An assay for social interaction in Drosophila fragile X mutants

We developed a novel assay to examine social interactions in Drosophila and, as a first attempt, apply it here at examining the behavior of Drosophila Fragile X Mental Retardation gene (dfmr1) mutants. Fragile X syndrome is the most common cause of single gene intellectual disability (ID) and is frequently associated with autism. Our results suggest that dfmr1 mutants are less active than wild-type flies and interact with each other less often. In addition, mutants for one allele of dfmr1, dfmr1B55, are more likely to come in close contact with a wild-type fly than another dfmr1B55 mutant. Our results raise the possibility of defective social expression with preserved receptive abilities. We further suggest that the assay may be applied in a general strategy of examining endophenoypes of complex human neurological disorders in Drosophila, and specifically in order to understand the genetic basis of social interaction defects linked with ID

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS

Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue

Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD

Leveraging Knowledge Graphs and Natural Language Processing for Automated Web Resource Labeling and Knowledge Mobilization in Neurodevelopmental Disorders: Development and Usability Study

BackgroundPatients and families need to be provided with trusted information more than ever with the abundance of online information. Several organizations aim to build databases that can be searched based on the needs of target groups. One such group is individuals with neurodevelopmental disorders (NDDs) and their families. NDDs affect up to 18% of the population and have major social and economic impacts. The current limitations in communicating information for individuals with NDDs include the absence of shared terminology and the lack of efficient labeling processes for web resources. Because of these limitations, health professionals, support groups, and families are unable to share, combine, and access resources. ObjectiveWe aimed to develop a natural language–based pipeline to label resources by leveraging standard and free-text vocabularies obtained through text analysis, and then represent those resources as a weighted knowledge graph. MethodsUsing a combination of experts and service/organization databases, we created a data set of web resources for NDDs. Text from these websites was scraped and collected into a corpus of textual data on NDDs. This corpus was used to construct a knowledge graph suitable for use by both experts and nonexperts. Named entity recognition, topic modeling, document classification, and location detection were used to extract knowledge from the corpus. ResultsWe developed a resource annotation pipeline using diverse natural language processing algorithms to annotate web resources and stored them in a structured knowledge graph. The graph contained 78,181 annotations obtained from the combination of standard terminologies and a free-text vocabulary obtained using topic modeling. An application of the constructed knowledge graph is a resource search interface using the ordered weighted averaging operator to rank resources based on a user query. ConclusionsWe developed an automated labeling pipeline for web resources on NDDs. This work showcases how artificial intelligence–based methods, such as natural language processing and knowledge graphs for information representation, can enhance knowledge extraction and mobilization, and could be used in other fields of medicine

Genomic characterization of chromosome 8 pericentric trisomy

Nestacionarno strujanje u centrifugalnom ventilatoru simulirano je metodama računalne mehanike fluida tehnikom simulacije odvojenih vrtloga (eng. DES). Ispitivane su četiri geometrijske konfiguracije radnoga kola u širokom rasponu masenih protoka, u cilju istraživanja nestacionarnih strujnih pojava, osobito rotirajućega prekida strujanja te predvrtloga u usisnoj cijevi, a koje se javljaju u vanprojektnim režimima rada pri protocima koji su niži od optimalnoga. Istovremeno su izvedena mjerenja radnih karakteristika te nestacionarnih fluktuacija tlaka na stacionarnim pozicijama u neposrednoj blizini ulaza u radno kolo, u cilju eksperimentalne validacije rezultata numeričke simulacije. Vizualizacijom i animacijama rezultata računalne simulacije pokazano je postojanje snažnoga natražnoga strujanja u rotorskim međulopatičnim kanalima zahvaćenima rotirajućim prekidom strujanja. Zastojne ćelije se premještaju ili miruju relativno u odnosu na radno kolo. Fluid u natražnom strujanju iz kanala u prekidu strujanja izbija u prostor ispred rotorskih lopatica gdje uzrokuje nastajanje precesijskih vrtloga. Precesijski vrtlozi se premještaju po unutarnjem obodu rotorskih lopatica. Mlazevi natražnoga toka penetriraju u usisnu cijev gdje se miješaju s dolaznom strujom. Mlazevi su nestacionarni, na mahove, a turbulentna difuzija vrtložne tangencijalne brzine koju posjeduju mlazevi je vrlo intenzivna. Kod nižih protoka cijela jezgra dolaznog toka se prožima vrtložnošću te se s precesijskim vrtlozima spaja u jedinstveni predvrtlog. Na početak i oblike pojave rotirajućeg prekida strujanja, kao i na početak pojave predvrtloga te njegov doseg unutar usisne cijevi snažno utječu broj lopatica, ulazni kut lopatica, omjer širine i duljine međulopatičnih kanala radnoga kola te veličina zazora između vrhova lopatica otvorenoga radnog kola i prednje ploče kućišta.Extensive numerical detached-eddy simulations of the unsteady flow in four different centrifugal fan impeller configurations and in a broad range of mass flow rates are conducted to investigate the unsteady flow phenomena at part-load conditions, particularly rotating impeller stall and formation of the prerotation swirl in the draft tube. Measurements of the performance curve and pressure fluctuations in the steady frame in vicinity of the impeller eye inlet are conducted to validate results of the numerical simulations. Visualisation of the CFD results shows significant reverse flow in the rotating stall affected blade passages. Stall cells are stationary or moving in the impeller frame of reference. Reverse flow from stalled passages is ejected into impeller eye generating precessing vortices along impeller blade inlet edges. Jets of the reverse flow penetrate into draft tube in unsteady manner causing rapid turbulent mixing and diffusion of the swirl velocity into the incoming flow. At smaller flow rates swirl vorticity pervades the core of the incoming flow and the precessing vortices coalesce into single prerotation vortex. All of the blade number configuration, blade inlet angle, blade passage width-to-length ratio and unshrouded impeller blade tip gap influence significantly the onset and the mode of the impeller stall and onset and extent of the unsteady prerotation swirl

Prenatal fruit juice exposure enhances memory consolidation in male post-weanling Sprague-Dawley rats.

OBJECTIVES:Nutritional intake during gestation is known to impact health outcomes for progeny. Correlational evidence in humans suggests that increased fruit consumption of pregnant mothers enhances infant cognitive development. Moreover, wild-type Drosophila supplemented with a combination of orange and tomato juice showed robust enhancements in performance on an associative olfactory memory task. The current study aimed to experimentally test the effects of prenatal fruit juice exposure in a non-human, mammalian model of learning and memory. METHODS:Across three separate birth cohorts, pregnant rats were given access to diluted tomato and orange juice (N = 2 per cohort), with control rats (N = 2 per cohort) receiving only water, in addition to standard rodent chow, throughout the duration of gestation, ending at parturition. Following weaning, male offspring were tested for learning and memory in a spatial version of the circular water maze and an auditory-cued fear-conditioning task. RESULTS:All pregnant rats increased fluid and food intake over the gestational period. Fruit juice-fed pregnant rats had increased fluid intake compared to control pregnant rats. When testing progeny, there were no effects of prenatal fruit juice on spatial learning, while it appeared to impair learning in fear conditioning relative to controls. However, we measured significant enhancements in both spatial memory and conditioned fear memory in the prenatal fruit-juice group compared to controls. Measures of vigilance, in response to the conditioned cue, were increased in prenatal fruit rats compared to controls, suggesting less generalized, and more adaptive, anxiety behaviours. DISCUSSION:Our results corroborate the human and Drosophila findings of prenatal fruit effects on behaviour, specifically that prenatal fruit juice exposure may be beneficial for early-life memory consolidation in rats

Image_1_Stress Odorant Sensory Response Dysfunction in Drosophila Fragile X Syndrome Mutants.jpg

<p>Sensory processing dysfunction (SPD) is present in most patients with intellectual disability (ID) and autism spectrum disorder (ASD). Silencing expression of the Fragile X mental retardation 1 (FMR1) gene leads to Fragile X syndrome (FXS), the most common single gene cause of ID and ASD. Drosophila have a highly conserved FMR1 ortholog, dfmr1. dfmr1 mutants display cognitive and social defects reminiscent of symptoms seen in individuals with FXS. We utilized a robust behavioral assay for sensory processing of the Drosophila stress odorant (dSO) to gain a better understanding of the molecular basis of SPD in FXS. Here, we show that dfmr1 mutant flies present significant defects in dSO response. We found that dfmr1 expression in mushroom bodies is required for dSO processing. We also show that cyclic adenosine monophosphate (cAMP) signaling via PKA is activated after exposure to dSO and that several drugs regulating both cAMP and cyclic guanosine monophosphate (cGMP) levels significantly improved defects in dSO processing in dfmr1 mutant flies.</p

Long-term Memory Testing in Children With Typical Development and Neurodevelopmental Disorders: Remote Web-based Image Task Feasibility Study

BackgroundNeurodevelopmental disorders (NDD) cause individuals to have difficulty in learning facts, procedures, or social skills. NDD has been linked to several genes, and several animal models have been used to identify potential therapeutic candidates based on specific learning paradigms for long-term and associative memory. In individuals with NDD, however, such testing has not been used so far, resulting in a gap in translating preclinical results to clinical practice. ObjectiveWe aim to assess if individuals with NDD could be tested for paired association learning and long-term memory deficit, as shown in previous animal models. MethodsWe developed an image-based paired association task, which can be performed at different time points using remote web-based testing, and evaluated its feasibility in children with typical development (TD), as well as NDD. We included 2 tasks: object recognition as a simpler task and paired association. Learning was tested immediately after training and also the next day for long-term memory. ResultsWe found that children aged 5-14 years with TD (n=128) and with NDD of different types (n=57) could complete testing using the Memory Game. Children with NDD showed deficits in both recognition and paired association tasks on the first day of learning, in both 5-9–year old (P<.001 and P=.01, respectively) and 10-14–year old groups (P=.001 and P<.001, respectively). The reaction times to stimuli showed no significant difference between individuals with TD or NDD. Children with NDD exhibited a faster 24-hour memory decay for the recognition task than those with TD in the 5-9–year old group. This trend is reversed for the paired association task. Interestingly, we found that children with NDD had their retention for recognition improved and matched with typically developing individuals by 10-14 years of age. The NDD group also showed improved retention deficits in the paired association task at 10-14 years of age compared to the TD group. ConclusionsWe showed that web-based learning testing using simple picture association is feasible for children with TD, as well as with NDD. We showed how web-based testing allows us to train children to learn the association between pictures, as shown in immediate test results and those completed 1 day after. This is important as many models for learning deficits in NDD target both short- and long-term memory for therapeutic intervention. We also demonstrated that despite potential confounding factors, such as self-reported diagnosis bias, technical issues, and varied participation, the Memory Game shows significant differences between typically developing children and those with NDD. Future experiments will leverage this potential of web-based testing for larger cohorts and cross-validation with other clinical or preclinical cognitive tasks