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.     

Initiation of focal adhesion assembly by talin and kindlin: A dynamic view

Focal adhesions (FAs) are integrin‐containing protein complexes regulated by a network of hundreds of protein–protein interactions. They are formed in a spatiotemporal manner upon the activation of integrin transmembrane receptors, which is crucial to trigger cell adhesion and many other cellular processes including cell migration, spreading and proliferation. Despite decades of studies, a detailed molecular level understanding on how FAs are organized and function is lacking due to their highly complex and dynamic nature. However, advances have been made on studying key integrin activators, talin and kindlin, and their associated proteins, which are major components of nascent FAs critical for initiating the assembly of mature FAs. This review will discuss the structural and functional findings of talin and kindlin and their immediate interaction network, which will shed light upon the architecture of nascent FAs and how they act as seeds for FA assembly to dynamically regulate diverse adhesion‐dependent physiological and pathological responses.     

Association between ABHD1 and DOK6 polymorphisms and susceptibility to Hirschsprung disease in Southern Chinese children

Hirschsprung disease (HSCR) is an infrequent congenital intestinal dysplasia. The known genetic variations are unable to fully explain the pathogenesis of HSCR. The α/β-hydratase domain 1 (ABHD1) interferes with the proliferation and migration of intestinal stem cells. Docking protein 6 (DOK6) is involved in neurodevelopment through RET signalling pathway. We examined the association of ABHD1 and DOK6 genetic variants with HSCR using 1470 controls and 1473 HSCR patients from Southern Chinese children. The results clarified that DOK6 rs12968648 G allele significantly increased HSCR susceptibility, in the allelic model (p = 0.034; OR = 1.12, 95%CI = 1.01~1.24) and the dominant model (p = 0.038; OR = 1.12, 95%CI = 1.01~1.25). Clinical stratification analysis showed that rs12968648 G allele was associated with increased risk of short-segment HSCR (S-HSCR), in the allelic model (p = 0.028; OR = 1.14, 95%CI = 1.01~1.28) and the additive model (p = 0.030; OR = 1.14, 95%CI = 1.01~1.28). ABHD1 rs2304678 C allele had higher risk to develop total colonic aganglionosis (TCA) in the allelic model (p = 7.04E-03; OR = 1.67, 95%CI = 1.15~2.43) and the dominant model (p = 4.12E-03; OR = 1.93, 95%CI = 1.23~3.04). DOK6 rs12968648 and ABHD1 rs2304678 had significant intergenic synergistic effect according to logical regression (p = 0.0081; OR = 0.76, 95%CI = 0.63~0.93) and multifactor dimensionality reduction (MDR, p = 0.0045; OR = 1.25, 95%CI = 1.07~1.46). This study verified two susceptible variations of HSCR on ABHD1 and DOK6. Their roles in HSCR should be conducted in further studies.     

A Novel Method for Fast Change-Point Detection on Simulated Time Series and Electrocardiogram Data

Although Kolmogorov-Smirnov (KS) statistic is a widely used method, some weaknesses exist in investigating abrupt Change Point (CP) problems, e.g. it is time-consuming and invalid sometimes. To detect abrupt change from time series fast, a novel method is proposed based on Haar Wavelet (HW) and KS statistic (HWKS). First, the two Binary Search Trees (BSTs), termed TcA and TcD, are constructed by multi-level HW from a diagnosed time series; the framework of HWKS method is implemented by introducing a modified KS statistic and two search rules based on the two BSTs; and then fast CP detection is implemented by two HWKS-based algorithms. Second, the performance of HWKS is evaluated by simulated time series dataset. The simulations show that HWKS is faster, more sensitive and efficient than KS, HW, and T methods. Last, HWKS is applied to analyze the electrocardiogram (ECG) time series, the experiment results show that the proposed method can find abrupt change from ECG segment with maximal data fluctuation more quickly and efficiently, and it is very helpful to inspect and diagnose the different state of health from a patient''s ECG signal.     

Nitric oxide regulates ganoderic acid biosynthesis by the S-nitrosylation of aconitase under heat stress in Ganoderma lucidum

Nitric oxide (NO) is an important signalling molecule in stress response of organisms. We previously reported that NO decreases heat stress (HS)-induced ganoderic acid (GA) accumulation in Ganoderma lucidum. To explore the mechanisms by which NO modulates GA biosynthesis under HS, the effect of NO on the reactive oxygen species (ROS) content was examined. The results showed that NO decreased the production of mitochondrial ROS (mitROS) by 60% under HS. Further research revealed that NO reduced the mitROS content by inhibiting aconitase (Acon) activity. The GA content in Acon-silenced (Aconi) strains treated with NO donor did not differ significantly from that in untreated Aconi strains. To study the mechanism by which Acon activity is inhibited, the S-nitrosylation level of Acon was determined. Biotin-switch technology and mass spectrometry analysis were used to show that Acon is S-nitrosylated at the Cys-594 amino acid residue. Substitution of Cys-594 with a Ser, which cannot be S-nitrosylated, abolished the responsiveness of Acon to the NO-induced reduction in its enzymatic activity. These findings demonstrate that NO inhibits Acon activity through S-nitrosylation at Cys-594. In summary, these findings describe mechanism by which NO regulates GA biosynthesis via S-nitrosylation of Acon under HS condition in G. lucidum.     

1991-2017年叶尔羌河流域冰川景观格局时空演变

冰川景观变化是全球环境和气候变化的共同"指示器"。随着全球气候变化加剧，干旱和半干旱地区的冰川景观将进一步变化。科学评估冰川景观格局时空演变特征，为应对冰川景观变化及其影响提供科学参考。基于1991-2017年Landsat TM/ETM+/OLI遥感影像，采用监督分类方法获取叶尔羌河流域冰川景观时空格局及变化数据，利用景观格局指数、质心迁移模型、分形维数等方法分析近26年叶尔羌河流域冰川景观格局时空演变特征。结果表明：（1）1991-2017年叶尔羌河流域冰川斑块面积呈消减趋势，但有所减缓，共减少799.50 km²（-13.09%）。冰川斑块面积消减主要集中在海拔5400-5800 m之间，相较之下，海拔4400 m以下的区域冰川斑块面积消减率最高，达63.68%；不同坡度冰川景观消减率存在差异，陡坡冰川斑块面积消减率最高（15.98%），急陡坡消减率最低（2.87%）；阴阳两坡冰川景观均呈消减趋势，阳坡冰川斑块面积消减速率显著高于阴坡。（2）近26年来，叶尔羌河流域冰川斑块数量、最大斑块指数均减小，而平均形状指数、平均周长面积比、分裂指数均增加，表明冰川景观不断消减，破碎化程度增加。（3）研究期间，叶尔羌河流域冰川景观质心发生迁移，整体呈现东北偏移趋势。（4）通过分形理论对叶尔羌河流域冰川景观空间结构特征进行分析表明，该流域冰川景观消减率略微降低，但仍然处于持续消融状态。     

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.     

A novel hypoxia gene signature indicates prognosis and immune microenvironments characters in patients with hepatocellular carcinoma

Due to the lack of a suitable gene signature, it is difficult to assess the hypoxic exposure of HCC tissues. The clinical value of assessing hypoxia in HCC is short of tissue-level evidence. We tried to establish a robust and HCC-suitable hypoxia signature using microarray analysis and a robust rank aggregation algorithm. Based on the hypoxia signature, we obtained a hypoxia-associated HCC subtypes system using unsupervised hierarchical clustering and a hypoxia score system was provided using gene set variation analysis. A novel signature containing 21 stable hypoxia-related genes was constructed to effectively indicate the exposure of hypoxia in HCC tissues. The signature was validated by qRT-PCR and compared with other published hypoxia signatures in multiple large-size HCC cohorts. The subtype of HCC derived from this signature had different prognosis and other clinical characteristics. The hypoxia score obtained from the signature could be used to indicate clinical characteristics and predict prognoses of HCC patients. Moreover, we reveal a landscape of immune microenvironments in patients with different hypoxia score. In conclusion, we identified a novel HCC-suitable 21-gene hypoxia signature that could be used to estimate the hypoxia exposure in HCC tissues and indicated prognosis and a series of important clinical features in HCCs. It may enable the development of personalized counselling or treatment strategies for HCC patients with different levels of hypoxia exposure.