Comprehensive Analysis of Market Conditions in the Foreign Exchange Market: Fluctuation Scaling and Variance-Covariance Matrix

We investigate quotation and transaction activities in the foreign exchange market for every week during the period of June 2007 to December 2010. A scaling relationship between the mean values of number of quotations (or number of transactions) for various currency pairs and the corresponding standard deviations holds for a majority of the weeks. However, the scaling breaks in some time intervals, which is related to the emergence of market shocks. There is a monotonous relationship between values of scaling indices and global averages of currency pair cross-correlations when both quantities are observed for various window lengths $\Delta t$.Comment: 13 pages, 10 figure

Fluctuation-Driven Neural Dynamics Reproduce Drosophila Locomotor Patterns.

The neural mechanisms determining the timing of even simple actions, such as when to walk or rest, are largely mysterious. One intriguing, but untested, hypothesis posits a role for ongoing activity fluctuations in neurons of central action selection circuits that drive animal behavior from moment to moment. To examine how fluctuating activity can contribute to action timing, we paired high-resolution measurements of freely walking Drosophila melanogaster with data-driven neural network modeling and dynamical systems analysis. We generated fluctuation-driven network models whose outputs-locomotor bouts-matched those measured from sensory-deprived Drosophila. From these models, we identified those that could also reproduce a second, unrelated dataset: the complex time-course of odor-evoked walking for genetically diverse Drosophila strains. Dynamical models that best reproduced both Drosophila basal and odor-evoked locomotor patterns exhibited specific characteristics. First, ongoing fluctuations were required. In a stochastic resonance-like manner, these fluctuations allowed neural activity to escape stable equilibria and to exceed a threshold for locomotion. Second, odor-induced shifts of equilibria in these models caused a depression in locomotor frequency following olfactory stimulation. Our models predict that activity fluctuations in action selection circuits cause behavioral output to more closely match sensory drive and may therefore enhance navigation in complex sensory environments. Together these data reveal how simple neural dynamics, when coupled with activity fluctuations, can give rise to complex patterns of animal behavior

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Selective Affimers Recognise the BCL‐2 Family Proteins BCL‐xL and MCL‐1 through Noncanonical Structural Motifs

The BCL‐2 family is a challenging group of proteins to target selectively due to sequence and structural homologies across the family. Selective ligands for the BCL‐2 family regulators of apoptosis are useful as probes to understand cell biology and apoptotic signalling pathways, and as starting points for inhibitor design. We have used phage display to isolate Affimer reagents (non‐antibody‐binding proteins based on a conserved scaffold) to identify ligands for MCL‐1, BCL‐xL, BCL‐2, BAK and BAX, then used multiple biophysical characterisation methods to probe the interactions. We established that purified Affimers elicit selective recognition of their target BCL‐2 protein. For anti‐apoptotic targets BCL‐xL and MCL‐1, competitive inhibition of their canonical protein‐protein interactions is demonstrated. Co‐crystal structures reveal an unprecedented mode of molecular recognition; where a BH3 helix is normally bound, flexible loops from the Affimer dock into the BH3 binding cleft. Moreover, the Affimers induce a change in the target proteins towards a desirable drug‐bound‐like conformation. These proof‐of‐concept studies indicate that Affimers could be used as alternative templates to inspire the design of selective BCL‐2 family modulators and more generally other protein‐protein interaction inhibitors

Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis

BACKGROUND: Amyloid is insoluble aggregated proteins deposited in the extra cellular space. About 25 different proteins are known to form amyloid in vivo and are associated with severe diseases such as Alzheimer's disease, prion diseases and type-2 diabetes. Light chain (AL) -amyloidosis is unique among amyloid diseases in that the fibril protein, a monoclonal immunoglobulin light chain, varies between individuals and that no two AL-proteins with identical primary structures have been described to date. The variability in tissue distribution of amyloid deposits is considerably larger in systemic AL-amyloidosis than in any other form of amyloidosis. The reason for this variation is believed to be based on the differences in properties of the amyloidogenic immunoglobulin light chain. However, there is presently no known relationship between the structure of an AL-protein and tissue distribution. METHODOLOGY/PRINCIPAL FINDINGS: We compared the pattern of amyloid deposition in four individuals with amyloid protein derived from variable light chain gene O18-O8, the source of a high proportion of amyloidogenic light chains, and in whom all or most of the fibril protein had been determined by amino acid sequencing. In spite of great similarities between the structures of the proteins, there was a pronounced variability in deposition pattern. We also compared the tissue distribution in these four individuals with that of four other patients with AL-amyloid derived from the L2-L16 gene. Although the interindividual variations were pronounced, liver and kidney involvement was much more evident in the latter four. CONCLUSIONS/SIGNIFICANCE: We conclude that although the use of a specific gene influences the tissue distribution of amyloid, each light chain exhibits one or more determinants of organ-specificity, which originate from somatic mutations and post-translational modifications. Eventual identification of such determinants could lead to improved treatment of patients with AL amyloidosis

Myeloma cells suppress osteoblasts through sclerostin secretion

Wingless-type (Wnt) signaling through the secretion of Wnt inhibitors Dickkopf1, soluble frizzled-related protein-2 and -3 has a key role in the decreased osteoblast (OB) activity associated with multiple myeloma (MM) bone disease. We provide evidence that another Wnt antagonist, sclerostin, an osteocyte-expressed negative regulator of bone formation, is expressed by myeloma cells, that is, human myeloma cell lines (HMCLs) and plasma cells (CD138+ cells) obtained from the bone marrow (BM) of a large number of MM patients with bone disease. We demonstrated that BM stromal cells (BMSCs), differentiated into OBs and co-cultured with HMCLs showed, compared with BMSCs alone, reduced expression of major osteoblastic-specific proteins, decreased mineralized nodule formation and attenuated the expression of members of the activator protein 1 transcription factor family (Fra-1, Fra-2 and Jun-D). Moreover, in the same co-culture system, the addition of neutralizing anti-sclerostin antibodies restored OB functions by inducing nuclear accumulation of β-catenin. We further demonstrated that the upregulation of receptor activator of nuclear factor κ-B ligand and the downregulation of osteoprotegerin in OBs were also sclerostin mediated. Our data indicated that sclerostin secretion by myeloma cells contribute to the suppression of bone formation in the osteolytic bone disease associated to MM

Human Probing Behavior of Aedes aegypti when Infected with a Life-Shortening Strain of Wolbachia

Mosquitoes transmit diseases when they are actively searching for a source of blood. This so called probing behavior comprises the “searching” time, the beginning of the feeding process until the first sign of blood can be seen within the insect body. The manipulation of this behavior can have important consequences for the mosquito's ability to transmit pathogens, such as dengue virus or Plasmodium. In this study we examined the probing behavior of the main vector of dengue viruses, Aedes aegypti, when infected with an intracellular bacterium, Wolbachia pipientis. This bacterium alters the probing behavior of older mosquitoes such that they take longer to find a feeding site and longer to imbibe blood, which may make them more susceptible to human defense responses. The bacterium appears to reduce mosquito feeding success by preventing the mosquito from successfully inserting its stylet into human skin. The old age onset of reduced mosquito feeding success due to Wolbachia could selectively promote a reduction in dengue transmission

Comparison of Three Commercially Available Dengue NS1 Antigen Capture Assays for Acute Diagnosis of Dengue in Brazil

Dengue is the one of the most prevalent arthropod-borne viral diseases in tropical regions of the world. Manifestations may vary from asymptomatic to potentially fatal complications. Laboratorial diagnosis is essential to diagnose dengue and differentiate it from other diseases. Dengue virus non-structural protein 1 (NS1) may be used as a marker of acute dengue virus infection. Our results, based in the comparison of three NS1 antigen capture assays available, have shown that this approach is reliable for the early diagnosis of dengue infections, especially in the first four days after the onset of the symptoms. A lower sensitivity was observed in DENV-3 cases. Serum positive by virus isolation were more often detected than those positive by RT-PCR by all three assays. Only the Platelia™ NS1 test showed a higher sensitivity in confirming primary infections than secondary ones. In conclusion, NS1 antigen capture commercial kits are useful for diagnosis of acute primary and secondary dengue infections and, in endemic countries where secondary infections are expected to occur, may be used in combination with MAC-ELISA to increase the overall sensitivity of both tests

Type and extent of trans-disciplinary co-operation to improve food security, health and household environment in low and middle income countries: systematic review

Acknowledgements: We are grateful to Dr Steve Turner and Dr Adam Price for their insightful comments that improved the manuscript. We would like to thank Heather Clark and Bimbola Kalejaiye for their help in data extraction. We are also grateful to Melanie Bickerton and Dr Amudha Poobalan for their systematic review advice.Peer reviewedPublisher PD