Retromer and Its Role in Regulating Signaling at Endosomes.

The retromer complex is a key element of the endosomal protein sorting machinery being involved in trafficking of proteins from endosomes to the Golgi and also endosomes to the cell surface. There is now accumulating evidence that retromer also has a prominent role in regulating the activity of many diverse signaling proteins that traffic through endosomes and this activity has profound implications for the functioning of many different cell and tissue types from neuronal cells to cells of the immune system to specialized polarized epithelial cells of the retina. In this review, the protein composition of the retromer complex will be described along with many of the accessory factors that facilitate retromer-mediated endosomal protein sorting to detail how retromer activity contributes to the regulation of several distinct signaling pathways

Broadband anti-reflection coating for the meter class Dark Energy Spectroscopic Instrument lenses

The Dark Energy Spectroscopic Instrument (DESI), currently under construction, will be used to measure the expansion history of the Universe using the Baryon Acoustic Oscillation technique. The spectra of 35 million galaxies and quasars over 14000 sq deg will be measured during the life of the experiment. A new prime focus corrector for the KPNO Mayall telescope will deliver light to 5000 fiber optic positioners. The fibers, in turn, feed ten broad-band spectrographs. We will describe the broadband AR coating (360 nm to 980nm) that was applied to the lenses of the camera system for DESI using ion assisted deposition techniques in a 3 m coating chamber. The camera has 6 lenses ranging in diameter from 0.8 m to 1.14 m, weighing from 84 kg to 237 kg and made from fused silica or BK7. The size and shape of the surfaces provided challenges in design, uniformity control, handling, tooling and process control. Single surface average transmission and minimum transmission met requirements. The varied optical surfaces and angle of incidence considerations meant the uniformity of the coating was of prime concern. The surface radius of curvature (ROC) for the 12 surfaces ranged from nearly flat to a ROC of 611 mm and a sag of 140 mm. One lens surface has an angle of incidence variation from normal incidence to 40°. Creating a design with a larger than required bandwidth to compensate for the non-uniformity and angle variation created the ability to reduce the required coating uniformity across the lens and a single design to be used for all common substrate surfaces. While a perfectly uniform coating is often the goal it is usually not practicable or cost effective for highly curved surfaces. The coating chamber geometry allowed multiple radial positions of the deposition sources as well as substrate height variability. Using these two variables we were able to avoid using any masking to achieve the uniformity required to meet radial and angle performance goals. Very broadband AR coatings usually have several very thin and optically important layers. The DESI coating design has layers approaching 3 nm in thickness. Having sensitive thin layers in the design meant controlling layer thickness and azimuthal variation were critical to manufacturing repeatability. Through use of strategically placed quartz crystal monitors combined with stable deposition plumes, the manufacturing variability was reduced to acceptable levels. Low deposition rates and higher rotation rates also provided some stability to azimuthal variation

Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling

Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex that orchestrates cargo retrieval and recycling and, importantly, is biochemically and functionally distinct from the established retromer pathway. We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of α5β1 integrin. Through quantitative proteomic analysis, we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, that require SNX17-retriever to maintain their surface levels. Our\ua0identification of retriever establishes a major endosomal retrieval and recycling pathway

Nutrition and cancer: A review of the evidence for an anti-cancer diet

It has been estimated that 30–40 percent of all cancers can be prevented by lifestyle and dietary measures alone. Obesity, nutrient sparse foods such as concentrated sugars and refined flour products that contribute to impaired glucose metabolism (which leads to diabetes), low fiber intake, consumption of red meat, and imbalance of omega 3 and omega 6 fats all contribute to excess cancer risk. Intake of flax seed, especially its lignan fraction, and abundant portions of fruits and vegetables will lower cancer risk. Allium and cruciferous vegetables are especially beneficial, with broccoli sprouts being the densest source of sulforophane. Protective elements in a cancer prevention diet include selenium, folic acid, vitamin B-12, vitamin D, chlorophyll, and antioxidants such as the carotenoids (α-carotene, β-carotene, lycopene, lutein, cryptoxanthin). Ascorbic acid has limited benefits orally, but could be very beneficial intravenously. Supplementary use of oral digestive enzymes and probiotics also has merit as anticancer dietary measures. When a diet is compiled according to the guidelines here it is likely that there would be at least a 60–70 percent decrease in breast, colorectal, and prostate cancers, and even a 40–50 percent decrease in lung cancer, along with similar reductions in cancers at other sites. Such a diet would be conducive to preventing cancer and would favor recovery from cancer as well

A global analysis of SNX27-retromer assembly and cargo specificity reveals a function in glucose and metal ion transport.

The PDZ domain-containing sorting nexin 27 (SNX27) promotes recycling of internalized transmembrane proteins from endosomes to the plasma membrane by linking PDZ-dependent cargo recognition to retromer-mediated transport. Here, we employed quantitative proteomics of the SNX27 interactome alongside quantification of the surface proteome of SNX27 and retromer-suppressed cells to dissect the assembly of the SNX27 complex and provide an unbiased global view of SNX27-mediated sorting. Over 100 cell surface proteins, many of which interact with SNX27, including the glucose transporter GLUT1, the Menkes disease copper transporter ATP7A, various zinc and amino acid transporters, and numerous signalling receptors require SNX27-retromer to prevent lysosomal degradation and maintain surface levels. Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. Our data identify the SNX27-retromer as a major endosomal recycling hub required to maintain cellular nutrient homeostasis