A novel Senescence-Based prognostic model unveils tumor interactions and drug resistance in colorectal cancer.

BACKGROUND: In China, CRC incidence is escalating. The main hurdles are heterogeneity and drug resistance. This research delves into cellular senescence in CRC, aiming to devise a prognostic model and pinpoint mechanisms impacting drug resistance. METHODS: Mendelian randomization (MR) analysis confirmed the association between CRC and cellular aging. The Cancer Genome Atlas (TCGA)-CRC data served as the training set, with GSE38832 and GSE39582 as validation sets. Various bioinformatics methods were employed to construct and validate a risk model. CRC cells with NADPH Oxidase 4 (NOX4) knockout were generated using CRISPR-Cas9 technology. Protein blotting and colony formation assays elucidated the role of NOX4 in CRC cell aging and drug resistance. RESULTS: A prognostic model, derived from dataset analysis, uncovered a link between high-risk groups and cancer progression. Notable differences in the tumor microenvironment were observed between risk groups. Finally, NOX4 was found to be linked with aging and drug resistance in CRC. CONCLUSION: This research presents a novel senescence-based CRC prognosis model. It identifies NOX4's role in CRC drug resistance, suggesting it is a potential treatment target.

Effect of Fe and Zn co-doping on LiCoPO4 cathode materials for High-Voltage Lithium-Ion batteries.

Lithium cobalt phosphate (LiCoPO4) has great potential to be developed as a cathode material for lithium-ion batteries (LIBs) due to its structural stability and higher voltage platform with a high theoretical energy density. However, the relatively low diffusion of lithium ions still needs to be improved. In this work, Fe and Zn co-doped LiCoPO4: LiCo0.9-xFe0.1ZnxPO4/C is utilized to enhance the battery performance of LiCoPO4. The electrochemical properties of LiCo0.85Fe0.1Zn0.05PO4/C demonstrated an initial capacity of 118 mAh/g, with 93.4 % capacity retention at 1C after 100 cycles, and a good capacity of 87 mAh/g remained under a high current density of 10C. In addition, the diffusion rate of Li ions was investigated, proving the improvement of the materials with doping. The impedance results also showed a smaller resistance of the doped materials. Furthermore, operando X-ray diffraction displayed a good reversibility of the structural transformation, corresponding to cycling stability. This work provided studies of both the electrochemical properties and structural transformation of Fe and Zn co-doped LiCoPO4, which showed that 10 % Fe and 5 % Zn co-doping enhanced the electrochemical performance of LiCoPO4 as a cathode material in LIBs.

Production and characterization of novel monoclonal antibodies against pathological human TDP-43 proteins.

The RNA/DNA-binding protein TDP-43 plays a pivotal role in the ubiquitinated inclusions characteristic of TDP-43 proteinopathies, including most cases of frontotemporal lobar degeneration (FTLD-TDP) and Alzheimer disease (AD). To understand the mechanisms of pathological TDP-43 processing and identify potential biomarkers, we generated novel phosphorylation-independent monoclonal antibodies (MAbs) using bacteria-expressed human full-length recombinant TDP-43. Remarkably, we identified a distinctive MAb, No. 9, targeting an epitope in amino acid (aa) region 311-360 of the C-terminus. This antibody showed preferential reactivity for pathological TDP-43 inclusions, with only mild reactivity for normal nuclear TDP-43. MAb No. 9 revealed more pathology in FTLD-TDP type A and type B brains and in AD brains compared to the commercial p409/410 MAb. Using synthetic phosphorylated peptides, we also obtained MAbs targeting the p409/410 epitope. Interestingly, MAb No. 14 was found to reveal additional pathology in AD compared to the commercial p409/410 MAb, specifically, TDP-43-immunopositive deposits with amyloid plaques in AD brains. These unique immunopositivities observed with MAbs No. 9 and No. 14 are likely attributed to their conformation-dependent binding to TDP-43 inclusions. We expect that this novel set of MAbs will prove valuable as tools for future patient-oriented investigations into TDP-43 proteinopathies.

Four Parallel Pathways in T4 Ligase-Catalyzed Repair of Nicked DNA with Diverse Bending Angles.

The structural diversity of biological macromolecules in different environments contributes complexity to enzymological processes vital for cellular functions. Fluorescence resonance energy transfer and electron microscopy are used to investigate the enzymatic reaction of T4 DNA ligase catalyzing the ligation of nicked DNA. The data show that both the ligase-AMP complex and the ligase-AMP-DNA complex can have four conformations. This finding suggests the parallel occurrence of four ligation reaction pathways, each characterized by specific conformations of the ligase-AMP complex that persist in the ligase-AMP-DNA complex. Notably, these complexes have DNA bending angles of ≈0°, 20°, 60°, or 100°. The mechanism of parallel reactions challenges the conventional notion of simple sequential reaction steps occurring among multiple conformations. The results provide insights into the dynamic conformational changes and the versatile attributes of T4 DNA ligase and suggest that the parallel multiple reaction pathways may correspond to diverse T4 DNA ligase functions. This mechanism may potentially have evolved as an adaptive strategy across evolutionary history to navigate complex environments.

Rapid detection of goose megrivirus using TaqMan real-time PCR technology.

The aim of this study was to develop an efficient and accurate platform for the detection of the newly identified goose megrivirus (GoMV). To achieve this goal, we developed a TaqMan real-time PCR technology for the rapid detection and identification of GoMV. Our data showed that the established TaqMan real-time PCR assay had high sensitivity, with the lowest detection limit of 67.3 copies/µL. No positive signal can be observed from other goose origin viruses (including AIV, GPV, GoCV, GHPyV, and GoAstV), with strong specificity. The coefficients of variation of repeated intragroup and intergroup tests were all less than 1.5%, with excellent repeatability. Clinical sample investigation data from domestic Minbei White geese firstly provided evidence that GoMV can be transmitted both horizontally and vertically. In conclusion, since the TaqMan real-time PCR method has high sensitivity, specificity, and reproducibility, it can be a useful candidate tool for GoMV epidemiological investigation.

Deciphering alternative splicing events and their therapeutic implications in colorectal Cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors with complex molecular regulatory mechanisms. Alternative splicing (AS), a fundamental regulatory process of gene expression, plays an important role in the occurrence and development of CRC. This study analyzed AS Percent Spliced In (PSI) values from 49 pairs of CRC and normal samples in the TCGA SpliceSeq database. Using Lasso and SVM, AS features that can differentiate colorectal cancer from normal were screened. Univariate COX regression analysis identified prognosis-related AS events. A risk model was constructed and validated using machine learning, Kaplan-Meier analysis, and Decision Curve Analysis. The regulatory effect of protein arginine methyltransferase 5 (PRMT5) on poly(RC) binding protein 1 (PCBP1) was verified by immunoprecipitation experiments, and the effect of PCBP1 on the AS of Obscurin (OBSCN) was verified by PCR. Five AS events, including HNF4A.59461.AP and HNF4A.59462.AP, were identified, which can distinguish CRC from normal tissue. A machine learning model using 21 key AS events accurately predicted CRC prognosis. High-risk patients had significantly shorter survival times. PRMT5 was found to regulate PCBP1 function and then influence OBSCN AS, which may drive CRC progression. The study concluded that some AS events is significantly different in CRC and normal tissues, and some of these AS events are related to the prognosis of CRC. In addition, PRMT family-driven arginine modifications play an important role in CRC-specific AS events.

Simultaneous detection and differentiation of DuCV-1 and DuCV-2 by high-resolution melting analysis.

Birds infected with duck circovirus (DuCV) can potentially cause immunosuppression by damaging lymphoid tissues, causing great losses in the duck breeding industry. Duck circovirus can be divided into two genotypes (DuCV-1 and DuCV-2), but simultaneous detection and differentiation of DuCV-1 and DuCV-2 by high-resolution melting (HRM) analysis is still lacking. Here, we designed specific primers according to the sequence characteristics of the newly identified ORF3 gene and then established a PCR-HRM method for the simultaneous detection and differentiation of DuCV-1 and DuCV-2 via high-resolution melting analysis. Our data showed that the established PCR-HRM assay had the advantages of specificity, with the lowest detection limits of 61.9 copies/µL (for DuCV-1) and 60.6 copies/µL (for DuCV-2). The melting curve of the PCR-HRM results indicated that the amplification product was specific, with no cross-reaction with common waterfowl origin pathogens and a low coefficient of variation less than 1.50% in both intra-batch and inter-batch repetitions, indicating the advantages of repeatability. We found that the percentage of DuCV-2-positive ducks was higher than that of DuCV-1-positive ducks, with 8.62% rate of DuCV-1 and DuCV-2 coinfection. In addition, we found DuCV-2-positive in geese firstly. In conclusion, this study provides a candidate PCR-HRM assay for the detection and accurate differentiation of DuCV-1 and DuCV-2 infection, which will help us for further epidemiological surveillance of DuCVs.

Elucidating the therapeutic mechanism of Hengqing II decoction in Alzheimer's disease using network pharmacology and molecular docking techniques.

PURPOSE: The aim of our research was to investigate the mechanism of the Hengqing II decoction in treating Alzheimer's disease (AD) through network pharmacology and experimental validation methods. METHODS: Firstly, the major chemical compounds of Hengqing II decoction were characterized by ultra-high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-Q-TOF-MS/MS), and the gene sets related to AD treatment by Hengqing II decoction were collected through the database of PubChem, Swiss TargetPrediction, and DisGeNET. Secondly, a multi-level molecular network of "Traditional Chinese medicine (TCM)-compound-target-disease" was constructed and visualized using the STRING platform and Cytoscape 3.9.1 software, and the enrichment analysis based on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway databases was performed to predict the potential active compounds and targets of Hengqing II decoction for treating AD. Finally, molecular docking simulation was applied to investigate the binding interactions between potential active compounds and key targets, and the western blotting technique was employed to examine the expression levels of AKT1, TNF-α, and NOS2 proteins affected by active compounds. RESULTS: Totally 120 compounds in Hengqing II decoction were characterized by UHPLC-Q-TOF-MS/MS. Network pharmacology results showed that potential active compounds in Hengqing II decoction in treating AD included catalpol, gastrodin, and rehmannioside D, etc., and the main target proteins were TNF-α, NOS2, and AKT1. Further functional enrichment analysis revealed that Hengqing II decoction mainly exerted its therapeutic effects on AD by regulating lipid and atherosclerosis signaling pathways, AD signaling pathways, AKT1 signaling pathways, and PTGS2 signaling pathways. CONCLUSION: Hengqing II decoction exerted therapeutic effects on AD through multi-component, multi-target, and multi-pathway regulation, and its action mechanisms were related to oxidative stress, neuroinflammation, autophagy, and other pathways. Our research laid the data foundation for further exploration of action mechanism and clarification of clinical positioning and provided new ideas and clues in TCM formula research.

Properties of Ophioglossum vulgatum L. extract Pickering emulsion stabilized by carbon dots and its potential use in cosmetics.

Ophioglossum vulgatum L. (O. vulgatum) is a species of fern used in traditional Chinese medicine, however, its application in cosmetics has not yet been studied. This study obtained O. vulgatum extract using 70% ethanol solution and evaporation. Fourier Transform Infrared Spectrometer (FTIR) analysis identified many active components in O. vulgatum extract, such as polyols, amino acids, and flavonoids. A Pickering emulsion of O. vulgatum extract was also prepared, stabilized by a type of carbon dot based on l-arginine (CDs-Arg). The prepared Pickering emulsion was characterized by metallographic microscope and contact angle measurement. The results demonstrated that it was a pH-responsive O/W emulsion. Facial cleanser was then created using the prepared Pickering emulsion as the main component. When squeezed onto hands, the cleanser produced many delicate foams and caused no skin irritation. The prepared Pickering emulsion facilitated the use of O. vulgatum in facial cleanser.

Text2Face: Text-based Face Generation with Geometry and Appearance Control.

Recent years have witnessed the emergence of various techniques proposed for text-based human face generation and manipulation. Such methods, targeting bridging the semantic gap between text and visual contents, provide users with a deft hand to turn ideas into visuals via text interface and enable more diversified multimedia applications. However, due to the flexibility of linguistic expressiveness, the mapping from sentences to desired facial images is clearly many-to-many, causing ambiguities during text-to-face generation. To alleviate these ambiguities, we introduce a local-to-global framework with two graph neural networks (one for geometry and the other for appearance) embedded to model the inter-dependency among facial parts. This is based upon our key observation that the geometry and appearance attributes among different facial components are not mutually independent, i.e., the combinations of part-level facial features are not arbitrary and thus do not conform to a uniform distribution. By learning from the dataset distribution and enabling recommendations given partial descriptions of human faces, these networks are highly suitable for our text-to-face task. Our method is capable of generating high-quality attribute-conditioned facial images from text. Extensive experiments have confirmed the superiority and usability of our method over the prior art.

Ultrasound Nanobubble Coupling Agent for Effective Noninvasive Deep-Layer Drug Delivery.

Conventional coupling agents (such as polyvinylpyrrolidone, methylcellulose, and polyurethane) are unable to efficiently transport drugs through the skin's dual barriers (the epidermal cuticle barrier and the basement membrane barrier between the epidermis and dermis) when exposed to ultrasound, hindering deep and noninvasive transdermal drug delivery. In this study, nanobubbles prepared by the double emulsification method and aminated hyaluronic acid are crosslinked with aldehyde-based hyaluronic acid by dynamic covalent bonding through the Schiff base reaction to produce an innovative ultrasound-nanobubble coupling agent. By amplifying the cavitation effect of ultrasound, drugs can be efficiently transferred through the double barrier of the skin and delivered to deep layers. In an in vitro model of isolated porcine skin, this agent achieves an effective penetration depth of 728 µm with the parameters of ultrasound set at 2 W, 650 kHz, and 50% duty cycle for 20 min. Consequently, drugs can be efficiently delivered to deeper layers noninvasively. In summary, this ultrasound nanobubble coupling agent efficiently achieves deep-layer drug delivery by amplifying the ultrasonic cavitation effect and penetrating the double barriers, heralding a new era for noninvasive drug delivery platforms and disease treatment.

How Modulator Binding at the Amyloidß-γ-Secretase Interface Enhances Substrate Binding and Attenuates Membrane Distortion.

Inhibition of γ-secretase, an intramembrane protease, to reduce secretion of Amyloid-ß (Aß) peptides has been considered for treating Alzheimer's disease. However, γ-secretase inhibitors suffer from severe side effects. As an alternative, γ-secretase modulators (GSM) reduce the generation of toxic peptides by enhancing the cleavage processivity without diminishing the enzyme activity. Starting from a known γ-secretase structure without substrate but in complex with an E2012 GSM, we generated a structural model that included a bound Aß43 peptide and studied interactions among enzyme, substrate, GSM, and lipids. Our result suggests that E2012 binding at the enzyme-substrate-membrane interface attenuates the membrane distortion by shielding the substrate-membrane interaction. The model predicts that the E2012 modulation is charge-dependent and explains the preserved hydrogen acceptor and the aromatic ring observed in many imidazole-based GSM. Predicted effects of γ-secretase mutations on E2012 modulation were confirmed experimentally. We anticipate that the study will facilitate the future development of effective GSMs.

Longitudinal reciprocal association between rheumatoid arthritis and chronic obstructive pulmonary disease and mediation of inflammation.

OBJECTIVES: To elucidate the longitudinal reciprocal association between rheumatoid arthritis (RA) and chronic obstructive pulmonary disease (COPD), and the mediating role of systemic inflammation in the association. METHODS: 403045 participants from UK Biobank were enrolled in this study. A cross-lagged panel model was used to investigate the longitudinal reciprocal association between RA and COPD. Cox-proportional hazard regression and logistic regression models were also conducted to examine the association between baseline RA and COPD during follow-up, and vice versa. Causal mediation analysis was then performed to explore the mediating roles of 160 systemic inflammatory biomarkers in the bidirectional association. RESULTS: At baseline, 4755 (1.2%) and 6989 (1.7%) individuals were diagnosed with RA and COPD, respectively. After adjusting for the covariates, the result of cross-lagged panel model revealed a bidirectional association between RA and COPD (ß = 0.018, P < 0.001 for RA→COPD path; ß = 0.010, P < 0.001 for COPD→RA path). In the non-COPD population, the risk of future COPD was increased in RA patients (Cox: HR = 1.65, 95% CI, 1.50-1.83; logistic: OR = 1.85, 95% CI, 1.66-2.07). In the non-RA population, baseline COPD was associated with a higher risk of RA during follow-up (Cox: HR = 1.67, 95% CI, 1.44-1.92; logistic: OR = 1.70, 95% CI, 1.47-1.97). Five inflammatory factors mediated the RA→COPD path, and C-reactive protein mediated the COPD→RA path (FDR < 0.05). CONCLUSIONS: A significant bidirectional association exists between RA and COPD, and it is partially mediated by systemic inflammation.

HDAC11 mediates the ubiquitin-dependent degradation of p53 and inhibits the anti-leukemia effect of PD0166285.

Cytarabine-resistant acute myeloid leukemia (AML) is a common phenomenon, necessitating the search for new chemotherapeutics. WEE1 participates in cell cycle checkpoint signaling and inhibitors targeting WEE1 (WEE1i) constitute a potential novel strategy for AML treatment. HDAC (histone deacetylase) inhibitors have been shown to enhance the anti-tumor effects of WEE1i but molecular mechanisms of HDAC remain poorly characterized. In this study, the WEE1 inhibitor PD0166285 showed a relatively good anti-leukemia effect. Notably, PD0166285 can arise the expression of HDAC11 which was negatively correlated with survival of AML patients. Moreover, HDAC11 can reduced the anti-tumor effect of PD0166285 through an effect on p53 stability and the changes in phosphorylation levels of MAPK pathways. Overall, the cell cycle inhibitor, PD0166285, is a potential chemotherapeutic drug for AML. These fundings contribute to a functional understanding of HDAC11 in AML.

APP substrate ectodomain defines amyloid-ß peptide length by restraining γ-secretase processivity and facilitating product release.

Sequential proteolysis of the amyloid precursor protein (APP) by γ-secretases generates amyloid-ß (Aß) peptides and defines the proportion of short-to-long Aß peptides, which is tightly connected to Alzheimer's disease (AD) pathogenesis. Here, we study the mechanism that controls substrate processing by γ-secretases and Aß peptide length. We found that polar interactions established by the APPC99 ectodomain (ECD), involving but not limited to its juxtamembrane region, restrain both the extent and degree of γ-secretases processive cleavage by destabilizing enzyme-substrate interactions. We show that increasing hydrophobicity, via mutation or ligand binding, at APPC99 -ECD attenuates substrate-driven product release and rescues the effects of Alzheimer's disease-associated pathogenic γ-secretase and APP variants on Aß length. In addition, our study reveals that APPC99 -ECD facilitates the paradoxical production of longer Aßs caused by some γ-secretase inhibitors, which act as high-affinity competitors of the substrate. These findings assign a pivotal role to the substrate ECD in the sequential proteolysis by γ-secretases and suggest it as a sweet spot for the potential design of APP-targeting compounds selectively promoting its processing by these enzymes.

Development of a two-beveled-fiber polarized fiber-optic Raman probe coupled with a ball lens for in vivo superficial epithelial Raman measurements in endoscopy.

We report on the development of a two-beveled-fiber polarized (TBFP) fiber-optic Raman probe coupled with a ball lens for in vivo superficial epithelial Raman measurements in endoscopy. The two-beveled fibers positioned symmetrically along a ball lens, in synergy with paired parallel-polarized polarizers integrated between the fibers and the ball lens, maximize the Raman signal excitation and collection from the superficial epithelium where gastrointestinal (GI) precancer arises. Monte Carlo (MC) simulations and two-layer tissue phantom experiments show that the probe developed detects ∼90% of the Raman signal from the superficial epithelium. The suitability of the probe developed for rapid (<3 s) superficial epithelial Raman measurements is demonstrated on fresh swine esophagus, stomach, and colon tissues, followed by their differentiation with high accuracies (92.1% for esophagus [sensitivity: 89.3%, specificity: 93.2%], 94.1% for stomach [sensitivity: 86.2%, specificity: 97.2%], and 94.1% for colon [sensitivity: 93.2%, specificity: 94.7%]). The presented results suggest the great potential of the developed probe for enhancing in vivo superficial epithelial Raman measurements in endoscopy.

LC-NeRF: Local Controllable Face Generation in Neural Radiance Field.

3D face generation has achieved high visual quality and 3D consistency thanks to the development of neural radiance fields (NeRF). However, these methods model the whole face as a neural radiance field, which limits the controllability of the local regions. In other words, previous methods struggle to independently control local regions, such as the mouth, nose, and hair. To improve local controllability in NeRF-based face generation, we propose LC-NeRF, which is composed of a Local Region Generators Module (LRGM) and a Spatial-Aware Fusion Module (SAFM), allowing for geometry and texture control of local facial regions. The LRGM models different facial regions as independent neural radiance fields and the SAFM is responsible for merging multiple independent neural radiance fields into a complete representation. Finally, LC-NeRF enables the modification of the latent code associated with each individual generator, thereby allowing precise control over the corresponding local region. Qualitative and quantitative evaluations show that our method provides better local controllability than state-of-the-art 3D-aware face generation methods. A perception study reveals that our method outperforms existing state-of-the-art methods in terms of image quality, face consistency, and editing effects. Furthermore, our method exhibits favorable performance in downstream tasks, including real image editing and text-driven facial image editing.

Spatiotemporal Landscape for the Sophisticated Transformation of Protein Assemblies Defined by Multiple Supramolecular Interactions.

Precise protein assemblies not only constitute a series of living machineries but also provide an advanced class of biomaterials. Previously, we developed the inducing ligand strategy to generate various fixed protein assemblies, without the formation of noncovalent interactions between proteins. Here, we demonstrated that controlling the symmetry and number of supramolecular interactions introduced on protein surfaces could direct the formation of unspecific interactions between proteins and induce various nanoscale assemblies, including coiling nanowires, nanotubes, and nanosheets, without manipulation of the protein's native surfaces. More importantly, these nanoscale assemblies could spontaneously evolve into more ordered architectures, crystals. We further showed that the transformation from the introduced supramolecular interactions to the interactions formed between proteins was crucial for pathway selection and outcomes of evolution. These findings reveal a transformation mechanism of protein self-assembly that has not been exploited before and may provide an approach to generate complex and transformable biomacromolecular self-assemblies.

Enzyme-substrate hybrid ß-sheet controls geometry and water access to the γ-secretase active site.

γ-Secretase is an aspartyl intramembrane protease that cleaves the amyloid precursor protein (APP) involved in Alzheimer's disease pathology and other transmembrane proteins. Substrate-bound structures reveal a stable hybrid ß-sheet immediately following the substrate scissile bond consisting of ß1 and ß2 from the enzyme and ß3 from the substrate. Molecular dynamics simulations and enhanced sampling simulations demonstrate that the hybrid ß-sheet stability is strongly correlated with the formation of a stable cleavage-compatible active geometry and it also controls water access to the active site. The hybrid ß-sheet is only stable for substrates with 3 or more C-terminal residues beyond the scissile bond. The simulation model allowed us to predict the effect of Pro and Phe mutations that weaken the formation of the hybrid ß-sheet which were confirmed by experimental testing. Our study provides a direct explanation why γ-secretase preferentially cleaves APP in steps of 3 residues and how the hybrid ß-sheet facilitates γ-secretase proteolysis.

What Makes a Good Protein-Protein Interaction Stabilizer: Analysis and Application of the Dual-Binding Mechanism.

Protein-protein interactions (PPIs) are essential for biological processes including immune reactions and diseases. Inhibition of PPIs by drug-like compounds is a common basis for therapeutic approaches. In many cases the flat interface of PP complexes prevents discovery of specific compound binding to cavities on one partner and PPI inhibition. However, frequently new pockets are formed at the PP interface that allow accommodation of stabilizers which is often as desirable as inhibition but a much less explored alternative strategy. Herein, we employ molecular dynamics simulations and pocket detection to investigate 18 known stabilizers and associated PP complexes. For most cases, we find that a dual-binding mechanism, a similar stabilizer interaction strength with each protein partner, is an important prerequisite for effective stabilization. A few stabilizers follow an allosteric mechanism by stabilizing the protein bound structure and/or increase the PPI indirectly. On 226 protein-protein complexes, we find in >75% of the cases interface cavities suitable for binding of drug-like compounds. We propose a computational compound identification workflow that exploits new PP interface cavities and optimizes the dual-binding mechanism and apply it to 5 PP complexes. Our study demonstrates a great potential for in silico PPI stabilizers discovery with a wide range of therapeutic applications.