Nucleocytoplasmic transport is tightly regulated by the nuclear pore complex (NPC). Among the thousands of molecules that cross the NPC, even very large (>15 nm) cargoes such as pathogens, mRNAs and ...pre-ribosomes can pass the NPC intact. For these cargoes, there is little quantitative understanding of the requirements for their nuclear import, especially the role of multivalent binding to transport receptors via nuclear localisation sequences (NLSs) and the effect of size on import efficiency. Here, we assayed nuclear import kinetics of 30 large cargo models based on four capsid-like particles in the size range of 17-36 nm, with tuneable numbers of up to 240 NLSs. We show that the requirements for nuclear transport can be recapitulated by a simple two-parameter biophysical model that correlates the import flux with the energetics of large cargo transport through the NPC. Together, our results reveal key molecular determinants of large cargo import in cells.
Docetaxel chemotherapy is a standard treatment option for metastatic castrate resistant prostate cancer (mCRPC) patients. To date, the genomic perturbations underlying the emergence of resistance in ...mCRPC patients during chemotherapy treatment have not been fully characterized. Previous studies have established that AR, TP53, RB1 and PTEN gene alterations are frequent at this stage of progression and that TP53, RB1 and PTEN, but not AR alterations are associated with poor outcome. However, the clonal dynamics of these key driver cancer genes during chemotherapy in mCRPC patients have not been described. Toward this goal, we performed a retrospective analysis of serially profiled cell-free DNA (cfDNA) alterations in blood samples collected from mCRPC patients before and after starting chemotherapy who were followed for response and clinical outcomes. While AR alterations and measures of mutational load were significantly reduced in patients with stable or decreased PSA levels after 3 cycles of chemotherapy, reductions in RB1, TP53 and PTEN alterations were relatively modest, which may represent the persistence of a clonal signature associated with the emergence of treatment-induced lineage plasticity (TILP) underlying resistance. The ability to monitor these driver gene clonal dynamics during chemotherapy may have utility in the clinical setting.
This paper proposes a structure composed of a horizontal metal strip resonator (SR) and four C-shaped ring resonators (CRR) to obtain a broadband electromagnetic induction transparency (EIT)–like ...effect. The SR and CRRs are divided into bright mode and dark mode according to whether they can be directly excited by the incident electromagnetic wave. The three-level
Λ
-type system and electric field are used to explain the mechanism of the EIT-like effect. Meanwhile, by decreasing the distance between the SR and CRRs, a transparency window with a relative bandwidth of 91.93% and a width of 1.4 THz is observed. It is found that when the bright and dark modes are directly contacted, the EIT window increases rapidly through conductive coupling, which can be explained by the surface current. Our work provides a new method for a wide band EIT-like effect, which has a certain value in the fields of slow light, filters, and non-linear optics.
Drug-eluting stent implantation suppresses the excessive proliferation of smooth muscle cells to reduce in-stent restenosis. However, the efficacy of drug-eluting stents remains limited due to ...delayed reendothelialization, impaired intimal remodeling, and potentially increased late restenosis. Here, we show that a drug-free coating formulation functionalized with tailored recombinant humanized type III collagen exerts one-produces-multi effects in response to injured tissue following stent implantation. We demonstrate that the one-produces-multi coating possesses anticoagulation, anti-inflammatory, and intimal hyperplasia suppression properties. We perform transcriptome analysis to indicate that the drug-free coating favors the endothelialization process and induces the conversion of smooth muscle cells to a contractile phenotype. We find that compared to drug-eluting stents, our drug-free stent reduces in-stent restenosis in rabbit and porcine models and improves vascular neointimal healing in a rabbit model. Collectively, the one-produces-multi drug-free system represents a promising strategy for the next-generation of stents.
In this paper, a reflective polarization convertor is proposed based on a sandwich structure consisting of an “I”-shaped resonator at the top, a medium layer of foam, and a metal layer at the bottom. ...The characteristics of ultra-wideband (UWB) and higher relative bandwidth (RB) have been achieved than previous structures. The structure effectively controls the polarization of electromagnetic waves in the terahertz band, which convert the incident linear-polarized (LP) wave to cross-polarized wave within 2.75–10.35THz, with a relative bandwidth of 116% and a polarization conversion ratio (PCR) greater than 90%. In addition, this structure also converts the incident linear-polarized wave to circular-polarized wave in the range of 2.28–2.65THz with axial ratio (AR) less than 3 dB. The characteristics are also analyzed based on the surface current distribution. The reason of realizing UWB polarization conversion is explained by polarization decomposition method. Our structure could provide many potential applications in radar antenna, metamaterial lens, and other electromagnetic wave and optical fields.
Nuclear pore complexes (NPCs) conduct selective, bidirectional transport across the nuclear envelope. The NPC passageway is lined by intrinsically disordered proteins that contain hydrophobic ...phenylalanine-glycine (FG) motifs, known as FG nucleoporins (FG nups), that play the key role in the NPC transport mechanism. Cohesive interactions among the FG nups, which arise from the combination of hydrophobic, electrostatic, and other forces, have been hypothesized to control the morphology of the assemblies of FG nups in the NPC, as well as their permeability with respect to the transport proteins. However, the role of FG nup cohesiveness is still vigorously debated. Using coarse-grained polymer theory and numerical simulations, we study the effects of cohesiveness on the selective permeability of in vitro FG nup assemblies in different geometries that have served as proxies for the morphological and transport properties of the NPC. We show that in high-density FG nup assemblies, increase in cohesiveness leads to the decrease in their permeability, in accordance with the accepted view. On the other hand, the permeability of low-density assemblies is a nonmonotonic function of the cohesiveness, and a moderate increase in cohesiveness can enhance permeability. The density- and cohesiveness-dependent effects on permeability are explained by considering the free-energy cost associated with penetrating the FG nup assemblies. We discuss the implications of these findings for the organization and function of the NPC.
The surface topographies of artificial implants including surface roughness, surface groove size and orientation, and surface pore size and distribution have a great influence on the adhesion, ...migration, proliferation, and differentiation of nerve cells in the nerve regeneration process. Optimizing the surface topographies of biomaterials can be a key strategy for achieving excellent cell performance in various applications such as nerve tissue engineering. In this review, we offer a comprehensive summary of the surface topographies of nerve implants and their effects on nerve cell behavior. This review also emphasizes the latest work progress of the layered structure of the natural extracellular matrix that can be imitated by the material surface topology. Finally, the future development of surface topographies on nerve regeneration was prospectively remarked.
The androgen receptor (AR) remains a critical driver in metastatic castration-resistant prostate cancer (mCRPC). Profiling AR aberrations in both circulating DNA and RNA may identify key predictive ...and/or prognostic biomarkers in the context of contemporary systemic therapy.
To profile AR aberrations in circulating nucleic acids and correlate with clinical outcomes.
We prospectively enrolled 67 mCRPC patients commencing AR pathway inhibitors (ARPIs; n = 41) or taxane chemotherapy (n = 26). Using a first-in-class next-generation sequencing-based assay, we performed integrated cell-free DNA (cfDNA) and cell-free RNA (cfRNA) profiling from a single 10 ml blood tube.
Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between clinical outcomes and the following AR aberrations: copy number variation, splice variants (AR-V7 and AR-V9) and somatic mutations.
Cell-free DNA and cfRNA were successfully sequenced in 67 (100%) and 59 (88%) patients, respectively. Thirty-six (54%) patients had one or more AR aberrations. AR gain and cumulative number of AR aberrations were independently associated with clinical/radiographic progression-free survival (PFS; hazard ratio HR 3.2, p = 0.01 and HR 3.0 for 0 vs ≥2, p = 0.04) and overall survival (HR 2.8, p = 0.04 and HR 2.9 for 0 vs ≥2, p = 0.03). Notably, concurrent AR gain and AR splice variant expression (AR gain/AR-V+) was associated with shorter prostate-specific antigen PFS on both ARPIs (HR 6.7, p = 0.009) and chemotherapy (HR 3.9, p = 0.04). Importantly, key findings were validated in an independent cohort of mCRPC patients (n = 40), including shorter OS in AR gain/AR-V+ disease (HR 3.3, p = 0.02). Limitations include sample size and follow-up period.
We demonstrate the utility of a novel, multianalyte liquid biopsy assay capable of simultaneously detecting AR alterations in cfDNA and cfRNA. Concurrent profiling of cfDNA and cfRNA may provide vital insights into disease biology and resistance mechanisms in mCRPC.
In this study of men with advanced prostate cancer, DNA and RNA abnormalities in the androgen receptor detected in blood were associated with poor outcomes on available drug treatments. This information could be used to better guide treatment of advanced prostate cancer.
We demonstrated, in two independent metastatic castration-resistant prostate cancer (mCRPC) cohorts, that simultaneous profiling of androgen receptor (AR) cell-free DNA and RNA aberrations provides important prognostic information in patients with mCRPC. Profiling of circulating AR aberrations may be of high clinical value, especially with increasing use of AR-targeted therapies earlier in the prostate cancer disease course.
PDF
