Geochemical evidence for widespread euxinia in the later Cambrian ocean

Widespread anoxia in the ocean is frequently invoked as a primary driver of mass extinction as well as a long-term inhibitor of evolutionary radiation on early Earth. In recent biogeochemical studies it has been hypothesized that oxygen deficiency was widespread in subsurface water masses of later Cambrian oceans, possibly influencing evolutionary events during this time. Physical evidence of widespread anoxia in Cambrian oceans has remained elusive and thus its potential relationship to the palaeontological record remains largely unexplored. Here we present sulphur isotope records from six globally distributed stratigraphic sections of later Cambrian marine rocks (about 499 million years old). We find a positive sulphur isotope excursion in phase with the Steptoean Positive Carbon Isotope Excursion (SPICE), a large and rapid excursion in the marine carbon isotope record, which is thought to be indicative of a global carbon cycle perturbation. Numerical box modelling of the paired carbon sulphur isotope data indicates that these isotope shifts reflect transient increases in the burial of organic carbon and pyrite sulphur in sediments deposited under large-scale anoxic and sulphidic (euxinic) conditions. Independently, molybdenum abundances in a coeval black shale point convincingly to the transient spread of anoxia. These results identify the SPICE interval as the best characterized ocean anoxic event in the pre-Mesozoic ocean and an extreme example of oxygen deficiency in the later Cambrian ocean. Thus, a redox structure similar to those in Proterozoic oceans may have persisted or returned in the oceans of the early Phanerozoic eon. Indeed, the environmental challenges presented by widespread anoxia may have been a prevalent if not dominant influence on animal evolution in Cambrian oceans.     

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.     

Dynamics of human adipose lipid turnover in health and metabolic disease

Adipose tissue mass is determined by the storage and removal of triglycerides in adipocytes. Little is known, however, about adipose lipid turnover in humans in health and pathology. To study this in vivo, here we determined lipid age by measuring (14)C derived from above ground nuclear bomb tests in adipocyte lipids. We report that during the average ten-year lifespan of human adipocytes, triglycerides are renewed six times. Lipid age is independent of adipocyte size, is very stable across a wide range of adult ages and does not differ between genders. Adipocyte lipid turnover, however, is strongly related to conditions with disturbed lipid metabolism. In obesity, triglyceride removal rate (lipolysis followed by oxidation) is decreased and the amount of triglycerides stored each year is increased. In contrast, both lipid removal and storage rates are decreased in non-obese patients diagnosed with the most common hereditary form of dyslipidaemia, familial combined hyperlipidaemia. Lipid removal rate is positively correlated with the capacity of adipocytes to break down triglycerides, as assessed through lipolysis, and is inversely related to insulin resistance. Our data support a mechanism in which adipocyte lipid storage and removal have different roles in health and pathology. High storage but low triglyceride removal promotes fat tissue accumulation and obesity. Reduction of both triglyceride storage and removal decreases lipid shunting through adipose tissue and thus promotes dyslipidaemia. We identify adipocyte lipid turnover as a novel target for prevention and treatment of metabolic disease.     

Crystal structure of the β2 adrenergic receptor-Gs protein complex

G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The β(2) adrenergic receptor (β(2)AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomeric β(2)AR and nucleotide-free Gs heterotrimer. The principal interactions between the β(2)AR and Gs involve the amino- and carboxy-terminal α-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the β(2)AR include a 14 ? outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an α-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR.     

Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7

Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.     

Reconstructed changes in Arctic sea ice over the past 1,450 years

Arctic sea ice extent is now more than two million square kilometres less than it was in the late twentieth century, with important consequences for the climate, the ocean and traditional lifestyles in the Arctic. Although observations show a more or less continuous decline for the past four or five decades, there are few long-term records with which to assess natural sea ice variability. Until now, the question of whether or not current trends are potentially anomalous has therefore remained unanswerable. Here we use a network of high-resolution terrestrial proxies from the circum-Arctic region to reconstruct past extents of summer sea ice, and show that-although extensive uncertainties remain, especially before the sixteenth century-both the duration and magnitude of the current decline in sea ice seem to be unprecedented for the past 1,450 years. Enhanced advection of warm Atlantic water to the Arctic seems to be the main factor driving the decline of sea ice extent on multidecadal timescales, and may result from nonlinear feedbacks between sea ice and the Atlantic meridional overturning circulation. These results reinforce the assertion that sea ice is an active component of Arctic climate variability and that the recent decrease in summer Arctic sea ice is consistent with anthropogenically forced warming.     

Modular and predictable assembly of porous organic molecular crystals

Nanoporous molecular frameworks are important in applications such as separation, storage and catalysis. Empirical rules exist for their assembly but it is still challenging to place and segregate functionality in three-dimensional porous solids in a predictable way. Indeed, recent studies of mixed crystalline frameworks suggest a preference for the statistical distribution of functionalities throughout the pores rather than, for example, the functional group localization found in the reactive sites of enzymes. This is a potential limitation for 'one-pot' chemical syntheses of porous frameworks from simple starting materials. An alternative strategy is to prepare porous solids from synthetically preorganized molecular pores. In principle, functional organic pore modules could be covalently prefabricated and then assembled to produce materials with specific properties. However, this vision of mix-and-match assembly is far from being realized, not least because of the challenge in reliably predicting three-dimensional structures for molecular crystals, which lack the strong directional bonding found in networks. Here we show that highly porous crystalline solids can be produced by mixing different organic cage modules that self-assemble by means of chiral recognition. The structures of the resulting materials can be predicted computationally, allowing in silico materials design strategies. The constituent pore modules are synthesized in high yields on gram scales in a one-step reaction. Assembly of the porous co-crystals is as simple as combining the modules in solution and removing the solvent. In some cases, the chiral recognition between modules can be exploited to produce porous organic nanoparticles. We show that the method is valid for four different cage modules and can in principle be generalized in a computationally predictable manner based on a lock-and-key assembly between modules.     

Human nutrition, the gut microbiome and the immune system

Marked changes in socio-economic status, cultural traditions, population growth and agriculture are affecting diets worldwide. Understanding how our diet and nutritional status influence the composition and dynamic operations of our gut microbial communities, and the innate and adaptive arms of our immune system, represents an area of scientific need, opportunity and challenge. The insights gleaned should help to address several pressing global health problems.