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Internet of Things (IoT) techniques have been employed in many areas, e.g., vehicles, smart home, and medicine. Among the applications of IoTs, the Internet of Vehicles (IoV) is one of the most popular techniques. IoVs are protected by public key cryptographic systems, such as RSA and ECC. However, such systems are vulnerable to quantum computer attacks. Thus, we improve the security of IoV-based post-quantum signatures, which can resist quantum computer attacks. The key operations are divisions in a finite field. Hence, we improve the security of IoV-based post-quantum signatures with division by employing systolic architectures. We propose a systolic architecture for computing division in composite fields. After that, we improve the IoT security-based post-quantum signatures with systolic divisions. We test and verify our design on a Field-Programmable Gate Array (FPGA); the experimental results confirm our estimates. Furthermore, the optimized method proposed can be further applied to various applications like solving system of linear equations and cryptographic applications for IoT security.

PDF file - 85K, Relationship between TP53 (A) or KRAS (B) gene status and TAK 960 concentration producing EC50 values. Each data point represents a mean concentration producing 50% efficacy (EC50) value for TAK 960 in an individual cell line.

PDF file - 144K, Comparison of dosing regimens.

PDF file - 61K

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide] is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G2–M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC50 values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC50 >1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested. In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 has entered clinical evaluation in patients with advanced cancers. Mol Cancer Ther; 11(3); 700–9. ©2011 AACR.

PDF file - 130K, Anti-tumor activity of TAK-960 in MV4-11luc disseminated leukemia model.

The blood-brain barrier (BBB) plays a critical role in preventing harmful endogenous and exogenous substances from penetrating the brain. Optimal brain penetration of small molecule CNS drugs is characterized by a high unbound brain/plasma ratio (Kp,uu). While various medicinal chemistry strategies and in silico models have been reported to improve BBB penetration, none were developed to predict Kp,uu directly. We describe a physics-based computational approach, solvation free energy calculations (energy of solvation or E-sol), to predict Kp,uu. Prospective application of this method to internal CNS drug discovery programs highlighted the utility and accuracy of this new method, which showed a categorical accuracy of 79% and a R2 of 0.61 from a linear regression model.

The generation frequency of grid-connected units determines the power supply reliability of the grid and primary frequency regulation, as the first guarantee to stabilize the grid frequency is affected by the category of generating units and operation mode and lacks systematic real-time optimization and monitoring means. This paper takes a 300MW sub-critical heating unit as the research object, and researches, and analyzes three aspects of signal homologation, multi-dimensional optimization, and intelligent decision-making to establish the evaluation model of the primary frequency regulation capability of the unit. The evaluation accuracy of the assessment model reaches 83%, develops the control platform based on autonomous controllable PLC, realizes intelligent dynamic control and the replacement of traditional optimization technology means, also improves the qualification rate of primary frequency regulation by about 23.2%.

This paper is concerned with the outer exponential synchronization of the drive-response complex dynamical networks subject to time-varying delays. The dynamics of nodes is complex valued, the interactions among of the nodes are directed, and the two coupling matrices in the drive system and the response system are also different. The intermittent pinning control is proposed to achieve outer exponential synchronization in the aperiodical way. Some novel sufficient conditions are derived to guarantee outer exponential synchronization of the considered complex-valued complex networks by using the Lyapunov functional method. Finally, two numerical examples are presented to illustrate the effectiveness of the proposed control protocols.

Histone demethylase LSDl (KDMlA) belongs to the flavin adenine dinucleotide (FAD) dependent family of monoamine oxidases and is vital in regulation of mammalian biology. Dysregulation and overexpression of LSD1 are hallmarks of a number of human diseases, particularly cancers that are characterized as morphologically poorly differentiated. As such, inhibitors of LSD1 have potential to be beneficial as a cancer therapy. The most clinically advanced inhibitors of LSDl are covalent inhibitors derived from tranylcypromine (TCP). Herein, we report the discovery of a novel series of reversible and selective LSDl inhibitors. Exploration of structure-activity relationships (SARs) and optimization of ADME properties resulted in the identification of clinical candidate CC-90011. CC-90011 exhibits potent on-target induction of cellular differentiation in acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials in patients with first line, extensive stage SCLC (ClinicalTrials.gov identifier: NCT03850067).

Among Internet of Things (IoTs), cloud-based IoTs help retain the confidentiality of both device-to-cloud and cloud-to-device messages by setting up individual identities and credentials for each IoT devices. As recently been emphasized by two American institutes, National Institute of Standards and Technology (NIST) and National Security Agency (NSA), cloud-based IoTs that use RSA and ECC signatures are insecure under quantum computer attacks. To ensure the security in the cloud-based IoTs under quantum computer attacks, there is a critical need for implementations of new quantum-resistance signature systems, such as Unbalanced Oil and Vinegar (UOV), for making the cloud-based IoTs more secure and reliable. In order to analyze the security of UOV for cloud-based IoTs, we present an efficient algorithm based on side channel analysis of UOV, which combines inducing faults and Hamming distance power analysis. We implement UOV signature schemes on Sakura-G FPGA board via using Verilog-HDL code and Xilinx ISE software, where the power collection uses a 350 MHz Keysights oscilloscope. Based on the experimental results, we successfully recover all the secret keys of UOV signature, which shows that we should protect UOV and related signatures against side channel attacks when they are adopted in cloud-based IoTs.

Multivariate signature belongs to Multivariate-Quadratic-Equations Public Key Cryptography (MPKC), which is secure to quantum computer attacks. Compared with RSA and ECC, it is required to speed up multivariate signature implementations. A high-speed hardware architecture for signature generations of a multivariate scheme is proposed in this paper. The main computations of signature generations of multivariate schemes are additions, multiplications, inversions, and solving systems of linear equations (LSEs) in a finite field. Thus, we improve the finite field multiplications via using composite field expression and design a finite field inversion via using binary trees. Besides, we improve solving LSEs in a finite field based on a variant algorithm of Gauss-Jordan elimination and use the XOR gates to compute additions. We implement the high-speed hardware architecture based on the above improvements on an Altera Stratix Field-Programmable Gate Array (FPGA), which shows that it takes only 90 clock cycles and 0.9 μs to generate a multivariate signature. The comparison shows that the hardware architecture is much faster than other implementations.

Introduction: MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a key mediator of the NF-κB signaling pathway, the main driver of a subset of B-cell lymphomas and functions by forming a complex with CARMA1 and BCL10 to mediate antigen receptor-induced lymphocyte activation. MALT1 is considered a potential therapeutic target for several subtypes of non-Hodgkin B-cell lymphomas and chronic lymphocytic leukemia (CLL). Previously, we described the discovery of novel and potent MALT1 inhibitors with anti-proliferative effects in non-Hodgkin B-cell lymphoma cells. Here, we highlight the strong anti-tumor activity of our MALT1 inhibitors across multiple tumor models and the combination potential with agents including standard-of-care. Results: Novel small molecule MALT1 inhibitors were identified using Schrodinger's proprietary physics-based free energy perturbation (FEP+) modeling technology. These molecules demonstrate strong MALT1 protein binding affinity, potent inhibition of MALT1 enzymatic activity and anti-proliferative activity in the activated B-cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL) cell lines such as OCI-LY3 and OCI-LY10. In combination with approved agents, these inhibitors demonstrate strong combination potential with Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib in ABC-DLBCL cell lines. In ABC-DLBCL CDX models, our representative MALT1 inhibitor induces tumor regression as a single agent and complete tumor regression in combination with ibrutinib. Our representative MALT1 inhibitor, when tested in LY2298 PDX models, demonstrates similar results. In addition, our representative MALT1 inhibitor was explored in a CDX model derived from a Mantle cell lymphoma REC-1 cell line, and demonstrates strong anti-tumor activity of ~78% tumor growth inhibition (TGI) as a single agent. Conclusions: Schrodinger's novel, potent MALT1 protease small molecule inhibitors are efficacious in in vitro B-cell lymphoma cell proliferation assays and in in vivo B-cell lymphoma xenograft models. These data suggest that targeting MALT1 may expand therapeutic options for patients with selected B-cell lymphomas, such as ABC-DLBCL, with the possibility of expanding into other B-cell lymphomas such as MCL. Furthermore, these small molecule MALT1 inhibitors demonstrate potential in combination with BTKi to overcome drug-induced resistance in patients with relapsed/refractory B-cell lymphomas. Taken together, the data presented here strongly underscore the therapeutic potential of our MALT1 inhibitor and support further evaluation in clinical trials. Disclosures Weiss: Schrodinger: Current Employment; ARTham Therapeutics: Membership on an entity's Board of Directors or advisory committees.

With the rapid growth of high-resolution remote sensing image-based applications, one of the fundamental problems in managing the increasing number of remote sensing images is automatic object detection. In this paper, we present a fusion feature-based deep learning approach to detect objects in high-resolution remote sensing images. It employs fine-tuning from ImageNet as a pre-training model to address the challenge of it lacking a large amount of training datasets in remote sensing. Besides, we improve the binarized normed gradients algorithm by multiple weak feature scoring models for candidate window selection and design a deep fusion feature extraction method with the context feature and object feature. Experiments are performed on different sizes of high-resolution optical remote sensing images. The results show that our model is better than regular models, and the average detection accuracy is 8.86% higher than objNet.

Knowledge of the geochemical behavior of selenium and strontium is critical for the safe disposal of radioactive wastes. Goethite, as one of the most thermodynamically stable and commonly occurring natural iron oxy-hydroxides, promisingly retains these elements. This work comprehensively studies the adsorption of Se(IV) and Sr(II) on goethite. Starting from electrokinetic measurements, the binary and ternary adsorption systems are investigated and systematically compared via batch experiments, EXAFS analysis, and CD-MUSIC modeling. Se(IV) forms bidentate inner-sphere surface complexes, while Sr(II) is assumed to form outer-sphere complexes at low and intermediate pH and inner-sphere complexes at high pH. Instead of a direct interaction between Se(IV) and Sr(II), our results indicate an electrostatically driven mutual enhancement of adsorption. Adsorption of Sr(II) is promoted by an average factor of 5 within the typical groundwater pH range from 6 to 8 for the concentration range studied here. However, the interaction between Se(IV) and Sr(II) at the surface is two-sided, Se(IV) promotes Sr(II) outer-sphere adsorption, but competes for inner-sphere adsorption sites at high pH. The complexity of surfaces is highlighted by the inability of adsorption models to predict isoelectric points without additional constraints.

Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide] is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G2–M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC50 values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC50 >1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested. In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 has entered clinical evaluation in patients with advanced cancers. Mol Cancer Ther; 11(3); 700–9. ©2011 AACR.

This paper deals with the root choice strategy for tree decomposition when multiple agents (processors) are deployed. Tree decomposition is one of the most important decompositions in graph theory. It not only plays a role in theoretical investigations but also has widely practical applications. The reason is that many hard problems can be divided into sub-problems within the nodes in tree decomposition. When solving problems in tree decomposition, the precedence constraints graph takes the form of a tree. The first step is to choose a root since tree decomposition does not define any root. In addition, the root choice affects the time complexity when parallel processing is employed. The main findings of this paper are: a) an algorithm for determining the root which makes the latest completion time minimum; b) some results of the allocation of the optimal root; c) an improved version algorithm using branch-and-bound strategy based on the results. In addition, remarks and future works are presented.

FabH (β-ketoacyl-acyl carrier protein synthase III) is unique in that it initiates fatty acid biosynthesis, is inhibited by long-chain fatty acids providing means for feedback control of the process, and dictates the fatty acid profile of the organism by virtue of its substrate specificity. We report the crystal structures of bacterial FabH enzymes from four different pathogenic species: Enterococcus faecalis, Haemophilus influenzae, Staphylococcus aureus and Escherichia coli. Structural data on the enzyme from different species show important differences in the architecture of the substrate-binding sites that parallel the inter-species diversity in the substrate specificities of these enzymes.