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Aims: Despite the tremendous improvement in therapeutic medication and intervention for coronary atherosclerotic disease (CAD), residual risks remain. Exome sequencing enables identification of rare variants and susceptibility genes for residual risks of early‐onset coronary atherosclerotic disease (EOCAD) with well‐controlled conventional risk factors. Methods: We performed whole‐exome sequencing of subjects who had no conventional risk factors, defined as higher body mass index, smoking, hypertension and dyslipidemia, screened from 1950 patients with EOCAD (age ≤ 45 years, at least 50% stenosis of coronary artery by angiography), and selected control subjects from 1006 elder (age ≥ 65 years) with < 30% coronary stenosis. Gene‐based association analysis and clinical phenotypic comparison were conducted. Results: Subjects without defined conventional risk factors accounted for 4.72% of young patients. Totally, 6 genes might be associated with residual risk of EOCAD, namely CABP1 (OR = 22.19, p = 0.02), HLA‐E (OR = 22.19, p = 0.02), TOE1 (OR = 33.6, p = 0.002), HPSE2 (OR = 11.1, p = 0.04), CHST14 (OR = 22.19, p = 0.02) as well as KLHL8 (OR = 22.19, p = 0.02). Phenotypic analysis displayed the levels of low‐density lipoprotein cholesterol in carriers of mutations from CABP1, HLA‐E, TOE1, and HPSE2 were significantly elevated compared to noncarriers. Notably, extracellular matrix‐associated CHST14 and fibrinogen‐associated KLHL8 both displayed possible correlation with increased neutrophil proportion and decreased monocyte percentage (both p < 0.05), exerting potential effects on the residual inflammatory risks of EOCAD. Conclusion: The study identified six genes related to dyslipidemia and inflammation pathways with potential association with residual risk of EOCAD, which will contribute to precision‐based prevention in these patients. Trial Registration: The GRAND study was registered at www.clinicaltrials.gov on July 14, 2015, and the registry number is NCT 02496858. [ABSTRACT FROM AUTHOR]

PARP inhibitors (PARPi) hold substantial promise in treating glioblastoma (GBM). However, the adverse effects have restricted their broad application. Through unbiased transcriptomic and proteomic sequencing, it is discovered that the BET inhibitor (BETi) Birabresib profoundly alters the processes of DNA replication and cell cycle progression in GBM cells, beyond the previously reported impact of BET inhibition on homologous recombination repair. Through in vitro experiments using established GBM cell lines and patient‐derived primary GBM cells, as well as in vivo orthotopic transplantation tumor experiments in zebrafish and nude mice, it is demonstrated that the concurrent administration of PARPi and BETi can synergistically inhibit GBM. Intriguingly, it is observed that DNA damage lingers after discontinuation of PARPi monotherapy, implying that sequential administration of PARPi followed by BETi can maintain antitumor efficacy while reducing toxicity. In GBM cells with elevated baseline replication stress, the sequential regimen exhibits comparable efficacy to concurrent treatment, protecting normal glial cells with lower baseline replication stress from DNA toxicity and subsequent death. This study provides compelling preclinical evidence supporting the development of innovative drug administration strategies focusing on PARPi for GBM therapy. [ABSTRACT FROM AUTHOR]

Inhibition of pathological cardiac hypertrophy is recognized as an important therapeutic strategy for heart failure, although effective targets are still lacking in clinical practice. Homeodomain interacting protein kinase 1 (HIPK1) is a conserved serine/threonine kinase that can respond to different stress signals, however, whether and how HIPK1 regulates myocardial function is not reported. Here, it is observed that HIPK1 is increased during pathological cardiac hypertrophy. Both genetic ablation and gene therapy targeting HIPK1 are protective against pathological hypertrophy and heart failure in vivo. Hypertrophic stress‐induced HIPK1 is present in the nucleus of cardiomyocytes, while HIPK1 inhibition prevents phenylephrine‐induced cardiomyocyte hypertrophy through inhibiting cAMP‐response element binding protein (CREB) phosphorylation at Ser271 and inactivating CCAAT/enhancer‐binding protein β (C/EBPβ)‐mediated transcription of pathological response genes. Inhibition of HIPK1 and CREB forms a synergistic pathway in preventing pathological cardiac hypertrophy. In conclusion, HIPK1 inhibition may serve as a promising novel therapeutic strategy to attenuate pathological cardiac hypertrophy and heart failure. [ABSTRACT FROM AUTHOR]

In situ high‐pressure Raman spectroscopy experiments have been performed to investigate the structural changes of parabanic acid (PA) up to ~12.0 GPa. The analysis of Raman spectroscopy reveals that PA undergoes two phase transitions. The collapse of spacing between molecular layers and the distortion of hydrogen‐bonding networks almost in ac‐plane are the main causes of the first phase transition above 2.1 GPa. The changes of Fermi resonance parameters also provide evidence for the first phase transitions. The second phase transition around 4.0 GPa can attribute to the further reduction of the molecular interlayer spacing and the resulting distortion of hydrogen‐bonding network. First‐principle calculations and Hirshfeld surfaces further confirm the analysis of the experimental results. The analysis of high‐pressure phase transition contributes a better explanation for the high‐pressure phase transition process of layered supramolecular materials with hydrogen‐bond self‐assembly. This study provides the possibility of two new polymorphs for PA under high pressure and is helpful for broadening its potential application of this material, especially in the field of supramolecular chemistry. [ABSTRACT FROM AUTHOR]

The aim of this research was to discuss Hederagenin's antitumor effects on glioma by in vitro study. U251 and U87 cell lines were used as research target in our research. In the first step, the different Hed concentrations were treated to U251 and U87 cell lines, and the second step is Nur77 transfection in U251 and U87 with Hed treatment; measuring cell proliferation by MTT and EdU staining; evaluating cell invasion and migration abilities by transwell assay and relative gene and protein expressions by RT‐qPCR and WB assay. Compared with NC group, U251 and U87 cell proliferation were significantly depressed with cell apoptosis significantly increasing, and cell invasion and migration abilities were significantly inhibited in Hed‐treated groups (p <.05, respectively); however, with Nur77 transfection, the Hed's antitumor effects disappeared. Meanwhile, with Hed supplement, Nur77, PI3K, and AKT gene expressions were significantly downregulated (p <.05, respectively) in Hed‐treated groups; and Nur77, p‐PI3K, and p‐AKT protein expressions were significantly decreased (p <.05, respectively) in Hed‐treated groups. Hed had antitumor effects on glioma cell biological activities via Nur77/PI3K/AKT pathway in vitro study. [ABSTRACT FROM AUTHOR]

The effects of ISG15 or ISGylation on tumor progression have been widely revealed; however, its roles in glioma progression are largely unknown. This study aims to explore the roles and underlying mechanisms of ISG15 in glioma progression. Here, ISG15 level was found to be upregulated in glioma tissues compared to the paired/unpaired normal tissues, and positively correlated with the level of stemness markers in glioma tissues. Loss of functional experiments indicated that ISG15 positively regulated glioma cell stemness, as evident by the increase of sphere formation ability, ALDH activity, stemness marker expression, and tumor‐initiating ability. Further mechanistic studies revealed that ISG15 directly interacted with Oct4 protein, a critical stemness promoter, induced the ISGylation of Oct4 protein, and thus enhanced Oct4 protein stability. Additionally, it was found that Oct4 was ISGylated at lysine 284 (K284), which has been confirmed to be the ubiquitination site of Oct4 protein, and ISG15 knockdown did not degrade K284R mutant Oct4. Furthermore, ISG15 knockdown‐induced downregulation of glioma cell stemness was rescued by Oct4 overexpression, but not by K284R mutant Oct4. Altogether, we suggest that ISG15‐induced ISGylation of Oct4 protein is essential for glioma cell stemness. [ABSTRACT FROM AUTHOR]

It has been reported that Cavin1 deficiency causes lipodystrophy in both humans and mice by affecting lipid metabolism. The ablation of Cavin1 in rodents also causes a significant deviation from Mendelian ratio at weaning in a background‐dependent manner, suggesting the presence of undiscovered functions of Cavin1. In the current study, the results show that Cavin1 deficiency causes neonatal death in C57BL/6J mice by dampening the storage and mobilization of glycogen in the liver, which leads to lethal neonatal hypoglycemia. Further investigation by electron microscopy reveals that Cavin1 deficiency impairs the fenestration in liver sinusoidal endothelial cells (LSECs) and impacts the permeability of endothelial barrier in the liver. Mechanistically, Cavin1 deficiency inhibits the RhoA‐Rho‐associated protein kinase 2‐LIM domain kinase‐Cofilin signaling pathway and suppresses the dynamics of the cytoskeleton, and eventually causes the reduction of fenestrae in LSECs. In addition, the defect of fenestration in LSECs caused by Cavin1 deficiency can be rescued by treatment with the F‐actin depolymerization reagent latrunculin A. In summary, the current study reveals a novel function of Cavin1 on fenestrae formation in LSECs and liver glycogen metabolism, which provide an explanation for the neonatal death of Cavin1 null mice and a potential mechanism for metabolic disorders in patients with Cavin1 mutation. [ABSTRACT FROM AUTHOR]

The crystal structure and hydrogen‐bonded chains of 1,3‐diphenylurea were found to have abrupt changes when the pressure increased to 1.8 GPa. Based on Raman spectra, the intermolecular interactions, the vibrations of chemical groups, and the molecular conformation were clearly distinguished from the initial state. The anisotropic compression of the original crystal structure and the occurrence of structural phase transition were confirmed by the results of in situ high‐pressure synchrotron X‐ray diffraction experiments. The new phase was stable up to about 10.0 GPa. The inevitable creasing of the N–H⋯O hydrogen‐bonded chains was derived from the remarkable shrink of distance between hydrogen‐bonded chains, which can be treated as the main reason leading to this phase transition. The first‐principle calculations and Hirshfeld surfaces further confirmed the analysis of the experimental results. This study demonstrates that excessively reducing the space between of hydrogen‐bonded chains will rearrange the self‐assembly of supramolecular materials. [ABSTRACT FROM AUTHOR]

Introduction: Although coronary artery disease (CAD) presentations and clinical outcomes differ by sex, little is known about premature CAD (PCAD). The present analysis aimed to evaluate the gender-related differences of PCAD in an Asian population from the FOCUS registry.Methods: A total of 1397 Asian young patients with angiographically confirmed CAD undergoing drug-eluting stent implantation were included in this analysis and divided into two groups according to the genders. Patients were followed up for three years and clinical outcomes were compared between groups.Results: Young women were older and more likely to have hypertension and diabetes than men (all p<0.001). In contrast, males with PCAD had higher BMI and higher prevalence of current smoking as well as previous vessel revascularizations (all p<0.05). Men were more likely to be manifested as total occlusive lesions (p<0.001). Regardless of the clinical characteristics, the cumulative incidences of adverse events such as major adverse cardiovascular event (MACE), cardiovascular death, and all-cause death were not significantly different at one- or three-year follow-up (all p>0.05).Conclusion: Despite remarkable differences in clinical characteristics between Asian males and females with PCAD, the two groups did not differ significantly in clinical outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Organic light‐emitting materials are centered on their excited states. However, excited‐state geometry is hardly solved. Herein, the planar distance of an anthracene excimer is determined by integrating a monodisperse dimeric anthracene stacking in crystal and high‐pressure technique. The crystal exhibits the pure excimer fluorescence at ambient conditions, and a unique photophysical phenomenon is observed under pressure: fluorescence peak keeps constant first and then starts a gradual redshift. The theoretical potential energy curve indicates that this starting point of redshift corresponds to the excimer equilibrium geometry, which will be innovative to determine the excited‐state π–π interplanar distance (Re) in experiment. Moreover, high‐pressure synchrotron powder X‐ray diffraction experiment tactfully determines Re = 3.330 Å at the pressure point of initial redshift. This work not only suggests the Re determination by an original pathway but also reports a unique excimer photophysics, which may provide a reference benchmark for the further theoretical and experimental studies on aromatic excimer. [ABSTRACT FROM AUTHOR]

The excited state properties of organic fluorescent materials are crucial for their photoelectronic performance. Here, a study on the highly efficient electrofluorescent material 4-(2-(4′-(diphenylamino)-[1,1′-biphenyl]-4-yl)-1H-phenanthro[9,10-d]imidazol-1-yl)benzonitrile (TBPMCN) is carried out, focusing mainly on its crystal structure and photophysical properties under pressure stimulation. The special triangular-cone (TC) configuration of triphenylamine group in TBPMCN crystal exhibits charge-transfer (CT)-dominated excited state property in TBPMCN, which gives rise to a blue-shifted emission in the crystal. Theoretical calculations prove that the TC conformation is a dynamically metastable state, which is higher in energy than the three-blade-propeller (TBP) configuration. In a further piezochromic experiment, a unique rehybridization-induced emission enhancement phenomenon is found in this crystal, which is essentially different from the aggregation-induced emission enhancement (AIEE) mechanism. It can be assigned to the change of excited state property from a CT-dominated state to a hybridized locally excited and charge-transfer state, as a result of the rehybridization of nitrogen atom upon the increased external pressure. This work provides deep insight into the relationship between molecular structure and excited state properties in crystal by means of the pressure stimulation and further enriches the AIEE mechanism. Additionally, the large red-shifted piezochromic phenomenon of this CT material is stressed. [ABSTRACT FROM AUTHOR]

In the donor‐acceptor molecule TBPMCN, crystal stacking causes a C‐N bond wagging on its electron donor triphenylamine (TPA). The sp3‐hybridized N atom in the resulting metastable triangular‐cone conformation, disables its contribution in luminescence. On page 1602276 B. Zhou, B. Yang, and co‐workers achieve rehybridization‐induced emission enhancement: the pressure of a diamond anvil cell gradually turns TPA into the stable three‐blade‐propeller conformation with a sp2‐hybridized N atom. [ABSTRACT FROM AUTHOR]

Background: Contemporary risk assessment in patients with coronary atherosclerotic disease (CAD) often relies on invasive angiography. However, we aimed to explore the potential of metabolomic biomarkers in reflecting residual risk in patients with CAD after moderate lipid-lowering therapy., Methods and Results: We analyzed serum metabolomic profile among 2560 patients with newly diagnosed CAD undergoing moderate lipid-lowering therapy, through nuclear magnetic resonance spectroscopy and quantified 175 metabolites, predominantly lipoproteins and their components. CAD severity was evaluated using Gensini score for plaque burden and circulating cardiac troponin T levels for plaque instability. The association of metabolites with CAD severity was examined using multivariate linear regression, and the underlying potential causality was explored using a 2-sample Mendelian randomization approach. Two composite metabolomic indices were constructed to reflect CAD severity using least absolute shrinkage and selection operator linear regression, and their associations with risk of major adverse cardiac events during a median follow-up of 3.8 years were evaluated using Cox models. Our investigation revealed that triglycerides and apolipoprotein B in low-density lipoprotein particles displayed stronger associations with CAD severity compared with the clinically used low-density lipoprotein cholesterol marker. In large high-density lipoprotein, components like cholesterol, cholesterol esters, triglyceride, apolipoprotein A1/A2 showed inverse associations with CAD severity. Certain metabolites, including apolipoprotein B and dihydrothymine, showed a putative causal link with Gensini score. Notably, per standard deviation increase in Gensini score-based metabolomic index was associated with 14.8% higher major adverse cardiac event risk (hazard ratio, 1.148 [95% CI, 1.018-1.295]) independent of demographic factors, medication use, and disease status., Conclusions: Our findings highlight the potential of nuclear magnetic resonance-based metabolomics in identifying novel biomarkers of plaque burden and instability. Metabolites related to plaque burden may facilitate noninvasive assessment of CAD prognosis.