Interpretation of personal genome sequencing data in terms of disease ranks based on mutual information

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract Background The rapid advances in genome sequencing technologies have resulted in an unprecedented number of genome variations being discovered in humans. However, there has been very limited coverage of interpretation of the personal genome sequencing data in terms of diseases. Methods In this paper we present the first computational analysis scheme for interpreting personal genome data by simultaneously considering the functional impact of damaging variants and curated disease-gene association data. This method is based on mutual information as a measure of the relative closeness between the personal genome and diseases. We hypothesize that a higher mutual information score implies that the personal genome is more susceptible to a particular disease than other diseases. Results The method was applied to the sequencing data of 50 acute myeloid leukemia (AML) patients in The Cancer Genome Atlas. The utility of associations between a disease and the personal genome was explored using data of healthy (control) people obtained from the 1000 Genomes Project. The ranks of the disease terms in the AML patient group were compared with those in the healthy control group using "Leukemia, Myeloid, Acute" (C04.557.337.539.550) as the corresponding MeSH disease term. The mutual information rank of the disease term was substantially higher in the AML patient group than in the healthy control group, which demonstrates that the proposed methodology can be successfully applied to infer associations between the personal genome and diseases. Conclusions Overall, the area under the receiver operating characteristics curve was significantly larger for the AML patient data than for the healthy controls. This methodology could contribute to consequential discoveries and explanations for mining personal genome sequencing data in terms of diseases, and have versatility with respect to genomic-based knowledge such as drug-gene and environmental-factor-gene interactions

Differentially altered social dominance- and cooperative-like behaviors in Shank2- and Shank3-mutant mice

Background: Recent progress in genomics has contributed to the identification of a large number of autism spectrum disorder (ASD) risk genes, many of which encode synaptic proteins. Our understanding of ASDs has advanced rapidly, partly owing to the development of numerous animal models. Extensive characterizations using a variety of behavioral batteries that analyze social behaviors have shown that a subset of engineered mice that model mutations in genes encoding Shanks, a family of excitatory postsynaptic scaffolding proteins, exhibit autism-like behaviors. Although these behavioral assays have been useful in identifying deficits in simple social behaviors, alterations in complex social behaviors remain largely untested. Methods: Two syndromic ASD mouse models—Shank2 constitutive knockout [KO] mice and Shank3 constitutive KO mice—were examined for alterations in social dominance and social cooperative behaviors using tube tests and automated cooperation tests. Upon naïve and salient behavioral experience, expression levels of c-Fos were analyzed as a proxy for neural activity across diverse brain areas, including the medial prefrontal cortex (mPFC) and a number of subcortical structures. Findings: As previously reported, Shank2 KO mice showed deficits in sociability, with intact social recognition memory, whereas Shank3 KO mice displayed no overt phenotypes. Strikingly, the two Shank KO mouse models exhibited diametrically opposed alterations in social dominance and cooperative behaviors. After a specific social behavioral experience, Shank mutant mice exhibited distinct changes in number of c-Fos+ neurons in the number of cortical and subcortical brain regions. Conclusions: Our results underscore the heterogeneity of social behavioral alterations in different ASD mouse models and highlight the utility of testing complex social behaviors in validating neurodevelopmental and neuropsychiatric disorder models. In addition, neural activities at distinct brain regions are likely collectively involved in eliciting complex social behaviors, which are differentially altered in ASD mouse models. © 2020, The Author(s).1

Protocol for Quantitative Analysis of Synaptic Vesicle Clustering in Axons of Cultured Neurons

Clustering of synaptic vesicles along the neuronal axons is a critical mechanism underpinning proper synaptic transmission. Here, we provide a detailed protocol for analyzing the distribution of synaptic vesicles in presynaptic boutons of cultured neurons. The protocol covers preparation of cultured neurons, expression of synaptic vesicle-enriched proteins, and quantification procedures. Utilizing neurons from postnatal transgenic mice, this method can be applied to investigate the roles of synaptic genes in regulating vesicle dynamics at synaptic sites. For complete details on the use and execution of this protocol, please refer to Han et al. (2020a). © 2020 The Author(s)1

Clear Cell Hidradenoma of the Axilla: a Case Report with Literature Review

Clear cell hidradenoma is an uncommon benign skin appendageal tumor that typically involves the dermal layer of the head, face, and extremities. The breast is a rare site for this lesion, with only two documented cases, which were determined based on mammogram and sonogram findings. We present a case of clear cell hidradenoma of the axillary tail with radiological findings and a literature review

Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions

Members of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs). However, how Slitrks participate in activation of intracellular signaling pathways in postsynaptic neurons remains largely unknown. Here we report that, among the six members of the Slitrk family, only Slitrk2 directly interacts with the PDZ domain-containing excitatory scaffolds, PSD-95 and Shank3. The interaction of Slitrk2 with PDZ proteins is mediated by the cytoplasmic COOH-terminal PDZ domain-binding motif (Ile-Ser-Glu-Leu), which is not found in other Slitrks. Mapping analyses further revealed that a single PDZ domain of Shank3 is responsible for binding to Slitrk2. Slitrk2 forms in vivo complexes with membrane-associated guanylate kinase (MAGUK) family proteins in addition to PSD-95 and Shank3. Intriguingly, in addition to its role in synaptic targeting in cultured hippocampal neurons, the PDZ domain-binding motif of Slitrk2 is required for Slitrk2 promotion of excitatory synapse formation, transmission, and spine development in the CA1 hippocampal region. Collectively, our data suggest a new molecular mechanism for conferring isoform-specific regulatory actions of the Slitrk family in orchestrating intracellular signal transduction pathways in postsynaptic neurons. © 2019, The Author(s).1