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Enzalutamide (ENZ) is a second-generation androgen receptor (AR) antagonist used for the treatment of castration-resistant prostate cancer (CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance (ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR (ARfl) or dominantly active androgen receptor splice variant 7 (ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.

Carbon dioxide (CO2) was converted into formate (HCO2−) in a catalytic reduction system mainly composed of potassium borohydride (KBH4) and nanoscale bimetallic nickel–copper alloy (NBN–C), in which, the average CO2 conversion efficiency of 41.92% was obtained under the optimal experimental conditions, with a HCO2− selectivity of 53.42%. Various characterization methods were employed to investigate the physicochemical properties of NBN–C and the results indicated that NBN–C was a core-shell mesoporous catalyst with key active sites containing Ni0 and Cu0, at which the catalytic reduction of CO2 took place. The reaction mechanism was proposed based on these characterizations and relevant literatures.

The simultaneous removal of SO2 and NO from flue gas was firstly carried out by heterogeneous UV-Fenton-like process using Iron-containing polyoxometalates complex (denoted as FeIIIAspPW) as catalyst. The results showed that SO2 achieved complete removal under all experimental conditions. The simultaneous removal efficiencies of 100% for SO2 and 84.27% for NO were obtained under the established optimal experimental conditions. The main reaction products were identified as nitrate and sulfate based on the characterization of ion chromatography (IC) and material balance summary. Especially, the physicochemical properties of the fresh and spent catalyst were characterized systematically by a series of techniques, which manifested the stability of the catalyst and the existence of redox pair Fe3+/Fe2+ during the catalytic process. In combination with correlative references, the reaction mechanism was proposed, which stemmed from the chemisorption of H2O2 by hydrogen bonding and the synergetic effect between the Fenton-like catalysis of ferric iron and photo-catalysis of PW12O403− occurred on the surface of FeIIIAspPW.

We experimentally study intracavity four-wave mixing (FWM) using Λ -type, three-level electromagnetically induced transparency (EIT) atoms confined in an optical ring cavity. The original dark-state peak disappears accompanying the generation of intracavity FWM when the coupling light is changed from traveling-wave to standing wave. Additionally, this FWM signal is on resonance with the optical cavity only when the coupling laser is detuned from the atomic resonance center, where the absorption is drastically reduced for both the probe and FWM fields. At last, we do theoretically analysis for the susceptibility of this composite atom–cavity system.

Sparsity and reconstruction error are two main objectives to be optimized in sparse signal reconstruction. In this paper, sparse signals are reconstructed by optimizing these two objectives simultaneously. This reconstruction method mainly consists of three steps. First, a one-dimension-dominated method is used to find a uniformly distributed optimal compromise solution set between these two objectives. Second, the Iterative Half Thresholding method is employed to improve the sparsity. Third, a robust selection method is proposed to choose a final solution from the solution set. The proposed method is compared with eight sparse reconstruction algorithms on twelve sparse test instances. Experimental results show that the proposed algorithm is able to reconstruct both noisy and noiseless sparse signals. In addition, the effectiveness of the proposed algorithm is demonstrated in practical application instances.

TAR DNA-binding protein 43 (TDP-43) is associated with a spectrum of neurodegenerative diseases. Although TDP-43 resembles heterogeneous nuclear ribonucleoproteins, its RNA targets and physiological protein partners remain unknown. Here we identify RNA targets of TDP-43 from cortical neurons by RNA immunoprecipitation followed by deep sequencing (RIP-seq). The canonical TDP-43 binding site (TG)(n) is 55.1-fold enriched, and moreover, a variant with adenine in the middle, (TG)(n)TA(TG)(m), is highly abundant among reads in our TDP-43 RIP-seq library. TDP-43 RNA targets can be divided into three different groups: those primarily binding in introns, in exons, and across both introns and exons. TDP-43 RNA targets are particularly enriched for Gene Ontology terms related to synaptic function, RNA metabolism, and neuronal development. Furthermore, TDP-43 binds to a number of RNAs encoding for proteins implicated in neurodegeneration, including TDP-43 itself, FUS/TLS, progranulin, Tau, and ataxin 1 and -2. We also identify 25 proteins that co-purify with TDP-43 from rodent brain nuclear extracts. Prominent among them are nuclear proteins involved in pre-mRNA splicing and RNA stability and transport. Also notable are two neuron-enriched proteins, methyl CpG-binding protein 2 and polypyrimidine tract-binding protein 2 (PTBP2). A PTBP2 consensus RNA binding motif is enriched in the TDP-43 RIP-seq library, suggesting that PTBP2 may co-regulate TDP-43 RNA targets. This work thus reveals the protein and RNA components of the TDP-43-containing ribonucleoprotein complexes and provides a framework for understanding how dysregulation of TDP-43 in RNA metabolism contributes to neurodegeneration.