Decoding complexity in biomolecular recognition of DNA i-motifs with microarrays.

DNA i-motifs (iMs) are non-canonical C-rich secondary structures implicated in numerous cellular processes. Though iMs exist throughout the genome, our understanding of iM recognition by proteins or small molecules is limited to a few examples. We designed a DNA microarray containing 10976 genomic iM sequences to examine the binding profiles of four iM-binding proteins, mitoxantrone and the iMab antibody. iMab microarray screens demonstrated that pH 6.5, 5% BSA buffer was optimal, and fluorescence was correlated with iM C-tract length. hnRNP K broadly recognizes diverse iM sequences, favoring 3-5 cytosine repeats flanked by thymine-rich loops of 1-3 nucleotides. Array binding mirrored public ChIP-Seq datasets, in which 35% of well-bound array iMs are enriched in hnRNP K peaks. In contrast, other reported iM-binding proteins had weaker binding or preferred G-quadruplex (G4) sequences instead. Mitoxantrone broadly binds both shorter iMs and G4s, consistent with an intercalation mechanism. These results suggest that hnRNP K may play a role in iM-mediated regulation of gene expression in vivo, whereas hnRNP A1 and ASF/SF2 are possibly more selective in their binding preferences. This powerful approach represents the most comprehensive investigation of how biomolecules selectively recognize genomic iMs to date.

Comprehensive analysis and prediction model of mitophagy and ferroptosis in primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is linked to specific pathogenic mechanisms, yet its relationship with mitophagy and ferroptosis is poorly understood. This study aimed to identify new biomarkers and explore the role of mitophagy and ferroptosis in ITP pathogenesis. Techniques such as differential analysis, Mfuzz expression pattern clustering, machine learning, gene set enrichment analysis, single-cell RNA sequencing (scRNA-seq) and immune infiltration analysis were employed to investigate the molecular pathways of pivotal genes. Two-sample Mendelian randomization (TSMR) assessed the causal effects in ITP. Key genes identified in the training set included GABARAPL1, S100A8, LIN28A, and GDF9, which demonstrated diagnostic potential in validation sets. Functional analysis indicated these genes' involvement in ubiquitin phosphorylation, PPAR signalling pathway and T-cell differentiation. Immune infiltration analysis revealed increased macrophage presence in ITP, related to the critical genes. scRNA-seq indicated reduced GABARAPL1 expression in ITP bone marrow macrophages. TSMR linked S100A8 with ITP diagnosis, presenting an OR of 0.856 (95% CI = 0.736-0.997, p = 0.045). The study pinpointed four central genes, GABARAPL1, S100A8, LIN28A, and GDF9, tied to mitophagy and ferroptosis in ITP. It posits that diminished GABARAPL1 expression may disrupts ubiquitin phosphorylation and PPAR signalling, impairing mitophagy and inhibiting ferroptosis, leading to immune imbalance.

Fluid shear stress regulates the survival of circulating tumor cells via nuclear expansion.

Distant metastasis mainly occurs through hematogenous dissemination, where suspended circulating tumor cells (CTCs) experience a considerable level of fluid shear stress. We recently reported that shear flow induced substantial apoptosis of CTCs, although a small subpopulation could still persist. However, how suspended tumor cells survive in shear flow remains poorly understood. This study finds that fluid shear stress eliminates the majority of suspended CTCs and increases nuclear size, whereas it has no effect on the viability of adherent tumor cells and decreases their nuclear size. Shear flow promotes histone acetylation in suspended tumor cells, the inhibition of which using one drug suppresses shear-induced nuclear expansion, suggesting that shear stress might increase nuclear size through histone acetylation. Suppressing histone acetylation-mediated nuclear expansion enhances shear-induced apoptosis of CTCs. These findings suggest that suspended tumor cells respond to shear stress through histone acetylation-mediated nuclear expansion, which protects CTCs from shear-induced destruction. Our study elucidates a unique mechanism underlying the mechanotransduction of suspended CTCs to shear flow, which might hold therapeutic promise for CTC eradication.

Photoreceptor-Mimetic Microflowers for Restoring Light Responses in Degenerative Retina through a 2D Nanopetal/Cell Biointerface.

Retinitis pigmentosa is the main cause of inherited human blindness and is associated with dysfunctional photoreceptors (PRs). Compared with traditional methods, optoelectronic stimulation can better preserve the structural integrity and genetic content of the retina. However, enhancing the spatiotemporal accuracy of stimulation is challenging. Quantum dot-doped ZnIn2S4 microflowers (MF) are utilized to construct a biomimetic photoelectric interface with a 0D/3D heterostructure, aiming to restore the light response in PR-degenerative mice. The MF bio interface has dimensions similar to those of natural PRs and can be distributed within the curved spatial region of the retina, mimicking cellular dispersion. The soft 2D nano petals of the MF provide a large specific surface area for photoelectric activation and simulate the flexibility interfacing between cells. This bio interface can selectively restore the light responses of seven types of retina ganglion cells that encode brightness. The distribution of responsive cells forms a pattern similar to that of normal mice, which may reflect the generation of the initial "neural code" in the degenerative retina. Patch-clamp recordings indicate that the bio interface can induce spiking and postsynaptic currents at the single-neuron level. The results will shed light on the development of a potential bionic subretinal prosthetic toolkit for visual function restoration.

Comprehensive Multipath Variational Kinetics Study on Hydrogen Abstraction Reactions from Three Typical Dimethylcyclohexane Isomers by Hydroxyl Radicals: from the Electronic Structure to Model Applications.

Cycloalkanes serve as an important class of chemical components in both fossil and alternative transportation fuels and have attracted considerable attention from the combustion community. Hydrogen abstractions from cycloalkanes by hydroxyl radicals initiate the fuel decomposition process and trigger off the subsequent chain reactions and thus play an important role in both combustion and atmospheric chemistry. The target of this study is to fill the vacancy in kinetics data toward the H-abstraction reactions by hydroxyl radical from three typical dimethylcyclohexane isomers through first-principles and direct dynamics. The rate constants involving 18 elementary reactions in total were accurately determined by the multipath canonical variational transition state theory with the multidimensional small-curvature correction for tunneling (MP-CVT/SCT), over a broad temperature range of 200-2000 K. The significant roles of multistructural torsional anharmonicity and recrossing effects were stressed per abstraction site, while the quantum tunneling effect was found to be slight at temperatures of interest in combustion. The discrepancies observed among different reaction systems at a similar abstraction site highlight the fuel molecular effects on site-specific rate constants. The comparison results of total rate constants given by different dynamics approaches prove the importance of considering the torsional anharmonicity, recrossing, and tunneling effects, and the robust feature of the simplified MS-CVT/SCT. The calculated total constants for dimethylcyclohexane isomers by OH are consistent with those measured for methylcyclohexane and 1,4-dimethylcyclohexane at low temperatures. The branching ratio analysis confirms the predominant role of the tertiary abstraction at low-to-intermediate temperatures and its growing competition with distinct secondary abstractions as temperature increases. The calculated rate constants were eventually fitted into the analytical expressions and incorporated into the kinetic models to learn about the influences on modeling performance.

SIRT5-mediated PRKAA2 succinylation ameliorates apoptosis of human placental trophoblasts in hypertensive disorder complicating pregnancy.

PURPOSE: Hypertensive disorder complicating pregnancy (HDCP) is a serious clinical disorder syndrome during pregnancy. This study aims at finding novel targets for HDCP therapy. METHODS: HDCP-related mRNAs were firstly screened out and subjected to gene enrichment analysis. We chose protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) as the research object. Thirty-nine HDCP patients at 32 to 40 weeks of gestation were selected as the HDCP group, and 39 normal controls who received cesarean section delivery at 37-42 weeks of pregnancy were enrolled in this study. Chorionic villi samples were collected within 30 min of delivery. The apoptosis of isolated placental trophoblasts was monitored to investigate the regulatory role of PRKAA2. RESULTS: PRKAA2 expression was further proven to be enhanced in the placental tissues of HDCP patients compared with that of normal puerpera. Subsequently, the results of flow cytometry analysis and western blot indicated that PRKAA2 overexpression accelerated primary placental cell apoptosis, while its knockdown attenuated cell apoptosis. Mechanistically, we determined that the level of PRKAA2 succinylation was elevated in the placental tissue of HDCP patients. Through in vitro succinylation assay and mutagenesis, we confirmed that sirtuin 5 (SIRT5) interacts with PRKAA2 at K69 and K260 to induce PRKAA2 desuccinylation. SIRT5 regulated primary HDCP cell apoptosis through PRKAA2. Finally, the animal study revealed that PRKAA2 elevates the systolic blood pressure of HDCP rat model. CONCLUSION: Our findings indicated that SIRT5-mediated PRKAA2 succinylation modulates placental cell apoptosis in HDCP, suggesting that PRKAA2 is a potential therapeutic target for HDCP treatment.

Amplified detection of SARS-COV-2 B.1.1.529 (Omicron) gene oligonucleotides based on exonuclease III-aided MoS2 /AIE nanoprobes.

The coronavirus disease-2019 pandemic reflects the underdevelopment of point-of-care diagnostic technology. Nuclei acid (NA) detection is the "gold standard" method for the early diagnosis of the B.1.1.529 (Omicron) variant of severe acute respiratory syndrome-coronavirus disease-2. Polymerase chain reaction is the main method for NA detection but requires considerable manpower and sample processing taking ≥ 3 h. To simplify the operation processes and reduce the detection time, exonuclease III (Exo III)-aided MoS2 /AIE nanoprobes were developed for rapid and sensitive detection of the oligonucleotides of Omicron. Molybdenum disulfide (MoS2 ) nanosheets with excellent optical absorbance and distinguishable affinity to single-strand and duplex DNAs were applied as quenchers, and aggregation-induced emission (AIE) molecules with high luminous efficiency were designed as donor in fluorescence resonance energy transfer-based nanoprobes. Exo III with catalytic capability was used for signal amplification to increase the sensitivity of detection. The composite nanoprobes detected the mutated nucleocapsid (N)-gene and spike (S)-gene oligonucleotides of Omicron within 40 min with a limit of detection of 4.7 pM, and showed great potential for application in community medicine.

Nanomanipulation of Ligand Nanogeometry Modulates Integrin/Clathrin-Mediated Adhesion and Endocytosis of Stem Cells.

Nanosubstrate engineering can be a biomechanical approach for modulating stem cell differentiation in tissue engineering. However, the study of the effect of clathrin-mediated processes on manipulating this behavior is unexplored. Herein, we develop integrin-binding nanosubstrates with confined nanogeometries that regulate clathrin-mediated adhesion- or endocytosis-active signaling pathways for modulating stem fates. Isotropically presenting ligands on the nanoscale enhances the expression of clathrin in cells, thereby facilitating uptake of dexamethasone-loaded nanoparticles (NPs) to boost osteogenesis of stem cells. In contrast, anisotropic ligand nanogeometry suppresses this clathrin-mediated NP entry by strengthening the association between clathrin and adhesion spots to reinforce mechanotransduced signaling, which can be abrogated by the pharmacological inhibition of clathrin. Meanwhile, inhibiting focal adhesion formation hinders cell spreading and enables a higher endocytosis efficiency. Our findings reveal the crucial roles of clathrin in both endocytosis and mechanotransduction of stem cells and provide the parameter of ligand nanogeometry for the rational design of biomaterials for tissue engineering.

SCARNA10 regulates p53 acetylation-dependent transcriptional activity.

The tumor suppressor p53 is involved in variety of cell progresses including cell cycle arrest, apoptosis, DNA repair, senescence, cell metabolism and ferroptosis. Here, we identified lncRNA SCARNA10 (Small Cajal Body-Specific RNA 10) as a novel cellular factor that interacts with the DNA binding domain (DBD) of p53. Upon binding the DBD of p53 and CREB-binding protein (CBP), SCARNA10 promotes the acetylation of p53, and activates p53-mediated transcriptional activation. Overexpress or knockdown SCARNA10 leads to up (or down)-regulation of p53-mediated transcriptional activation, whereas not affecting p53 protein levels. Moreover, SCARNA10 directly activates transcription by increasing the acetylation of p53 C-terminal domain (CTD) without affecting p53 phosphorylation at Ser15. These results indicate that SCARNA10 is a novel factor which regulates p53 acetylation-dependent transcriptional activity and tumor suppression.

A Multilayered Mesoporous Gold Nanoarchitecture for Ultraeffective Near-Infrared Light-Controlled Chemo/Photothermal Therapy for Cancer Guided by SERS Imaging.

Surface-enhanced Raman scattering (SERS) imaging has emerged as a promising tool for guided cancer diagnosis and synergistic therapies, such as combined chemotherapy and photothermal therapy (chemo-PTT). Yet, existing therapeutic agents often suffer from low SERS sensitivity, insufficient photothermal conversion, or/and limited drug loading capacity. Herein, a multifunctional theragnostic nanoplatform consisting of mesoporous silica-coated gold nanostar with a cyclic Arg-Gly-Asp (RGD)-coated gold nanocluster shell (named RGD-pAS@AuNC) is reported that exhibits multiple "hot spots" for pronouncedly enhanced SERS signals and improved near-infrared (NIR)-induced photothermal conversion efficiency (85.5%), with a large capacity for high doxorubicin (DOX) loading efficiency (34.1%, named RGD/DOX-pAS@AuNC) and effective NIR-triggered DOX release. This nanoplatform shows excellent performance in xenograft tumor model of HeLa cell targeting, negligible cytotoxicity, and good stability both in vitro and in vivo. By SERS imaging, the optimal temporal distribution of injected RGD/DOX-pAS@AuNCs at the tumor site is identified for NIR-triggered local chemo-PTT toward the tumor, achieving ultraeffective therapy in tumor cells and tumor-bearing mouse model with 5 min of NIR irradiation (0.5 W cm-2 ). This work offers a promising approach to employing SERS imaging for effective noninvasive tumor treatment by on-site triggered chemo-PTT.

Mitochondrial energy metabolism is downregulated in repeated implantation failure patients related to alteration of PGC-1α acetylation level.

Herein we aimed at exploring mitochondrial energy metabolism status in patients with repeated implantation failure (RIF) and whether key regulatory factor PGC-1α of energy metabolism is involved in the decidualization of endometrial stromal cells. Mitochondrial oxidative phosphorylation level and ATP synthesis were compared in primary endometrial stromal cells from RIF and control group. At the same time, as one of key transcription regulators of mitochondrial energy metabolism, the expression level and acetylation level of PGC-1α were compared with two groups. Then, we downregulated the acetylation levels of PGC-1α, and the expression of decidual markers (PRL and IGFBP1) was observed further. Mitochondrial energy metabolism, showing by mitochondrial oxidative phosphorylation level and ATP synthesis, was decreased in the endometrial stromal cells of the RIF group (RIF-hEnSCs). Meanwhile, PGC-1α acetylation levels were significantly higher in RIF-hEnSCs. When we reduced the acetylation levels of PGC-1α in RIF-hEnSCs, the basal O2 consumption rate and maximal respiration were increased, and also the PRL and IGFBP1. Overall, our data indicated that the endometrial stromal cells of the RIF patients had low level of mitochondrial energy metabolism. Reducing acetylation level of key energy metabolism regulator PGC-1α can increase the decidualization level of RIF-hEnSCs. These findings may inspire new ideas about the treatment of RIF.

Mechanistic Insights into the Metal-Free Deoxygenative Borylation of Ketones and Aldehydes with Bis(catecholato)diborane.

The mechanisms of direct deoxygenative borylation of acetone and benzaldehyde with bis(catecholato)diborane (B2 cat2 ) in the solvent N,N-dimethylacetamide (DMA) are investigated through detailed density functional theory calculations. These calculations show that the isomer 1,2-B2 cat2 in situ generated from 1,1-B2 cat2 induced by DMA is the reactive boron intermediate for the reactions. The addition of the B-B bond of 1,2-B2 cat2 to the C=O bond of acetone or benzaldehyde via a concerted [2σ+2π]-cycloaddition-like transition state is the rate-limiting step for both the triboration reaction of acetone and the monoboration reaction of benzaldehyde. DMA not only acts as the solvent but also promotes the structural isomerization of B2 cat2 , the deoxygenation of acetone to form the vinyl boronate intermediate and subsequent diboration of vinyl boronate with 1,2-B2 cat2 , as well as the protodeboronation of the gem-diboronate intermediate in the deoxygenative borylation of benzaldehyde. The presented computational results can explain the observed experimental facts and provide insight into the roles of the isomeric 1,2-B2 cat2 and the solvent DMA in related reactions.

Cost-Effectiveness of Tepotinib Versus Capmatinib for the Treatment of Adult Patients With Metastatic Non-Small Cell Lung Cancer Harboring Mesenchymal-Epithelial Transition Exon 14 Skipping.

OBJECTIVES: From the US Medicare perspective, this study compared the cost-effectiveness of tepotinib and capmatinib for treating metastatic non-small cell lung cancer with tumors harboring mesenchymal-epithelial transition factor gene exon 14 skipping. METHODS: A 3-state partitioned survival model assessed outcomes over a lifetime horizon. Parametric survival analysis of the phase 2 VISION trial informed clinical inputs for tepotinib. Capmatinib inputs were captured using hazard ratios derived from an unanchored matching-adjusted indirect comparison study and published literature. National cost databases, trial data, and literature furnished drug, treatment monitoring, and disease/adverse event management expenditures (2021 US dollars) and utility inputs. Outcomes were discounted at 3% annually. RESULTS: In the base case, tepotinib dominated capmatinib in frontline settings (incremental discounted quality-adjusted life-years [QALYs] and costs of 0.2127 and -$47 756, respectively) while realizing an incremental cost-effectiveness ratio of $274 514/QALY in subsequent lines (incremental QALYs and costs of 0.3330 and $91 401, respectively). In a line agnostic context, tepotinib produced an incremental cost-effectiveness ratio of $105 383/QALY (incremental QALYs and costs of 0.2794 and $29 447, respectively). Sensitivity and scenarios analyses for individual lines typically supported the base case, whereas those for the line agnostic setting suggested sensitivity to drug acquisition costs and efficacy inputs. CONCLUSIONS: Tepotinib could be cost-effective versus capmatinib in frontline and line agnostic contexts, considering the range of willingness-to-pay thresholds recommended by the Institute for Clinical and Economic Review ($100 000-$150 000/QALY). Tepotinib could be cost-effective in subsequent lines at higher willingness-to-pay levels. These results are to be interpreted cautiously, considering uncertainty in key model inputs.

Health Utility Analysis of Tepotinib in Patients With Non-Small Cell Lung Cancer Harboring MET Exon 14 Skipping.

OBJECTIVES: The VISION trial showed durable activity of tepotinib in MET exon 14 (METex14) skipping non-small cell lung cancer. We analyzed health state utilities using patient-reported outcomes from VISION. METHODS: 5-level version of EQ-5D (EQ-5D-5L) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 responses were collected at baseline, every 6 to 12 weeks during treatment, and at the end of treatment and safety follow-up. EQ-5D-5L and European Organisation for Research and Treatment of Cancer Quality of Life Utility Measure-Core 10 Dimensions (QLU-C10D) utilities were derived using United States, Canada, United Kingdom, and Taiwan value sets, where available. Utilities were analyzed with linear mixed models including covariates for progression or time-to-death (TTD). RESULTS: Utilities were derived for 273/291 patients (EQ-5D-5L, 1545 observations; QLU-C10D, 1546 observations). Mean (± SD) US EQ-5D-5L utilities increased after tepotinib initiation, from 0.687 ± 0.287 at baseline to 0.754 ± 0.250 before independently assessed progression, and decreased post progression (0.704 ± 0.288). US QLU-C10D utilities showed similar trends (0.705 ± 0.215, 0.753 ± 0.195, and 0.708 ± 0.209, respectively). Progression-based models demonstrated a statistically significant impact of progression on utilities and predicted higher utilities pre versus post progression. TTD-based models showed statistically significant associations of TTD with utilities and predicted declining utilities as TTD decreased. Prior treatment (yes/no) did not significantly predict utilities in progression- or TTD-based models. Utilities for Canada, United Kingdom, and Taiwan showed comparable trends. CONCLUSIONS: In this first analysis of health state utilities in patients with METex14 skipping non-small cell lung cancer, who received tepotinib, utilities were significantly associated with progression and TTD, but not prior treatment.

Multi-structural variational kinetics study on hydrogen abstraction reactions of cyclopentanol and cyclopentane by hydroperoxyl radical with anharmonicity, recrossing and tunneling effects.

To date, it is still a challenge to accurately predict the reaction kinetics of H-atom abstractions by the HO2 radical in cycloalkanes and cyclic alcohols, which plays a fundamental role in both atmospheric and combustion chemistry. Cyclopentanol (CPL) is a novel alternative fuel derived from lignocellulosic biomass, while cyclopentane (CPT) is a representative component in conventional fossil fuels. Both are promising gasoline additives due to their high-octane and knock-resistant features, and therefore selected as our target molecules for detailed theoretical investigation in this work. The rate constants of H-abstraction by HO2 over a wide temperature range of 200-2000 K were calculated using multi-structural variational transition state theory (MS-CVT) in multi-dimensional small-curvature tunneling approximation (SCT) including multiple structural and torsional potential anharmonicity (MS-T), recrossing and tunneling effects. For comparison, the "single-structural rigid-rotor quasiharmonic oscillator" (SS-QH) rate constants corrected by multi-structural local harmonic approximation (MS-LH) and different quantum tunneling methods including one-dimensional Eckart and zero-curvature tunneling (ZCT) were also obtained in this work. The importance of considering the anharmonicity, recrossing and multi-dimensional tunneling effects was stressed by analyzing the MS-T and MS-LH factors and transmission coefficients for each studied reaction. In general, the MS-T anharmonicity was found to increase the rate constants by certain values especially at high temperatures; the multi-dimensional tunneling effect significantly increased the rate constants at low temperatures as expected; and the recrossing effect decreased the rate constants but it was only remarkable for the α and ß carbon sites in CPL and the secondary carbon site in CPT. The comparison of the results from the different theoretical kinetic corrections in this work or empirically estimated methods from the literature showed significant deviations in the site-specific rate constants, branching ratios (competition of different channels) and Arrhenius activation energies with pronounced temperature dependence.

Improved confidence estimation for the binomial proportion with applications to clinical studies.

In this paper, we establish a frequentist framework that incorporates all confidence sets with guaranteed frequentist coverage probability for the binomial proportion, where different confidence sets are completely characterized by their tail functions. Based on measures of precision in the form of interval length, probability of false coverage, and a new evaluation criterion utilizing prior information, we construct the optimal confidence set for the binomial proportion. The newly proposed methodology is applied to clinical studies. It is shown that confidence intervals obtained via the tail functions are often better than prevailing confidence intervals in view of precision.

Characteristics of sodium and water retention in rats with nephrotic syndrome induced by puromycin aminonucleoside.

INTRODUCTION: Nephrotic syndrome (NS) is characterized by renal sodium and water retention. The mechanisms are not fully elucidated. METHODS: The NS rat model was established by single intraperitoneal injection of 100 mg/kg puromycin aminonucleoside (PAN). The plasma electrolyte level and urinary sodium excretion were monitored dynamically. The changes of some sodium transporters, including epithelial Na+ channel (ENaC), Na+/H+ exchanger 3 (NHE3), Na+-K+-2Cl- cotransporter 2 (NKCC2) and Na+-Cl- cotransporter (NCC) in renal cortex at different time points and the level of peripheral circulation factors were detected. RESULTS: The urinary sodium excretion of the model group increased significantly on the first day, then decreased compared with the control group, and there was no significant difference between the model group and the control group on the 12th day. The changes of peripheral circulation factors were not obvious. Some sodium transporters in renal cortex increased in varying degrees, while NKCC2 decreased significantly compared with the control group. CONCLUSIONS: The occurrence of NS edema may not be related to the angiotensin system. The decrease of urinary sodium excretion is independent of the development of albuminuria. During the 18 days of observation, it can be divided into three stages: sodium retention, sodium compensation, and simple water retention. The mechanism is related to the increased expression of α-ENaC, γ-ENaC, NHE3 and NCC in a certain period of time, the compensatory decrease of NKCC2 expression and the continuous increase of aquaporin 2 (AQP2) expression.

Targeting a noncanonical, hairpin-containing G-quadruplex structure from the MYCN gene.

The MYCN gene encodes the transcription factor N-Myc, a driver of neuroblastoma (NB). Targeting G-quadruplexes (G4s) with small molecules is attractive strategy to control the expression of undruggable proteins such as N-Myc. However, selective binders to G4s are challenging to identify due to the structural similarity of many G4s. Here, we report the discovery of a small molecule ligand (4) that targets the noncanonical, hairpin containing G4 structure found in the MYCN gene using small molecule microarrays (SMMs). Unlike many G4 binders, the compound was found to bind to a pocket at the base of the hairpin region of the MYCN G4. This compound stabilizes the G4 and has affinity of 3.5 ± 1.6 µM. Moreover, an improved analog, MY-8, suppressed levels of both MYCN and MYCNOS (a lncRNA embedded within the MYCN gene) in NBEB neuroblastoma cells. This work indicates that the approach of targeting complex, hybrid G4 structures that exist throughout the human genome may be an applicable strategy to achieve selectivity for targeting disease-relevant genes including protein coding (MYCN) as well as non-coding (MYCNOS) gene products.

Fast Fourier Transform-weighted Photoacoustic Imaging by In Vivo Magnetic Alignment of Hybrid Nanorods.

Photoacoustic (PA) imaging uses photon-phonon conversion for high-resolution tomography of biological tissues and functions. Exogenous contrast agents are often added to improve the image quality, but the interference from endogenous molecules diminishes the imaging sensitivity and specificity. We report a background-free PA imaging technique based on the active modulation of PA signals via magnetic alignment of Fe3O4@Au hybrid nanorods. Switching the field direction creates enhanced and deactivated PA imaging modalities, enabling a simple pixel subtraction to effectively minimize background noises. Under an alternating magnetic field, the nanorods exhibit PA signals of coherently periodic changes that can be converted into a sharp peak in a frequency domain via the fast Fourier transform. Automatic pixel-wise screening of nanorod signals performed using a computational algorithm across a time-sequence set of PA images regenerates a background-free PA image with significantly improved contrast, specificity, and fidelity.

Flotation separation of coal dust from foundry dust enhanced by pre-soaking assisted mechanical stirring.

Foundry dust is the main refractory solid waste in the foundry industry, and its resource utilization is a top priority for realizing green and cleaner production. The massive amount of coal dust in foundry dust is a potential impediment to the recycling of foundry dust, and the efficient separation of coal dust is crucial to solving the above problems. In this paper, the flotation separation of coal dust from foundry dust enhanced by pre-soaking assisted mechanical stirring was reported. The influence of pre-soaking, stirring speed, and stirring time on the flotation results of foundry dust was systematically studied, and the enhancement mechanism was analyzed based on the microstructure and hydrophobicity of foundry dust. Flotation kinetics experiments with different stirring time were conducted to clarify the flotation process of foundry dust. The results indicate that the pre-soaking of foundry dust is beneficial for the water-absorbing swelling of clay minerals coated on the surface of coal dust, and the subsequent mechanical stirring pretreatment promotes the monomer dissociation of foundry dust, which increases the contact angle of foundry dust and considerably improves the flotation results. The optimal stirring speed and stirring time were 2400 rpm and 30 min, respectively. The classical first-order model presented the highest degree of fitting with the flotation data among the five flotation kinetics models. Therefore, the pre-soaking assisted mechanical stirring is a promising method for promoting flotation separation and the complete recycling of foundry dust.