Evidence suggests that insulin delivery to skeletal muscle interstitium is the rate-limiting step in insulin-stimulated muscle glucose uptake and that this process is impaired by insulin resistance. In this review we examine the basis for the hypothesis that insulin acts on the vasculature at three discrete steps to enhance its own delivery to muscle: (1) relaxation of resistance vessels to increase total blood flow; (2) relaxation of pre-capillary arterioles to increase the microvascular exchange surface perfused within skeletal muscle (microvascular recruitment); and (3) the trans-endothelial transport (TET) of insulin. Insulin can relax resistance vessels and increase blood flow to skeletal muscle. However, there is controversy as to whether this occurs at physiological concentrations of, and exposure times to, insulin. The microvasculature is recruited more quickly and at lower insulin concentrations than are needed to increase total blood flow, a finding consistent with a physiological role for insulin in muscle insulin delivery. Microvascular recruitment is impaired by obesity, diabetes and nitric oxide synthase inhibitors. Insulin TET is a third potential site for regulating insulin delivery. This is underscored by the consistent finding that steady-state insulin concentrations in plasma are approximately twice those in muscle interstitium. Recent in vivo and in vitro findings suggest that insulin traverses the vascular endothelium via a trans-cellular, receptor-mediated pathway, and emerging data indicate that insulin acts on the endothelium to facilitate its own TET. Thus, muscle insulin delivery, which is rate-limiting for its metabolic action, is itself regulated by insulin at multiple steps. These findings highlight the need to further understand the role of the vascular actions of insulin in metabolic regulation.

The change in the phenology of plants or animals reflects the response of living systems to climate change. Numerous studies have reported a consistent earlier spring phenophases in many parts of middle and high latitudes reflecting increasing temperatures with the exception of China. A systematic analysis of Chinese phenological response could complement the assessment of climate change impact for the whole Northern Hemisphere. Here, we analyze 1263 phenological time series (1960-2011, with 20+ years data) of 112 species extracted from 48 studies across 145 sites in China. Taxonomic groups include trees, shrubs, herbs, birds, amphibians and insects. Results demonstrate that 90.8% of the spring/summer phenophases time series show earlier trends and 69.0% of the autumn phenophases records show later trends. For spring/summer phenophases, the mean advance across all the taxonomic groups was 2.75 days decade(-1) ranging between 2.11 and 6.11 days decade(-1) for insects and amphibians, respectively. Herbs and amphibians show significantly stronger advancement than trees, shrubs and insect. The response of phenophases of different taxonomic groups in autumn is more complex: trees, shrubs, herbs and insects show a delay between 1.93 and 4.84 days decade(-1), while other groups reveal an advancement ranging from 1.10 to 2.11 days decade(-1) . For woody plants (including trees and shrubs), the stronger shifts toward earlier spring/summer were detected from the data series starting from more recent decades (1980s-2000s). The geographic factors (latitude, longitude and altitude) could only explain 9% and 3% of the overall variance in spring/summer and autumn phenological trends, respectively. The rate of change in spring/summer phenophase of woody plants (1960s-2000s) generally matches measured local warming across 49 sites in China (R=-0.33, P<0.05).

The CD18 hypomorphic (CD18 hypo ) PL/J mouse model clinically resembling human psoriasis is characterized by reduced expression of the common chain of b 2 integrins (CD11/CD18) to only 2-16% of WT levels. Previously we found that this chronic psoriasiform skin inflammation also depends on the presence of CD4 + T cells. Herein we investigated the role of macrophages in this CD18 hypo mouse model. Activated macrophages were significantly increased in lesional skin as well as in inflamed skin draining lymph nodes (DLNs) of affected CD18 hypo mice and were identified as being an important source of TNF-a in vivo. Both depletion of macrophages and neutralization of TNF-a resulted in a significant alleviation of psoriasiform skin inflammation. As monocyte chemotactic protein 1 was enhanced in lesional skin of affected CD18 hypo mice, we intradermally injected recombinant murine monocyte chemotactic protein-1 (rJE/MCP-1) alone or in combination with rTNF-a into the skin of healthy CD18 hypo mice. Only simultaneous injection of rJE/MCP-1 and rTNF-a, but neither substance alone, resulted in the induction of psoriasiform skin inflammation around the injection sites with recruitment and activation of macrophages. Collectively, our data suggest that maintenance of psoriasiform skin inflammation critically depends on efficient recruitment and activation of macrophages with sufficient release of TNF-a.

Corresponding authors: C Wu (wucy@igsnrr.ac.cn), H Wang (wanghj@igsnrr.ac.cn) 38 and Q Ge (geqs@igsnrr.ac.cn). 39 2 Plant phenology is a sensitive indicator of climate change 1-4 , and plays a significant role in 40 regulating carbon uptake by plants [5][6][7] . Previous studies have focused on spring leaf-out by 41 daytime temperature and the onset of snowmelt time 8-9 , but the drivers controlling leaf 42 senescence date (LSD) in autumn remain largely unknown 10-12 . Using long-term ground 43 phenological records (14536 time series since the 1900s) and satellite greenness 44 observations dating back to the 1980s, we show that rising preseason maximum daytime 45 (Tday) and minimum nighttime (Tnight) temperatures had contrasting effects on the timing of 46 autumn LSD in the Northern Hemisphere (>20°N). If higher Tday leads to an earlier or later 47 leaf-out and flowering dates and hence extends the growing season 8,[14][15] . In contrast to 62 those extensive research efforts on spring phenology, autumn phenology, particularly leaf 63 senescence date (LSD), is more challenging to understand, and has not received 64 sufficient attention 16,17 , while also serving as an important indicator of changing foliar