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With a great success of the generative model via deep neural networks, monocular depth estimation has been actively studied by exploiting various encoder-decoder architectures. However, the decoding process in most previous methods, which repeats simple up-sampling operations, probably fails to fully utilize underlying properties of well-encoded features for monocular depth estimation. To resolve this problem, we propose a simple but effective scheme by incorporating the Laplacian pyramid into the decoder architecture. Specifically, encoded features are fed into different streams for decoding depth residuals, which are defined by decomposition of the Laplacian pyramid, and corresponding outputs are progressively combined to reconstruct the final depth map from coarse to fine scales. This is fairly desirable to precisely estimate the depth boundary as well as the global layout. We also propose to apply weight standardization to pre-activation convolution blocks of the decoder architecture, which gives a great help to improve the flow of gradients and thus makes optimization easier. Experimental results on benchmark datasets constructed under various indoor and outdoor environments demonstrate that the proposed method is effective for monocular depth estimation compared to state-of-the-art models. The code and model are publicly available at: | https://github.com/tjqansthd/LapDepth-release |.

DNA-encoded libraries are a powerful tool to identify hit compounds for drug discovery. Now, two papers have reported new advances in this technology. One paper reports a method to screen for binders inside a living cell, and the other investigates the effects of stereo- and regiochemistry on ligand discovery.

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that ligate amino acids to tRNAs and translate the genetic code during protein synthesis. Their function in pathogen-derived infectious diseases has been well established, which has led to the development of small molecule therapeutics. The applicability of ARS inhibitors for other human diseases, such as fibrosis, has recently been explored in the clinical setting. There are active studies to find small molecule therapeutics for cancers. Studies on central nervous system (CNS) disorders are burgeoning as well. In this regard, we present a concise analysis of the recent development of ARS inhibitors based on small molecules from the discovery research stage to clinical studies as well as a recent patent analysis from the medicinal chemistry point of view.

DNA-encoded library technology (DELT) was introduced to our medicinal chemistry society more than 20 years ago. The application of DELT in the development of clinical candidates has been actively reported in the literature recently. A few representative examples include RIP1K inhibitors for inflammatory diseases and sEH inhibitors for endothelial dysfunction or abnormal tissue repair, among many others. Here, the authors would like to recall the recent developments in on-DNA synthetic methodologies for DEL construction and to analyze recent examples in the literature of DELT-based drug development efforts pursued in both the academic and industrial sectors. With this perspective, we hope to provide a useful summary of recent DELT-based drug discovery research and to discuss the future scope of DELT in medicinal chemistry.

Transglutaminase 2 (TGase2, TG2) activity has been implicated in the pathogenesis of a number of unrelated disorders, including celiac, neurological, and renal diseases, and various forms of cancer. It has been suggested that TGase2 activity, such as cross-linking, deamidation, and GTP-related activity, is associated with each disease. Continuing efforts to develop small molecule TG2 inhibitors are ongoing. To develop a new class of TG2 inhibitors, the factors impeding the development of TG2 inhibitors have been identified. Additionally, the conformational effect of TG2 enzyme in regard to its pathological roles, in vitro screening methods, recently discovered TG2 inhibitors, and preclinical evaluations are discussed with a brief summary of current TG2 inhibitor pipelines under the clinical setting.

Transglutaminase 2 (TGase 2) catalyzes a crosslink between protein bound-glutamine and -lysine. We proposed the mechanism of TGase 2 activation depends on conformation change from unfolded monomer to unfolded dimer. We found that TGase 2 has temperature-sensitive conformation change system at 30 °C. Small-angle X-ray scattering analysis showed that the enzyme was maintained as an unfolded monomer at temperatures below 30 °C, but changed to an unfolded dimer at over 30 °C. Mass analysis revealed that the C-terminus of TGase 2 was the critical region for dimerization. Furthermore, this conformational switch creates new biochemical reactivity that catalyzed inter-molecular crosslink at above 30 °C as an unfolded dimer of TGase 2 while catalyzed intra-molecular crosslink at below 30 °C as an unfolded monomer of TGase 2. The mechanism of TGase 2 activation depends on temperature-sensitive conformation change from unfolded monomer to unfolded dimer at over 30 °C. Furthermore, inter-molecular crosslinking activity is generated by the dimeric form of TGase 2. TGase 2 switches its conformation from a monomer to a dimer following a change in temperature, which engendered unique catalytic function of enzyme as inter-molecular crosslinking activity with calcium.

Glutaminase (GLS), which is responsible for the conversion of glutamine to glutamate, plays a vital role in up-regulating cell metabolism for tumor cell growth and is considered to be a valuable therapeutic target for cancer treatment. Based on this important function of glutaminase in cancer, several GLS inhibitors have been developed in both academia and industry. Most importantly, Calithera Biosciences Inc. is actively developing the glutaminase inhibitor CB-839 for the treatment of various cancers, and it is currently being evaluated in phase 1 and 2 clinical trials. In this review, recent efforts to develop small molecule glutaminase inhibitors that target glutamine metabolism in both preclinical and clinical studies are discussed. In particular, more emphasis is placed on CB-839 because it is the only small molecule GLS inhibitor being studied in a clinical setting. The inhibition mechanism is also discussed based on X-ray structure studies of thiadiazole derivatives present in glutaminase inhibitor BPTES. Finally, recent medicinal chemistry efforts to develop a new class of GLS inhibitors are described in the hopes of providing useful information for the next generation of GLS inhibitors.

Phosphorylation of sodium alginate salt (NaAlg) was carried out using H3PO4/P2O5/Et3PO4 followed by acid-base reaction with Ca(OAc)2 to give phosphorylated alginic acid calcium complexes (CaPAlg), as a water dispersible alginic acid derivative. The modified alginate derivatives including phosphorylated alginic acid (PAlg) and CaPAlg were characterized by nuclear magnetic resonance spectroscopy for (1)H, and (31)P nuclei, high resolution inductively coupled plasma optical emission spectroscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis. CaPAlg hydrogels were prepared simply by mixing CaPAlg solution (2w/v%) with NaAlg solution (2w/v%) in various ratios (2:8, 4:6, 6:4, 8:2) of volume. No additional calcium salts such as CaSO4 or CaCl2 were added externally. The gelation was completed within about 3-40min indicating a high potential of hydrogel delivery by injection in vivo. Their mechanical properties were tested to be ≤6.7kPa for compressive strength at break and about 8.4kPa/mm for elastic modulus. SEM analysis of the CaPAlg hydrogels showed highly porous morphology with interconnected pores of width in the range of 100-800μm. Cell culture results showed that the injectable hydrogels exhibited comparable properties to the pure alginate hydrogel in terms of cytotoxicity and 3D encapsulation of cells for a short time period. The developed injectable hydrogels showed suitable physicochemical and mechanical properties for injection in vivo, and could therefore be beneficial for the field of soft tissue engineering.

A new chimeric fusion transcript of KIF5B (the kinesin family 5B gene) and the RET (Rearranged during Transcription) oncogene, KIF5B-RET, was found in 1-2% of lung adenocarcinomas (LADCs) in late 2011. Several related clinical trials for non-small-cell lung cancer (NSCLC) with KIF5B-RET rearrangements using existing RET inhibitors, such as lenvatinib, vandetanib, sunitinib, ponatinib, cabozantinib, and AUY922, have been swiftly initiated by the discovery of the KIF5B-RET fusion gene. Anti-RET activity and the status of clinical development of these known RET tyrosine kinase inhibitors (TKIs) for KIF5B-RET fusion-positive NSCLC are discussed. A kinase inhibitor that can target a driver mutation specifically may lead to a superior clinical benefit compared with broad-spectrum kinase inhibitors. In this regard, an analysis of the structure of RET kinase and its complex with known RET inhibitors are also briefly discussed.

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and is known to be the 10th most common type of cancer in the world. Most of the currently available RCC drugs are tyrosine kinase inhibitors (TKIs). However, combination therapies of TKIs and immune checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed cell death protein 1 ligand 1 (PD-L1) inhibitors are the focus of most of the final stage clinical trials. Meanwhile, other small molecule therapies for RCC that target indoleamine-2,3-dioxygenase (IDO1), glutaminase, C-X-C chemokine receptor 4 (CXCR4), and transglutaminase 2 (TG2) are emerging as the next generation of therapeutics. In this review, these three major streams for the development of small molecule drugs for RCC are described.

Transglutaminase 2 (TGase2, TG2) activity has been implicated in the pathogenesis of a number of unrelated disorders, including celiac, neurological, and renal diseases, and various forms of cancer. It has been suggested that TGase2 activity, such as cross-linking, deamidation, and GTP-related activity, is associated with each disease. Continuing efforts to develop small molecule TG2 inhibitors are ongoing. To develop a new class of TG2 inhibitors, the factors impeding the development of TG2 inhibitors have been identified. Additionally, the conformational effect of TG2 enzyme in regard to its pathological roles, in vitro screening methods, recently discovered TG2 inhibitors, and preclinical evaluations are discussed with a brief summary of current TG2 inhibitor pipelines under the clinical setting.

We present CNT bucky-sponges prepared using CS-NH 2 /CNT-cement (CNT nanohybrid molecules individually wrapped with chitosan molecules) as a construction material and an imidazolium based room temperature ionic liquid (RTIL) as a liquid porogen. The nano-sized and micro-sized pores with various width (respectively, about 2 /g and 0.022–3.22 Ω cm. The prepared CNT sponges showed important characteristics indicating broad applicability as a conductive polymer framework, drug carrying scaffold, catalyst support, oil adsorbents, and molecular sieve membrane.

Anacetrapib is a potent and selective CETP inhibitor and is undergoing phase III clinical trials for the treatment of dyslipidemia. A simple and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the quantification of anacetrapib in rat plasma was developed and validated using an easily purchasable compound, chlorpropamide, as an internal standard (IS). A minimal volume of rat plasma sample (20 μL) was prepared by a single-step deproteinization procedure with 80 μL of acetonitrile. Chromatographic separation was performed using Kinetex C

Traumatic brain injury (TBI) leads to a rapid and excessive increase in glutamate concentration in the extracellular milieu, which is strongly associated with excitotoxicity and neuronal degeneration. N-acetylaspartylglutamate (NAAG), a prevalent peptide neurotransmitter in the vertebrate nervous system, is released along with glutamate and suppresses glutamate release by actions at pre-synaptic metabotropic glutamate autoreceptors. Extracellular NAAG is hydrolyzed to N-acetylaspartate and glutamate by peptidase activity. In the present study PGI-02776, a newly designed di-ester prodrug of the urea-based NAAG peptidase inhibitor ZJ-43, was tested for neuroprotective potential when administered intraperitoneal 30 min after lateral fluid percussion TBI in the rat. Stereological quantification of hippocampal CA2-3 degenerating neurons at 24 hrs post injury revealed that 10 mg/kg PGI-02776 significantly decreased the number of degenerating neurons (p

The kainoid family of marine natural products has attracted considerable interest due to the potent pharmacological properties of compounds in this class.[1] By serving as conformationally restricted analogues of glutamate, this group of natural products displays potent neuroexcitatory activity, and the more complex members of the domoic acid type have been responsible for outbreaks of poisioning from mussel toxins.[2] The kainic acid and domoic acid families of natural products include a diverse range of structures that possess highly functionalized pyrrolidine di- or triacid motifs (Scheme 1).[3] Kainic and allokainic acids possess a simple C4 propenyl substituent, whereas domoic acid and its isomers possess more complex C4 functionality. Our interest in the synthesis of members of this class of compounds has led to the development of a number of nickel-catalyzed processes, including the alkylative cyclization of enoate-alkyne and enoate-allene substrates. These processes have served as key steps in the total syntheses of kainic acid (1), allokainic acid (2), and isodomoic acids G (3) and H (4).[4-6] We envisioned that the development of a related cyclization method involving cyclization of an enoate tethered with a chiral allene would allow synthesis of the remaining members of the domoic acid class, including domoic acid (5), that do not possess the C4 exocyclic functionality seen in isodomoic acids G and H. Herein, we describe an initial investigation of this strategy, and the synthesis of a model substructure of domoic acid.

Addition of vinylaluminum NMO reagents to N-(p-toluenesufinyl)- and N-(2-methypropanesulfinyl)-derived sulfinimines gives N-sulfinyl aza-Morita-Baylis-Hillman products (dr = 7:1 to 12:1) that result from addition of the reagent from the least hindered direction. Hydrogenation of the aza-MBH adducts with a Rh(I) catalyst affords anti-alpha-substituted N-sulfinyl-beta-amino esters in good yield and high dr (10:1 to 21:1).

A new chimeric fusion transcript of KIF5B (the kinesin family 5B gene) and the RET (Rearranged during Transcription) oncogene, KIF5B-RET, was found in 1-2% of lung adenocarcinomas (LADCs) in 2012. Several related clinical trials for non-small cell lung cancer (NSCLC) with KIF5B-RET rearrangements using existing RET inhibitors, such as cabozantinib, lenvatinib, vandetanib, sunitinib, ponatinib, and AUY922, have been swiftly initiated by the discovery of the KIF5B-RET fusion gene. Anti-RET activity and the status of clinical development of cabozantinib for KIF5B-RET fusion-positive NSCLC are discussed.

Iodocyclization of sulfinimine-derived enantiopure homoallylic sulfonamides affords trans-2,5-disubstituted 3-iodopyrrolidines and represents valuable methodology for the asymmetric synthesis of this important heterocyclic ring system.

Immediately following traumatic brain injury (TBI) and TBI with hypoxia, there is a rapid andpathophysiological increase in extracellula r glutamate, subsequent neuronal damage andultimately diminished moto r and cognitive function. N-acetyl-aspartyl glutamate (NAAG), aprevalent neuropeptide in the CNS, is co-relea sed with glutamate, binds to the presynapticgroup II metabotropic glutamate receptor subtype 3 (mGluR3) and suppresses glutamaterelease. However, the catalytic enzyme glutamate carboxypeptidase II (GCP II) rapidly hydro-lyzes NAAG into NAA and glutamate. Inhibition of the GCP II enzyme with NAAG peptidaseinhibitors reduces the concentration of glutamate both by increasing the duration of NAAGactivity on mGluR3 and by reducing degradation into NAA and glutamate resulting in reducedcelldeathinmodelsofTBIandTBIwithhypoxia. In the following study, rats wereadministered the NAAG peptidase inhibitor PGI-02776 (10 mg/kg) 30 min following TBIcombined with a hypoxic second insult. Over t he two weeks following injury, PGI-02776-treated rats had signi ficantly improved motor function as measured by increased duration onthe rota-rod and a trend toward improved performance on the beam walk. Furthermore, twoweeks post-injury, PGI-02776-treated animals had a signi ficant decrease in latency to find thetarget platform in the Morris water maze as co mpared to vehicle-treated animals. Thesefindings demonstrate that the application o f NAAG peptidase inhibitors can reduce thedeleterious motor and cognitive effects of TBI combined with a second hypoxic insult in theweeks following injury.& 2013 Elsevier B.V. All rights reserved.0006-8993/$-see front matter & 2013 Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.brainres.2013.03.043

Anacetrapib is a potent and selective CETP inhibitor and is undergoing phase III clinical trials for the treatment of dyslipidemia. A simple and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the quantification of anacetrapib in rat plasma was developed and validated using an easily purchasable compound, chlorpropamide, as an internal standard (IS). A minimal volume of rat plasma sample (20 μL) was prepared by a single-step deproteinization procedure with 80 μL of acetonitrile. Chromatographic separation was performed using Kinetex C18 column with a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid at a flow rate of 0.3 mL/min. Mass spectrometric detection was performed using selected reaction monitoring modes at the mass/charge transitions m/z 638 → 283 for anacetrapib and m/z 277 → 175 for IS. The assay was validated to demonstrate the selectivity, linearity, precision, accuracy, recovery, matrix effect and stability. The lower limit of quantification was 5 ng/mL. This LC-MS/MS assay was successfully applied in the rat plasma protein binding and pharmacokinetic studies of anacetrapib. The fraction of unbound anacetrapib was determined to be low (ranging from 5.66 to 12.3%), and the absolute oral bioavailability of anacetrapib was 32.7%.

한 · 일 양국은 중화(中華) 질서하의 상호호혜적 교환과 갈등의 교류라는 역사적 경험을 공유하고 있다. 상기와 같은 상황에서 본고는 인터넷 가상공간에서 나타나는 한일 양국간의 넷우익의 등장과 전개, 넷우익과 혐한 · 반일의 정의 및 현황과 특성을 고찰하고, 그들의 혐한 · 반일 담화의 위상과 특질 등을 살펴보았다. 결론은 한일 양국간에 격화되고 있는 우경화 현상과 넷우익의 특질을 자민족주의적 관점에서 비교 연구하여 그 의미를 어떻게 볼 것인가에 대하여 논하면서. 원론적이기는 하지만, “정치적 · 외교적 곤란을 극복하기 위해서는 상호이해와 감동의 기회를 마련해 공감할 수 있는 감성을 키워가면서 모든 지식을 전수하는 장소에서 ‘미움으로 결집하기보다는 열림과 소통으로 결집’하는 ‘시대적 성향’을 만들어 내기 위한 부단한 작업을 중지해서는 안 된다는 것이다.

Traumatic brain injury (TBI) leads to a rapid and excessive glutamate elevation in the extracellular milieu, resulting in neuronal degeneration and astrocyte damage. Posttraumatic hypoxia is a clinically relevant secondary insult that increases the magnitude and duration of glutamate release following TBI. N-acetyl-aspartyl glutamate (NAAG), a prevalent neuropeptide in the CNS, suppresses presynaptic glutamate release by its action at the mGluR3 (a group II metabotropic glutamate receptor). However, extracellular NAAG is rapidly converted into NAA and glutamate by the catalytic enzyme glutamate carboxypeptidase II (GCPII) reducing presynaptic inhibition. We previously reported that the GCPII inhibitor ZJ-43 and its prodrug di-ester PGI-02776 reduce the deleterious effects of excessive extracellular glutamate when injected systemically within the first 30 minutes following injury. We now report that PGI-02776 (10 mg/kg) is neuroprotective when administered 30-minutes post-injury in a model of TBI plus 30 minutes of hypoxia (FiO2 = 11%). 24-hrs following TBI with hypoxia, significant increases in neuronal cell death in the CA1, CA2/3, CA3c, hilus and dentate gyrus were observed in the ipsilateral hippocampus. Additionally, there was a significant reduction in the number of astrocytes in the ipsilateral CA1, CA2/3 and in the CA3c/hilus/dentate gyrus. Administration of PGI-02776 immediately following the cessation of hypoxia significantly reduced neuronal and astrocytic cell death across all regions of the hippocampus. These findings indicate that NAAG peptidase inhibitors administered post-injury can significantly reduce the deleterious effects of TBI combined with a secondary hypoxic insult.

While the “normal” cycloaddition between dienes and alkynes leads to formation of six-membered Diels—Alder or hetero-Diels—Alder ring products, the reductive cycloaddition using BEt3 as the active reducing agent and MeOH as the proton donor allows the synthesis of either cyclopentenols (from enals and alkynes) or cyclopentenones (from enoates and alkynes).

Strategies for the reductive cycloaddition of enals or enoates with alkynes have been developed. The enal-alkyne cycloaddition directly affords cyclopentenols, whereas the enoate-alkyne cycloaddition affords the analogous cyclopentenones. The mechanism of these processes likely involves formation and protonation of a metallacyclic intermediate. The general strategy provides a straightforward entry to five-membered ring products from simple, stable π-systems.

We report on the generation of narrow-bandwidth and frequency-modulated cascaded emission of two photons from a collimated Yb atomic beam. Efficient population transfer from the ground state ($6{s}^{2}$ ${}^{1}{S}_{0}$) to upper state ($6s7s$ ${}^{1}{S}_{0}$), of which direct transition at 291.1 nm is dipole forbidden, is achieved through a resonant two-photon excitation enhanced by the electromagnetically induced transparency mediated by the intermediate state ($6s6p$ ${}^{1}{P}_{1}$). Then cascaded emission of two photons with a bandwidth of 54 MHz at 611.3 nm (idler) and 555.8 nm (signal) occurs in sequence from the upper state via the spin triplet state ($6{s}^{2}$ ${}^{3}{P}_{1}$). Numerical calculations of the density matrix equations taking into account the residual Doppler effect and strong driving fields successfully explain the experimental results for the idler and signal beam intensities depending on the various parameters of the driving fields. Synchronized optical switching and frequency-modulation characteristics of the idler and signal beams are also reported.

We present an efficient fluorescence detector in the visible region of the spectrum with a photon detection dynamic range over 10 (6) photons/s made of a temperature-stabilized Si-based multi-pixel photon counter at temperature down to 5 degrees C. We show that effective cooling of the device by means of a compact thermo-electric cooler brings several advantages, such as high gain, low dark noise rate, and thus high signal-to-noise ratio in the efficient fluorescence detection at 398.9 nm from the (1)S(0) ? (1)P(1) transition of the ytterbium atoms in an effusive atomic beam. We present also a comparison of the fluorescence detection efficiencies between the device and a side-on photo-multiplier tube with known gain positioned at the symmetric location from the ytterbium atomic beam.

Syn-alpha-substituted beta-amino Weinreb amides are new chiral building blocks for asymmetric synthesis of syn-alpha-substituted beta-amino acids, aldehydes, and ketones and are prepared by addition of prochiral lithium enolates of Weinreb amides to sulfinimines (N-sulfinyl imines).

Cyclizations of allenyl aldehydes and intermolecular couplings of allenes and aldehydes provide a direct procedure for the preparation of homoallylic alcohols. The couplings and cyclizations involve the use of diorganozinc reagents as reducing agents and Ni(COD) 2 as the catalyst.

The direct cyclization of allenyl aldehydes with organozincs in the presence of Ni(COD)(2) provides synthetically versatile homoallylic alcohols. Both monosubstituted and 1,3-disubstituted allenes participate in the process, with the latter allowing preparation of stereochemically defined trisubstituted alkenes. [reaction: see text]

We present a transportable effusive atomic beam apparatus for cascaded two-photon spectroscopy of the dipole-forbidden transition (6s(2)(1)S0↔ 6s7s (1)S0) of Yb atoms. An ohmic-heating effusive oven is designed to have a reservoir volume of 1.6 cm(3) and a high degree of atomic beam collimation angle of 30 mrad. The new atomic beam apparatus allows us to detect the spontaneously cascaded two-photons from the 6s7s(1)S0 state via the intercombination 6s6p(3)P1 state with a high signal-to-noise ratio even at the temperature of 340 °C. This is made possible in our apparatus because of the enhanced atomic beam flux and superior detection solid angle.

The first total asymmetric synthesis of the poison frog alkaloid (-)-221T, a 5,6,8-trisubstituted indolizidine is described. The key core piperidine ring was constructed via an acid catalyzed intramolecular cascade Mannich cyclization reaction of a N-sulfinyl syn-alpha-methyl beta-amino ketone and crotonaldehyde. The beta-amino ketone was prepared via the reaction of prochiral lithium Weinreb amide enolate with an enantiopure N-2,4,6-triisopropylphenylsulfinyl imine.

A self-starting passively modelocked extended-cavity diode laser (ECDL) in the Littrow configuration is demonstrated for the first time by using a near-infrared ridge-waveguide GaAs diode laser at the gain saturation regime.

We present a compact coupled optoelectronic oscillator consisting of an actively mode-locked external cavity diode laser and microwave feed-back loop, generaing an optical frequency comb with a stabilized repetition rate of 2.298 GHz at 852 nm.