Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders

A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS) disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC)-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer’s Disease (AD), and the psychiatric disorder schizophrenia (SZ), we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature data in order to c

An efficient platform for astrocyte differentiation from human induced pluripotent stem cells

Summary: Growing evidence implicates the importance of glia, particularly astrocytes, in neurological and psychiatric diseases. Here, we describe a rapid and robust method for the differentiation of highly pure populations of replicative astrocytes from human induced pluripotent stem cells (hiPSCs), via a neural progenitor cell (NPC) intermediate. We evaluated this protocol across 42 NPC lines (derived from 30 individuals). Transcriptomic analysis demonstrated that hiPSC-astrocytes from four individuals are highly similar to primary human fetal astrocytes and characteristic of a non-reactive state. hiPSC-astrocytes respond to inflammatory stimulants, display phagocytic capacity, and enhance microglial phagocytosis. hiPSC-astrocytes also possess spontaneous calcium transient activity. Our protocol is a reproducible, straightforward (single medium), and rapid (<30 days) method to generate populations of hiPSC-astrocytes that can be used for neuron-astrocyte and microglia-astrocyte co-cultures for the study of neuropsychiatric disorders. : Brennand, Goate, and colleagues report a rapid and robust method for the differentiation of highly pure populations of replicative astrocytes from human induced pluripotent stem cells (hiPSCs) via a neural progenitor cell (NPC) intermediate. hiPSC-astrocytes resemble primary human fetal astrocytes, have a transcriptional signature consistent with a non-reactive state, respond to inflammatory stimulants, and enhance microglial phagocytosis. Keywords: human induced pluripotent stem cell, iPSC, astrocyt

Face the Music and Glance: How Nonverbal Behaviour Aids Human Robot Relationships Based in Music

It is our hypothesis that improvised musical interaction will be able to provide the extended engagement often failing others during long term Human Robot Interaction (HRI) trials. Our previous work found that simply framing sessions with their drumming robot Mortimer as social interactions increased both social presence and engagement, two factors we feel are crucial to developing and maintaining a positive and meaningful relationship between human and robot. For this study we investigate the inclusion of the additional social modalities, namely head pose and facial expression, as nonverbal behaviour has been shown to be an important conveyor of information in both social and musical contexts. Following a 6 week experimental study using automatic behavioural metrics, results demonstrate those subjected to nonverbal behaviours not only spent more time voluntarily with the robot, but actually increased the time they spent as the trial progressed. Further, that they interrupted the robot less during social interactions and played for longer uninterrupted. Conversely, they also looked at the robot less in both musical and social contexts. We take these results as support for open ended musical activity providing a solid grounding for human robot relationships and the improvement of this by the inclusion of appropriate nonverbal behaviours

Three-body correlations in Borromean halo nuclei

Three-body correlations in the dissociation of two-neutron halo nuclei are explored using a technique based on intensity interferometry and Dalitz plots. This provides for the combined treatment of both the n-n and core-n interactions in the exit channel. As an example, the breakup of 14Be into 12Be+n+n by Pb and C targets has been analysed and the halo n-n separation extracted. A finite delay between the emission of the neutrons in the reaction on the C target was observed and is attributed to 13Be resonances populated in sequential breakup.Comment: 5 pages, 4 figures, submitted to PR

Light-particle emission from the fissioning nuclei 126Ba, 188Pt and (266,272,278)/110: theoretical predictions and experimental results

We present a comparison of our model treating fission dynamics in conjunction with light-particle (n, p, alpha) evaporation with the available experimental data for the nuclei 126Ba, 188Pt and three isotopes of the element Z=110. The dynamics of the symmetric fission process is described through the solution of a classical Langevin equation for a single collective variable characterizing the nuclear deformation along the fission path. A microscopic approach is used to evaluate the emission rates for pre-fission light particles. Entrance-channel effects are taken into account by generating an initial spin distribution of the compound nucleus formed by the fusion of two deformed nuclei with different relative orientations

Reduced LYNX1 expression in transcriptome of human iPSC-derived neural progenitors modeling fragile X syndrome

Lack of FMR1 protein results in fragile X syndrome (FXS), which is the most common inherited intellectual disability syndrome and serves as an excellent model disease to study molecular mechanisms resulting in neuropsychiatric comorbidities. We compared the transcriptomes of human neural progenitors (NPCs) generated from patient-derived induced pluripotent stem cells (iPSCs) of three FXS and three control male donors. Altered expression of RAD51C, PPIL3, GUCY1A2, MYD88, TRAPPC4, LYNX1, and GTF2A1L in FXS NPCs suggested changes related to triplet repeat instability, RNA splicing, testes development, and pathways previously shown to be affected in FXS. LYNX1 is a cholinergic brake of tissue plasminogen activator (tPA)-dependent plasticity, and its reduced expression was consistent with augmented tPA-dependent radial glial process growth in NPCs derived from FXS iPSC lines. There was evidence of human iPSC line donor-dependent variation reflecting potentially phenotypic variation. NPCs derived from an FXS male with concomitant epilepsy expressed differently several epilepsy-related genes, including genes shown to cause the auditory epilepsy phenotype in the murine model of FXS. Functional enrichment analysis highlighted regulation of insulin-like growth factor pathway in NPCs modeling FXS with epilepsy. Our results demonstrated potential of human iPSCs in disease modeling for discovery and development of therapeutic interventions by showing early gene expression changes in FXS iPSC-derived NPCs consistent with the known pathophysiological changes in FXS and by revealing disturbed FXS progenitor growth linked to reduced expression of LYNX1, suggesting dysregulated cholinergic system.Peer reviewe

Structure of 13^{13}Be probed via secondary beam reactions

The low-lying level structure of the unbound neutron-rich nucleus $^{13}$Be has been investigated via breakup on a carbon target of secondary beams of $^{14,15}$B at 35 MeV/nucleon. The coincident detection of the beam velocity $^{12}$Be fragments and neutrons permitted the invariant mass of the $^{12}$Be+$n$ and $^{12}$Be+$n$+$n$ systems to be reconstructed. In the case of the breakup of $^{15}$B, a very narrow structure at threshold was observed in the $^{12}$Be+$n$ channel. Contrary to earlier stable beam fragmentation studies which identified this as a strongly interacting $s$-wave virtual state in $^{13}$Be, analysis here of the $^{12}$Be+$n$+$n$ events demonstrated that this was an artifact resulting from the sequential-decay of the $^{14}$Be(2$^+$) state. Single-proton removal from $^{14}$B was found to populate a broad low-lying structure some 0.70 MeV above the neutron-decay threshold in addition to a less prominent feature at around 2.4 MeV. Based on the selectivity of the reaction and a comparison with (0-3)$\hbar\omega$ shell-model calculations, the low-lying structure is concluded to most probably arise from closely spaced J$^\pi$=1/2$^+$ and 5/2$^+$ resonances (E$_r$=0.40$\pm$0.03 and 0.85$^{+0.15}_{-0.11}$ MeV), whilst the broad higher-lying feature is a second 5/2$^+$ level (E$_r$=2.35$\pm$0.14 MeV). Taken in conjunction with earlier studies, it would appear that the lowest 1/2$^+$ and 1/2$^-$ levels lie relatively close together below 1 MeV.Comment: 14 pages, 13 figures, 2 tables. Accepted for publication in Physical Review

PNAS plus: plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state

The human malaria parasite Plasmodium falciparum is auxotrophic for most amino acids. Its amino acid needs are met largely through the degradation of host erythrocyte hemoglobin; however the parasite must acquire isoleucine exogenously, because this amino acid is not present in adult human hemoglobin. We report that when isoleucine is withdrawn from the culture medium of intraerythrocytic P. falciparum, the parasite slows its metabolism and progresses through its developmental cycle at a reduced rate. Isoleucine-starved parasites remain viable for 72 h and resume rapid growth upon resupplementation. Protein degradation during starvation is important for maintenance of this hibernatory state. Microarray analysis of starved parasites revealed a 60% decrease in the rate of progression through the normal transcriptional program but no other apparent stress response. Plasmodium parasites do not possess a TOR nutrient-sensing pathway and have only a rudimentary amino acid starvation-sensing eukaryotic initiation factor 2α (eIF2α) stress response. Isoleucine deprivation results in GCN2-mediated phosphorylation of eIF2α, but kinase-knockout clones still are able to hibernate and recover, indicating that this pathway does not directly promote survival during isoleucine starvation. We conclude that P. falciparum, in the absence of canonical eukaryotic nutrient stress-response pathways, can cope with an inconsistent bloodstream amino acid supply by hibernating and waiting for more nutrient to be provided

The detection of neutron clusters

A new approach to the production and detection of bound neutron clusters is presented. The technique is based on the breakup of beams of very neutron-rich nuclei and the subsequent detection of the recoiling proton in a liquid scintillator. The method has been tested in the breakup of 11Li, 14Be and 15B beams by a C target. Some 6 events were observed that exhibit the characteristics of a multineutron cluster liberated in the breakup of 14Be, most probably in the channel 10Be+4n. The various backgrounds that may mimic such a signal are discussed in detail.Comment: 11 pages, 12 figures, LPCC 01-1