Whole-genome sequencing of multiple Arabidopsis thaliana populations

The plant Arabidopsis thaliana occurs naturally in many different habitats throughout Eurasia. As a foundation for identifying genetic variation contributing to adaptation to diverse environments, a 1001 Genomes Project to sequence geographically diverse A. thaliana strains has been initiated. Here we present the first phase of this project, based on population-scale sequencing of 80 strains drawn from eight regions throughout the species' native range. We describe the majority of common small-scale polymorphisms as well as many larger insertions and deletions in the A. thaliana pan-genome, their effects on gene function, and the patterns of local and global linkage among these variants. The action of processes other than spontaneous mutation is identified by comparing the spectrum of mutations that have accumulated since A. thaliana diverged from its closest relative 10 million years ago with the spectrum observed in the laboratory. Recent species-wide selective sweeps are rare, and potentially deleterious mutations are more common in marginal populations.     

Determination of the connectivity of newborn neurons in mammalian olfactory circuits

The mammalian olfactory bulb is a forebrain structure just one synapse downstream from the olfactory sensory neurons and performs the complex computations of sensory inputs. The formation of this sensory circuit is shaped through activity-dependent and cell-intrinsic mechanisms. Recent studies have revealed that cell-type specific connectivity and the organization of synapses in dendritic compartments are determined through cell-intrinsic programs already preset in progenitor cells. These progenitor programs give rise to subpopulations within a neuron type that have distinct synaptic organizations. The intrinsically determined formation of distinct synaptic organizations requires factors from contacting cells that match the cell-intrinsic programs. While certain genes control wiring within the newly generated neurons, other regulatory genes provide intercellular signals and are only expressed in neurons that will form contacts with the newly generated cells. Here, the olfactory system has provided a useful model circuit to reveal the factors regulating assembly of the highly structured connectivity in mammals.     

Insights from studying human sleep disorders

Problems with sleep are one of the commonest reasons for seeking medical attention. Knowledge gained from basic research into sleep in animals has led to marked advances in the understanding of human sleep, with important diagnostic and therapeutic implications. At the same time, research guided by human sleep disorders is leading to important basic sleep concepts. For example, sleep may not be a global, but rather a local, brain phenomenon. Furthermore, contrary to common assumptions, wakefulness, rapid eye movement (REM) and non-REM sleep are not mutually exclusive states. This striking realization explains a fascinating range of clinical phenomena.     

Vascular respiratory uncoupling increases blood pressure and atherosclerosis

The observations that atherosclerosis often occurs in non-smokers without elevated levels of low-density lipoprotein cholesterol, and that most atherosclerosis loci so far identified in mice do not affect systemic risk factors associated with atherosclerosis, suggest that as-yet-unidentified mechanisms must contribute to vascular disease. Arterial walls undergo regional disturbances of metabolism that include the uncoupling of respiration and oxidative phosphorylation, a process that occurs to some extent in all cells and may be characteristic of blood vessels being predisposed to the development of atherosclerosis. To test the hypothesis that inefficient metabolism in blood vessels promotes vascular disease, we generated mice with doxycycline-inducible expression of uncoupling protein-1 (UCP1) in the artery wall. Here we show that UCP1 expression in aortic smooth muscle cells causes hypertension and increases dietary atherosclerosis without affecting cholesterol levels. UCP1 expression also increases superoxide production and decreases the availability of nitric oxide, evidence of oxidative stress. These results provide proof of principle that inefficient metabolism in blood vessels can cause vascular disease.     

Ecology: is speciation driven by species diversity?

Emerson and Kolm show that the proportion of species endemic to an island is positively related to its species richness and, assuming that endemism indexes speciation rate, they infer that greater species diversity accelerates diversification. Here we demonstrate that the same correlation between species richness and percentage endemism can arise even if within-island speciation is negligible, particularly when both endemism and species richness depend on attributes of islands (such as area) that influence the average age of resident populations. Island biogeography theory indicates that, where the average time to extinction is relatively long, diversity increases through colonization, irrespective of whether new species are formed; at the same time, islands on which populations persist for longer accumulate more endemic species as local populations differentiate and populations on neighbouring islands become extinct. We therefore suggest that species richness and endemism are correlated fortuitously owing to their mutual dependence on the life spans of populations on islands, which is unrelated to speciation itself.     

Characterization of a common precursor population for dendritic cells

Dendritic cells (DCs) are essential for the establishment of immune responses against pathogens and tumour cells, and thus have great potential as tools for vaccination and cancer immunotherapy trials. Experimental evidence has led to a dual DC differentiation model, which involves the existence of both myeloid- and lymphoid-derived DCs. But this concept has been challenged by recent reports demonstrating that both CD8- and CD8+ DCs, considered in mice as archetypes of myeloid and lymphoid DCs respectively, can be generated from either lymphoid or myeloid progenitors. The issue of DC physiological derivation therefore remains an open question. Here we report the characterization of a DC-committed precursor population, which has the capacity to generate all the DC subpopulations present in mouse lymphoid organs---including CD8- and CD8+ DCs, as well as the B220+ DC subset---but which is devoid of myeloid or lymphoid differentiation potential. These data support an alternative model of DC development, in which there is an independent, common DC differentiation pathway.     

The bacteriophage straight phi29 portal motor can package DNA against a large internal force

As part of the viral infection cycle, viruses must package their newly replicated genomes for delivery to other host cells. Bacteriophage straight phi29 packages its 6.6-microm long, double-stranded DNA into a 42 x 54 nm capsid by means of a portal complex that hydrolyses ATP. This process is remarkable because entropic, electrostatic and bending energies of the DNA must be overcome to package the DNA to near-crystalline density. Here we use optical tweezers to pull on single DNA molecules as they are packaged, thus demonstrating that the portal complex is a force-generating motor. This motor can work against loads of up to 57 pN on average, making it one of the strongest molecular motors reported to date. Movements of over 5 microm are observed, indicating high processivity. Pauses and slips also occur, particularly at higher forces. We establish the force-velocity relationship of the motor and find that the rate-limiting step of the motor's cycle is force dependent even at low loads. Notably, the packaging rate decreases as the prohead is filled, indicating that an internal force builds up to approximately 50 pN owing to DNA confinement. Our data suggest that this force may be available for initiating the ejection of the DNA from the capsid during infection.     

Using neural networks for recognizing matching among terms

Some experiments have been carried out in order to identify a class of neural networks that would receive as inputs (n+1) terms {T_l,…T_n.T} and would suggest which T_is are matched by a subterm of T, with varying n. A particular net was found that is able to solve the problem for n=1 with a good degree of accuracy. It is shown that the performance of the net is relatively independent of the size of the training set while it is strongly related to the length of the term T. This net was then used as building block for larger nets that were applied to solve the problem for higher values of n. Results of testing such nets are presented.