Large subglacial lakes in East Antarctica at the onset of fast-flowing ice streams

Water plays a crucial role in ice-sheet stability and the onset of ice streams. Subglacial lake water moves between lakes and rapidly drains, causing catastrophic floods. The exact mechanisms by which subglacial lakes influence ice-sheet dynamics are unknown, however, and large subglacial lakes have not been closely associated with rapidly flowing ice streams. Here we use satellite imagery and ice-surface elevations to identify a region of subglacial lakes, similar in total area to Lake Vostok, at the onset region of the Recovery Glacier ice stream in East Antarctica and predicted by ice-sheet models. We define four lakes through extensive, flat, featureless regions of ice surface bounded by upstream troughs and downstream ridges. Using ice velocities determined using interferometric synthetic aperture radar (InSAR), we find the onset of rapid flow (moving at 20 to 30 m yr(-1)) of the tributaries to the Recovery Glacier ice stream in a 280-km-wide segment at the downslope margins of these four subglacial lakes. We conclude that the subglacial lakes initiate and maintain rapid ice flow through either active modification of the basal thermal regime of the ice sheet by lake accretion or through scouring bedrock channels in periodic drainage events. We suggest that the role of subglacial lakes needs to be considered in ice-sheet mass balance assessments.     

Sequential interactions with Sec23 control the direction of vesicle traffic

How the directionality of vesicle traffic is achieved remains an important unanswered question in cell biology. The Sec23p/Sec24p coat complex sorts the fusion machinery (SNAREs) into vesicles as they bud from the endoplasmic reticulum (ER). Vesicle tethering to the Golgi begins when the tethering factor TRAPPI binds to Sec23p. Where the coat is released and how this event relates to membrane fusion is unknown. Here we use a yeast transport assay to demonstrate that an ER-derived vesicle retains its coat until it reaches the Golgi. A Golgi-associated kinase, Hrr25p (CK1δ orthologue), then phosphorylates the Sec23p/Sec24p complex. Coat phosphorylation and dephosphorylation are needed for vesicle fusion and budding, respectively. Additionally, we show that Sec23p interacts in a sequential manner with different binding partners, including TRAPPI and Hrr25p, to ensure the directionality of ER-Golgi traffic and prevent the back-fusion of a COPII vesicle with the ER. These events are conserved in mammalian cells.     

Detection of prokaryotic mRNA signifies microbial viability and promotes immunity

Live vaccines have long been known to trigger far more vigorous immune responses than their killed counterparts. This has been attributed to the ability of live microorganisms to replicate and express specialized virulence factors that facilitate invasion and infection of their hosts. However, protective immunization can often be achieved with a single injection of live, but not dead, attenuated microorganisms stripped of their virulence factors. Pathogen-associated molecular patterns (PAMPs), which are detected by the immune system, are present in both live and killed vaccines, indicating that certain poorly characterized aspects of live microorganisms, not incorporated in dead vaccines, are particularly effective at inducing protective immunity. Here we show that the mammalian innate immune system can directly sense microbial viability through detection of a special class of viability-associated PAMPs (vita-PAMPs). We identify prokaryotic messenger RNA as a vita-PAMP present only in viable bacteria, the recognition of which elicits a unique innate response and a robust adaptive antibody response. Notably, the innate response evoked by viability and prokaryotic mRNA was thus far considered to be reserved for pathogenic bacteria, but we show that even non-pathogenic bacteria in sterile tissues can trigger similar responses, provided that they are alive. Thus, the immune system actively gauges the infectious risk by searching PAMPs for signatures of microbial life and thus infectivity. Detection of vita-PAMPs triggers a state of alert not warranted for dead bacteria. Vaccine formulations that incorporate vita-PAMPs could thus combine the superior protection of live vaccines with the safety of dead vaccines.     

Woody cover and hominin environments in the past 6 million years

The role of African savannahs in the evolution of early hominins has been debated for nearly a century. Resolution of this issue has been hindered by difficulty in quantifying the fraction of woody cover in the fossil record. Here we show that the fraction of woody cover in tropical ecosystems can be quantified using stable carbon isotopes in soils. Furthermore, we use fossil soils from hominin sites in the Awash and Omo-Turkana basins in eastern Africa to reconstruct the fraction of woody cover since the Late Miocene epoch (about 7 million years ago). (13)C/(12)C ratio data from 1,300 palaeosols at or adjacent to hominin sites dating to at least 6 million years ago show that woody cover was predominantly less than ～40% at most sites. These data point to the prevalence of open environments at the majority of hominin fossil sites in eastern Africa over the past 6 million years.     

RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.     

Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan-McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice.     

Human metabolic individuality in biomedical and pharmaceutical research

Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.     

The Early Development of the Algebraic Theory of Semigroups

In the history of mathematics, the algebraic theory of semigroups is a relative new-comer, with the theory proper developing only in the second half of the twentieth century. Before this, however, much groundwork was laid by researchers arriving at the study of semigroups from the directions of both group and ring theory. In this paper, we will trace some major strands in the early development of the algebraic theory of semigroups. We will begin with the aspects of the theory which were directly inspired by, and were analogous to, existing results for both groups and rings, before moving on to consider the first independent theorems on semigroups: theorems with no group or ring analogues. Dedicated to the memory of Professor W. Douglas Munn. This article was begun when the author was an EPSRC-funded research student at the University of York, UK, and completed at CAUL under FCT post-doctoral research grant SFRH/BPD/34698/2007.