Construction of a novel Au@Os mediated TMB-H2O2 platform with dual-signal output for rapid and accurate detection of ziram in food.

The 3,3',5,5'-tetramethylbenzidine-H2O2 (TMB-H2O2) platform has gained widespread use for rapid detection of various analytes in foods. However, the existing TMB-H2O2 platforms suffer from limited accuracy, as their signal output is confined to the visible region, which is prone to interference from various food colorants in real samples. To address this challenge, a novel Au@Os-mediated TMB-H2O2 platform is developed for both rapid and accurate detection of analytes in foods. The prepared Au@Os NPs exhibit remarkable peroxidase-like activity, making the platform display dual absorption peaks in visible and near-infrared (NIR) regions, respectively. This Au@Os-mediated TMB-H2O2 platform exhibited three linear ranges across different concentrations of ziram from 1-100, 150-600, and 800-2000 nM with limit of detection (LOD) 7.9 nM and limit of quantification (LOQ) 24.15 nM respectively. Further, the Au@Os-mediated TMB-H2O2 platform was also used for rapid and accurate detection of ziram in real food samples like apple, tomato, and black tea.

Tuning triplet excitons and dynamic afterglow based on host-guest doping.

Designing persistent dual-band afterglow materials with thermally activated delayed fluorescence (TADF) and room temperature phosphorescence (RTP) contributed to solving the problems of homogenization and singularity in long afterglow materials. Here, six aryl acetonitrile (CBM) and aryl dicyanoaniline (AMBT) derivatives, used as host and guest materials respectively, were successfully designed and synthesized based on the isomerization effect. Among of them, 0.1 % m-CBM/p-AMBT showed the longest dual-band TADF (540 ms) and RTP lifetimes (721 ms), as well as persistent afterglow over 8 s, whose fluorescence (ΦFL), TADF (ΦT) and RTP (ΦP) quantum yields were 0.11, 0.06 and 0.22 in sequence. More interestingly, some doping systems constructed by CBM and AMBT series compounds showed persistent triple-band emissions composed of TADF, unimolecular and aggregated AMBT series compounds. What's more, ΦFL, ΦT and ΦP of 1 % o-AMBT@PMMA film were up to 0.17, 0.17, 0.23 in turn, with TADF, RTP and afterglow lifetimes of 606 ms, 727 ms, and 10 s respectively. TADF and RTP emission of CBM/AMBT series doping systems was attributed to host sensitized guest emission. Besides, the comparison displayed AMBT series compounds had bigger intensity ratios between TADF and RTP emission in PMMA films compared to in CBM series compounds. Finally, a series of data encryption were successfully constructed based on different afterglow lifetimes of the doping systems, and a dynamic anti-counterfeiting pattern was prepared by using different temperature responses of TADF and RTP emissions.

A dual-channel fluorescent probe targeting lysosomes for differential detection of Cys/Hcy and GSH: Applications in food, pharmaceutical analysis and bioimaging.

Thiols function as antioxidants in food, prolonging shelf life and enhancing flavor. Moreover, thiols are vital biomolecules involved in enzyme activity, cellular signal transduction, and protein folding among critical biological processes. In this paper, the fluorescent probe PYL-NBD was designed and synthesized, which utilized the fluorescent molecule pyrazoline, the lysosome-targeted morpholine moiety, and the sensing moiety NBD. Probe PYL-NBD was tailored for the recognition of biothiols through single-wavelength excitation, yielding distinct fluorescence emission signals: blue for Cys, Hcy, and GSH; green for Cys, Hcy. Probe PYL-NBD exhibited rapid reaction kinetics (<10 min), distinct fluorescence response signals, and low detection limits (15.7 nM for Cys, 14.4 nM for Hcy, and 12.6 nM for GSH). Probe PYL-NBD enabled quantitative determination of Cys content in food samples and L-cysteine capsules. Furthermore, probe PYL-NBD had been successfully applied for confocal imaging with dual-channel detection of biothiols in various biological specimens, including HeLa cells, zebrafish, tumor sections, and Arabidopsis thaliana.

Mitochondrial 'Birth-Death' coordinator: An intelligent hydrogen nanogenerator to enhance intervertebral disc regeneration.

Currently, mitochondrial dysfunction caused by oxidative stress is a growing concern in degenerative diseases, notably intervertebral disc degeneration (IVDD). Dysregulation of the balance of mitochondrial quality control (MQC) has been considered the key contributor, while it's still challenging to effectively harmonize different MQC components in a simple and biologically safe way. Hydrogen gas (H2) is a promising mitochondrial therapeutic molecule due to its bio-reductivity and diffusibility across cellular membranes, yet its relationship with MQC regulation remains unknown. Herein, we propose a mitochondrial 'Birth-Death' coordinator achieved by an intelligent hydrogen nanogenerator (Fe@HP-OD), which can sustainably release H2 in response to the unique microenvironment in degenerated IVDs. Both in vitro and in vivo results prove alleviation of cellular oxidative stress and restoration of nucleus pulposus cells function, thereby facilitating successful IVD regeneration. Significantly, this study for the first time proposes the mitochondrial 'Birth-Death' coordination mechanism: 1) attenuation of overactivated mitochondrial 'Death' process (UPRmt and unselective mitophagy); and 2) activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway for mitochondrial 'Birth-Death' balance (mitochondrial biogenesis and controlled mitophagy). These pioneering findings can fill in the gaps in molecular mechanisms for H2 regulation on MQC homeostasis, and pave the way for future strategies towards restoring equilibrium of MQC system against degenerative diseases.

A comparison of dislocation risk between dual mobility and traditional constructs used in proximal femoral replacement.

Background: Proximal femoral replacement (PFR) is a reconstruction technique after tumor resection or for revision of failed total hip arthroplasty (THA). However, despite acceptable long-term oncologic and functional outcomes, extensive soft tissue or bone loss increases the risk for prosthetic instability. Instability may depend on the construct chosen for reconstruction, with current options including bipolar, constrained, or dual mobility implants. Clinical studies comparing patient outcomes after PFR with these three different constructs are limited. Methods: This study retrospectively examined a single tertiary academic institution's experience with PFR over a fifteen-year period. The medical records of patients who underwent PFR for indications such as tumor and failed THA with bone loss were reviewed. Patients were stratified into cohorts based on use of bipolar, constrained, or dual mobility implants. Patient demographics, disease characteristics, perioperative data, and data on prosthetic dislocations were recorded. ANOVA and chi-square testing was performed for continuous and categorical variables, respectively. The threshold for statistical significance was set to p < 0.05. Results: 106 patients were identified who underwent PFR. 46 underwent PFR with bipolar prosthesis (follow-up: 20 ± 24.57 months), 42 with constrained liner (follow-up: 30.45 ± 35.32 months), and 18 with dual mobility (follow-up: 15.38 ± 15.67 months). Only BMI (p = 0.036) and smoking history (P = 0.002) differed between groups. Dislocations occurred in 4 (8.7 %) patients who underwent reconstruction with bipolar prosthesis, compared to 8 (19.0 %) with constrained liner, and 3 (16.7 %) patients with dual mobility. Mean time to dislocation was significantly longer in dual mobility patients (P = 0.009). There were no differences in instances of early dislocation between groups (P = 00.238). Conclusion: While study numbers are low, mean time to dislocation was significantly longer with dual mobility. Additional large-scale longitudinal studies are needed to fully elucidate the differences in outcomes amongst these three treatments.

Tumor-targeted delivery of hyaluronic acid/polydopamine-coated Fe2+-doped nano-scaled metal-organic frameworks with doxorubicin payload for glutathione depletion-amplified chemodynamic-chemo cancer therapy.

Chemodynamic therapy (CDT), an emerging cancer treatment modality, uses multivalent metal elements to convert endogenous hydrogen peroxide (H2O2) to toxic hydroxyl radicals (•OH) via a Fenton or Fenton-like reaction, thus eliciting oxidative damage of cancer cells. However, the antitumor potency of CDT is largely limited by the high glutathione (GSH) concentration and low catalytic efficiency in the tumor sites. The combination of CDT with chemotherapy provides a promising strategy to overcome these limitations. In this work, to enhance antitumor potency by tumor-targeted and GSH depletion-amplified chemodynamic-chemo therapy, the hyaluronic acid (HA)/polydopamine (PDA)-decorated Fe2+-doped ZIF-8 nano-scaled metal-organic frameworks (FZ NMs) were fabricated and utilized to load doxorubicin (DOX), a chemotherapy drug, via hydrophobic, π-π stacking and charge interactions. The attained HA/PDA-covered DOX-carrying FZ NMs (HPDFZ NMs) promoted DOX and Fe2+ release in weakly acidic and GSH-rich milieu and exhibited acidity-activated •OH generation. Through efficient CD44-mediated endocytosis, the HPDFZ NMs internalized by CT26 cells not only prominently enhanced •OH accumulation by consuming GSH via PDA-mediated Michael addition combined with Fe2+/Fe3+ redox couple to cause mitochondria damage and lipid peroxidation, but also achieved intracellular DOX release, thus eliciting apoptosis and ferroptosis. Importantly, the HPDFZ NMs potently inhibited CT26 tumor growth in vivo at a low DOX dose and had good biosafety, thereby showing promising potential in tumor-specific treatment.

Nickel-based dual single atom electrocatalysts for the nitrate reduction reaction.

Electrochemical nitrate (NO3-) reduction reaction (NO3-RR) to ammonium (NH4+) or nitrogen (N2) provides a green route for nitrate remediation. However, nitrite generation and hydrogen evolution reactions hinder the feasibility of the process. Herein, dual single atom catalysts were rationally designed by introducing Ag/Bi/Mo atoms to atomically dispersed NiNC moieties supported by nitrogen-doped carbon nanosheet (NCNS) for the NO3-RR. Ni single atoms loaded on NCNS (Ni/NCNS) tend to reduce NO3- to valuable NH4+ with a high selectivity of 77.8 %. In contrast, the main product of NO3-RR catalyzing by NiAg/NCNS, NiBi/NCNS, and NiMo/NCNS was changed to N2, giving rise to N2 selectivity of 48.4, 47.1 and 47.5 %, respectively. Encouragingly, Ni/NCNS, NiBi/NCNS, and NiAg/NCNS showed excellent durability in acidic electrolytes, leading to nitrate conversion rates of 70.3, 91.1, and 93.2 % after a 10-h reaction. Simulated wastewater experiments showed that NiAg/NCNS could remove NO3- up to 97.8 % at -0.62 V after 9-h electrolysis. This work afforded a new strategy to regulate the reaction pathway and improve the conversion efficiency of the NO3-RR via engineering the dual atomic sites of the catalysts.

Co-doped bismuth vanadate/zinc tungstate heterojunction with dual internal electric fields for efficient photocatalytic reduction of carbon dioxide.

Enhanced carriers separation on photocatalysts is crucial for improving photocatalytic activity. In this paper, the Co-doped BiVO4/ZnWO4 S-scheme heterojunctions were constructed to induce double internal electric fields (IEFs) for enhancing charges separation and transfer for efficient photocatalytic reduction of CO2. The photocatalytic CO2 reduction efficiencies of the heterojunctions were significantly enhanced as compared with the counterparts. The optimized Co-doped BiVO4/ZnWO4 exhibited the highest CO yield of 138.4 µmol·g-1·h-1, which were 86.5 and 1.4 folds of the BiVO4 and Co-doped BiVO4. Results of X-ray photoelectron spectroscopy (XPS), electron spin resonance (ESR), and work function demonstrated that charge transfer path of Co-doped BiVO4/ZnWO4 conformed to S-scheme heterojunction mechanism. The kelvin probe force microscopy (KPFM) and density functional theory (DFT) calculations of the differential charge distributions confirmed the existence of double IEFs, which accelerated carrier separation and improved CO2 adsorption and activation. In addition, in-situ Fourier transform infrared spectroscopy (ISFT-IR) revealed that HCOO- was the major intermediate during the CO2 reaction. This study provides a feasible means to develop composite photocatalysts with dual IEFs for effective photocatalytic CO2 reduction.

Validation of Golden Gate Assemblies Using Highly Multiplexed Nanopore Amplicon Sequencing.

Golden Gate cloning has revolutionized synthetic biology. Its concept of modular, highly characterized libraries of parts that can be combined into higher order assemblies allows engineering principles to be applied to biological systems. The basic parts, typically stored in Level 0 plasmids, are sequence validated by the method of choice and can be combined into higher order assemblies on demand. Higher order assemblies are typically transcriptional units, and multiple transcriptional units can be assembled into multi-gene constructs. Higher order Golden Gate assembly based on defined and validated parts usually does not introduce sequence changes. Therefore, simple validation of the assemblies, e.g., by colony polymerase chain reaction (PCR) or restriction digest pattern analysis is sufficient. However, in many experimental setups, researchers do not use defined parts, but rather part libraries, resulting in assemblies of high combinatorial complexity where sequencing again becomes mandatory. Here, we present a detailed protocol for the use of a highly multiplexed dual barcode amplicon sequencing using the Nanopore sequencing platform for in-house sequence validation. The workflow, called DuBA.flow, is a start-to-finish procedure that provides all necessary steps from a single colony to the final easy-to-interpret sequencing report.

Facile construction of heterogeneous dual-ionic poly(ionic liquid)s for efficient and mild conversion of CO2 into cyclic carbonates.

In the context of peaking carbon dioxide emissions and carbon neutrality, development of feasible methods for converting CO2 into high value-added chemicals stands out as a hot subject. In this study, P[D+COO-][Br-][DBUH+], a series of novel heterogeneous dual-ionic poly(ionic liquid)s (PILs) were synthesized readily from 2-(dimethylamino) ethyl methacrylate (DMAEMA), bromo-substituted aliphatic acids, organic bases and divinylbenzene (DVB). The structures, compositions and morphologies were characterized or determined by nuclear magnetic resonance (NMR), thermal gravimetric analysis (TGA), infrared spectroscopy (IR), scanning electron microscopes (SEM), and Brunauer-Emmett-Teller analysis (BET), etc. Application of the P[D+COO-][Br-][DBUH+] series as catalysts in converting CO2 into cyclic carbonates showed that P[D+COO-][Br-][DBUH+]-2/1/0.6 was able to catalyze epiclorohydrin-CO2 cycloaddition the most efficiently. This afforded chloropropylene carbonate (CPC) in 98.4% yield with ≥ 99% selectivity in 24 hr under solvent- and additive-free conditions at atmospheric pressure. Reusability experiments showed that recycling of the catalyst 6 times only resulted in a slight decline in the catalytic performance. In addition, it could be used for the synthesis of a variety of differently substituted cyclic carbonates in good to excellent yields. Finally, key catalytic active sites were probed, and a reasonable mechanism was proposed accordingly. In summary, this work poses an efficient strategy for heterogenization of dual-ionic PILs and provides a mild and environmentally benign approach to the fixation and utilization of carbon dioxide.

Dual-Responsive MnO2-Loaded Carbonaceous Nanobottle Motors Fabricated by Interfacial Superassembly for On-The-Fly MicroRNA Sensing.

Diverse nanomotors with advanced motion manipulation have been proposed to revolutionize the way problems in many fields are solved. However, rational and controllable synthetic methods of multifunctional nanomotor are still limited. Herein, dual-responsive MnO2-loaded carbonaceous nanobottle motors (MnO2 NBMs) are developed through an interfacial superassembly strategy. Asymmetric carbonaceous nanobottles are first synthesized, and the reductive carbonaceous shell induces an oxidation-reduction reaction with KMnO4 for in-situ growth of MnO2 nanosheets, which enables the nanomotor to perform either self-diffusiophoretic or self-thermophoretic motion in response to H2O2 and near-infrared light, respectively. Inspired by bioaffinity sensing, the nanomotors are sequentially assembled with functional nanoparticles and hairpin DNA to construct swimming functional MnO2 NBMs (MnO2 FNBMs) probes. The probes can move around complex samples to improve target miRNA transport and accelerate receptor-target interaction. Coupling with the photocurrent-signal amplification, the self-assembly of photoelectrochemical (PEC) biosensors has been achieved for sensitive microRNA detection. Trace amounts of miRNA-155 can be quickly detected with a wide detection range (100 fM to 100 nM). Moreover, the direct detection of microRNA in tumor cell lysates by the biosensor is demonstrated. Given the merits of automation and miniaturization, the proposed strategy provides a promising method for fast and effective self-assembly of biosensors.

The identification of potent dual-target monopolar spindle 1 (MPS1) and histone deacetylase 8 (HDAC8) inhibitors through pharmacophore modeling, molecular docking, molecular dynamics simulations, and biological evaluation.

Background: Overexpression of monopolar spindle 1 (MPS1) and histone deacetylase 8 (HDAC8) is associated with the proliferation of liver cancer cells, so simultaneous inhibition of both MPS1 and HDAC8 could offer a promising therapeutic approach for the treatment of liver cancer. Dual-targeted MPS1/HDAC8 inhibitors have not been reported. Methods: A combined approach of pharmacophore modeling and molecular docking was used to identify potent dual-target inhibitors of MPS1 and HDAC8. Enzyme inhibition assays were performed to evaluate the optimal compound with the strongest inhibitory activity against MPS1 and HDAC8. The selectivity of MPH-5 for MPS1 and HDAC8 was assessed on a panel of 68 kinases and other histone deacetylases. Subsequently, molecular dynamics (MD) simulation verified the binding stability of the optimal compound to MPS1 and HDAC8. Ultimately, in vitro cellular assays and in vivo antitumor assays evaluated the antitumor efficacy of the most promising compound for the treatment of hepatocellular carcinoma. Results: Six dual-target compounds (MPHs 1-6) of both MPS1 and HDAC8 were identified from the database using a combined virtual screening protocol. Notably, MPH-5 showed nanomolar inhibitory effect on both MPS1 (IC50 = 4.52 ± 0.21 nM) and HDAC8 (IC50 = 6.07 ± 0.37 nM). MD simulation indicated that MPH-5 stably binds to both MPS1 and HDAC8. Importantly, cellular assays revealed that MPH-5 exhibited significant antiproliferative activity against human liver cancer cells, especially HepG2 cells. Moreover, MPH-5 exhibited low toxicity and high efficacy against tumor cells, and it overcomes drug resistance to some extent. In addition, MPH-5 may exert its antitumor effects by downregulating MPS1-driven phosphorylation of histone H3 and upregulating HDAC8-mediated K62 acetylation of PKM2. Furthermore, MPH-5 showed potent inhibition of HepG2 xenograft tumor growth in mice with no apparent toxicity and presented favorable pharmacokinetics. Conclusion: The study suggests that MPH-5 is a potent, selective, high-efficacy, and low-toxicity antitumor candidate for the treatment of hepatocellular carcinoma.

Dual-targeted treatment for inflammatory bowel disease: Whether fecal microbiota transplantation can be an important part of it.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disease. With the emergence of biologics and other therapeutic methods, two biologics or one biologic combined with a novel small-molecule drug has been proposed in recent years to treat IBD. Although treatment strategies for IBD are being optimized, their efficacy and risks still warrant further consideration. This editorial explores the current risks associated with dual-targeted treatment for IBD and the great potential that fecal microbiota transplantation (FMT) may have for use in combination therapy for IBD. We are focused on addressing refractory IBD or biologically resistant IBD based on currently available dual-targeted treatment by incorporating FMT as part of this dual-targeted treatment. In this new therapy regimen, FMT represents a promising combination therapy.

Characteristics of the imaging diagnosis of alveolar echinococcosis.

Alveolar echinococcosis (AE) primarily manifests in the liver and exhibits characteristics resembling those of slow-growing malignant tumours. Untreated Echinococcus multilocularis infection can be lethal. By infiltrating the vascular systems, biliary tracts, and the hilum of the liver, it might lead to various problems. Due to its ability to infiltrate neighbouring tissues or metastasize to distant organs, AE can often be mistaken for malignancies. We present a concise overview of the epidemiological and pathophysiological characteristics of AE, as well as the clinical manifestations of the disease. This article primarily examines the imaging characteristics of AE using various imaging techniques such as ultrasonography, computed tomography (CT), magnetic resonance imaging, diffusion-weighted imaging, and virtual non-enhanced dual-energy CT. We additionally examined the contribution of radiography in the diagnosis, treatment, and monitoring of the condition.

Clustered ultra-small iron oxide nanoparticles as potential T1/T2dual-modal magnetic resonance imaging contrast agents and application to tumor model.

Many studies have been conducted on the use of ultra-small iron oxide nanoparticles (USIONs) (d < 3 nm) as potential positive magnetic resonance imaging (MRI)-contrast agents (CAs); however, there is dearth of research on clustered USIONs. In this study, nearly monodispersed clustered USIONs were synthesized using a simple two-step one-pot polyol method. First, USIONs (d = 2.7 nm) were synthesized, and clustered USIONs (d = 27.9 nm) were subsequently synthesized through multiple cross-linking of USIONs with poly(acrylic acid-co-maleic acid) (PAAMA) polymers with many -COOH groups. The clustered PAAMA-USIONs exhibited very weak ferromagnetism owing to the magnetic interaction between superparamagnetic USIONs; this was evidenced by their appreciable r1= 3.9 s‒1mM‒1and high r2/r1ratio of 14.6. Their ability to function as a dual-modal T1/T2MRI-CA in T1-weighted MRI was demonstrated when they simultaneously exhibited positive and negative contrasts in T1-weighted MRI of tumor model mice after intravenous injection. They displayed positive contrasts at the kidneys, bladder, heart, and aorta and negative contrasts at the liver and tumor. .

Head-orienting behaviors during simultaneous speech detection and localization.

Head movement plays a vital role in auditory processing by contributing to spatial awareness and the ability to identify and locate sound sources. Here we investigate head-orienting behaviors using a dual-task experimental paradigm to measure: (a) localization of a speech source; and (b) detection of meaningful speech (numbers), within a complex acoustic background. Ten younger adults with normal hearing and 20 older adults with mild-to-severe sensorineural hearing loss were evaluated in the free field on two head-movement conditions: (1) head fixed to the front and (2) head moving to a source location; and two context conditions: (1) with audio only or (2) with audio plus visual cues. Head-tracking analyses quantified the target location relative to head location, as well as the peak velocity during head movements. Evaluation of head-orienting behaviors revealed that both groups tended to undershoot the auditory target for targets beyond 60° in azimuth. Listeners with hearing loss had higher head-turn errors than the normal-hearing listeners, even when a visual location cue was provided. Digit detection accuracy was better for the normal-hearing than hearing-loss groups, with a main effect of signal-to-noise ratio (SNR). When performing the dual-task paradigm in the most difficult listening environments, participants consistently demonstrated a wait-and-listen head-movement strategy, characterized by a short pause during which they maintained their head orientation and gathered information before orienting to the target location.

Unveiling electron transfer and radical transformation pathways in coupled electrocatalysis and persulfate oxidation reactions for complex pollutant removal.

The degradation of multiple organic pollutants in wastewater via advanced oxidation processes might involve different radicals, of which the types and concentrations vary upon interacting with different pollutants. In this study, electrochemical activation of peroxymonosulfate (E/PMS) using advanced activated carbon cloth (ACC) as electrode was applied for simultaneous degradation of mixed pollutants, e.g., metronidazole (MNZ) and p-chloroaniline (PCA). 92.5 % of MNZ and 91.4 % of PCA can be degraded at the cathode and anode at a low current density and PMS concentration, respectively. The rate constants for the simultaneous removal of MNZ and PCA in the E/PMS/MNZ(PCA) system were 118 times and 6 times higher than those in the sole PMS system, and 2.5 times and 1.6 times higher than those in the E/Na2SO4/MNZ(PCA) system, respectively. Different electrochemical characteristics, EPR spectra and radical quenching tests verified that the degradation of MNZ and PCA in the optimal system proceeded primarily through non-radical-dominated oxidation, involving electron transfer and 1O2 effect. The system also exhibited low energy consumption (0.215 kWh/m-3·order-1), broad operational pH range, excellent removal efficiency for water matrix, and low by-products toxicity, indicating its strong potential for practical applications. The ACC, with its super stable, low cost, and electrochemical activity, make it as a promising materials applicable in the E/PMS system for degradation of multiple pollutants. The study further elucidated the mechanism of pollutant interaction with electrode materials in terms of radical and non-radical transformation, providing fundamental insight into the application of this system for treatment of complex wastewater.

Design, synthesis, and evaluation of dual son of sevenless 1 (SOS1) and epidermal growth factor receptor (EGFR) inhibitors for the treatment of cancers.

The treatment of KRAS mutant tumors remains challenging and dual-targeted small-molecule drugs are considered to be innovative therapeutic alternatives. Herein, we discovered a series of SOS1 and EGFR dual inhibitors by employing a fused pharmacophore strategy and structural optimization. Notably, compound 4 exhibited potent SOS1 (IC50 = 8.3 nM) and EGFR (IC50 = 14.6 nM) inhibitory activities and markedly inhibited the proliferation of other KRAS-mutant cancer cell lines. Furthermore, Western blot analysis confirmed that compound 4 effectively reduced the level of downstream p-ERK. These results indicated that compound 4 could serve as a potential compound for treating KRAS mutant tumors.

Real-time analysis of the biomolecular interaction between gelsolin and Aß1-42 monomer and its implication for Alzheimer's disease.

Biomolecular interaction acts a pivotal part in understanding the mechanisms underlying the development of Alzheimer's disease (AD). Herein, we built a biosensing platform to explore the interaction between gelsolin (GSN) and different ß-amyloid protein 1-42 (Aß1-42) species, including Aß1-42 monomer (m-Aß), Aß1-42 oligomers with both low and high levels of aggregation (LLo-Aß and HLo-Aß) via dual polarization interferometry (DPI). Real-time molecular interaction process and kinetic analysis showed that m-Aß had the strongest affinity and specificity with GSN compared with LLo-Aß and HLo-Aß. The impact of GSN on inhibiting aggregation of Aß1-42 and solubilizing Aß1-42 aggregates was evaluated by circular dichroism (CD) spectroscopy. The maintenance of random coil structure of m-Aß and the reversal of ß-sheet structure in HLo-Aß were observed, demonstrating the beneficial effects of GSN on preventing Aß from aggregation. In addition, the structure of m-Aß/GSN complex was analyzed in detail by molecular dynamics (MD) simulation and molecular docking. The specific binding sites and crucial intermolecular forces were identified, which are believed to stabilize m-Aß in its soluble state and to inhibit the fibrilization of Aß1-42. Combined theoretical simulations and experiment results, we speculate that the success of GSN sequestration mechanism and the balance of GSN levels in cerebrospinal fluid and plasma of AD subjects may contribute to a delay in AD progression. This research not only unveils the molecular basis of the interaction between GSN and Aß1-42, but also provides clues to understanding the crucial functions of GSN in AD and drives the development of AD drugs and therapeutic approaches.