Well-defined gradients of the lipid mediator sphingosine-1-phosphate (S1P) direct chemotactic egress of mature thymocytes from the thymus into the circulation. Although it is known that these gradients result from low S1P levels in the thymic parenchyma and high S1P concentrations at the exit sites and in the plasma, the biochemical mechanisms that regulate these differential S1P levels remain unclear. Several studies demonstrated that ceramide synthase 2 (Cers2) regulates the levels of the S1P precursor sphingosine. We, therefore, investigated whether Cers2 is involved in the regulation of S1P gradients and S1P-dependent egress into the circulation. By analyzing Cers2-deficient mice, we demonstrate that Cers2 limits the levels of S1P in thymus and blood to maintain functional S1P gradients that mediate thymocyte emigration into the circulation. This function is specific for Cers2, as we also show that Cers4 is not involved in the regulation of thymic egress. Our study identified Cers2 as an important regulator of S1P-dependent thymic egress, and thus contributes to the understanding of how S1P gradients are maintained in vivo.

Impaired proinsulin-to-insulin processing in pancreatic β-cells is a key defective step in both type 1 diabetes and type 2 diabetes (T2D) (refs. 1,2), but the mechanisms involved remain to be defined. Altered metabolism of sphingolipids (SLs) has been linked to development of obesity, type 1 diabetes and T2D (refs. 3–8); nonetheless, the role of specific SL species in β-cell function and demise is unclear. Here we define the lipid signature of T2D-associated β-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. β-cell-specific ablation of CerS2, the enzyme necessary for generation of very-long-chain SLs, selectively reduces insulin content, impairs insulin secretion and disturbs systemic glucose tolerance in multiple complementary models. In contrast, ablation of long-chain-SL-synthesizing enzymes has no effect on insulin content. By quantitatively defining the SL–protein interactome, we reveal that CerS2 ablation affects SL binding to several endoplasmic reticulum–Golgi transport proteins, including Tmed2, which we define as an endogenous regulator of the essential proinsulin processing enzyme Pcsk1. Our study uncovers roles for specific SL subtypes and SL-binding proteins in β-cell function and T2D-associated β-cell failure.

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Insulin plays a central role in regulating metabolic homeostasis and guanine-nucleotide exchange factors of the cytohesin family have been suggested to be involved in insulin signal transduction. The Drosophila homolog of cytohesin-3, steppke , has been shown to be essential for insulin signaling during larval development. However, genetic evidence for the functional importance of cytohesin-3 in mammals is missing. We therefore analyzed the consequences of genetic cytohesin-3-deficiency on insulin signaling and function in young and aged mice, using normal chow or high-fat diet (HFD). Insulin-receptor dependent signaling events are significantly reduced in liver and adipose tissue of young cytohesin-3-deficient mice after insulin-injection, although blood glucose levels and other metabolic parameters remain normal in these animals. Interestingly, however, cytohesin-3-deficient mice showed a reduced age- and HFD-induced weight gain with a significant reduction of body fat compared to wild-type littermates. Furthermore, cytohesin-3-deficient mice on HFD displayed no alterations in energy expenditure, but had an increased lipid excretion instead, as well as a reduced expression of genes essential for bile acid synthesis. Our findings show for the first time that an intact cyth3 locus is required for full insulin signaling in mammals and might constitute a novel therapeutic target for weight reduction.

<p>Concerning the Perspective 3-Point (P3P) Problem, Grunert's system of three quadratic equations has a repeated solution if and only if the cubic polynomial introduced by Finsterwalder has a repeated root. This polynomial is here shown to be obtainable from a particularly simple cubic polynomial with complex coefficients via a simple Möbius transformation. This provides surprising geometric insight into the P3P problem. In particular, (1) the discriminant of Finsterwalder's polynomial can be written using the formula for the standard deltoid curve, and (2) this discriminant vanishes on a surface that approaches a deltoid shape when the camera is moved infinitely far from the control points in a direction perpendicular to the control points plane (the "limit case"). These two facts have been previously reported, but obscure reasoning was required to establish them. In contrast, the present article uses the newly discovered cubic polynomial to easily produce the first fact, which then provides a basis for better understanding the second fact. A detailed geometric description of the P3P solution points in the "limit case" is also provided.</p>

No abstract

<p>Concerning the Perspective 3-Point (P3P) Problem, Grunert's system of three quadratic equations has a repeated solution if and only if the cubic polynomial introduced by Finsterwalder has a repeated root. This polynomial is shown to be equivalent to a particularly simple cubic polynomial with complex coefficients that provides surprising geometric insight into the P3P problem. In particular, (1) its discriminant can be written using the formula for the standard deltoid, and (2) this discriminant vanishes on a surface that approaches a deltoid shape when the camera is moved infinitely far from the control points in a direction perpendicular to the control points plane (the ``limit case"). These two facts have been previously reported, but obscure reasoning was required to establish them. In contrast, the present article uses the newly discovered cubic polynomial to easily produce the first fact, which then provides a basis for better understanding the second fact. Geometric insight into the P3P solution points in the limit case is also provided.</p>

<p>Concerning the Perspective 3-Point (P3P) Problem, Grunert's system of three quadratic equations has a repeated solution if and only if the cubic polynomial introduced by Finsterwalder has a repeated root. This polynomial is shown to be equivalent to a particularly simple cubic polynomial with complex coefficients that provides surprising geometric insight into the P3P problem. In particular, (1) its discriminant can be written using the formula for the standard deltoid, and (2) this discriminant vanishes on a surface that approaches a deltoid shape when the camera is moved infinitely far from the control points in a direction perpendicular to the control points plane (the ``limit case"). These two facts have been previously reported, but obscure reasoning was required to establish them. In contrast, the present article uses the newly discovered cubic polynomial to easily produce the first fact, which then provides a basis for better understanding the second fact. Geometric insight into the P3P solution points in the limit case is also provided.</p>