YQ36: A Novel Bisindolylmaleimide Analogue Induces KB/VCR Cell Death

Overexpression of multidrug resistance proteins P-glycoprotein (P-gp, MDR1) causes resistance of the tumor cells against a variety of chemotherapeutic agents. 3-(1-methyl-1H-indol-3-yl)-1-phenyl-4-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-1H-pyrrole-2,5-dione (YQ36) is a novel analogue of bisindolylmaleimide, which has been reported to overcome multidrug resistance. Here, we dedicated to investigate the anticancer activity of YQ36 on KB/VCR cells. The results revealed that YQ36 exhibited great antiproliferative activity on three parental cell lines and MDR1 overexpressed cell lines. Moreover, the hypersensitivity of YQ36 was confirmed on the base of great apoptosis induction and unaltered intracellular drug accumulation in KB/VCR cells. Further results suggested that YQ36 could not be considered as a substrate of P-gp, which contributed to its successfully escaping from the efflux mediated by P-gp. Interestingly, we observed that YQ36 could accumulate in nucleus and induce DNA damage. YQ36 could also induce the activation of caspase-3, imposing effects on the mitochondrial function. Collectively, our data demonstrated that YQ36 exhibited potent activities against MDR cells, inducing DNA damage and triggering subsequent apoptosis via mitochondrial pathway

ObFuzzer: Object-Oriented Hybrid Fuzzer for Binaries

In recent years, coverage-guided technology has become the mainstream method of fuzzing. A coverage-guided fuzzer can guide a program to a new path (edge) so that previously untested code can be tested. As coverage-guided fuzzers have become more popular, the difficulty of discovering vulnerabilities has increased significantly. This paper proposes ObFuzzer, an object-oriented binary hybrid fuzzer based on a new assumption. Namely, the object which has been operated more times and operated in more positions is more likely to have defects. Our ObFuzzer consists of the following steps. First, ObFuzzer obtains the inner relations of object operations in the target program through static analysis and analyzes the riskiness of the basic blocks containing such operations. Then, ObFuzzer generates test cases that can guide the program to the basic blocks that this paper considers to be the most dangerous by symbolic execution. Finally, fuzzing is performed using the riskiness of the object operations rather than code coverage. To demonstrate the effectiveness of ObFuzzer over a traditional coverage-guided fuzzer, this paper evaluates its performance in a real program. When facing object-oriented programs, ObFuzzer has a 29% to 40% increase in object operation complexity during execution. These more complex object operations can enhance the ability to discover vulnerabilities related to object operations. Eventually, ObFuzzer found five unique vulnerabilities and one logic error without a crash in “xpdf”

EtWExplorer: Multi-Priority Scheduling Path Exploration Technology Based on Abstract Syntax Tree Analysis

Symbolic execution is well known as a dynamic vulnerability discovery technique. Its greatest advantage is the capability to analyze the execution information of the program and to explore the path in the program deterministically. This is a more accurate way to determine if there are vulnerabilities in a program than randomized testing by fuzzing. In addition, symbolic execution does not suffer from the problem of decreasing the capability to discover new paths as more paths are discovered, similar to that caused by random-based fuzzing. However, the reason why symbolic execution is not widely used in vulnerability discovery is mainly due to the state space explosion in the program. The state space explosion severely affects the applicability of symbolic execution. To further improve the applicability of symbolic execution, this paper proposes a path exploration technology based on abstract syntax tree analysis. With the distance between the expression generated by the symbolic execution of the repeat location and the “unsatisfiable” condition of the “unsat” state, we can perform multi-priority scheduling for the repeat location state, thus mitigating the impact of the state space explosion on path exploration. We proposed and implemented EtWExplorer, a multi-priority scheduling technique based on abstract syntax tree analysis. With this technique, we can significantly improve the capability of symbolic execution to discover unknown paths even in state space exploration. Experiments show that EtWExplorer introduces a performance overhead of 72% in the worst case and can improve performance by 294% in the best case. EtWExplorer has a 95% improvement in state space explosion mitigation capability and a 199% to 983% improvement in the path exploration capability of block coverage and a 181% to 1047% improvement in the path exploration capability of edge coverage when facing programs that cause a state space explosion

EtWExplorer: Multi-Priority Scheduling Path Exploration Technology Based on Abstract Syntax Tree Analysis

Symbolic execution is well known as a dynamic vulnerability discovery technique. Its greatest advantage is the capability to analyze the execution information of the program and to explore the path in the program deterministically. This is a more accurate way to determine if there are vulnerabilities in a program than randomized testing by fuzzing. In addition, symbolic execution does not suffer from the problem of decreasing the capability to discover new paths as more paths are discovered, similar to that caused by random-based fuzzing. However, the reason why symbolic execution is not widely used in vulnerability discovery is mainly due to the state space explosion in the program. The state space explosion severely affects the applicability of symbolic execution. To further improve the applicability of symbolic execution, this paper proposes a path exploration technology based on abstract syntax tree analysis. With the distance between the expression generated by the symbolic execution of the repeat location and the “unsatisfiable” condition of the “unsat” state, we can perform multi-priority scheduling for the repeat location state, thus mitigating the impact of the state space explosion on path exploration. We proposed and implemented EtWExplorer, a multi-priority scheduling technique based on abstract syntax tree analysis. With this technique, we can significantly improve the capability of symbolic execution to discover unknown paths even in state space exploration. Experiments show that EtWExplorer introduces a performance overhead of 72% in the worst case and can improve performance by 294% in the best case. EtWExplorer has a 95% improvement in state space explosion mitigation capability and a 199% to 983% improvement in the path exploration capability of block coverage and a 181% to 1047% improvement in the path exploration capability of edge coverage when facing programs that cause a state space explosion

A spectroscopic-imaging scanning tunneling microscope in vector magnetic field

Funding: This work was supported by the Alexander von Humboldt Foundation. A.W.R. acknowledges support by EPSRC Grant No. EP/P024564/1.Cryogenic scanning tunneling microscopy and spectroscopy (STM/STS) performed in a high vector magnetic field provide unique possibilities for imaging surface magnetic structures and anisotropic superconductivity and exploring spin physics in quantum materials with atomic precision. Here, we describe the design, construction, and performance of a low-temperature, ultra-high-vacuum (UHV) spectroscopic-imaging STM equipped with a vector magnet capable of applying a field of up to 3 T in any direction with respect to the sample surface. The STM head is housed in a fully bakeable UHV compatible cryogenic insert and is operational over variable temperatures ranging from ∼300 down to 1.5 K. The insert can be easily upgraded using our home-designed 3He refrigerator. In addition to layered compounds, which can be cleaved at a temperature of either ∼300, ∼77, or ∼4.2 K to expose an atomically flat surface, thin films can also be studied by directly transferring using a UHV suitcase from our oxide thin-film laboratory. Samples can be treated further with a heater and a liquid helium/nitrogen cooling stage on a three-axis manipulator. The STM tips can be treated in vacuo by e-beam bombardment and ion sputtering. We demonstrate the successful operation of the STM with varying the magnetic field direction. Our facility provides a way to study materials in which magnetic anisotropy is a key factor in determining the electronic properties such as in topological semimetals and superconductors.PostprintPeer reviewe

P-Fuzz: A Parallel Grey-Box Fuzzing Framework

Fuzzing is an effective technology in software testing and security vulnerability detection. Unfortunately, fuzzing is an extremely compute-intensive job, which may cause thousands of computing hours to find a bug. Current novel works generally improve fuzzing efficiency by developing delicate algorithms. In this paper, we propose another direction of improvement in this field, i.e., leveraging parallel computing to improve fuzzing efficiency. In this way, we develop P-fuzz, a parallel fuzzing framework that can utilize massive, distributed computing resources to fuzz. P-fuzz uses a database to share the fuzzing status such as seeds, the coverage information, etc. All fuzzing nodes get tasks from the database and update their fuzzing status to the database. Also, P-fuzz handles some data races and exceptions in parallel fuzzing. We compare P-fuzz with AFL and a parallel fuzzing framework Roving in our experiment. The result shows that P-fuzz can easily speed up AFL about 2.59× and Roving about 1.66× on average by using 4 nodes

Association of Serum Melatonin Level with Mild Cognitive Impairment in Type 2 Diabetic Patients: A Cross-Sectional Study

Objectives. Melatonin is an essential neuroendocrine hormone that participates in the regulation of sleep rhythm and cognitive function. This study aimed to determine serum melatonin levels with mild cognitive impairment (MCI) in patients with type 2 diabetes (T2DM). Methods. A total of 247 T2DM patients were recruited in this retrospective study and divided into 75 subjects with MCI and 172 with normal cognition. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA). Their blood sample was examined for the level of melatonin and other biochemical parameters. Results. Melatonin concentration was decreased in MCI patients to non-MCI patients (P < 0.001). Melatonin level was negatively correlated with age (r = −0.202; P = 0.001), diabetes duration (r = −0.282; P < 0.001), serum HbA1c (r = −0.195; P = 0.002), hs-CRP (r = −0.324; P < 0.001), and TSH (r = −0.184; P = 0.004) levels and positively correlated with MoCA score, serum HDL-C (r = 0.145; P < 0.001), FT3 (r = 0.241; P < 0.001), and FT4 (r = 0.169; P = 0.008) levels. The multivariable analysis indicated that fewer years of formal education, longer diabetes duration, higher serum HbA1c, higher serum hs-CRP, and lower serum melatonin are the predisposing factors for MCI. Conclusion. Lower melatonin level was associated with cognitive impairment in patients with T2DM. Melatonin might serve as a potential protective molecule against cognitive dysfunction in T2DM

Revealing the relationship between nitrogen use efficiency‐related QTLs and carbon and nitrogen metabolism regulation in poplar

Abstract Poplar provides a large amount of bioenergy and wood, but the lack of soil nitrogen in poplar plantations has seriously restricted its wood production. Using Populus deltoides ‘Danhong’, P. simonii ‘Tongliao1’, and their F1 populations as materials, nitrogen fertilizer and no nitrogen fertilizer were applied in the field. Under different nitrogen conditions, the wood yield of ‘Danhong’ was much higher than that of ‘Tongliao 1’, which indicated that ‘Danhong’ had excellent genetic resources related to nitrogen use efficiency (NUE). Based on a high‐density genetic map, we performed quantitative trait loci (QTL) analyses for ground diameter, plant height, stem biomass, and nitrogen response index. A total of 276 QTLs and 774 candidate genes were identified. We analysed the metabolites related to carbon and nitrogen metabolism and the transcriptome of the developing xylem in 10 clones under high‐ and low‐nitrogen conditions. Through weighted gene coexpression network analysis, it was found that the MEyellow module was closely related to biomass, carbon, and nitrogen metabolism, and a gene coexpression network was established. Finally, candidate genes NRT3.1, NPF5.1, NPF5.10, and NPF8.1 related to nitrogen transport; transcription factors NLP8.1, NLP8.2, and NLP2 regulating nitrogen transport; genes Potri.010G070900, GDH2, and SHM2 related to amino acid metabolism; and genes Necap2, Dscr3, trappc2l, Potri.013G072600, and LAX2 related to carbon metabolism were identified. This work provides abundant genetic resources for the genetic improvement of poplar NUE and provides new insights into the linkage mechanism between NUE and biomass yield

Genome-Wide Analysis of the <i>AAAP</i> Gene Family in <i>Populus</i> and Functional Analysis of <i>PsAAAP21</i> in Root Growth and Amino Acid Transport

The adventitious root (AR) is the basis for successful propagation by plant cuttings and tissue culture and is essential for maintaining the positive traits of a variety. Members of the amino acid/auxin permease (AAAP) gene family play indispensable roles in various plant metabolisms and have few studies on root growth and amino acid transport. In this study, with a systematic bioinformatics analysis of the Populus AAAP family, 83 PtrAAAPs were identified from Populus trichocarpa and grouped into 8 subfamilies. Subsequently, chromosomal distribution, genetic structure, cis-elements analysis, and expression pattern analysis of the AAAP family were performed and the potential gene AAAP21 regulating root development was screened by combining the results of RNA-Seq and QTL mapping. PsAAAP21 was proven as promoting root development by enhancing AR formation. Differentially expressed genes (DEGs) from RNA-seq results of overexpressing lines were enriched to multiple amino acid-related pathways, and the amino acid treatment to transgenic lines indicated that PsAAAP21 regulated amino acid transport, including tyrosine, methionine, and arginine. Analysis of the AAAP gene family provided a theoretical basis for uncovering the functions of AAAP genes. The identification of PsAAAP21 on root promotion and amino acid transport in Populus will help with breeding new woody plant species with strong rooting ability

Transcriptome Analysis of Developing Xylem Provides New Insights into Shade Response in Three Poplar Hybrids

Poplars have a strong response to light, and shade is one of the main environmental factors that limits the growth and development of poplars. Exploring the response mechanism of the developing xylem of poplar under shady conditions is of great reference significance for improving wood yields. In this study, three excellent hybrids of poplar (Populus euramericana &lsquo;Zhonglin46&rsquo; (Pe), Populus deltoides &lsquo;27-17&rsquo; (Pd), Populus &times; &lsquo;Wq156&rsquo; (Pw) were studied under shady conditions. Based on the phenotypic data and developing a xylem transcriptome analysis, the molecular mechanism of poplars&rsquo; response to shade was preliminarily revealed, and the core regulatory genes responding to shade were identified by a weighted co-expression network analysis (WGCNA). The results showed that Pw growth was significantly affected by shade, while Pe growth was slightly affected by shade. An enrichment analysis of 13,675 differentially expressed genes (DEGs) found that shade affected the expression of genes related to the glutathione metabolic pathway. The WGCNA analysis identified two modules (&ldquo;Brown&rdquo; and &ldquo;Purple&rdquo;) related to the shade response and discovered seven hub genes. These hub genes were related to xylem development, vascular cambium division, stomatal development, and phytochrome A signal transduction. These results provide important basic information for gaining insight into the molecular response to shade in different poplar hybrids