Interspecific and annual variation in pre-dispersal seed predation by a granivorous bird in two East Asian hackberries, Celtis biondii and Celtis sinensis

Pre-dispersal seed predation by granivorous birds has potential to limit fruit removal and subsequent seed dispersal by legitimate avian seed dispersers in bird-dispersed plants, especially when the birds form flocks. We monitored pre-dispersal seed predation by the Japanese grosbeak, Eophona personata, of two bird-dispersed hackberry species (Cannabaceae), Celtis biondii (four trees) and Celtis sinensis (10 trees), for 3 years (2005, 2007 and 2008) in a fragmented forest in temperate Japan. Throughout the 3 years, predation was more intense on C. biondii, which, as a consequence, lost a larger part of its fruit crop. Grosbeaks preferred C. biondii seeds that had a comparatively lower energy content and lower hardness than C. sinensis, suggesting an association between seed hardness and selective foraging by grosbeaks. In C. biondii, intensive predation markedly reduced fruit duration and strongly limited fruit removal by seed dispersers, especially in 2007 and 2008. In C. sinensis, seed dispersers consumed fruits throughout the fruiting seasons in all 3 years. In C. biondii, variation in the timing of grosbeak migration among years was associated with annual variation in this bird's effects on fruit removal. Our results demonstrate that seed predation by flocks of granivorous birds can dramatically disrupt seed dispersal in fleshy-fruited plants and suggest the importance of understanding their flocking behaviour.     

SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice

Chondrocyte hypertrophy is crucial for endochondral ossification, but the mechanism underlying this process is not fully understood. We report that salt-inducible kinase 3 (SIK3) deficiency causes severe inhibition of chondrocyte hypertrophy in mice. SIK3-deficient mice showed dwarfism as they aged, whereas body size was unaffected during embryogenesis. Anatomical and histological analyses revealed marked expansion of the growth plate and articular cartilage regions in the limbs, accumulation of chondrocytes in the sternum, ribs and spine, and impaired skull bone formation in SIK3-deficient mice. The primary phenotype in the skeletal tissue of SIK3-deficient mice was in the humerus at E14.5, where chondrocyte hypertrophy was markedly delayed. Chondrocyte hypertrophy was severely blocked until E18.5, and the proliferative chondrocytes occupied the inside of the humerus. Consistent with impaired chondrocyte hypertrophy in SIK3-deficient mice, native SIK3 expression was detected in the cytoplasm of prehypertrophic and hypertrophic chondrocytes in developing bones in embryos and in the growth plates in postnatal mice. HDAC4, a crucial repressor of chondrocyte hypertrophy, remained in the nuclei in SIK3-deficient chondrocytes, but was localized in the cytoplasm in wild-type hypertrophic chondrocytes. Molecular and cellular analyses demonstrated that SIK3 was required for anchoring HDAC4 in the cytoplasm, thereby releasing MEF2C, a crucial facilitator of chondrocyte hypertrophy, from suppression by HDAC4 in nuclei. Chondrocyte-specific overexpression of SIK3 induced closure of growth plates in adulthood, and the SIK3-deficient cartilage phenotype was rescued by transgenic SIK3 expression in the humerus. These results demonstrate an essential role for SIK3 in facilitating chondrocyte hypertrophy during skeletogenesis and growth plate maintenance.     

Molecular modeling study of cyclic pentapeptide CXCR4 antagonists: new insight into CXCR4-FC131 interactions

CXCR4 is a G-protein coupled receptor that is associated with many diseases such as breast cancer metastasis, HIV infection, leukemic disease and rheumatoid arthritis, and is thus considered an attractive drug target. Previously, we identified a cyclic pentapeptide, FC131, that is a potent antagonist for CXCR4. In this study, we constructed a three dimensional model of the CXCR4-FC131 complex. To investigate the backbone flexibility of FC131, we performed molecular dynamics simulations of FC131 based on the NMR structure of FC131, and obtained snapshot structures from the trajectories which were used to model the docking pose of FC131 into CXCR4. Our final model of the CXCR4-FC131 complex is partially different from the X-ray crystal structure of CXCR4-CVX15 and suggests water-mediated interactions. Nevertheless, this docking pose is consistent with the experimental data. We believe our model will aid in the discovery and development of small-molecule antagonists for CXCR4.     

Effects of Caragana microphylla patch and its canopy size on “islands of fertility” in a Mongolian grassland ecosystem

In arid and semiarid regions, variations in “islands of fertility” accompanied by discontinuous vegetation is frequently observed. However, the effects of vegetation patches on soil, including the influence of canopy size, are not fully understood, particularly under conditions of severe grazing. We examined the effects of patches of mound-forming shrub, Caragana microphylla, and the plant’s canopy size on these islands of fertility in a heavily grazed Mongolian grassland. In 11 patches with various canopy sizes (32.5–180 cm in diameter), we compared the chemical properties of soils among three microsites: Mound, Below, and Around, which were inside, below, and outside of C. microphylla mounds, respectively. Total carbon (C) and most essential elements for the plants were more concentrated in Mound, but total nitrogen (N) and nonlimiting elements, such as exchangeable sodium (Na), did not significantly differ among microsites. Larger canopies more strongly affected the enrichment of total C and most essential elements, including total N, in Mound. These results suggest that C. microphylla patches substantially enrich total C and most essential elements and that the extent of enrichment was intensified with canopy size. However, under severe grazing, total N may be relatively more affected by the redistribution of resources through grazing, particularly when the canopy size is small.     

Angelica keiskei extract improves insulin resistance and hypertriglyceridemia in rats fed a high-fructose drink

Angelica keiskei is a traditional herb peculiar to Japan and abundantly contains vitamins, dietary fiber and such polyphenols as chalcone. We investigated in the present study the effect of A. keiskei on insulin resistance and hypertriglyceridemia in fructose-drinking rats as a model for the metabolic syndrome. Male Wistar rats were given a 15% fructose solution as drinking water for 11 weeks. Fructose significantly increased the levels of serum insulin and triglyceride (TG) compared with the control level. Treatment with an ethanol extract of A. keiskei (AE) significantly reduced the levels of blood glucose (-16.5%), serum insulin (-47.3%), HOMA-R (-56.4%) and TG (-24.2%). A hepatic gene analysis showed that fructose reduced the expression of the genes related to fatty acid β-oxidation and high-density lipoprotein (HDL) production. Treatment with AE enhanced the expression of the acyl-CoA oxidase 1 (ACO1), medium-chain acyl-CoA dehydrogenase (MCAD), ATP-binding membrane cassette transporter A1 (ABCA1) and apolipoprotein A1 (Apo-A1) genes. These results suggest that AE improved the insulin resistance and hypertriglyceridemia of the fructose-drinking rats.     

ERK Inhibition Rescues Defects in Fate Specification of Nf1-Deficient Neural Progenitors and Brain Abnormalities

Germline mutations in the RAS/ERK signaling pathway underlie several related developmental disorders collectively termed neuro-cardio-facial-cutaneous (NCFC) syndromes. NCFC patients manifest varying degrees of cognitive impairment, but the developmental basis of their brain abnormalities remains largely unknown. Neurofibromatosis type 1 (NF1), an NCFC syndrome, is caused by loss-of-function heterozygous mutations in the NF1 gene, which encodes neurofibromin, a RAS GTPase-activating protein. Here, we show that biallelic Nf1 inactivation promotes Erk-dependent, ectopic Olig2 expression specifically in transit-amplifying progenitors, leading to increased gliogenesis at the expense of neurogenesis in neonatal and adult subventricular zone (SVZ). Nf1-deficient brains exhibit enlarged corpus callosum, a structural defect linked to severe learning deficits in NF1 patients. Strikingly, these NF1-associated developmental defects are rescued by transient treatment with an MEK/ERK inhibitor during neonatal stages. This study reveals a critical role for Nf1 in maintaining postnatal SVZ-derived neurogenesis and identifies a potential therapeutic window for treating NF1-associated brain abnormalities.     

A Novel Mechanism for the Autonomous Termination of Pre-B Cell Receptor Expression via Induction of Lysosome-Associated Protein Transmembrane 5

The expression of the pre-B cell receptor (BCR) is confined to the early stage of B cell development, and its dysregulation is associated with anomalies of B-lineage cells, including leukemogenesis. Previous studies suggested that the pre-BCR signal might trigger the autonomous termination of pre-BCR expression even before the silencing of pre-BCR gene expression to prevent sustained pre-BCR expression. However, the underlying mechanism remains ill defined. Here we demonstrate that the pre-BCR signal induces the expression of lysosome-associated protein transmembrane 5 (LAPTM5), which leads to the prompt downmodulation of the pre-BCR. While LAPTM5 induction had no significant impact on the internalization of cell surface pre-BCR, it elicited the translocation of a large pool of intracellular pre-BCR from the endoplasmic reticulum to the lysosomal compartment concomitantly with a drastic reduction of the level of intracellular pre-BCR proteins. This reduction was inhibited by lysosomal inhibitors, indicating the lysosomal degradation of the pre-BCR. Notably, the LAPTM5 deficiency in pre-B cells led to the augmented expression level of surface pre-BCR. Collectively, the pre-BCR induces the prompt downmodulation of its own expression through the induction of LAPTM5, which promotes the lysosomal transport and degradation of the intracellular pre-BCR pool and, hence, limits the supply of pre-BCR to the cell surface.