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Aurora kinase inhibitors, such as alisertib, can destabilize MYC-family oncoproteins and have demonstrated compelling antitumor efficacy. In this study, we report 6K465, a novel pyrimidine-based Aurora A inhibitor, that reduces levels of c-MYC and N-MYC oncoproteins more potently than alisertib. In an analysis of the antiproliferative effect of 6K465, the sensitivities of small cell lung cancer (SCLC) and breast cancer cell lines to 6K465 were strongly associated with the protein levels of c-MYC and/or N-MYC. We also report DBPR728, an acyl-based prodrug of 6K465 bearing fewer hydrogen-bond donors, that exhibited 10-fold improved oral bioavailability. DBPR728 induced durable tumor regression of c-MYC- and/or N-MYC-overexpressing xenografts including SCLC, triple-negative breast cancer, hepatocellular carcinoma, and medulloblastoma using a 5-on-2-off or once-a-week dosing regimen on a 21-day cycle. A single oral dose of DBPR728 at 300 mg/kg induced c-MYC reduction and cell apoptosis in the tumor xenografts for more than 7 days. The inhibitory effect of DBPR728 at a reduced dosing frequency was attributed to its uniquely high tumor/plasma ratio (3.6-fold within 7 days) and the long tumor half-life of active moiety 6K465. Furthermore, DBPR728 was found to synergize with the mTOR inhibitor everolimus to suppress c-MYC- or N-MYC-driven SCLC. Collectively, these results suggest DBPR728 has the potential to treat cancers overexpressing c-MYC and/or N-MYC., (©2024 American Association for Cancer Research.)

Globally, nations are increasingly focusing on green innovation in their environmental protection efforts as part of sustainable development, and digital finance is playing a vital role in enhancing green innovation. Employing annual data from 220 prefecture-level cities between 2011 and 2019, we empirically analyze the connections among environmental performance, digital finance, and green innovation via the Karavias panel unit root test with structural breaks, the Gregory-Hansen structural break cointegration test and pooled mean group (PMG) estimation. The following four points are the key conclusions: (1) The results support cointegration links between these variables when structural breaks are considered. (2) The PMG estimation outcomes indicate that green innovation and digital finance may have a favorable long-term effect on environmental performance. (3) For better environmental performance and more green innovation, the level of digitalization of digital finance is crucial. (4) The potential of digital finance and green innovation to improve environmental performance has not been fully realized in the western region of China., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor and a therapeutic target for metabolic disorders. Numerous CB1 antagonists have been developed, but their functional selectivities and bias towards G protein or β-arrestin signaling have not been systemically characterized. In this study, we analyzed the binding affinities and downstream signaling of two series of pyrazole derivatives bearing 1-aminopiperidine (Series I) or 4-aminothiomorpholine 1,1-dioxide (Series II) moieties, as well as the well-known CB1 antagonists rimonabant and taranabant. Analyses of the results for the Series I and II derivatives showed that minor structure modifications to their functional groups and especially the incorporation of 1-aminopiperidine or 4-aminothiomorpholine 1,1-dioxide motifs can profoundly affect their bias toward G protein or β-arrestin signaling, and that their binding affinity and functional activity can be disassociated. Docking and molecular dynamics simulations revealed that the binding modes of Series I and II antagonists differed primarily in that Series I antagonists formed an additional hydrogen bond with the receptor, whereas those in Series II formed a water bridge., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Rapidly increasing cryptocurrency prices have encouraged cryptocurrency miners to participate in cryptocurrency production, increasing network hashrates and electricity consumption. Growth in network hashrates has further crowded out small cryptocurrency investors owing to the heightened costs of mining hardware and electricity. These changes prompt cryptocurrency miners to become new investors, leading to cryptocurrency price increases. The potential bidirectional relationship between cryptocurrency price and electricity consumption remains unidentified. Hence, this research thus utilizes July 31 2015-July 12 2019 data from 13 cryptocurrencies to investigate the short- and long-run causal effects between cryptocurrency transaction and electricity consumption. Particularly, we consider structural breaks induced by external shocks through stationary analysis and comovement relationships. Over the examined time period, we found that the series of cryptocurrency transaction and electricity consumption gradually returns to mean convergence after undergoing daily shocks, with prices trending together with hashrates. Transaction fluctuations exert both a temporary effect and permanent influence on electricity consumption. Therefore, owing to the computational power deployed to wherever high profit is found, transactions are vital determinants of electricity consumption., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2023.)

Maintaining the stability of the carbon market is of great significance for China to meet its goal of "Double Carbon," but at the beginning of 2020 the COVID-19 pandemic emerged and the economy was greatly affected. A natural question is whether it impacted domestic carbon markets. This paper thus presents the event research method on eight carbon emission trading markets in China, because it can timely exhibit the benefits investors gained during the COVID-19 pandemic and also can overcome the difficulty of separating those benefits from the overall performance of the carbon market via high-frequency data. The results herein confirm that China's carbon market has reacted negatively to the COVID-19 pandemic, which mainly relates to the mandatory blockade and isolation policy adopted by the central government. The production and operation activities of enterprises decreased along with the demand for carbon quotas. Because of the panic, investors also had a negative attitude towards the carbon market, influencing the supply and demand curve of carbon quotas and causing a decline in carbon prices. Under the effectiveness of government epidemic prevention and control policies, we further find that the negative impact was gradually eliminated. Overall, our findings offer some important information for the decision-making of governments, carbon market investors, and policymakers., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Nature B.V. 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Purpose: This study examined interrelationships among insomnia, stress, anxiety, and metabolic risk factors. Methods : A total of 124 college students were included in the analysis (age = 21 ± 1 years). Insomnia, stress of life events, and anxiety were assessed using self-reported questionnaires. Fasting blood samples were assayed for glucose, insulin, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-cholesterol), and low-density lipoprotein cholesterol (LDL-cholesterol). Results : Insomnia was positively associated with stress of life events (β = 0.28, p  < .001) and anxiety (β = 0.46, p  < .001). Insomnia was related to elevated fasting insulin (β = 0.12, p  = .04) and triglyceride level (β = 1.85, p  < .001). An inverse association was found between insomnia and HDL-cholesterol (β = -0.45, p  = .03). Sobel's test for mediation showed that stress of life events ( p  = .020) and anxiety ( p  = .013) mediated the relationship between insomnia and hypertriglyceridemia. Conclusions : Reducing stress and anxiety among college students with insomnia may influence subsequent cardiovascular health.

Using daily data of novel coronavirus pneumonia (COVID-19) covering 118 countries from January 1 to April 13, 2021, this research examines the relationship between the government response stringency index ( GRSI ) and COVID-19 pandemic. The empirical results show that GRSI significantly negatively impacts confirmed cases, and the effects are especially larger around 14 to 21 days after the implementation of the government response. These results are robust through analysis with sub-samples of Asian countries and non-Asian countries, proving that public prevention policies of being isolated for 14 days and being observed for 7 days are effective. The Dumitrescu-Hurlin causality test uncovers a statistically significant bi-directional correlation between government response stringency and COVID-19 pandemic when analyzing the full samples. In terms of the sub-samples, a bi-directional relationship exists between government response stringency and confirmed cases, while one-way causality runs only from government response stringency to deaths in Asian countries. We offer a policy implication that countries all over the world should continue to carry out public prevention policies, and governments in non-Asian countries should be more concerned about confirmed cases., (© 2021 Elsevier B.V. All rights reserved.)

Owing to economics are usually linked with energy production, economic policy may have an instantaneous adjustment according to the current monetary, financial, cultural circumstances. This research thus investigates the dynamic co-movement as well as cointegration relationships between economic policy uncertainty (EPU) and disparate energy productions, i.e., Chinese coal, natural gas, crude oil, electricity as well as renewable energy, during the period from January 1995 to October 2019 in China. We compare the two EPU indices and make empirical and robust analysis to get more evidence for the time-varying co-movement between energy production and EPU. The empirical results show that there are stationary properties and cointegration relationships between energy production and EPU. By utilizing wavelet co-movement analysis in the time-frequency domain, our results show a significant positive co-movement among disparate energy productions and EPU at high frequencies, i.e., in the short term, but weaker co-movement at low frequencies, i.e., in the long term. Hence, the phase-difference series are mostly around the zero line, implying the variables behave to the dynamics of the co-movement with positive causality. Policy recommendations are offered in accordance with our finding., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound 13 was identified, which potently (IC 50 < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of 13 by prodrug strategies resulted in orally bioavailable 25 , which demonstrated an 8-fold higher oral AUC ( F = 62.3%). Pharmacodynamic studies of 25 showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of 25 for the treatment of MYC -amplified cancers including SCLC.

In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10 -9 ). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10 -10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the high-expression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.

The SARS-CoV-2 replication and transcription complex (RTC) comprising nonstructural protein (nsp) 2-16 plays crucial roles in viral replication, reducing the efficacy of broad-spectrum nucleoside analog drugs such as remdesivir and evading innate immune responses. Most studies target a specific viral component of the RTC such as the main protease or the RNA-dependent RNA polymerase. In contrast, our strategy is to target multiple conserved domains of the RTC to prevent SARS-CoV-2 genome replication and to create a high barrier to viral resistance and/or evasion of antiviral drugs. We show that the clinically safe Zn-ejector drugs disulfiram and ebselen can target conserved Zn 2+ sites in SARS-CoV-2 nsp13 and nsp14 and inhibit nsp13 ATPase and nsp14 exoribonuclease activities. As the SARS-CoV-2 nsp14 domain targeted by disulfiram/ebselen is involved in RNA fidelity control, our strategy allows coupling of the Zn-ejector drug with a broad-spectrum nucleoside analog that would otherwise be excised by the nsp14 proofreading domain. As proof-of-concept, we show that disulfiram/ebselen, when combined with remdesivir, can synergistically inhibit SARS-CoV-2 replication in Vero E6 cells. We present a mechanism of action and the advantages of our multitargeting strategy, which can be applied to any type of coronavirus with conserved Zn 2+ sites., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

The spillover effects of European Union Allowances (EUA) spot and futures markets are important for investors in order to understand the relevance and risk management of product prices. This paper uses non-linear methods of Granger causality to test the mean spillover relationship between the two markets and then analyzes volatility spillovers between the two by the non-linear TVP-VAR spillover index. The results show that (1) the non-linear Granger causality test better reflects the mean spillover relationship between EUA spot and futures; (2) there is a bidirectional non-linear mean spillover effect between EUA spot and futures prices for the European Union Emissions Trading Scheme (EU ETS) phases II and III; and (3) volatility spillovers, appearing in EUA spot and future markets in both phases, work increasingly strong over time and are vulnerable to financial crises and extreme events.

We examine the short-term and long-term causal effects between epidemics and electricity CO 2 emissions by using panel data from 30 countries over the period of 1990 to 2017. The results show that there is bidirectional relationship between epidemics and electricity CO 2 emissions, especially in OECD and Asian countries., (© Springer Nature B.V. 2020.)

Tylophorine-based compounds and natural cardiotonic steroids (cardenolides and bufadienolides) are two classes of transmissible gastroenteritis coronavirus inhibitors, targeting viral RNA and host cell factors, respectively. We tested both types of compounds against two types of coronaviruses, to compare and contrast their antiviral properties, and with view to their further therapeutic development. Examples of both types of compounds potently inhibited the replication of both feline infectious peritonitis virus and human coronavirus OC43 with EC 50 values of up to 8 and 16 nM, respectively. Strikingly, the tylophorine-based compounds tested inhibited viral yields of HCoV-OC43 to a much greater extent (7-8 log magnitudes of p.f.u./ml) than the cardiotonic steroids (about 2-3 log magnitudes of p.f.u./ml), as determined by end point assays. Based on these results, three tylophorine-based compounds were further examined for their anti-viral activities on two other human coronaviruses, HCoV-229E and SARS-CoV-2. These three tylophorine-based compounds inhibited HCoV-229E with EC 50 values of up to 6.5 nM, inhibited viral yields of HCoV-229E by 6-7 log magnitudes of p.f.u./ml, and were also found to inhibit SARS-CoV-2 with EC 50 values of up to 2.5-14 nM. In conclusion, tylophorine-based compounds are potent, broad-spectrum inhibitors of coronaviruses including SARS-CoV-2, and could be used for the treatment of COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Yang, Lee, Hsu, Jan, Lin, Chang, Peng, Yang, Liang, Liao, Chao, Pang, Kao, Huang, Lin, Chang, Niu, Wu, Sytwu, Chen and Lee.)

This paper studies the impact of international sanctions on environmental performance by using the panel fixed effect model for 22 sanctioned states over the period 2002-2016 while considering several cases of international sanctions (unilateral, plurilateral, U.S., EU, UN, economic, and intensity) and measures environmental performance by the Environmental Performance Index (EPI). Overall, we find that the imposition of unilateral, plurilateral, U.S., EU, and economic sanctions has a significantly negative impact on EPI, dropping their EPI scores respectively by 0.114, 0.060, 0.045, 0.084, and 0.063, while a level increase of intensity results in EPI dropping by 0.028. Moreover, the simultaneous-equation models and Sobel tests show that the intermediate effect about GDP between international sanctions on environmental performance is significantly negative. We believe that our empirical findings can contribute to policy formulation by those sanctioned countries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Machine learning is a well-known approach for virtual screening. Recently, deep learning, a machine learning algorithm in artificial neural networks, has been applied to the advancement of precision medicine and drug discovery. In this study, we performed comparative studies between deep neural networks (DNN) and other ligand-based virtual screening (LBVS) methods to demonstrate that DNN and random forest (RF) were superior in hit prediction efficiency. By using DNN, several triple-negative breast cancer (TNBC) inhibitors were identified as potent hits from a screening of an in-house database of 165,000 compounds. In broadening the application of this method, we harnessed the predictive properties of trained model in the discovery of G protein-coupled receptor (GPCR) agonist, by which computational structure-based design of molecules could be greatly hindered by lack of structural information. Notably, a potent (~ 500 nM) mu-opioid receptor (MOR) agonist was identified as a hit from a small-size training set of 63 compounds. Our results show that DNN could be an efficient module in hit prediction and provide experimental evidence that machine learning could identify potent hits in silico from a limited training set.

To investigate the effects of regulation on environmental pollution under Chinese-style fiscal decentralization, this research analyzes annual data over the period 2003 to 2017 covering 30 provinces in China with the spatial economic model. The empirical results show significant spatial agglomeration effects on the emissions of wastewater, sulfur dioxide, and solid waste. Environmental regulation helps reduce discharge of wastewater and solid waste, but does not help reduce the emission of sulfur dioxide; because there is significantly positive externality in treating pollutants with high fluidity, cost is larger than revenue for local governments. The relationship between fiscal decentralization and pollutants shapes an inverted U-shaped curve. We finally offer some implications in accordance with our empirical finding, such as the intensity of environmental regulation should be suitable for economic development, different measures should be taken based on the fluidity of pollutants, and a new evaluation system should be established.

This paper investigates the long-run cointegration relationship between shale gas production and natural gas prices during the period from January 2007 to December 2016 for 16 states in the U.S., by utilizing the Generalized Least Squares (GLS) based univariate unit root test, the PANICCA panel unit root test, the cointegration tests of Gregory and Hansen (1996), Westerlund and Edgerton (2008) as well as Banerjee and Carrión-i-Silvestre (2015) tests with structural breaks. The empirical finding shows that the mean-reverting property exists in both variables, and most structural breaks emerge around 2007-2009 and 2011-2014, during the period when shale gas production sharply increased, the global financial crisis erupted, and external energy shocks emerged. We also find a strong cointegrated relationship, denoting a long-run equilibrium property appears among the variables. Overall, we demonstrate an interaction nexus between price and production variables and put forward some vital implications for authorities and gas market participants., Competing Interests: Declaration of competing interest None for all authors, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Loss of the neuromonitoring signal (LOS) during thyroidectomy signifies recurrent laryngeal nerve (RLN) injury, which is one of the common complications, especially by traction injury. Transient intraoperative LOS means spontaneous recovery of nerve function during surgery or within 6-month post-surgery. Few articles discuss intraoperative recovery time and transient LOS, and there is no consensus on the risk factors for RLN traction injury and its recovery course; thus, we wanted to determine the maximum intraoperative recovery time., Materials and Methods: This retrospective study included patients who had undergone thyroidectomies at Tainan National Cheng Kung University Hospital between January 2015 and August 2018. A total of 775 patients (with 1000 nerves at risk) who underwent intermittent intraoperative neuromonitoring during thyroidectomy were included in this study. The LOS nerves were divided into 4 groups based on the LOS subtype and the intraoperative status of the recovery. The postoperative vocal cord function was determined by thyroid ultrasound and/or laryngoscope. All the patients would be followed up postoperatively in 2-3 days, 1 week, 2 weeks, and 4-6 weeks., Results: LOS occurred in 67 of 775 (8.6%) patients and in 70 of 1000 nerves at risk (7.0%). There were 2 in 70 nerves (2.9%) with LOS type 1 (segmental nerve traction injury) with intraoperative recovery (Group 1), 5 (7.1%) with LOS type 1 without intraoperative recovery (Group 2), 47 (67.1%) with LOS type 2 (global injury) with intraoperative recovery (Group 3), and 16 (22.8%) with LOS type 2 without intraoperative recovery (Group 4). All LOS type 1 (segmental nerve injury) nerves had pathologic lesions near the RLN or vagus nerve, but none had invaded the nerves (p < 0.05). The resolving time intraoperatively in the 2 patients in Group 1 was 5 min and 10 min, respectively. The resolving time intraoperatively in Group 3 was 1-20 min, and the average time was 4.8 min. In Group 2, 3 injured nerves recovered within 6 weeks postoperatively, and 2 nerves in 12 weeks. In Group 4, all the 16 injured nerves recovered within 6 weeks postoperatively., Conclusion: Applying intermittent intraoperative neuromonitoring during thyroidectomy, traction recurrent laryngeal nerve injury still happened in 7.0%. 70% of the injured nerves recovered the function intraoperatively after releasing the traction, and the longest duration of recovery is 20 min.

To investigate the effects of government environmental regulation and industrial structure changes on carbon dioxide emissions, this research analyzes annual data over the period 2003-2015 covering 30 provinces in China (except for Tibet) with the panel smooth transition regression (PSTR) model. The empirical results show obvious non-linear effects of environmental regulation and industrial structure on carbon dioxide emission. Taking the effects of both linearity and non-linearity into consideration, environmental regulation will reduce carbon emissions with the change of industrial structure rationalization (SR). When the level of industrial structure optimization (SH) is low, environmental regulation promotes carbon dioxide emissions. When the level of industrial structure optimization (SH) is high, environmental regulation plays a significant inhibitive role on carbon dioxide emissions. The Kuznets relationship between GDP per capita (PGDP) and carbon dioxide emissions is influenced by local industrial structure rationalization and industrial structure optimization. Therefore, environmental regulation policies suitable for local conditions should be made based on the transition of the local industrial structure.

The [ 18 F] isotope-labelled CB1 inverse agonist 3 was elaborated and synthesized for positron emission tomography scanning studies. After immediate purification and calibration with its unlabeled counterpart, compound 3 was intravenously injected in mice and revealed that its distribution percentage in brain over 90-min scans among five region of interests, including brain, liver, heart, thigh muscle and kidney was lower than 1%, thus providing direct evidence to justify itself as a peripherally restricted CB1 antagonist., (Copyright © 2018. Published by Elsevier Ltd.)

Political incentive is one of the most efficient methods to promote local officials to push for both economic growth and environmental progress in the context of China. Since previous scholars have never investigated the relationships between political turnover and environmental governance at the municipal level, in this work, we proxy pollution by SO 2 , COD, SOOT, and NHx and examine whether environmental performance affects the political turnover of the municipal party secretary by exploiting a panel conditional logit with a fixed-effect model for the period 2002-2013. The results indicate that environmental performance does not significantly impact the turnover of municipal party secretaries, offering evidence that an increase of SO 2 is associated with the likelihood of promotion under the panel multinomial logit approach. However, a higher GDP growth rate plays the determinant factor affecting the promotion of China's municipal party secretaries. Specific policy recommendations are proposed in accordance with our empirical findings.

Twenty five novel chemical analogs of the previously reported Aurora kinase inhibitor BPR1K653 (1-(4-(2-((5-chloro-6-phenylfuro[2,3-d]pyrimidin-4-yl)amino)ethyl)phenyl)-3-(2-((dimethylamino)methyl)phenyl)urea) have been designed, synthesized, and evaluated by Aurora-A and Aurora-B enzymatic kinase activity assays. Similar to BPR1K653, analogs 3b-3h bear alkyl or tertiary amino group at the ortho position of the phenylurea, and showed equal or better inhibition activity for Aurora-B over Aurora-A. Conversely, preferential Aurora-A inhibition activity was observed when the same functional group was moved to the meta position of the phenylurea. Compounds 3m and 3n, both of which harbor a tertiary amino group at the meta position of the phenylurea, showed 10-16 fold inhibition selectivity for Aurora-A over Aurora-B. The in vitro kinase inhibition results were verified by Western blot analysis, and indicated that compounds 3m and 3n were more than 75-fold superior in inhibiting T-loop autophosphorylation of Aurora-A (Thr288), compared to Aurora-B (Thr232) in HCT116 colon carcinoma cells. The computational docking analysis suggested that the tertiary amine at the meta position of the phenylurea formed a more stable interaction with residues in the back pocket of Aurora-A than in Aurora-B, a possible explanation for the observed discrepancy in the selectivity. These results support an alternative small molecule design strategy targeting the back pocket of Aurora kinases for selective isoform inhibition., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous amyloidosis characterized by generalized hyperpigmentation mottled with small hypopigmented macules on the trunks and limbs. Affected families and sporadic case subjects have been reported predominantly in East and Southeast Asian ethnicities; however, the genetic cause has not been elucidated. We report here that the compound heterozygosity or homozygosity of GPNMB truncating alleles is the cause of autosomal-recessive ACD. Six nonsense or frameshift mutations were identified in nine individuals diagnosed with ACD. Immunofluorescence analysis of skin biopsies showed that GPNMB is expressed in all epidermal cells, with the highest staining observed in melanocytes. GPNMB staining is significantly reduced in the lesional skin of affected individuals. Hyperpigmented lesions exhibited significantly increased amounts of DNA/keratin-positive amyloid deposits in the papillary dermis and infiltrating macrophages compared with hypo- or depigmented macules. Depigmentation of the lesions was attributable to loss of melanocytes. Intracytoplasmic fibrillary aggregates were observed in keratinocytes scattered in the lesional epidermis. Thus, our analysis indicates that loss of GPNMB, which has been implicated in melanosome formation, autophagy, phagocytosis, tissue repair, and negative regulation of inflammation, underlies autosomal-recessive ACD and provides insights into the etiology of amyloidosis and pigment dyschromia., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Spondylocarpotarsal synostosis syndrome (SCT) is a distinct group of disorders characterized by short stature, disrupted vertebral segmentation with vertebral fusion, scoliosis, lordosis, carpal/tarsal synostosis, and lack of rib anomalies. Mutations in filamin B (FLNB) and MYH3 have been reported for autosomal-recessive and autosomal-dominant SCT, respectively. We present a family with two patients suffering from autosomal-recessive SCT with rib anomalies, including malalignment, crowding, and uneven size and shape of ribs. Whole-exome sequencing revealed a novel p.S2542Lfs * 82 (c.7621dup) frameshift mutation in FLNB. This frameshift mutation lies in the C-terminal-most domain involved in FLNB dimerization and resulted in a 20-residue elongation, with complete familial segregation and absence in 376 normal controls. The mutant p.S2542Lfs * 82 FLNB demonstrated a complete loss of ability to form a functional dimer in transiently transfected HEK293T cells. The p.S2542Lfs * 82 mutation also led to significantly reduced protein levels and accumulation of the mutant protein in the Golgi apparatus. This is the first identified mutation in the dimerization domain of FLNB. This loss-of-function frameshift mutation in FLNB causes autosomal-recessive SCT with rarely reported rib anomalies. This report demonstrates the involvement of rib anomaly in SCT and its causative mutation in the dimerization domain of FLNB., (© 2017 Wiley Periodicals, Inc.)

Background: The GLA IVS4+919G>A which is linked to late-onset Fabry disease shows high frequency in Taiwan., Methods: To determine whether IVS4+919G>A is a frequent cause of heart disease, we genotyped it in normal controls and other disease cohorts (type 2 diabetes, heart failure, ventricular tachycardia, atrial fibrillation and coronary artery disease). Normal controls and diabetes patients carrying the variant were evaluated for their cardiac condition. Minigene constructs were used to study GLA splicing patterns in different cell lines., Results: GLA IVS4+919A was found in 4/1634 males (0.245%) and 2/1634 females (0.123%) in normal controls and in 4/2133 males (0.188%) and 7/1816 females (0.385%) in the type 2 diabetes cohort. Of all the 17 IVS4+919A carriers in these two groups, only two males reported heart-related disease (myocardial infarction and hypertensive heart disease). Furthermore, in the heart disease cohort (n=649), only one male carried the variant. Minigene constructs showed that the AGS (stomach) cell line showed a distinct GLA splicing pattern., Conclusion: Most subjects carrying GLA IVS4+919A did not show abnormal cardiac phenotypes. The near-absence of GLA IVS4+919A in heart disease cohort suggested that this variant is not a frequent cause of overt heart diseases in Taiwan and that the genotype-phenotype correlation and natural course of the disease need further investigation. We also showed that the GLA IVS4+919G>A nucleotide change did influence alternative splicing in a tissue-specific manner., Synopsis: The GLA IVS4+919G>A variant is not a frequent cause of overt heart disease in Taiwan., (Copyright © 2017. Published by Elsevier Inc.)

Series of N -substituted carbazole analogues bearing an indole ring were synthesized as anti-methicillin-resistant Staphylococcus aureus (MRSA) agents from a molecular hybridization approach. The representative compound 19 showed an MIC = 1 μg/mL against a panel of MRSA clinical isolates as it possessed comparable in vitro activities to that of vancomycin. Moreover, compound 19 also exhibited MIC = 1 μg/mL activities against a recent identified Z172 MRSA strain (vancomycin-intermediate and daptomycin-nonsusceptible phenotype) and the vancomycin-resistant Enterococcus faecalis (VRE) strain. In a mouse model with lethal infection of MRSA (4N216), a 75% survival rate was observed after a single dose of compound 19 was intravenously administered at 20 mg/kg. In light of their equipotent activities against different MRSA isolates and VRE strain, the data underscore the importance of designed hybrid series for the development of new N -substituted carbazoles as potential anti-MRSA agents.

Telomerase is the enzyme involved in extending telomeric DNA. Control of telomerase activity by modulating its access to chromosome ends is one of the most important fundamental mechanisms. This study established an in vitro yeast telomerase reconstitution system that resembles telomere replication in vivo. In this system, a tailed-duplex DNA formed by telomeric DNA was employed to mimic the structure of telomeres. The core catalytic components of telomerase Est2/Tlc1 RNA were used as the telomeric DNA extension machinery. Using the reconstituted systems, this study found that binding of Cdc13 to telomeric DNA inhibited the access of telomerase to its substrate. The result was further confirmed by a single-molecule approach using the tethered-particle motion (TPM)-based telomerase assay. The findings also showed that the inhibitory effect can be relieved by telomerase-associated protein Est1, consistent with the role of Cdc13 and Est1 in regulating telomere extension in vivo. Significantly, this study found that the DNA binding property of Cdc13 was altered by Est1, providing the first mechanistic evidence of Est1 regulating the access of telomerase to its substrate. Thus, the roles of Cdc13 and Est1 in modulating telomerase activity were clearly defined using the in vitro reconstituted system.

We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound 19 mobilized CXCR4(+) cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed 1 (AMD3100) with subcutaneous administration at the same dose (6 mg/kg) in mice. This series of compounds thus provides a set of valuable tools to study diseases mediated by the CXCR4/SDF-1 axis, including myocardial infarction, ischemic stroke, and cancer metastasis. More importantly, treatment with compound 19 significantly lowered levels of blood urea nitrogen and serum creatinine in rats with renal ischemia-reperfusion injury, providing evidence for its therapeutic potential in preventing ischemic acute kidney injury. CXCR4 antagonists such as 19 might also be useful to increase circulating levels of adult stem cells, thereby exerting beneficial effects on damaged and/or inflamed tissues in diseases that currently are not treated by standard approaches.

Motivated by the pivotal role of CXCR4 as an HIV entry co-receptor, we herein report a de novo hit-to-lead effort on the identification of subnanomolar purine-based CXCR4 antagonists against HIV-1 infection. Compound 24, with an EC50 of 0.5 nM against HIV-1 entry into host cells and an IC50 of 16.4 nM for inhibition of radioligand stromal-derived factor-1α (SDF-1α) binding to CXCR4, was also found to be highly selective against closely related chemokine receptors. We rationalized that compound 24 complementarily interacted with the critical CXCR4 residues that are essential for binding to HIV-1 gp120 V3 loop and subsequent viral entry. Compound 24 showed a 130-fold increase in anti-HIV activity compared to that of the marketed CXCR4 antagonist, AMD3100 (Plerixafor), whereas both compounds exhibited similar potency in mobilization of CXCR4(+)/CD34(+) stem cells at a high dose. Our study offers insight into the design of anti-HIV therapeutics devoid of major interference with SDF-1α function.

Background: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment., Methods: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample., Results: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing., Conclusions: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

After extensive synthetic efforts, we found that many structurally diverse bioisosteres could be generated via derivatizing the C-4 alkyl chain on the pyrazole ring of compound 3 (B/P = 1/33) with different electronegative groups. Especially when a sulfonamide or sulfamide moiety was added, resulting compounds exhibited not only potent CB1R activity but also a desired tPSA value over 90 Å(2), a threshold considered to possess a low probability to cross BBB, leading to the identification of compound 4 (B/P = 1/64) as a peripherally restricted CB1R antagonist. Apart from its significant weight-loss efficacy in DIO mice, compound 4 also displays 163 clean off-target profiles and is currently under development for treating obesity and the related metabolic syndrome.

Specific interactions between Src homology 2 (SH2) domain-containing proteins and the phosphotyrosine-containing counterparts play significant role in cellular protein tyrosine kinase (PTK) signaling pathways. The SH2 domain inhibitors could potentially serve as drug candidates in treating human diseases. Here we have incorporated a novel phosphotyrosine mimetic, which is an unusual amino acid carrying a cyclosaligenyl (cycloSal) phosphodiester moiety, into dipeptides to investigate the inhibitory effect on SH2 domain-containing proteins. A plate-based assay was also established to screen for inhibitors that disrupt the interaction between a phosphopeptide of SLAM (signaling lymphocytic activation molecule) and its interacting protein SAP (SLAM-associated protein). We identified a number of inhibitors with IC50 values in the range of 17-35 μM, implying that the cycloSal phosphodiester-carrying amino acid could mimic the phosphotyrosyl residue. Our results also raise the possibility of integrating the newly developed phosphotyrosine mimetic moiety into inhibitors designed for other SH2 domain-containing proteins.

Under catalysis with ZnI(2), an effective annulation process of ω-silylacetylenic α-cyano ketones, leading to the formation of various bicyclic frameworks characterized with a TMS-containing methylenecyclopentane ring, has been developed.

The purpose of this study was to determine the effect of zinc supplementation on radiation-induced mucositis in patients with nasopharyngeal carcinoma (NPC) and those with oral cancers (OC). A total of 100 patients with head and neck cancers engaged in a randomized double blind study. All participants were placed into two randomized groups (experimental and control). The experimental group received a standard dose of zinc supplements, and the control group was given a placebo. Subgroup analyses were performed between 40 NPC and 43 OC patients. It was found that patients with OC in the control group developed Grade 2 and Grade 3 mucositis sooner than those in the experimental group. However, the benefits were not found to extend to patients with NPC. The results indicated that zinc supplementation prescribed in conjunction with radiotherapy postponed the development of severe mucositis solely for patients with OC. The pretreatment oral mucosa condition and areca chewing habit might account for such discrepancy.

By using the active metabolite 5 as an initial template, further structural modifications led to the identification of the titled compound 24 (BPR-890) as a highly potent CB1 inverse agonist possessing an excellent CB2/1 selectivity and remarkable in vivo efficacy in diet-induced obese mice with a minimum effective dose as low as 0.03 mg/kg (po qd) at the end of the 30-day chronic study. Current SAR studies along with those of many existing rimonabant-mimicking molecules imply that around the pyrazole C3-position, a rigid and deep binding pocket should exist for CB1 receptor. In addition, relative to the conventional carboxamide carbonyl, serving as a key hydrogen-bond acceptor during ligand-CB1 receptor interaction, the corresponding polarizable thione carbonyl might play a more critical role in stabilizing the Asp366-Lys192 salt bridge in the proposed CB1-receptor homology model and inducing significant selectivity for CB1R over CB2R.

Replacing the conventional pyrazole 5-aryl substituent of 1 (SR141716A) with the 2-thienyl moiety appended with an appropriate alkynyl unit, a novel class of 5-(5-alkynyl-2-thienyl)pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB1/2 selectivity, was discovered, many of which, as typified by compound 18, showed significant weight reduction in diet-induced obese mouse model, thus pharmacologically validating that the bioisosteric replacement described above is viable. Also encouraging was the finding that a subtle structural modification of the newly developed series could result in a distinct difference in the intrinsic property, as demonstrated by compounds 12 (NA) and its methylated structural isomers 15 (PA) and 18 (IA). Moreover, current structure-activity relationship studies revealed that around the pyrazole 5-position of 1, a deep and flat crevice surrounded by a sequence of hydrophobic/aromatic residues as indicated by the CB1-receptor homology model might exist in the binding site.