The resistance to anoikis, mediated by Spp1, and the evasion of immune surveillance facilitate the invasion and metastasis of hepatocellular carcinoma.

Anoikis-Related Genes (ARGs) lead to the organism manifesting resistance to anoikis and are associated with unfavorable prognostic outcomes across various malignancies.Therefore, it is crucial to identify the pivotal target genes related to anoikis in HCC .We found that ARGs were significantly correlated with prognosis and immune responses in HCC. The core gene, SPP1, notably promoted anoikis resistance and metastasis in HCC through both in vivo and in vitro studies. The PI3K-Akt-mTOR pathway played a critical role in anoikis suppression within HCC contexts. Our research unveiled SPP1's role in enhancing PKCα phosphorylation, which in turn activated the PI3K-Akt-mTOR cascade. Additionally, SPP1 was identified as a key regulator of MDSCs and Tregs migration, directly affecting their immunosuppressive capabilities.These findings indicate that in HCC, SPP1 promoted anoikis resistance and facilitated immune evasion by modulating MDSCs and Tregs.

The emerging role of fibrin(ogen) in cardiovascular disease.

OBJECTIVE: A coagulation factor called fibrinogen is produced by the liver and is proteolyzed by thrombin to become fibrin. The latest studies have revealed that fibrin(ogen) palys an essential role in the regulation of cardiovascular disease. Understanding the relationship and mechanism between fibrin(ogen) and cardiovascular disease is of great significance for maintaining overall health. The objective of this review is to discuss the specific involvement and underlying mechanisms of fibrin(ogen) in cardiovascular disease. METHODS: A review was conducted using the PubMed database to identify and analyze the emerging role of fibrinogen in cardiovascular disease. RESULTS: The literature review revealed that fibrin(ogen) plays a pivotal role in maintaining cardiovascular disease and are involved in the pathogenesis of cardiovascular disease. Fibrin(ogen) mainly influence various pathophysiological processes, such as participating in thrombosis formation, stimulating the inflammatory response, and other molecular pathways. CONCLUSION: This review focuses on the involvement of fibrin(ogen) in cardiovascular disease, with a particular emphasis on the main functions and underlying mechanisms by which fibrin(ogen) influence the pathogenesis and progression of these conditions. This review underscores the potential of fibrin(ogen) as therapeutic targets in managing cardiovascular disease.

Nanofluidic Device for Detection of Lysine Methylpeptides and Sensing of Lysine Methylation.

Protein methylation is the smallest possible yet vitally important post-translational modification (PTM). This small and chemically inert addition in proteins makes the analysis of methylation more challenging, thus calling for an efficient tool for the sake of recognition and detection. Herein, we present a nanofluidic electric sensing device based on a functionalized nanochannel that was constructed by introducing monotriazole-containing p-sulfonatocalix[4]arene (TSC) into a single asymmetric polymeric nanochannel via click chemistry. The device can selectively detect lysine methylpeptides with subpicomole sensitivity, distinguish between different lysine methylation states, and monitor the lysine methylation process by methyltransferase at the peptide level in real time. The introduced TSC molecule, with its confined asymmetric configuration, presents the remarkable ability to selectively bind to lysine methylpeptides, which, coupled with the release of the complexed Cu ions, allows the device to transform the molecular-level recognition to the discernible change in ionic current of the nanofluidic electric device, thus enabling detection. This work could serve as a stepping stone to the development of a new methyltransferase assay and the chemical that specifically targets lysine methylation in PTM proteomics.

Recent Progress in Iron-Based Microwave Absorbing Composites: A Review and Prospective.

With the rapid development of communication technology in civil and military fields, the problem of electromagnetic radiation pollution caused by the electromagnetic wave becomes particularly prominent and brings great harm. It is urgent to explore efficient electromagnetic wave absorption materials to solve the problem of electromagnetic radiation pollution. Therefore, various absorbing materials have developed rapidly. Among them, iron (Fe) magnetic absorbent particle material with superior magnetic properties, high Snoek's cut-off frequency, saturation magnetization and Curie temperature, which shows excellent electromagnetic wave loss ability, are kinds of promising absorbing material. However, ferromagnetic particles have the disadvantages of poor impedance matching, easy oxidation, high density, and strong skin effect. In general, the two strategies of morphological structure design and multi-component material composite are utilized to improve the microwave absorption performance of Fe-based magnetic absorbent. Therefore, Fe-based microwave absorbing materials have been widely studied in microwave absorption. In this review, through the summary of the reports on Fe-based electromagnetic absorbing materials in recent years, the research progress of Fe-based absorbing materials is reviewed, and the preparation methods, absorbing properties and absorbing mechanisms of iron-based absorbing materials are discussed in detail from the aspects of different morphologies of Fe and Fe-based composite absorbers. Meanwhile, the future development direction of Fe-based absorbing materials is also prospected, providing a reference for the research and development of efficient electromagnetic wave absorbing materials with strong absorption performance, frequency bandwidth, light weight and thin thickness.

Improved Stretchable and Sensitive Fe Nanowire-Based Strain Sensor by Optimizing Areal Density of Nanowire Network.

Flexible strain sensors, when considering high sensitivity and a large strain range, have become a key requirement for current robotic applications. However, it is still a thorny issue to take both factors into consideration at the same time. Here, we report a sandwich-structured strain sensor based on Fe nanowires (Fe NWs) that has a high GF (37-53) while taking into account a large strain range (15-57.5%), low hysteresis (2.45%), stability, and low cost with an areal density of Fe NWs of 4.4 mg/cm2. Additionally, the relationship between the contact point of the conductive network, the output resistance, and the areal density of the sensing unit is analyzed. Microscopically, the contact points of the conductive network directly affect the sensor output resistance distribution, thereby affecting the gauge factor (GF) of the sensor. Macroscopically, the areal density and the output resistivity of the strain sensor have the opposite percolation theory, which affects its linearity performance. At the same time, there is a positive correlation between the areal density and the contact point: when the stretching amount is constant, it theoretically shows that the areal density affects the GF. When the areal density reaches this percolation threshold range, the sensing performance is the best. This will lay the foundation for rapid applications in wearable robots.

Discerning Tyrosine Phosphorylation from Multiple Phosphorylations Using a Nanofluidic Logic Platform.

Discerning tyrosine phosphorylation (pTyr) catalyzed by Tyr kinase is central to the revelation of oncogenic mechanisms and the development of targeted anticancer drugs. Despite some techniques, this goal remains challenging, especially when faced with the interference of multiple phosphorylation events, including serine (pSer) and threonine phosphorylation (pThr). We describe here a functional polymer-modified artificial ion nanochannel, which enables the sensitive and selective recognition of phosphotyrosine (pY) peptide by the distinct ionic current change. Such a recognition effect allows for the nanochannel to work in a complex protein digest condition. Further, the implementation of nanofluidic logic functions with the addition of Ca2+ dramatically improves the selectivity of the nanochannel to pY peptide and thus can discern pTyr by the Tyr kinase from pSer by the Ser/Thr kinase through simultaneously monitoring multisite phosphorylation at the same or different peptide substrates in one-pot. This logic sensing platform displays the potential in differentiating Tyr kinase and Ser/Thr kinase and assessing multi-kinase activities in multi-targeted drug design.

What Is Hidden Behind Schiff Base Hydrolysis? Dynamic Covalent Chemistry for the Precise Capture of Sialylated Glycans.

The aberrant expression of sialylated glycans (SGs) is closely associated with the occurrence, progression, and metastasis of various cancers, and sialylated glycoproteins have been widely used as clinical biomarkers for cancers. However, the identification and comprehensive analysis of SGs are exceptionally complex, which urgently need an innovative and effective method of capturing SGs from biosamples prior to MS analysis. Here, we report that a novel dynamic covalent chemistry strategy based on Schiff base hydrolysis can be applied to the precise capture of SGs. The prepared glucopyranoside-Schiff base-modified silica gel displays extraordinary enrichment selectivity (even at a ratio of 1:5000 with interference), high adsorption capacity (120 mg·g-1), and satisfying enrichment recovery (95.5%) toward sialylated glycopeptides, contributing to a highly specific, efficient, mild, and reversible SG capturing approach that can remarkably promote the development of glycoproteomics and sialic acid sensing devices and can be considerably promising in cancer biomarker discovery. Meanwhile, the facile hydrolysis characteristic of our Schiff base material completely subverts conventional knowledge of enrichment materials, the chemical stability of which is usually regarded as a prerequisite. Importantly, we find an exciting story hidden behind the Schiff base hydrolysis reaction, which demonstrates the unique advantage of dynamic covalent chemistry in glycoproteomics and biomolecule sensing.

Functional Nanochannels for Sensing Tyrosine Phosphorylation.

Tyrosine phosphorylation (pTyr), much of which occurred on localized multiple sites, initiates cellular signaling, governs cellular functions, and its dysregulation is implicated in many diseases, especially cancers. pTyr-specific sensing is of great significance for understanding disease states and developing targeted anticancer drugs, however, it is very challenging due to the slight difference from serine (pSer) or threonine phosphorylation (pThr). Here we present polyethylenimine-g-phenylguanidine (PEI-PG)-modified nanochannels that can address the challenge. Rich guanidinium groups enabled PEI-PG to form multiple interactions with phosphorylated residues, especially pTyr residue, which triggered the conformational change of PEI-PG. By taking advantage of the "OFF-ON" change of the ion flux arising from the conformational shrinkage of the grafted PEI-PG, the nanochannels could distinguish phosphorylated peptide (PP) from nonmodified peptide, recognize PPs with pSer, pThr, or pTyr residue and PPs with different numbers of identical residues, and importantly could sense pTyr peptides in a biosample. Benefiting from the strong interaction between the guanidinium group and the pTyr side-chain, the specific sensing of pTyr peptide was achieved by performing a simple logic operation based on PEI-PG-modified nanochannels when Ca2+ was introduced as an interferent. The excellent pTyr sensing capacity makes the nanochannels available for real-time monitoring of the pTyr process by c-Abl kinase on a peptide substrate, even under complicated conditions, and the proof-of-concept study of monitoring the kinase activity demonstrates its potential in kinase inhibitor screening.

Highly Efficient Separation of Methylated Peptides Utilizing Selective Complexation between Lysine and 18-Crown-6.

Protein methylation is one of the most common and important post-translational modifications, and it plays vital roles in epigenetic regulation, signal transduction, and chromatin metabolism. However, due to the diversity of methylation forms, slight difference between methylated sites and nonmodified ones, and ultralow abundance, it is extraordinarily challenging to capture and separate methylated peptides from biological samples. Here, we introduce a simple and highly efficient method to separate methylated and nonmethylated peptides using 18-crown-6 as a mobile phase additive in high-performance liquid chromatography. Selective complexation between lysine and 18-crown-6 remarkably increases the retention of the peptides on a C18 stationary phase, leading to an excellent baseline separation between the lysine methylated and nonmethylated peptides. A possible binding mechanism is verified by nuclear magnetic resonance titration, biolayer interferometry technology, and quantum chemistry calculation. Through establishment of a simple enrichment methodology, a good selectivity is achieved and four methylated peptides with greatly improved signal-to-noise (S/N) ratios are successfully separated from a complex peptide sample containing 10-fold bovine serum albumin tryptic digests. By selecting rLys N as an enzyme to digest histone, methylation information in the histone could be well identified based on our enrichment method. This study will open an avenue and provide a novel insight for selective enrichment of lysine methylated peptides in post-translational modification proteomics.

High-Efficiency Phosphopeptide and Glycopeptide Simultaneous Enrichment by Hydrogen Bond-based Bifunctional Smart Polymer.

Aberrant protein phosphorylation and glycosylation are closely associated with a number of diseases. In particular, an interplay between phosphorylation and glycosylation regulates the hyperphosphorylation of protein tau, which is regarded as one of the pathologic features of Alzheimer's disease (AD). However, simultaneous characterization of these two types of post-translational modifications (PTMs) in the complex biological samples is challenging. TiO2 and the immobilized ion affinity chromatography (IMAC)-based enrichment method suffers from low selectivity and/or low recovery of phosphopeptides and glycopeptides because of the inherent limitations in intermolecular interactions. Here, we introduce a hydrogen bond-based poly[(N-isopropylacrylamide-co-4-(3-acryloylthioureido)benzoic acid0.2] (referred to as PNI-co-ATBA0.2) as a bifunctional enrichment platform to solve this bottleneck problem. Benefited from multiple hydrogen bonding interactions of ATBA with N-acetylneuraminic acid (Neu5Ac) located at the terminals of sialylated glycans and from favorable conformational transition of the copolymer chains, the smart copolymer has high adsorption capacity (370 mg·g-1) and high recovery (ranging from 74.1% ± 7.0% to 106% ± 5.0% (n = 3)) of sialylated glycopeptides. The smart copolymer also has high selectivity (79%) for simultaneous enrichment of glycopeptides and phosphopeptides from 50 µg HeLa cell lysates, yielding 721 unique phosphorylation sites from 631 phosphopeptides and 125 unique glycosylation sites from 120 glycopeptides. This study will open a new avenue and provide a novel insight for the design of enrichment materials used in PTM-proteomics.

Chiral effect at protein/graphene interface: a bioinspired perspective to understand amyloid formation.

Protein misfolding to form amyloid aggregates is the main cause of neurodegenerative diseases. While it has been widely acknowledged that amyloid formation in vivo is highly associated with molecular surfaces, particularly biological membranes, how their intrinsic features, for example, chirality, influence this process still remains unclear. Here we use cysteine enantiomer modified graphene oxide (GO) as a model to show that surface chirality strongly influences this process. We report that R-cysteine modification suppresses the adsorption, nucleation, and fiber elongation processes of Aß(1-40) and thus largely inhibits amyloid fibril formation on the surface, while S-modification promotes these processes. And surface chirality also greatly influences the conformational transition of Aß(1-40) from α-helix to ß-sheet. More interestingly, we find that this effect is highly related to the distance between chiral moieties and GO surface, and inserting a spacer group of about 1-2 nm between them prevents the adsorption of Aß(1-40) oligomers, which eliminates the chiral effect. Detailed study stresses the crucial roles of GO surface. It brings novel insights for better understanding the amyloidosis process on surface from a biomimetic perspective.

Highly Crystalized MAPbX3 Perovskite Triangular Nanowire Arrays for Optoelectronic Applications.

Here, a facile fabrication approach for the high-quality 1D perovskite triangular nanowire (TNW) array synthesis through space-confined effect is reported. A soft stamp containing 1D triangular linear array pattern is used to confine the MAPbX3 solution and to guide the growth of the nanowires along the prescribed direction with good crystallinity. The further constructed photodetectors based on the obtained MAPbI3 TNWs exhibit superior photoresponse properties with a responsivity of (125.2 ± 2.5) A W-1 and detectivity of (2.8 ± 0.8) × 1013 Jones at the wavelength of 650 nm. This excellent performance is attributed to the highly crystalline TNW with optical anisotropy and a small asymptotic height, which reduces the probability of the photon reflection and promotes the carrier transport. More interestingly, the increased surface area of the triangular device can present superior flexibility after a couple of thousands of bending cycles. Furthermore, by fabricating 7 × 7 photodetector arrays, the potential image sensor application is demonstrated. The perovskite nanowire fabrication approach is scalable and compatible with current semiconductor manufacturing, which indicates their great potential in broad applications.

Tunable Periodic Nanopillar Array for MAPbI3 Perovskite Photodetectors with Improved Light Absorption.

In the field of optoelectronic applications, the vigorous development of organic-inorganic hybrid perovskite materials, such as methylammonium lead triiodide (MAPbI3), has spurred continuous research on methods to enhance the photodetection performance. Periodic nanoarrays can effectively improve the light absorption of perovskite thin films. However, there are still challenges in fabricating tunable periodic patterned and large-area perovskite nanoarrays. In this study, we present a cost-effective and facile approach utilizing nanosphere lithography and dry etching techniques to create a large-area Si nanopillar array, which is employed for patterning MAPbI3 thin films. The scanning electron microscopy (SEM) and X-ray diffraction (XRD) results reveal that the introduction of nanopillar structures did not have a significant adverse effect on the crystallinity of the MAPbI3 thin film. Light absorption tests and optical simulations indicate that the nanopillar array enhances the light intensity within the perovskite films, leading to photodetectors with a responsivity of 11.2 A/W and a detectivity of 7.3 × 1010 Jones at 450 nm in wavelength. Compared with photodetectors without nanostructures, these photodetectors exhibit better visible light absorption. Finally, we demonstrate the application of these photodetector arrays in a prototype image sensor.

m6A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation.

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction (MI) can lead to heart failure. RNA N6-methyladenosine (m6A) methylation has been shown to play a pivotal role in the occurrence and development of many illnesses. In investigating the biological function of the m6A reader YTHDF1 in cardiac fibrosis, adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts, and MI surgery in vivo and transforming growth factor-ß (TGF-ß)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models. Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis, whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development. Mechanistically, zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter. YTHDF1 augmented AXL translation and activated the TGF-ß-Smad2/3 signaling pathway, thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis. Consistently, our data indicated that YTHDF1 was involved in activation, proliferation, and migration to participate in cardiac fibrosis in vitro. Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.

Precise Structural Analysis of Neutral Glycans Using Aerolysin Mutant T240R Nanopore.

Glycans play vital roles in nearly all life processes of multicellular organisms, and understanding these activities is inseparable from elucidating the biological significance of glycans. However, glycan research has lagged behind that of DNA and protein due to the challenges posed by structural heterogeneity and isomerism (i.e., structures with equal molecular weights) the lack of high-efficiency structural analysis techniques. Nanopore technology has emerged as a sensitive single-molecule biosensor, shining a light on glycan analysis. However, a significant number of glycans are small and uncharged, making it challenging to elicit identifiable nanopore signals. Here we introduce a R-binaphthyl tag into glycans, which enhances the cation-π interaction between the derivatized glycan molecules and the nanopore interface, enabling the detection of neutral glycans with an aerolysin nanopore. This approach allows for the distinction of di-, tri-, and tetrasaccharides with monosaccharide resolution and has the potential for group discrimination, the monitoring of enzymatic transglycosylation reactions. Notably, the aerolysin mutant T240R achieves unambiguous identification of six disaccharide isomers, trisaccharide and tetrasaccharide linkage isomers. Molecular docking simulations reveal that multiple noncovalent interactions occur between residues R282, K238, and R240 and the glycans and R-binaphthyl tag, significantly slowing down their translocation across the nanopore. Importantly, we provide a demonstration of the kinetic translocation process of neutral glycan isomers, establishing a solid theoretical foundation for glycan nanopore analysis. The development of our technology could promote the analysis of glycan structural isomers and has the potential for nanopore-based glycan structural determination and sequencing.

Oxidative Stress Mediated by N6-Methyladenosine Methylation Contributes to High-Fat Diet Induced Male Reproductive Dysfunction.

OBJECTIVE: To determine the mechanism of oxidative stress mediated by N6-methyladenosine (m6A) methylation contributing to high fat diet-induced reproductive dysfunction. RESULTS: In vivo, compared with those in the Control group, the sperm count and sperm motility decrease significantly; the testosterone, luteinizing hormone levels, hyaluronidase, acrosomal enzyme levels, and total antioxidant capacity decrease significantly; malondialdehyde increases significantly in the DIO and DIO-R groups. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 1 (SOD1), and NAD(P)H quinone dehydrogenase 1 (NQO1) decreases significantly in the DIO and DIO-R groups; m6A levels in testis tissue in the DIO and DIO-R groups increase; the enrichment of m6A-modified Nrf2 mRNA in testis in the DIO group and DIO-R group increases significantly. Also the m6A regulatory proteins increase significantly in the DIO group and DIO-R group. In vitro, compared to palmitic acid treated cells, the reactive oxygen species (ROS) level significantly decreases in STM2457, S-Adenosylhomocysteine treated cells and YTHDC2, YTHDF2 gene silence cells; however, Nrf2 expression increases in all treated cells. In addition, m6A expression decreases. CONCLUSIONS: Oxidative stress mediates by methylation of m6A may contribute to high fat diet-induced male reproductive dysfunction.

Genome-wide identification, characterization, evolution and expression analysis of the DIR gene family in potato (Solanum tuberosum).

The dirigent (DIR) gene is a key player in environmental stress response and has been identified in many multidimensional tube plant species. However, there are few studies on the StDIR gene in potato. In this study, we used genome-wide identification to identify 31 StDIR genes in potato. Among the 12 potato chromosomes, the StDIR gene was distributed on 11 chromosomes, among which the third chromosome did not have a family member, while the tenth chromosome had the most members with 11 members. 22 of the 31 StDIRs had a classical DIR gene structure, with one exon and no intron. The conserved DIR domain accounts for most of the proteins in the 27 StDIRs. The structure of the StDIR gene was analyzed and ten different motifs were detected. The StDIR gene was divided into three groups according to its phylogenetic relationship, and 22 duplicate genes were identified. In addition, four kinds of cis-acting elements were detected in all 31 StDIR promoter regions, most of which were associated with biotic and abiotic stress. The findings demonstrated that the StDIR gene exhibited specific responses to cold stress, salt stress, ABA, and drought stress. This study provides new candidate genes for improving potato's resistance to stress.

Survival analysis and development of a prognostic nomogram for patients with hepatitis B virus-associated hepatocellular carcinoma.

Background and aims: Hepatitis B virus (HBV) is a common cause of hepatocellular carcinoma (HCC) in China, and this study aimed to identify high-risk factors for overall survival and develop a nomogram prediction model. Methods: In the present retrospective cohort study, patients with HBV-associated HCC diagnosed from January 2009 to December 2018 were enrolled. Their clinical characteristics and time-to-event information were retrieved from electronic medical records. The zero time was the date of HCC diagnosis, and the endpoint was death or liver transplantation. Multivariable COX proportional hazard regression was used to screen independent risk factors for overall survival; then a nomogram model was developed to predict the survival probability of HCC patients. Results: A total of 1723 patients were enrolled, with 82.7 % male and a median age of 54.0 years. During a median follow-up time of 41.3 months, 672 cases (39.0 %) died. Age ≥60 years (HR = 1.209), Male (HR = 1.293), ALB <35 g/L (HR = 1.491), AST ≥80 U/L (HR = 1.818); AFP 20-400 ng/mL (HR = 2.284), AFP ≥400 ng/mL (HR = 2.746); LSM 9-22 kPa (HR = 2.266), LSM ≥22 kPa (HR = 4.326); BCLC stage B/C (HR = 4.079) and BCLC stage D (HR = 16.830) were the independent high-risk factors associated with HCC survival. A prognostic nomogram with a consistency index of 0.842 (95 % CI: 0.827-0.858) was developed. The calibration curve for long-term survival rate fitted well. Conclusions: This study identified independent risk factors affecting the survival of patients with HBV-associated HCC and constructed a predictive nomogram model, which can individually predict the overall survival and has good clinical application value.