Tbx1 and Brn4 regulate retinoic acid metabolic genes during cochlear morphogenesis

<p>Abstract</p> <p>Background</p> <p>In vertebrates, the inner ear is comprised of the cochlea and vestibular system, which develop from the otic vesicle. This process is regulated via inductive interactions from surrounding tissues. <it>Tbx1</it>, the gene responsible for velo-cardio-facial syndrome/DiGeorge syndrome in humans, is required for ear development in mice. <it>Tbx1 </it>is expressed in the otic epithelium and adjacent periotic mesenchyme (POM), and both of these domains are required for inner ear formation. To study the function of <it>Tbx1 </it>in the POM, we have conditionally inactivated <it>Tbx1 </it>in the mesoderm while keeping expression in the otic vesicle intact.</p> <p>Results</p> <p>Conditional mutants (<it>TCre-KO</it>) displayed malformed inner ears, including a hypoplastic otic vesicle and a severely shortened cochlear duct, indicating that <it>Tbx1 </it>expression in the POM is necessary for proper inner ear formation. Expression of the mesenchyme marker <it>Brn4 </it>was also lost in the <it>TCre-KO</it>. <it>Brn4</it>^-;<it>Tbx1</it>^+/-embryos displayed defects in growth of the distal cochlea. To identify a potential signal from the POM to the otic epithelium, expression of retinoic acid (RA) catabolizing genes was examined in both mutants. <it>Cyp26a1 </it>expression was altered in the <it>TCre-KO</it>, while <it>Cyp26c1 </it>showed reduced expression in both <it>TCre-KO </it>and <it>Brn4</it>^-;<it>Tbx1</it>^+/-embryos.</p> <p>Conclusion</p> <p>These results indicate that <it>Tbx1 </it>expression in the POM regulates cochlear outgrowth potentially via control of local retinoic acid activity.</p

The University of California San Francisco, Brain Metastases Stereotactic Radiosurgery (UCSF-BMSR) MRI Dataset

The University of California San Francisco Brain Metastases Stereotactic Radiosurgery (UCSF-BMSR) dataset is a public, clinical, multimodal brain MRI dataset consisting of 560 brain MRIs from 412 patients with expert annotations of 5136 brain metastases. Data consists of registered and skull stripped T1 post-contrast, T1 pre-contrast, FLAIR and subtraction (T1 pre-contrast - T1 post-contrast) images and voxelwise segmentations of enhancing brain metastases in NifTI format. The dataset also includes patient demographics, surgical status and primary cancer types. The UCSF-BSMR has been made publicly available in the hopes that researchers will use these data to push the boundaries of AI applications for brain metastases.Comment: 15 pages, 2 tables, 2 figure

Germline ERBB2/HER2 Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms

Familial cases of myeloproliferative neoplasms (MPN) are relatively common, yet few inherited risk factors have been identified. Exome sequencing of a kindred with a familial cancer syndrome characterized by both MPN and melanoma produced a germline variant in the ERBB2/HER2 gene that co-segregates with disease. To further investigate whether germline ERBB2 variants contribute to MPN predisposition, the frequency of ERBB2 variants was analyzed in 1604 cases that underwent evaluation for hematologic malignancy, including 236 cases of MPN. MPN cases had a higher frequency of rare germline ERBB2 coding variants compared to non-MPN hematologic malignancies (8.9% vs. 4.1%, OR 2.4, 95% CI: 1.4 to 4.0, p = 0.0028) as well as cases without a blood cancer diagnosis that served as an internal control (8.9% vs. 2.7%, OR 3.5, 95% CI: 1.4 to 8.3, p = 0.0053). This finding was validated via comparison to an independent control cohort of 1587 cases without selection for hematologic malignancy (8.9% in MPN cases vs. 5.2% in controls, p = 0.040). The most frequent variant identified, ERBB2 c.1960A &gt; G; p.I654V, was present in MPN cases at more than twice its expected frequency. These data indicate that rare germline coding variants in ERBB2 are associated with an increased risk for development of MPN. The ERBB2 gene is a novel susceptibility locus which likely contributes to cancer risk in combination with additional risk alleles

Characterization of human neural progenitor cell (hNPC) derived neurons during neuronal differentiation.

<p>(A). Representative confocal scan images of MAP2 and GABA neurons. Four weeks after neuronal differentiation, hNPC-derived neurons from <i>PIGA</i>wt and <i>PIGA</i>c.1234C>T hNPCs were stained with anti-human MAP2 (microtubule-associated protein 2, red) and anti-human GABA (γ-amino butyric acid, green); nuclei were stained with DAPI (blue). Scale bars represent 50μm. Comparison of hNPC-derived neurons from <i>PIGA</i>wt (top) and <i>PIGA</i>c.1234C>T (bottom) showed dramatically reduced gro<i>wt</i>h in the neurons from the <i>PIGA</i>c.1234C>T cell line (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0174074#pone.0174074.s002" target="_blank">S2 Fig</a>). (B). Representative confocal images of immunofluorescence staining for Synapsin (red) and VGLuT1 (vesicular glutamate transporter-1, green) in hNPC-derived neurons from <i>PIGA</i>wt and <i>PIGA</i>c.1234C><i>T</i> cell lines. After 4 weeks of neuronal differentiation, neuron proliferation was markedly decreased in <i>PIGA</i>c.1234C>T. The density of Synapsin and VGLuT1 was substantially decreased in hNPC-derived neurons from <i>PIGA</i>c.1234C>T compared to the <i>PIGA</i>wt cell line. Scale bars represent 100 μm. (C). Quantification of VGLuT1 density in hNPC-derived neurons from <i>PIGA</i>wt and <i>PIGA</i>c.1234C>T. The number of VGLuT1 positive neurons was counted and plotted. Values represent the mean ± SD. (D). Representative confocal images showing the density of VGAT (vesicular GABA transporter, green) and Synapsin (red) in hNPC-derived neurons from <i>PIGA</i>wt and <i>PIGA</i>c.1234C>T cell lines. There was decreased density of VGAT and synapse formation in the hNPC-derived neurons from <i>PIGA</i>c.1234C>T cells compared to the control cell line (<i>PIGA</i>wt) (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0174074#pone.0174074.s003" target="_blank">S3 Fig</a>). Scale bars represent 20 μm. (E). Density of VGAT per 100 μm in <i>PIGA</i>wt and <i>PIGA</i>c.1234C>T derived neurons. Values represent the mean ± SD.</p