Agonist-Induced Functional Analysis and Cell Sorting is a novel tool to uncover interneuron impairment: Fragile X Syndrome as a proof of concept
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ORGANISM(S): Mus musculus
PROVIDER: GSE142274 | GEO | 2020/08/31
REPOSITORIES: GEO
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Project description:Agonist-Induced Functional Analysis and Cell Sorting is a novel tool to uncover interneuron impairment: Fragile X Syndrome as a proof of concept
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Project description:In a sensory or consumer setting, panelists are commonly asked to rank a set of stimuli, either by the panelist's liking of the samples, or by the samples' perceived intensity of a particular sensory note. Ranking is seen as a "simple" task for panelists, and thus is usually performed with minimal (or no) specific instructions given to panelists. Despite its common usage, seemingly little is known about the specific cognitive task that panelists are performing when ranking samples. It becomes quickly unruly to suggest a series of paired comparisons between samples, with 45 individual paired comparisons needed to rank 10 samples. Comparing a number of elements with regards to a scaled value is common in computer science, with a number of differing sorting algorithms used to sort arrays of numerical elements. We compared the efficacy of the most basic sorting algorithm, Bubble Sort (based on comparing each element to its neighbor, moving the higher to the right, and repeating), vs a more advanced algorithm, Merge Sort (based on dividing the array into sub arrays, sorting these sub arrays, and then combining), in a sensory ranking task of 6 ascending concentrations of sucrose (n = 73 panelists). Results confirm that as seen in computer science, a Merge Sort procedure performs better than Bubble Sort in sensory ranking tasks, although the perceived difficulty of the approach suggests panelists would benefit from a longer period of training. Lastly, through a series of video recorded one-on-one interviews, and an additional sensory ranking test (n = 78), it seems that most panelists natively follow a similar procedure to Bubble Sorting when asked to rank without instructions, with correspondingly inferior results to those that may be obtained if a Merge Sorting procedure was applied. Results suggests that ranking may be improved if panelists were given a simple set of instructions on the Merge Sorting procedure.
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Project description:BACKGROUND:Individuals diagnosed with fragile X syndrome (FXS), the most common known inherited form of intellectual disability, commonly exhibit significant impairments in social gaze behavior during interactions with others. Although this behavior can restrict social development and limit educational opportunities, behavioral interventions designed to improve social gaze behavior have not been developed for this population. In this proof of concept (PoC) study, we examined whether administering a behavioral skills training package-discrete trial instruction (DTI) plus relaxation training-could increase social gaze duration in males with FXS. METHODS:As part of a larger clinical trial, 20 boys with FXS, aged 8 to 18 years, were randomized to receive DTI plus relaxation training administered at one of two prescribed doses over a 2-day period at our research center. Potential improvements in social gaze behavior were evaluated by direct observations conducted across trials during the training, and generalization effects were examined by administering a social challenge before and after the treatment. During the social challenge, social gaze behavior was recorded using an eye tracker and physiological arousal levels were simultaneously recorded by monitoring the child's heart rate. RESULTS:Levels of social gaze behavior increased significantly across blocks of training trials for six (60%) boys who received the high-dose behavioral treatment and for three (30%) boys who received the low-dose behavioral treatment. Boys who received the high-dose treatment also showed greater improvements in social gaze behavior during the social challenge compared to boys who received the low-dose treatment. There was no effect of the treatment on physiological arousal levels recorded on the heart rate monitor at either dose. CONCLUSIONS:These results suggest that appropriate social gaze behavior can be successfully taught to boys with FXS using a standardized behavioral skills training approach. Future studies will need to evaluate whether younger children with FXS might benefit from this treatment, and/or whether more naturalistic forms of behavioral skills training might be beneficial, before social gaze avoidance becomes established in the child's repertoire. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02616796 . Registered 30 November 2015.
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Project description:Today, novel candidate therapeutics are identified in an environment which is intrinsically different from the clinical context in which they are ultimately evaluated. We present a strategy that allows biological relevance to be assessed in the early stages of drug discovery. Using molecular phenotyping and an in vitro model of diabetic cardiomyopathy, we show that by quantifying pathway reporter gene expression, molecular phenotyping can cluster compounds based on pathway profiles and dissect associations between pathway activities and disease phenotypes simultaneously. Molecular phenotyping identified a class of calcium-signaling modulators that can reverse disease-regulated pathways and phenotypes, which was validated by structurally distinct compounds of relevant classes. The technique was applicable to compounds with a range of binding specificities and detected false-positive hits missed by classical phenotypic assays. Our results advocate application of molecular phenotyping in drug discovery, promoting biological relevance as a key selection criterion early in the drug development cascade.
2017-05-24 | GSE89972 | GEO
Project description:This study aimed to demonstrate the sensitivity of virtual reality (VR)/motion tracking to detect global functional gait impairment resulting from an emulated knee disability as a prelude to describing mobility changes following lower limb injury/treatment. Participants walked in a figure-8 around two virtual posts placed 6m apart while viewing the computer-generated environment in a helmet-mounted display. Three-dimensional position and orientation of the participant's head were tracked and used to update the virtual scenes, measure walking path and speed, and control task parameters with real-time feedback. Participants walked with/without an emulated lower extremity disability (splint preventing normal knee flexion). Participants performed the task at self-selected Natural (NAT) speed providing a baseline measure of their turning speed and area. Turning speed and area were then in turn maintained fixed (controlled speed, CS; controlled path, CP) while the other variable was measured as a gait impairment indicator. Different adaptive strategies were used to cope with the emulated deficit during the NAT scenario: maintaining turning speed while altering path geometry; decreasing turning speed while maintaining path geometry; and combining the previous two strategies. This resulted, on average, in decreased turning speeds and increased turning areas. The CS and CP manipulations respectively generated even greater turning areas and more consistent speed decreases. The three subtests acted as intertwined filters enabling the detection of functional gait impairment in all subjects regardless of their adaptive strategies. This proof-of-concept study demonstrated how VR/motion tracking technology can be used to detect and quantitatively characterize global functional mobility impairment.
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Project description:Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance.
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Project description:Sepsis is the primary cause of burn-related mortality and morbidity. Traditional indicators of sepsis exhibit poor performance when used in this unique population due to their underlying hypermetabolic and inflammatory response following burn injury. To address this challenge, we developed the Machine Intelligence Learning Optimizer (MILO), an automated machine learning (ML) platform, to automatically produce ML models for predicting burn sepsis. We conducted a retrospective analysis of 211 adult patients (age???18 years) with severe burn injury (??20% total body surface area) to generate training and test datasets for ML applications. The MILO approach was compared against an exhaustive "non-automated" ML approach as well as standard statistical methods. For this study, traditional multivariate logistic regression (LR) identified seven predictors of burn sepsis when controlled for age and burn size (OR 2.8, 95% CI 1.99-4.04, P?=?0.032). The area under the ROC (ROC-AUC) when using these seven predictors was 0.88. Next, the non-automated ML approach produced an optimal model based on LR using 16 out of the 23 features from the study dataset. Model accuracy was 86% with ROC-AUC of 0.96. In contrast, MILO identified a k-nearest neighbor-based model using only five features to be the best performer with an accuracy of 90% and a ROC-AUC of 0.96. Machine learning augments burn sepsis prediction. MILO identified models more quickly, with less required features, and found to be analytically superior to traditional ML approaches. Future studies are needed to clinically validate the performance of MILO-derived ML models for sepsis prediction.
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Project description:BackgroundCancer stem cells (CSC) are thought to be responsible for tumor maintenance and heterogeneity. Bona fide CSC purified from tumor biopsies are limited in supply and this hampers study of CSC biology. Furthermore, purified stem-like CSC subpopulations from existing tumor lines are unstable in culture. Finding a means to overcome these technical challenges would be a useful goal. In a first effort towards this, we examined whether a chemical probe that promotes survival of murine embryonic stem cells without added exogenous factors can alter functional characteristics in extant tumor lines in a fashion consistent with a CSC phenotype.Methodology/principal findingsThe seven tumor lines of the NCI60 colon subpanel were exposed to SC-1 (pluripotin), a dual kinase and GTPase inhibitor that promotes self-renewal, and then examined for tumorigenicity under limiting dilution conditions and clonogenic activity in soft agar. A statistically significant increase in tumor formation following SC-1 treatment was observed (p<0.04). Cloning efficiencies and expression of putative CSC surface antigens (CD133 and CD44) were also increased. SC-1 treatment led to sphere formation in some colon tumor lines. Finally, SC-1 inhibited in vitro kinase activity of RSK2, and another RSK2 inhibitor increased colony formation implicating a role for this kinase in eliciting a CSC phenotype.Conclusions/significanceThese findings validate a proof of concept study exposure of extant tumor lines to a small molecule may provide a tractable in vitro model for understanding CSC biology.
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