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311.
The venoms of predatory cone snails harbor a rich repertoire of peptide toxins that are valuable research tools, but recently
have also proven to be useful drugs. Among the conotoxins with several disulfide bridges, the O-superfamily toxins are characterized
by a conserved cysteine knot pattern: C-C-CC-C-C. While ω-conotoxins and κ-conotoxins block Ca2+ and K+ channels, respectively, the closely related δ- and μO-conotoxins affect voltage-gated Na+ channels (Nav channels). δ-conotoxins mainly remove the fast inactivation of Nav channels and, thus, functionally resemble long-chain scorpion α-toxins. μO-conotoxins are functionally similar to μ-conotoxins,
since they inhibit the ion flow through Nav channels. Recent results from functional and structural assays have gained insight into the underlying molecular mechanisms.
Both types of toxins are voltage-sensor toxins interfering with the voltage-sensor elements of Nav channels.
Received 27 December 2006; received after revision 30 January 2007; accepted 19 February 2007 相似文献
312.
Pancreatitis is usually inflammation of the pancreas without infection. Our understanding of pancreatitis has been built on autopsy studies, surgical biopsies and surrogate markers of inflammation and fibroses, including abdominal imaging techniques and pancreatic functional studies. However, the discovery that a number of different environmental factors and various genetic abnormalities are seen in patients with similar appearing pancreatitis phenotypes teaches us that end-stage pathology is not the disorder. Understanding complex associations and interactions requires that the components and their interactions be organized, stratified and functionally defined. Systems biology, in the broad sense, provides the approach and tools to define the complex mechanisms driving pathology. As the mathematics behind these pathways and mechanisms are defined and calibrated, the potential pathology of patients with early signs of disease can be predicted, and a number of patient-specific targets for intervention can be defined. 相似文献
313.
Lanigan F O'Connor D Martin F Gallagher WM 《Cellular and molecular life sciences : CMLS》2007,64(24):3159-3184
During its lifetime, the mammary gland undergoes many phases of development and differentiation. Much of this occurs during
puberty, when the ductal epithelium expands by branching morphogenesis, invading the surrounding fat pad to form an organised
mammary tree. Throughout its existence, the epithelium will go through several cycles of proliferation and cell death during
pregnancy, lactation and involution. Many of the signalling mechanisms which control the initial invasion of the fat pad by
the epithelium, and regulate its continuing plasticity, can be harnessed or corrupted by tumour cells in order to support
their aberrant growth and progression towards invasion. This is true not just for the epithelial cells themselves but also
for cells in the surrounding microenvironment, including fibroblasts, macrophages and adipocytes. This review examines the
complex web of signalling and adhesion interactions controlling branching morphogenesis, and how their alteration can promote
malignancy. Current in vivo and in vitro mammary gland models are also discussed. (Part of a Multi-author Review) 相似文献
314.
Scherthan H 《Cellular and molecular life sciences : CMLS》2007,64(2):117-124
Telomeres are important segments of chromosomes that protect chromosome ends from nucleolytic degradation and fusion. At meiosis telomeres display an unprecedented behavior which involves their attachment and motility along the nuclear envelope. The movements become restricted to a limited nuclear sector during the so-called bouquet stage, which is widely conserved among species. Recent observations suggest that telomere clustering involves actin and/or microtubules, and is altered in the presence of impaired recombinogenic and chromosome related functions. This review aims to provide an overview of what is currently known about meiotic telomere attachment, dynamics and regulation in synaptic meiosis. 相似文献
315.
Lindahl E Nyman U Melles E Sigmundsson K Ståhlberg M Wahren J Obrink B Shafqat J Joseph B Jörnvall H 《Cellular and molecular life sciences : CMLS》2007,64(4):479-486
Proinsulin C-peptide is known to bind specifically to cell membranes and to exert intracellular effects, but whether it is
internalized in target cells is unknown. In this study, using confocal microscopy and immunostained or rhodamine-labeled peptide,
we show that C-peptide is internalized and localized to the cytosol of Swiss 3T3 and HEK-293 cells. In addition, transport
into nuclei was found using the labeled peptide. The internalization was followed at 37°C for up to 1 h, and was reduced at
4°C and after preincubation with pertussis toxin. Hence, it is concluded to occur via an energy-dependent, pertussis toxin-sensitive
mechanism and without detectable degradation within the experimental time course. Surface plasmon resonance measurements demonstrated
binding of HEK-293 cell extract components to C-peptide, and subsequent elution of bound material revealed the components
to be intracellular proteins. The identification of C-peptide cellular internalization, intracellular binding proteins, absence
of rapid subsequent C-peptide degradation and apparent nuclear internalization support a maintained activity similar to that
of an intracrine peptide hormone. Hence, the data suggest the possibility of one further C-peptide site of action.
Received 31 October 2006; received after revision 27 December 2006; accepted 30 December 2006 相似文献
316.
Periodic circadian (24-h) cycles play an important role in daily hormonal and behavioural rhythms. Usually our sleep/wake
cycle, temperature and melatonin rhythms are internally synchronized with a stable phase relationship. When there is a desynchrony
between the sleep/wake cycle and circadian rhythm, sleep disorders such as advanced and delayed sleep phase syndrome can arise
as well as transient chronobiologic disturbances, for example from jet lag and shift work. Appropriately timed bright light
is effective in re-timing the circadian rhythm and sleep pattern to a more desired time, ameliorating these disturbances.
Other less potent retiming effects may also be obtained from the judicious use of melatonin and exercise. 相似文献
317.
Romeo S Pennacchio LA Fu Y Boerwinkle E Tybjaerg-Hansen A Hobbs HH Cohen JC 《Nature genetics》2007,39(4):513-516
Resequencing genes provides the opportunity to assess the full spectrum of variants that influence complex traits. Here we report the first application of resequencing to a large population (n = 3,551) to examine the role of the adipokine ANGPTL4 in lipid metabolism. Nonsynonymous variants in ANGPTL4 were more prevalent in individuals with triglyceride levels in the lowest quartile than in individuals with levels in the highest quartile (P = 0.016). One variant (E40K), present in approximately 3% of European Americans, was associated with significantly lower plasma levels of triglyceride and higher levels of high-density lipoprotein cholesterol in European Americans from the Atherosclerosis Risk in Communities Study and in Danes from the Copenhagen City Heart Study. The ratio of nonsynonymous to synonymous variants was higher in European Americans than in African Americans (4:1 versus 1.3:1), suggesting population-specific relaxation of purifying selection. Thus, resequencing of ANGPTL4 in a multiethnic population allowed analysis of the phenotypic effects of both rare and common variants while taking advantage of genetic variation arising from ethnic differences in population history. 相似文献
318.
Roberts AE Araki T Swanson KD Montgomery KT Schiripo TA Joshi VA Li L Yassin Y Tamburino AM Neel BG Kucherlapati RS 《Nature genetics》2007,39(1):70-74
Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation. 相似文献
319.
320.
Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis 总被引:4,自引:0,他引:4