Modulating the affinity and signaling bias of cannabinoid receptor 1 antagonists.

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 ß-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 ß-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.

Identifying the nexus among environmental performance, digital finance, and green innovation: New evidence from prefecture-level cities in China.

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.

Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans.

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.

Association of an IGHV3-66 gene variant with Kawasaki disease.

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.

Traction Injury of Recurrent Laryngeal Nerve During Thyroidectomy.

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.

Fluorine-18 isotope labeling for positron emission tomography imaging. Direct evidence for DBPR211 as a peripherally restricted CB1 inverse agonist.

The [18F] 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.

Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies.

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.

Variant GADL1 and response to lithium therapy in bipolar I disorder.

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.).

Genetic epidemiological study doesn't support GLA IVS4+919G>A variant is a significant mutation in Fabry disease.

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.

Discovery of a Long Half-Life AURKA Inhibitor to Treat MYC-Amplified Solid Tumors as a Monotherapy and in Combination with Everolimus.

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.

What are the pandemic's shocks on carbon emission trading? The different management applications.

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.

The transaction behavior of cryptocurrency and electricity consumption.

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.

Stress of life events and anxiety as mediators of the association between insomnia and triglycerides in college students.

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 (ß = 0.28, p < .001) and anxiety (ß = 0.46, p < .001). Insomnia was related to elevated fasting insulin (ß = 0.12, p = .04) and triglyceride level (ß = 1.85, p < .001). An inverse association was found between insomnia and HDL-cholesterol (ß = -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.

Conia-ene annulation of the α-cyano ß-TMS-capped alkynyl cycloalkanone system and its synthetic application.

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.

Economic policy uncertainty and energy production in China.

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.

Spillover effect between carbon spot and futures market: evidence from EU ETS.

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.

Epidemics and electricity CO2 emissions: a feedback investigation.

We examine the short-term and long-term causal effects between epidemics and electricity CO2 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 CO2 emissions, especially in OECD and Asian countries.

What is the relationship between government response and COVID-19 pandemics? Global evidence of 118 countries.

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.

Synergistic Inhibition of SARS-CoV-2 Replication Using Disulfiram/Ebselen and Remdesivir.

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 Zn2+ 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 Zn2+ sites.

Correction to "Synergistic Inhibition of SARS-CoV-2 Replication Using Disulfiram/Ebselen and Remdesivir".

[This corrects the article DOI: 10.1021/acsptsci.1c00022.].