Project description:Translation in cognitive neuroscience remains beyond the horizon, brought no closer by supposed major advances in our understanding of the brain. Unless our explanatory models descend to the individual level-a cardinal requirement for any intervention-their real-world applications will always be limited. Drawing on an analysis of the informational properties of the brain, here we argue that adequate individualisation needs models of far greater dimensionality than has been usual in the field. This necessity arises from the widely distributed causality of neural systems, a consequence of the fundamentally adaptive nature of their developmental and physiological mechanisms. We discuss how recent advances in high-performance computing, combined with collections of large-scale data, enable the high-dimensional modelling we argue is critical to successful translation, and urge its adoption if the ultimate goal of impact on the lives of patients is to be achieved.
Project description:Sympathovagal imbalance contributes to progressive worsening of HF (HF) and is associated with untoward clinical outcomes. Based on compelling pre-clinical studies which supported the role of autonomic modulation in HF models, a series of clinical studies were initiated using spinal cord stimulation (SCS), vagus nerve stimulation (VNS) and baroreceptor activation therapy (BAT) in patients with HF with a reduced ejection fraction (HFrEF). While the phase II studies with BAT remain encouraging, the larger clinical studies with SCS and VNS have yielded disappointing results. Here we will focus on the pre-clinical studies that supported the role of neuromodulation in the failing heart, as well provide a critical review of the recent clinical trials that have sought to modulate autonomic tone in HF patients. This review will conclude with an analysis of some of the difficulties in translating device-based modulation of the autonomic nervous from pre-clinical models into successful clinical trials, as well as provide suggestions for how to move the field of neuromodulation forward.
Project description:Lymphangioleiomyomatosis (LAM) is a cystic lung disease of women resulting from mutations in tuberous sclerosis complex (TSC) genes that suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway. mTORC1 activation enhances a plethora of anabolic cellular functions, mainly via the activation of mRNA translation through stimulation of ribosomal protein S6 kinase (S6K1)/ribosomal protein S6 (S6) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1)/eukaryotic translation initiation factor 4E (eIF4E). Rapamycin (sirolimus), an allosteric inhibitor of mTORC1, stabilises lung function in many but not all LAM patients and, upon cessation of the drug, disease progression resumes. At clinically tolerable concentrations, rapamycin potently inhibits the ribosomal S6K1/S6 translation ribosome biogenesis and elongation axis, but not the translation 4E-BP1/eIF4E initiation axis. In this mini-review, we propose that inhibition of mTORC1-driven translation initiation is an obvious but underappreciated therapeutic strategy in LAM, TSC and other mTORC1-driven diseases.
Project description:MicroRNAs (miRNAs) are endogenous, ~22-nucleotide-long, noncoding RNAs that play critical roles in physiology and disease via mechanisms that remain obscure. Although numerous studies implicate miRNAs in repression of translation, more recent reports suggest that the major role of miRNAs is in reduction of target mRNA stability. Because mRNA translation and stability are intimately connected, it has been a challenge to establish whether miRNAs induce translational repression, mRNA decay, or both. If miRNAs reduce both mRNA translation and stability, the timing and contribution of each process to overall repression is unclear. Indeed, it has been debated whether mRNA decay is a cause or consequence of miRNA-mediated translational repression. On the other hand, if these events are mutually exclusive, what determines which mechanism is used? In a recent issue of Science, Bazzini et al (2012) use genome-wide ribosome footprinting and RNA sequencing (RNA-Seq) to demonstrate that in developing zebrafish embryos, miR-430 naturally represses translation initiation of target mRNAs, followed by their deadenylation and decay.
Project description:Land transport is an unavoidable experience for most livestock, yet there is limited research comparing animal welfare under different conditions. We video recorded sheep responses during short (2 h) commercial road transport journeys. Using Qualitative Behavioural Assessment, observers (blinded to the treatments) scored the behavioural expression of sheep and reached significant consensus in their scoring patterns (p < 0.001). There were also significant effects of vehicle crate design (sheep transported in a 'standard' crate were more calm/relaxed than those transported in a 'convertible' crate), deck position (sheep on upper decks were more curious/alert than those on lower decks), and sheep breed (fat-tail sheep were more agitated/distressed than merino sheep) on observer scores. We only found marginal differences for sheep originating from feedlot or saleyard. Significant effects of vehicle driver (included as a random factor in all but one of our analyses) suggest driving patterns contributed to demeanour of the sheep. Finally, the fourteen drivers who participated in the study were asked their opinions on livestock transport; none of the factors we tested were identified by drivers as important for sheep welfare during transport. This study supports the use of qualitative measures in transport and revealed differences that could inform truck design.
Project description:Neuroimaging studies implicate the ventromedial prefrontal cortex (vmPFC) in a wide range of emotional and cognitive functions, and changes in activity within vmPFC have been linked to the aetiology and successful treatment of depression. However, this is a large, structurally heterogeneous region and the extent to which this structural heterogeneity reflects functional heterogeneity remains unclear. Causal studies in animals should help address this question but attempts to map findings from vmPFC studies in rodents onto human imaging studies highlight cross-species discrepancies between structural homology and functional analogy. Bridging this gap, recent studies in marmosets - a species of new world monkey in which the overall organization of vmPFC is more like humans than that of rodents - have revealed that over-activation of the caudal subcallosal region of vmPFC, area 25, but not neighbouring area 32, heightens reactivity to negatively valenced stimuli whilst blunting responsivity to positively valenced stimuli. These co-occurring states resemble those seen in depressed patients, which are associated with increased activity in caudal subcallosal regions. In contrast, only reward blunting but not heightening of threat reactivity is seen following over-activation of the structurally homologous region in rodents. To further advance understanding of the role of vmPFC in the aetiology and treatment of depression, future work should focus on the behaviourally specific networks by which vmPFC regions have their effects, together with characterization of cross-species similarities and differences in function.
Project description:This article discusses challenges of language differences in qualitative research, when participants and the main researcher have the same non-English native language and the non-English data lead to an English publication. Challenges of translation are discussed from the perspective that interpretation of meaning is the core of qualitative research. As translation is also an interpretive act, meaning may get lost in the translation process. Recommendations are suggested, aiming to contribute to the best possible representation and understanding of the interpreted experiences of the participants and thereby to the validity of qualitative research.
Project description:Cytoplasmic localization of the prion protein (PrP) has been observed in different species and cell types. We have investigated this poorly understood phenomenon by expressing fusion proteins of sheep prion protein and green fluorescent protein ((GFP)PrP) in N2a cells, with variable sequence context surrounding the start codon Met(1). (GFP)PrP expressed with the wild-type sequence was transported normally through the secretory pathway to the cell surface with acquisition of N-glycan groups, but two N-terminal fragments of (GFP)PrP were detected intracellularly, starting in frame from Met(17). When (GFP)PrP was expressed with a compromised Kozak sequence ((GFP)PrP*), dispersed intracellular fluorescence was observed. A similar switch from pericellular to intracellular PrP localization was seen when analogous constructs of sheep PrP, without inserted GFP, were expressed, showing that this phenomenon is not caused by the GFP tag. Western blotting revealed a reduction in glycosylated forms of (GFP)PrP*, whereas the N-terminal fragments starting from Met(17) were still present. Formation of these N-terminal fragments was completely abolished when Met(17) was replaced by Thr, indicating that leaky ribosomal scanning occurs for normal sheep PrP and that translation from Met(17) is the cause of the aberrant cytoplasmic localization observed for a fraction of the protein. In contrast, the same phenomenon was not detected upon expression of similar constructs for mouse PrP. Analysis of samples from sheep brain allowed immunological detection of N-terminal PrP fragments, indicating that sheep PrP is subject to similar processing mechanisms in vivo.