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Supplementary Figure Legends, Table Legend

In vivo efficacy studies comparing PF-06463922 treatment at 10 mg/kg/day (5 mg/kg BID) and 3 mg/kg/day (1.5 mg/kg BID) with crizotinib treatment at 100 mg/kg QD in: A, Felix-PDX xenografts and B, SH-SY5Y xenografts.

PF-06463922 is potent against ALK-mutated NB cell lines in vitro. Mean (n=3) IC50 values ({plus minus} SD) for crizotinib and PF-06463922 are listed for 10 NB cell lines harboring the indicated ALK aberrations, plus one NSCLC cell line (NCI-H3122). Fold increases in the IC50 values with crizotinib over those measured for PF-06463922 are also listed in the right-most column.

Neuroblastomas harboring activating point mutations in anaplastic lymphoma kinase (ALK) are differentially sensitive to the ALK inhibitor crizotinib, with certain mutations conferring intrinsic crizotinib resistance. To overcome this clinical obstacle, our goal was to identify inhibitors with improved potency that can target intractable ALK variants such as F1174L. We find that PF-06463922 has high potency across ALK variants and inhibits ALK more effectively than crizotinib in vitro. Most importantly, PF-06463922 induces complete tumor regression in both crizotinib-resistant and crizotinib-sensitive xenograft mouse models of neuroblastoma, as well as in patient-derived xenografts harboring the crizotinib-resistant F1174L or F1245C mutations. These studies demonstrate that PF-06463922 has the potential to overcome crizotinib resistance and exerts unprecedented activity as a single targeted agent against F1174L and F1245C ALK-mutated xenograft tumors, while also inducing responses in an R1275Q xenograft model. Taken together, these results provide the rationale to move PF-06463922 into clinical trials for treatment of patients with ALK-mutated neuroblastoma.Significance: The next-generation ALK/ROS1 inhibitor PF-06463922 exerts unparalleled activity in ALK-driven neuroblastoma models with primary crizotinib resistance. Our biochemical and in vivo data provide the preclinical rationale for fast-tracking the development of this agent in children with relapsed/refractory ALK-mutant neuroblastoma. Cancer Discov; 6(1); 96–107. ©2015 AACR.See related commentary by Versteeg and George, p. 20.This article is highlighted in the In This Issue feature, p. 1

Purpose:EGFR exon 19 deletion (Ex19Del) mutations account for approximately 60% of lung cancer–associated EGFR mutations and include a heterogeneous group of mutations. Although they are associated with benefit from tyrosine kinase inhibitors (TKI), the relative inhibitor sensitivity of individual Ex19Del mutations is unknown.Experimental Design: We studied the TKI sensitivity and structural features of common Ex19Del mutations and the consequences for patient outcomes on TKI treatment.Results:We found that the L747-A750>P mutation, which represents about 4% of all Ex19Del mutations, displays unique inhibitor selectivity. L747-A750>P differs from other Ex19Del mutations in not being suppressed completely by erlotinib or osimertinib, yet is completely inhibited by low doses of afatinib. The HCC4006 cell line (with the L747-A750>P mutation) exhibited increased sensitivity to afatinib over erlotinib and osimertinib, and computational modeling suggests explanations for this sensitivity pattern. Clinically, patients with EGFR L747-A750>P mutant tumors showed inferior outcomes when treated with erlotinib than patients with E746-A750 mutant tumors.Conclusions:These results highlight important differences between specific Ex19Del mutations that may be relevant for optimizing TKI choice for patients.

Supplementary Figure Legends

Radical pairs generated in crystalline solids by bond cleavage reactions of triplet ketones offer the unique opportunity to explore a frontier of spin dynamics where rigid radicals are highly entangled as the result of short inter-radical distances, large singlet-triplet energy gaps (ΔEST), and limited spin-lattice relaxation mechanisms. Here we report the pulsed laser generation and detection of strongly entangled triplet acyl-alkyl radical pairs generated in nanocrystalline suspensions of 1,1-diphenylmethyl 2-ketones with various 3-admantyl substituents. The sought-after triplet acyl-alkyl radical pairs could be studied for the first time in the solid state by taking advantage of the efficient triplet excited state α-cleavage reactions of 1,1-diphenylmethyl ketones and the slow rate of CO loss from the acyl radicals, which would have to generate highly unstable phenyl and primary alkyl radicals or relatively unstable secondary and tertiary alkyl radicals. With the loss of CO prevented, the lifetime of the triplet acyl-alkyl radical pair intermediates is determined by intersystem crossing to the singlet radical pair state, which is followed by immediate bond formation to the ground state starting ketone. Experimental results revealed biexponential kinetics with long-lived components that account for ca. 87-92% of the transient population and lifetimes that extend to the range of 53-63 μs, the longest reported so far for this type of radical pair. Structural information inferred from the starting ketone will make it possible to analyze the affects of proximity and orientation of the singly occupied orbitals and potentially help set a path for the use of triplet radical pairs as qubits in quantum information technologies.

Pharmaceutical toxicity evaluations often use in vitro systems involving primary cells, cell lines or red blood cells (RBCs). Cell-based analyses ('bioassays') can be cumbersome and typically rely on hard-to-standardize biological materials. Amphotericin B (AmB) toxicity evaluations are primarily based on potassium release from RBCs and share these limitations. This study evaluates the potential substitution of two physicochemical AmB toxicity approaches for the bioassay: Ultraviolet-visible spectroscopy (UV-vis) and in vitro drug release kinetics. UV-vis spectral analyses indicated that liposomal AmB's (L-AmB) main peak position (λ

In this paper, an integrated transformer design methodology for dual-active-bridge (DAB) converters, which basically utilize leakage inductance so as to substitute a cumbersome inductor in the conventional DAB converters, is newly proposed. The proposed integrated transformer with integrated leakage inductance inherently includes leakage inductance and magnetizing inductance, whose values can be appropriately selected by modulating the number of turns and the center-core air-gap. Based on the theoretical analysis of the DAB converters, the major parameters, i.e., primary and secondary current levels and its phase difference, can be derived, and these values are utilized for magnetic analysis of the proposed integrated transformer. Considering core loss and copper loss of the proposed integrated transformer in the DAB converters, optimal values of the center-core air-gap $l_{g}$ and the optimal number of turns $N_{\mathrm {1,}op} ~\&~ N_{\mathrm {2,}op}$ can be determined so that high power efficiency is achieved at a normal operating point of the DAB converters. The 20W prototypes of the DAB converter with EER2834 and EER3019 of the ferrite cores were fabricated and verified by simulation and experiment. The design results showed that the optimal number of turns at $l_{g} =2.0$ mm are found to be 11 and 10, for the EER2834 and EER3019, respectively. Compared to 94.5% and 96.3% of AC efficiencies for the conventional transformer and inductor set, the proposed integrated transformer achieved 95.8% and 96.9% of AC efficiencies at maximum power transfer point of $\theta _{p} = \pi $ /2 for EER2834 and EER3019, respectively.

This study aimed to test the mediating effect of self-transcendence on the relationship between academic self-efficacy and life satisfaction. Data were analyzed through multiple regression using Ba...

The physicochemical properties of complex drug formulations, including liposomes, suspensions, and emulsions, are important for understanding drug release mechanisms, quality control, and regulatory assessment. It is ideal to characterize these complex drug formulations in their native hydrated state. This article describes the characterization of complex drug formulations in a frozen-hydrated state using cryogenic scanning electron microscopy (cryo-SEM). In comparison to other techniques, such as optical microscopy or room-temperature scanning electron microscopy, cryo-SEM combines the advantage of studying hydrated samples with high-resolution imaging capability. Detailed information regarding cryo-fixation, cryo-fracture, freeze-etching, sputter-coating, and cryo-SEM imaging is included in this article. A multivesicular liposomal complex drug formulation is used to illustrate the impact of different cryogenic sample preparation conditions. In addition to drug formulations, this approach can also be applied to biological samples (e.g., cells, bacteria) and soft-matter samples (e.g., hydrogels). © Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Basic Protocol 1: Cryo-fixation to preserve the native structure of samples using planchettes Alternate Protocol: Cryo-fixation to preserve the native structure of biological samples on sapphire disks Basic Protocol 2: Sample preparation for cross-sectional cryo-SEM imaging Basic Protocol 3: Cryo-SEM imaging and microanalysis.

Methods to catalog and computationally assess the mutational landscape of proteins in human cancers are desirable. One approach is to adapt evolutionary or data-driven methods developed for predicting whether a single-nucleotide polymorphism (SNP) is deleterious to protein structure and function. In cases where understanding the mechanism of protein activation and regulation is desired, an alternative approach is to employ structure-based computational approaches to predict the effects of point mutations. Through a case study of mutations in kinase domains of three proteins, namely, the anaplastic lymphoma kinase (ALK) in pediatric neuroblastoma patients, serine/threonine-protein kinase B-Raf (BRAF) in melanoma patients, and erythroblastic oncogene B 2 (ErbB2 or HER2) in breast cancer patients, we compare the two approaches above. We find that the structure-based method is most appropriate for developing a binary classification of several different mutations, especially infrequently occurring ones, concerning the activation status of the given target protein. This approach is especially useful if the effects of mutations on the interactions of inhibitors with the target proteins are being sought. However, many patients will present with mutations spread across different target proteins, making structure-based models computationally demanding to implement and execute. In this situation, data-driven methods-including those based on machine learning techniques and evolutionary methods-are most appropriate for recognizing and illuminate mutational patterns. We show, however, that, in the present status of the field, the two methods have very different accuracies and confidence values, and hence, the optimal choice of their deployment is context-dependent.

Significance High-risk tumors are genomically heterogeneous, harboring gene amplifications and mutations. The activation status of mutated proteins in cancer can profoundly impact disease progression, patient response, and drug sensitivity. Yet, outside of a few hotspot mutations, functional studies of clinically observed mutations are not commonly pursued. We report a combined experimental profiling and computational analysis of the effects of clinically observed and “test” mutations in the kinase domain of anaplastic lymphoma kinase (ALK), a known oncogenic driver in pediatric neuroblastoma. We find that the activation status of the mutated protein is a good indicator of the transforming ability in NIH 3T3 cells. We also report biophysical as well as data-driven models with predictive power to profile these mutant kinases in silico., Kinases play important roles in diverse cellular processes, including signaling, differentiation, proliferation, and metabolism. They are frequently mutated in cancer and are the targets of a large number of specific inhibitors. Surveys of cancer genome atlases reveal that kinase domains, which consist of 300 amino acids, can harbor numerous (150 to 200) single-point mutations across different patients in the same disease. This preponderance of mutations—some activating, some silent—in a known target protein make clinical decisions for enrolling patients in drug trials challenging since the relevance of the target and its drug sensitivity often depend on the mutational status in a given patient. We show through computational studies using molecular dynamics (MD) as well as enhanced sampling simulations that the experimentally determined activation status of a mutated kinase can be predicted effectively by identifying a hydrogen bonding fingerprint in the activation loop and the αC-helix regions, despite the fact that mutations in cancer patients occur throughout the kinase domain. In our study, we find that the predictive power of MD is superior to a purely data-driven machine learning model involving biochemical features that we implemented, even though MD utilized far fewer features (in fact, just one) in an unsupervised setting. Moreover, the MD results provide key insights into convergent mechanisms of activation, primarily involving differential stabilization of a hydrogen bond network that engages residues of the activation loop and αC-helix in the active-like conformation (in >70% of the mutations studied, regardless of the location of the mutation).

The mTORC1 (mechanistic target of rapamycin complex 1) protein kinase regulates growth in response to nutrients and growth factors. Nutrients promote its translocation to the lysosomal surface, where its Raptor subunit interacts with the Rag guanosine triphosphatase (GTPase)-Ragulator complex. Nutrients switch the heterodimeric Rag GTPases among four different nucleotide-binding states, only one of which (RagA/B•GTP-RagC/D•GDP) permits mTORC1 association. We used cryo-electron microscopy to determine the structure of the supercomplex of Raptor with Rag-Ragulator at a resolution of 3.2 angstroms. Our findings indicate that the Raptor α-solenoid directly detects the nucleotide state of RagA while the Raptor "claw" threads between the GTPase domains to detect that of RagC. Mutations that disrupted Rag-Raptor binding inhibited mTORC1 lysosomal localization and signaling. By comparison with a structure of mTORC1 bound to its activator Rheb, we developed a model of active mTORC1 docked on the lysosome.

BACKGROUND Postoperative sore throat and airway injuries are relatively common after double-lumen tube (DLT) intubation. OBJECTIVE The current study aimed to evaluate the effects of fibreoptic-guided advance of DLT on postoperative sore throat and airway injuries associated with intubation. DESIGN A randomised controlled study. SETTING Tertiary hospital, Seongnam, Korea, from January 2018 to January 2019. PATIENTS One hundred twenty three patients undergoing one-lung ventilation with a left-side DLT were randomised into two groups: 62 in the conventional group and 61 in the fibreoptic-guided group. INTERVENTION After entering the glottis, the DLT was rotated left 90° and advanced blindly into the left main bronchus in the conventional group. In the fibreoptic-guided group, DLT was advanced into the main bronchus under the guide of fibreoptic bronchoscope, which had been passed through the bronchial lumen and inserted into the left main bronchus. MAIN OUTCOME MEASURES The primary outcome was postoperative sore throat at 24 h after operation. The airway injuries were also examined using a bronchoscope during extubation. RESULTS At postoperative 24 h, the fibreoptic-guided group showed lower pain score (P = 0.001) and lower incidence (risk ratio [95% CI]: 0.2 [0.1 to 0.5], P

Recent work has shown that diarylmethyl radicals generated by pulsed laser excitation in nanocrystalline (NC) suspensions of tetraarylacetones constitute a valuable probe for the detailed mechanistic analysis of the solid-state photodecarbonylation reaction. Using a combination of reaction quantum yields and laser flash photolysis in nanocrystalline suspensions of ketones with different substituents on one of the α-carbons, we are able to suggest with confidence that a significant fraction of the initial α-cleavage reaction takes place from the ketone singlet excited state, that the originally formed diarylmethyl-acyl radical pair loses CO in the crystal with time constants in the sub-nanosecond regime, and that the secondary bis(diarylmethyl) triplet radical pair has a lifetime limited by the rate of intersystem crossing of ca. 70 ns.

Taking advantage of an operationally simple technique to perform transmission pump–probe spectroscopy in crystalline solids, based on the use nanocrystalline suspensions in water, we analyzed the intermediates in the photodenitrogenation of a Δ2-1,2,3-triazoline bearing a benzophenone group that served as an internal triplet sensitizer. Measurements carried out in acetonitrile solution revealed the formation of a transient with a λmax= 570 nm with a lifetime of 70 ns. Measurements in the solid state displayed an analogous blue-shifted transient with a λmax= 510 nm that first grows and then decays with time constants of 63 and 270 ns, respectively. Based on the comparison of the observed transient spectra with the one obtained from an independently generated aminyl radical, we assign it to the corresponding 1,3,-alkyl-aminyl biradical. We conclude that triplet state denitrogenation and the subsequent intersystem crossing-limited product formation are slower in the solid state than in solution.

Aqueous nanocrystalline suspensions provide a simple and efficient medium for performing transmission spectroscopy measurements in the solid state. In this Letter we describe the use of laser flash photolysis methods to analyze the photochemistry of 2-azidobiphenyl and several aryl-substituted derivatives. We show that all the crystalline compounds analyzed in this study transform quantitatively into carbazole products via a crystal-to-crystal reconstructive phase transition. While the initial steps of the reaction cannot be followed within the time resolution of our instrument (ca. 8 ns), we detected the primary isocarbazole photoproducts and analyzed the kinetics of their formal 1,5-H shift reactions, which take place in time scales that range from a few nanoseconds to several microseconds. It is worth noting that the high reaction selectivity observed in the crystalline state translates into a clean and simple kinetic process compared to that in solution.

Biological sequence alignment has been used in many application areas of computational biology and bioinformatics and both non-heuristic and heuristic algorithms have been developed and used. Although the high accuracy is guaranteed, non-heuristic approaches, such as Smith-Waterman algorithm, are not popularly used in the real world due to the quadratic time complexity. However, recent technological development on HPC systems made researchers propose a diversified acceleration approaches of the Smith-Waterman algorithm, including GPU based approaches. In this paper, we propose efficient CPU-GPU collaborated computation models for protein sequence alignment based on the Smith-Waterman algorithm to exploit the maximum efficiency on the heterogeneous system with multicore processor(s) and GPU(s). The proposed approach implements the full functionalities of the local sequence alignment, which are BLAST compatible, and uses efficient strategies for work load balancing and exploiting the maximum performance on the heterogeneous system. Our experimental results showed that the best CPU-GPU collaborated computation model outperforms the corresponding serial and the basic GPU computation models with 30.5x and 2.78x speedups, respectively, on the system with two Xeon E5-2670 processors and a Tesla M2075 GPU.

Dysregulated mTORC1 signaling alters a wide range of cellular processes, contributing to metabolic disorders and cancer. Defining the molecular details of downstream effectors is thus critical for uncovering selective therapeutic targets. We report that mTORC1 and its downstream kinase S6K enhance eIF4A/4B-mediated translation of Wilms’ tumor 1-associated protein (WTAP), an adaptor for the N(6)-methyladenosine (m(6)A) RNA methyltransferase complex. This regulation is mediated by 5’UTR of WTAP mRNA that is targeted by eIF4A/4B. Single nucleotide-resolution m(6)A mapping revealed that MAX dimerization protein 2 (MXD2) mRNA contains m(6)A, and increased m(6)A modification enhances its degradation. WTAP induces cMyc-MAX association by suppressing MXD2 expression, which promotes cMyc transcriptional activity and proliferation of mTORC1-activated cancer cells. These results elucidate a mechanism whereby mTORC1 stimulates oncogenic signaling via m(6)A RNA modification and illuminates WTAP-MXD2-cMyc axis as a potential therapeutic target for mTORC1-driven cancers.

The problem of finding unknown motifs in DNA sequences has been studied seriously in last three decades and a variety of solution approaches have appeared in the literature. We present an efficient combinatorial approach of finding the optimum motif(s) with the maximum accuracy based on a couple of hash based heuristics, which greatly reduce the searching space and unnecessary computations used in the traditional tree based branch and bound mechanism. The proposed approach was tested for performance with various sized real world datasets and our experimental results showed that the proposed approach achieved the maximum accuracy within the practical time, even better than some popularly used approximate and suffix tree based approaches in most of the cases we tested in our practice.

In this paper, we propose an efficient three-module pedagogical system for embedded systems learning, which will provide students effective ways of learning embedded systems through basic concepts, current technology for hardware and software design, and team projects. The proposed pedagogical approach is based on the systematic learning through evidence-based teaching, knowledge mobilization, and research strategies. In our approach, it is recommended to use two platforms, µVision (simulator) and one microcontroller (hardware), such as Arduino or Raspberry Pi. Raspberry Pi is a small single-board computer, which can be used as a brain for innovative computing projects, such as network monitoring tool, at a reasonable cost. Arduino is the most popular microcontroller (based on the ATmega328), which is a flexible and easy-to-use device for conducting various embedded systems projects. Those platforms have been used for many embedded systems projects, including home automation, Internet of Things, robots, games, and servers. We evaluated our proposed three modules based on student performance and feedback. As a result, we conclude that the proposed modules work better than a traditional learning methodology.

Taking advantage of an operationally simple technique to perform transmission pump-probe spectroscopy in crystalline solids, based on the use nanocrystalline suspensions in water, we analyzed the intermediates in the photodenitrogenation of a Δ

Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.

The nanosecond electronic spectra and kinetics of the radical pairs from various crystalline tetraarylacetones were obtained using transmission laser flash photolysis methods by taking advantage of aqueous nanocrystalline suspensions in the presence of submicellar CTAB, which acts as a surface passivator. After showing that all tetraarylacetones react efficiently by a photodecarbonylation reaction in the crystalline state, we were able to detect the intermediate radical pairs within the ca. 8 ns laser pulse of our laser setup. We showed that the solid-state spectra of the radical pairs are very similar to those detected in solution, with λmax in the 330–360 nm range. Kinetics in the solid state was observed to be biexponential and impervious to the presence of oxygen or variations in laser power. A relatively short-lived component (0.3–1.7 μs) accounts for only 3–8% of the total decay with a longer-lived component having a time constant in the range of 40–90 μs depending on the nature of the substituents.

As with other groups of protein kinases, approximately 10% of the RTKs (receptor tyrosine kinases) in the human proteome contain intracellular pseudokinases that lack one or more conserved catalytically important residues. These include ErbB3, a member of the EGFR (epidermal growth factor receptor) family, and a series of unconventional Wnt receptors. We showed previously that, despite its reputation as a pseudokinase, the ErbB3 TKD (tyrosine kinase domain) does retain significant, albeit weak, kinase activity. This led us to suggest that a subgroup of RTKs may be able to signal even with very inefficient kinases. Recent work suggests that this is not the case, however. Other pseudokinase RTKs have not revealed significant kinase activity, and mutations that impair ErbB3′s weak kinase activity have not so far been found to exhibit signalling defects. These findings therefore point to models in which the TKDs of pseudokinase RTKs participate in receptor signalling by allosterically regulating associated kinases (such as ErbB3 regulation of ErbB2) and/or function as regulated ‘scaffolds’ for other intermolecular interactions central to signal propagation. Further structural and functional studies, particularly of the pseudokinase RTKs involved in Wnt signalling, are required to shed new light on these intriguing signalling mechanisms.

To evaluate the suitability of the Weaponeering tool for the Surface to Surface Guided Missile at the AboveGround Buildings, we analyzed the relation among SSPD,   , CEP and the number of missiles, expected damage etc.. According to the analysis, if the target Length is 100m, and    is longer than the target length, the tool is suitable but shorter than it, the tool is not suitable. So Morris Driels's Weaponeering Tool needs new adaptive algorithm to Translate as the Target size and  .

Activating mutations in protein kinases drive many cancers. While how recurring point mutations affect kinase activity has been described, the effect of in-frame deletions is not well understood. We show that oncogenic deletions within the β3-αC loop of HER2 and BRAF are analogous to the recurrent EGFR exon 19 deletions. We identify pancreatic carcinomas with BRAF deletions mutually exclusive with KRAS mutations. Crystal structures of BRAF deletions reveal the truncated loop restrains αC in an active "in" conformation, imparting resistance to inhibitors like vemurafenib that bind the αC "out" conformation. Characterization of loop length explains the prevalence of five amino acid deletions in BRAF, EGFR, and HER2 and highlights the importance of this region for kinase activity and inhibitor efficacy.

The nar promoter, a dissolved oxygen (DO)-dependent promoter in Escherichia coli, is simply induced and functional in any cell growth phase, which are advantageous for producing biochemicals/fuels on an industrial scale. To demonstrate the feasibility of using the nar promoter in the metabolic engineering of biochemicals/biofuels in E. coli, three target pathways were examined: the d-lactate, 2,3-butandiol (2,3-BDO), and 1,3-propanediol (1,3-PDO) pathways consisting of one, three, and six genes, respectively. Each pathway gene was expressed under the control of the nar promoter. When the ldhD gene was expressed in fed-batch culture, the titer, yield, and productivity of d-lactate were 113.12 ± 2.37 g/L, 0.91 ± 0.07 g/g-glucose, and 4.19 ± 0.09 g/L/h, respectively. When three 2,3-BDO pathway genes (ilvBN, aldB, bdh1) were expressed in fed-batch culture, the titer, yield, and productivity of (R,R)-2,3-BDO were 48.0 ± 8.48 g/L, 0.43 ± 0.07 g/g glucose, and 0.76 ± 0.13 g/L/h, respectively. When six 1,3-PDO pathway genes (dhaB1B2B3, yqhD, gdrA, and gdrB) were expressed in fed-batch culture, the titer, yield, and productivity of 1,3-PDO were 15.8 ± 0.62 g/L, 0.35 ± 0.01 g/g-glycerol, and 0.25 ± 0.01 g/L/h, respectively. Based on the reasonable performance comparable to that observed in previous studies using different promoters in metabolic engineering, the nar promoter can serve as a controlled expression tool for developing a microbial system to efficiently produce biochemicals and biofuels. Biotechnol. Bioeng. 2017;114: 468-473. © 2016 Wiley Periodicals, Inc.

The heterodimeric receptor tyrosine kinase complex formed by HER2 and HER3 can act as an oncogenic driver and is also responsible for rescuing a large number of cancers from a diverse set of targeted therapies. Inhibitors of these proteins, particularly HER2, have dramatically improved patient outcomes in the clinic, but recent studies have demonstrated that stimulating the heterodimeric complex, either via growth factors or by increasing the concentrations of HER2 and HER3 at the membrane, significantly diminishes the activity of the inhibitors. To identify an inhibitor of the active HER2-HER3 oncogenic complex, we developed a panel of Ba/F3 cell lines suitable for ultra-high-throughput screening. Medicinal chemistry on the hit scaffold resulted in a previously uncharacterized inhibitor that acts through preferential inhibition of the active state of HER2 and, as a result, is able to overcome cellular mechanisms of resistance such as growth factors or mutations that stabilize the active form of HER2.

A technique to communicate with a smart sensor device using the Web is currently being developed. When the user approaches the device, like a beacon, the device sends a URL to the built-in sensor to the user’s smartphone. With this URL, the user can communicate with the smart sensor device through a Web interface. When communicating with a beacon using a Web interface, encryption is required for secure communication between the Web browser and beacon. In this paper, we propose secure communication using a symmetric key distribution. Our method prevents malicious applications from eavesdropping on messages and replaying a message. In addition, we evaluated the execution time.