E1E_1-degeneration and d′d′′d'd''-lemma

For a double complex $(A, d', d'')$, we show that if it satisfies the $d'd''$-lemma and the spectral sequence $\{E^{p, q}_r\}$ induced by $A$ does not degenerate at $E_0$, then it degenerates at $E_1$. We apply this result to prove the degeneration at $E_1$ of a Hodge-de Rham spectral sequence on compact bi-generalized Hermitian manifolds that satisfy a version of $d'd''$-lemma

Molecular Dynamics Simulations of Scorpion Toxin Recognition by the Ca²⁺-Activated Potassium Channel KCa3.1

The Ca²⁺-activated channel of intermediate-conductance (KCa3.1) is a target for antisickling and immunosuppressant agents. Many small peptides isolated from animal venoms inhibit KCa3.1 with nanomolar affinities and are promising drug scaffolds. Although the inhibitory effect of peptide toxins on KCa3.1 has been examined extensively, the structural basis of toxin-channel recognition has not been understood in detail. Here, the binding modes of two selected scorpion toxins, charybdotoxin (ChTx) and OSK1, to human KCa3.1 are examined in atomic detail using molecular dynamics (MD) simulations. Employing a homology model of KCa3.1, we first determine conduction properties of the channel using Brownian dynamics and ascertain that the simulated results are in accord with experiment. The model structures of ChTx-KCa3.1 and OSK1-KCa3.1 complexes are then constructed using MD simulations biased with distance restraints. The ChTx-KCa3.1 complex predicted from biased MD is consistent with the crystal structure of ChTx bound to a voltage-gated K(+) channel. The dissociation constants (Kd) for the binding of both ChTx and OSK1 to KCa3.1 determined experimentally are reproduced within fivefold using potential of mean force calculations. Making use of the knowledge we gained by studying the ChTx-KCa3.1 complex, we attempt to enhance the binding affinity of the toxin by carrying out a theoretical mutagenesis. A mutant toxin, in which the positions of two amino acid residues are interchanged, exhibits a 35-fold lower Kd value for KCa3.1 than that of the wild-type. This study provides insight into the key molecular determinants for the high-affinity binding of peptide toxins to KCa3.1, and demonstrates the power of computational methods in the design of novel toxins.This work was supported by the National Health and Medical Research Council of Australia and The Medical Advances Without Animals Trust (MAWA)

Structural Basis of the Selective Block of Kv1.2 by Maurotoxin from Computer Simulations

The 34-residue polypeptide maurotoxin (MTx) isolated from scorpion venoms selectively inhibits the current of the voltage-gated potassium channel Kv1.2 by occluding the ion conduction pathway. Here using molecular dynamics simulation as a docking method, the binding modes of MTx to three closely related channels (Kv1.1, Kv1.2 and Kv1.3) are examined. We show that MTx forms more favorable electrostatic interactions with the outer vestibule of Kv1.2 compared to Kv1.1 and Kv1.3, consistent with the selectivity of MTx for Kv1.2 over Kv1.1 and Kv1.3 observed experimentally. One salt bridge in the bound complex of MTx-Kv1.2 forms and breaks in a simulation period of 20 ns, suggesting the dynamic nature of toxin-channel interactions. The toxin selectivity likely arises from the differences in the shape of the channel outer vestibule, giving rise to distinct orientations of MTx on block. Potential of mean force calculations show that MTx blocks Kv1.1, Kv1.2 and Kv1.3 with an IC(50) value of 6 µM, 0.6 nM and 18 µM, respectively.This work was supported by the National Health and Medical Research Council of Australia (http://www.nhmrc.gov.au). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Partition Function of Chiral Boson on 2-Torus from Floreanini-Jackiw Lagrangian

We revisit the problem of quantizing a chiral boson on a torus. The conventional approach is to extract the partition function of a chiral boson from the path integral of a non-chiral boson. Instead we compute it directly from the chiral boson Lagrangian of Floreanini and Jackiw modified by topological terms involving auxiliary fields. A careful analysis of the gauge-fixing condition for the extra gauge symmetry reproduces the correct results for the free chiral boson, and has the advantage of being applicable to a wider class of interacting chiral boson theories.Comment: 31 pages, minor modificatio

Re-evaluation of the surface ruptures of the November 1951 earthquake series in eastern Taiwan, and its neotectonic implications

The earthquakes of November 1951 constitute the most destructive seismic episode in the recorded history of the Longitudinal Valley, eastern Taiwan. However, information about their source parameters is sparse. To understand the relationship between the 1951 ruptures and new interpretations of the regional neotectonic architecture of the Longitudinal Valley, we re-evaluated the November 1951 ruptures by analyzing old documents, reports and photographs, and by interviewing local residents who experienced the earthquake. As a result, we have revised significantly the rupture map previously published. We divide the surface ruptures from south to north into the Chihshang, Yuli, and Rueisuei sections. The first shock of the 1951 series probably resulted from the Chihshang rupture, and the second shock probably resulted from the Yuli and Rueisuei ruptures. The lengths of these ruptures indicate that the two shocks had similar magnitudes. The Chihshang and Rueisuei ruptures are along segments of the Longitudinal Valley fault, a left-lateral oblique fault along which the Coastal Range thrusts westward over the Longitudinal Valley. The Yuli rupture, on the other hand, appears to be part of a separate, left-lateral strike-slip Yuli fault, which traverses the middle of the Longitudinal Valley. The complex behavior of these structures and interaction between them are important in understanding the future seismic hazard of the area

Metabolism and Toxicity of D- and L-a,Y-Diaminobutyric Acids

Chemistr

Liquid biopsy genotyping in lung cancer: ready for clinical utility?

Liquid biopsy is a blood test that detects evidence of cancer cells or tumor DNA in the circulation. Despite complicated collection methods and the requirement for technique-dependent platforms, it has generated substantial interest due, in part, to its potential to detect driver oncogenes such as epidermal growth factor receptor (EGFR) mutants in lung cancer. This technology is advancing rapidly and is being incorporated into numerous EGFR tyrosine kinase inhibitor (EGFR-TKI) development programs. It appears ready for integration into clinical care. Recent studies have demonstrated that biological fluids such as saliva and urine can also be used for detecting EGFR mutant DNA through application other user-friendly techniques. This review focuses on the clinical application of liquid biopsies to lung cancer genotyping, including EGFR and other targets of genotype-directed therapy and compares multiple platforms used for liquid biopsy

Localization method for device-to-device through user movement

International audienceIndoor positioning system is a key component for developing various location based services such as indoor navigation in large complex buildings (e.g., commercial center and hospital). Meanwhile, it is challenging to design a cost effective solution which is able to provide high accuracy. A new method, namely Two-Step Movement (2SM), was proposed in [1] to demonstrate how to build a positioning system which requires only one Reference Point (RP) by exploiting user movement. The method can offer good precision and minimize the number of RPs required so as to reduce system implementation cost. Built on 2SM, here we first improve the positioning performance through multi-sampling technique to combat measurement noise. Secondly, we propose the Generalized Two-Step Movement (G2SM) method for device-to-device (D2D) systems in which both the mobile terminal (MT) and RP can be mobile device. The mobile user's position can be derived analytically and given in simple closed-form expression. Its effectiveness in the presence of noise is shown in simulation results