In the vertebrate neural tube, regional Sonic hedgehog (Shh) signaling invokes a time-and concentration-dependent induction of six different cell populations mediated through Gli transcriptional regulators. Elsewhere in the embryo, Shh/Gli responses invoke different tissue-appropriate regulatory programs. A genome-scale analysis of DNA binding by Gli1 and Sox2, a pan-neural determinant, identified a set of shared regulatory regions associated with key factors central to cell fate determination and neural tube patterning. Functional analysis in transgenic mice validates core enhancers for each of these factors and demonstrates the dual requirement for Gli1 and Sox2 inputs for neural enhancer activity. Furthermore, through an unbiased determination of Gli-binding site preferences and analysis of binding site variants in the developing mammalian CNS, we demonstrate that differential Gli-binding affinity underlies threshold-level activator responses to Shh input. In summary, our results highlight Sox2 input as a contextspecific determinant of the neural-specific Shh response and differential Gli-binding site affinity as an important cis-regulatory property critical for interpreting Shh morphogen action in the mammalian neural tube.

SUMMARY Injection of the peptide hormone ghrelin stimulates food intake in mice and humans. However, mice born without ghrelin demonstrate no significant loss of appetite. This paradox suggests either that compensation develops in mice born without ghrelin or that ghrelin is not essential for appetite control. To distinguish these possibilities, we generated transgenic mice (Ghrl-DTR) that express the diphtheria toxin receptor in ghrelin-secreting cells. Injection of diphtheria toxin in adulthood ablated ghrelin cells and reduced plasma ghrelin by 80-95%. Ghrelin cell-ablated mice exhibited no loss of appetite or body weight and no resistance to a high fat diet. To stimulate food intake in mice by ghrelin injection, we had to raise plasma levels many-fold above normal. Like germline ghrelin-deficient mice, the ghrelin cell-ablated mice developed profound hypoglycemia when subjected to prolonged calorie restriction, confirming that ghrelin acts to maintain blood glucose under famine conditions.

Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness.

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To the Editor: Recent literature has called for action to improve the quality and availability of clinical photography and kodachromes featuring dark skin. [1][2][3] This article provides a practical guide for clinicians and staff to improve clinical photography for darkskinned patients in a typical dermatology practice. These recommendations should improve clinical photography for all skin tones; however, the challenges of capturing dermatologic pathology on dark Table I. Outline of specific recommendations for measures to improve clinical photography of dark skin in the typical dermatology practice Setup 1. Prepare the skin. Gently clean the skin that will be photographed to remove any makeup and foreign debris. Remove all jewelry and excess hair from the area. Avoid removing secondary features, such as crust or scale, while cleaning. 2. Clean the lens. Use a soft cloth to wipe the camera lens prior to every use to ensure that the lens is clean. 3. Stabilize the camera. Use a tripod to stabilize the camera in order to clearly capture finite details. Details, especially subtle ones, may be somewhat obscured by melanin; therefore, high resolution is crucial. If unable to use a tripod, stabilize the camera by resting the bottom edge on a table or flat, steady surface.4. Position the camera at an appropriate distance from the skin, about 3-4 feet away. Use zoom as necessary to obtain closer images. While photographing diffuse pathology, take both overview and focal photographs. Avoid zooming more than half of the capability of the camera because this may compromise the resolution of the image. This does not apply while using a macro lens. With these lenses, the camera can be held closer to the surface of the skin.5. Use a plain, nonreflective backdrop. Use a plain wall or, when possible, a sheet as a backdrop. The background should provide moderate contrast to the tone of the skin; however, it should not be too light because this might lead to overexposed dark skin. The background should not be overly reflective because this may cast glare on the pathology. Do not compromise the quality of lighting for the sake of the backdrop. Light-to medium-toned royal-blue backdrops generally provide contrast to dark skin tones without casting abnormal hues onto the skin. Felt or other wrinkle-resistant fabric or matte photography background paper will provide the ideal backdrop texture, which should be uniform and nonreflective. Foam core sheets can be purchased at a craft store and used as an accessible and cost-effective background. Lighting 1. Invest in an appropriate light source. Avoid the use of the built-in flash on a camera because these flashes reflect light off of the surface of the skin directly back into the lens, causing glare. An LED light source produces less glare while providing high-quality, uniform light. An LED ring light can be purchased at a low cost and can provide high-quality light and flexibility in positioning of the light for optimal clinical photography. 2. Angle the light source to avoid glare. Fo...

This article is available online at http://www.jlr.org endoplasmic reticulum (ER) to Golgi, where they are processed proteolytically to yield active nuclear forms. When cells are sterol-replete, Insig , an ER-resident membrane protein, binds Scap and retains the Scap-SREBP complex in the ER, thereby preventing the proteolytic activation of SREBPs ( 2, 3 ).In cells lacking Scap, SREBP transport to the Golgi is abolished, blocking SREBP proteolysis and leading to reduced rates of de novo cholesterol and fatty acid synthesis. As a result, Scap-defi cient cultured cells cannot grow without supplementation with exogenous cholesterol and fatty acids ( 4 ). The in vivo function of Scap has been explored most thoroughly in the liver, which is quantitatively the most important organ for cholesterol synthesis in most mammals ( 5 ). When Scap is ablated through gene knockout in rodent livers, nuclear SREBPs are not detectable, leading to reduced rates of hepatic cholesterol and fatty acid synthesis and reduced levels of cholesterol and triglycerides in the liver and plasma ( 6 ). Mice with defi ciency of Scap in the liver appear phenotypically normal and have grossly normal liver function. These mice are protected from development of fatty liver and carbohydrate-induced hypertriglyceridemia, suggesting that Scap inhibition may be a potential therapeutic strategy for the treatment of nonalcoholic fatty liver disease and hyperlipidemia ( 7 ).Determining the extrahepatic role of Scap is of interest both to elucidate the role of SREBP-mediated lipid homeostasis in extrahepatic tissues and to assess for toxicity arising from Scap inhibition in the context of the whole Grant HL-20948. M.R.M. is an Howard Hughes Medical Institute International Student Research Fellow. L.J.E. was supported by NIH Institutional Training Grant 2T32-DK-007745-16 and by NIH Grant 1K08DK102652-01. Manuscript received 31 March 2015 and in revised form 17 April 2015. Published, JLR Papers in Press, April 20, 2015 DOI 10.1194 Scap is required for sterol synthesis and crypt growth in intestinal mucosa Abbreviations: 4-OHT, 4-hydroxytamoxifen; ChgA, chromogranin A; CREB, cAMP response element binding protein; ER, endoplasmic reticulum; H&E, hematoxylin and eosin; HMGR, HMG-CoA reductase; IEC, intestinal epithelial cell; LGR5, leucine-rich repeat containing G protein-coupled receptor 5; M ␤ CD, methyl-␤ -cyclodextrin; NGS, normal goat serum; NPC1L1, Niemann-Pick C1-like 1 protein; PAS/AB, periodic acid-Schiff-Alcian Blue; QPCR, quantitative real-time RT-PCR; Scap, SREBP cleavage-activating protein; SREBP, sterol regulatory element-binding protein; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling .

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