Eastern Pacific cooling and Atlantic overturning circulation during the last deglaciation

Surface ocean conditions in the equatorial Pacific Ocean could hold the clue to whether millennial-scale global climate change during glacial times was initiated through tropical ocean-atmosphere feedbacks or by changes in the Atlantic thermohaline circulation. North Atlantic cold periods during Heinrich events and millennial-scale cold events (stadials) have been linked with climatic changes in the tropical Atlantic Ocean and South America, as well as the Indian and East Asian monsoon systems, but not with tropical Pacific sea surface temperatures. Here we present a high-resolution record of sea surface temperatures in the eastern tropical Pacific derived from alkenone unsaturation measurements. Our data show a temperature drop of approximately 1 degrees C, synchronous (within dating uncertainties) with the shutdown of the Atlantic meridional overturning circulation during Heinrich event 1, and a smaller temperature drop of approximately 0.5 degrees C synchronous with the smaller reduction in the overturning circulation during the Younger Dryas event. Both cold events coincide with maxima in surface ocean productivity as inferred from 230Th-normalized carbon burial fluxes, suggesting increased upwelling at the time. From the concurrence of equatorial Pacific cooling with the two North Atlantic cold periods during deglaciation, we conclude that these millennial-scale climate changes were probably driven by a reorganization of the oceans' thermohaline circulation, although possibly amplified by tropical ocean-atmosphere interaction as suggested before.     

Ecology: mechanisms for consumer diversity

A variety of mechanisms can theoretically produce competitive coexistence in nature, making it hard to identify a single explanation for the maintenance of diversity in any particular system. Based on laboratory experiments with a consumer-resource system of crustacean Daphnia eating algae, Nelson et al. suggest that maintenance of genetic diversity in the consumer populations they studied depends only on the dynamics of the population structure of the consumer. We suggest that the differences in Daphnia genetic diversity that they find for different experimental treatments could equally be explained by a simple, well known mechanism: the number of coexisting competitors cannot exceed the number of shared resources. Here we confirm this possibility by using a simple mathematical model and suggest that more than one mechanism may account for the maintenance of genetic diversity observed by Nelson et al. in their system.     

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.     

Independent evolution of bitter-taste sensitivity in humans and chimpanzees

It was reported over 65 years ago that chimpanzees, like humans, vary in taste sensitivity to the bitter compound phenylthiocarbamide (PTC). This was suggested to be the result of a shared balanced polymorphism, defining the first, and now classic, example of the effects of balancing selection in great apes. In humans, variable PTC sensitivity is largely controlled by the segregation of two common alleles at the TAS2R38 locus, which encode receptor variants with different ligand affinities. Here we show that PTC taste sensitivity in chimpanzees is also controlled by two common alleles of TAS2R38; however, neither of these alleles is shared with humans. Instead, a mutation of the initiation codon results in the use of an alternative downstream start codon and production of a truncated receptor variant that fails to respond to PTC in vitro. Association testing of PTC sensitivity in a cohort of captive chimpanzees confirmed that chimpanzee TAS2R38 genotype accurately predicts taster status in vivo. Therefore, although Fisher et al.'s observations were accurate, their explanation was wrong. Humans and chimpanzees share variable taste sensitivity to bitter compounds mediated by PTC receptor variants, but the molecular basis of this variation has arisen twice, independently, in the two species.     

Kant and the nature of matter: Mechanics,chemistry, and the life sciences

Kant believed that the ultimate processes that regulate the behavior of material bodies can be characterized exclusively in terms of mechanics. In 1790, turning his attention to the life sciences, he raised a potential problem for his mechanically-based account, namely that many of the operations described in the life sciences seemed to operate teleologically. He argued that the life sciences do indeed require us to think in teleological terms, but that this is a fact about us, not about the processes themselves. Nevertheless, even were we to concede his account of the life sciences, this would not secure the credentials of mechanics as a general theory of matter. Hardly any material properties studied in the second half of the eighteenth century were, or could have been, conceived in mechanical terms. Kant's concern with teleology is tangential to the problems facing a general matter theory grounded in mechanics, for the most pressing issues have nothing to do with teleology. They derive rather from a lack of any connection between mechanical forces and material properties. This is evident in chemistry, which Kant dismisses as being unscientific on the grounds that it cannot be formulated in mechanical terms.     

Dynamic assembly of silent chromatin during thymocyte maturation

Considerable knowledge has been gained from temporal analyses of molecular events culminating in gene activation, but technical hurdles have hindered comparable studies of gene silencing. Here we describe the temporal assembly of silent chromatin at the mouse terminal transferase gene (Dntt), which is silenced and repositioned to pericentromeric heterochromatin during thymocyte maturation. Silencing was nucleated at the Dntt promoter by the ordered deacetylation of histone H3 at Lys9 (H3-Lys9), loss of methylation at H3-Lys4 and acquisition of methylation at H3-Lys9, followed by bidirectional spreading of each event. Deacetylation at H3-Lys9 coincided with pericentromeric repositioning, and neither of these early events required de novo protein synthesis. CpG methylation increased primarily in mature T cells that had left the thymus. A transformed thymocyte line supported reversible inactivation of Dntt without repositioning. In these cells, histone modification changes were nucleated at the promoter but did not spread. These results provide a foundation for elucidating the mechanisms of silent chromatin assembly during development.     

Changes in fisheries discard rates and seabird communities

It is clear that discards from commercial fisheries are a key food resource for many seabird species around the world. But predicting the response of seabird communities to changes in discard rates is problematic and requires historical data to elucidate the confounding effects of other, more 'natural' ecological processes. In the North Sea, declining stocks, changes in technical measures, changes in population structure and the establishment of a recovery programme for cod (Gadus morhua) will alter the amount of fish discarded. This region also supports internationally important populations of seabirds, some of which feed extensively, but facultatively, on discards, in particular on undersized haddock (Melanogrammus aeglefinus) and whiting (Merlangius merlangus). Here we use long-term data sets from the northern North Sea to show that there is a direct link between discard availability and discard use by a generalist predator and scavenger--the great skua (Stercorarius skua). Reduced rates of discarding, particularly when coupled with reduced availability of small shoaling pelagic fish such as sandeel (Ammodytes marinus), result in an increase in predation by great skuas on other birds. This switching of prey by a facultative scavenger presents a potentially serious threat to some seabird communities.     

In situ analyses of genome instability in breast cancer

Transition through telomere crisis is thought to be a crucial event in the development of most breast carcinomas. Our goal in this study was to determine where this occurs in the context of histologically defined breast cancer progression. To this end, we assessed genome instability (using fluorescence in situ hybridization) and other features associated with telomere crisis in normal ductal epithelium, usual ductal hyperplasia, ductal carcinoma in situ and invasive cancer. We modeled this process in vitro by measuring these same features in human mammary epithelial cell cultures during ZNF217-mediated transition through telomere crisis and immortalization. Taken together, the data suggest that transition through telomere crisis and immortalization in breast cancer occurs during progression from usual ductal hyperplasia to ductal carcinoma in situ.     

Human genes that limit AIDS

Discernable genetic variation among people and populations has an important role in infectious disease epidemics, including that of acquired immune deficiency syndrome (AIDS). Genetic association analysis of several large AIDS cohorts implicate 14 AIDS restriction genes, polymorphic variants in loci that regulate HIV-1 cell entry, acquired and innate immunity, and cytokine defenses to HIV-1. The influence and translational impact of these genes on individual and population sensitivity to AIDS is considerable.     

CpG island hypermethylation is maintained in human colorectal cancer cells after RNAi-mediated depletion of DNMT1

The role of the primary mammalian DNA methyltransferase, DNMT1, in maintaining CpG island methylation in human colon cancer cells has recently been questioned. This controversy has arisen from discrepancies between genetic knockout and RNA interference-mediated knockdown studies. Here, we re-examined the RNA interference-based approach and found that hypermethylation of single-copy genes is maintained in cells transiently and stably depleted of DNMT1.