Modeling and Rescue of RP2 Retinitis Pigmentosa Using iPSC-Derived Retinal Organoids

RP2 mutations cause a severe form of X-linked retinitis pigmentosa (XLRP). The mechanism of RP2-associated retinal degeneration in humans is unclear, and animal models of RP2 XLRP do not recapitulate this severe phenotype. Here, we developed gene-edited isogenic RP2 knockout (RP2 KO) induced pluripotent stem cells (iPSCs) and RP2 patient-derived iPSC to produce 3D retinal organoids as a human retinal disease model. Strikingly, the RP2 KO and RP2 patient-derived organoids showed a peak in rod photoreceptor cell death at day 150 (D150) with subsequent thinning of the organoid outer nuclear layer (ONL) by D180 of culture. Adeno-associated virus-mediated gene augmentation with human RP2 rescued the degeneration phenotype of the RP2 KO organoids, to prevent ONL thinning and restore rhodopsin expression. Notably, these data show that 3D retinal organoids can be used to model photoreceptor degeneration and test potential therapies to prevent photoreceptor cell death

Integrated Visualization of Human Brain Connectome Data

Visualization plays a vital role in the analysis of multi-modal neuroimaging data. A major challenge in neuroimaging visualization is how to integrate structural, functional and connectivity data to form a comprehensive visual context for data exploration, quality control, and hypothesis discovery. We develop a new integrated visualization solution for brain imaging data by combining scientific and information visualization techniques within the context of the same anatomic structure. New surface texture techniques are developed to map non-spatial attributes onto the brain surfaces from MRI scans. Two types of non-spatial information are represented: (1) time-series data from resting-state functional MRI measuring brain activation; (2) network properties derived from structural connectivity data for different groups of subjects, which may help guide the detection of differentiation features. Through visual exploration, this integrated solution can help identify brain regions with highly correlated functional activations as well as their activation patterns. Visual detection of differentiation features can also potentially discover image based phenotypic biomarkers for brain diseases

Incorporating predicted functions of nonsynonymous variants into gene-based analysis of exome sequencing data: a comparative study

Next-generation sequencing has opened up new avenues for the genetic study of complex traits. However, because of the small number of observations for any given rare allele and high sequencing error, it is a challenge to identify functional rare variants associated with the phenotype of interest. Recent research shows that grouping variants by gene and incorporating computationally predicted functions of variants may provide higher statistical power. On the other hand, many algorithms are available for predicting the damaging effects of nonsynonymous variants. Here, we use the simulated mini-exome data of Genetic Analysis Workshop 17 to study and compare the effects of incorporating the functional predictions of single-nucleotide polymorphisms using two popular algorithms, SIFT and PolyPhen-2, into a gene-based association test. We also propose a simple mixture model that can effectively combine test results based on different functional prediction algorithms

5D gravity and the discrepant G measurements

It is shown that 5D Kaluza-Klein theory stabilized by an external bulk scalar field may solve the discrepant laboratory G measurements. This is achieved by an effective coupling between gravitation and the geomagnetic field. Experimental considerations are also addressed.Comment: 13 pages, to be published in: Proceedings of the 18th Course of the School on Cosmology and Gravitation: The gravitational Constant. Generalized gravitational theories and experiments (30 April-10 May 2003, Erice). Ed. by G. T. Gillies, V. N. Melnikov and V. de Sabbata, (Kluwer), 13pp. (in print) (2003

Pan-Chromatic observations of the Recurrent Nova LMC 2009a (LMC 1971b)

Nova LMC 2009a is confirmed as a Recurrent Nova (RN) from positional coincidence with nova LMC 1971b. The observational data set is one of the most comprehensive for any Galactic or extragalactic RN: optical and near-IR photometry from outburst until over 6 years later; optical spectra for the first 6 months, and Swift satellite Ultraviolet and X-ray observations from 9 days to almost 1 year post-outburst. We find $M_V = -8.4\pm0.8_{\mathrm{r}}\pm0.7_{\mathrm{s}}$ and expansion velocities between 1000 and 4000 km s$^{-1}$. Coronal line emission before day 9 indicates shocks in the ejecta. Strengthening of He II $\lambda$4686 preceded the emergence of the Super-Soft Source (SSS) in X-rays at $\sim63-70$ days, which was initially very variable. Periodic modulations, $P=1.2$ days, most probably orbital in nature, were evident in the UV and optical from day 43. Subsequently, the SSS shows an oscillation with the same period but with a delay of 0.28P. The progenitor system has been identified; the secondary is most likely a sub-giant feeding a luminous accretion disk. Properties of the SSS infer a white dwarf (WD) mass $1.1 \mathrm{M}_\odot \lesssim M_{\rm WD} \lesssim 1.3 \mathrm{M}_\odot$. If the accretion occurs at constant rate, $\dot{\it{M}}_{\rm acc} \simeq 3.6^{+4.7}_{-2.5} \times 10^{-7} \mathrm{M}_\odot$ yr$^{-1}$ is needed, consistent with nova models for an inter-eruption interval of 38 years, low outburst amplitude, progenitor position in the color-magnitude diagram, and spectral energy distribution at quiescence. We note striking similarities between LMC 2009a and the Galactic nova KT Eri, suggesting that KT Eri is a candidate RN

The Role of the Mucus Barrier in Digestion

Mucus forms a protective layer across a variety of epithelial surfaces. In the gastrointestinal (GI) tract, the barrier has to permit the uptake of nutrients, while excluding potential hazards, such as pathogenic bacteria. In this short review article, we look at recent literature on the structure, location, and properties of the mammalian intestinal secreted mucins and the mucus layer they form over a wide range of length scales. In particular, we look at the structure of the gel-forming glycoprotein MUC2, the primary intestinal secreted mucin, and the influence this has on the properties of the mucus layer. We show that, even at the level of the protein backbone, MUC2 is highly heterogeneous and that this is reflected in the networks it forms. It is evident that a combination of charge and pore size determines what can diffuse through the layer to the underlying gut epithelium. This information is important for the targeted delivery of bioactive molecules, including nutrients and pharmaceuticals, and for understanding how GI health is maintained

f(R) Theories of Supergravities and Pseudo-supergravities

We present f(R) theories of ten-dimensional supergravities, including the fermionic sector up to the quadratic order in fermion fields. They are obtained by performing the conformal scaling on the usual supergravities to the f(R) frame in which the dilaton becomes an auxiliary field and can be integrated out. The f(R) frame coincides with that of M-theory, D2-branes or NS-NS 5-branes. We study various BPS p-brane solutions and their near-horizon AdS \times sphere geometries in the context of the f(R) theories. We find that new solutions emerge with global structures that do not exist in the corresponding solutions of the original supergravity description. In lower dimensions, We construct the f(R) theory of N=2, D=5 gauged supergravity with a vector multiplet, and that for the four-dimensional U(1)^4 gauged theory with three vector fields set equal. We find that some previously-known BPS singular "superstars" become wormholes in the f(R) theories. We also construct a large class of f(R) (gauged) pseudo-supergravities. In addition we show that the breathing mode in the Kaluza-Klein reduction of Gauss-Bonnet gravity on S^1 is an auxiliary field and can be integrated out.Comment: Latex, 46 page

Species Difference of CD137 Ligand Signaling in Human and Murine Monocytes

BACKGROUND: Stimulation of CD137 ligand on human monocytes has been shown to induce DC differentiation, and these CD137L-DCs are more potent than classical DCs, in stimulating T cell responses in vitro. To allow an in vivo evaluation of the potency of CD137L-DCs in murine models we aimed at generating murine CD137L-DCs. METHODOLOGY/PRINCIPAL FINDINGS: When stimulated through CD137 ligand murine monocytes responded just as human monocytes with an increased adherence, morphological changes, proliferation and an increase in viable cell numbers. But CD137 ligand signaling did not induce expression of inflammatory cytokines and costimulatory molecules in murine monocytes and these cells had no T cell stimulatory activity. Murine monocytes did not differentiate to inflammatory DCs upon CD137 ligand signaling. Furthermore, while CD137 ligand signaling induces maturation of human immature classical DCs it failed to do so with murine immature classical DCs. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that both human and murine monocytes become activated by CD137 ligand signaling but only human and not murine monocytes differentiate to inflammatory DCs

Epidermal growth factor receptor kinase domain mutations are rare in salivary gland carcinomas

Activating mutations within the epidermal growth factor (EGFR) tyrosine kinase domain identify non-small cell lung cancer patients with improved clinical response to tyrosine kinase inhibitor therapy. Recently, we identified two EGFR mutations in a cohort of 25 salivary gland carcinomas (SGCs) by screening the tumour samples for the both most common hotspot mutations in exons 19 and 21 by allele-specific PCR. Here, we present a comprehensive sequencing analysis of the entire critical EGFR tyrosine kinase domain in 65 SGC of the main histopathological types. We found EGFR mutations in the tyrosine kinase domain to be a rare event in SGCs. No additional mutations other than the two known exon 19 deletions (c.2235_2249del15) in a mucoepidermoid carcinoma and an adenoid cystic carcinoma have been detected. Other putative predictive markers for EGFR-targeted therapy in SGCs might be relevant and should be investigated