rudyvdbrink/CitationDatabase huggingface dataset:
Non-invasive imaging of disrupted protein homeostasis induced by proteasome inhibitor treatment using chemical exchange saturation transfer MRI.
Scientific reports, 2018

Proteasome inhibitors (PIs) are now standard of care for several cancers, and noninvasive biomarkers of treatment response are critically required for early patient stratification and treatment personalization. The present study evaluated whether chemical exchange (CEST) magnetic resonance imaging (MRI) can provide measurements that can be used as the noninvasive biomarkers of proteasome inhibition, alongside diffusion MRI and relaxometry. The sensitivity of human colorectal carcinoma cells to the PI Ixazomib was assessed via in vitro and in vivo dose-response experiments. Acute in vivo response to Ixazomib was assessed at three dosing concentrations, using CEST MRI (amide, amine, hydroxyl signals), diffusion MRI (ADC) and relaxometry (T
A conserved role for sleep in supporting Spatial Learning in Drosophila.
Sleep, 2021

Sleep loss and aging impair hippocampus-dependent Spatial Learning in mammalian systems. Here we use the fly Drosophila melanogaster to investigate the relationship between sleep and Spatial Learning in healthy and impaired flies. The Spatial Learning assay is modeled after the Morris Water Maze. The assay uses a "thermal maze" consisting of a 5 × 5 grid of Peltier plates maintained at 36-37°C and a visual panorama. The first trial begins when a single tile that is associated with a specific visual cue is cooled to 25°C. For subsequent trials, the cold tile is heated, the visual panorama is rotated and the flies must find the new cold tile by remembering its association with the visual cue. Significant learning was observed with two different wild-type strains-Cs and 2U, validating our design. Sleep deprivation prior to training impaired Spatial Learning. Learning was also impaired in the classic learning mutant rutabaga (rut); enhancing sleep restored learning to rut mutants. Further, we found that flies exhibited a dramatic age-dependent cognitive decline in Spatial Learning starting at 20-24 days of age. These impairments could be reversed by enhancing sleep. Finally, we find that Spatial Learning requires dopaminergic signaling and that enhancing dopaminergic signaling in aged flies restored learning. Our results are consistent with the impairments seen in rodents and humans. These results thus demonstrate a critical conserved role for sleep in supporting Spatial Learning, and suggest potential avenues for therapeutic intervention during aging.
Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology.
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2020

The cytoprotective PTEN-induced kinase 1 (PINK1)-parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65-Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways are early features of Alzheimer's disease (AD), mitophagy impairments may contribute to the pathogenesis.
Criticality in the conformational phase transition among self-similar groups in intrinsically disordered proteins: Probed by salt-bridge dynamics.
Biochimica et biophysica acta. Proteins and proteomics, 2020

Intrinsically disordered proteins (IDP) serve as one of the key components in the global proteome. In contrast to globular proteins, they harbor an enormous amount of physical flexibility enforcing them to be retained in conformational ensembles rather than stable folds. Previous studies in an aligned direction have revealed the importance of transient dynamical phenomena like that of salt-bridge formation in IDPs to support their physical flexibility and have further highlighted their functional relevance. For this characteristic flexibility, IDPs remain amenable and accessible to different ordered binding partners, supporting their potential multi-functionality. The current study further addresses this complex structure-functional interplay in IDPs using phase transition dynamics to conceptualize the underlying (avalanche type) mechanism of their being distributed across and hopping around degenerate structural states (conformational ensembles). For this purpose, extensive molecular dynamics simulations have been done and the data analyzed from a statistical physics perspective. Investigation of the plausible scope of 'self-organized criticality' (SOC) to fit into the complex dynamics of IDPs was found to be assertive, relating the conformational degeneracy of these proteins to their functional multiplicity. In accordance with the transient nature of 'salt-bridge dynamics', the study further uses it as a probe to explain the structural basis of the proposed criticality in the conformational phase transition among self-similar groups in IDPs. The analysis reveal scale-invariant self-similar fractal geometries in the structural conformations of different IDPs. The insights from the study has the potential to be extended further to benefit structural tinkering of IDPs in their functional characterization and drugging.
Temporal orienting in Parkinson's disease.
The European journal of neuroscience, 2021

Temporal orienting of attention can affect multiple stages of processing to guide adaptive behaviour. We tested whether temporal expectation in different task contexts is compromised in individuals with Parkinson's disease (PD). In Experiment 1 two temporal-orienting tasks were used: a speeded task emphasizing motor preparation and a non-speeded task emphasizing perceptual discrimination using rapid serial visual presentation. In both tasks, auditory cues indicated the likelihood of a target appearing after a short or long interval. In the speeded-response task, participants used the cues to anticipate an easily detectable target stimulus. In the non-speeded perceptual-discrimination task, participants used the cues to help discriminate a target letter embedded in a stream of letters. Relative to healthy participants, participants with PD did not show altered temporal orienting effects in the speeded-response task. However, they were impaired in using temporal cues to improve perceptual discrimination. In Experiment 2, we tested whether the temporal-orienting deficits in the perceptual-discrimination task depended on the requirement to ignore temporally distracting stimuli. We replicated the impaired temporal orienting for perceptual discrimination in an independent group of individuals with PD, and showed the impairment was abolished when individuals were on their dopaminergic medication. In a task without any distracting letters, however, patients off or on medication benefited normally from temporal orienting cues. Our findings suggest that deficits in temporal orienting in individuals with PD interact with specific task demands, such as the requirement to select target from temporally competing distractors.
Negative Life Events as Predictors of Anxiety Outcomes: An Examination of Event Type.
Research on child and adolescent psychopathology, 2021

Long-term follow-up studies of anxiety treatment have found that greater exposure to negative life events (NLEs) predicts poorer anxiety outcomes, but none have examined whether specific types of NLEs are differentially associated with child outcomes. This study examined the frequency of NLEs and whether specific types of NLEs were associated with increased risk of having an anxiety disorder 6.5 years post randomization. Participants were 319 adolescents and adults, ages 11 to 26 (M = 17), enrolled in Child/Adolescent Anxiety Multimodal Extended Long-term Study. At their first follow-up visit, participants completed a diagnostic interview and a 40-item Life Events Scale that reflected whether specific events occurred since their last post treatment assessment. Life events were categorized into domains (i.e., family, academic, health, and social) via researcher consensus. Participants reported having experienced an average of four NLEs. Participants with an anxiety disorder at follow-up were significantly more likely to have failed a grade in school (OR = 5.9) and experienced a negative change in acceptance by peers (OR = 4.9; ps < 0.001). After controlling for gender, age, race, and SES, a greater number of NLEs in the academic domain increased the odds of having an anxiety disorder at follow-up (OR = 2.4, p < 0.001). No other domains were predictive of disorder status at follow-up. Findings highlight the value of examining specific NLEs in relation to the long-term child anxiety outcomes.
When does cultural transmission favour or instead substitute for general intelligence?
The Behavioral and brain sciences, 2017

The cultural intelligence hypothesis is an exciting new development. The hypothesis that it encourages general intelligence is intriguing, but it presents a paradox insofar as social learning is often suggested to instead reduce reliance on individual cognition and exploration. There is thus a need to specify more clearly the contexts in which cultural transmission may select for general intelligence.
Fatigue in multiple sclerosis is associated with multimodal interoceptive abnormalities.
Multiple sclerosis (Houndmills, Basingstoke, England), 2020

Fatigue ranks among the most common and disabling symptoms in multiple sclerosis (MS). Recent theoretical works have surmised that this trait might be related to alterations across interoceptive mechanisms. However, this hypothesis has not been empirically evaluated.
Patterns of motor recovery and structural neuroplasticity after basal ganglia infarcts.
Neurology, 2020

To elucidate the timeframe and spatial patterns of cortical reorganization after different stroke-induced basal ganglia lesions, we measured cortical thickness at 5 time points over a 6-month period. We hypothesized that cortical reorganization would occur very early and that, along with motor recovery, it would vary based on the stroke lesion site.
Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids.
Translational psychiatry, 2020

Maternal alcohol exposure during pregnancy can substantially impact the development of the fetus, causing a range of symptoms, known as fetal alcohol spectrum disorders (FASDs), such as cognitive dysfunction and psychiatric disorders, with the pathophysiology and mechanisms largely unknown. Recently developed human cerebral organoids from induced pluripotent stem cells are similar to fetal brains in the aspects of development and structure. These models allow more relevant in vitro systems to be developed for studying FASDs than animal models. Modeling binge drinking using human cerebral organoids, we sought to quantify the downstream toxic effects of alcohol (ethanol) on neural pathology phenotypes and signaling pathways within the organoids. The results revealed that alcohol exposure resulted in unhealthy organoids at cellular, subcellular, bioenergetic metabolism, and gene expression levels. Alcohol induced apoptosis on organoids. The apoptotic effects of alcohol on the organoids depended on the alcohol concentration and varied between cell types. Specifically, neurons were more vulnerable to alcohol-induced apoptosis than astrocytes. The alcohol-treated organoids exhibit ultrastructural changes such as disruption of mitochondria cristae, decreased intensity of mitochondrial matrix, and disorganized cytoskeleton. Alcohol exposure also resulted in mitochondrial dysfunction and metabolic stress in the organoids as evidenced by (1) decreased mitochondrial oxygen consumption rates being linked to basal respiration, ATP production, proton leak, maximal respiration and spare respiratory capacity, and (2) increase of non-mitochondrial respiration in alcohol-treated organoids compared with control groups. Furthermore, we found that alcohol treatment affected the expression of 199 genes out of 17,195 genes analyzed. Bioinformatic analyses showed the association of these dysregulated genes with 37 pathways related to clinically relevant pathologies such as psychiatric disorders, behavior, nervous system development and function, organismal injury and abnormalities, and cellular development. Notably, 187 of these genes are critically involved in neurodevelopment, and/or implicated in nervous system physiology and neurodegeneration. Furthermore, the identified genes are key regulators of multiple pathways linked in networks. This study extends for the first time animal models of binge drinking-related FASDs to a human model, allowing in-depth analyses of neurotoxicity at tissue, cellular, subcellular, metabolism, and gene levels. Hereby, we provide novel insights into alcohol-induced pathologic phenotypes, cell type-specific vulnerability, and affected signaling pathways and molecular networks, that can contribute to a better understanding of the developmental neurotoxic effects of binge drinking during pregnancy.
Cortical plasticity in patients with Parkinson's disease a window for therapeutic non-invasive neuromodulation.
Archives italiennes de biologie, 2014

Several evidences in animal models have consistently an alteration of cortico-striatal plasticity, which is related to the degeneration of the substantia nigra. An alteration of plasticity have also been reported in humans by recording evoked field potentials in the substantia nigra pars reticulata of PD patients undergoing subthalamic nucleus (STN) stimulation where high-frequency (HF) in the OFF state did not induce a lasting change in field potential amplitude in the substantia nigra. In addition protocols of non-invasive brain stimulation, such as paired associative stimulation (PAS) and theta-burst stimulation (TBS), can be used to investigate cortical plasticity of the human primary motor cortex. Despite data reported in literature are apparently controversial with some studies showing a reduced or increased or even normal LTP and LTD like plasticity, recent evidences suggest the hypothesis that these different pat- terns of cortical plasticity likely depend on the stage of the disease and on the concomitant administration of L-DOPA. The current review will provide an up-to-date of these issues on cortical plasticity in PD discussing the clinical implications in rehabilitation. In addition in the last section we will review the state of art of non invasive neuro- modulation as adjuvant treatment in the advanced stage of the disease.
Regulation of progranulin expression and location by sortilin in oxygen-glucose deprivation/reoxygenation injury.
Neuroscience letters, 2020

Progranulin is a secreted glycoprotein expressed in neurons and microglial cells that is involved in maintaining physiological functions. Many studies have found that progranulin may play a protective role against ischemic brain injury, but little is known about how the expression level and cellular localization status of progranulin is regulated after hypoxia-ischemia. Research has confirmed that sortilin, encoded by SORT1, can bind with progranulin and deliver a mature secretory isoform of progranulin to lysosomes, and progranulin is then cleaved. In the present study, we aimed to figure out whether sortilin could affect the expression and cellular localization of progranulin and regulate cell apoptosis during hypoxia-ischemia. In this study, oxygen-glucose deprivation/reoxygenation (OGD/R) in primary cortical neurons was used to mimic hypoxic-ischemic episodes. After OGD/R, the neuroprotective effects of progranulin against hypoxia-ischemia were examined, and primary cortical neurons were transduced with a SORT1 knockdown lentivirus to inhibit the expression of sortilin. The results showed that sortilin inhibition increased PGRN expression and alleviated cell injury induced by hypoxia-ischemia. Additionally, sortilin inhibition was associated with less PGRN localization in lysosomes. All of these findings suggest that sortilin can regulate the expression of PGRN, most likely by transporting it to lysosomes and affecting the cell injury in hypoxia-ischemia.
Translational research needs us to go back to basics and collaborate: interview with Lars Sundstrom.
Future science OA, 2016

Lars Sundstrom is Director of Enterprise and Translation at the West of England Academic Health Sciences Network [1] (UK), a Professor of Practice in Translational Medicine and Co-Director of the Elizabeth Blackwell Institute for Health Research at Bristol University [2] (UK), and an honorary Professor of Medicine at Cardiff University (UK). He has extensive experience in translational medicine and clinical neurosciences, holding positions at several eminent universities. He has also held executive and board-level positions at several SMEs, developing new therapeutics for neurological conditions and tools for drug discovery. He has also been an advisor to several UK and local government task forces and to the European Commission and the European Federation of Pharmaceutical Industry Associations. He was a founding member of the European Brain Council in Brussels, and set up the Severnside Alliance for Translational Research, developing a regional network partnership to link clinical and basic scientists. He was also involved in the creation of Health Research Wales.
Regulation of microRNAs by IRE1α in apoptosis: implications for the pathomechanism of neurodegenerative diseases.
The International journal of neuroscience, 2020

Although there are large differences in clinical and pathological features, age-related neurodegenerative diseases (NDs) share common pathogenetic mechanisms involving aggregation and deposition of misfolded proteins, which leads to progressive dysfunction and death of neurons. Up to now, it seems that apoptosis is one major form of neuronal cell death. This review provides an overview of recent progress in unfolded protein response (UPR) during apoptosis induced by abnormal protein aggregation and emphasizes on the potential role of inositol requiring enzyme 1 alpha (IRE1α)-microRNAs (miRNAs) mediated apoptosis in NDs, which will provide new insights in the pathogenesis of neurodegenerative diseases and novel therapeutic targets for the treatment of NDs.
Measuring movements in adolescents with psychosis using the Microsoft Kinect sensor: a pilot study exploring a new tool for assessing aspects of antipsychotic-induced parkinsonism.
Child and adolescent mental health, 2020

The assessment of motor disturbances in antipsychotic-treated adolescent patients is often limited to the use of observer-based rating scales with interobserver variability. The objectives of this pilot study were to measure movement patterns associated with antipsychotic-induced parkinsonism in young patients with psychosis and initiating/treated with antipsychotics, using a computer application connected with the Microsoft Kinect sensor (Motorgame).
Causality in Cognitive Neuroscience: Concepts, Challenges, and Distributional Robustness.
Journal of cognitive neuroscience, 2021

Whereas probabilistic models describe the dependence structure between observed variables, causal models go one step further: They predict, for example, how cognitive functions are affected by external interventions that perturb neuronal activity. In this review and perspective article, we introduce the concept of causality in the context of cognitive neuroscience and review existing methods for inferring causal relationships from data. Causal inference is an ambitious task that is particularly challenging in cognitive neuroscience. We discuss two difficulties in more detail: the scarcity of interventional data and the challenge of finding the right variables. We argue for distributional robustness as a guiding principle to tackle these problems. Robustness (or invariance) is a fundamental principle underlying causal methodology. A (correctly specified) causal model of a target variable generalizes across environments or subjects as long as these environments leave the causal mechanisms of the target intact. Consequently, if a candidate model does not generalize, then either it does not consist of the target variable's causes or the underlying variables do not represent the correct granularity of the problem. In this sense, assessing generalizability may be useful when defining relevant variables and can be used to partially compensate for the lack of interventional data.
A model to predict postoperative complications for otorhinolaryngology and maxillofacial surgery procedures in elderly patients.
European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery, 2020

All kinds of ear, nose, and throat and maxillofacial surgery (ENT/MFS) procedures are being increasingly performed in the elderly although old age is a major risk factor for increased postoperative complications. With only scarce evidence on the topic, surgeons are asked to critically evaluate their procedures' indications and outcomes to balance the treatment risks and benefits. Our primary aim was to identify predictive factors for surgical outcomes in this setting and to create a predictive model for a tailored risk assessment.
One Size Does Not Fit All: Choosing Practical Cognitive Screening Tools for Your Practice.
Journal of the American Geriatrics Society, 2020

Every year, millions of patients worldwide undergo cognitive testing. Unfortunately, new barriers to the use of free open access cognitive screening tools have arisen over time, making accessibility of tools unstable. This article is in follow-up to an editorial discussing alternative cognitive screening tools for those who cannot afford the costs of the Mini-Mental State Examination and Montreal Cognitive Assessment (see www.dementiascreen.ca). The current article outlines an emerging disruptive "free-to-fee" cycle where free open access cognitive screening tools are integrated into clinical practice and guidelines, where fees are then levied for the use of the tools, resulting in clinicians moving on to other tools. This article provides recommendations on means to break this cycle, including the development of tool kits of valid cognitive screening tools that authors have contracted not to charge for (i.e., have agreed to keep free open access). The PRACTICAL.1 Criteria (PRACTIcing Clinician Accessibility and Logistical Criteria Version 1) are introduced to help clinicians select from validated cognitive screening tools, considering barriers and facilitators, such as whether the cognitive screening tools are easy to score and free of cost. It is suggested that future systematic reviews embed the PRACTICAL.1 criteria, or refined future versions, as part of the standard of review. Methodological issues, the need for open access training to insure proper use of cognitive screening tools, and the need to anticipate growing ethnolinguistic diversity by developing tools that are less sensitive to educational, cultural, and linguistic bias are discussed in this opinion piece. J Am Geriatr Soc 68:2207-2213, 2020.