Effects of a nanoscopic filler on the structure and dynamics of a simulated polymer melt and the relationship to ultra-thin films

We perform molecular dynamics simulations of an idealized polymer melt surrounding a nanoscopic filler particle to probe the effects of a filler on the local melt structure and dynamics. We show that the glass transition temperature $T_g$ of the melt can be shifted to either higher or lower temperatures by appropriately tuning the interactions between polymer and filler. A gradual change of the polymer dynamics approaching the filler surface causes the change in the glass transition. We also find that while the bulk structure of the polymers changes little, the polymers close to the surface tend to be elongated and flattened, independent of the type of interaction we study. Consequently, the dynamics appear strongly influenced by the interactions, while the melt structure is only altered by the geometric constraints imposed by the presence of the filler. Our findings show a strong similarity to those obtained for ultra-thin polymer films (thickness $\lesssim 100$ nm) suggesting that both ultra-thin films and filled-polymer systems might be understood in the same context

Ground-based and JWST observations of SN 2022pul. I. Unusual signatures of carbon, oxygen, and circumstellar interaction in a peculiar type Ia supernova

Nebular-phase observations of peculiar Type Ia supernovae (SNe Ia) provide important constraints on progenitor scenarios and explosion dynamics for both these rare SNe and the more common, cosmologically useful SNe Ia. We present observations from an extensive ground- and space-based follow-up campaign to characterize SN 2022pul, a super-Chandrasekhar mass SN Ia (alternatively "03fg-like" SN), from before peak brightness to well into the nebular phase across optical to mid-infrared (MIR) wavelengths. The early rise of the light curve is atypical, exhibiting two distinct components, consistent with SN Ia ejecta interacting with dense carbon–oxygen (C/O)-rich circumstellar material (CSM). In the optical, SN 2022pul is most similar to SN 2012dn, having a low estimated peak luminosity (MB = −18.9 mag) and high photospheric velocity relative to other 03fg-like SNe. In the nebular phase, SN 2022pul adds to the increasing diversity of the 03fg-like subclass. From 168 to 336 days after peak B-band brightness, SN 2022pul exhibits asymmetric and narrow emission from [O i] λλ6300, 6364 (FWHM ≈ 2000 km s−1), strong, broad emission from [Ca ii] λλ7291, 7323 (FWHM ≈ 7300 km s−1), and a rapid Fe iii to Fe ii ionization change. Finally, we present the first ever optical-to-MIR nebular spectrum of an 03fg-like SN Ia using data from JWST. In the MIR, strong lines of neon and argon, weak emission from stable nickel, and strong thermal dust emission (with T ≈ 500 K), combined with prominent [O i] in the optical, suggest that SN 2022pul was produced by a white dwarf merger within C/O-rich CSM

Ground-based and JWST Observations of SN 2022pul. II. Evidence from nebular spectroscopy for a violent merger in a peculiar type Ia supernova

We present an analysis of ground-based and JWST observations of SN 2022pul, a peculiar "03fg-like" (or "super-Chandrasekhar") Type Ia supernova (SN Ia), in the nebular phase at 338 days postexplosion. Our combined spectrum continuously covers 0.4–14 μm and includes the first mid-infrared spectrum of a 03fg-like SN Ia. Compared to normal SN Ia 2021aefx, SN 2022pul exhibits a lower mean ionization state, asymmetric emission-line profiles, stronger emission from the intermediate-mass elements (IMEs) argon and calcium, weaker emission from iron-group elements (IGEs), and the first unambiguous detection of neon in a SN Ia. A strong, broad, centrally peaked [Ne ii] line at 12.81 μm was previously predicted as a hallmark of "violent merger" SN Ia models, where dynamical interaction between two sub-MCh white dwarfs (WDs) causes disruption of the lower-mass WD and detonation of the other. The violent merger scenario was already a leading hypothesis for 03fg-like SNe Ia; in SN 2022pul it can explain the large-scale ejecta asymmetries seen between the IMEs and IGEs and the central location of narrow oxygen and broad neon. We modify extant models to add clumping of the ejecta to reproduce the optical iron emission better, and add mass in the innermost region (<2000 km s−1) to account for the observed narrow [O i] λλ6300, 6364 emission. A violent WD–WD merger explains many of the observations of SN 2022pul, and our results favor this model interpretation for the subclass of 03fg-like SNe Ia

Human pregnane X receptor is activated by dibenzazepine carbamate-based inhibitors of constitutive androstane receptor

Unintentional activation of xenosensing nuclear receptors pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR) by clinical drug use is known to produce severe side effects in patients, which may be overcome by co-administering antagonists. However, especially antagonizing CAR is hampered by the lack of specific inhibitors, which do not activate PXR. Recently, compounds based on a dibenzazepine carbamate scaffold were identified as potent CAR inhibitors. However, their potential to activate PXR was not thoroughly investigated, even if the lead compound was named "CAR inhibitor not PXR activator 1" (CINPA1). Thus, we performed a comprehensive analysis of the interaction of CINPA1 and four analogs with PXR. Cellular assays were used to investigate intra- and intermolecular interactions and transactivation activity of PXR as a function of the compounds. Modulation of PXR target gene expression was analyzed in primary human hepatocytes. Ligand binding to PXR was investigated by molecular docking and limited proteolytic digestion. We show here that CINPA1 induced the assembly of the PXR ligand-binding domain, released co-repressors from and recruited co-activators to the receptor. CINPA1 and its analogs induced the PXR-dependent activation of a CYP3A4 reporter gene and CINPA1 induced the expression of endogenous cytochrome P450 genes in primary hepatocytes, while not consistently inhibiting CAR-mediated induction. Molecular docking revealed favorable binding of CINPA1 and analogs to the PXR ligand-binding pocket, which was confirmed in vitro. Altogether, our data provide consistent evidence that compounds with a dibenzazepine carbamate scaffold, such as CINPA1 and its four analogs, bind to and activate PXR

Identification of approved drugs as potent inhibitors of pregnane X receptor activation with differential receptor interaction profiles

Activation of pregnane X receptor (PXR) results in the induction of first-pass metabolism and drug efflux. Hereby, PXR may cause adverse drug reactions or therapeutic failure of drugs. PXR inhibition is thus an attractive option to minimise adverse effects or to improve therapeutic efficiencies; however, only a limited number of antagonists have been identified so far. We performed a cell-based high-throughput screen to identify PXR antagonists, using a library of approved and investigational drugs. Two approved drugs, pimecrolimus and pazopanib, emerged as novel potent antagonists of PXR activation, with IC50 values of 1.2 and 4.1 µM, respectively. We further characterised these with respect to receptor specificity, assembly of the PXR ligand-binding domain (LBD) and interactions with co-factors. In vitro and in silico assays were carried out to identify the site(s) of interaction with the PXR LBD. Primary human hepatocytes were used to investigate antagonism of the induction of endogenous PXR target genes. Pimecrolimus and pazopanib did not affect the transcriptional activity of other nuclear receptors. Both induced the release of co-repressor from PXR and likewise interfered with agonist-induced recruitment of co-activator. Cumulative evidence from cellular and in vitro assays, as well as molecular docking, suggested additional or exclusive binding outside the PXR ligand-binding pocket for both. The compounds differentially antagonised the induction of PXR-regulated genes by rifampicin in primary human hepatocytes. In conclusion, we here have identified two approved drugs as novel potent PXR inhibitors with differential receptor interaction profiles and gene selectivity in primary human hepatocytes

An advanced non-animal model for cultivation and pharmacological perturbation of human tumor tissue

Question: Tumors in patients are appropriately described as pathological organs. In their in vivo environment these tumor organs are entangled in a complex interplay of the genotypically and phenotypically heterogeneous tumor cells and healthy host cell. This tumor milieu plays a key role in tumor development, progression and response to therapy. To preserve the complex in vivo tumor environment in a preclinical model we developed a device to culture slices of tumor in a perfusion air culture (PAC) system. We analyzed PAC cultivation and pharmacological perturbation of tumor tissue slices from patients. Methods: To facilitate continuous supply with nutrients, oxygen and drugs, we developed a perfusion air culture (PAC) system to culture tumor slices. The precision-cut tumor slices (250 μm to 300 μm thickness) are kept in-between two organotypic supports and fixed in a special chamber. The chamber is settled vertically inside of an air-permeable tube and connected with a syringe pump via a silicon tube allowing continuous perfusion of medium and drugs. Regular culture conditions are achieved by placing the PAC system in a standard CO2-incubator. In vivo therapy is simulated by adding of Cisplatin to the supplied culture medium. To investigate the drug effects common biomarkers (Ki67, γH2AX, HIF1α, GMNN, cleaved caspase-3) were analyzed in IHC staining. Results: Primary tumor tissue from high grade serous ovarian carcinoma was cut in 280 μm slices and cultured in the PAC system. Using de-cellularised porcine intestine as organotypic supports in the PAC system, we can culture the primary ovarian tumor tissue slices more than 7 days with good morphology. For pharmacological perturbation experiments culture medium was supplemented with 13 μM Cisplatin and constantly delivered to slices for 72 h, mimicking the in vivo situation in patients. Biomarkers showed the expected response to Cisplatin. Interestingly, tumor cells derived from slices can be further cultured as tumoroids in Matrigel, passaged and cryopreserved. Conclusion: The PAC system facilitates the cultivation and pharmacological perturbation of tumor tissue slices in the context of the complex tumor microenvironment. Due to the flexibility and adjustability of all culture conditions (e.g. oxygen, scaffolds, flow rate and drug supply) the PAC system closely resembles the in vivo situation and is suitable for individual testing of drug efficacy