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Rechargeable fluoride ion batteries (FIBs) are one of the most promising energy storage candidates in view of high energy density and low cost. The development of highly F‐conductive, safe, and flexible electrolytes is the central task for the construction of high‐performance FIBs. Hereby, this work first proposes a polyvinyl alcohol (PVA)‐borax‐glycerol (PBG) polymer electrolyte. The F− transport along one PVA chain is realized by the interaction between F− and ‐OH on the PVA chain and the motion of PVA chain would facilitate the migration of F−. The B(OH)4− dissociated from borax can be used as a cross‐linking agent, and react with the hydroxyl groups on PVA by a dehydration process to form a polymer with a 3D cross‐linked structure. The optimized ionic conductivity (as high as 2.82 × 10−4 S cm−1 at 30 °C and 1.08 × 10−3 S cm−1 at 60 °C) of PBG can be obtained. The flat and soft surface of PBG electrolytes can significantly reduce the activation energy for the interfacial transport process. Benefitting from the high ionic conductivity and easier interfacial transport, the PBG electrolyte makes the all‐solid‐state FIBs enable reversible cycling at a high current density of 125 mA g−1. [ABSTRACT FROM AUTHOR]

Fluoride ion batteries (FIBs) are regarded as one of the most promising candidates for next‐generation energy storage systems to achieve lower cost and higher energy density. However, the appropriate electrolyte design strategy is still lacking for FIBs to simultaneously settle the issues of fluoride salt dissolution and metal cation shuttle. Herein, a novel fluoride ion shuttle electrolyte with the synergistic high‐donor solvent (N, N‐dimethylacetamide, DMA) and alcohol anion acceptor (benzyl alcohol, BA) is developed. BA enables the promotion of solubility of inorganic fluoride salt (CsF). Meanwhile, benefiting from the re‐configuration of hydrogen bonding network by DMA, the solvation structures of anions and cations are regulated with reduced hindrance to F− shuttle and mitigated dissolution of active material. This electrolyte formation achieves superior interfacial stability with cathode, high F− conductivity (2.05 mS cm−1), and transference number (0.53). After matching CuF2 cathode and Pb anode, the full cell exhibits the highly reversible conversion reaction process with an initial discharge capacity of 300.8 mAh g−1 and a reversible capacity of 245.5 mAh g−1 after 43 cycles. This study proposes a solution to high‐performance rechargeable FIBs at room temperature by synergistically manipulating the anionic and cationic solvation chemistry. [ABSTRACT FROM AUTHOR]

Chicken claw products with their unique texture are loved by consumers, and cooking is a key step to affect the taste of chicken claw consumption, through the moderate hydrolysis of proteins and a series of physicochemical changes, so that the chicken claw gets tender and presents a crispy taste, but the current research on the optimal cooking conditions for chicken claw is still relatively small. In the present work, combinations of time (11, 13, 15, 17, and 19 min) and temperature (82, 86, 90, 94, and 98°C) were applied to the cooking of chicken claws. The effects of different cooking conditions on the quality characteristics of chicken claws were investigated, with special emphasis on the cooking loss rate, color, texture properties, lipid oxidation, myofibrillar fragmentation index (MFI), and total sulfhydryl content. The results showed that the cooking loss rate, lipid oxidation, and MFI value of chicken claws gradually increased, and the total color difference (∆E), puncture force, shear force, and total sulfhydryl content gradually decreased with the increase of cooking temperature and cooking time. Overall, chicken claws cooked at 86, 90, and 94°C for 15 and 17 min had better texture and flavor. Cooking treatment had a significant effect on the quality characteristics of chicken claws. Overall, chicken claws cooked at 86, 90 and 94°C for 15 and 17 min had better texture and flavor. [ABSTRACT FROM AUTHOR]

The ultimate goal of this work is to create an engineered aerosol that acts as one‐way smoke, i.e. it creates an asymmetric vision environment in which the ability to image objects depends on the viewing direction. To this end, a rapid, one‐pot synthesis of copper‐based microclubs is developed that consists of a Cu2O octahedron attached to a Cu2O@Cu shaft. Millions of synthesized particles are analyzed in minutes with a FlowCam to provide a robust statistical analysis of their geometry, and rapidly elucidate the roles of the reaction constituents on the particle shape and yield. The combination of asymmetry in both shape and composition introduces a 30% difference in scattering of light propagating parallel to the microclub axis from opposing directions. This work represents a first step toward the creation of an asymmetric imaging environment with an aerosol consisting of acoustically aligned microclubs. [ABSTRACT FROM AUTHOR]

Magnesium metal batteries (MMBs) currently face challenges suffering from severe Mg metal passivation and extremely high overpotential in conventional electrolytes. Herein, a strategy of using a low‐cost deep eutectic solution (DES) is proposed to modify Mg anode with the monolithic and compact coating of a MgCl2‐Al‐MgCl2 sandwich structure, enabling the stable and reversible Mg plating–stripping behavior. An organic/nanocrystal hybrid interphase is in‐situ built through a facile Mg‐Al displacement reaction between aluminum‐chloro clusters and Mg in AlCl3/Et3NHCl solution, and it can effectively minimize the adverse interfacial passivation reaction and surface diffusion barrier, affording the high ion‐conduction and electronic insulation. This DES‐assisted method guarantees a highly reversible cycling of Mg metal anode (over 5000 h at 0.1 mA cm−2 and 400 h at 2.0 mAh cm−2) in Mg(TFSI)2/DME electrolyte with the improved interfacial kinetics and low overpotential. Even at a much higher current density of 1 mA cm−2, the overpotential only undergoes a slight increase from 0.2 V (at 0.1 mA cm−2) to 0.23 V. The corresponding full cells with CuS and phenanthraquinone cathodes deliver satisfactory cyclic performance. The DES modification strategy provides a new solution to the design of robust and conductive solid electrolyte interphase for achieving high‐voltage and durable MMBs. [ABSTRACT FROM AUTHOR]

The finite periodic arrangement of functional nanomaterials on the two‐dimensional scale enables the integration and enhancement of individual properties, making them an important research topic in the field of tuneable nanodevices. Although layer‐controllable lattices such as graphene have been successfully synthesized, achieving similar control over colloidal nanoparticles remains a challenge. DNA origami technology has achieved remarkable breakthroughs in programmed nanoparticle assembly. Based on this technology, we proposed a hierarchical assembly strategy to construct a universal DNA origami platform with customized layer properties, which we called 2.5‐dimensional (2.5D) DNA origami crystals. Methodologically, this strategy divides the assembly procedure into two steps: 1) array synthesis, and 2) lattice synthesis, which means that the layer properties, including layer number, interlayer distance, and surface morphology, can be flexibly customized based on the independent designs in each step. In practice, these synthesized 2.5D crystals not only pioneer the expansion of the DNA origami crystal library to a wider range of dimensions, but also highlight the technological potential for templating 2.5D colloidal nanomaterial lattices. [ABSTRACT FROM AUTHOR]

Liver hepatocellular carcinoma (LIHC) is a significant global health issue with limited treatment options. In this study, single‐cell RNA sequencing (scRNA‐seq) data were used to explore the molecular mechanisms of LIHC development and identify potential targets for therapy. The expression of peroxisome proliferator‐activated receptors (PPAR)‐related genes was analysed in LIHC samples, and primary cell populations, including natural killer cells, T cells, B cells, myeloid cells, endothelial cells, fibroblasts and hepatocytes, were identified. Analysis of the differentially expressed genes (DEGs) between normal and tumour tissues revealed significant changes in gene expression in various cell populations. PPAR activity was evaluated using the 'AUCell' R software, which indicated higher scores in the normal versus the malignant hepatocytes. Furthermore, the DEGs showed significant enrichment of pathways related to lipid and glucose metabolism, cell development, differentiation and inflammation. A prognostic model was then constructed using 8 PPARs‐related genes, including FABP5, LPL, ACAA1, PPARD, FABP4, PLIN1, HMGCS2 and CYP7A1, identified using least absolute shrinkage and selection operator‐Cox regression analysis, and validated in the TCGA‐LIHC, ICGI‐LIRI and GSE14520 datasets. Patients with low‐risk scores had better prognosis in all cohorts. Based on the expression of the eight model genes, two clusters of patients were identified by ConsensusCluster analysis. We also predicted small‐molecule drugs targeting the model genes, and identified perfluorohexanesulfonic acid, triflumizole and perfluorononanoic acid as potential candidates. Finally, wound healing assay confirmed that PPARD can promote the migration of liver cancer cells. Overall, our study offers novel perspectives on the molecular mechanisms of LIHC and potential areas for therapeutic intervention, which may facilitate the development of more effective treatment regimens. [ABSTRACT FROM AUTHOR]

Ferroptosis is a necrotic form of iron‐dependent regulatory cell death. Estrogen withdrawal can interfere with iron metabolism, which is responsible for the pathogenesis of postmenopausal osteoporosis (PMOP). Here, it is demonstrated that estrogen withdrawal induces iron accumulation in the skeleton and the ferroptosis of osteocytes, leading to reduced bone mineral density. Furthermore, the facilitatory effect of ferroptosis of osteocytes is verified in the occurrence and development of postmenopausal osteoporosis is associated with over activated osteoclastogenesis using a direct osteocyte/osteoclast coculture system and glutathione peroxidase 4 (GPX4) knockout ovariectomized mice. In addition, the nuclear factor erythroid derived 2‐related factor‐2 (Nrf2) signaling pathway is confirmed to be a crucial factor in the ferroptosis of osteocytic cells. Nrf2 regulates the expression of nuclear factor kappa‐B ligand (RANKL) by regulating the DNA methylation level of the RANKL promoter mediated by DNA methyltransferase 3a (Dnmt3a), which is as an important mechanism in osteocytic ferroptosis‐mediated osteoclastogenesis. Taken together, this data suggests that osteocytic ferroptosis is involved in PMOP and can be targeted to tune bone homeostasis. [ABSTRACT FROM AUTHOR]

The Ilizarov technique has been continuously innovated to utilize tensile stress (TS) for inducing a bone development‐like regenerative process, aiming to achieve skeletal elongation and reconstruction. However, it remains uncertain whether this distraction osteogenesis (DO) process induced by TS involves the pivotal coupling of angiogenesis and osteogenesis mediated by type H endothelial cells (THECs). In this study, it is demonstrated that the Ilizarov technique induces the formation of a metaphysis‐like architecture composed of THECs, leading to segmental bone regeneration during the DO process. Mechanistically, cell‐matrix interactions‐mediated activation of yes‐associated protein (YAP)/transcriptional co‐activator with PDZ‐binding motif (TAZ) transcriptionally upregulates the expression of Notch1 and Delta‐like ligand 4, which act as direct positive regulators of THECs phenotype, in bone marrow endothelial cells (BMECs) upon TS stimulation. Simultaneously, the Notch intracellular domain enhances YAP/TAZ activity by transcriptionally upregulating YAP expression and stabilizing TAZ protein, thus establishing the YAP/TAZ‐Notch circuit. Additionally, TS‐stimulated BMECs secrete exosomes enriched with vital molecules in this positive feedback pathway, which can be utilized to promote segmental bone defect healing, mimicking the therapeutic effects of Ilizarov technique. The findings advance the understanding of TS‐induced segmental bone regeneration and establish the foundation for innovative biological therapeutic strategies aimed at activating THECs. [ABSTRACT FROM AUTHOR]

Solid‐state fluoride ion batteries (SSFIBs) are anion‐shuttle‐driven and alkali‐metal‐free emerging energy storage systems, and have the advantages of low cost, high safety, and energy density. However, the current major challenges of SSFIBs or quasi‐SSFIBs are the lack of high‐conductivity fluoride electrolytes and the difficulty of mild‐temperature operation of full cells. Here, a 2D fluoride conductor (KSn2F5) synthesized by mechanochemical method is employed as the compatible solid electrolyte with a high F‐ion conductivity of 10−4 S cm−1 at 60 °C. The high concentration and frequent hopping of charge carriers in F‐vacancy‐rich KSn2F5 contribute to the higher ionic conductivity compared to most reported fluoride structures. Integrating this layered electrolyte with high‐voltage CuF2 cathode and Sn/SnF2 anode, a highly reversible cycling of conversion‐type quasi‐SSFIBs with a discharge capacity of 150 mAh g−1 for at least 70 cycles at 60 °C is achieved. The interface engineering aided by tetra‐n‐butylammonium fluoride salt facilitates the F‐ion transfer between cathode and electrolyte and fluorination/defluorination conversion mechanism of CuF2 cathode with optimized multiphase and nanodomain distributions. [ABSTRACT FROM AUTHOR]

The garnet‐type solid‐state Li‐metal batteries are promising to develop into the high‐energy‐density system when coupled with the high‐capacity conversion reaction cathodes. However, the high interfacial resistance and poor contact between garnet electrolyte and Li anode are still a challenge. Here, an alloyable viscous fluid strategy is proposed for Li/garnet interface welding to enable highly reversible fluoride conversion solid‐state batteries. The super‐assembled phenide polymer with liquid metal property can serve as "oily" interlayer to in situ construct an ionic/electronic mixed conduction network by thermal and electrochemical lithiation. The resultant healing effect of contact voids between garnet and Li enables a dramatic reduction of interfacial resistance to 6 Ω cm2. The confinement and compaction of conversion products by garnet electrolyte endow the FeF3 based batteries with long‐cycling and high‐rate performance (520 and 330 mAh g−1 at 0.2 and 2 C respectively). This ceramic configuration also endows the CuF2 conversion battery with much better rechargeability (instead as widely known primary battery). [ABSTRACT FROM AUTHOR]

Aim: To investigate the relationship between systemic exposure to hydroxychloroquine (HCQ) and its metabolite desethylhydroxychloroquine (DHCQ) and clinical outcome in severely ill patients treated with a standard oral dose regimen of HCQ during the first wave of COVID‐19 in New York City. Methods: We correlated retrospective clinical data with drug exposure prospectively assessed from convenience samples using population pharmacokinetics and Bayesian estimation. Systemic exposure was assessed in 215 patients admitted to ICU or COVID‐ward for whom an interleukin‐6 level was requested and who were still alive 24 hours after the last dose of HCQ. Patients received oral HCQ 600 mg twice daily on day 1 followed by 4 days of 400 mg daily. Results: Fifty‐three precent of the patients were intubated at 5.4 ± 6.4 days after admission and 26.5% died at an average of 32.2 ± 19.1 days. QTc at admission was 448 ± 34 ms. Systemic exposure to HCQ and DHCQ demonstrated substantial variability. Cumulative area under the serum concentration–time curve up to infinity for HCQ was 71.4 ± 19.3 h mg/L and for DHCQ 56.5 ± 28.3 h mg/L. Variability in systemic exposure was not clearly explained by renal function, liver function or inflammatory state. In turn, systemic exposure did not correlate with intubation status, survival or QTc prolongation. Conclusion: This study in severely ill patients was not able to find any relationship between systemic exposure to HCQ and DHCQ and clinical outcome at a routine dose regimen and adds to the growing body of evidence that oral HCQ does not alter the course of disease in COVID‐19 patients. [ABSTRACT FROM AUTHOR]

Aims: Cabotegravir delivered as a long‐acting intramuscular injection has shown superior efficacy to oral tenofovir‐emtricitabine as pre‐exposure prophylaxis (PrEP) for HIV. Cabotegravir pharmacokinetics (PK), like those of other long‐acting depot preparations, exhibit variability between individuals and between injection occasions. The aim of this study is to describe the population pharmacokinetics of long‐acting cabotegravir (CAB‐LA). Methods: Using available PK measurements from 133 participants in the HIV Prevention Trials Network (HPTN) 077 trial, we analysed CAB‐LA PK data using nonlinear mixed‐effects modelling to develop a population PK model. Results: A two‐compartment model with first order absorption best described the CAB‐LA PK. The analysis identified between‐occasion variability (BOV, i.e., differences in PK within one individual from one injection to the next) as a significant covariate affecting the absorption rate, with an estimated contribution of BOV to PK variability on the absorption rate (ka) of 38.5%. Sex and body weight were identified as significant covariates influencing the absorption rate and apparent clearance of CAB‐LA after intramuscular injection at various doses and frequencies. Male participants had 67% higher ka than female participants. Serially adding to the model body weight on clearance, sex on ka, and BOV on ka led to a decrease in the objective function value (OFV) of 24.4, 36 and 321.4, respectively. Conclusion: The public availability of this model will facilitate and enable a wide variety of future clinically relevant simulations to inform the optimal use of CAB‐LA. [ABSTRACT FROM AUTHOR]

Migrating cells must deform their stiff cell nucleus to move through pores and fibers in tissue. Lamin A/C is known to hinder cell migration by limiting nuclear deformation and passage through confining channels, but its role in nuclear deformation and passage through fibrous environments is less clear. Cell and nuclear migration through discrete, closely spaced, slender obstacles which mimic the mechanical properties of collagen fibers are studied. Nuclei bypass slender obstacles while preserving their overall morphology by deforming around them with deep local invaginations of little resisting force. The obstacles do not impede the nuclear trajectory and do not cause rupture of the nuclear envelope. Nuclei likewise deform around single collagen fibers in cells migrating in 3D collagen gels. In contrast to its limiting role in nuclear passage through confining channels, lamin A/C facilitates nuclear deformation and passage through fibrous environments; nuclei in lamin‐null (Lmna−/−) cells lose their overall morphology and become entangled on the obstacles. Analogous to surface tension‐mediated deformation of a liquid drop, lamin A/C imparts a surface tension on the nucleus that allows nuclear invaginations with little mechanical resistance, preventing nuclear entanglement and allowing nuclear passage through fibrous environments. [ABSTRACT FROM AUTHOR]

Objective: To establish in an exploratory neuroimaging study whether γ‐hydroxybutyrate (sodium oxybate [SO]), a sedative, anti‐narcoleptic drug with abuse potential, transiently inhibits striatal dopamine release in the human. Methods: Ten healthy participants (30 years; 6M, 4F) and one participant with narcolepsy received a baseline positron emission tomography scan of [C‐11]raclopride, a D2/3 dopamine receptor radioligand sensitive to dopamine occupancy, followed approximately one week later by an oral sedative 3g dose of SO and two [C‐11]raclopride scans (1 h, 7 h post SO). Plasma SO levels and drowsiness duration were assessed. Results: No significant changes were detected in [C‐11]raclopride binding in striatum overall 1 or 7 h after SO, but a small non‐significant increase in [C‐11]raclopride binding, implying decreased dopamine occupancy, was noted in limbic striatal subdivision at one hour (+6.5%; p uncorrected = 0.045; +13.2%, narcolepsy participant), returning to baseline at 7 h. A positive correlation was observed between drowsiness duration and percent change in [C‐11]raclopride binding in limbic striatum (r = 0.73; p = 0.017). Conclusions: We did not find evidence in this sample of human subjects of a robust striatal dopamine change, as was reported in non‐human primates. Our preliminary data, requiring extension, suggest that a 3g sedative SO dose might cause slight transient inhibition of dopamine release in limbic striatum. [ABSTRACT FROM AUTHOR]

Simple (Bosniak I) renal cysts are considered acceptable in living kidney donor selection in terms of cancer risk. However, they tend to increase in number and size over time and might compromise renal function in donors. To clarify their implications for long‐term renal function, we characterized the prevalence of renal cysts in 454 individuals who donated at our center from 2000 to 2007. We estimated the association between the presence of cysts in the kidney remaining after nephrectomy (ie, retained cysts) and postdonation eGFR trajectory using mixed‐effects linear regression. Donors with retained cysts (N = 86) were older (P <.001) and had slightly lower predonation eGFR (median 94 vs 98 mL/min/1.73 m2, P <.01) than those without cysts. Over a median 7.8 years, donors with retained cysts had lower baseline eGFR (−8.7 −5.6 −2.3 mL/min/1.73 m2, P <.01) but similar yearly change in eGFR (−0.4 0.02 0.4 mL/min/1.73 m2, P =.2) compared to those without retained cysts. Adjusting for predonation characteristics, there was no difference in baseline eGFR (P =.6) or yearly change in eGFR (P >.9). There continued to be no evidence of an association when we considered retained cyst(s) ≥10 mm or multiple retained cysts (all P >.05). These findings reaffirm current practices of accepting candidates with simple renal cysts for donor nephrectomy. [ABSTRACT FROM AUTHOR]

Abstract: The long‐term impact of Amazonian drought on canopy structure has been observed in ground and remote sensing measurements. However, it is still unclear whether it is caused by biotic (e.g., plant structure damage) or environmental (e.g., water deficiency) factors. We used the Community Land Model version 4.5 (CLM4.5) and radar backscatter observations from SeaWinds Scatterometer on board QuikSCAT (QSCAT) satellite to investigate the relative role of biotic and environmental factors in controlling the forest canopy disturbance and recovery processes after the 2005 Amazonian drought. We validated the CLM4.5 simulation of the drought impact and the recovery of leaf carbon (C) pool, an indicator of canopy structure, over southwestern Amazonia with QSCAT backscatter observations, which are sensitive to canopy structure change. We found that the leaf C pool simulated by CLM4.5 recovered to the 2000–2009 mean level (343 g C m−2) in 3 years after a sharp decrease in 2005, consistent with the QSCAT observed slow recovery. Through sensitivity experiments, we found that the slow C recovery was primarily due to biotic factors represented by the canopy damage and reduction of plant C pools. The recovery of soil water and the coupling between water and C pools, which is an environmental factor, only contributes ~24% to the leaf C recovery. The results showed (1) the strength of scatterometer backscatter measurements in capturing canopy damage over tropical forests and in validating C cycle models and (2) the biotic factors play the dominant role in regulating the drought induced disturbance and persistent canopy changes in CLM4.5. [ABSTRACT FROM AUTHOR]

Photovoltaic (PV) power generation levels in the three phases of a multilevel cascaded H‐bridge (CHB) converter can be significantly unbalanced, owing to different irradiance levels and ambient temperatures over a large‐scale solar PV power plant. Injection of a zero‐sequence voltage is required to maintain three‐phase balanced grid currents with unbalanced power generation. This study theoretically compares power balance capabilities of various zero‐sequence injection methods based on two metrics which can be easily generalised for all CHB applications to PV systems. Experimental results based on a 430 V, 10 kW, three‐phase, seven‐level cascaded H‐bridge converter prototype confirm superior performance of the optimal zero‐sequence injection technique. [ABSTRACT FROM AUTHOR]

Hollow BiVO4 microspheres are prepared in the presence of ethylenediaminetetraacetic acid (EDTA) through a hydrothermal method, and used as a template for the fabrication of Ag-nanoparticle-decorated BiVO4 (BiVO4/Ag) composite microspheres. The morphology and structure are characterized by transmission electron microscopy and scanning electron microscopy. It is found that EDTA plays an important role in the formation of the hollow microspheres, and the possible formation mechanism is discussed. UV/visible spectrometry analysis shows that the BiVO4/Ag composite microspheres exhibit a distinct surface plasmon absorption band compared with pure BiVO4 microspheres. The photocatalytic activities of the BiVO4/Ag composite microspheres are examined by studying the degradation of rhodamine 6G (R6G) solutions under visible-light irradiation (>400 nm). The results show clearly that the BiVO4/Ag composite microspheres possess a much higher photocatalytic activity than pure BiVO4 microspheres and P25. In addition, Raman analyses show that the BiVO4/Ag composite microspheres exhibit an excellent surface-enhanced Raman scattering (SERS) performance. [ABSTRACT FROM AUTHOR]

L7587 --> 922.5 --> Anticancer drug response is determined by genetic and epigenetic mechanisms. To identify the epigenetic regulators of anticancer drug response, we conducted a chemical epigenetics screen using chemical probes that target different epigenetic modulators. In this screen, we tested 31 epigenetic probes in combination with 14 mechanistically diverse anticancer agents and measured the viability in A549 lung adenocarcinoma cells by the Resazurin assay. We identified 6 epigenetic probes that significantly potentiated the cytotoxicity of TAK‐243, a first‐in‐class ubiquitin‐activating enzyme (UBA1) inhibitor evaluated in several solid and hematologic malignancies. These probes include TP‐472, GSK‐864, A‐196, UNC1999, SGC‐CBP30 and PFI‐4, and target BRD9/7, mutant IDH1, SUV420H1/H2, EZH2/H1, p300/CBP and BRPF1B, respectively. To validate the screen results, we assessed the viability after combination of TAK‐243 and the identified probes and observed 4‐ to 30‐fold potentiation of TAK‐243 cytotoxicity in myeloma cells. Moreover, we tested the identified probes in 13 additional cell lines and observed profound potentiation. Upon combination with a panel of anticancer agents, epigenetic probes did not potentiate their cytotoxicity suggesting the observed effects are selective for TAK‐243. In contrast to epigenetic probes, negative chemical controls did not have a significant impact on TAK‐243 cytotoxicity. As assessed by immunoblotting, potentiation of TAK‐243 cytotoxicity was associated with reduced ubiquitylation and induction of apoptosis. Using the cellular thermal shift assay (CETSA), UBA1 displayed increased engagement with TAK‐243, suggesting the epigenetic probes enhanced intracellular drug accumulation. Mechanistically, the epigenetic probes exerted their potentiation by inhibiting the efflux transporter ABCG2 without inducing significant changes in ubiquitylation pathways or ABCG2 expression levels. Additionally, the identified probes shared significant chemical scaffold similarities with TAK‐243. Based on the screen results, we developed a cell‐based assay that exploits TAK‐243 and ABCG2‐overexpressing cells to reliably quantify the ABCG2‐inhibitory activity of novel compounds. In conclusion, our study identifies epigenetic probes that profoundly potentiate TAK‐243 cytotoxicity through off‐target ABCG2 inhibition. We also provide experimental evidence of the inability of negative controls to exclude a subset of off‐target effects of chemical probes. Finally, we have developed a robust cell‐based assay that can quantitatively evaluate ABCG2 inhibition by drug candidates. [ABSTRACT FROM AUTHOR]

Background This Mendelian randomization study aims to investigate causal associations between genetically predicted insomnia and 14 cardiovascular diseases (CVDs) as well as the potential mediator role of 17 cardiometabolic risk factors. Methods and Results Using genetic association estimates from large genome-wide association studies and UK Biobank, we performed a 2-sample Mendelian randomization analysis to estimate the associations of insomnia with 14 CVD conditions in the primary analysis. Then mediation analysis was conducted to explore the potential mediator role of 17 cardiometabolic risk factors using a network Mendelian randomization design. After correcting for multiple testing, genetically predicted insomnia was consistent significantly positively associated with 9 of 14 CVDs, those odds ratios ranged from 1.13 (95% CI, 1.08-1.18) for atrial fibrillation to 1.24 (95% CI, 1.16-1.32) for heart failure. Moreover, genetically predicted insomnia was consistently associated with higher body mass index, triglycerides, and lower high-density lipoprotein cholesterol, each of which may act as a mediator in the causal pathway from insomnia to several CVD outcomes. Additionally, we found very little evidence to support a causal link between insomnia with abdominal aortic aneurysm, thoracic aortic aneurysm, total cholesterol, low-density lipoprotein cholesterol, glycemic traits, renal function, and heart rate increase during exercise. Finally, we found no evidence of causal associations of genetically predicted body mass index, high-density lipoprotein cholesterol, or triglycerides on insomnia. Conclusions This study provides evidence that insomnia is associated with 9 of 14 CVD outcomes, some of which may be partially mediated by 1 or more of higher body mass index, triglycerides, and lower high-density lipoprotein cholesterol.