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:Although sheep are commonly transported long distances, and sheep welfare during transport is a topic of research and policy discussion, the subject of their fatigue during transport has been under-researched. The current qualitative study, focused on the EU and UK, aimed to critically analyse stakeholder views on issues relating to sheep fatigue, including behavioural indications of fatigue, the interplay between fatigue and other factors, and the practicalities of identifying fatigue in commercial transport conditions. Insight into stakeholder perceptions of these issues could contribute to the body of knowledge regarding sheep fatigue during transport, potentially playing a part in future efforts to improve fatigue understanding and detection. Eighteen experts from different stakeholder groups were interviewed. Reflexive thematic analysis of interview data yielded four themes and three sub-themes. The first theme, "Let's anthropomorphise it a little bit", underscores the pervasiveness of anthropomorphism and suggests using it in a conscious and deliberate way to drive stakeholder engagement and policy change. The second theme, "We think that they're like we are and they're not", cautions against wholesale transfer of human experiences to animals. The third theme, 'See the whole animal', advocates using Qualitative Behaviour Analysis (QBA), proven reliable in other contexts, to deepen and enrich our current understanding of fatigue. The fourth theme, 'Fatigue "never comes up"', highlights the fact that fatigue is rarely if ever discussed in the context of sheep transport. These themes suggest several avenues for future research, including developing QBA-based assessments for fatigue to improve welfare during transport.
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: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:Preclinical animal research has long been a cornerstone in evaluating the efficacy, toxicity, and safety of potential drug treatments before they proceed to human clinical trials. However, given the intricate nature of human physiology and the complexities of diseases such as cancer, this paper critically examines the role of animal experimentation in translational research, both from epistemological and ethical viewpoints. We argue that the ethical obligation to protect animals extends beyond their instrumental value for human benefit; it is rooted in the intrinsic value of their well-being. Consequently, we advocate for a paradigm shift in medical research: the adoption of new approach methodologies (NAMs) not merely as supplementary tools but as complete replacements for animal use in medical studies. In this context, replacement emerges as the key principle-an imperative that should be prioritized over all other considerations.