APOBEC3B cytosine deaminase activity has recently emerged as a significant mutagenic factor in human cancer. APOBEC activity is induced in virally infected cells, and APOBEC signature mutations occur ...at high frequency in cervical cancers (CESC), over 99% of which are caused by human papillomavirus (HPV). We tested whether APOBEC-mediated mutagenesis is particularly important in HPV-associated tumors by comparing the exomes of HPV+ and HPV− head and neck squamous cell carcinomas (HNSCCs) sequenced by The Cancer Genome Atlas project. As expected, HPV− HNSCC displays a smoking-associated mutational signature, whereas our data suggest that reduced exposure to exogenous carcinogens in HPV+ HNSCC creates a selective pressure that favors emergence of tumors with APOBEC-mediated driver mutations. Finally, we provide evidence that APOBEC activity is responsible for the generation of helical domain hot spot mutations in the PIK3CA gene across multiple cancers. Our findings implicate APOBEC activity as a key driver of PIK3CA mutagenesis and HPV-induced transformation.
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•APOBEC-mediated mutagenesis is increased in the HPV+ subset of head and neck cancer•APOBEC enzymes likely generate many of the driver mutations in HPV-associated cancers•APOBECs are implicated in generating the oncogenic E542K and E545K PIK3CA mutations
The APOBEC family of cytidine deaminases, which combat viral infection by hyperediting viral DNA, has recently been implicated in producing somatic mutations in human tumors. By analyzing mutation data from The Cancer Genome Atlas project, Henderson et al. provide evidence that this process plays a key role in tumor development by generating oncogenic hot spot mutations in the PIK3CA gene. This mechanism appears particularly prominent in tumors caused by the human papillomavirus, in which APOBEC activity accounts for a high fraction of the total mutational burden.
Abstract
In a small lake, where flows were dominated by internal waves with 10–32-h period, slow but persistent mean transport of water over many wave periods was examined. Acoustic Doppler profilers ...(ADPs) and a vertical string of temperature loggers were deployed where the lower thermocline intersected the sloping lakebed. Near (<1 m above) the bed, internal waves, coherent with a lakewide seiche, propagated upslope at ~0.023 m s
−1
. Near-bed wave-induced water velocity fluctuations had a standard deviation of <0.02 m s
−1
. Near the surface, velocity fluctuations had similar magnitude, but lateral wave propagation was unclear. Averaged over many wave periods, the near-bed Eulerian velocity flowed downslope at ~0.01 m s
−1
, and was roughly cancelled by an upslope internal-wave Stokes drift (estimated by assuming that weakly nonlinear waves propagated without change of form). To examine net transport, while relaxing approximations used to estimate the Stokes drift, the observed temperature range (9°–25°C) was divided into 0.5°C increments, and the depth-integrated, wave-averaged flux of water in each temperature class was calculated. The coldest (near-bed) water was slowly transported onshore, opposite the Eulerian mean velocity. Onshore flux of warm near-surface water was comparable to an Eulerian-mean flux, indicating minimal near-surface Stokes drift. Intermediate water, from the middle of the water column and the outer boundary layer, was transported offshore by an offshore Stokes drift. The downslope near-bed Eulerian mean velocity, together with intensification of mean stratification within 0.4 m of the bed, may enhance boundary layer mixing.
Topological domains are key architectural building blocks of chromosomes, but their functional importance and evolutionary dynamics are not well defined. We performed comparative high-throughput ...chromosome conformation capture (Hi-C) in four mammals and characterized the conservation and divergence of chromosomal contact insulation and the resulting domain architectures within distantly related genomes. We show that the modular organization of chromosomes is robustly conserved in syntenic regions and that this is compatible with conservation of the binding landscape of the insulator protein CTCF. Specifically, conserved CTCF sites are co-localized with cohesin, are enriched at strong topological domain borders, and bind to DNA motifs with orientations that define the directionality of CTCF’s long-range interactions. Conversely, divergent CTCF binding between species is correlated with divergence of internal domain structure, likely driven by local CTCF binding sequence changes, demonstrating how genome evolution can be linked to a continuous flux of local conformation changes. We also show that large-scale domains are reorganized during genome evolution as intact modules.
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•Multi-species Hi-C comparisons reveal robust conservation of chromosome organization•CTCF binding has evolved under two regimes with different effects on structure•Oriented CTCF motifs determine the directionality of CTCF-mediated interactions
To explore the mechanisms underlying the evolution of chromosomal domain structures, Vietri Rudan et al. compare four mammalian species and reveal a direct link between insulator site divergence and the evolution of chromatin domain structure. Their data point to a direct role for CTCF/cohesin in driving structural change in the genome.
Intelligent machines increasingly outperform human experts, raising the question of when (and why) humans should remain ‘in the loop’ of decision-making. One common answer focuses on outcomes: ...relying on intuition and experience, humans are capable of identifying interpretive errors—sometimes disastrous errors—that elude machines. Though plausible today, this argument will wear thin as technology evolves.
In this Article, we seek out sturdier ground: a defense of human judgment that focuses on the normative integrity of decision-making. Specifically, we propose an account of democratic equality as ‘role-reversibility.’ In a democracy, those tasked with making decisions should be susceptible, reciprocally, to the impact of decisions; there ought to be a meaningful sense in which the participants’ roles in the decisional process could always be inverted. Role-reversibility infuses the act of judgment with a ‘there but for the grace of god’ dynamic and, in doing so, casts judgment as the result of self-rule.
After defending role-reversibility in concept, we show how it bears out in the paradigm case of criminal jury trials. Although it was not the historical impetus behind the jury trial—at least, not in any strong sense—we argue that role-reversibility explains some of the institution’s core features and stands among the best reasons for its preservation. Finally, for the sci-fi enthusiasts among us, role-reversibility offers a prescription as to when the legal system will be ready for robo-jurors and robo-judges: when it incorporates robo-defendants.
We derive an analytical model for the wave‐forced movement of single‐stem vegetation and test the model against observed vegetation motion in a natural salt marsh. Solutions for constant diameter and ...tapered stems are expanded using normal mode solutions to the Euler‐Bernoulli problem for a cantilevered beam. These solutions are compared with motion of water and of the sedge Schoenoplectus americanus observed (using synchronized current meters and video) in a shallow salt marsh (depth < 1 m). Consistent with theory, sedge motion led water motion, with the phase decreasing (from 90 to 0 degrees) with increasing wave frequency. After tuning of a single free parameter (Young's modulus), the theory successfully predicted the transfer function between measured water and stem motion. Formulae predicting frequency‐dependent wave dissipation by flexible vegetation are derived. For the moderately flexible stems observed, the model predicted total dissipation was about 30% of the dissipation for equivalent rigid stems.
Increased expression of Notch signaling pathway components is observed in Kaposi sarcoma (KS) but the mechanism underlying the manipulation of the canonical Notch pathway by the causative agent of ...KS, Kaposi sarcoma herpesvirus (KSHV), has not been fully elucidated. Here, we describe the mechanism through which KSHV directly modulates the expression of the Notch ligands JAG1 and DLL4 in lymphatic endothelial cells. Expression of KSHV-encoded vFLIP induces JAG1 through an NFkappaB-dependent mechanism, while vGPCR upregulates DLL4 through a mechanism dependent on ERK. Both vFLIP and vGPCR instigate functional Notch signalling through NOTCH4. Gene expression profiling showed that JAG1- or DLL4-stimulated signaling results in the suppression of genes associated with the cell cycle in adjacent lymphatic endothelial cells, indicating a role for Notch signaling in inducing cellular quiescence in these cells. Upregulation of JAG1 and DLL4 by KSHV could therefore alter the expression of cell cycle components in neighbouring uninfected cells during latent and lytic phases of viral infection, influencing cellular quiescence and plasticity. In addition, differences in signaling potency between these ligands suggest a possible complementary role for JAG1 and DLL4 in the context of KS.
Within a wave‐exposed mangrove forest, novel field observations are presented, comparing millimeter‐scale turbulent water velocity fluctuations with contemporaneous subtidal bed elevation changes. ...High‐resolution velocity and bed level measurements were collected from the unvegetated mudflat, at the mangrove forest fringe, and within the forest interior over multiple tidal cycles (flood–ebb) during a 2‐week period. Measurements demonstrated that the spatial variability in vegetation density is a control on sediment transport at sub‐meter scales. Scour around single and dense clusters of pneumatophores was predicted by a standard hydraulic engineering equation for wave‐induced scour around regular cylinders, when the cylinder diameter in the equations was replaced with the representative diameter of the dense pneumatophore clusters. Waves were dissipated as they propagated into the forest, but dissipation at infragravity periods (> 30 s) was observed to be less than dissipation at shorter periods (< 30 s), consistent with the predictions of a simple model. Cross‐wavelet analysis revealed that infragravity‐frequency fluctuations in the bed level were occasionally coherent with velocity, possibly indicating scour upstream of dense pneumatophore patches when infragravity waves reinforced tidal currents. Consequently, infragravity waves were a likely driver of sediment transport within the mangrove forest. Near‐bed turbulent kinetic energy, estimated from the turbulent dissipation rate, was also correlated with bed level changes. Specifically, within the mangrove forest and over the unvegetated mudflat, high‐energy events were associated with erosion or near‐zero bed level change, whereas low‐energy events were associated with accretion. In contrast, no single relationship between bed level changes and mean current velocity was applicable across both vegetated and unvegetated regions. These observations support the theory that sediment mobilization scales with turbulent energy, rather than mean velocity, a distinction that becomes important when vegetation controls the development of turbulence.
Infragravity waves are likely driver of sediment transport in mangroves across large (forest‐wide) scales. Mangrove roots generate near‐bed turbulence through drag forces, which affects sediment transport over small (< 1 m2) scales.
Metabolic changes within the cell and its niche affect cell fate and are involved in many diseases and disorders including cancer and viral infections. Kaposi's sarcoma-associated herpesvirus (KSHV) ...is the etiological agent of Kaposi's sarcoma (KS). KSHV latently infected cells express only a subset of viral genes, mainly located within the latency-associated region, among them 12 microRNAs. Notably, these miRNAs are responsible for inducing the Warburg effect in infected cells. Here we identify a novel mechanism enabling KSHV to manipulate the metabolic nature of the tumour microenvironment. We demonstrate that KSHV infected cells specifically transfer the virus-encoded microRNAs to surrounding cells via exosomes. This flow of genetic information results in a metabolic shift toward aerobic glycolysis in the surrounding non-infected cells. Importantly, this exosome-mediated metabolic reprogramming of neighbouring cells supports the growth of infected cells, thereby contributing to viral fitness. Finally, our data show that this miRNA transfer-based regulation of cell metabolism is a general mechanism used by other herpesviruses, such as EBV, as well as for the transfer of non-viral onco-miRs. This exosome-based crosstalk provides viruses with a mechanism for non-infectious transfer of genetic material without production of new viral particles, which might expose them to the immune system. We suggest that viruses and cancer cells use this mechanism to shape a specific metabolic niche that will contribute to their fitness.
Angus L. Macdonald Henderson, T. Stephen
Angus L. Macdonald,
c2007, 20070421, 2007, 2007-01-01, 2007-04-21, 20070101
eBook
This new work by T. Stephen Henderson is the first academic biography of Macdonald, whose life provides a framework for the study of Canada's pre- and post-war transformation, and a rare opportunity ...to compare the political history of the two periods.
MicroRNAs are small, non-coding RNAs that negatively regulate gene expression. It has been proposed that microRNAs could function in the regulation of innate immunity, but this has not been ...demonstrated for viral infection. Here we test this hypothesis using the human pathogenic virus Kaposi's sarcoma-associated herpesvirus (KSHV) and one of its putative natural cellular targets, primary lymphatic endothelial cells (LECs). We show that an early antiviral microRNA response (6 h post-infection) includes expression of microRNAs that enhance viral gene expression. In particular, the CREB-induced miR-132 microRNA is highly upregulated after infection and has a negative effect on the expression of interferon-stimulated genes, facilitating viral replication. We show a similar function for miR-132 during infection of monocytes with herpes simplex virus-1 (HSV-1) and human cytomegalovirus (HCMV). miR-132 regulates innate antiviral immunity by inhibiting expression of the p300 transcriptional co-activator. p300 is downregulated early after KSHV infection, and inhibition of miR-132 induction restores p300 expression. Furthermore, p300 regulates miR-132 levels, revealing a dynamic equilibrium between miR-132 and p300. By targeting p300, rather than a transcription factor or signalling protein, miR-132 has a broad role in the regulation of antiviral immunity.
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