Consequences of climate change on the tree of life in Europe

Many species are projected to become vulnerable to twenty-first-century climate changes, with consequent effects on the tree of life. If losses were not randomly distributed across the tree of life, climate change could lead to a disproportionate loss of evolutionary history. Here we estimate the consequences of climate change on the phylogenetic diversities of plant, bird and mammal assemblages across Europe. Using a consensus across ensembles of forecasts for 2020, 2050 and 2080 and high-resolution phylogenetic trees, we show that species vulnerability to climate change clusters weakly across phylogenies. Such phylogenetic signal in species vulnerabilities does not lead to higher loss of evolutionary history than expected with a model of random extinctions. This is because vulnerable species have neither fewer nor closer relatives than the remaining clades. Reductions in phylogenetic diversity will be greater in southern Europe, and gains are expected in regions of high latitude or altitude. However, losses will not be offset by gains and the tree of life faces a trend towards homogenization across the continent.     

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.     

Structure of the human histamine H1 receptor complex with doxepin

The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H(1) receptor (H(1)R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H(1)R complex with doxepin, a first-generation H(1)R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp?428(6.48), a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H(1)R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys?191(5.39) and/or Lys?179(ECL2), both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H(1)R antagonist specificity against H(1)R.     

Verbal and non-verbal intelligence changes in the teenage brain

Intelligence quotient (IQ) is a standardized measure of human intellectual capacity that takes into account a wide range of cognitive skills. IQ is generally considered to be stable across the lifespan, with scores at one time point used to predict educational achievement and employment prospects in later years. Neuroimaging allows us to test whether unexpected longitudinal fluctuations in measured IQ are related to brain development. Here we show that verbal and non-verbal IQ can rise or fall in the teenage years, with these changes in performance validated by their close correlation with changes in local brain structure. A combination of structural and functional imaging showed that verbal IQ changed with grey matter in a region that was activated by speech, whereas non-verbal IQ changed with grey matter in a region that was activated by finger movements. By using longitudinal assessments of the same individuals, we obviated the many sources of variation in brain structure that confound cross-sectional studies. This allowed us to dissociate neural markers for the two types of IQ and to show that general verbal and non-verbal abilities are closely linked to the sensorimotor skills involved in learning. More generally, our results emphasize the possibility that an individual's intellectual capacity relative to their peers can decrease or increase in the teenage years. This would be encouraging to those whose intellectual potential may improve, and would be a warning that early achievers may not maintain their potential.     

A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours

Angiogenesis is critical during tumour initiation and malignant progression. Different strategies aimed at blocking vascular endothelial growth factor (VEGF) and its receptors have been developed to inhibit angiogenesis in cancer patients. It has become increasingly clear that in addition to its effect on angiogenesis, other mechanisms including a direct effect of VEGF on tumour cells may account for the efficiency of VEGF-blockade therapies. Cancer stem cells (CSCs) have been described in various cancers including squamous tumours of the skin. Here we use a mouse model of skin tumours to investigate the impact of the vascular niche and VEGF signalling on controlling the stemness (the ability to self renew and differentiate) of squamous skin tumours during the early stages of tumour progression. We show that CSCs of skin papillomas are localized in a perivascular niche, in the immediate vicinity of endothelial cells. Furthermore, blocking VEGFR2 caused tumour regression not only by decreasing the microvascular density, but also by reducing CSC pool size and impairing CSC renewal properties. Conditional deletion of Vegfa in tumour epithelial cells caused tumours to regress, whereas VEGF overexpression by tumour epithelial cells accelerated tumour growth. In addition to its well-known effect on angiogenesis, VEGF affected skin tumour growth by promoting cancer stemness and symmetric CSC division, leading to CSC expansion. Moreover, deletion of neuropilin-1 (Nrp1), a VEGF co-receptor expressed in cutaneous CSCs, blocked VEGF's ability to promote cancer stemness and renewal. Our results identify a dual role for tumour-cell-derived VEGF in promoting cancer stemness: by stimulating angiogenesis in a paracrine manner, VEGF creates a perivascular niche for CSCs, and by directly affecting CSCs through Nrp1 in an autocrine loop, VEGF stimulates cancer stemness and renewal. Finally, deletion of Nrp1 in normal epidermis prevents skin tumour initiation. These results may have important implications for the prevention and treatment of skin cancers.     

A tension-induced mechanotransduction pathway promotes epithelial morphogenesis

Mechanotransduction refers to the transformation of physical forces into chemical signals. It generally involves stretch-sensitive channels or conformational change of cytoskeleton-associated proteins. Mechanotransduction is crucial for the physiology of several organs and for cell migration. The extent to which mechanical inputs contribute to development, and how they do this, remains poorly defined. Here we show that a mechanotransduction pathway operates between the body-wall muscles of Caenorhabditis elegans and the epidermis. This pathway involves, in addition to a Rac GTPase, three signalling proteins found at the hemidesmosome: p21-activated kinase (PAK-1), the adaptor GIT-1 and its partner PIX-1. The phosphorylation of intermediate filaments is one output of this pathway. Tension exerted by adjacent muscles or externally exerted mechanical pressure maintains GIT-1 at hemidesmosomes and stimulates PAK-1 activity through PIX-1 and Rac. This pathway promotes the maturation of a hemidesmosome into a junction that can resist mechanical stress and contributes to coordinating the morphogenesis of epidermal and muscle tissues. Our findings suggest that the C. elegans hemidesmosome is not only an attachment structure, but also a mechanosensor that responds to tension by triggering signalling processes. We suggest that similar pathways could promote epithelial morphogenesis or wound healing in other organisms in which epithelial cells adhere to tension-generating contractile cells.     

Spin-orbit-coupled Bose-Einstein condensates

Spin-orbit (SO) coupling--the interaction between a quantum particle's spin and its momentum--is ubiquitous in physical systems. In condensed matter systems, SO coupling is crucial for the spin-Hall effect and topological insulators; it contributes to the electronic properties of materials such as GaAs, and is important for spintronic devices. Quantum many-body systems of ultracold atoms can be precisely controlled experimentally, and would therefore seem to provide an ideal platform on which to study SO coupling. Although an atom's intrinsic SO coupling affects its electronic structure, it does not lead to coupling between the spin and the centre-of-mass motion of the atom. Here, we engineer SO coupling (with equal Rashba and Dresselhaus strengths) in a neutral atomic Bose-Einstein condensate by dressing two atomic spin states with a pair of lasers. Such coupling has not been realized previously for ultracold atomic gases, or indeed any bosonic system. Furthermore, in the presence of the laser coupling, the interactions between the two dressed atomic spin states are modified, driving a quantum phase transition from a spatially spin-mixed state (lasers off) to a phase-separated state (above a critical laser intensity). We develop a many-body theory that provides quantitative agreement with the observed location of the transition. The engineered SO coupling--equally applicable for bosons and fermions--sets the stage for the realization of topological insulators in fermionic neutral atom systems.     

The unusual minimum of sunspot cycle 23 caused by meridional plasma flow variations

Direct observations over the past four centuries show that the number of sunspots observed on the Sun's surface varies periodically, going through successive maxima and minima. Following sunspot cycle 23, the Sun went into a prolonged minimum characterized by a very weak polar magnetic field and an unusually large number of days without sunspots. Sunspots are strongly magnetized regions generated by a dynamo mechanism that recreates the solar polar field mediated through plasma flows. Here we report results from kinematic dynamo simulations which demonstrate that a fast meridional flow in the first half of a cycle, followed by a slower flow in the second half, reproduces both characteristics of the minimum of sunspot cycle 23. Our model predicts that, in general, very deep minima are associated with weak polar fields. Sunspots govern the solar radiative energy and radio flux, and, in conjunction with the polar field, modulate the solar wind, the heliospheric open flux and, consequently, the cosmic ray flux at Earth.