BMAL1 functions as a cAMP-responsive coactivator of HDAC5 to regulate hepatic gluconeogenesis

Dear Editor, Gluconeogenesis is one of the major mechanisms to main- tain hepatic glucose homeostasis and dysregulation of hepatic gluconeogenesis contributes to hyperglycemia in type 2 diabetes. Under fasted conditions, increases in cir- culating glucagon promote hepatic glucose production through activation of gluconeogenic pathway by HDAC5 and CREB coactivator CRTC2 （Lv et al., 2016; Lv et al., 2017; Qiu et al., 2017）. The circadian clock coordinates behavior and metabolism into rhythms not only in the central hypothalamus but also in peripheral tissues （Marcheva et al., 2010; Vollmers et al., 2009）. Transcription factor BMAL1 heterodimerizes with CLOCK to activate the expression of Per and Cry, which in turn suppress CLOCK/BMAL1 activity （Reppert ＆ Weaver, 2002）. Although BMAL1 knockout mice show fasting hypoglycemia （Rudic et al., 2004）, the detailed mechanism of BMAL1 regulation on hepatic gluco- neogenesis has not been thoroughly understood.

A Note on Submodularity Preserved Involving the Rank Functions

In many kinds of games with economic significance,it is very important to study the submodularity of functions.In this paper,wemainly study the problem of maximizing a concave function over an intersection of two matroids.We obtain that the submod-ularity may not be preserved,but it involves one maximal submodular problem(or minimal supermodular problem)with some conditions.Moreover,we also present examples showing that these conditions can be satisfied.

Progress and bottleneck in induced pluripotency

With their capability to undergo unlimited self-renewal and to differentiate into all cell types in the body,induced pluripotent stem cells(iPSCs),reprogrammed from somatic cells of individual patients with defined factors,have unlimited potential in cell therapy and in modeling complex human diseases.Significant progress has been achieved to improve the safety of iPSCs and the reprogramming efficiency.To avoid the cancer risk and spontaneous reactivation of the reprogramming factors associated with the random integration of viral vectors into the genome,several approaches have been established to deliver the reprogramming factors into the somatic cells without inducing genetic modification.In addition,a panel of small molecule compounds,many of which targeting the epigenetic machinery,have been identified to increase the reprogramming efficiency.Despite these progresses,recent studies have identified genetic and epigenetic abnormalities of iPSCs as well as the immunogenicity of some cells derived from iPSCs.In addition,due to the oncogenic potential of the reprogramming factors and the reprogramming-induced DNA damage,the critical tumor suppressor pathways such as p53 and ARF are activated to act as the checkpoints that suppress induced pluripotency.The inactivation of these tumor suppression pathways even transiently during reprogramming processes could have significant adverse impact on the genome integrity.These safety concerns must be resolved to improve the feasibility of the clinic development of iPSCs into human cell therapy.