65 research outputs found
The 3rd Anti-UAV Workshop & Challenge: Methods and Results
The 3rd Anti-UAV Workshop & Challenge aims to encourage research in
developing novel and accurate methods for multi-scale object tracking. The
Anti-UAV dataset used for the Anti-UAV Challenge has been publicly released.
There are two main differences between this year's competition and the previous
two. First, we have expanded the existing dataset, and for the first time,
released a training set so that participants can focus on improving their
models. Second, we set up two tracks for the first time, i.e., Anti-UAV
Tracking and Anti-UAV Detection & Tracking. Around 76 participating teams from
the globe competed in the 3rd Anti-UAV Challenge. In this paper, we provide a
brief summary of the 3rd Anti-UAV Workshop & Challenge including brief
introductions to the top three methods in each track. The submission
leaderboard will be reopened for researchers that are interested in the
Anti-UAV challenge. The benchmark dataset and other information can be found
at: https://anti-uav.github.io/.Comment: Technical report for 3rd Anti-UAV Workshop and Challenge. arXiv admin
note: text overlap with arXiv:2108.0990
The Chronic Lymphocytic Leukemia (CLL) Microenvironment and Novel Targeted Therapies
Activation of the B-cell receptor (BCR), and subsequent signalling via the Bruton's tyrosine kinase (BTK), phosphoinositide-3 kinase (PI3K) and mitogen-activated protein kinase (MAPK), plays a significant role in the pathogenesis of CLL. This thesis aimed to better understand the role of the CLL microenvironment and to investigate novel treatment strategies for targeting CLL cells in the lymph nodes or bone marrow. We demonstrated using the DotScan cluster of differentiation (CD) antibody microarray, that immunophenotypic changes induced on CLL cells by co-culture with fibroblasts expressing the CD40 ligand can be blocked by ibrutinib or idelalisib. These data provide insight on the mechanisms underlying the lymphocytosis observed in patients treated with these agents. We demonstrated that as a single agent the MEK1/2 inhibitor, binimetinib was effective against CLL cells under certain in vitro conditions and that the drug was effective and synergistic with the AKT inhibitor, MK2206, but not idelalisib. These data suggest that this combination of drugs may represent a novel therapeutic option for CLL effective against CLL cells in the tumour microenvironment. Next, we demonstrated efficacy of the dual PI3K/PIM inhibitor, IBL-202 and showed high synergy with the Bcl-2 inhibitor, venetoclax against CLL cells under conditions that mimic the tumour microenvironment and against a TP53 knock-out cell line we derived from the OSU-CLL cell line using the CRISPR-Cas9 system. This combination was synergistic in terms of apoptosis and inhibition of both the proliferative and migratory capacities of CLL cells. These data suggest that IBL-202 in combination with venetoclax may be an effective treatment option for high risk CLL disease. Collectively, the data presented highlight several pathways and novel drugs that may contribute to the development of therapeutic strategies for CLL patients
GPU-Accelerated Implementation of Continuous Constant pH Molecular Dynamics in Amber: pKa Predictions with Single-pH Simulations
This paper reports a GPU-accelerated implementation and testing data of the generalized Born based continuous constant pH molecular dynamics method in the Amber package
Conformational Activation of a Transmembrane Proton Channel from Constant pH Molecular Dynamics
Proton-coupled transmembrane
proteins play important roles in human
health and diseases; however, detailed mechanisms are often elusive.
Experimentally resolving proton positions and structural details is
challenging, and conventional molecular dynamics simulations are performed
with preassigned and fixed protonation states. To address this challenge,
here we illustrate the use of the state-of-the-art continuous constant
pH molecular dynamics (CpHMD) to directly describe the activation
of the M2 channel of influenza virus, for which abundant experimental
data are available. Starting from the closed crystal structure, simulation
reveals a pH-dependent conformational switch to an activated state
that resembles the open crystal structure. Importantly, simulation
affords the free energy of channel opening coupled to the titration
of a histidine tetrad, thereby providing a thermodynamic mechanism
for M2 activation, that is consistent with NMR data and resolves the
controversy with crystal structures obtained at different pH values.
This work illustrates the utility of CpHMD in offering previously
unattainable conformational details and thermodynamic information
for proton-coupled transmembrane channels and transporters
Mechanism of pH-dependent activation of the sodium-proton antiporter NhaA
Data files to accompany the article in Nature Communications, in press.Escherichia coli NhaA is a prototype sodium-proton antiporter, which has been
extensively characterized by X-ray crystallography, biochemical and biophysical
experiments. However, the identities of proton carriers and details of pH-regulated
mechanism remain controversial. Here we report constant pH molecular dynamics data,
which reveal that NhaA activation involves a net charge switch of a pH sensor at the
entrance of the cytoplasmic funnel and opening of a hydrophobic gate at the end of the
funnel. The latter is triggered by charging of Asp164, the first proton carrier. The second
proton carrier Lys300 forms a salt bridge with Asp163 in the inactive state, and releases
a proton when a sodium ion binds Asp163. These data reconcile current models and
illustrate the power of state-of-the-art molecular dynamics simulations in providing
atomic details of proton-coupled transport across membrane, which is challenging to
elucidate by experimental techniques
PB1934: MEASURED OPTIMUM ANTI-SPIKE LEVEL VACCINATION STRATEGY AND ANTI-VIRAL ACCESS RESULT IN LOW COVID HOSPITALISATION AND MORTALITY IN CLL AND MBL
Generalized Born Based Continuous Constant pH Molecular Dynamics in Amber: Implementation, Benchmarking and Analysis
Solution
pH plays an important role in structure and dynamics of
biomolecular systems; however, pH effects cannot be accurately accounted
for in conventional molecular dynamics simulations based on fixed
protonation states. Continuous constant pH molecular dynamics (CpHMD)
based on the λ-dynamics framework calculates protonation states
on the fly during dynamical simulation at a specified pH condition.
Here we report the CPU-based implementation of the CpHMD method based
on the GBNeck2 generalized Born (GB) implicit-solvent model in the <i>pmemd</i> engine of the Amber molecular dynamics package. The
performance of the method was tested using pH replica-exchange titration
simulations of Asp, Glu and His side chains in 4 miniproteins and
7 enzymes with experimentally known p<i>K</i><sub>a</sub>’s, some of which are significantly shifted from the model
values. The added computational cost due to CpHMD titration ranges
from 11 to 33% for the data set and scales roughly linearly as the
ratio between the titrable sites and number of solute atoms. Comparison
of the experimental and calculated p<i>K</i><sub>a</sub>’s using 2 ns per replica sampling yielded a mean unsigned
error of 0.70, a root-mean-squared error of 0.91, and a linear correlation
coefficient of 0.79. Though this level of accuracy is similar to the
GBSW-based CpHMD in CHARMM, in contrast to the latter, the current
implementation was able to reproduce the experimental orders of the
p<i>K</i><sub>a</sub>’s of the coupled carboxylic
dyads. We quantified the sampling errors, which revealed that prolonged
simulation is needed to converge p<i>K</i><sub>a</sub>’s
of several titratable groups involved in salt-bridge-like interactions
or deeply buried in the protein interior. Our benchmark data demonstrate
that GBNeck2-CpHMD is an attractive tool for protein p<i>K</i><sub>a</sub> predictions
Effects of Intercritical Annealing Temperature on Mechanical Properties of Fe-7.9Mn-0.14Si-0.05Al-0.07C Steel
A medium Mn steel has been designed to achieve an excellent combination of strength and ductility based on the TRIP (Transformation Induced Plasticity) concept for automotive applications. Following six passes of hot rolling at 850 °C, the Fe-7.9Mn-0.14Si-0.05Al-0.07C (wt.%) steel was warm-rolled at 630 °C for seven passes and subsequently air cooled to room temperature. The sample was subsequently intercritically annealed at various temperatures for 30 min to promote the reverse transformation of martensite into austenite. The obtained results show that the highest volume fraction of austenite is 39% for the sample annealed at 600 °C. This specimen exhibits a yield stress of 910 MPa and a high ultimate tensile stress of 1600 MPa, with an elongation-to-failure of 0.29 at a strain rate of 1 × 10−3/s. The enhanced work-hardening ability of the investigated steel is closely related to martensitic transformation and the interaction of dislocations. Especially, the alternate arrangement of acicular ferrite (soft phase) and ultrafine austenite lamellae (50–200 nm, strong and ductile phase) is the key factor contributing to the excellent combination of strength and ductility. On the other hand, the as-warm-rolled sample also exhibits the excellent combination of strength and ductility, with elongation-to-failure much higher than those annealed at temperatures above 630 °C
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