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Development of the gastrointestinal system occurs after gut tube closure, guided by spatial and temporal control of gene expression. However, it remains unclear what forces regulate these spatiotemporal gene expression patterns. Here we perform single-cell chromatin profiling of the primitive gut tube to reveal organ-specific chromatin patterns that reflect the anatomical patterns of distinct organs. We generate a comprehensive map of epigenomic changes throughout gut development, demonstrating that dynamic chromatin accessibility patterns associate with lineage-specific transcription factor binding events to regulate organ-specific gene expression. Additionally, we show that loss of Sox2 and Cdx2, foregut and hindgut lineage-specific transcription factors, respectively, leads to fate shifts in epigenomic patterns, linking transcription factor binding, chromatin accessibility, and lineage fate decisions in gut development. Notably, abnormal expression of Sox2 in the pancreas and intestine impairs lineage fate decisions in both development and adult homeostasis. Together, our findings define the chromatin and transcriptional mechanisms of organ identity and lineage plasticity in development and adult homeostasis. The primitive gut tube gives rise to all major internal organs, while underlying regulatory mechanisms are unclear. Here, the authors analyze its chromatin landscape at the single-cell level and define the epigenetic regulation of lineage fate decisions and plasticity in organ development and homeostasis. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a deadly cancer in which cancer stem cells (CSCs) sustain tumor growth and contribute to therapeutic resistance. Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a promising target in GBM. Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. We show that PRMT5 inhibition causes widespread disruption of splicing across the transcriptome, particularly affecting cell cycle gene products. We identify a GBM splicing signature that correlates with the degree of response to PRMT5 inhibition. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM. The arginine methyltransferase PRMT5 is over-expressed in cancer and has a role in the maintenance of stem cells. Here, the authors show that PRMT5 inhibitors can block the growth of patient derived glioblastoma stem cell cultures in vitro and in vivo, suggesting that PRMT5 inhibition may be a useful therapeutic strategy [ABSTRACT FROM AUTHOR]

The nondetection of dark matter (DM) particles in increasingly stringent laboratory searches has encouraged alternative gravity theories where gravity is sourced only from visible matter. Here, we consider whether such theories can pass a two-dimensional test posed by gravitational lensing—to reproduce a particularly detailed Einstein ring in the core of the galaxy cluster A3827. We find that when we require the lensing mass distribution to strictly follow the shape (ellipticity and position angle) of the light distribution of cluster member galaxies, intracluster stars, and the X-ray emitting intracluster medium, we cannot reproduce the Einstein ring, despite allowing the mass-to-light ratios of these visible components to freely vary with radius to mimic alternative gravity theories. Alternatively, we show that the detailed features of the Einstein ring are accurately reproduced by allowing a smooth, freely oriented DM halo in the lens model, with relatively small contributions from the visible components at a level consistent with their observed brightnesses. This dominant DM component is constrained to have the same orientation as the light from the intracluster stars, indicating that the intracluster stars trace the gravitational potential of this component. The Einstein ring of A3827 therefore presents a new challenge for alternative gravity theories: not only must such theories find agreement between the total lensing mass and visible mass, but they must also find agreement between the projected sky distribution of the lensing mass and that of the visible matter, a more stringent test than has hitherto been posed by lensing data. [ABSTRACT FROM AUTHOR]

There is a growing awareness that complex 3-dimensional (3D) organs are not well represented by monolayers of a single cell type – the standard format for many drug screens. To address this deficiency, and with the goal of improving screens so that drugs with good efficacy and low toxicity can be identified, microphysiological systems (MPS) are being developed that better capture the complexity of in vivo physiology. We have previously described an organ-on-a-chip platform that incorporates perfused microvessels, such that survival of the surrounding tissue is entirely dependent on delivery of nutrients through the vessels. Here we describe an arrayed version of the platform that incorporates multiple vascularized micro-organs (VMOs) on a 96-well plate. Each VMO is independently-addressable and flow through the micro-organ is driven by hydrostatic pressure. The platform is easy to use, requires no external pumps or valves, and is highly reproducible. As a proof-of-concept we have created arrayed vascularized micro tumors (VMTs) and used these in a blinded screen to assay a small library of compounds, including FDA-approved anti-cancer drugs, and successfully identified both anti-angiogenic and anti-tumor drugs. This 3D platform is suitable for efficacy/toxicity screening against multiple tissues in a more physiological environment than previously possible. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Recessive X-linked dystonia-parkinsonism almost exclusively affects men. We investigated the genetic mechanisms causing this disorder in a female patient. Methods We confirmed the presence of an X-linked dystonia-parkinsonism-specific change in our patient by sequencing. In addition, we employed quantitative real-time PCR and array comparative genomic hybridization to determine the patient's X-chromosome copy number. Results The patient's sequence electropherogram suggested a higher amount of the mutated allele compared with the wild-type allele. Subsequently, extensive gene dosage analyses revealed a copy number of the X chromosomes between 1 and 2, indicating loss of 1 X chromosome in a subset of cells. Phenotypic reevaluation of the patient showed several clinical features of Turner syndrome. Conclusions Our female X-linked dystonia-parkinsonism patient suffered from an undiagnosed X-chromosome monosomy in a subset of cells (45,X/46,XX), suggesting an atypical Turner syndrome and contributing the first molecular explanation for the manifestation of an X-linked dystonia-parkinsonism phenotype in women. © 2013 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Mechanical feedback is one of the most common difficulties encountered when fitting hearing aids for toddlers and young children. We described the use of 3D printing to tailor a protective cap for a toddler with bilateral microtia/canal atresia to facilitate bone-anchoring hearing aid use. [ABSTRACT FROM AUTHOR]

Precipitating antibodies prepared in rabbits with human seminal plasma (HSP) have been used in a preliminary study to define the antigenicity of HSP by use of gel precipitin methods. Also, a method for evaluating and preserving liquid precipitates of acid phosphatase in polyacrylamide is described. Some ten or eleven antigens were demonstrated by Ouchterlony agar immunodiffusion (ID). Eight of these appeared to be HSP-specific and two or three were also found in normal human serum (NILS). Five of the HSP-specific antigens were shown by agar immunoelectrophoresis (IEP) and by ID to be acid phosphatase. Four of these constituted the basic isoenzyme pattern and were shown by IEP and ID to be shared by prostatic fluid (HPF). Titration of HPF by ID yielded antigen titres of 46, 33, 17 and 3 for the four isoenzymes. IEP patterns obtained with lISP and HPF showed two isoenzymes migrating to the a-globulin zone. The third isoenzyme migrated to the a-2-fast β area, while a fourth was seen as a slow beta precipitin arc formed consistently by HPF, and variably by HSP. HSP contained a fifth isoenzyme which also migrated to the slow β area. Human prostate extract (HPE) showed only two, sometimes three, of these components, one of the slower components being frequently faint in appearance or absent. In HSP and HPF isoenzyme migrating to the a-2-fast β zone exhibited two distinct characteristics: biphasic migration and limited diffusion, suggesting a heterogeneous high molecular weight isoenzyme or an isoenzyme complex. However, observed differences between HSP, HPF and HPE in migration rate, relative concentrations of subfractions, lateral diffusion, etc. leave open the question of the nature of the heterogeneity. [ABSTRACT FROM AUTHOR]

Medulloblastoma (MB) is a neoplasm linked to dysregulated cerebellar development. Previously, we demonstrated that the Sonic Hedgehog (SHH) subgroup grows hierarchically, with Sox2+ cells at the apex of tumor progression and relapse. To test whether this mechanism is rooted in a normal developmental process, we studied the role of Sox2 in cerebellar development. We find that the external germinal layer (EGL) is derived from embryonic Sox2+ precursors and that the EGL maintains a rare fraction of Sox2+ cells during the first postnatal week. Through lineage tracing and single-cell analysis, we demonstrate that these Sox2+ cells are within the Atoh1+ lineage, contribute extensively to adult granule neurons, and resemble Sox2+ tumor cells. Critically, constitutive activation of the SHH pathway leads to their aberrant persistence in the EGL and rapid tumor onset. We propose that failure to eliminate this rare but potent developmental population is the tumor initiation mechanism in SHH-subgroup MB. • A rare and transient population of Sox2+ cells is identified in the developing EGL • These stem-like Sox2+ cells contribute extensively to the granule lineage • Constitutive activation of SHH in Sox2+ cells leads to their abnormal persistence • Medulloblastoma arises from the sustained hierarchical output from these Sox2+ cells Selvadurai et al. demonstrate that the developing cerebellar external germinal layer contains a transient population of more primitive cells expressing Sox2. Aberrant activation of the SHH signaling pathway in these cells causes persistent hierarchical growth, leading to medulloblastoma. [ABSTRACT FROM AUTHOR]