The access of Transcription Factors (TFs) to their cognate DNA binding motifs requires a precise control over nucleosome positioning. This is especially important following DNA replication and during mitosis, both resulting in profound changes in nucleosome organization over TF binding regions. Using mouse Embryonic Stem (ES) cells, we show that the TF CTCF displaces nucleosomes from its binding site and locally organizes large and phased nucleosomal arrays, not only in interphase steady-state but also immediately after replication and during mitosis. Correlative analyses suggest this is associated with fast gene reactivation following replication and mitosis. While regions bound by other TFs (Oct4/Sox2), display major rearrangement, the post-replication and mitotic nucleosome positioning activity of CTCF is not unique: Esrrb binding regions are also characterized by persistent nucleosome positioning. Therefore, selected TFs such as CTCF and Esrrb act as resilient TFs governing the inheritance of nucleosome positioning at regulatory regions throughout the cell-cycle.

An important question in sea turtle biology is the number of males that contribute to the fertilization of a clutch of eggs. Previous studies on other sea turtle species have indicated little to no multiple paternity. We conclude here that female Kemp's ridleys, Lepidochelys kempi, are polyandrous. DNA from 26 mother and offspring groups was analysed at three microsatellite loci to identify paternal alleles. Three paternal alleles were observed among 14 of the clutches; four paternal alleles were observed among the offspring of an additional female. A maximum likelihood analysis not only rejects the model of single paternity, but also rejects the model of equal paternal contribution to the clutch. By explicitly addressing the high mutation rate of microsatellite markers, our analysis rejected mutation as the sole cause of multiple paternal alleles.

Sympatric speciation is now accepted as theoretically plausible and a likely explanation for divergence in a handful of taxa, but its contribution to large-scale patterns of speciation remains contentious. A major problem is that it is difficult to differentiate between alternate scenarios of geographic speciation when species ranges have shifted substantially in the past. Previous studies have searched for a signal of the geographic mode of speciation by testing for a correlation between time since speciation and range overlap. Here we use simulations to show that the proportion of species showing zero or complete range overlap are more reliable indicators of the geography of speciation than is the correlation between time since speciation and overlap. We then apply these findings to the distributions of 291 pairs of avian sister species. Although 49% of pairs show some overlap in their ranges, our simulations show that this is not surprising under allopatric models of speciation. More revealingly, less than 2% show complete range overlap. Our simulations demonstrate that the observed patterns are most consistent with a model in which allopatric speciation is dominant but in which sympatric speciation is also present and contributes 5% of speciation events.

The maintenance of pluripotency in mouse embryonic stem cells (ESCs) is governed by the action of an interconnected network of transcription factors. Among them, only Oct4 and Sox2 have been shown to be strictly required for the self-renewal of ESCs and pluripotency, particularly in culture conditions where differentiation cues are chemically inhibited. Here, we report that the conjunct activity of two orphan nuclear receptors, Esrrb and Nr5a2, parallels the importance of that of Oct4 and Sox2 in naïve ESCs. By occupying a large common set of regulatory elements, these two factors control the binding of Oct4, Sox2 and Nanog to DNA. Consequently, in their absence the pluripotency network collapses and the transcriptome is substantially deregulated, leading to the differentiation of ESCs. Altogether, this work identifies orphan nuclear receptors, previously thought to be performing supportive functions, as a new set of core regulators of naïve pluripotency.

Mammalian genomes harbor a large number of retroviral elements acquired as germ line insertions during evolution. Although many of the endogenous retroviruses are defective, several contain one or more intact viral genes that are expressed under certain physiological or pathological conditions. This is true of the endogenous polytropic retroviruses that generate recombinant polytropic murine leukemia viruses (MuLVs). In these recombinants the env gene sequences of exogenous ecotropic MuLVs are replaced with env gene sequences from an endogenous polytropic retrovirus. Although replication-competent endogenous polytropic retroviruses have not been observed, the recombinant polytropic viruses are capable of replicating in numerous species. Recombination occurs during reverse transcription of a virion RNA heterodimer comprised of an RNA transcript from an endogenous polytropic virus and an RNA transcript from an exogenous ecotropic MuLV RNA. It is possible that homodimers corresponding to two full-length endogenous RNA genomes are also packaged. Thus, infection by an exogenous virus may result not only in recombination with endogenous sequences, but also in the mobilization of complete endogenous retrovirus genomes via pseudotyping within exogenous retroviral virions. We report that the infection of mice with an ecotropic virus results in pseudotyping of intact endogenous viruses that have not undergone recombination. The endogenous retroviruses infect and are integrated into target cell genomes and subsequently replicate and spread as pseudotyped viruses. The mobilization of endogenous retroviruses upon infection with an exogenous retrovirus may represent a major interaction of exogenous retroviruses with endogenous retroviruses and may have profound effects on the pathogenicity of retroviral infections.

Polytropic murine leukemia viruses (MuLVs) are generated by recombination of ecotropic MuLVs with env genes of a family of endogenous proviruses in mice, resulting in viruses with an expanded host range and greater virulence. Inbred mouse strains contain numerous endogenous proviruses that are potential donors of the env gene sequences of polytropic MuLVs; however, the precise identification of those proviruses that participate in recombination has been elusive. Three different structural groups of proviruses in NFS/N mice have been described and different ecotropic MuLVs preferentially recombine with different groups of proviruses. In contrast to other ecotropic MuLVs such as Friend MuLV or Akv that recombine predominantly with a single group of proviruses, Moloney MuLV (M-MuLV) recombines with at least two distinct groups. In this study, we determined that only three endogenous proviruses, two of one group and one of another group, are major participants in recombination with M-MuLV. Furthermore, the distinction between the polytropic MuLVs generated by M-MuLV and other ecotropic MuLVs is the result of recombination with a single endogenous provirus. This provirus exhibits a frameshift mutation in the 3 region of the surface glycoproteinencoding sequences that is excluded in recombinants with M-MuLV. The sites of recombination between the env genes of M-MuLV and endogenous proviruses were confined to a short region exhibiting maximum homology between the ecotropic and polytropic env sequences and maximum stability of predicted RNA secondary structure. These observations suggest a possible mechanism for the specificity of recombination observed for different ecotropic MuLVs.

More than 4% of men and 3% of women in the UK are known to have type 2 diabetes. Furthermore, an ageing population and increasing prevalence of obesity, both associated with the onset of diabetes, mean that the number of people with the condition is expected to rise dramatically. Uncontrolled diabetes can lead to the development of complications such as retinopathy, neuropathy and myocardial infarction, the treatment of which places an ever increasing burden on health care services. The incidence of such complications can be reduced by adequate glycaemic control, and this can be achieved using an evolving therapeutic strategy which comprises a variety of treatment options involving oral hypoglycaemic agents and insulin preparations, tailored to meet the progressive nature of the condition. Diet and lifestyle modifications have limited long‐term success in maintaining glycaemic control, and it is recommended that metformin, an oral hypoglycaemic agent, is introduced from diagnosis. Meal‐related blood glucose peaks pose a particular challenge to achieving overall glycaemic control, and the introduction of prandial insulin using short‐acting insulin analogues is effective in quickly lowering postprandial blood glucose. This article presents an algorithm that has been developed to provide guidance to health care professionals on the use of prandial insulin to control excessive post‐meal glycaemic excursions in persons with type 2 diabetes inadequately controlled (HbA1c >7%) on basal insulin, with or without oral hypoglycaemic agents. Copyright ©2009 John Wiley & Sons.

The training of back propagation networks involves adjusting the weights between the computing nodes in the artificial neural network to minimize the errors between the network's predictions and the known outputs in the training set. This leastsquares minimization problem is conventionally solved by an iterative fixed-step technique, using gradient descent, which occasionally exhibits instabilities and converges slowly. We show that the training of the back propagation network can be expressed as a problem of solving coupled ordinary differential equations for the weights as a (continuous) function of time. These differential equations are usually mathematically stiff. The use of a stiff differential equation solver ensures quick convergence to the nearest leastsquares minimum. Training proceeds at a rapidly accelerating rate as the accuracy of the predictions increases, in contrast with gradient descent and conjugate gradient methods. The number of presentations required for accurate training is reduced by up to several orders of magnitude over the conventional method.