生物标记物之警示信号

寻找生物标记——能对阿尔茨海默氏症的侵入发出警告信号的标记物——的工作一直在进行着。而开展这项研究的目的旨在赢得对这一疾病治疗的主动权．探索阿尔茨海默氏症防治的新模式     

Assortative mating in soldier beetles (Cantharidae: Chaulignathus ): test of the mate-choice hypothesis

Soldier beetles of 2 species, Chauliognathus basalis and C. deceptus , were examined to test the Crespi hypothesis that positive assortative mating by size is caused by mate choices. Specifically, we tested the prediction that if mate choice involves choosing the largest mate available, then mating individuals will be larger than nonmating individuals. Four samples were taken, at different times during the mating season, from each of 2 sites. Each sample consisted of mating pairs, nonmanting males, and nonmating females. Some of the samples contained beetles of both species; others contained beetles of a single species. For each gender elytron lengths of mating individuals were compared with elytron lengths of nonmating individuals. We found no effect of mating status (mating vs. nonmating) on elytron lengths in samples that exhibited assertive mating (which occurs where 2 species coexist). Surprisingly, we found a consistent effect of mating status on elytron lengths in samples that did not exhibit assortative mating (which occurs where only 1 species exists). Our results do not support the mate-choice hypothesis. Instead, mate choice and assortative mating appear to be alternative mating patterns in which mate choice occurs where a single species exists and assortative mating occurs where 2 species coexist.     

The quantum liar experiment in Cramer's transactional interpretation

Cramer's Transactional Interpretation (TI) is applied to the “quantum liar experiment” (QLE). It is shown how some apparently paradoxical features can be explained naturally, albeit nonlocally (since TI is an explicitly nonlocal interpretation, at least from the vantage point of ordinary spacetime). At the same time, it is proposed that in order to preserve the elegance and economy of the interpretation, it may be necessary to consider offer and confirmation waves as propagating in a “higher space” of possibilities.     

Self-incompatibility in Papaver targets soluble inorganic pyrophosphatases in pollen

In higher plants, sexual reproduction involves interactions between pollen and pistil. A key mechanism to prevent inbreeding is self-incompatibility through rejection of incompatible ('self') pollen. In Papaver rhoeas, S proteins encoded by the stigma interact with incompatible pollen, triggering a Ca2+-dependent signalling network resulting in pollen tube inhibition and programmed cell death. The cytosolic phosphoprotein p26.1, which has been identified in incompatible pollen, shows rapid, self-incompatibility-induced Ca2+-dependent hyperphosphorylation in vivo. Here we show that p26.1 comprises two proteins, Pr-p26.1a and Pr-p26.1b, which are soluble inorganic pyrophosphatases (sPPases). These proteins have classic Mg2+-dependent sPPase activity, which is inhibited by Ca2+, and unexpectedly can be phosphorylated in vitro. We show that phosphorylation inhibits sPPase activity, establishing a previously unknown mechanism for regulating eukaryotic sPPases. Reduced sPPase activity is predicted to result in the inhibition of many biosynthetic pathways, suggesting that there may be additional mechanisms of self-incompatibility-mediated pollen tube inhibition. We provide evidence that sPPases are required for growth and that self-incompatibility results in an increase in inorganic pyrophosphate, implying a functional role for Pr-p26.1.     

Targeting C-reactive protein for the treatment of cardiovascular disease

Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.     

Vigorous exchange between the Indian and Atlantic oceans at the end of the past five glacial periods

The magnitude of heat and salt transfer between the Indian and Atlantic oceans through 'Agulhas leakage' is considered important for balancing the global thermohaline circulation. Increases or reductions of this leakage lead to strengthening or weakening of the Atlantic meridional overturning and associated variation of North Atlantic Deep Water formation. Here we show that modern Agulhas waters, which migrate into the south Atlantic Ocean in the form of an Agulhas ring, contain a characteristic assemblage of planktic foraminifera. We use this assemblage as a modern analogue to investigate the Agulhas leakage history over the past 550,000 years from a sediment record in the Cape basin. Our reconstruction indicates that Indian-Atlantic water exchange was highly variable: enhanced during present and past interglacials and largely reduced during glacial intervals. Coherent variability of Agulhas leakage with northern summer insolation suggests a teleconnection to the monsoon system. The onset of increased Agulhas leakage during late glacial conditions took place when glacial ice volume was maximal, suggesting a crucial role for Agulhas leakage in glacial terminations, timing of interhemispheric climate change and the resulting resumption of the Atlantic meridional overturning circulation.     

Dicer is essential for mouse development

To address the biological function of RNA interference (RNAi)-related pathways in mammals, we disrupted the gene Dicer1 in mice. Loss of Dicer1 lead to lethality early in development, with Dicer1-null embryos depleted of stem cells. Coupled with our inability to generate viable Dicer1-null embryonic stem (ES) cells, this suggests a role for Dicer, and, by implication, the RNAi machinery, in maintaining the stem cell population during early mouse development.     

Closing gaps in the human genome with fosmid resources generated from multiple individuals

The human genome sequence has been finished to very high standards; however, more than 340 gaps remained when the finished genome was published by the International Human Genome Sequencing Consortium in 2004. Using fosmid resources generated from multiple individuals, we targeted gaps in the euchromatic part of the human genome. Here we report 2,488,842 bp of previously unknown euchromatic sequence, 363,114 bp of which close 26 of 250 euchromatic gaps, or 10%, including two remaining euchromatic gaps on chromosome 19. Eight (30.7%) of the closed gaps were found to be polymorphic. These sequences allow complete annotation of several human genes as well as the assignment of mRNAs. The gap sequences are 2.3-fold enriched in segmentally duplicated sequences compared to the whole genome. Our analysis confirms that not all gaps within 'finished' genomes are recalcitrant to subcloning and suggests that the paired-end-sequenced fosmid libraries could prove to be a rich resource for completion of the human euchromatic genome.     

Model for signal sequence recognition from amino-acid sequence of 54K subunit of signal recognition particle

Protein targeting to the endoplasmic reticulum in mammalian cells is catalysed by signal recognition particle (SRP). Cross-linking experiments have shown that the subunit of relative molecular mass 54,000 (Mr 54K; SRP54) interacts directly with signal sequences as they emerge from the ribosome. Here we present the sequence of a complementary DNA clone of SRP54 which predicts a protein that contains a putative GTP-binding domain and an unusually methionine-rich domain. The properties of this latter domain suggest that it contains the signal sequence binding site. A previously uncharacterized Escherichia coli protein has strong homology to both domains. Closely homologous GTP-binding domains are also found in the alpha-subunit of the SRP receptor (SR alpha, docking protein) in the endoplasmic reticulum membrane and in a second E. coli protein, ftsY, which resembles SR alpha. Recent work has shown that SR alpha is a GTP-binding protein and that GTP is required for the release of SRP from the signal sequence and the ribosome on targeting to the endoplasmic reticulum membrane. We propose that SRP54 and SR alpha use GTP in sequential steps of the targeting reaction and that essential features of such a pathway are conserved from bacteria to mammals.     

Expression of human adenosine deaminase in murine haematopoietic progenitor cells following retroviral transfer

Adenosine deaminase (ADA) deficiency, an autosomal recessive inborn error of metabolism, leads to severe combined immune deficiency in man. This enzyme, although constitutively expressed in most tissues, is expressed at high level in immature T cells, and study of the pathophysiology of the disorder indicates that increased deoxyadenosine or altered methylation capacity have toxic effects on T-cell maturation. Although bone marrow transplantation can correct the immune deficiency, this therapy is associated with graft-versus-host disease and incomplete immune restoration, and so our laboratory and others have sought to develop a method of gene replacement as a possible treatment for the disease. Moreover, characterization of the complementary DNA of the human ADA gene and some of its mutants makes it possible to design gene transfer strategies. We have now subcloned a human adenosine deaminase cDNA into the retrovirus shuttle vector pZIP-SV(B), and in this way have isolated a cell line, 4.2T, which produces high titres of replication-defective retrovirus which have been used to transfer the gene for human ADA to mouse bone marrow cells. Transfer and expression of the neomycin-resistance gene (neo) and the ADA gene in murine bone marrow colony-forming units (CFU) was demonstrated by in vitro colony formation in the presence of the antibiotic G418 or 9-xylofuranosyladenine plus deoxycoformycin, respectively. Isoenzyme analysis also showed human ADA expression in the cultured mouse bone marrow.