DIA-Based Proteomics Identifies IDH2 as a Targetable Regulator of Acquired Drug Resistance in Chronic Myeloid Leukemia

Drug resistance is a critical obstacle to effective treatment in patients with chronic myeloid leukemia. To understand the underlying resistance mechanisms in response to imatinib mesylate (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for 2 months to generate derivative cells with mild, intermediate, and severe resistance to the drugs as defined by their increasing resistance index. PulseDIA-based (DIA [data-independent acquisition]) quantitative proteomics was then employed to reveal the proteome changes in these resistant cells. In total, 7082 proteins from 98,232 peptides were identified and quantified from the dataset using four DIA software tools including OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA. Sirtuin signaling pathway was found to be significantly enriched in both ADR-resistant and IMA-resistant K562 cells. In particular, isocitrate dehydrogenase (NADP(+)) 2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated isocitrate dehydrogenase (NADP(+)) 2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR.     

The Optimal Solution of a Non-Convex State-Dependent LQR Problem and Its Applications

This paper studies a Non-convex State-dependent Linear Quadratic Regulator (NSLQR) problem, in which the control penalty weighting matrix in the performance index is state-dependent. A necessary and sufficient condition for the optimal solution is established with a rigorous proof by Euler-Lagrange Equation. It is found that the optimal solution of the NSLQR problem can be obtained by solving a Pseudo-Differential-Riccati-Equation (PDRE) simultaneously with the closed-loop system equation. A Comparison Theorem for the PDRE is given to facilitate solution methods for the PDRE. A linear time-variant system is employed as an example in simulation to verify the proposed optimal solution. As a non-trivial application, a goal pursuit process in psychology is modeled as a NSLQR problem and two typical goal pursuit behaviors found in human and animals are reproduced using different control weighting . It is found that these two behaviors save control energy and cause less stress over Conventional Control Behavior typified by the LQR control with a constant control weighting , in situations where only the goal discrepancy at the terminal time is of concern, such as in Marathon races and target hitting missions.     

Draft Genome Sequence of a Novel Bacterial Strain,LSJC7, Belonging to the Family Enterobacteriaceae with Dual Resistance to Arsenic and Tetracycline

Strain LSJC7, with dual resistance to arsenic and tetracycline, was isolated from an antimony tailing in China. Its 16S rRNA gene sequence has the highest similarity to that of Enterobacter cloacae subsp. dissolvens LMG 2683^T (97.02%). Here we present the approximately 4.6-Mbp draft genome sequence of strain LSJC7.     

INTRASPECIFIC VARIATION AND THE ROLE OF SUPERPARASITISM IN DIAPAUSE INDUCTION OF TRICHOGRAMMA EVANESCENS WEST-WOOD*

Abstract The diapause of two populations of Trichogramma evanescens Westwood (T. evanescens A and T. evanescens B), collected from different Iranian insect pests, was studied. T. evunescens A in the eggs of Corcyra cephalonica was easily induced to stable diapause with constant 8°C, 15 % and fluctuating temperature (11–23) C -11C. T. evanescens B could not be induced to diapause with the same temperatural regime and host. The experiments showed that the host of maternal generations and the ability of avoiding super-parasitism may play an important role in intraspecific variation of T. evunescens in diapause induction.     

Membrane-trafficking RabA4c involved in the effect of glycine betaine on recovery from chilling stress in Arabidopsis

Glycine betaine (GB) can confer tolerance to several types of stress at low concentrations, either after application to plants or in transgenics engineered to overproduce GB. Based on earlier studies on levels of GB in plants and evidence for effects on gene expression, we hypothesized that at least part of this effect could be ascribed to the activation of the expression of stress tolerance genes. Using a strategy based on high-throughput gene expression analysis with microarrays followed by confirmation with northern blots, we identified Arabidopsis genes upregulated in roots that reinforce intracellular processes protecting cells from oxidative damage and others that appear to be involved in reinforcing a scavenging system for reactive oxygen species (ROS) in cell walls. Upregulated genes in roots include those for the membrane-trafficking RabA4c, the root-specific NADPH-dependent ferric reductase (FRO2) localized to the plasma membrane, mitochondrial catalase 2 and the cell wall peroxidase ATP3a. Comparative studies with wild-type Arabidopsis and knockout mutants for the membrane-trafficking RabA4c gene demonstrated that the mutants respond only slightly to GB, if at all, compared with wild-type in relation to root growth recovery after chilling stress, demonstrating the role of RabA4c in relation to the GB effect. The results point toward links between oxidative stress, gene expression, membrane trafficking and scavenging of ROS such as superoxide and hydrogen peroxide in relation to GB effects on chilling tolerance in plants.     

Protein local structure alignment under the discrete Fréchet distance.

Protein structure alignment is a fundamental problem in computational and structural biology. While there has been lots of experimental/heuristic methods and empirical results, very few results are known regarding the algorithmic/complexity aspects of the problem, especially on protein local structure alignment. A well-known measure to characterize the similarity of two polygonal chains is the famous Fréchet distance, and with the application of protein-related research, a related discrete Fréchet distance has been used recently. In this paper, following the recent work of Jiang et al. we investigate the protein local structural alignment problem using bounded discrete Fréchet distance. Given m proteins (or protein backbones, which are 3D polygonal chains), each of length O(n), our main results are summarized as follows: * If the number of proteins, m, is not part of the input, then the problem is NP-complete; moreover, under bounded discrete Fréchet distance it is NP-hard to approximate the maximum size common local structure within a factor of n(1-epsilon). These results hold both when all the proteins are static and when translation/rotation are allowed. * If the number of proteins, m, is a constant, then there is a polynomial time solution for the problem.