Canadian epilepsy priority-setting partnership: Toward a new national research agenda

Background: Health research agendas are often set by researchers or by industry and may not reflect the needs and priorities of end users. This priority-setting partnership (PSP) for epilepsy was undertaken to identify the most pressing unanswered questions about epilepsy and seizures from the perspective of people with epilepsy (PWE) and their care providers. Methods: Using the methodology developed by the James Lind Alliance (JLA), evidence uncertainties were gathered via online surveys from stakeholders across Canada. Submissions were formed into summary questions and checked against existing evidence to determine if they were true uncertainties. Verified uncertainties were then ranked by patients, caregivers, and healthcare providers and a final workshop was held to reach a consensus on the top 10 priorities. Results: The final top 10 list reflects the priority areas of focus for research as identified by the Canadian epilepsy community, including genetic markers for diagnosis and treatment, concerns about living with the long-term effects of epilepsy, and addressing knowledge gaps in etiology and treatment approaches. Conclusion: This project represents the first systematic evidence of patient- and clinician-centered research priorities for epilepsy. The results of this priority-setting exercise provide an opportunity for researchers and funding agencies to align their agendas with the values and needs of the epilepsy community in order to improve clinical outcomes and quality of life (QOL) for PWE

First Universities Allied for Essential Medicines (UAEM) Neglected Diseases and Innovation Symposium

Universities Allied for Essential Medicines organized its first Neglected Diseases and Innovation Symposium to address expanding roles of public sector research institutions in innovation in research and development of biomedical technologies for treatment of diseases, particularly neglected tropical diseases. Universities and other public research institutions are increasingly integrated into the pharmaceutical innovation system. Academic entities now routinely undertake robust high-throughput screening and medicinal chemistry research programs to identify lead compounds for small molecule drugs and novel drug targets. Furthermore, product development partnerships are emerging between academic institutions, non-profit entities, and biotechnology and pharmaceutical companies to create diagnostics, therapies, and vaccines for diseases of the poor. With not for profit mission statements, open access publishing standards, open source platforms for data sharing and collaboration, and a shift in focus to more translational research, universities and other public research institutions are well-placed to accelerate development of medical technologies, particularly for neglected tropical diseases

Circadian Transcription Contributes to Core Period Determination in Drosophila

The Clock–Cycle (CLK–CYC) heterodimer constitutes a key circadian transcription complex in Drosophila. CYC has a DNA-binding domain but lacks an activation domain. Previous experiments also indicate that most of the transcriptional activity of CLK–CYC derives from the glutamine-rich region of its partner CLK. To address the role of transcription in core circadian timekeeping, we have analyzed the effects of a CYC–viral protein 16 (VP16) fusion protein in the Drosophila system. The addition of this potent and well-studied viral transcriptional activator (VP16) to CYC imparts to the CLK–CYC-VP16 complex strongly enhanced transcriptional activity relative to that of CLK–CYC. This increase is manifested in flies expressing CYC-VP16 as well as in S2 cells. These flies also have increased levels of CLK–CYC direct target gene mRNAs as well as a short period, implicating circadian transcription in period determination. A more detailed examination of reporter gene expression in CYC-VP16–expressing flies suggests that the short period is due at least in part to a more rapid transcriptional phase. Importantly, the behavioral effects require a period (per) promoter and are therefore unlikely to be merely a consequence of generally higher PER levels. This indicates that the CLK–CYC-VP16 behavioral effects are a consequence of increased per transcription. All of this also suggests that the timing of transcriptional activation and not the activation itself is the key event responsible for the behavioral effects observed in CYC-VP16-expressing flies. The results taken together indicate that circadian transcription contributes to core circadian function in Drosophila

Linking the Teneurin-latrophilin Interaction with Glucose Metabolism: Role of the teneurin C-terminal Associated Peptide (TCAP)-1

A newly discovered neuropeptide called teneurin C-terminal associated peptide (TCAP) exists in four isoforms, and is functionally related to its proprotein ‘teneurin’. TCAP-1 is expressed as a separate mRNA distinct from teneurin-1 and its mature peptide binds to the latrophilin (LPHN) G-protein coupled receptors (GPCRs) and associates with β-dystroglycan, to activate a neurotrophic-like signal cascade, stimulating energy production and regulating cytoskeletal development. I found reduced levels of diacylglycerol (DAG), but not inositol triphosphate (IP3), in TCAP-1-treated hippocampal cells, indicating that TCAP-1 may downregulate the LPHN pathway. Immunocytochemical analyses show TCAP-1 co-localizes with LPHN-1 in hippocampal cells. I also confirm the endogenous mRNA expression of LPHN-1 and -3, and all four teneurins and TCAPs in mouse hippocampal and hypothalamic cells. An in vivo approach established that TCAP-1 significantly reduces serum glucose levels in diabetic rodents. Thus, the teneurin/TCAP-1-LPHN interaction may strengthen synapse formation and increase brain glucose utilization during stressful conditions.M.Sc

Auditory and visual interhemispheric communication in musicians and non-musicians.

The corpus callosum (CC) is a brain structure composed of axon fibres linking the right and left hemispheres. Musical training is associated with larger midsagittal cross-sectional area of the CC, suggesting that interhemispheric communication may be faster in musicians. Here we compared interhemispheric transmission times (ITTs) for musicians and non-musicians. ITT was measured by comparing simple reaction times to stimuli presented to the same hemisphere that controlled a button-press response (uncrossed reaction time), or to the contralateral hemisphere (crossed reaction time). Both visual and auditory stimuli were tested. We predicted that the crossed-uncrossed difference (CUD) for musicians would be smaller than for non-musicians as a result of faster interhemispheric transfer times. We did not expect a difference in CUDs between the visual and auditory modalities for either musicians or non-musicians, as previous work indicates that interhemispheric transfer may happen through the genu of the CC, which contains motor fibres rather than sensory fibres. There were no significant differences in CUDs between musicians and non-musicians. However, auditory CUDs were significantly smaller than visual CUDs. Although this auditory-visual difference was larger in musicians than non-musicians, the interaction between modality and musical training was not significant. Therefore, although musical training does not significantly affect ITT, the crossing of auditory information between hemispheres appears to be faster than visual information, perhaps because subcortical pathways play a greater role for auditory interhemispheric transfer

Crossed-uncrossed reaction time differences of visual and auditory modalities in musicians and non-musicians.

<p>CUDs in milliseconds (ms) were calculated by subtracting the mean reaction times of the uncrossed condition from the mean reaction times of the crossed condition. <b>The interaction between Musicianship and Modality is not significant (</b><b><i>p</i></b><b> =  0.22).</b></p

Teneurins, TCAP, and latrophilins: roles in the etiology of mood disorders

Mood disorders, including anxiety and depression, are thought to be characterized by disrupted neuronal synapses and altered brain plasticity. The etiology is complex, involving numerous regions of the brain, comprising a multitude of neurotransmitter and neuromodulator systems. Recently, new studies on the teneurins, an evolutionary ancient family of type II transmembrane proteins have been shown to interact with latrophilins (LPHN), a similarly phylogenetically old family of adhesion G protein-coupled receptors (GPCR) forming a transsynaptic adhesion and ligand-receptor pair. Each of the four teneurin proteins contains bioactive sequences termed the teneurin C-terminal associated peptides (TCAP-1–4), which possess a number of neuromodulatory effects. The primary structures of the TCAP are most closely similar to the corticotropin-releasing factor (CRF) family of peptides. CRF has been implicated in a number of diverse mood disorders. Via an association with dystroglycans, synthetic TCAP-1 administration to both embryonic and primary hippocampal cultures induces long-term changes in neuronal structure, specifically increased neurite outgrowth, dendritic branching, and axon growth. Rodent models treated with TCAP-1 show reduced anxiety responses in the elevated plus-maze, openfield test, and acoustic startle test and inhibited CRF-mediated cocaine-seeking behaviour. Thus the teneurin/TCAP-latrophilin interaction may play a major role in the origin, development and treatment of mood disorders

Interleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection

Il-13 is expressed in neurons and IL-13 ko causes memory impairment. Here, authors show that IL-13 and its receptor IL-13Ra1 are pre- and post-synaptic proteins, respectively, involved in synaptic signaling, plasticity and neuroprotection