Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk

To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 × 10(-9)) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 × 10(-15)). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 × 10(-7)). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights.     

Genome-wide association analysis identifies susceptibility loci for migraine without aura

Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10(-4); combined P = 7.06 × 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 × 10(-4); combined P = 1.17 × 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10(-8) and P = 0.02; combined P = 3.86 × 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.     

T cells become licensed in the lung to enter the central nervous system

The blood–brain barrier (BBB) and the environment of the central nervous system (CNS) guard the nervous tissue from peripheral immune cells. In the autoimmune disease multiple sclerosis, myelin-reactive T-cell blasts are thought to transgress the BBB and create a pro-inflammatory environment in the CNS, thereby making possible a second autoimmune attack that starts from the leptomeningeal vessels and progresses into the parenchyma. Using a Lewis rat model of experimental autoimmune encephalomyelitis, we show here that contrary to the expectations of this concept, T-cell blasts do not efficiently enter the CNS and are not required to prepare the BBB for immune-cell recruitment. Instead, intravenously transferred T-cell blasts gain the capacity to enter the CNS after residing transiently within the lung tissues. Inside the lung tissues, they move along and within the airways to bronchus-associated lymphoid tissues and lung-draining mediastinal lymph nodes before they enter the blood circulation from where they reach the CNS. Effector T cells transferred directly into the airways showed a similar migratory pattern and retained their full pathogenicity. On their way the T cells fundamentally reprogrammed their gene-expression profile, characterized by downregulation of their activation program and upregulation of cellular locomotion molecules together with chemokine and adhesion receptors. The adhesion receptors include ninjurin 1, which participates in T-cell intravascular crawling on cerebral blood vessels. We detected that the lung constitutes a niche not only for activated T cells but also for resting myelin-reactive memory T cells. After local stimulation in the lung, these cells strongly proliferate and, after assuming migratory properties, enter the CNS and induce paralytic disease. The lung could therefore contribute to the activation of potentially autoaggressive T cells and their transition to a migratory mode as a prerequisite to entering their target tissues and inducing autoimmune disease.     

Twenty-first-century warming of a large Antarctic ice-shelf cavity by a redirected coastal current

The Antarctic ice sheet loses mass at its fringes bordering the Southern Ocean. At this boundary, warm circumpolar water can override the continental slope front, reaching the grounding line through submarine glacial troughs and causing high rates of melting at the deep ice-shelf bases. The interplay between ocean currents and continental bathymetry is therefore likely to influence future rates of ice-mass loss. Here we show that a redirection of the coastal current into the Filchner Trough and underneath the Filchner-Ronne Ice Shelf during the second half of the twenty-first century would lead to increased movement of warm waters into the deep southern ice-shelf cavity. Water temperatures in the cavity would increase by more than 2 degrees Celsius and boost average basal melting from 0.2 metres, or 82 billion tonnes, per year to almost 4 metres, or 1,600 billion tonnes, per year. Our results, which are based on the output of a coupled ice-ocean model forced by a range of atmospheric outputs from the HadCM3 climate model, suggest that the changes would be caused primarily by an increase in ocean surface stress in the southeastern Weddell Sea due to thinning of the formerly consolidated sea-ice cover. The projected ice loss at the base of the Filchner-Ronne Ice Shelf represents 80 per cent of the present Antarctic surface mass balance. Thus, the quantification of basal mass loss under changing climate conditions is important for projections regarding the dynamics of Antarctic ice streams and ice shelves, and global sea level rise.     

Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH

The control by Na+/H+ antiporters of sodium/proton concentration and cell volume is crucial for the viability of all cells. Adaptation to high salinity and/or extreme pH in plants and bacteria or in human heart muscles requires the action of Na+/H+ antiporters. Their activity is tightly controlled by pH. Here we present the crystal structure of pH-downregulated NhaA, the main antiporter of Escherichia coli and many enterobacteria. A negatively charged ion funnel opens to the cytoplasm and ends in the middle of the membrane at the putative ion-binding site. There, a unique assembly of two pairs of short helices connected by crossed, extended chains creates a balanced electrostatic environment. We propose that the binding of charged substrates causes an electric imbalance, inducing movements, that permit a rapid alternating-access mechanism. This ion-exchange machinery is regulated by a conformational change elicited by a pH signal perceived at the entry to the cytoplasmic funnel.     

Implementation of the Deutsch-Jozsa algorithm on an ion-trap quantum computer

Determining classically whether a coin is fair (head on one side, tail on the other) or fake (heads or tails on both sides) requires an examination of each side. However, the analogous quantum procedure (the Deutsch-Jozsa algorithm) requires just one examination step. The Deutsch-Jozsa algorithm has been realized experimentally using bulk nuclear magnetic resonance techniques, employing nuclear spins as quantum bits (qubits). In contrast, the ion trap processor utilises motional and electronic quantum states of individual atoms as qubits, and in principle is easier to scale to many qubits. Experimental advances in the latter area include the realization of a two-qubit quantum gate, the entanglement of four ions, quantum state engineering and entanglement-enhanced phase estimation. Here we exploit techniques developed for nuclear magnetic resonance to implement the Deutsch-Jozsa algorithm on an ion-trap quantum processor, using as qubits the electronic and motional states of a single calcium ion. Our ion-based implementation of a full quantum algorithm serves to demonstrate experimental procedures with the quality and precision required for complex computations, confirming the potential of trapped ions for quantum computation.