Quantifying the resolution of spatial and temporal representation in children with 22q11.2 deletion syndrome.

ObjectivesOur ability to generate mental representation of magnitude from sensory information affects how we perceive and experience the world. Reduced resolution of the mental representations formed from sensory inputs may generate impairment in the proximal and distal information processes that utilize these representations. Impairment of spatial and temporal information processing likely underpins the non-verbal cognitive impairments observed in 22q11.2 deletion syndrome (22q11DS). The present study builds on prior research by seeking to quantify the resolution of spatial and temporal representation in children with 22q11DS, sex chromosome aneuploidy (SCA), and a typically developing (TD) control group.Participants and methodsChildren (22q11DS = 70, SCA = 49, TD = 46) responded to visual or auditory stimuli with varying difference ratios. The participant's task was to identify which of two sequentially presented stimuli was of larger magnitude in terms of, size, duration, or auditory frequency. Detection threshold was calculated as the minimum difference ratio between the "standard" and the "target" stimuli required to achieve 75% accuracy in detecting that the two stimuli were different.ResultsChildren with 22q11DS required larger magnitude difference between spatial stimuli for accurate identification compared with both the SCA and TD groups (% difference from standard: 22q11DS = 14; SCA = 8; TD: 7; F  = 8.42, p < 0.001). Temporal detection threshold was also higher for the 22q11DS group to both visual (% difference from standard: 22q11DS = 14; SCA = 8; TD = 7; F  = 8.33, p < 0.001) and auditory (% difference from standard: 22q11DS = 23; SCA = 12; TD: 8; F  = 8.99, p < 0.001) stimuli compared with both the SCA and TD groups, while the SCA and TD groups displayed equivalent performance on these measures (p's > 0.05). Pitch detection threshold did not differ among the groups (p's > 0.05).ConclusionsThe observation of higher detection thresholds to spatial and temporal stimuli indicates further evidence for reduced resolution in both spatial and temporal magnitude representation in 22q11DS, that does not extend to frequency magnitude representation (pitch detection), and which is not explained by generalized cognitive impairment alone. These findings generate further support for the hypothesis that spatiotemporal hypergranularity of mental representations contributes to the non-verbal cognitive impairment seen in 22q11DS

Information-based methods for predicting gene function from systematic gene knock-downs

<p>Abstract</p> <p>Background</p> <p>The rapid annotation of genes on a genome-wide scale is now possible for several organisms using high-throughput RNA interference assays to knock down the expression of a specific gene. To date, dozens of RNA interference phenotypes have been recorded for the nematode <it>Caenorhabditis elegans</it>. Although previous studies have demonstrated the merit of using knock-down phenotypes to predict gene function, it is unclear how the data can be used most effectively. An open question is how to optimally make use of phenotypic observations, possibly in combination with other functional genomics datasets, to identify genes that share a common role.</p> <p>Results</p> <p>We compared several methods for detecting gene-gene functional similarity from phenotypic knock-down profiles. We found that information-based measures, which explicitly incorporate a phenotype's genomic frequency when calculating gene-gene similarity, outperform non-information-based methods. We report the presence of newly predicted modules identified from an integrated functional network containing phenotypic congruency links derived from an information-based measure. One such module is a set of genes predicted to play a role in regulating body morphology based on their multiply-supported interactions with members of the TGF-<it>β </it>signaling pathway.</p> <p>Conclusion</p> <p>Information-based metrics significantly improve the comparison of phenotypic knock-down profiles, based upon their ability to enhance gene function prediction and identify novel functional modules.</p

Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression.

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease

A global analysis of genetic interactions in Caenorhabditis elegans

Abstract Background Understanding gene function and genetic relationships is fundamental to our efforts to better understand biological systems. Previous studies systematically describing genetic interactions on a global scale have either focused on core biological processes in protozoans or surveyed catastrophic interactions in metazoans. Here, we describe a reliable high-throughput approach capable of revealing both weak and strong genetic interactions in the nematode Caenorhabditis elegans. Results We investigated interactions between 11 'query' mutants in conserved signal transduction pathways and hundreds of 'target' genes compromised by RNA interference (RNAi). Mutant-RNAi combinations that grew more slowly than controls were identified, and genetic interactions inferred through an unbiased global analysis of the interaction matrix. A network of 1,246 interactions was uncovered, establishing the largest metazoan genetic-interaction network to date. We refer to this approach as systematic genetic interaction analysis (SGI). To investigate how genetic interactions connect genes on a global scale, we superimposed the SGI network on existing networks of physical, genetic, phenotypic and coexpression interactions. We identified 56 putative functional modules within the superimposed network, one of which regulates fat accumulation and is coordinated by interactions with bar-1(ga80), which encodes a homolog of β-catenin. We also discovered that SGI interactions link distinct subnetworks on a global scale. Finally, we showed that the properties of genetic networks are conserved between C. elegans and Saccharomyces cerevisiae, but that the connectivity of interactions within the current networks is not. Conclusions Synthetic genetic interactions may reveal redundancy among functional modules on a global scale, which is a previously unappreciated level of organization within metazoan systems. Although the buffering between functional modules may differ between species, studying these differences may provide insight into the evolution of divergent form and function

The Neuro-Symbolic Inverse Planning Engine (NIPE): Modeling Probabilistic Social Inferences from Linguistic Inputs

Human beings are social creatures. We routinely reason about other agents, and a crucial component of this social reasoning is inferring people's goals as we learn about their actions. In many settings, we can perform intuitive but reliable goal inference from language descriptions of agents, actions, and the background environments. In this paper, we study this process of language driving and influencing social reasoning in a probabilistic goal inference domain. We propose a neuro-symbolic model that carries out goal inference from linguistic inputs of agent scenarios. The "neuro" part is a large language model (LLM) that translates language descriptions to code representations, and the "symbolic" part is a Bayesian inverse planning engine. To test our model, we design and run a human experiment on a linguistic goal inference task. Our model closely matches human response patterns and better predicts human judgements than using an LLM alone.Comment: To appear at ICML Workshop on Theory of Mind in Communicating Agent

Horizontal transfer of expressed genes in a parasitic flowering plant

Background: Recent studies have shown that plant genomes have potentially undergone rampant horizontal gene transfer (HGT). In plant parasitic systems HGT appears to be facilitated by the intimate physical association between the parasite and its host. HGT in these systems has been invoked when a DNA sequence obtained from a parasite is placed phylogenetically very near to its host rather than with its closest relatives. Studies of HGT in parasitic plants have relied largely on the fortuitous discovery of gene phylogenies that indicate HGT, and no broad systematic search for HGT has been undertaken in parasitic systems where it is most expected to occur. Results: We analyzed the transcriptomes of the holoparasite Rafflesia cantleyi Solms-Laubach and its obligate host Tetrastigma rafflesiae Miq. using phylogenomic approaches. Our analyses show that several dozen actively transcribed genes, most of which appear to be encoded in the nuclear genome, are likely of host origin. We also find that hundreds of vertically inherited genes (VGT) in this parasitic plant exhibit codon usage properties that are more similar to its host than to its closest relatives. Conclusions: Our results establish for the first time a substantive number of HGTs in a plant host-parasite system. The elevated rate of unidirectional host-to- parasite gene transfer raises the possibility that HGTs may provide a fitness benefit to Rafflesia for maintaining these genes. Finally, a similar convergence in codon usage of VGTs has been shown in microbes with high HGT rates, which may help to explain the increase of HGTs in these parasitic plants.Organismic and Evolutionary Biolog

Efficacy of miniaturized imacor trans-esophageal echocardiografm (TEE) prove in mechanical circulatory support.

Application of the miniaturized ImaCor Trans-Esophageal Echocardiogram (TEE) probe in Heart Transplant/Mechanical Cardiac Support Patients In the surgical cardiac care unit (SCCU), therapeutic interventions often need to be done at the bedside, necessitating the need for a rapidly employable diagnostic tool for the cardiac intensivist. We report the clinical utility of the miniature ImaCor TEE-probe in guiding management of post heart transplant (H-Txp) and mechanical cardiac support patients (MCS) and describe the economic benefit of such a device. This is an IRB approved retrospective review of MCS/H-Txp patients who had ImaCor TEE monitoring in the SCCU of our institution in 2011. The effect on management was stratified into 3 categories; Major (tamponade/device selection/RV failure), Moderate (weaning support device guidance/ inotrope management/fluid management/hemodynamic instability) and Minor (line placement/useful data). The ImaCor TEE-Probe was utilized in a total of 34 patients, of which 21 were either supported by MCS or were post H-Txp. Of these, 13 were on ECMO, 9 were post-VAD, 3 supported by the Impella device and 4 were post-H-Txp. 6 patients were placed on more than 1 method of MCS and 1 patient was supported by ECMO after a H-Txp. The device had a Major effect on management in 4 patients (19%), Moderate effect in 13 (62%) and a Minor effect in 4 (19%). The cost difference between this new device and the traditional TEE is also significant (900 USD vs 4000 USD). Our institution saved in excess of 150,000 USD with the use of this device instead of traditional TEE. This figure did not include the ability of this probe to be used repeatedly within a 72-hour time frame, and the potential cost of going to the operating theatre for further management. This device has proven to be an invaluable new adjunct in the SCCU by allowing previously unobtainable continuous real time monitoring of the MCS/H-Txp patient. Use of the ImaCor TEE-probe provides the cardiac intensivist with timely important clinical data that improves patient care and is economically advantageous

Neurotransmitter signaling regulates distinct phases of multimodal human interneuron migration

Inhibitory GABAergic interneurons migrate over long distances from their extracortical origin into the developing cortex. In humans, this process is uniquely slow and prolonged, and it is unclear whether guidance cues unique to humans govern the various phases of this complex developmental process. Here, we use fused cerebral organoids to identify key roles of neurotransmitter signaling pathways in guiding the migratory behavior of human cortical interneurons. We use scRNAseq to reveal expression of GABA, glutamate, glycine, and serotonin receptors along distinct maturation trajectories across interneuron migration. We develop an image analysis software package, TrackPal, to simultaneously assess 48 parameters for entire migration tracks of individual cells. By chemical screening, we show that different modes of interneuron migration depend on distinct neurotransmitter signaling pathways, linking transcriptional maturation of interneurons with their migratory behavior. Altogether, our study provides a comprehensive quantitative analysis of human interneuron migration and its functional modulation by neurotransmitter signaling