Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis

Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner.     

The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9

ADAM17/TACE is a metalloproteinase responsible for the shedding of the proinflammatory cytokine TNF-α and many other cell surface proteins involved in development, cell adhesion, migration, differentiation, and proliferation. Despite the important biological function of ADAM17, the mechanisms of regulation of its metalloproteinase activity remain largely unknown. We report here that the tetraspanin CD9 and ADAM17 partially co-localize on the surface of endothelial and monocytic cells. In situ proximity ligation, co-immunoprecipitation, crosslinking, and pull-down experiments collectively demonstrate a direct association between these molecules. Functional studies reveal that treatment with CD9-specific antibodies or neoexpression of CD9 exert negative regulatory effects on ADAM17 sheddase activity. Conversely, CD9 silencing increased the activity of ADAM17 against its substrates TNF-α and ICAM-1. Taken together, our results show that CD9 associates with ADAM17 and, through this interaction, negatively regulates the sheddase activity of ADAM17.     

Cdk5 targets active Src for ubiquitin-dependent degradation by phosphorylating Src(S75)

The non-receptor tyrosine kinase Src is a critical regulator of cytoskeletal contraction, cell adhesion, and migration. In normal cells, Src activity is stringently controlled by Csk-dependent phosphorylation of Src(Y530), and by Cullin-5-dependent ubiquitinylation, which affects active Src(pY419) exclusively, leading to its degradation by the proteosome. Previous work has shown that Src activity is also limited by Cdk5, a proline-directed kinase, which has been shown to phosphorylate Src(S75). Here we show that this phosphorylation promotes the ubiquitin-dependent degradation of Src, thus restricting the availability of active Src. We demonstrate that Src(S75) phosphorylation occurs in vivo in epithelial cells, and like ubiquitinylation, is associated only with active Src. Preventing Cdk5-dependent phosphorylation of Src(S75), by site-specific mutation of S75 or by Cdk5 inhibition or suppression, increases Src(Y419) phosphorylation and kinase activity, resulting in Src-dependent cytoskeletal changes. In transfected cells, ubiquitinylation of Src(S75A) is about 35% that of wild-type Src-V5, and its half-life is approximately 2.5-fold greater. Cdk5 suppression leads to a comparable decrease in the ubiquitinylation of endogenous Src and a similar increase in Src stability. Together, these findings demonstrate that Cdk5-dependent phosphorylation of Src(S75) is a physiologically significant mechanism of regulating intracellular Src activity.     

The histidine triad nucleotide-binding protein 1 supports mu-opioid receptor–glutamate NMDA receptor cross-regulation

A series of pharmacological and physiological studies have demonstrated the functional cross-regulation between MOR and NMDAR. These receptors coexist at postsynaptic sites in midbrain periaqueductal grey (PAG) neurons, an area implicated in the analgesic effects of opioids like morphine. In this study, we found that the MOR-associated histidine triad nucleotide-binding protein 1 (HINT1) is essential for maintaining the connection between the NMDAR and MOR. Morphine-induced analgesic tolerance is prevented and even rescued by inhibiting PKC or by antagonizing NMDAR. However, in the absence of HINT1, the MOR becomes supersensitive to morphine before suffering a profound and lasting desensitization that is refractory to PKC inhibition or NMDAR antagonism. Thus, HINT1 emerges as a key protein that is critical for sustaining NMDAR-mediated regulation of MOR signaling strength. Thus, HINT1 deficiency may contribute to opioid-intractable pain syndromes by causing long-term MOR desensitization via mechanisms independent of NMDAR.     

新疆旅游业对经济增长影响的实证分析

近年来,旅游业已经成为很多地区拉动经济增长的重要产业之一。新疆具有浓郁的民族风情以及各种得天独厚的旅游资源,这为旅游业蓬勃发展提供了坚实基础。首先介绍了新疆旅游业的基本发展状况及趋势;其次,针对新疆2005-2017年的统计数据,运用Stata14.0软件对该数据进行多元回归,分析了旅游业对地区经济增长的贡献,并对新疆经济增长与旅游业之间的影响机制进行研究;最后根据实证分析得出的结论,提出了若干对策建议。     

Respiration as the main determinant of carbon balance in European forests

Carbon exchange between the terrestrial biosphere and the atmosphere is one of the key processes that need to be assessed in the context of the Kyoto Protocol. Several studies suggest that the terrestrial biosphere is gaining carbon, but these estimates are obtained primarily by indirect methods, and the factors that control terrestrial carbon exchange, its magnitude and primary locations, are under debate. Here we present data of net ecosystem carbon exchange, collected between 1996 and 1998 from 15 European forests, which confirm that many European forest ecosystems act as carbon sinks. The annual carbon balances range from an uptake of 6.6 tonnes of carbon per hectare per year to a release of nearly 1 t C ha(-1) yr(-1), with a large variability between forests. The data show a significant increase of carbon uptake with decreasing latitude, whereas the gross primary production seems to be largely independent of latitude. Our observations indicate that, in general, ecosystem respiration determines net ecosystem carbon exchange. Also, for an accurate assessment of the carbon balance in a particular forest ecosystem, remote sensing of the normalized difference vegetation index or estimates based on forest inventories may not be sufficient.     

Optimization of the cellular import of functionally active SH2-domain-interacting phosphopeptides

Phosphopeptides interacting with src homology 2 (SH2) domains can activate essential signaling enzymes in vitro. When delivered to cells, they may disrupt protein-protein interactions, thereby influencing intracellular signaling. We showed earlier that phosphopeptides corresponding to the inhibitory motif of Fcγ receptor IIb and a motif of the Grb2-associated binder 1 adaptor protein activate SH2-containing tyrosine phosphatase 2 in vitro. To study the ex vivo effects of these peptides, we have now compared different methods for peptide delivery: (i) permeabilization of the target cells and (ii) the use of cell-permeable vectors, which are potentially able to transport biologically active compounds into B cells. We found octanoyl-Arg₈ to be an optimal carrier for the delivery of phosphopeptides to the cells. With this strategy, the function of cell-permeable SHP-2-binding phosphopeptides was analyzed. These peptides modulated the protein phosphorylation in B cells in a dose- and time-dependent manner. Received 27 July 2006; received after revision 4 September 2006; accepted 18 September 2006     

Trying times for human insulin.

The introduction of human insulin to treat diabetics seemed straightforward. What can account for the problems that have followed?     

A Study of a Stand- Alone Type Variable Speed Wind Tur bine System with Synchronous Generator

Most recently produced wind generators use variable-speed systems for high-efficiency operation and low mechanical stress.In this study of a variable-speed standalone system that uses a synchronous machine,a power converter for the system was developed and tested.The maximum power points were approximated in a line according to the wind speed changes,and the linear approximation MPPT algorithm was used to determine the duty ratio that corresponds to the intersection point of the observed power and linearized line using the power generated from the generator at a point.With the fabricated converter,it was verified that the voltage,current and theta were normal with the varied load current.