The Role of c-Kit Receptor Tyrosine Kinase in Beta-Cell Proliferation, Function and Survival

c-Kit, a receptor tyrosine kinase, interacts with Stem Cell Factor (SCF), mediating cell differentiation, function, and survival. c-Kit is critical for the development and maintenance of beta-cell function in both rodents and humans. The mutation of c-Kit at W locus (c-KitWv/+) in mice results in an early onset of diabetes. However, the underlying mechanisms by which c-Kit deficiency leads to beta-cell failure are unknown. Therefore, studying SCF/c-Kit downstream signaling pathways is essential to understanding the precise mechanism by which c-Kit regulates beta-cell survival and function in vivo. We identified that dysregulated Akt/Glycogen synthase kinase 3β (Gsk3β)/cyclin D1 pathway, downstream of c-Kit, is responsible for reduced beta-cell proliferation, leading to a severe loss of beta-cell mass in c-KitWv/+ mice. An up-regulation of Fas-mediated caspase-dependent apoptotic machinery is also associated with beta-cell death in c-KitWv/+ mouse islets. The loss of functional Fas (lpr mutation) reversed beta-cell apoptosis and dysfunction in c-KitWv/+;Faslpr/lpr double mutant mice, demonstrating that a balance between c-Kit and Fas signaling is critical for beta-cell survival and function. To further delineate the primary functional role of c-Kit in beta-cells, we developed a transgenic (c-KitβTg) mouse model with beta-cell specific c-KIT overexpression. c-KitβTg mice exhibited increased beta-cell mass with improved insulin secretion, which is mediated by up-regulation of Akt/Gsk3β/cyclin D1 pathway. c-KIT overexpression in beta-cells not only protected islet function from 4 weeks of high-fat-diet (HFD) challenge, but also recused the onset of diabetes observed in c-KitWv/+ mice. We also found that c-Kit signaling plays a critical role in islet vascularization. c-Kit mediates VEGF-A production via the Akt/mTOR pathway in vivo. c-KIT overexpression in beta-cells rescued the islet vascular defects in c-KitWv/+ mice. However, under long-term HFD challenge, c-KitβTg mouse islets displayed dilated vessels with reduced beta-cell mass and increased beta-cell apoptosis. The observed beta-cell failure was likely associate with expanded islet vasculature causing increased islet inflammatory response. In conclusion, this series of studies represent an integrated in vitro and in vivo approach aimed at unraveling the cellular mechanisms by which SCF/c-Kit regulates beta-cell survival and function

Reduced Kiselev black hole

The Kiselev model describes a black hole surrounded by a fluid with equations of state $p_r/\rho=-1$ and $p_t/\rho=(3w+1)/2$ respectively in radial and tangential directions. It has been extensively studied in the parameter region $-1<w<-1/3$. If one rids off the black hole and turns to the region $-1/3<w<0$, i.e. $p_t>0$, then a new horizon of black hole type will emerge. This case has been mentioned in Kiselev's pioneer work but seldom investigated in the literature. Referring to it as reduced Kiselev black hole, we revisit this case with attention to its causal structure, thermodynamics, shadow cast and weak-field limit. An alternative interpretation and extensions of the black hole are also discussed.Comment: 8 pages, 5 figure

Evaluating Feynman integrals by the hypergeometry

The hypergeometric function method naturally provides the analytic expressions of scalar integrals from concerned Feynman diagrams in some connected regions of independent kinematic variables, also presents the systems of homogeneous linear partial differential equations satisfied by the corresponding scalar integrals. Taking examples of the one-loop $B_{_0}$ and massless $C_{_0}$ functions, as well as the scalar integrals of two-loop vacuum and sunset diagrams, we verify our expressions coinciding with the well-known results of literatures. Based on the multiple hypergeometric functions of independent kinematic variables, the systems of homogeneous linear partial differential equations satisfied by the mentioned scalar integrals are established. Using the calculus of variations, one recognizes the system of linear partial differential equations as stationary conditions of a functional under some given restrictions, which is the cornerstone to perform the continuation of the scalar integrals to whole kinematic domains numerically with the finite element methods. In principle this method can be used to evaluate the scalar integrals of any Feynman diagrams.Comment: 39 pages, including 2 ps figure