共查询到20条相似文献,搜索用时 15 毫秒
1.
Nurminsky DI 《Cellular and molecular life sciences : CMLS》2001,58(1):125-134
Analysis of DNA variation is a powerful tool for detecting adaptation at the genomic level. The contribution of adaptive
evolution is evident from examples of rapidly evolving genes, which represent the likely targets for strong selection. More
subtle adaptation is also an integral component of routine maintenance of gene performance, continuously applied to every
gene. Adaptive changes in the population are accomplished through selective sweeps, i.e. complete or partial fixation of beneficial
alleles. The evidence is accumulating that selective sweeps are quite frequent events which, together with associated genetic
hitchhiking, represent dominant forces that influence molecular evolution by shaping the variability pattern in the genome.
Received 5 May 2000; revised 22 August 2000; accepted 24 August 2000 相似文献
2.
Prajit K. Basu 《Studies in history and philosophy of science》2003,34(2):351-368
This paper attempts to argue for the theory-ladenness of evidence. It does so by employing and analysing an episode from the history of eighteenth century chemistry. It delineates attempts by Joseph Priestley and Antoine Lavoisier to construct entirely different kinds of evidence for and against a particular hypothesis from a set of agreed upon observations or (raw) data. Based on an augmented version of a distinction, drawn by J. Bogen and J. Woodward, between data and phenomena it is shown that the role of theoretical auxiliary assumptions is very important in constructing evidence for (or against) a theory from observation or (raw) data. In revolutionary situations, rival groups hold radically different theories and theoretical auxiliary assumptions. These are employed to construct very different evidence from the agreed upon set of observations or (raw) data. Hence, theory resolution becomes difficult. It is argued that evidence construction is a multi-layered exercise and can be disputed at any level. What counts as unproblematic observation or (raw) data at one level may become problematic at another level. The contingency of these constructions and the (un)problematic nature of evidence are shown to be partially dependent upon the scientific knowledge that the scientific community possesses. 相似文献
3.
Hazel F. O’Connor Jon M. Huibregtse 《Cellular and molecular life sciences : CMLS》2017,74(18):3363-3375
Protein ubiquitylation is an important post-translational modification, regulating aspects of virtually every biochemical pathway in eukaryotic cells. Hundreds of enzymes participate in the conjugation and deconjugation of ubiquitin, as well as the recognition, signaling functions, and degradation of ubiquitylated proteins. Regulation of ubiquitylation is most commonly at the level of recognition of substrates by E3 ubiquitin ligases. Characterization of the network of E3–substrate relationships is a major goal and challenge in the field, as this expected to yield fundamental biological insights and opportunities for drug development. There has been remarkable success in identifying substrates for some E3 ligases, in many instances using the standard protein–protein interaction techniques (e.g., two-hybrid screens and co-immunoprecipitations paired with mass spectrometry). However, some E3s have remained refractory to characterization, while others have simply not yet been studied due to the sheer number and diversity of E3s. This review will discuss the range of tools and techniques that can be used for substrate profiling of E3 ligases. 相似文献
4.
It has recently been argued that successful evidence-based policy should rely on two kinds of evidence: statistical and mechanistic. The former is held to be evidence that a policy brings about the desired outcome, and the latter concerns how it does so. Although agreeing with the spirit of this proposal, we argue that the underlying conception of mechanistic evidence as evidence that is different in kind from correlational, difference-making or statistical evidence, does not correctly capture the role that information about mechanisms should play in evidence-based policy. We offer an alternative account of mechanistic evidence as information concerning the causal pathway connecting the policy intervention to its outcome. Not only can this be analyzed as evidence of difference-making, it is also to be found at any level and is obtainable by a broad range of methods, both experimental and observational. Using behavioral policy as an illustration, we draw the implications of this revised understanding of mechanistic evidence for debates concerning policy extrapolation, evidence hierarchies, and evidence integration. 相似文献
5.
Pinho SS Seruca R Gärtner F Yamaguchi Y Gu J Taniguchi N Reis CA 《Cellular and molecular life sciences : CMLS》2011,68(6):1011-1020
Several mechanisms have been proposed to explain the E-cadherin dysfunction in cancer, including genetic and epigenetic alterations.
Nevertheless, a significant number of human carcinomas have been seen that show E-cadherin dysfunction that cannot be explained
at the genetic/epigenetic level. A substantial body of evidence has appeared recently that supports the view that other mechanisms
operating at the post-translational level may also affect E-cadherin function. The present review addresses molecular aspects
related to E-cadherin N-glycosylation and evidence is presented showing that the modification of N-linked glycans on E-cadherin can affect the adhesive function of this adhesion molecule. The role of glycosyltransferases
involved in the remodeling of N-glycans on E-cadherin, including N-acetylglucosaminyltransferase III (GnT-III), N-acetylglucosaminyltransferase V (GnT-V), and the α1,6 fucosyltransferase (FUT8) enzyme, is also discussed. Finally, this
review discusses an alternative functional regulatory mechanism for E-cadherin operating at the post-translational level, N-glycosylation, that may underlie the E-cadherin dysfunction in some carcinomas. 相似文献
6.
Significance of the variation in haemolymph copper-protein ratio in the crabScylla serrata (Forskal) during different hours of the day 总被引:1,自引:0,他引:1
Summary InScylla serrata, haemolymph copper is bound to protein and it can be more reliably determined by the 2,2 biquinoline method than by other spectrophotometric methods. Ionic or free copper is absent from the haemolymph. The lack of significant time-of-day variation in copper concentration and the occurrence of variation in total protein concentration and copper-protein ratio, indicate fluctuations in copper-free proteins, which may either be periodically sequestered or released by the tissues during different hours of the day. 相似文献
7.
François Bernier 《Cellular and molecular life sciences : CMLS》2013,70(17):3045-3056
DING proteins, named after their conserved N-terminus, form an overlooked protein family whose members were generally discovered through serendipity. It is characterized by an unusually high sequence conservation, even between distantly related species, and by an outstanding diversity of activities and ligands. They all share a demonstrated capacity to bind phosphate with high affinity or at least a predicted phosphate-binding site. However, DING protein genes are conspicuously absent from databases. The many novel family members identified in recent years have confirmed that DING proteins are ubiquitous not only in animals and plants but probably also in prokaryotes. At the functional level, there is increasing evidence that they participate in many health-related processes such as cancers as well as bacterial (Pseudomonas) and viral (HIV) infections, by mechanisms that are now beginning to be understood. They thus represent potent targets for the development of novel therapeutic approaches, especially against HIV. The few genomic sequences that are now available are starting to give some clues on why DING protein genes and mRNAs are well conserved and difficult to clone. This could open a new era of research, of both fundamental and applied importance. 相似文献
8.
Nicholas J. Bradshaw Mirian A. F. Hayashi 《Cellular and molecular life sciences : CMLS》2017,74(7):1191-1210
NDE1 (Nuclear Distribution Element 1, also known as NudE) and NDEL1 (NDE-Like 1, also known as NudEL) are the mammalian homologues of the fungus nudE gene, with important and at least partially overlapping roles for brain development. While a large number of studies describe the various properties and functions of these proteins, many do not directly compare the similarities and differences between NDE1 and NDEL1. Although sharing a high degree structural similarity and multiple common cellular roles, each protein presents several distinct features that justify their parallel but also unique functions. Notably both proteins have key binding partners in dynein, LIS1 and DISC1, which impact on neurodevelopmental and psychiatric illnesses. Both are implicated in schizophrenia through genetic and functional evidence, with NDE1 also strongly implicated in microcephaly, as well as other neurodevelopmental and psychiatric conditions through copy number variation, while NDEL1 possesses an oligopeptidase activity with a unique potential as a biomarker in schizophrenia. In this review, we aim to give a comprehensive overview of the various cellular roles of these proteins in a “bottom-up” manner, from their biochemistry and protein–protein interactions on the molecular level, up to the consequences for neuronal differentiation, and ultimately to their importance for correct cortical development, with direct consequences for the pathophysiology of neurodevelopmental and mental illness. 相似文献
9.
Elfriede Ruderer 《Cellular and molecular life sciences : CMLS》1959,15(1):9-10
Summary In artificial populations ofDrosophila subobscura, arising from the mating of strains of different origin and different chromosomal structure, it was demonstrated that also in the X-chromosome an adaptive equilibrium is reached between two different structural types, although heterosis only acts in the females. There is a significant excess of females in the hybrid-generation in both reciprocal matings, especially at low temperature. The sexratio of the pure strains is 1:1. The excess may be caused by a selective advantage of the structurally heterozygous females in competition with the hemizygous males. 相似文献
10.
David J. Koss Benjamin D. Drever Sandra Stoppelkamp Gernot Riedel Bettina Platt 《Cellular and molecular life sciences : CMLS》2013,70(14):2585-2601
Several genetically engineered models exist that mimic aspects of the pathological and cognitive hallmarks of Alzheimer’s disease (AD). Here we report on a novel mouse model generated by targeted knock-in of transgenes containing mutated human amyloid precursor protein (APP) and microtubule-associated protein tau genes, inserted into the HPRT locus and controlled by the CaMKIIα regulatory element. These mice were crossed with an asymptomatic presenilin1A246E overexpressing line to generate PLB1Triple mice. Gene expression analysis and in situ hybridization confirmed stable, forebrain-specific, and gene-dose-dependent transgene expression. Brain tissue harvested from homozygous, heterozygous, and wild-type cohorts aged between 3 and 24 months was analyzed immunohistochemically and electrophysiologically. Homozygous PLB1Triple offspring presented with mostly intracellular cortical and hippocampal human APP/amyloid, first detected reliably at 6 months. Human tau was already uncovered at 3 months (phospho-tau at 6 months) and labeling intensifying progressively with age. Gene-dose dependence was confirmed in age-matched heterozygous females that accumulated less tau and amyloid protein. General excitability of hippocampal neurones was not altered in slices from PLB1Triple mice up to 12 months, but 2-year-old homozygous PLB1Triple mice had smaller synaptically evoked postsynaptic potentials compared with wild types. Synaptic plasticity (paired-pulse depression/facilitation and long-term potentiation) of synaptic CA1 pyramidal cell responses was deficient from 6 months of age. Long-term depression was not affected at any age or in any genotype. Therefore, despite comparatively subtle gene expression and protein build-up, PLB1Triple mice develop age-dependent progressive phenotypes, suggesting that aggressive protein accumulation is not necessary to reconstruct endophenotypes of AD. 相似文献
11.
Evidence of undiscovered cell regulatory mechanisms: phosphoproteins and protein kinases in mitochondria 总被引:3,自引:0,他引:3
Thomson M 《Cellular and molecular life sciences : CMLS》2002,59(2):213-219
The finding that mitochondria contain substrates for protein kinases lead to the discovery that protein kinases are located
in the mitochondria of certain tissues and species. These include pyruvate dyhydrogenase kinase, branched-chain α-ketoacid dehydrogenase kinase, protein kinase A, protein kinase Cδ, stress-activated kinase and A-Raf as well as unidentified kinases. Recent evidence suggests that mitochondrial protein kinases
may be involved in physiological processes such as apoptosis and steroidogenesis. Additionally, the novel finding of low-molecular-weight
GTP-binding proteins in mitochondria suggests the possibility that these may interact with mitochondrial protein kinases to
regulate the activity of mitochondrial effector proteins. The fact that there are components of cellular regulatory systems
in mitochondria indicates the exciting possibility of undiscovered systems regulating mitochondrial physiology.
Received 19 June 2001; received after revision 7 August 2001; accepted 8 August 2001 相似文献
12.
Birke J. Benedikter Antje R. Weseler Emiel F. M. Wouters Paul H. M. Savelkoul Gernot G. U. Rohde Frank R. M. Stassen 《Cellular and molecular life sciences : CMLS》2018,75(13):2321-2337
Extracellular vesicles (EVs), including microvesicles and exosomes, are emerging as important regulators of homeostasis and pathophysiology. During pro-inflammatory and pro-oxidant conditions, EV release is induced. As EVs released under such conditions often exert pro-inflammatory and procoagulant effects, they may actively promote the pathogenesis of chronic diseases. There is evidence that thiol group-containing antioxidants can prevent EV induction by pro-inflammatory and oxidative stimuli, likely by protecting protein thiols of the EV-secreting cells from oxidation. As the redox state of protein thiols greatly impacts three-dimensional protein structure and, consequently, function, redox modifications of protein thiols may directly modulate EV release in response to changes in the cell’s redox environment. In this review article, we discuss targets of redox-dependent thiol modifications that are known or expected to be involved in the regulation of EV release, namely redox-sensitive calcium channels, N-ethylmaleimide sensitive factor, protein disulfide isomerase, phospholipid flippases, actin filaments, calpains and cell surface-exposed thiols. Thiol protection is proposed as a strategy for preventing detrimental changes in EV signaling in response to inflammation and oxidative stress. Identification of the thiol-containing proteins that modulate EV release in pro-oxidant environments could provide a rationale for broad application of thiol group-containing antioxidants in chronic inflammatory diseases. 相似文献
13.
14.
Martelli AM Bortul R Tabellini G Bareggi R Manzoli L Narducci P Cocco L 《Cellular and molecular life sciences : CMLS》2002,59(7):1129-1137
Several independent groups have shown that lipid-dependent signal transduction systems operate in the nucleus and that they
are regulated independently from their membrane and cytosolic counterparts. A sizable body of evidence suggests that nuclear
lipid signaling controls critical biological functions such as cell proliferation and differentiation. Diacylglycerol is a
fundamental lipid second messenger which is produced in the nucleus. The levels of nuclear diacylglycerol fluctuate during
the cell cycle progression, suggesting that such a molecule has important regulatory roles. Most likely, nuclear diacylglycerol
serves as a chemoattractant for some isoforms of protein kinase C that migrate to the nucleus in response to a variety of
agonists. The nucleus also contains diacylglycerol kinases, i.e. the enzymes that, by converting diacylglycerol into phosphatidic
acid, terminate diacylglycerol-dependent events. A number of diacylglycerol kinases encoded by separate genes are present
in the mammalian genome. This review aims at highlighting the different isotypes of diacylglycerol kinases identified at the
nuclear level as well as at discussing their potential function and regulation.
Received 4 December 2001; received after revision 28 January 2002; accepted 31 January 2002 相似文献
15.
Li-Chun Wang Kuan-Yu Chen Huichin Pan Chia-Chieh Wu Po-Hsuan Chen Yuan-Ting Liao Chin Li Min-Lang Huang Kuang-Ming Hsiao 《Cellular and molecular life sciences : CMLS》2011,68(7):1255-1267
We have utilized Caenorhabditis elegans as a model to investigate the toxicity and underlying mechanism of untranslated CAG repeats in comparison to CUG repeats.
Our results indicate that CAG repeats can be toxic at the RNA level in a length-dependent manner, similar to that of CUG repeats.
Both CAG and CUG repeats of toxic length form nuclear foci and co-localize with C. elegans muscleblind (CeMBL), implying that CeMBL may play a role in repeat RNA toxicity. Consistently, the phenotypes of worms expressing
toxic CAG and CUG repeats, including shortened life span and reduced motility rate, were partially reversed by CeMbl over-expression. These results provide the first experimental evidence to show that the RNA toxicity induced by expanded
CAG and CUG repeats can be mediated, at least in part, through the functional alteration of muscleblind in worms. 相似文献
16.
17.
Apiruck Watthanasurorot Kenneth Söderhäll Pikul Jiravanichpaisal Irene Söderhäll 《Cellular and molecular life sciences : CMLS》2011,68(2):315-323
Invertebrate circulating hemocytes are key players in the innate immune defense and their continuous renewal from hematopoietic
tissues is tightly regulated in crustaceans by astakine, a new family of cytokines sharing a prokineticin (PROK) domain. In
vertebrates, brain PROKs function as transmitters of circadian rhythms and we present evidence that hemocyte release from
hematopoietic tissues in crayfish is under circadian regulation, a direct result of rhythmic expression of astakine. We demonstrate
that the observed variation in astakine expression has an impact on innate immunity assessed as susceptibility to a pathogenic
Pseudomonas species. These findings enlighten the importance of comparing immune responses at fixed times not to neglect circadian regulation
of innate immunity. Moreover, our results entail an evolutionary conserved function for prokineticins as mediators of circadian
rhythm, and for the first time show a role for this domain in circadian regulation of hematopoiesis that may have implications
also in vertebrates. 相似文献
18.
Töröcsik D Bárdos H Nagy L Adány R 《Cellular and molecular life sciences : CMLS》2005,62(18):2132-2139
Factor XIII subunit A of blood coagulation (FXIII-A) is known to be synthesized but not secreted by the monocyte/macrophage cell line. On the basis of its intracellular localization and substrate profile, FXIII-A is thought to be involved in certain intracellular processes. Our present study was designed to monitor the changes in FXIII-A gene expression and protein production in long-term culture of human monocytes during their differentiation into macrophages in the presence of activating agents (interleukin-4, interferon-γ, Mycobacterium bovis BCG) inducing classical and alternative activation pathways. By using quantitative RT-PCR and fluorescent image analysis at the single-cell level we demonstrated that the expression of FXIII-A both at the mRNA as well as at the protein level is inversely regulated during the two activation programmes. Here we conclude that FXIII-A expression is an intracellular marker for alternatively activated macrophages, while its absence in monocyte-derived macrophages indicates their classically activated state.Received 2 June 2005; received after revision 12 July 2005; accepted 22 July 2005 相似文献
19.
Deamidation and isoaspartate formation in proteins:
unwanted alterations or surreptitious signals? 总被引:9,自引:0,他引:9
Formation of -linked Asp-Xaa peptide bonds – isoaspartyl (isoAsp) sites
– arise in proteins via succinimide–linked deamidation of asparagine or dehydration of
aspartate, reactions which represent a major source of spontaneous protein damage under physiological
conditions. Accumulation of atypical isoaspartyl sites is minimized in vivo by the activity of
protein L-isoaspartyl
O–methyltransferase (PIMT), which regenerates a normal
peptide bond. Loss of PIMT has harmful consequences, especially in neurons; thus, formation of
isoAsp sites and their subsequent correction by PIMT is widely believed to constitute an important
pathway of protein damage and repair. Recent evidence is mounting, however, that deamidation
and isoaspartate formation may, in some instances, constitute a novel mechanism for intentional
modification of protein structure. Herein we describe the mechanism of Asx rearrangement, summarize
the evidence that PIMT serves an important repair function, and then focus on emerging evidence
that deamidation and isoAsp formation may sometimes have a useful function.Received 16 October 2002; received after revision 11 December 2002; accepted 12 December 2002 相似文献
20.
T. Sasaki 《Cellular and molecular life sciences : CMLS》1990,46(6):611-616
Summary Glycolipid transfer protein (GL-TP), a nonglycosylated protein with a molecular weight of 22,000 K, has been purified from pig brain. The protein transfers, by a carrier mechanism, glycolipids with a -glucosyl or -galactosyl residue directly linked to either ceramide or diacylglycerol. GL-TP appears to be present in most animal cells, and evidence has been obtained which indicates that it is a cytoplasmic protein. Little is known about the function of GL-TP. Current evidence indicates that glycosphingolipid glycosylation occurs at the luminal side of the Golgi apparatus, except for the glucosylation of ceramide, which has been shown to occur at the cytoplasmic side of the Golgi or endoplasmic membrane. It appears most likely that GL-TP participates in the intracellular traffic of glucosylceramide. 相似文献