New correction procedures for the fast field program which extend its range

A fast field program (FFP) algorithm was developed based on the method of Lee et al., for the prediction of sound pressure level from low frequency, high intensity sources. In order to permit accurate predictions at distances greater than 2 km, new correction procedures have had to be included in the algorithm. Certain functions, whose Hankel transforms can be determined analytically, are subtracted from the depth dependent Green's function. The distance response is then obtained as the sum of these transforms and the Fast Fourier Transformation (FFT) of the residual k dependent function. One procedure, which permits the elimination of most complex exponentials, has allowed significant changes in the structure of the FFP algorithm, which has resulted in a substantial reduction in computation time

Unfinished Business: a Review of the Implementation of the Provisions of United Nations General Assembly Resolutions 61/105 and 64/72, Related to the Management of Bottom Fisheries in Areas Beyond National Jurisdiction

In 2006 the General Assembly adopted resolution 61/105, based on a compromise proposal offered by deep-sea fishing nations, which committed States and regional fisheries management organisations [RFMOs] to take specific measures to protect vulnerable marine ecosystems [VMEs] from the adverse impacts of bottom fisheries in the high seas and to ensure the longterm sustainability of deep-sea fish stocks. These measures included conducting impact assessments to determine whether significant adverse impacts[SAIs] to VMEs would occur, managing fisheries to prevent SAIs on VMEs, and closing areas of the high seas to bottom fishing where VMEs are known or likely to occur, unless regulations are in place to prevent SAIs and to manage sustainably deep-sea fish stocks. Based on a review in 2009 of the actions taken by States and RFMOS, the UNGA adoptedresolution 64/72 that reaffirmed resolution 61/105 and strengthened the call for action through committing States, inter alia, to ensure that vessels do not engage in bottom fishing until impact assessments have been carried out and to not authorise bottom fishing activities until the measures in resolutions 64/72 and 61/105 have been adopted andimplemented

The tarantula toxin GxTx detains K+ channel gating charges in their resting conformation.

Allosteric ligands modulate protein activity by altering the energy landscape of conformational space in ligand-protein complexes. Here we investigate how ligand binding to a K+ channel's voltage sensor allosterically modulates opening of its K+-conductive pore. The tarantula venom peptide guangxitoxin-1E (GxTx) binds to the voltage sensors of the rat voltage-gated K+ (Kv) channel Kv2.1 and acts as a partial inverse agonist. When bound to GxTx, Kv2.1 activates more slowly, deactivates more rapidly, and requires more positive voltage to reach the same K+-conductance as the unbound channel. Further, activation kinetics are more sigmoidal, indicating that multiple conformational changes coupled to opening are modulated. Single-channel current amplitudes reveal that each channel opens to full conductance when GxTx is bound. Inhibition of Kv2.1 channels by GxTx results from decreased open probability due to increased occurrence of long-lived closed states; the time constant of the final pore opening step itself is not impacted by GxTx. When intracellular potential is less than 0 mV, GxTx traps the gating charges on Kv2.1's voltage sensors in their most intracellular position. Gating charges translocate at positive voltages, however, indicating that GxTx stabilizes the most intracellular conformation of the voltage sensors (their resting conformation). Kinetic modeling suggests a modulatory mechanism: GxTx reduces the probability of voltage sensors activating, giving the pore opening step less frequent opportunities to occur. This mechanism results in K+-conductance activation kinetics that are voltage-dependent, even if pore opening (the rate-limiting step) has no inherent voltage dependence. We conclude that GxTx stabilizes voltage sensors in a resting conformation, and inhibits K+ currents by limiting opportunities for the channel pore to open, but has little, if any, direct effect on the microscopic kinetics of pore opening. The impact of GxTx on channel gating suggests that Kv2.1's pore opening step does not involve movement of its voltage sensors

Rotavirus infections and climate variability in Dhaka, Bangladesh: a time-series analysis.

Attempts to explain the clear seasonality of rotavirus infections have been made by relating disease incidence to climate factors; however, few studies have disentangled the effects of weather from other factors that might cause seasonality. We investigated the relationships between hospital visits for rotavirus diarrhoea and temperature, humidity and river level, in Dhaka, Bangladesh, using time-series analysis adjusting for other confounding seasonal factors. There was strong evidence for an increase in rotavirus diarrhoea at high temperatures, by 40.2% for each 1 degrees C increase above a threshold (29 degrees C). Relative humidity had a linear inverse relationship with the number of cases of rotavirus diarrhoea. River level, above a threshold (4.8 m), was associated with an increase in cases of rotavirus diarrhoea, by 5.5% per 10-cm river-level rise. Our findings provide evidence that factors associated with high temperature, low humidity and high river-level increase the incidence of rotavirus diarrhoea in Dhaka

Movers and shakers: Granular damping in microgravity

The response of an oscillating granular damper to an initial perturbation is studied using experiments performed in microgravity and granular dynamics mulations. High-speed video and image processing techniques are used to extract experimental data. An inelastic hard sphere model is developed to perform simulations and the results are in excellent agreement with the experiments. The granular damper behaves like a frictional damper and a linear decay of the amplitude is bserved. This is true even for the simulation model, where friction forces are absent. A simple expression is developed which predicts the optimal damping conditions for a given amplitude and is independent of the oscillation frequency and particle inelasticities.Comment: 9 pages, 9 figure

Regulating repression : roles for the Sir4 N-terminus in linker DNA protection and stabilization of epigenetic states

The Gasser laboratory is supported by the Novartis Research Foundation and the EU training network Nucleosome 4D. SK was supported by an EMBO long-term fellowship, a Schrodinger fellowship from the FWF, and the Swiss SystemsX.ch initiative/C-CINA; HCF by an EMBO long-term fellowship.Silent information regulator proteins Sir2, Sir3, and Sir4 form a heterotrimeric complex that represses transcription at subtelomeric regions and homothallic mating type (HM) loci in budding yeast. We have performed a detailed biochemical and genetic analysis of the largest Sir protein, Sir4. The N-terminal half of Sir4 is dispensable for SIR-mediated repression of HM loci in vivo, except in strains that lack Yku70 or have weak silencer elements. For HM silencing in these cells, the C-terminal domain (Sir4C, residues 747-1,358) must be complemented with an N-terminal domain (Sir4N; residues 1-270), expressed either independently or as a fusion with Sir4C. Nonetheless, recombinant Sir4C can form a complex with Sir2 and Sir3 in vitro, is catalytically active, and has sedimentation properties similar to a full-length Sir4-containing SIR complex. Sir4C-containing SIR complexes bind nucleosomal arrays and protect linker DNA from nucleolytic digestion, but less effectively than wild-type SIR complexes. Consistently, full-length Sir4 is required for the complete repression of subtelomeric genes. Supporting the notion that the Sir4 N-terminus is a regulatory domain, we find it extensively phosphorylated on cyclin-dependent kinase consensus sites, some being hyperphosphorylated during mitosis. Mutation of two major phosphoacceptor sites (S63 and S84) derepresses natural subtelomeric genes when combined with a serendipitous mutation (P2A), which alone can enhance the stability of either the repressed or active state. The triple mutation confers resistance to rapamycin-induced stress and a loss of subtelomeric repression. We conclude that the Sir4 N-terminus plays two roles in SIR-mediated silencing: it contributes to epigenetic repression by stabilizing the SIR-mediated protection of linker DNA; and, as a target of phosphorylation, it can destabilize silencing in a regulated manner.Publisher PDFPeer reviewe

MR Elastography-Based Assessment of Matrix Remodeling at Lesion Sites Associated With Clinical Severity in a Model of Multiple Sclerosis

Magnetic resonance imaging (MRI) with gadolinium based contrast agents (GBCA) is routinely used in the clinic to visualize lesions in multiple sclerosis (MS). Although GBCA reveal endothelial permeability, they fail to expose other aspects of lesion formation such as the magnitude of inflammation or tissue changes occurring at sites of blood-brain barrier (BBB) disruption. Moreover, evidence pointing to potential side effects of GBCA has been increasing. Thus, there is an urgent need to develop GBCA-independent imaging tools to monitor pathology in MS. Using MR-elastography (MRE), we previously demonstrated in both MS and the animal model experimental autoimmune encephalomyelitis (EAE) that inflammation was associated with a reduction of brain stiffness. Now, using the relapsing-remitting EAE model, we show that the cerebellum-a region with predominant inflammation in this model-is especially prone to loss of stiffness. We also demonstrate that, contrary to GBCA-MRI, reduction of brain stiffness correlates with clinical disability and is associated with enhanced expression of the extracellular matrix protein fibronectin (FN). Further, we show that FN is largely expressed by activated astrocytes at acute lesions, and reflects the magnitude of tissue remodeling at sites of BBB breakdown. Therefore, MRE could emerge as a safe tool suitable to monitor disease activity in MS

Gender agreement on adverbs in Spanish

In this article we explore the exceptional gender agreement of the Spanish adverb mucho (‘much’), when it modifies comparative adjectives inside DPs that contain a particular type of noun (as in muchafem mejor intenciónfem, ‘much better intention’). This phenomenon, which we describe in detail, raises crucial questions both about the mechanisms of agreement and about the nature of gender in a language such as Spanish. We will argue on the basis of our analysis that agreement is not semantically motivated, but blindly triggered by certain formal configurations. We will also argue that –at least in languages such as Spanish– gender information is scattered in two different positions inside the DP.Peer reviewe

Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

Drugs do not act solely by canonical ligand–receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein–ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogues. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure–activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT’s membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported

The Quantum Mellin transform

We uncover a new type of unitary operation for quantum mechanics on the half-line which yields a transformation to ``Hyperbolic phase space''. We show that this new unitary change of basis from the position x on the half line to the Hyperbolic momentum $p_\eta$, transforms the wavefunction via a Mellin transform on to the critial line $s=1/2-ip_\eta$. We utilise this new transform to find quantum wavefunctions whose Hyperbolic momentum representation approximate a class of higher transcendental functions, and in particular, approximate the Riemann Zeta function. We finally give possible physical realisations to perform an indirect measurement of the Hyperbolic momentum of a quantum system on the half-line.Comment: 23 pages, 6 Figure