Functional Similarities Research Articles

From keywords to key embeddings – contrasting French and Swedish web registers using multilingual deep learning

Abstract The pervasiveness of the internet has given web language use a central role in society. However, the lack of multilingual corpora and scalable methods has led to the focus on English in web language research. To address this gap, the present paper sets itself in the register research tradition and explores French and Swedish web registers from a cross-linguistic angle. Methodologically we combine keyword analysis with multilingual deep learning, suggesting an approach that enables computational comparisons across languages. Specifically, we extract keywords for French and Swedish web registers, then associate the keywords with fastText word embeddings, and finally, cluster these key embeddings. The findings indicate that there are topical and functional clusters, and they are linguistically motivated and multilingual. The same clusters occur within the same registers in both languages pointing to shared topical and functional similarities – the registers are strikingly similar. The dissimilarities, in contrast, indicate that certain registers like Narrative blogs are to some extent different in French and Swedish. Moreover, grammatical specificities such as the location of adjectives explain some dissimilarities.

The resultative construction with “verbs of cooking” and “verbs of colouring” in English and Spanish: a contrastive lexical-constructional study

Despite the extensive interest in cross-linguistic constructional research over the past few decades, the resultative construction in Spanish has largely been overlooked. Unlike its high productivity in English, in Spanish, this construction is confined to very specific contexts such as the culinary or gastronomic scenario or situations involving chromatic change. The present study is contrastive in two senses: on the one hand, it provides a descriptive analysis of the formal and functional differences and similarities of this construction in both languages, and on the other hand, it adopts a lexical-constructional approach combining the theoretical and methodological principles of Goldberg’s (1995) and Boas’s (2003) Construction Grammars. Both principles, traditionally opposed in the literature, aim to determine to what extent the observed properties of the construction under study can be predicted from Goldberg’s generalisations at the constructional level, the event-frame evoked by the predicate as advocated by Boas, or any other factor such as contextual background information or pragmatics. The results of this study are based on the analysis of 1,173 corpus examples of English and Spanish resultative expressions with verbs of cooking and colouring drawn from Levin’s (1993) classification. The data reveal distinctive traits of the Spanish resultative construction with no parallel in English: (i) the unacceptability of inanimate instrument subjects and the prepositional form of the resultative phrase in resultatives with verbs of cooking, (ii) the preference for the prepositional realization of the resultative phrase in examples with verbs of colouring, (iii) the collocational restrictions of the predicates pintar (“paint”) and manchar (“stain”) with regards to the semantic nature of the subject or the form of the RP respectively. In addition, this study demonstrates that finergrained analyses of the predicates’ event-frames, as those put forward by Boas (2003), make it possible to arrive at more accurate predictions about the idiosyncratic properties of each language than Goldberg’s (1995) broad-scale generalizations, some of which have been refuted. Furthermore, it demonstrates that contextual background information largely determines the observed syntactic, semantic, and pragmatic features of the resultative construction.

ADMET evaluation in drug discovery: 21. Application and industrial validation of machine learning algorithms for Caco-2 permeability prediction

The Caco-2 cell model has been widely used to assess the intestinal permeability of drug candidates in vitro, owing to its morphological and functional similarity to human enterocytes. While Caco-2 cell assay is considered safe and cost-effective, it is also characterized by being time-consuming. Therefore, computational models that achieve high accuracies in predicting Caco-2 permeability are crucial for enhancing the efficiency of oral drug development. In this study, we conducted an in-depth analysis of the characteristics of an augmented Caco-2 permeability dataset, and evaluated a diverse range of machine learning algorithms in combination with different molecular representations. The results indicated that XGBoost generally provided better predictions than comparable models for the test sets. In addition, we investigated the transferability of machine learning models trained on publicly available data to internal pharmaceutical industry datasets. Our findings, based on the Shanghai Qilu’s in-house dataset, showed that the boosting models retained a degree of predictive efficacy when applied to industry data. Furthermore, Y-randomization test and applicability domain analysis were employed to assess the robustness and generalizability of these models. Matched Molecular Pair Analysis (MMPA) was utilized to extract chemical transformation rules. We believe that the model developed in this study could represent a reliable tool for assessing Caco-2 permeability during early-stage drug discovery and the chemical transformation rules derived here could provide insights for optimizing Caco-2 permeability.Scientific contributionA comprehensive validation of various machine learning algorithms combined with diverse molecular representations on a large dataset for predicting Caco-2 permeability was reported. The transferability of machine learning models trained on publicly available data to internal pharmaceutical industry datasets was also investigated. Matched molecular pair analysis was carried out to provide reasonable suggestions for researchers to improve the Caco-2 permeability of compounds.Graphical

Comparison of cholesterol transport capacity of peptide- and polymer-based lipid Nanodiscs.

Apolipoprotein-based, synthetic high-density lipoprotein (sHDL) nanodiscs have been extensively studied as a potential therapeutic agent for cardiovascular disease due to their ability to promote reverse cholesterol transport. Recently, polymer-based nanodiscs have been made possible with the development of novel polymeric materials such as styrene-maleic anhydride copolymer (SMA). While the polymer-based nanodiscs resemble the discoidal structure of sHDLs, their functional similarity with sHDL has not been investigated. In the present study, we compared the SMA-based and peptide-based sHDL nanodiscs focusing on their cholesterol mobilization effects. Results showed that SMA-based nanoparticles presented similar particle size and in vitro cholesterol efflux effect to those of sHDL nanodiscs. However, SMA nanodiscs induced less cholesterol mobilization in vivo, possibly due to insufficient cholesterol esterification by lecithin:cholesterol acyltransferase.

Roles of the CDCA gene family in breast carcinoma

Cell division cycle-associated (CDCA) genes are dysregulated in carcinomas. Our study aims to identify similarities and differences of the clinical roles of CDCAs in breast cancer (BRCA) and to explore their potential mechanisms. In GEPIA, compared to normal tissues, expressions of CDCAs were higher in BRCA and sub-types. In addition, CDCAs were significantly positively related to stages and predicted worse survival in BRCA. In CancerSEA, expression levels of most CDCAs were strongly positively related to cell cycle, DNA damage, DNA repair, and proliferation. In TIMER, CDCAs were linked with immune infiltration levels of BRCA, including Dendritic cell, B cell and so on, and were positively related to most of the common markers of immune cells, especially CD38 of B cell and IL12RB2 of Th1. In GeneMANIA, there were complex interactions and co-expression relationships between CDCAs and cell division-associated genes. In addition, CDCA1, CDCA3, CDCA5, CDCA6 and CDCA8 had a high proportion of amplification in BRCA, and CDCA1, CDCA2, CDCA5, CDCA7 and CDCA8 had high levels of body DNA methylation. Among 11 transcription factors possibly combining promoters of all CDCAs, FOXP3 and YY1 were significantly higher in BRCA in comparison to normal tissues, and both had a positive relationship with all CDCAs in GEPIA and IHC. In addition, silencing FOXP3 or YY1 decreased levels of CDCAs in MDA-MB-231. In summary, CDCAs have various similarities in clinical functions, functional states, immune infiltration, and mechanisms, and they may become novel potential biomarkers for BRCA.

Similarity in the microbial community structure of tobacco from geographically similar regions

To investigate the structural and functional similarities of microbial communities in burnt-sweetness alcoholized tobacco as a function of distance from the equator and their effects on tobacco quality, we sampled alcoholized tobacco from Chenzhou, Hunan Province, China and from Brazil and Zimbabwe, which are also burnt-sweetness-type tobacco producing regions, and performed high-throughput sequencing of tobacco bacterial and fungal communities along with an analysis of the main chemical constituents of the tobacco to analyze differences in the quality of the tobacco and similarities in the structure of the microbial communities. The total nitrogen, nicotine and starch contents of Chenzhou tobacco were greater than those of Brazilian and Zimbabwean tobacco, and the total sugar and reducing sugar contents of the Brazilian and Zimbabwean tobacco were greater than those of the Chenzhou tobacco (P < 0.05). The alpha diversity indices of the bacterial communities in Chenzhou tobacco were lower than those in the Brazilian and Zimbabwean tobacco, and the alpha diversity indices of the fungal communities in Chenzhou tobacco were greater than those in the Brazilian and Zimbabwean tobacco (P < 0.05). In the ecological networks, bacterial–fungal interactions in the Brazilian and Zimbabwean tobacco were more complex than those in the Chenzhou tobacco, and the microbial ecological networks of the burnt-sweetness-type tobacco from three different regions were dominated by competitive relationships. The microbial community composition of Chenzhou tobacco was similar to that of Brazilian tobacco at the bacterial genus and fungal phylum level, with Sphingomonas being a significantly enriched genus in Brazilian tobacco and a key genus in the Chenzhou network that is able to participate in the degradation of polyphenols and aromatic compounds. Functional microbes related to aromatic compounds and cellulose degradation were significantly more abundant in the Brazilian and Zimbabwean tobacco than in Chenzhou tobacco, and the related degradation of tobacco substances was responsible for the better quality of the Brazilian and Zimbabwean tobacco. In conclusion, there are similarities in the structure, composition and functional flora of microbial communities in tobacco from Chenzhou and Brazil because these regions have similar latitudinal distributions. This study provides theoretical support for selecting cultivation regions for the burnt-sweetness-type alcoholized tobacco and for the alcoholization of tobacco leaves.

LCRAnnotationsDB: a database of low complexity regions functional and structural annotations

Low Complexity Regions (LCRs) are segments of proteins with a low diversity of amino acid composition. These regions play important roles in proteins. However, annotations describing these functions are dispersed across databases and scientific literature. LCRAnnotationsDB aims to consolidate knowledge about LCRs and store relevant annotations in a single place. To unify redundant annotations, we assigned them categories based on similarity in function, protein structure, and biological process. Categories are organized hierarchically by linking them to Gene Ontology terms. The LCRAnnotationsDB database can be accessed at https://lcrannotdb.lcr-lab.org/.

Memristive Ion Dynamics to Enable Biorealistic Computing.

Conventional artificial intelligence (AI) systems are facing bottlenecks due to the fundamental mismatches between AI models, which rely on parallel, in-memory, and dynamic computation, and traditional transistors, which have been designed and optimized for sequential logic operations. This calls for the development of novel computing units beyond transistors. Inspired by the high efficiency and adaptability of biological neural networks, computing systems mimicking the capabilities of biological structures are gaining more attention. Ion-based memristive devices (IMDs), owing to the intrinsic functional similarities to their biological counterparts, hold significant promise for implementing emerging neuromorphic learning and computing algorithms. In this article, we review the fundamental mechanisms of IMDs based on ion drift and diffusion to elucidate the origins of their diverse dynamics. We then examine how these mechanisms operate within different materials to enable IMDs with various types of switching behaviors, leading to a wide range of applications, from emulating biological components to realizing specialized computing requirements. Furthermore, we explore the potential for IMDs to be modified and tuned to achieve customized dynamics, which positions them as one of the most promising hardware candidates for executing bioinspired algorithms with unique specifications. Finally, we identify the challenges currently facing IMDs that hinder their widespread usage and highlight emerging research directions that could significantly benefit from incorporating IMDs.

STRUCTURAL AND FUNCTIONAL PROTOTYPING OF THE EXECUTIVE PART OF THE ANGULAR MANIPULATOR ROBOT

In today's conditions of total digitization and informatization of all spheres of activity, more and more agro-industrial enterprises direct their resources to the development and implementation of modern technical and technological solutions, to modernize their own production capacities, with the prospect of ensuring competitiveness on domestic and foreign markets. In turn, such technological renewal of the agricultural sector of the economy is usually based on the use of high-tech systems of management, monitoring, control, management and automation of production processes, with the use of highly integrated SMART systems and the involvement of artificial intelligence technologies. Taking into account the significant volumes of cargo processing, agricultural enterprises, in particular in warehouses, a promising direction and reserve for ensuring high labor productivity is the use of robotic manipulators, and research is devoted to increasing their functionality and maneuverability, including through the use of intelligent control systems and optimization of the structure of executive mechanisms. relevant and will have practical value. The article substantiates the conditions for ensuring functional and structural similarity and proposes criterion equations of similarity for a large-scale transition from a natural sample of an industrial manipulator to a physical model-prototype. On the basis of the obtained criteria and using the scaling factors, the design parameters of the prototype were determined, a computer 3D model was developed, and based on the analysis of the trajectories, corrections were made to the linear dimensions of the manipulator and the ranges of angular movements of the links, as well as the compliance of the created prototype with the conditions of physical modeling was checked, according to the criteria of similarity. Also, the article presents the process of manufacturing an angular manipulator by using additive technologies of layer-by-layer build-up of parts on a 3D printer.

Reconstructing damaged fNIRS signals with a generative deep learning model

Functional near-infrared spectroscopy (fNIRS) imaging offers a promising avenue for measuring brain function in both healthy and diseased cohorts. However, signal quality in fNIRS data frequently encounters challenges, such as low signal-to-noise ratio or substantial motion artifacts in one or multiple measurement channels, impeding the comprehensive exploitation of the data. Developing a valid method to improve the quality of damaged fNIRS signals is crucial, particularly given the extensive use of wearable fNIRS devices in natural settings where noise issues are even more unavoidable. Here, we proposed a generative deep learning approach to recover damaged fNIRS signals in one or more measurement channels. The model captured spatial and temporal variations in the time series of fNIRS data by integrating multiscale convolutional layers, gated recurrent units (GRUs), and linear regression analyses. We trained the model on a resting-state fNIRS dataset from healthy elderly individuals and evaluated its performance in terms of reconstruction accuracy and functional connectivity matrix similarity. Collectively, the proposed model exhbited an excellent performance for the reconstruction of damaged fNIRS time series. In individual channel-level, the model can accurately reconstruct damaged fNIRS time series (mean correlation = 0.80 ± 0.14) while preserving intervariable relationships (correlation = 0.93). In multiple channel-level, the model maintained robust reconstruction accuracy and consistency in terms of functional connectivity. Our findings underscore the potential of generative deep learning techniques in reconstructing damaged fNIRS signals, providing a novel perspective for the efficient utilization of data in clinical diagnosis and brain research.

Genome-wide analysis and identification of nuclear factor Y gene family in switchgrass (Panicum virgatum L.)

NF-Y is a class of heterotrimeric transcription factor composed of three subunits; NF-YA, NF-YB, and NF-YC. This complex binds to the CCAAT box found in eukaryotic promoters and is involved in the plant development and proliferation at various stages. Although many studies were conducted on NF-Y gene family in various species, but no study has been reported yet in switchgrass (Panicum virgatum L.). In this study, 47 PvNF-Y genes (17 PvNF-YA, 18 PvNF-YB, and 12 PvNF-YC) have been identified and named according to their subfamily. Chromosome location analysis revealed that all 47 PvNF-Y genes are randomly distributed across nine chromosomes. Moreover, multiple sequence alignment showed the DNA-binding domain and NF-YA/NFYB interacting domains flanking with non-conserved domains. In addition, prediction of functional similarities among PvNF-Ys genes phylogenetic tree was constructed corresponding to Arabidopsis. The gene structure, conserved domains and motifs analysis of PvNF-Ys genes demonstrated their specificity and functional conservation. Cis-regulatory elements analysis identified numerous key CREs that are significantly associated with light, hormone, stress and plant development responses. Expression profiling indicated higher expression levels of many PvNF-YA genes during drought and heat stress. Additionally, qRT-PCR analysis showed that some PvNF-Ys genes have high expression level in root. In conclusion, the findings of this study could provide a foundation for further cloning and functional analysis of NF-Y genes in switchgrass.

Unveiling MHC-DAB Polymorphism Within the Western Balkan Salmonid Hotspot: Preliminary Outcomes from Native Trouts of Ohrid Lake and the Drin-Skadar Drainage (Albania).

Due to their involvement in pathogen-mediated immune responses, the hypervariable genes of the Major Histocompatibility Complex (MHC) have become a paradigm for investigating the evolution and maintenance of genetic (adaptive) diversity, contextually providing insight into the viability of wild populations, which is meaningful for conservation. Here, we provide the first preliminary characterization of MHC polymorphism and evolution in trouts from Albania, a known hotspot of Salmonid diversity harboring ecologically and phylogenetically distinct native (threatened) taxa. Overall, 36 trout-including Lake Ohrid-endemic Salmo ohridanus and S. letnica, and both riverine and lacustrine native brown trout (the S. trutta complex) from the Drin-Skadar drainage-were genotyped at the MHC-DAB locus through next-generation amplicon sequencing. We identified 34 alleles (including 30 novel alleles), unveiling remarkable population/taxon MHC-DAB distinctiveness. Despite apparent functional (supertype) similarity, S. letnica and the S. trutta complex showed MHC-typical high sequence/allele diversity and evidence of global/codon-specific positive selection, particularly at antigen-binding sites. Conversely, deep-water-adapted S. ohridanus revealed unexpectedly reduced allelic/supertype diversity and relaxed selection. Evolution by reticulation and signals of trans-species polymorphism emerged from sequence genealogies. Further investigations and increased sampling will provide a deeper understanding of the evolutionary mechanisms yielding the observed pattern of MHC diversity across Albanian trout taxa and populations.

IN SILICO ANALYSIS OF IDENTIFIED MOST FREQUENT MUTATIONS IN EXON 10, CODON 618 OF THE HUMAN RET GENE

Background: The Rearranged during Transfection (RET) gene mutations are known to be responsible for Hirschsprung disease (HSCR), as well as the multiple endocrine neoplasia (MEN) types 2A, 2B and familial medullary thyroid carcinoma (FMTC). Aim: In this study we analyse mutations of codon 618 (Cys618Phe, Cys618Arg, Cys618Ser, Cys618Tyr) in exon 10, in terms of their structural similarities, stability, conservation and interaction with their close interactor GFRA3 protein. Material and Methods: In the present study, multiple bioinformatics software was used, including HGMD and UniProt for the data collection. The structural prediction of different mutations at codon 618 was performed by using PSIPRED for secondary structure prediction and I-TASSER for 3D structure modelling. The mutated proteins stability was determined, using I- Mutant and MuPro, while the evolutionary amino acids conservation was assessed with the ConSurf tool. The wildtype RET and mutant proteins were independently docked with their nearby interactor protein GFRA3.Findings: The analysis indicates that among the examined mutations, the Cys618Phe displayed the greatest structural and functional similarity to the wildtype RET protein. The interaction analysis suggested that the Cys618Phe demonstrated stronger binding with GFRA3 compared to other mutations. Conclusion: This study highlights the impact of codon 618 mutations in exon 10 of the RET gene on protein stability, structure, and interactions with GFRA3. We find mutation Cys618Phe comparatively similar to RET wildtype protein while dissimilar mutation Cys618Tyr. These findings could help a molecular geneticist in analyzing mutations at codon 618 for both research and diagnostic purpose.

Вплив релігійних засад на формування правової ідеології

Abstract. The article clarifies the influence of the religious factor on the formation of the legal ideology of Ukrainian society in modern realities, which often has an ambiguous and contradictory character in the formation of the newest mechanism for the realization of human and citizen rights and freedoms. The approach to the religious factor based on the principle of political theology makes it possible to use the factor of religious organizations and the church in the process of building a nation-state in Ukraine, which is of great importance for the formation of a strong, democratic and legal state, which is capable of protecting national interests and resisting threats to national security. This approach also makes it possible to consider Ukrainian religious organizations and churches as an element of Christian civilization, where there is a place for Catholics, Orthodox and Protestants. This approach creates a platform for cooperation within Western institutions (EU, NATO) of states dominated by different Christian denominations. It has been proven that Christian norms and religious legal awareness are formed in objective conditions and closely interact, and thus influence legal awareness, shape the perception of members of society about their rights and obligations, about the proper legal order. From its side, legal consciousness affects religious norms, determines the practice of their application in the interests of believers, religious communities in the realization of their religious interests by the latter, determining the nature of law enforcement, rule-making activity, the mechanism of legal regulation, etc. That is, Christian norms act as the most important regulators of various social relations, factors in the formation of legal norms, the attitude of individuals to legal institutions and the manifestation of illegal or lawful behavior. It was noted that the influence of religious organizations and churches is changing and transforming into new ideas, legal and political. The structural component of ideology is the religious basis, and this does not apply exclusively to theocratic and clerical states, since religious norms have become the basis of the moral foundations of society. Despite the fact that in the digital age, religious values, although they lose their former meaning as a "sacred image" of the world, and even if they do not have a direct impact on the legal system, they still play an important role in legal life, because the European legal culture was created under the influence Christianity, the Christian view of the world. And modern European legal systems function in a social system that has absorbed Christian religious values. Keywords: law; religion; ideology; legal ideology; religious ideology; religious factor; religious norms; Christian principles; human rights and freedoms; religious organizations; church; legal order; functions of religion; functional similarity of law and religion; state-religious relations.

Versatile roles for neutrophil proteinase 3 in hematopoiesis and inflammation.

Neutrophil proteinase 3 (PR3), cathepsin G, elastase, and neutrophil serine protease 4 constitute the neutrophil serine protease family. These four members share varying sequence homology and functional similarities with each other. However, PR3 stands out as a unique autoantigen, serving as a primary autoantigen in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Numerous studies have documented or reviewed the molecular pathogenesis or diagnostic utility of PR3 in ANCA-associated vasculitis. Nevertheless, the role of PR3 in other areas, particularly within the hematopoietic system, appears to have been overlooked. Indeed, beyond its involvement in vasculitis, PR3 contributes to cell apoptosis, hematopoietic abnormalities, diabetic ketoacidosis, and various other inflammatory diseases. In this study, we aim to summarize the research on the function of neutrophil PR3 in hematopoiesis and to elucidate its potential role in neutrophil aging and inflammatory diseases.

Orthrus: Towards Evolutionary and Functional RNA Foundation Models.

In the face of rapidly accumulating genomic data, our ability to accurately pre-dict key mature RNA properties that underlie transcript function and regulation remains limited. Pre-trained genomic foundation models offer an avenue to adapt learned RNA representations to biological prediction tasks. However, existing genomic foundation models are trained using strategies borrowed from textual or visual domains that do not leverage biological domain knowledge. Here, we intro-duce Orthrus, a Mamba-based mature RNA foundation model pre-trained using a novel self-supervised contrastive learning objective with biological augmentations. Orthrus is trained by maximizing embedding similarity between curated pairs of RNA transcripts, where pairs are formed from splice isoforms of 10 model organ-isms and transcripts from orthologous genes in 400+ mammalian species from the Zoonomia Project. This training objective results in a latent representation that clusters RNA sequences with functional and evolutionary similarities. We find that the generalized mature RNA isoform representations learned by Orthrus significantly outperform existing genomic foundation models on five mRNA prop-erty prediction tasks, and requires only a fraction of fine-tuning data to do so. Finally, we show that Orthrus is capable of capturing divergent biological function of individual transcript isoforms.

Decoding the hidden variabilities in mPFC descending pathways across emotional states.

Effective emotional regulation, crucial for adaptive behavior, is mediated by the medial prefrontal cortex (mPFC) via connections to the basolateral amygdala (BLA) and nucleus accumbens (NAc), traditionally considered functionally similar in modulating reward and aversion responses. However, how the mPFC balances these descending pathways to control behavioral outcomes remains unclear. We found that while overall firing patterns appeared consistent across emotional states, deeper analysis revealed distinct variabilities. Specifically, mPFC→BLA neurons, especially "center-ON" neurons, exhibited heightened activity during anxiety-related behaviors, highlighting their role in anxiety encoding. Conversely, mPFC→NAc neurons were more active during exploratory behaviors, implicating them in processing positive emotional states. Notably, mPFC→NAc neurons showed significant pattern decorrelation during social interactions, suggesting a pivotal role in encoding social preference. Additionally, chronic emotional states affected these pathways differently: positive states enhanced mPFC→NAc activity, while negative states boosted mPFC→BLA activity. These findings challenge the assumed functional similarity and highlight distinct contributions to emotional regulation, suggesting new avenues for therapeutic interventions.

Integrating bioinformatics and experimental validation to Investigate IRF1 as a novel biomarker for nucleus pulposus cells necroptosis in intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is a prevalent spinal disorder and the principal cause of lower back pain (LBP). Diverse forms of programmed cell death (PCD) have been identified as the key phenotypes of the disease and have the potential to serve as new indicators for the diagnosis and prognosis of IDD. However, the mechanism underlying necroptosis in IDD remains unclear. This study aimed to identify novel biomarkers that promote nucleus pulposus cell necroptosis in IDD using bioinformatic analysis and experimental validation. We analyzed multiple datasets of IDD from the Gene Expression Omnibus (GEO) database to identify necroptosis-related IDD differential genes (NRDEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed, followed by logistic least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive (SVM) algorithms to identify key genes. Gene set enrichment analysis (GSEA) and logistic regression analysis were used to ascertain the potential functions of these genes and to identify key genes, respectively. We then constructed mRNA-miRNA, mRNA-TF, mRNA-drug, and functional similarity gene interaction networks for the seven key genes identified. We used IDD clinical samples and necroptotic cell model to validate our findings. Immunohistochemical staining, RT-qPCR, and western blotting results indicated that IRF1 may be a hub necroptosis-related gene. To further elucidate the function of IRF1, we constructed IRF1 knockdown and overexpression models, which revealed that IRF1 promotes necroptosis in rat nucleus pulposus cells, increases mitochondrial ROS levels, and decreases ATP levels. These findings provide new insights into the development of necroptosis in IDD and, for the first time, validate the role of IRF1 as a novel biomarker for the diagnosis and treatment of IDD.

Exosomes derived from minor salivary gland mesenchymal stem cells: a promising novel exosome exhibiting pro-angiogenic and wound healing effects similar to those of adipose-derived stem cell exosomes

BackgroundsMinor salivary gland mesenchymal stem cells (MSGMSCs) can be easily extracted and have a broad range of sources. Applying exosomes to wounds is a highly promising method for promoting wound healing. Exosomes derived from different stem cell types have been proven to enhance wound healing, with adipose-derived stem cell (ADSC)-derived exosomes being the most extensively researched. Considering that MSGMSCs have advantages such as easier extraction compared to ADSCs, MSGMSCs should also be a very promising type of stem cell in exosome therapy. However, whether MSGMSC-derived exosomes (MSGMSC-exos) can promote wound healing and how they compare to ADSC-derived exosomes (ADSC-exos) in the wound healing process remain unclear.MaterialsThe effects of MSGMSC-exos and ADSC-exos on angiogenesis in wound healing were investigated in vitro using CCK-8, scratch assays, and tube formation assays. Subsequently, the promotion of wound healing by MSGMSC-exos and ADSC-exos was evaluated in vivo using a full-thickness wound defect model in mice. Immunohistochemistry was used to verify the effects of MSGMSC-exos and ADSC-exos on promoting collagen deposition, angiogenesis, and cell proliferation in the wound. Immunofluorescence staining was performed to investigate the role of MSGMSC-exos and ADSC-exos in modulating the inflammatory response in the wound. Furthermore, proteomic sequencing was conducted to investigate the functional similarities and differences between the proteomes of MSGMSC-exos and ADSC-exos, with key protein contents verified by ELISA.ResultsMSGMSC-exos exhibited similar effects as ADSC-exos in promoting the migration, proliferation, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro, with a comparable dose-dependent effect. In vivo experiments confirmed that MSGMSC-exos have similar wound healing-promoting functions as ADSC-exos. MSGMSC-exos promoted the neovascularization and maturation of blood vessels in vivo at a level comparable to ADSC-exos. Despite MSGMSC-exos showing less collagen deposition than ADSC-exos, they exhibited stronger anti-scar formation and anti-inflammatory effects. Proteomic analysis revealed that the proteins promoting wound healing in both MSGMSC-exos and ADSC-exos were relatively conserved, with ITGB1 identified as a critical protein for angiogenesis. Further differential analysis revealed that the functions specifically enriched in MSGMSC-exos and ADSC-exos reflected the functions of their source tissue.ConclusionsOur study confirms that MSGMSC-exos exhibit highly similar wound healing and angiogenesis-promoting functions compared to ADSC-exos, and the proteins involved in promoting wound healing in both are relatively conserved. Moreover, MSGMSC-exos show stronger anti-scar formation and anti-inflammatory effects than ADSC-exos. This suggests that MSGMSCs are a promising stem cell source with broad applications in wound healing treatment.

Generation and characterization of zebrafish f9l mutant confirmed that f9l is f10 like gene.

This study aimed to create an f9l mutant zebrafish using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) and characterize its coagulation properties to investigate its functional similarity to human FX and explore the potential synergy between f9l and f10. Three gRNAs targeting exon 8 encoded by the catalytic domain of the f9l gene were injected into 300 single-cell zebrafish embryos using CRISPR/Cas9 technology. DNA from the resulting adults was extracted from tail tips, and PCR was used to detect indels. The identified founder mutant was bred to homozygosity, and functional assays, kinetic Russel viper venom time, bleeding assay in adults, and venous laser injury on larvae were conducted to assess its hemostatic function. Additionally, f10 was knocked down in f9l homozygous embryos using f10 antisense morpholinos to study their interaction by monitoring its survival. DNA from 60 adults was screened for indels, resulting in a fish with a heritable complex mutation involving one insertion and two deletions in exon 8. The f9l homozygous mutants exhibited impaired F10 activity, mild bleeding after mechanical injury, and developmental deformities in early larval stages. The caudal vein thrombosis assay showed variable occlusion times, indicating a bleeding phenotype with incomplete penetrance. Knocking down f10 in f9l homozygous embryos resulted in 50% mortality within five dpf, compared to f9l homozygous embryos injected with control morpholinos. In summary, we generated f9l knockout and showed it is a paralog to f10. We also found a synergy between f9l and f10 genes, highlighting its importance in hemostasis.