Genome-wide binding analysis unveils critical implication of B-Myb-mediated transactivation in cancers.

B-Myb, also known as MYB proto-oncogene like 2 (MYBL2), is an important transcription factor implicated in transcription regulation, cell cycle and tumorigenesis. However, the molecular mechanism underlying B-Myb-controlled transactivation in different cell contexts as well as its functional implication in cancers remains elusive. In this study, we have conducted a comprehensive genome-wide analysis of B-Myb binding sites in multiple immortalized or cancer cell lines and identified its critical target genes. The results revealed that B-Myb regulates a common set of core cell cycle genes and cell type-specific genes through collaboration with other important transcription factors (e.g. NFY and MuvB complex) and binding to cell type-invariant promoters and cell type-specific enhancers and super-enhancers. KIF2C, UBE2C and MYC were further validated as B-Myb target genes. Loss-of-function analysis demonstrated that KIF2C knockdown inhibited tumor cell growth both in vitro and in vivo, suppressed cell motility and cell cycle progression, accompanied with defects in microtubule organization and mitosis, strongly suggesting that KIF2C is a critical regulator of cancer cell growth and mitosis, and maintains high cancer cell motility ability and microtubule dynamics. Pan-cancer transcriptomic analysis revealed that the overexpression of both B-Myb and KIF2C presents as independent prognostic markers in various types of cancer. Notably, B-Myb associates with NFYB, binds to target gene promoters, enhancers and super-enhancers, and provokes a cascade of oncogenic gene expression profiles in cancers. Overall, our results highly suggest the critical implication of B-Myb-mediated gene regulation in cancers, and the promising therapeutic and prognostic potentials of B-Myb and KIF2C for cancer diagnosis and treatment.

Effect of straw decomposition on hexavalent chromium removal by straw: Significant roles of surface potential and dissolved organic matter.

Mobility and bioavailability of hexavalent chromium (Cr(VI)) in agricultural soils are affected by interactions between Cr(VI) and returned crop straws. However, the effect of straw decomposition on Cr(VI) removal and underlying mechanisms remain unclear. In this study, Cr(VI) removal by pristine and decomposed rice/rape straws was investigated by batch experiments and a series of spectroscopies. The results showed that straw decomposition inhibited Cr(VI) removal, regardless of straw types. However, the potential mechanisms of the inhibition were distinct for the two straws. For the rice straw, a lower zeta potential after decomposition suppressed Cr(VI) sorption and subsequent reduction. In addition, less Cr(VI) was reduced by the decomposed rice straw-derived dissolved organic matter (DOM) than the pristine one. In contrast, for the rape straw, due to the increased zeta potential after decomposition, the decreased Cr(VI) removal was mainly ascribed to less Cr(VI) reduction by the rape straw-derived DOM. These results emphasized the significant roles of straw surface potential and DOM in Cr(VI) removal, depending on straw types and decomposition, which facilitate the fundamental understanding of Cr(VI) removal by straws and are helpful for predicting the environmental risk of Cr and rational straw return in Cr(VI)-contaminated fields.

Sequence-Dependent Single-Molecule DNA Sensing Using Covalent Organic Framework Nanopores.

Enzyme-free single-molecule sequencing has the potential to significantly expand the application of nanopore technology to DNA, proteins, and saccharides. Despite their advantages over biological nanopores and natural suitability for enzyme-free single-molecule sequencing, conventional solid-state nanopores have not yet achieved single-molecule DNA sequencing. The biggest challenge for the accuracy of single-molecule sequencing using solid-state nanopores lies in the precise control of the pore size and conformity. In this study, we fabricated nanopore devices by covering the tip of a quartz nanopipette with ultrathin two-dimensional (2D) covalent organic framework (COF) nanosheets (pore size ≈ 1.1 nm). The size of the periodically arranged nanopores in COF is comparable to that of protein nanopores, and the structure of each COF nanopore is consistent at the atomic scale. The COF nanopore device could roughly distinguish dAMP, dCMP, dGMP, and dTMP. Furthermore, a certain percentage of the current blockades originating from 150 nucleotides model DNA molecules (13.5% for dA50dC50dA50 and 11.1% for dC50dA50dC50) show distinct DNA sequence-specific concave and convex resistive current patterns. The finite element simulation confirmed that the current blockade pattern of a DNA molecule passing through a COF nanopore is dependent on the relative location of the nanopore with respect to the wall of the nanopipette. Our study is a significant step toward single-molecule DNA sequencing by solid-state nanopores.

A combination model of CT-based radiomics and clinical biomarkers for staging liver fibrosis in the patients with chronic liver disease.

A combined model was developed using contrast-enhanced CT-based radiomics features and clinical characteristics to predict liver fibrosis stages in patients with chronic liver disease (CLD). We retrospectively analyzed multiphase CT scans and biopsy-confirmed liver fibrosis. 160 CLD patients were randomly divided into 7:3 training/validation ratio. Clinical laboratory indicators associated with liver fibrosis were identified using Spearman's correlation and multivariate logistic regression correlation. Radiomic features were extracted after segmenting the entire liver from multiphase CT images. Feature dimensionality reduction was performed using RF-RFE, LASSO, and mRMR methods. Six radiomics-based models were developed in the training cohort of 112 patients. Internal validation was conducted on 48 randomly assigned patients. Receptor Operating Characteristic (ROC) curves and confusion matrices were constructed to evaluate model performance. The radiomics model exhibited robust performance, with AUC values of 0.810 to 1.000 for significant fibrosis, advanced fibrosis, and cirrhosis. The integrated clinical-radiomics model had superior diagnostic efficacy in the validation cohort, with AUC values of 0.836 to 0.997. Moreover, these models outperformed established biomarkers such as the aspartate aminotransferase to platelet ratio index (APRI) and the fibrosis 4 score (FIB-4), as well as the gamma glutamyl transpeptidase to platelet ratio (GPR), in predicting the fibrotic stages. The clinical-radiomics model holds considerable promise as a non-invasive diagnostic tool for the assessment and staging of liver fibrosis in the patients with CLD, potentially leading to better patient management and outcomes.

High-Throughput Single-Molecule Surface-Enhanced Raman Spectroscopic Profiling of Single-Amino Acid Substitutions in Peptides by a Gold Plasmonic Nanopore.

Simultaneous detection and structural characterization of protein variants on a single platform are highly desirable but technically challenging. Herein, we present a single-molecule spectral system based on a gold plasmonic nanopore for analyzing two peptides and their single-point mutated variants. The gold plasmonic nanopore enabled the high-throughput acquisition of surface-enhanced Raman scattering (SERS) spectra at the single-molecule level by electrically driving analytes into hot spots. Furthermore, a statistical method based on Boolean operations was developed to extract prominent features from fluctuated single-molecule SERS spectra. The effects of the single-amino acid substitutions on both the intramolecular interactions and the peptide conformations were directly characterized by the nanopore system, and the results agreed with the predictions by AlphaFold2. This study highlights the mutual benefits of spectroscopy and nanopore technology, whereby the gold plasmonic nanopore offers a powerful tool for the structural analysis of single-molecule proteins.

Birth weight and risk of cerebral aneurysm: A multivariable Mendelian randomization study.

BACKGROUND: Birth weight has been linked with various health outcomes. The association between birth weight and cerebral aneurysm remains unknown. METHODS: The two-sample Mendelian randomization (MR) approach was used to evaluate the causal effect of birth weight on cerebral aneurysm based on genome-wide association studies (GWAS), comprising 261,932 UKB participants for birth weight and 204,060 FinnGen participants for cerebral aneurysm. The inverse variance weighted (IVW) method was used as the primary method. Alternative methods were used for comparison. Sensitivity analysis was conducted to evaluate the robustness of the results. Multivariable MR (MVMR) was further conducted to evaluate the direct effect of the birth weight on cerebral aneurysm. RESULTS: The IVW detected a causal association between higher birth weight and increased risk of cerebral aneurysm (OR = 0.521, 95% CI = 0.356 ∼ 0.763, P = 7.88 × 10-4), which was supported by alternative MR models. Sensitivity analysis did not find any evidence of heterogeneity or pleiotropy. MVMR further identified a direct effect of birth weight on cerebral aneurysm, independent of obesity-related traits or smoking. CONCLUSION: This MR study found evidence of the association between birth weight and cerebral aneurysm, providing novel insight into the etiology of cerebral aneurysm, indicating the promising role of birth weight as a marker for screening populations at higher risk of cerebral aneurysm.

Cinnamaldehyde protects SH-SY5Y cells against advanced glycation end-products induced ectopic cell cycle re-entry.

Accumulation of advanced glycation end-products (AGEs) in the brain contributes significantly to cognitive impairment in patients with diabetes by disrupting the post-mitotic state of neuronal cells, thereby triggering ectopic cell cycle re-entry (CCR) and subsequent neuronal apoptosis. Cinnamaldehyde (CINA), a potential mitigator of cognitive impairment due to its blood glucose-lowering properties, warrants exploration for its role in counteracting diabetes-related neurological damage. In this study, we examined the neuroprotective effect of CINA on AGE-damaged SH-SY5Y human neuroblastoma cells differentiated in vitro. We investigated the impact of CINA on AGE-induced neuronal CCR and apoptosis, finding that it substantially suppressed aberrant DNA replication, precluded cells from entering the mitotic preparatory phase, and diminished apoptosis. Additionally, CINA inhibited the expression of eIF4E without altering S6K1 phosphorylation. These findings indicate that CINA safeguards neuronal cells from AGE-related damage by preventing abnormal CCR, preserving the post-mitotic state of neuronal cells, and reducing AGE-induced apoptosis, potentially through the inhibition of eIF4E-controlled cell proliferation. Our results highlight the prospective utility of CINA in managing diabetic neuropathy.

Closed Bipolar Nanoelectrode Array for Ultra-Sensitive Detection of Alkaline Phosphatase and Two-Dimensional Imaging of Epidermal Growth Factor Receptors.

The combination of closed bipolar electrodes (cBPE) with electrochemiluminescence (ECL) imaging has demonstrated remarkable capabilities in the field of bioanalysis. Here, we established a cBPE-ECL platform for ultrasensitive detection of alkaline phosphatase (ALP) and two-dimensional imaging of epidermal growth factor receptor (EGFR). This cBPE-ECL system consists of a high-density gold nanowire array in anodic aluminum oxide (AAO) membrane as the cBPE coupled with ECL of highly luminescent cadmium selenide quantum dots (CdSe QDs) luminophores to achieve cathodic electro-optical conversion. When an enzyme-catalyzed amplification effect of ALP with 4-aminophenyl phosphate monosodium salt hydrate (p-APP) as the substrate and 4-aminophenol (p-AP) as the electroactive probe is introduced, a significant improvement of sensing sensitivity with a detection limit as low as 0.5 fM for ALP on the cBPE-ECL platform can be obtained. In addition, the cBPE-ECL sensing system can also be used to detect cancer cells with an impressive detection limit of 50 cells/mL by labeling ALP onto the EGFR protein on A431 human epidermal cancer cell membranes. Thus, two-dimensional (2D) imaging of the EGFR proteins on the cell surface can be achieved, demonstrating that the established cBPE-ECL sensing system is of high resolution for spatiotemporal cell imaging.

Nanometer-Resolved Mapping of Organic Cation Migration Behavior in Methylammonium Lead Halide Perovskites.

The performance and stability of organic metal halide perovskite (OMHP) optoelectronic devices have been associated with ion migration. Understanding of nanoscale resolved organic cation migration mechanism would facilitate structure engineering and commercialization of OMHP. Here, we report a three-dimensional approach for in situ nanoscale infrared imaging of organic ion migration behavior in OMHPs, enabling to distinguish migrations along grain boundary and in crystal lattice. Our results reveal that organic cation migration along OMHP film surface and grain boundaries (GBs) occurs at lower biases than in crystal lattice. We visualize the transition of organic cation migration channels from GBs to volume upon increasing electric field. The temporal resolved results demonstrate the fast MA+ migration kinetics at GBs, which is comparable to diffusivity of halide ions. Our findings help understand the role of organic cations in the performance of OMHP devices, and the proposed approach holds broad applicability for revealing migration mechanisms of organic ions in OMHPs based optoelectronic devices.

Mogroside Alleviates Diabetes Mellitus and Modulates Intestinal Microflora in Type 2 Diabetic Mice.

Mogroside, the main component of Siraitia grosvenorii (Swingle) C. Jeffrey (Cucurbitaceae) is a natural product with hypoglycemic and intestinal microbiota regulating properties. However, whether the alteration of intestinal microbiota is associated with the antidiabetic effect of mogroside remains poorly understood. This study investigated the mechanism underlying the hypoglycemic effect of mogroside in regulating intestinal flora and attenuating metabolic endotoxemia. Kunming mice with type 2 diabetes mellitus (T2DM) induced by high-fat diet and intraperitoneal injection of streptozotocin were randomly divided into model, pioglitazone (2.57 mg/kg) and mogroside (200, 100, and 50 mg/kg) groups. After 28 d of administration, molecular changes related to glucose metabolism and metabolic endotoxemia in mice were evaluated. The levels of insulin receptor substrate-1 (IRS-1), cluster of differentiation 14 (CD14) and toll-like receptor 4 (TLR4) mRNAs were measured, and the composition of intestinal microflora was determined by 16s ribosomal DNA (rDNA) sequencing. The results showed that mogroside treatment significantly improved hepatic glucose metabolism in T2DM mice. More importantly, mogroside treatment considerably reduced plasma endotoxin (inhibition rate 65.93%, high-dose group) and inflammatory factor levels, with a concomitant decrease in CD14 and TLR4 mRNA levels. Moreover, mogroside treatment reduced the relative abundance of Firmicutes and Proteobacteria (the inhibition rate of Proteobacteria was 85.17% in the low-dose group) and increased the relative abundance of Bacteroidetes (growth rate up to 40.57%, high-dose group) in the intestines of diabetic mice. This study reveals that mogroside can relieve T2DM, regulating intestinal flora and improving intestinal mucosal barrier, indicating that mogroside can be a potential therapeutic agent or intestinal microbiota regulator in the treatment of T2DM.

Surface-phonon-polariton-enhanced photoinduced dipole force for nanoscale infrared imaging.

The photoinduced dipole force (PiDF) is an attractive force arising from the Coulombic interaction between the light-induced dipoles on the illuminated tip and the sample. It shows extreme sample-tip distance and refractive index dependence, which is promising for nanoscale infrared (IR) imaging of ultrathin samples. However, the existence of PiDF in the mid-IR region has not been experimentally demonstrated due to the coexistence of photoinduced thermal force (PiTF), typically one to two orders of magnitude higher than PiDF. In this study, we demonstrate that, with the assistance of surface phonon polaritons, the PiDF of c-quartz can be enhanced to surpass its PiTF, enabling a clear observation of PiDF spectra reflecting the properties of the real part of permittivity. Leveraging the detection of the PiDF of phonon polaritonic substrate, we propose a strategy to enhance the sensitivity and contrast of photoinduced force responses in transmission images, facilitating the precise differentiation of the heterogeneous distribution of ultrathin samples.

Efficacy of ketamine versus esketamine in the treatment of perioperative depression: A review.

Depression is a significant factor contributing to postoperative occurrences, and patients diagnosed with depression have a higher risk for postoperative complications. Studies on cardiovascular surgery extensively addresses this concern. Several studies report that people who undergo coronary artery bypass graft surgery have a 20% chance of developing postoperative depression. A retrospective analysis of medical records spanning 21 years, involving 817 patients, revealed that approximately 40% of individuals undergoing coronary artery bypass grafting (CABG) were at risk of perioperative depression. Patients endure prolonged suffering from illness because each attempt with standard antidepressants requires several weeks to be effective. In addition, multi-drug combination adjuvants or combination medication therapy may alleviate symptoms for some individuals, but they also increase the risk of side effects. Conventional antidepressants primarily modulate the monoamine system, whereas different therapies target the serotonin, norepinephrine, and dopamine systems. Esketamine is a fast-acting antidepressant with high efficacy. Esketamine is the S-enantiomer of ketamine, a derivative of phencyclidine developed in 1956. Esketamine exerts its effect by targeting the glutaminergic system the glutaminergic system. In this paper, we discuss the current depression treatment strategies with a focus on the pharmacology and mechanism of action of esketamine. In addition, studies reporting use of esketamine to treat perioperative depressive symptoms are reviwed, and the potential future applications of the drug are presented.

Synergistic Al-Al Dual-Atomic Site for Efficient Artificial Nitrogen Fixation.

Synthesis of ammonia by electrochemical nitrogen reduction reaction (NRR) is a promising alternative to the Haber-Bosch process. However, it is commonly obstructed by the high activation energy. Here, we report the design and synthesis of an Al-Al bonded dual atomic catalyst stabilized within an amorphous nitrogen-doped porous carbon matrix (Al2NC) with high NRR performance. The dual atomic Al2-sites act synergistically to catalyze the complex multiple steps of NRR through adsorption and activation, enhancing the proton-coupled electron transfer. This Al2NC catalyst exhibits a high Faradaic efficiency of 16.56±0.3 % with a yield rate of 29.22±1.2 µg h-1 mgcat -1. The dual atomic Al2NC catalyst shows long-term repeatable, and stable NRR performance. This work presents an insight into the identification of synergistic dual atomic catalytic site and mechanistic pathway for the electrochemical conversion of N2 to NH3.

Single-Molecule Discrimination of Saccharides Using Carbon Nitride Nanopores.

Structural complexity brings a huge challenge to the analysis of sugar chains. As a single-molecule sensor, nanopores have the potential to provide fingerprint information on saccharides. Traditionally, direct single-molecule saccharide detection with nanopores is hampered by their small size and weak affinity. Here, a carbon nitride nanopore device is developed to discern two types of trisaccharide molecules (LeApN and SLeCpN) with minor structural differences. The resolution of LeApN and SLeCpN in the mixture reaches 0.98, which has never been achieved in solid-state nanopores so far. Monosaccharide (GlcNAcpN) and disaccharide (LacNAcpN) can also be discriminated using this system, indicating that the versatile carbon nitride nanopores possess a monosaccharide-level resolution. This study demonstrates that the carbon nitride nanopores have the potential for conducting structure analysis on single-molecule saccharides.

Customizable Organic Charge-Transfer Cocrystals for the Dual-Mode Optoelectronics in the NIR (II) Window.

Organic molecules have been regarded as ideal candidates for near-infrared (NIR) optoelectronic active materials due to their customizability and ease of large-scale production. However, constrained by the intricate molecular design and severe energy gap law, the realization of optoelectronic devices in the second near-infrared (NIR (II)) region with required narrow band gaps presents more challenges. Herein, we have originally proposed a cocrystal strategy that utilizes intermolecular charge-transfer interaction to drive the redshift of absorption and emission spectra of a series BFXTQ (X = 0, 1, 2, 4) cocrystals, resulting in the spectra located at NIR (II) window and reducing the optical bandgap to ∼0.98 eV. Significantly, these BFXTQ-based optoelectronic devices can exhibit dual-mode optoelectronic characteristics. An investigation of a series of BFXTQ-based photodetectors exhibits detectivity (D*) surpassing 1013 Jones at 375 to 1064 nm with a maximum of 1.76 × 1014 Jones at 1064 nm. Moreover, the radiative transition of CT excitons within the cocrystals triggers NIR emission over 1000 nm with a photoluminescence quantum yield (PLQY) of ∼4.6% as well as optical waveguide behavior with a low optical-loss coefficient of 0.0097 dB/µm at 950 nm. These results promote the advancement of an emerging cocrystal approach in micro/nanoscale NIR multifunctional optoelectronics.

The inverted U-shaped relationship between epinephrine and pancreatic ductal adenocarcinoma patients' survival with compensation of lymphocyte.

BACKGROUND: The relationship between epinephrine and cancer can be dose-dependent in in vivo study. Whether it is the same in human body still needs verification. METHOD: We used frozen human pancreatic ductal adenocarcinoma (PDAC) tissues to detect epinephrine content and analyzed its relationship with survival using the K-M method and Cox regression. Disturbance of blood cell count and C-reactive protein and identification of related potent intermediary factors were also analyzed. RESULTS: K-M plot and Cox regression all showed the inverted U-shaped relationship between epinephrine and PDAC survival. Lymphocyte adjustment can increase the HRs of epinephrine for PDAC death by >10%. CONCLUSION: Epinephrine played an anti-tumor or pro-tumor effect depending on the specific concentration. Circulating lymphocyte count was elevated and might acted as a compensation pathway to reduce the pro-tumor effect of epinephrine to PDAC.

Panax notoginseng saponins prevent dementia and oxidative stress in brains of SAMP8 mice by enhancing mitophagy.

BACKGROUND: Mitochondrial dysfunction is one of the distinctive features of neurons in patients with Alzheimer's disease (AD). Intraneuronal autophagosomes selectively phagocytose and degrade the damaged mitochondria, mitigating neuronal damage in AD. Panax notoginseng saponins (PNS) can effectively reduce oxidative stress and mitochondrial damage in the brain of animals with AD, but their exact mechanism of action is unknown. METHODS: Senescence-accelerated mouse prone 8 (SAMP8) mice with age-related AD were treated with PNS for 8 weeks. The effects of PNS on learning and memory abilities, cerebral oxidative stress status, and hippocampus ultrastructure of mice were observed. Moreover, changes of the PTEN-induced putative kinase 1 (PINK1)-Parkin, which regulates ubiquitin-dependent mitophagy, and the recruit of downstream autophagy receptors were investigated. RESULTS: PNS attenuated cognitive dysfunction in SAMP8 mice in the Morris water maze test. PNS also enhanced glutathione peroxidase and superoxide dismutase activities, and increased glutathione levels by 25.92% and 45.55% while inhibiting 8-hydroxydeoxyguanosine by 27.74% and the malondialdehyde production by 34.02% in the brains of SAMP8 mice. Our observation revealed the promotion of mitophagy, which was accompanied by an increase in microtubule-associated protein 1 light chain 3 (LC3) mRNA and 70.00% increase of LC3-II/I protein ratio in the brain tissues of PNS-treated mice. PNS treatment increased Parkin mRNA and protein expression by 62.80% and 43.80%, while increasing the mRNA transcription and protein expression of mitophagic receptors such as optineurin, and nuclear dot protein 52. CONCLUSION: PNS enhanced the PINK1/Parkin pathway and facilitated mitophagy in the hippocampus, thereby preventing cerebral oxidative stress in SAMP8 mice. This may be a mechanism contributing to the cognition-improvement effect of PNS.

Molecular architectures of iron complexes for oxygen reduction catalysis-Activity enhancement by hydroxide ions coupling.

Developing cost-effective and high-performance electrocatalysts for oxygen reduction reaction (ORR) is critical for clean energy generation. Here, we propose an approach to the synthesis of iron phthalocyanine nanotubes (FePc NTs) as a highly active and selective electrocatalyst for ORR. The performance is significantly superior to FePc in randomly aggregated and molecularly dispersed states, as well as the commercial Pt/C catalyst. When FePc NTs are anchored on graphene, the resulting architecture shifts the ORR potentials above the redox potentials of Fe2+/3+ sites. This does not obey the redox-mediated mechanism operative on conventional FePc with a Fe2+-N moiety serving as the active sites. Pourbaix analysis shows that the redox of Fe2+/3+ sites couples with HO- ions transfer, forming a HO-Fe3+-N moiety serving as the ORR active sites under the turnover condition. The chemisorption of ORR intermediates is appropriately weakened on the HO-Fe3+-N moiety compared to the Fe2+-N state and thus is intrinsically more ORR active.

Regulating ion affinity and dehydration of metal-organic framework sub-nanochannels for high-precision ion separation.

Membrane consisting of ordered sub-nanochannels has been pursued in ion separation technology to achieve applications including desalination, environment management, and energy conversion. However, high-precision ion separation has not yet been achieved owing to the lack of deep understanding of ion transport mechanism in confined environments. Biological ion channels can conduct ions with ultrahigh permeability and selectivity, which is inseparable from the important role of channel size and "ion-channel" interaction. Here, inspired by the biological systems, we report the high-precision separation of monovalent and divalent cations in functionalized metal-organic framework (MOF) membranes (UiO-66-(X)2, X = NH2, SH, OH and OCH3). We find that the functional group (X) and size of the MOF sub-nanochannel synergistically regulate the ion binding affinity and dehydration process, which is the key in enlarging the transport activation energy difference between target and interference ions to improve the separation performance. The K+/Mg2+ selectivity of the UiO-66-(OCH3)2 membrane reaches as high as 1567.8. This work provides a gateway to the understanding of ion transport mechanism and development of high-precision ion separation membranes.