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41.
Many functionally important cellular peptides and proteins, including hormones, neuropeptides, and growth factors, are synthesized
as inactive precursor polypeptides, which require post-translational proteolytic processing to become biologically active
polypeptides. This is achieved by the action of a relatively small number of proteases that belong to a family of seven subtilisin-like
proprotein convertases (PCs) including furin. In view of this, this review focuses on the importance of privileged secondary
structures and of given amino acid residues around basic cleavage sites in substrate recognition by these endoproteases. In
addition to their participation in normal cell functions, PCs are crucial for the initiation and progress of many important
diseases. Hence, these proteases constitute potential drug targets in medicine. Accordingly, this review also discusses the
approaches used to shed light on the cleavage preference and the substrate specificity of the PCs, a prerequisite to select
which PCs are promising drug targets in each disease. 相似文献
42.
43.
Laurie NA Donovan SL Shih CS Zhang J Mills N Fuller C Teunisse A Lam S Ramos Y Mohan A Johnson D Wilson M Rodriguez-Galindo C Quarto M Francoz S Mendrysa SM Guy RK Marine JC Jochemsen AG Dyer MA 《Nature》2006,444(7115):61-66
Most human tumours have genetic mutations in their Rb and p53 pathways, but retinoblastoma is thought to be an exception. Studies suggest that retinoblastomas, which initiate with mutations in the gene retinoblastoma 1 (RB1), bypass the p53 pathway because they arise from intrinsically death-resistant cells during retinal development. In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumour progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Our data provide evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, they support the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma. 相似文献
44.
45.
Liu Z Moore PH Ma H Ackerman CM Ragiba M Yu Q Pearl HM Kim MS Charlton JW Stiles JI Zee FT Paterson AH Ming R 《Nature》2004,427(6972):348-352
Many diverse systems for sex determination have evolved in plants and animals. One involves physically distinct (heteromorphic) sex chromosomes (X and Y, or Z and W) that are homozygous in one sex (usually female) and heterozygous in the other (usually male). Sex chromosome evolution is thought to involve suppression of recombination around the sex determination genes, rendering permanently heterozygous a chromosomal region that may then accumulate deleterious recessive mutations by Muller's ratchet, and fix deleterious mutations by hitchhiking as nearby favourable mutations are selected on the Y chromosome. Over time, these processes may cause the Y chromosome to degenerate and to diverge from the X chromosome over much of its length; for example, only 5% of the human Y chromosome still shows X-Y recombination. Here we show that papaya contains a primitive Y chromosome, with a male-specific region that accounts for only about 10% of the chromosome but has undergone severe recombination suppression and DNA sequence degeneration. This finding provides direct evidence for the origin of sex chromosomes from autosomes. 相似文献
46.
Brigitte Cambon de Lavalette Charles Tijus Christine Leproux Olivier Bauer 《Foundations of Science》2005,10(1):25-45
Taxonomy Based modeling was applied to describe drivers’ mental models of variable message signs (VMS’s) displayed on expressways.
Progress in road telematics has made it possible to introduce variable message signs (VMS’s). Sensors embedded in the carriageway
every 500m record certain variables (speed, flow rate, etc.) that are transformed in real time into “driving times” to a given
destination if road conditions do not change.
VMS systems are auto-regulative Man-Machine (AMMI) systems which incorporate a model of the user: if the traffic flow is too
high, then drivers should choose alternative routes. In so doing, the traffic flow should decrease. The model of the user
is based on suppositions such as: people do not like to waste time, they fully understand the displayed messages, they trust
the displayed values, they know of alternative routes. However, people also have a model of the way the system functions.
And if they do not believe the contents of the message, they will not act as expected.
We collected data through interviews with drivers using the critical incidents technique (Flanagan, 1985). Results show that
the mental models that drivers have of the way the VMS system works are various but not numerous and that most of them differ
from the“ideal expert” mental model. It is clear that users don’t have an adequate model of how the VMS system works and that
VMS planners have a model of user behaviour that does not correspond to the behaviour of the drivers we interviewed. Finally,
Taxonomy Based Modeling is discussed as a tool for mental model remediation. 相似文献
47.
Defects in whirlin,a PDZ domain molecule involved in stereocilia elongation,cause deafness in the whirler mouse and families with DFNB31 总被引:22,自引:0,他引:22
Mburu P Mustapha M Varela A Weil D El-Amraoui A Holme RH Rump A Hardisty RE Blanchard S Coimbra RS Perfettini I Parkinson N Mallon AM Glenister P Rogers MJ Paige AJ Moir L Clay J Rosenthal A Liu XZ Blanco G Steel KP Petit C Brown SD 《Nature genetics》2003,34(4):421-428
The whirler mouse mutant (wi) does not respond to sound stimuli, and detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs). BAC-mediated transgene correction of the mouse phenotype and mutation analysis identified the causative gene as encoding a novel PDZ protein called whirlin. The gene encoding whirlin also underlies the human autosomal recessive deafness locus DFNB31. In the mouse cochlea, whirlin is expressed in the sensory IHC and OHC stereocilia. Our findings suggest that this novel PDZ domain-containing molecule acts as an organizer of submembranous molecular complexes that control the coordinated actin polymerization and membrane growth of stereocilia. 相似文献
48.
Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis 总被引:10,自引:0,他引:10
Parviz F Matullo C Garrison WD Savatski L Adamson JW Ning G Kaestner KH Rossi JM Zaret KS Duncan SA 《Nature genetics》2003,34(3):292-296
Although advances have been made in understanding cell differentiation, only rudimentary knowledge exists concerning how differentiated cells form tissues and organs. We studied liver organogenesis because the cell and tissue architecture of this organ is well defined. Approximately 60% of the adult liver consists of hepatocytes that are arranged as single-cell anastomosing plates extending from the portal region of the liver lobule toward the central vein. The basal surface of the hepatocytes is separated from adjacent sinusoidal endothelial cells by the space of Disse, where the exchange of substances between serum and hepatocytes takes place. The hepatocyte's apical surface forms bile canaliculi that transport bile to the hepatic ducts. Proper liver architecture is crucial for hepatic function and is commonly disrupted in disease states, including cirrhosis and hepatitis. Here we report that hepatocyte nuclear factor 4alpha (Hnf4alpha) is essential for morphological and functional differentiation of hepatocytes, accumulation of hepatic glycogen stores and generation of a hepatic epithelium. We show that Hnf4alpha is a dominant regulator of the epithelial phenotype because its ectopic expression in fibroblasts induces a mesenchymal-to-epithelial transition. Most importantly, the morphogenetic parameters controlled by Hnf4alpha in hepatocytes are essential for normal liver architecture, including the organization of the sinusoidal endothelium. 相似文献
49.
The production of defects in flow-aligning nematic liquid crystals under simple shear flow is analyzed by linear stability analysis based on Leslie-Ericksen theory. It is pointed out that the equation of motion of the nematic director under simple shear flow conforms to the driven over-damped sine-Gordon equation and has a soliton solution of amplitude π. It has also been shown that the stationary state with the director uniformly oriented at a Leslie angle is only a metastable state and that the potential, which governs the motion of the director, has infinite numbers of stable stationary states. Therefore, the defects, appearing as a stable solitary solution, can be nucleated from a uniformly aligned flow-aligning type of nematic liquid crystal by shear flow. On the other hand, the bands with long axis parallel to the vorticity axis, appearing as an unstable solution, can be observed as transient patterns at low shear rate and low shear strain value. The theoretical predictions are compared with previous experimental observations. 相似文献
50.
Kenia Pedrosa Nunes Christine S. Rigsby R. Clinton Webb 《Cellular and molecular life sciences : CMLS》2010,67(22):3823-3836
RhoA/Rho-kinase pathway plays an important role in many pathological conditions. RhoA participates in the regulation of smooth
muscle tone and activates many downstream kinases. The best characterized are the serine/threonine kinase isoforms (Rho-kinase
or ROCK), ROCKα/ROCK2 and ROCKβ/ROCK1. ROCK is necessary for diverse functions such as local blood flow, arterial/pulmonary
blood pressure, airway resistance and intestinal peristalsis. ROCK activation permits actin/myosin interactions and smooth
muscle cells contraction by maintaining the activity of myosin light-chain kinase, independently of the free cytosolic calcium
level. The sensitization of smooth muscle myofilaments to calcium has been implicated in many pathological states, such as
hypertension, diabetes, heart attack, stroke, pulmonary hypertension, erectile dysfunction, and cancer. The focus of this
review is on the involvement of RhoA/Rho-kinase in diseases. We will briefly describe the ROCK isoforms and the role of RhoA/Rho-kinase
in the vasculature, before exploring the most recent findings regarding this pathway and various diseases. 相似文献