Extended Kalman Filter-Based Vehicle Tracking Using Uniform Planar Array for Vehicle Platoon Systems.

We develop an extended Kalman filter-based vehicle tracking algorithm, specifically designed for uniform planar array layouts and vehicle platoon scenarios. We first propose an antenna placement strategy to design the optimal antenna array configuration for precise vehicle tracking in vehicle-to-infrastructure networks. Furthermore, a vehicle tracking algorithm is proposed to improve the position estimation performance by specifically considering the characteristics of the state evolution model for vehicles in the platoon. The proposed algorithm enables the sharing of corrected error transition vectors among platoon vehicles, for the purpose of enhancing the tracking performance for vehicles in unfavorable positions. Lastly, we propose an array partitioning algorithm that effectively divides the entire antenna array into sub-arrays for vehicles in the platoon, aiming to maximize the average tracking performance. Numerical studies verify that the proposed tracking and array partitioning algorithms improve the position estimation performance.

Development of a Dual-Factor Activatable Covalent Targeted Photoacoustic Imaging Probe for Tumor Imaging.

Photoacoustic imaging (PAI) is an emerging modality in biomedical imaging with superior imaging depth and specificity. However, PAI still has significant limitations, such as the background noise from endogenous chromophores. To overcome these limitations, we developed a covalent activity-based PAI probe, NOx-JS013, targeting NCEH1. NCEH1, a highly expressed and activated serine hydrolase in aggressive cancers, has the potential to be employed for the diagnosis of cancers. We show that NOx-JS013 labels active NCEH1 in live cells with high selectivity relative to other serine hydrolases. NOx-JS013 also presents its efficacy as a hypoxia-responsive imaging probe in live cells. Finally, NOx-JS013 successfully visualizes aggressive prostate cancer tumors in mouse models of PC3, while being negligibly detected in tumors of non-aggressive LNCaP mouse models. These findings show that NOx-JS013 has the potential to be used to develop precision PAI reagents for detecting metastatic progression in various cancers.

Structure-activity relationship of 7-aryl-2-anilino-pyrrolopyrimidines as Mer and Axl tyrosine kinase inhibitors.

The TAM (Axl, Mer, and Tyro3) family is implicated in the survival and chemoresistance of tumours and has emerged as a potential therapeutic target. A novel series of 7-aryl-2-anilino-pyrrolopyrimidines were identified as potent Axl/Mer tyrosine kinase inhibitors without significant inhibition of Tyro3. A representative compound 27 exhibited IC50 values of 2 nM and 16 nM for Mer and Axl, respectively, and considerable inhibition for Mer phosphorylation in cells. Docking studies suggested that the formation of a salt bridge between the nitrogen of the aniline moiety with ASP678 of the Mer kinase domain as well as an interaction with the hinge region that most kinase inhibitors have in common would be essential to retain activity. These results could provide useful information for finding promising inhibitors of Axl/Mer for the treatment of cancer.

Synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as TAK1 inhibitors.

The importance of transforming growth factor beta-activated kinase 1 (TAK1) to cell survival has been demonstrated in many studies. TAK1 regulates signalling cascades, the NF-κB pathway and the mitogen-activated protein kinase (MAPK) pathway. TAK1 inhibitors can induce the apoptosis of cancerous cells, and irreversible inhibitors such as (5Z)-7-oxozeaenol are highly potent. However, they can react non-specifically with cysteine residues in proteins, which may have serious adverse effects. Reversible covalent inhibitors have been suggested as alternatives. We synthesised imidazopyridine derivatives as novel TAK1 inhibitors, which have 2-cyanoacrylamide moiety that can form reversible covalent bonding. A derivative with 2-cyano-3-(6-methylpyridin-2-yl)acrylamide (13h) exhibited potent TAK1 inhibitory activity with an IC50 of 27 nM. It showed a reversible reaction with ß-mercaptoethanol, which supports its potential as a reversible covalent inhibitor.

Visual Prognostic Factors of Epiretinal Membrane Surgery in Patients with Pseudophakia.

PURPOSE: To evaluate the visual prognostic factors in patients with pseudophakic epiretinal membrane (ERM) after vitrectomy using spectral domain optical coherence tomography (SD-OCT). METHOD: A retrospective review of patients with pseudophakic ERM having undergone vitrectomy was conducted. Best corrected visual acuity (BCVA) and SD-OCT were conducted before and 1, 3, and 6 months after vitrectomy. Known visual prognostic factors, such as inner-retina irregularity index, central foveal thickness (CFT), central inner retinal layer thickness (CIRLT), cone outer segment tip defect length, and photoreceptor outer segment length, were reviewed and their correlation with BCVA was analyzed. RESULTS: Forty-three patients (mean age: 64.88 ± 10.46 years) with pseudophakic ERM were included. BCVA significantly improved after vitrectomy (logMAR 0.30 ± 0.24 vs. 0.11 ± 0.14, p < 0.001). The preoperative high inner-retina irregularity index significantly correlated with poor postoperative BCVA in patients with pseudophakic ERM (correlation coefficient 0.583, p < 0.001). Postoperative improvements of inner retinal SD-OCT findings, such as inner-retina irregularity index, CFT, and CIRLT, were significantly associated with the amount of BCVA improvement after ERM surgery (correlation coefficients were as follows: inner-retina irregularity index - 0.711, p < 0.001; CFT - 0.462, p = 0.002; CIRLT - 0.596, p < 0.001). However, preoperative outer retinal SD-OCT findings were not associated with postoperative visual prognosis. CONCLUSION: From this study, we determined the visual prognostic factors of ERM surgery without confounding factors, such as visual acuity improvement following combined cataract surgery, and inner retinal SD-OCT findings more significantly associated with the visual prognosis of ERM surgery compared to outer retinal SD-OCT findings.

Full-Duplex Relay for Millimeter Wave Vehicular Platoon Communciations.

The safety and consistency of platoon-based driving are guaranteed via reliable communication between vehicles in a platoon. In this paper, we propose to exploit a full-duplex (FD) relay vehicle for millimeter-wave vehicular communications in platoon-based driving. Considering that a lead vehicle broadcasts information to all vehicles in a platoon, we consider two power allocation problems-maximizing broadcast information rates with a power constraint and minimizing power consumption with a quality-of-service constraint. In particular, for a four-vehicle platoon communication, we derive closed-form solutions for optimal power allocation and present numerical results to verify the performance of the proposed FD relay vehicles.

Click chemistry for improvement in selectivity of quinazoline-based kinase inhibitors for mutant epidermal growth factor receptors.

Discovery of mutant-selective kinase inhibitors is one of the challenges in medicinal chemistry and is a main issue for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. We tried to improve the selectivity of pan-HER inhibitors for mutant EGFRs. Utilizing click chemistry, triazole-tethered quinazoline derivatives were synthesized, based on a quinazoline scaffold showing pan-HER inhibition. The representative compound 5j exhibited 17- and 52-fold improved selectivity for EGFR L858R/T790M over wild-type EGFR and HER2, respectively, and demonstrated 6.7-fold more potent antiproliferative activity against PC9 cells harboring EGFR-activating mutation than gefitinib. Although the described quinazolines did not surpass pyrimidines as 3rd generation EGFR inhibitors in terms of selectivity for mutant EGFRs, our approach might provide information that would help in the identification of mutant-selective compounds among pan-HER inhibitors using the quinazoline scaffold.

Design, synthesis and cytotoxicity of chimeric erlotinib-alkylphospholipid hybrids.

Two series of erlotinib-alkylphospholipid hybrids were prepared and evaluated for their antiproliferative activities against a panel of four cell lines representing lung, breast, liver and skin cancers using erlotinib and miltefosine as reference standards. Amide analogs elicited more enhanced cytotoxic activity than analogous esters. Amide derivatives 8d and 8e exhibited promising broad-spectrum antiproliferative activity and higher efficacy than reference erlotinib and miltefosine. Their cellular GI50 values was in the ranges of 24.7-46.9 µM and 26.8-43.1 µM for 8e and 8d respectively. Assay results of the inhibitory activity of the prepared compounds on EGFR kinase reaction and Akt phosphorylation in conjugation with statistical correlation analysis indicated that other mechanisms might contribute to their elicited cytotoxicities. In addition, statistical correlation analysis revealed that mechanisms of elicited cytotoxicities for amide series might be different from ester series. In addition, correlation analysis indicated variations in the mechanisms according to the types of cell line.

Mechanochemical actuators of embryonic epithelial contractility.

Spatiotemporal regulation of cell contractility coordinates cell shape change to construct tissue architecture and ultimately directs the morphology and function of the organism. Here we show that contractility responses to spatially and temporally controlled chemical stimuli depend much more strongly on intercellular mechanical connections than on biochemical cues in both stimulated tissues and adjacent cells. We investigate how the cell contractility is triggered within an embryonic epithelial sheet by local ligand stimulation and coordinates a long-range contraction response. Our custom microfluidic control system allows spatiotemporally controlled stimulation with extracellular ATP, which results in locally distinct contractility followed by mechanical strain pattern formation. The stimulation-response circuit exposed here provides a better understanding of how morphogenetic processes integrate responses to stimulation and how intercellular responses are transmitted across multiple cells. These findings may enable one to create a biological actuator that actively drives morphogenesis.

Identification of arylsulfonamides as ExoU inhibitors.

ExoU is a potent virulence factor of Pseudomonas aeruginosa and is considered a potential therapeutic target. In order to discover novel ExoU inhibitors, we screened an in-house chemical library utilizing a yeast-based screening system. Some sulfonamides displayed significant activity without nonspecific cytotoxicity. We describe a series of sulfonamides as novel ExoU inhibitors, along with a brief structure-activity relationship.

MMS 1001 inhibits melanin synthesis via ERK activation.

Melanin plays major a role in pigmentation of hair, eyes, and skin in mammals. In this study, the inhibitory effects of MMS 1001 on alpha-MSH-stimulated melanogenesis were investigated in B16F10 melanoma cells. MMS 1001 did not show cytotoxic effects up to 10 microM. Melanin content and intracellular tyrosinase activity were inhibited by MMS 1001 treatment in a dose-dependent manner. In Western blot analysis, MITF expression was decreased by MMS 1001. In addition, tyrosinase expressions were also reduced after MMS 1001 treatment. Further results showed that the phosphorylation of ERK was induced by MMS 1001. Moreover, a specific MEK inhibitor, PD98059, abrogated the inhibitory effects of MMS 1001 on melanin production and tyrosinase expression. These results indicate that the hypopigmentary effects of MMS 1001 resulted from the inhibition of MITF and tyrosinase expression via phosphorylation of ERK. Thus, MMS 1001 could be developed as a new effective skin-whitening agent.

Discovery of small molecules that inhibit melanogenesis via regulation of tyrosinase expression.

5,6,7,8-Tetrahydro-4H-cyclohepta[d]isoxazole derivatives were synthesized and evaluated as a novel class of inhibitors for α-melanocyte-stimulating hormone (α-MSH) induced melanogenesis in a mouse melanoma B16F10 cell line. Compound 8e (IC(50)=0.67 µM), 8h (IC(50)=1.01 µM) and 9b (IC(50)=0.99 µM) exhibited a potent inhibitory activity approximately 85- to 126-fold greater than kojic acid, a well-known potent inhibitor. A biochemical study indicates that the activity of this series should be displayed via down-regulation of the expression of tyrosinase.

Small molecules that regulate zymosan phagocytosis of macrophage through deactivation of Rho GTPases.

Phagocytosis and subsequent degradation of pathogens by macrophages play a pivotal role in host innate immune response to microbial infections. To find small molecule regulators for the investigation of complicated phagocytic process, we screened our in-house chemical library and found chemicals which inhibit phagocytosis of zymosan by macrophages. A representative compound 5a reduced phagocytosis of zymosan in both peritoneal macrophages and RAW264.7 cells in a dose-dependent manner. Treatment of 5a led to downregulate the key regulators of phagocytosis, Rac1, Rac2 and Cdc42, and slightly reduced phosphorylation of Akt by zymosan.

Simple method of measuring ocular rotation in supine position during small incision lenticule extraction.

AIM: To introduce a novel measurement method of static cyclotorsion in small incision lenticule extraction (SMILE) and to investigate the effect of preoperative parameters on cyclotorsion and the effect of cyclotorsion on postoperative outcomes. METHODS: The medical records of 242 patients and 484 eyes who underwent SMILE surgery were retrospectively reviewed. Preoperative intraocular pressure, refractive error, and corneal thickness were investigated. Refractive values and visual acuity were measured at 1d, 1, 3, and 6mo. Ocular cyclotorsion in the supine position was measured by calculating the location and angle of the incision site of the cornea in the anterior slit photograph taken after surgery. RESULTS: Of the total 484 eyes in 242 patients, preoperative mean spherical equivalent (SE) was -4.10±1.64 D, and the mean astigmatism was -0.82±0.74 D. Uncorrected distance visual acuity (UCVA) and SE improved significantly after the surgery. Moreover, 219 (45.2%) eyes had excyclotorsion, 235 (48.6%) eyes had incyclotorsion, and 30 (6.2%) eyes had no torsion. The right eyes tended to be excyclotorted, and the left eyes tended to be incyclotorted (P<0.01). The mean cyclotorsion was 1.18°±3.69°, and the mean absolute value of cyclotorsion was 3.14°±2.26°. The range of cyclotorsion was 0.5°-11.4°. It was found that the smaller the preoperative sphere, the higher the amount of cyclotorsion (r=0.11, P=0.016). There was no significant association between the amount of cyclotorsion and preoperative astigmatism. There was no correlation between sex, preoperative corneal thickness, preoperative intraocular pressure, amount of cyclotorsion, and direction of cyclotorsion. The ratio of right eye excyclotorsion and left eye incyclotorsion on 1d was higher than that at 1, 3, and 6mo (all P<0.01). There was no difference between the 1, 3, and 6mo results in the right and left eyes (P=0.15, P=0.16, respectively). CONCLUSION: The newly devised ocular cyclotorsion measurement method can be used to evaluate ocular cyclotorsion after SMILE. Preoperative SE is associated with the amount of cyclotorsion, however, cyclotorsion doesn't have a significant effect on the results of SMILE surgery.

A transcription factor hijacking to regulate RARα by using a chimeric molecule of retinoic acid and a DNA alkylator.

As a model compound for the transcription factor hijacking mechanism of action of DNA damaging agent that simultaneously bind to the nuclear receptor, we designed and synthesized a chimeric molecule, RA-mustard, which can bind with both retinoic acid receptor α (RARα) and DNA. The interaction between RA-mustard with RARα was confirmed by binding assay using RARα-overexpressing cell extract. RA-mustard-modified DNA diminished the RARα-dependent luciferase expression in the RARα-abundant cells.

Discovery of small molecules that enhance astrocyte differentiation in rat fetal neural stem cells.

1,3,4-Oxadiazole derivatives were found to enhance astrocyte differentiation in rat fetal neural stem cells (NSCs). Differentiation activity was assessed by immunocytochemistry and analysis of mRNA expression of astrocyte markers, GFAP and S100. Compounds 7 and 8 showed approximately a two-fold increase in astrocyte differentiation without engagement of neuronal differentiation and detectable cytotoxicity.

Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity.

ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.

Exogenous Addition of 25-Hydroxycholesterol Reduces Level of Very Long-Chain Fatty Acids in X-Linked Adrenoleukodystrophy.

X-Linked adrenoleukodystrophy (X-ALD) is a severe metabolic disorder characterized by the accumulation of very long-chain fatty acids (VLCFAs). Recently, we demonstrated that levels of 25-hydroxycholesterol (25-HC) and cholesterol 25-hydroxylase (CH25H) were found to be elevated in X-ALD. Herein, we report that the exogenous addition of 25-HC significantly reduces C26:0 levels in X-ALD patient-derived fibroblasts and oligodendrocytes differentiated from induced pluripotent stem cells (iPSCs) derived from X-ALD patients. Moreover, 25-HC treatment was found to down-regulate the expression of ELOVL1, a key enzyme for the synthesis of C26. In addition, activation of liver X receptor (LXR), a molecular target of endogenous 25-HC, also reduced C26:0 level. The reduction of C26:0 levels by 25-HC treatment might result, at least partially, from the decrease of ELOVL1 expression as well as the activation of LXR. Our findings could provide a better understanding of the role of 25-HC in X-ALD and useful information to find therapeutic agents to treat X-ALD.

A 3D microvascular network model to study the impact of hypoxia on the extravasation potential of breast cell lines.

Hypoxia is a common feature of the tumor microenvironment. Accumulating evidence has demonstrated hypoxia to be an important trigger of tumor cell invasion or metastasizes via hypoxia-signaling cascades, including hypoxia-inducible factors (HIFs). Microfluidic model can be a reliable in vitro tool for systematically interrogating individual factors and their accompanying downstream effects, which may otherwise be difficult to study in complex tumor tissues. Here, we used an in vitro model of microvascular networks in a microfluidic chip to measure the extravasation potential of breast cell lines subjected to different oxygen conditions. Through the use of HIF-1α knock-down cell lines, we also validated the importance of HIF-1α in the transmigration ability of human breast cell lines. Three human breast cell lines derived from human breast tissues (MCF10A, MCF-7 and MDA-MB-231) were used in this study to evaluate the role of hypoxia in promoting metastasis at different stages of cancer progression. Under hypoxic conditions, HIF-1α protein level was increased, and coincided with changes in cell morphology, viability and an elevated metastatic potential. These changes were accompanied by an increase in the rate of extravasation compared to normoxia (21% O2). siRNA knockdown of HIF-1α in hypoxic tumors significantly decreased the extravasation rates of all the cell lines tested and may have an effect on the function of metastatic and apoptotic-related cellular processes.

Effect of Gravity Acceleration on Choroidal and Retinal Nerve Fiber Layer Thickness: A Swept-Source Optical Coherence Tomography Study.

Purpose: The purpose of this study was to evaluate the effect of gravity acceleration on choroidal and retinal nerve fiber layer (RNFL) thickness using swept-source optical coherence tomography (SS-OCT). Methods: Thirteen healthy volunteers who planned to participate in human centrifuge training as part of the flight surgeon selection process enrolled this study. During centrifuge training, gravity was gradually increased up to six times that of sea level. All subjects underwent complete ophthalmologic examination and three-dimensional wide-scanning SS-OCT imaging (DRI OCT-1 Atlantis; Topcon, Tokyo, Japan). Imaging was performed before (baseline), immediately after, and 15, 30, and 60 minutes after centrifuge training. Changes in choroidal thickness, choroidal volume, retinal thickness, and RNFL thickness after centrifuge training were analyzed. Results: Mean choroidal thickness significantly and transiently decreased immediately (258.19 ± 73.54 µm, P < 0.001), 15 minutes (258.54 ± 75.12 µm, P = 0.001), and 30 minutes (254.31 ± 66.92, P = 0.001) after human centrifuge training, relative to baseline (273.35 ± 80.80 µm). However, the decreased choroidal thickness returned to baseline levels 1 hour after centrifuge training (270.12 ± 71.69 µm, P = 0.437). Mean retinal thickness and RNFL thickness were not significantly affected by human centrifuge training. In participants who suffered from gravity-force induced loss of consciousness (G-LOC) during training, the amount of the choroidal thickness decrease was larger than in participants who did not experience G-LOC. However, because of the small sample size, the difference, although large, was not statistically significant. Conclusions: Choroidal thickness and volume significantly and transiently decreased after human centrifuge training, which might reflect that choroidal perfusion was transiently decreased during human centrifuge training. Considering choroidal thickness decreased after human centrifuge training, long-term exposure to a high gravity environment may lead to ischemic injury to ocular structures.