old, physicians were more comfortable prescribing sildenafil than any of the other three agents. When queried as to the reasons they answered as they did, the most prominent concerns physicians expressed were issues of safety that were not offset by the benefit afforded the individual, even in the face of explicit safety claims. Moreover, many physicians indicated that they viewed safety claims with considerable skepticism. It has become routine for safety to be raised and summarily dismissed as an issue in the debate over pharmacological cognitive enhancement; the observation that physicians were so skeptical in the face of explicit safety claims suggests that such a conclusion may be premature. Thus, physician attitudes suggest that greater weight be placed upon the balance between safety and benefit in consideration of pharmacological cognitive enhancement

The minimal kinome of Giardia lamblia illuminates early kinase evolution and unique parasite biology

Background: The major human intestinal pathogen Giardia lamblia is a very early branching eukaryote with a minimal genome of broad evolutionary and biological interest. Results: To explore early kinase evolution and regulation of Giardia biology, we cataloged the kinomes of three sequenced strains. Comparison with published kinomes and those of the excavates Trichomonas vaginalis and Leishmania major shows that Giardia's 80 core kinases constitute the smallest known core kinome of any eukaryote that can be grown in pure culture, reflecting both its early origin and secondary gene loss. Kinase losses in DNA repair, mitochondrial function, transcription, splicing, and stress response reflect this reduced genome, while the presence of other kinases helps define the kinome of the last common eukaryotic ancestor. Immunofluorescence analysis shows abundant phospho-staining in trophozoites, with phosphotyrosine abundant in the nuclei and phosphothreonine and phosphoserine in distinct cytoskeletal organelles. The Nek kinase family has been massively expanded, accounting for 198 of the 278 protein kinases in Giardia. Most Neks are catalytically inactive, have very divergent sequences and undergo extensive duplication and loss between strains. Many Neks are highly induced during development. We localized four catalytically active Neks to distinct parts of the cytoskeleton and one inactive Nek to the cytoplasm. Conclusions: The reduced kinome of Giardia sheds new light on early kinase evolution, and its highly divergent sequences add to the definition of individual kinase families as well as offering specific drug targets. Giardia's massive Nek expansion may reflect its distinctive lifestyle, biphasic life cycle and complex cytoskeleton

Immunotherapy with MVA-BN®-HER2 induces HER-2-specific Th1 immunity and alters the intratumoral balance of effector and regulatory T cells

MVA-BN®-HER2 is a new candidate immunotherapy designed for the treatment of HER-2-positive breast cancer. Here, we demonstrate that a single treatment with MVA-BN®-HER2 exerts potent anti-tumor efficacy in a murine model of experimental pulmonary metastasis. This anti-tumor efficacy occurred despite a strong tumor-mediated immunosuppressive environment characterized by a high frequency of regulatory T cells (Treg) in the lungs of tumor-bearing mice. Immunogenicity studies showed that treatment with MVA-BN®-HER2 induced strongly Th1-dominated HER-2-specific antibody and T-cell responses. MVA-BN®-HER2-induced anti-tumor activity was characterized by an increased infiltration of lungs with highly activated, HER-2-specific, CD8+CD11c+ T cells accompanied by a decrease in the frequency of Treg cells in the lung, resulting in a significantly increased ratio of effector T cells to Treg cells. In contrast, administration of HER2 protein formulated in Complete Freund’s Adjuvant (CFA) induced a strongly Th2-biased immune response to HER-2. However, this did not lead to significant infiltration of the tumor-bearing lungs by CD8+ T cells or the decrease in the frequency of Treg cells nor did it result in anti-tumor efficacy. In vivo depletion of CD8+ cells confirmed that CD8 T cells were required for the anti-tumor activity of MVA-BN®-HER2. Furthermore, depletion of CD4+ or CD25+ cells demonstrated that tumor-induced Treg cells promoted tumor growth and that CD4 effector cells also contribute to MVA-BN®-HER2-mediated anti-tumor efficacy. Taken together, our data demonstrate that treatment with MVA-BN®-HER2 controls tumor growth through mechanisms including the induction of Th1-biased HER-2-specific immune responses and the control of tumor-mediated immunosuppression

The Virtual Teacher (VT) Paradigm: Learning New Patterns of Interpersonal Coordination Using the Human Dynamic Clamp

The Virtual Teacher paradigm, a version of the Human Dynamic Clamp (HDC), is introduced into studies of learning patterns of inter-personal coordination. Combining mathematical modeling and experimentation, we investigate how the HDC may be used as a Virtual Teacher (VT) to help humans co-produce and internalize new inter-personal coordination pattern(s). Human learners produced rhythmic finger movements whilst observing a computer-driven avatar, animated by dynamic equations stemming from the well-established Haken-Kelso-Bunz (1985) and Schöner-Kelso (1988) models of coordination. We demonstrate that the VT is successful in shifting the pattern co-produced by the VT-human system toward any value (Experiment 1) and that the VT can help humans learn unstable relative phasing patterns (Experiment 2). Using transfer entropy, we find that information flow from one partner to the other increases when VT-human coordination loses stability. This suggests that variable joint performance may actually facilitate interaction, and in the long run learning. VT appears to be a promising tool for exploring basic learning processes involved in social interaction, unraveling the dynamics of information flow between interacting partners, and providing possible rehabilitation opportunities