The design, synthesis and bioactivity evaluation of novel androgen receptor degraders based on hydrophobic tagging.

Prostate Cancer (PCa) easily progress to metastatic Castration-Resistant Prostate Cancer (mCRPC) that remains a significant cause of cancer-related death. Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Proteolysis-targeting chimaera (PROTAC) technology based on Hydrophobic Tagging (HyT) represents an intriguing strategy to regulate the function of therapeutically androgen receptor proteins. In the present study, we have designed, synthesized, and evaluated a series of PROTAC-HyT AR degraders using AR antagonists, RU59063, which were connected with adamantane-based hydrophobic moieties by different alkyl chains. Compound D-4-6 exhibited significant AR protein degradation activity, with a degradation rate of 57 % at 5 µM and nearly 90 % at 20 µM in 24 h, and inhibited the proliferation of LNCaP cells significantly with an IC50 value of 4.77 ± 0.26 µM in a time-concentration-dependent manner. In conclusion, the present study lays the foundation for the development of a completely new class of therapeutic agents for the treatment of mCRPC, and further design and synthesis of AR-targeting degraders are currently in progress for better degradation rate.

Assessing the Efficacy of Pixel-Level Fusion Techniques for Ultra-High-Resolution Imagery: A Case Study of BJ-3A.

Beijing Satellite 3 is a high-performance optical remote sensing satellite with a spatial resolution of 0.3-0.5 m. It can provide timely and independent ultra-high-resolution spatial big data and comprehensive spatial information application services. At present, there is no relevant research on the fusion method of BJ-3A satellite images. In many applications, high-resolution panchromatic images alone are insufficient. Therefore, it is necessary to fuse them with multispectral images that contain spectral color information. Currently, there is a lack of research on the fusion method of BJ-3A satellite images. This article explores six traditional pixel-level fusion methods (HPF, HCS, wavelet, modified-IHS, PC, and Brovey) for fusing the panchromatic image and multispectral image of the BJ-3A satellite. The fusion results were analyzed qualitatively from two aspects: spatial detail enhancement capability and spectral fidelity. Five indicators, namely mean, standard deviation, entropy, correlation coefficient, and average gradient, were used for quantitative analysis. Finally, the fusion results were comprehensively evaluated from three aspects: spectral curves of ground objects, absolute error figure, and object-oriented classification effects. The findings of the research suggest that the fusion method known as HPF is the optimum and appropriate technique for fusing panchromatic and multispectral images obtained from BJ-3A. These results can be utilized as a guide for the implementation of BJ-3A panchromatic and multispectral data fusion in real-world scenarios.

In situ vertical alignment of 2D MoS2 layers on GO film: enhanced electrochemical properties for PD-L1 sensing.

There is an urgent need for a flexible and simple programmed cell death ligand 1 (PD-L1) dynamic measurement method enabling real-time monitoring of cancer progression and assessment of immunotherapy efficacy. In the current study, we show facile in situ synthesis of vertical alignment two-dimensional molybdenum disulfide (2D MoS2) layers on graphene-oxide-modified ITO (MoS2┴GO-ITO) using a hydrothermal approach and demonstrate the importance of the alignment of 2D in achieving high-probe capturing, enhanced electrochemical properties and target selectivity during sensing. After modification of designed PD-L1 binding peptides on the MoS2┴GO-ITO, a sensitive PD-L1 electrochemical sensor was designed using vertical alignment MoS2 to capture more probes for PD-L1 recognition and excellent in plane electron transport to accelerate electrochemical signals. The fabricated electrochemical sensor could sensitively determine PD-L1 in a wide linear range of 25-500 ng/mL and exhibit desirable accuracy and reliability in clinical samples application. This simple and sensitive method is likely to investigate further research into the exploration of the perpendicular alignment of 2D surfaces for diverse applications.

Multifunctional DNA scaffold mediated gap plasmon resonance: Application to sensitive PD-L1 sensor.

The introduction of noble metal nanoparticles with good LSPR characteristics can greatly improve the sensitivity of SPR through resonance coupling effect. The plasma resonance response and optical properties of film coupling nanoparticle systems largely depends on the ingenious design of gap structures. Nucleic acid nanostructures have good stability, flexibility, and high biocompatibility, making them ideal materials for gap construction. 2D MOF (Cu-Tcpp) has a large conjugated surface similar to graphene, which can provide a stable substrate for the directional fixation of nucleic acid nanostructures. However, research on gap coupling plasmon based on nucleic acid nanostructures and 2D MOF is still rarely reported. By integrating the advantages of Cu-Tcpp assembled film and DNA tetrahedron immobilization, a nano gap with porous scaffold structure between the gold film and gold nanorod was build. The rigidity of DNA tetrahedron can precisely control the gap size, and its unique programmability allows us to give the coupling structure greater flexibility through the design of nucleic acid chain. The experimental results and FDTD simulation show that the film coupling nanoparticle systems constructed with DNA tetrahedrons greatly enhance the electric field strength near the chip surface and effectively improve the sensitivity of SPR. This research shows the huge potential of nucleic acid nanomaterials in the construction of SPR chip surface microstructures.

Sunlight propelled two-dimensional nanorobots with enhanced mechanical damage of bacterial membrane.

Bacterial pollution in water sources poses a serious threat to human health and causes a water crisis. To treat it efficiently and ecologically, many studies have explored the antibacterial properties of two-dimensional nanomaterials in water, but their static antibacterial modes limit their effectiveness. In this work, we designed a facile and effective antibacterial nanorobots by loading super small gold nanorods (sAuNR) onto the surface of MXene nanosheets (MXene@sAuNR). The plasmon resonance effect of sAuNR can enhance the optical absorption cross section of the nanorobots, thereby improving their motion ability under irradiation and then causing cell membrane mechanical damage to bacteria. Our research proved that nanorobots with good optical driving characteristics displayed gratifying antibacterial properties even at ultra-low concentration as 5 µg/mL within 30 min. Furthermore, the nanorobots showed satisfactory antibacterial efficiency in real river samples under sunlight irradiation. These nanorobots presented in this study provides valuable insights towards designing self-energy collection and self-driving antibacterial materials that overcome the shortcomings of conventional static antibacterial methods. As sunlight is the cheapest and natural light source, these nanorobots have opened an effective and sustainable way for large-scale treatment of bacterial pollution in water.

PD-L1 exosomes electrochemical sensor based on coordination of AgNCs and Zr4+: Multivalent peptide enhancing target capture efficiency and antifouling performance.

Programmed death ligand 1 (PD-L1) exosomes are important biomarkers of immune activation in the initial stages of treatment and can predict clinical responses to PD-1 blockade in various cancer patients. However, traditional PD-L1 exosome bioassays face challenges such as high interface fouling in complex detection environments, limited detection specificity, and poor clinical serum applicability. Inspired by the multi-branched structure of trees, a biomimetic tree-like multifunctional antifouling peptide (TMAP)-assisted electrochemical sensor was developed for high-sensitivity exosomes detection. Multivalent interaction of TMAP significantly enhances the binding affinity of PD-L1 exosomes, thanks to the designed branch antifouling sequence, TMAPs antifouling performance is further improved. The addition of Zr4+ forms coordination bonds with the exosome's lipid bilayer phosphate groups to achieve highly selective and stable binding without interference from protein activity. The specific coordination between AgNCs and Zr4+ contributes to a dramatic change in the electrochemical signals, and lowing detection limit. The designed electrochemical sensor exhibited excellent selectivity and a wide dynamic response within the PD-L1 exosome concentration range from 78 to 7.8 × 107 particles/mL. Overall, the multivalent binding ability of TMAP and the signal amplification characteristics of AgNCs have a certain driving role in achieving clinical detection of exosomes.

Relationship Between Post-traumatic Stress Symptoms and Anticipatory Grief in Family Caregivers of Patients With Advanced Lung Cancer: The Mediation Role of Illness Uncertainty.

Objective: To explore the interrelationship between post-traumatic stress symptoms (PTSS), illness uncertainty (IU), and anticipatory grief (AG). Methods: Structural equation modeling with bootstrapping estimation was conducted using data from a convenience sample of 254 family caregivers of patients with advanced lung cancer in China. Participants were recruited from a public cancer hospital in Shenyang, China. The family caregivers completed the Impact of Events Scale-Revised, Uncertainty in Illness Scale Family Caregiver Version, and Anticipatory Grief Scale. Results: The measurement model has good reliability and validity, and the final model fit the data well. PTSS positively influenced AG (direct effect estimate = 0.391, p = 0.002). Moreover, IU was found to mediate the relationship between PTSS and AG (Indirect effects estimate = 0.168, p = 0.005). The mediating effect of IU accounted for up to 30.1% of the total effect. Conclusion: IU mediated the relationship between PTSS and AG. Healthcare professionals should continuously assess PTSS, IU and AG levels in FCs and provide effective intervention options for mitigation.

Immobilization for Lipase: Enhanced Activity and Stability by Flexible Combination and Solid Support.

In this study, an enhanced activity and stability method for immobilizing porcine pancreatic lipase (PPL) was developed based on ZIF-8 encapsulated supramolecular-modified gold nanoparticle complexes (pSC4-AuNPs@ZIF-8). Supramolecular calix[4]arene (pSC4) can recognize the amino group of PPL through non-covalent force, and this flexible binding method protected the structure of PPL during the immobilization process. Due to the hydrophilic of pSC4-AuNPs and hydrophobic of ZIF-8, PPL can maintain a "lid open" conformation, which can enhance the stability of PPL structure and reduce PPL activity loss. ZIF-8 was used to immobilize PPL to avoid the difficult recovery of free PPL. Compared with the native form of PPL, it exhibited 70.6% maintained activity with terrific pH and temperature stability, and had good performance in thermal stability, time stability, and reusability. In addition, three immobilized PPL methods were designed to further clarify the influence of synthetic methods and additives on the activity and stability of PPL. Importantly, the loading rate of pSC4-AuNPs@ZIF-8@PPL was up to 51.2% among these immobilized PPL systems. Therefore, pSC4-AuNPs@ZIF-8 may serve as a versatile and promising immobilization system for enzymes.

Rapid and sensitive detection of PD-L1 exosomes using Cu-TCPP 2D MOF as a SPR sensitizer.

Two-dimensional metal organic framework (2D MOF Cu-TCPP) with significantly enhanced photoelectric properties was synthesized by a simple hydrothermal method. The π-stacked electroactive porphyrin molecules of TCPP-based 2D MOF carry out charge transport in the MOF structure. The d-d band transition of Cu2+ and its 2D ultra-thin characteristics can produce excellent near-infrared light absorption to couple with SPR. Three key parameters including the refractive index sensitivity, detection accuracy and quality factor were improved significantly for 2D MOF modified gold chips. Especially, the refractive index sensitivity was increased from 98 to 137.67°/RIU after modified with 2D MOF. Thus, for the first time, we applied it as a signal enhancer to improve direct SPR assay for the Programmed death ligand-1 (PD-L1) exosomes. Owning to its large specific surface area, excellent photoelectric properties, highly ordered structure, good dispersion and biocompatibility, the LOD of the SPR sensor was 16.7 particles/mL. The reliability and practicability were further validated by analysis of PD-L1 exosomes in human serum samples. The recovery rate was 93.43 %-102.35%, with RSD of 5.79 %-14.6%. Given their excellent signal amplification ability, 2D MOF Cu-TCPP could serve as an ideal SPR sensitizer for rapid and sensitive detection of trace disease markers.

Copper metal organic framework as natural oxidase mimic for effective killing of Gram-negative and Gram-positive bacteria.

Nanozymes have been widely studied as substitutes for natural enzymes. However, the delicacy of their structures and their unclear catalytic sites make it difficult to maintain their structural robustness and catalytic durability. By mimicking active catalytic sites of natural enzymes and combining them with distinct channels of metal organic frameworks (MOFs), an active copper mimetic oxidase enzyme (Cu-MOF) was designed and synthesized with good structure and clear catalytic sites for improvement in catalytic activity. The Cu-MOFs showed excellent oxidase-like activity with a low Km of 1.09 mM and exogenous ROS generation capacity. The Cu-MOFs exhibited antibacterial efficacy at a low concentration of 12.5 µg mL-1 by an oxidative stress response. These Cu-MOFs with their simple design and effective oxidase mimicking show attractive application prospects in the field of antibacterial and enzyme catalysis.

Ku80 gene is related to non-homologous end-joining and genome stability in Aspergillus niger.

In this study, the ku70 and ku80 homologs from the Aspergillus niger genome were identified and their function was analyzed using targeted mutagenesis. The role of the ku80 gene in non-homologous end-joining (NHEJ) was investigated by calculating the frequency of homologous recombination. The transformation test verified that the frequency of homologous recombination significantly increased, from 1.78 to 65.6% in ku80 single deletion strains and to 100% in ku70/ku80 double deletion strains. These results suggest that the ku80 gene is important for non-homologous end-joining. Although the morphology of the ku deletion strains colonies was similar to that of the wildtype strain, mutants were more sensitive to the mutagen phleomycin. Furthermore, the purified ku80 deletion strain produced some sectored colonies on hygromycin B-containing plates. This result suggests that the ku80 gene deletion leads to genomic instability in A. niger.

One dimensional magneto-optical nanocomplex from silver nanoclusters and magnetite nanorods containing ordered mesocages for sensitive detection of PD-L1.

Programmed death ligand 1 (PD-L1) is a typical immune checkpoint protein, whose up-regulation on the membrane of different tumor cells inhibits the immune response of T cells and leads to the escape of tumor cells. In this work, we designed a facile and highly specific surface plasmon resonance (SPR) biosensor to detect PD-L1 in human plasma based on magnetite nanorods containing ordered mesocages (MNOM) and silver nanoclusters (AgNCs). Magneto-optical nanocomplex MNOM@AgNCs with superior magneto-optical properties and high signal-to-noise ratio were fabricated to improve the detection sensitivity owing to the high specific surface area of MNOM and excellent localized SPR of AgNCs. The PD-L1 Antibody on the surface of gold chip and the PD-L1 aptamer on MNOM@AgNCs could realize dual selective recognition of PD-L1, providing the specificity of the sensor and reducing non-specific binding. The SPR sensor showed a good linear range of PD-L1 from 10 ng/mL to 300 ng/mL with the detection limit of 3.29 ng/mL. The practical performance of this immunosensing platform had been successfully verified by clinical samples which included healthy donors and cancer patients. Based on the analysis, the developed immunosensor provided a new strategy for point-of-care detection of PD-L1 and could be used as clinical companion diagnosis of PD-1/PD-L1 inhibitor therapy.

Magnetic field-aligned Fe3O4-coated silver magnetoplasmonic nanochain with enhanced sensitivity for detection of Siglec-15.

Noble metal nanoparticles could provide a significant gain in sensitivity of surface plasmon resonance (SPR) sensor by electromagnetic field coupling between the localized plasmon resonance of nanoparticles and gold film. A facile and cost-effective SPR sensor based on magnetic field-aligned Fe3O4-coated silver magnetoplasmonic nanoparticles (Ag@MNPs) nanochain (M-Ag@MNPs) was proposed to improve the sensitivity of the sensor, which gave access to detect clinical targets at low concentration. Optimization experiments proved that 80 ng mL-1 M-Ag@MNPs-based SPR sensor showed high refractive index sensitivity and increased detection accuracy and quality factor when comparing with those of bare gold. Sialic acid binding Ig like lectins-15 (Siglec-15) was used as proof of concept to verify the sensitivity enhancement performance of M-Ag@MNPs in the actual detection process. SPR angle shifts of M-Ag@MNPs/gold sensor were significantly higher than those of traditional gold sensor under the same concentration of Siglec-15, which was consistent with previous performance analysis. Also, the detection limit of M-Ag@MNPs/gold sensor was calculated to be 1.36 pg mL-1. All these results had proved that aligning M-Ag@MNPs onto the gold chip could improve the performance of the SPR sensor and achieve sensitive detection of small amounts of clinical biomarkers.

A Mechanochemical Route for ZnS Nanocrystals, and Batch Sorting along Size Distribution.

The assistances of sodium dodecyl benzene sulfonate (SDBS) and aging treatment were introduced to further improve the room-temperature mechanochemical synthesis of the quantum-sized zinc sulfide (ZnS) nanocrystals. As a result, a green strategy for synthesizing the monodisperse nanocrystals with tunable size and crystallinity was developed, holding convenient, highly efficient and low pollution. Size evolution shows a gradually increasing trend along the aging-temperature. A model that the independent reaction cells constructed by SDBS-wrapped reactant packages (solid state vesicles, SSVs) for the confined growth of ZnS nanocrystals was proposed to access the formation mechanism of ZnS quantized crystal in a solid-state synthesis system. The band gaps and band-edge luminescent emissions of as-prepared ZnS nanocrystals experienced the size-dependent quantum confinement effect, while the trap-state emissions exhibited the lattice integrity-dependence. Furthermore, ZnS quantum-sized nanocrystals with narrower size distribution can be obtained by a batch-sorting process through adjusting the centrifugal speed.

Assessment of the Pig-a, micronucleus, and comet assay endpoints in rats treated by acute or repeated dosing protocols with procarbazine hydrochloride and ethyl carbamate.

The utility and sensitivity of the newly developed flow cytometric Pig-a gene mutation assay have become a great concern recently. In this study, we have examined the feasibility of integrating the Pig-a assay as well as micronucleus and Comet endpoints into acute and subchronic general toxicology studies. Male Sprague-Dawley rats were treated for 3 or 28 consecutive days by oral gavage with procarbazine hydrochloride (PCZ) or ethyl carbamate (EC) up to the maximum tolerated dose. The induction of CD59-negative reticulocytes and erythrocytes, micronucleated reticulocytes in peripheral blood, micronucleated polychromatic erythrocytes in bone marrow, and Comet responses in peripheral blood, liver, kidney, and lung were evaluated at one, two, or more timepoints. Both PCZ and EC produced positive responses at most analyzed timepoints in all tissue types, both with the 3-day and 28-day treatment regimens. Furthermore, comparison of the magnitude of the genotoxicity responses indicated that the micronucleus and Comet endpoints generally produced greater responses with the higher dose, short-term treatments in the 3-day study, while the Pig-a assay responded better to the cumulative effects of the lower dose, but repeated subchronic dosing in the 28-day study. Collectively, these results indicate that integration of several in vivo genotoxicity endpoints into a single routine toxicology study is feasible and that the Pig-a assay may be particularly suitable for integration into subchronic dose studies based on its ability to accumulate the mutations that result from repeated treatments. This characteristic may be especially important for assaying lower doses of relatively weak genotoxicants. Environ. Mol. Mutagen. 60:56-71, 2019. © 2018 Wiley Periodicals, Inc.