8,362 research outputs found

    Overcoming drug resistance: targeting the BCL-2 family and the long non-coding RNA HCP5 in medulloblastoma and colorectal cancer

    Get PDF
    Colorectal cancer (CRC) is one of the most common cancers in the UK and medulloblastoma is a common cancer found in children. While there has been a progressive improvement in treatment outcomes, success has been marred by drug resistance and severe side effects. Therefore, this project focused on two aspects of chemotherapeutic drug resistance, the first using the antimitotic agent vincristine in combination with inhibitors of the anti-apoptotic Bcl-2 family proteins, while the second investigated the role of the long non-coding RNA (lncRNA), HCP5 in the resistance of cells to genotoxic agents. In the first part, three medulloblastoma cell lines (DAOY, MB03, ONS76) were analysed for the expression of Bcl-xL and ONS76 cells found to have the highest level of this anti-apoptotic protein. Subsequent results indicated that Bcl-xL encourages mitotic slippage and stemness and that knockdown of Bcl-xL in the high expressing ONS76 cells, reduces these and sensitizes the cells to the anti-mitotic agent vincristine. Thus, pharmacological inhibition of Bcl-xL should sensitize medulloblastoma cells to low doses of vincristine. Regarding the lncRNA HCP5, results showed that HCP5 was generally more highly expressed in a panel of CRC cell lines than the three medulloblastoma cell lines, corroborating data from an in-silico analysis for the corresponding tumours. One function of HCP5 is to translocate the multifunctional YB-1 protein from the cytoplasm to the nucleus where it carries out many of its functions. Knockdown of HCP5 followed by immunofluorescence indicated a reduction in the amount of YB-1 in the nucleus, confirming this function. Subsequently, HCP5 silencing sensitized all cell lines tested to the DNA damaging agents, cisplatin, oxaliplatin and tert-butyl hydroperoxide and also resulted in an increase in double-strand breaks as determined by H2AX formation. Finally, fluorescence activated cell sorting using Annexin V and propidium iodide confirmed a decrease in cell viability in HCP5 knockdown cells following treatment with genotoxic agents and that this was mirrored by an increased apoptotic fraction. Together, these studies indicate the possibilities of using novel therapeutics to increase the functionality of existing treatments to combat acquired drug resistance in cancer patients

    Endogenous measures for contextualising large-scale social phenomena: a corpus-based method for mediated public discourse

    Get PDF
    This work presents an interdisciplinary methodology for developing endogenous measures of group membership through analysis of pervasive linguistic patterns in public discourse. Focusing on political discourse, this work critiques the conventional approach to the study of political participation, which is premised on decontextualised, exogenous measures to characterise groups. Considering the theoretical and empirical weaknesses of decontextualised approaches to large-scale social phenomena, this work suggests that contextualisation using endogenous measures might provide a complementary perspective to mitigate such weaknesses. This work develops a sociomaterial perspective on political participation in mediated discourse as affiliatory action performed through language. While the affiliatory function of language is often performed consciously (such as statements of identity), this work is concerned with unconscious features (such as patterns in lexis and grammar). This work argues that pervasive patterns in such features that emerge through socialisation are resistant to change and manipulation, and thus might serve as endogenous measures of sociopolitical contexts, and thus of groups. In terms of method, the work takes a corpus-based approach to the analysis of data from the Twitter messaging service whereby patterns in users’ speech are examined statistically in order to trace potential community membership. The method is applied in the US state of Michigan during the second half of 2018—6 November having been the date of midterm (i.e. non-Presidential) elections in the United States. The corpus is assembled from the original posts of 5,889 users, who are nominally geolocalised to 417 municipalities. These users are clustered according to pervasive language features. Comparing the linguistic clusters according to the municipalities they represent finds that there are regular sociodemographic differentials across clusters. This is understood as an indication of social structure, suggesting that endogenous measures derived from pervasive patterns in language may indeed offer a complementary, contextualised perspective on large-scale social phenomena

    Aerosol modelling : Improving the understanding of aerosol processes and their effects on the climate at process and global-scale

    Get PDF
    Atmospheric aerosol particles have the ability to affect climate through cloud interactions and direct scattering and absorption of radiation. These aerosol particles can also affect human health through respiratory system. Aerosol particles are emitted to the atmosphere through direct sources or they can be formed through chemical processes from gas phase precursors. The different atmospheric processes and climate feedbacks of aerosol particles can be studied using process-scale models as well as larger global-scale models. In recent years, it has been found out that certain aerosol species lack information on their thermodynamic properties, causing uncertainties in process-scale modelling as well as global-scale modelling. In addition, transport of aerosols to remote regions, where emissions of aerosol particles are low, is poorly modelled in global-scale models. Furthermore, sources for formed secondary organic aerosol (SOA) include uncertainties in global aerosol-climate models, which causes uncertainty to estimating the radiative forcing (RF). In this thesis, these aspects relating to uncertainties are addressed using process and global-scale modelling. This was done first by evaluating the capability of thermodynamic equilibrium model to reproduce observed hygroscopicity in terms of dimethylamine, sulfuric acid and ammonia containing particles. Second, an in-cloud wet deposition scheme was developed (hereafter referred to as the newly-developed scheme) for global models which use sectional aerosol description. The newlydeveloped wet deposition scheme was tested using ECHAM-HAMMOZ global aerosol-climate model with Sectional Aerosol model for Large-Scale Applications (SALSA) in terms of aerosol vertical distributions and lifetimes. Third, the biotic stress effects to trees over boreal region and their effects to SOA formation, clouds and radiative effects were studied using ECHAM-HAMMOZ with SALSA. The results showed that when the thermodynamic equilibrium model was used to model particles with sizes of the order of couple of tens of nanometers, it was inadequate in estimating the hygroscopic growth of dimethylamine (DMA), sulfuric acid (SA) and ammonia containing particles. Thus, more investigation is needed in terms of thermodynamics of DMA containing systems to properly evaluate its effects to climate. Global aerosol-climate models are very complex and thus making aerosol processes more physically sound can even impair the results. This was seen in the results of the newly-developed, more physical, in-cloud wet deposition scheme as it produced spurious vertical profiles and atmospheric black carbon lifetime when compared to the preexisting scheme. Especially, the atmospheric lifetime of black carbon, in the newly-developed scheme, was 1.6 times longer than in the pre-existing scheme and over 2.6 times longer than has been suggested by experimental studies. Thus, the sensitivity of the newly-developed scheme was tested in terms of internal mixing and emission size distribution of black carbon as well as ageing of aerosol species. These results showed that mixing black carbon with soluble substances produced best results in comparison with the observations as well as atmospheric lifetimes of aerosol species when compared to AEROCOM model means. Lastly, the results studying the biotic stress effects on climate showed that increasing the extent of stress in boreal trees enhanced SOA formation as the emissions of volatile organic compounds (VOCs) were increased. The enhanced SOA formation increased cloud droplet number concentration (CDNC) at cloud top and caused stronger negative RF in both all-sky and clear-sky cases. In the future, aerosol model development should investigate further on the thermodynamic properties of aerosol species, especially with respect to DMA. The wet removal and extent of internal mixing of different aerosol species, especially black carbon, should be further investigated and revised, in global climate models, to properly evaluate the transport of aerosol particles. In addition, sources of atmospheric SOA needs further investigation to properly describe its behaviour in the atmosphere as well as the effects on the climate.Ilmakehän aerosolihiukkasilla on kyky vaikuttaa ilmastoon pilvivuorovaikutusten kautta sekä suoraan sirottamalla ja absorboimalla itseensä säteilyä. Nämä aerosolihiukkaset voivat myös vaikuttaa ihmisterveyteen hengityselimien kautta. Aerosolihiukkasia vapautuu ilmakehään suorien lähteiden kautta tai ne voivat syntyä kemiallisissa prosesseissa kaasufaasin esiasteista. Eri aerosoliprosesseja ja aerosolihiukkasten ilmastovaikutuksia voidaan tutkia käyttäen prosessi- ja globaalin mittakaavan malleja. Viime vuosina on havaittu, että tietyiltä aerosoliyhdisteiltä puuttuu tietoja niiden termodynaamisista ominaisuuksista, joka aiheuttaa epävarmuutta prosessi- ja globaalitason mallinnuksessa. Lisäksi aerosolien kaukokulkeuma syrjäisille alueille, joilla aerosolihiukkasten päästöt ovat vähäisiä, on heikosti mallinnettu globaalin mittakaavan malleissa. Lisäksi sekundaarisen orgaanisen aerosolin (SOA) päästölähteet sisältävät epävarmuuksia globaalin mittakaavan malleissa, joka aiheuttaa epävarmuutta säteilypakotteen arvioinnissa. Tässä työssä näitä näkökohtia, jotka liittyvät kyseisiin epävarmuuksiin, käsitellään käyttäen prosessi- ja globaalin mittakaavan mallinnusta. Tämä tehtiin ensiksi arvioimalla termodynaamisen tasapainomallin kykyä kuvata dimetyyliamiinia, rikkihappoa ja ammoniakkia sisältävien hiukkasten vedenottokykyä verrattuna mittauksiin. Toiseksi työssä kehitettiin pilven sisäinen märkäpoistumajärjestelmä globaalitason malleille, jotka käyttävät kokoon perustuvaa aerosolikuvausta. Vasta kehitettyä märkäpoistumajärjestelmää testattiin aerosolien pystyprofiilien ja elinikien suhteen käyttämällä ECHAM-HAMMOZ globaalia aerosoli-ilmastomallia, joka sisälsi ”Sectional Aerosol model for Large-Scale Applications (SALSA)” -mikrofysiikkakuvauksen. Kolmanneksi tutkittiin havumetsävyöhykkeen puihin kohdistuneen bioottisen stressin vaikutusta SOA:n muodostumiseen, pilviin ja säteilyvaikutuksiin käyttämällä ECHAM-HAMMOZ:ia SALSA:n kanssa. Tulokset osoittivat, että kun termodynaamista tasapainomallia käytettiin mallinnettaessa hiukkasia, joiden koko oli muutamien kymmenien nanometrien luokkaa, malli oli epäpätevä arvioimaan dimetyyliamiinia (DMA), rikkihappoa ja ammoniakkia sisältävien hiukkasten hygroskooppisuutta. Näin ollen lisätutkimuksia tarvitaan DMA:a sisältävien systeemien termodynamiikasta, jotta voidaan arvioida kunnolla sen vaikutusta ilmastoon. Globaalit aerosoli-ilmastomallit ovat erittäin monimutkaisia ja siksi aerosoliprosessien muuttaminen fysikaalisemmaksi voi jopa heikentää tuloksia. Tämä havaittiin vasta kehitetyn, fysikaalisemman, märkäpoistumajärjestelmän tuottamista tuloksista, jotka osoittivat kehitetyn menetelmän tuottavan harhaanjohtavia pystyprofiileja sekä vääristävän mustan hiilen elinikää verrattuna aiempaan järjestelmään. Erityisesti mustan hiilen elinikä, vasta kehitetyssä järjestelmässä, oli 1.6 kertaa pidempi kuin aiemmassa järjestelmässä ja yli 2.6 kertaa pidempi kuin kokeellisissa tutkimuksissa on ehdotettu. Siksi vasta kehitetyn järjestelmän herkkyyttä testattiin mustan hiilen sisäisen sekoittumisen ja päästökokojakauman sekä aerosoliyhdisteiden ikääntymisen kannalta. Nämä tulokset osoittivat, että mustan hiilen sekoittaminen liukoisten yhdisteiden kanssa tuotti parhaat tulokset verrattuna havaintoihin sekä aerosoliyhdisteiden eliniät verrattuna AEROCOM mallien keskiarvoihin. Lopuksi tulokset, joissa tutkittiin bioottisen stressin vaikutusta ilmastoon, osoittivat, että stressin lisääminen havumetsävyöhykkeen puissa lisäsi SOA:n muodostumista, koska haihtuvien orgaanisten yhdisteiden päästöt lisääntyivät. Lisääntynyt SOA:n muodostus lisäsi myös pilvipisaroiden lukumäärää pilvien yläpinnassa sekä aiheutti voimakkaamman negatiivisen säteilypakotteen. Tulevaisuudessa aerosolimallikehityksessä tulisi tutkia tarkemmin aerosoliyhdisteiden termodynaamisia ominaisuuksia erityisesti DMA:n suhteen. Märkäpoistumaa sekä eri aerosoliyhdisteiden, erityisesti mustan hiilen, sisäisen sekoittumisen määrää tulisi tutkia ja uudistaa globaaleissa ilmastomalleissa, jotta aerosolihiukkasten kaukokulkeumaa voitaisiin arvioida kunnolla. Lisäksi ilmakehän SOA:n lähteet tarvitsevat lisätutkimusta, jotta sen käyttäytymistä ilmakehässä ja ilmastovaikutuksia voitaisiin kuvata oikein

    Artificial Intelligence, Robots, and Philosophy

    Get PDF
    This book is a collection of all the papers published in the special issue “Artificial Intelligence, Robots, and Philosophy,” Journal of Philosophy of Life, Vol.13, No.1, 2023, pp.1-146. The authors discuss a variety of topics such as science fiction and space ethics, the philosophy of artificial intelligence, the ethics of autonomous agents, and virtuous robots. Through their discussions, readers are able to think deeply about the essence of modern technology and the future of humanity. All papers were invited and completed in spring 2020, though because of the Covid-19 pandemic and other problems, the publication was delayed until this year. I apologize to the authors and potential readers for the delay. I hope that readers will enjoy these arguments on digital technology and its relationship with philosophy. *** Contents*** Introduction : Descartes and Artificial Intelligence; Masahiro Morioka*** Isaac Asimov and the Current State of Space Science Fiction : In the Light of Space Ethics; Shin-ichiro Inaba*** Artificial Intelligence and Contemporary Philosophy : Heidegger, Jonas, and Slime Mold; Masahiro Morioka*** Implications of Automating Science : The Possibility of Artificial Creativity and the Future of Science; Makoto Kureha*** Why Autonomous Agents Should Not Be Built for War; István Zoltán Zárdai*** Wheat and Pepper : Interactions Between Technology and Humans; Minao Kukita*** Clockwork Courage : A Defense of Virtuous Robots; Shimpei Okamoto*** Reconstructing Agency from Choice; Yuko Murakami*** Gushing Prose : Will Machines Ever be Able to Translate as Badly as Humans?; Rossa Ó Muireartaigh**

    Commercialization of Separated Human Body Parts - Unpacking Instrumentalization Approach

    Get PDF
    The principle of non-commercialization, which prohibits trade in separated human body parts, has long been firmly embedded in many European legal orders and has become an integral part of them. However, many new uses for human biomaterials have now been discovered, and the need for them has reached a historical climax. This paper aims to explain the main tenets of non-commercialization theory, including such principles as human dignity and need to protect human’s health, and to show that these categories have so far been understood in a very one-sided and visceral way, and largely in contradiction to their true spirit. We will not dwell on a critique of the existing approach, but will propose an instrumental approach to human health based primarily on the will of the individual. At the end of this paper, we will describe possible legal constructs through which the market for separated human body parts can function, and the outcomes of adoption of one or another model

    METROPOLITAN ENCHANTMENT AND DISENCHANTMENT. METROPOLITAN ANTHROPOLOGY FOR THE CONTEMPORARY LIVING MAP CONSTRUCTION

    Get PDF
    We can no longer interpret the contemporary metropolis as we did in the last century. The thought of civil economy regarding the contemporary Metropolis conflicts more or less radically with the merely acquisitive dimension of the behaviour of its citizens. What is needed is therefore a new capacity for imagining the economic-productive future of the city: hybrid social enterprises, economically sustainable, structured and capable of using technologies, could be a solution for producing value and distributing it fairly and inclusively. Metropolitan Urbanity is another issue to establish. Metropolis needs new spaces where inclusion can occur, and where a repository of the imagery can be recreated. What is the ontology behind the technique of metropolitan planning and management, its vision and its symbols? Competitiveness, speed, and meritocracy are political words, not technical ones. Metropolitan Urbanity is the characteristic of a polis that expresses itself in its public places. Today, however, public places are private ones that are destined for public use. The Common Good has always had a space of representation in the city, which was the public space. Today, the Green-Grey Infrastructure is the metropolitan city's monument that communicates a value for future generations and must therefore be recognised and imagined; it is the production of the metropolitan symbolic imagery, the new magic of the city

    Meta-ontology fault detection

    Get PDF
    Ontology engineering is the field, within knowledge representation, concerned with using logic-based formalisms to represent knowledge, typically moderately sized knowledge bases called ontologies. How to best develop, use and maintain these ontologies has produced relatively large bodies of both formal, theoretical and methodological research. One subfield of ontology engineering is ontology debugging, and is concerned with preventing, detecting and repairing errors (or more generally pitfalls, bad practices or faults) in ontologies. Due to the logical nature of ontologies and, in particular, entailment, these faults are often both hard to prevent and detect and have far reaching consequences. This makes ontology debugging one of the principal challenges to more widespread adoption of ontologies in applications. Moreover, another important subfield in ontology engineering is that of ontology alignment: combining multiple ontologies to produce more powerful results than the simple sum of the parts. Ontology alignment further increases the issues, difficulties and challenges of ontology debugging by introducing, propagating and exacerbating faults in ontologies. A relevant aspect of the field of ontology debugging is that, due to the challenges and difficulties, research within it is usually notably constrained in its scope, focusing on particular aspects of the problem or on the application to only certain subdomains or under specific methodologies. Similarly, the approaches are often ad hoc and only related to other approaches at a conceptual level. There are no well established and widely used formalisms, definitions or benchmarks that form a foundation of the field of ontology debugging. In this thesis, I tackle the problem of ontology debugging from a more abstract than usual point of view, looking at existing literature in the field and attempting to extract common ideas and specially focussing on formulating them in a common language and under a common approach. Meta-ontology fault detection is a framework for detecting faults in ontologies that utilizes semantic fault patterns to express schematic entailments that typically indicate faults in a systematic way. The formalism that I developed to represent these patterns is called existential second-order query logic (abbreviated as ESQ logic). I further reformulated a large proportion of the ideas present in some of the existing research pieces into this framework and as patterns in ESQ logic, providing a pattern catalogue. Most of the work during my PhD has been spent in designing and implementing an algorithm to effectively automatically detect arbitrary ESQ patterns in arbitrary ontologies. The result is what we call minimal commitment resolution for ESQ logic, an extension of first-order resolution, drawing on important ideas from higher-order unification and implementing a novel approach to unification problems using dependency graphs. I have proven important theoretical properties about this algorithm such as its soundness, its termination (in a certain sense and under certain conditions) and its fairness or completeness in the enumeration of infinite spaces of solutions. Moreover, I have produced an implementation of minimal commitment resolution for ESQ logic in Haskell that has passed all unit tests and produces non-trivial results on small examples. However, attempts to apply this algorithm to examples of a more realistic size have proven unsuccessful, with computation times that exceed our tolerance levels. In this thesis, I have provided both details of the challenges faced in this regard, as well as other successful forms of qualitative evaluation of the meta-ontology fault detection approach, and discussions about both what I believe are the main causes of the computational feasibility problems, ideas on how to overcome them, and also ideas on other directions of future work that could use the results in the thesis to contribute to the production of foundational formalisms, ideas and approaches to ontology debugging that can properly combine existing constrained research. It is unclear to me whether minimal commitment resolution for ESQ logic can, in its current shape, be implemented efficiently or not, but I believe that, at the very least, the theoretical and conceptual underpinnings that I have presented in this thesis will be useful to produce more foundational results in the field

    DeepHTLV: a Deep Learning Framework for Detecting Human T-Lymphotrophic Virus 1 Integration Sites

    Get PDF
    In the 1980s, researchers found the first human oncogenic retrovirus called human T-lymphotrophic virus type 1 (HTLV-1). Since then, HTLV-1 has been identified as the causative agent behind several diseases such as adult T-cell leukemia/lymphoma (ATL) and a HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP). As part of its normal replication cycle, the genome is converted into DNA and integrated into the genome. With several hundreds to thousands of unique viral integration sites (VISs) distributed with indeterminate preference throughout the genome, detection of HTLV-1 VISs is a challenging task. Experimental studies typically use molecular biology techniques such as fluorescent in-situ hybridization (FISH) or using rt-qPCR (reverse transcriptase quantitative PCR) to detect VISs. While these methods are accurate, they cannot be applied in a high throughput manner. Next generation sequencing (NGS) has generated vast amounts of data, resulting in the development of several computational methods for VIS detection such as VERSE, VirusFinder, or DeepVISP for the task of rapid detection VIS across an entire genome. However, no such model exists for predicting HTLV-1 VISs. In this study, we have developed DeepHTLV: the first deep neural network for accurate detection of HTLV-1 insertion sites. We focused on 1) accurately predicting HTLV-1 VISs by extracting and generating superior feature representations and 2) uncovering the cis-regulatory features surrounding the insertion sites. DeepHTLV was implemented as a deep convolutional neural network (CNN) with self-attention architecture after comparing with several other deep neural network structures. To improve model accuracy, we trained the model using a bootstrap balanced sampling method with 10-fold CV. Furthermore, we demonstrated that this model has higher accuracy than several traditional machine learning models, with a modest improvement in area under the curve (AUC) values by 3-10%. To study the cis-regulatory features around HTLV-1 insertion sites, we extracted informative motifs from convolutional layer. Clustering of these motifs yielded eight unique consensus sequence motifs that represented potential integration sites in humans. The informative motif sequences were matched with a known transcription factor (TF) binding profile database, JASPAR2020, with the sequence matching tool TOMTOM. 79 TFs associations were enriched in regions surrounding HTLV-1 VISs. Furthermore, literature screening of HTLV-1, ATL, and HAM/TSP validated nearly half (34) of the predicted TFs interactions. This work demonstrates that DeepHTLV can accurately identify HTLV-1 VISs, elucidate surrounding features regulating these insertion sites, and make biologically meaningful predictions about cis-regulatory elements surrounding the insertion sites

    Temporary career transition: a case study of the loan transfer process and experience in the English professional football environment

    Get PDF
    The current PhD explores loan transfers in English professional football as a temporary transition. In sport, career termination has initially been prioritised, with wider transitions gaining greater attention over time (see: Ivarsson et al., 2018; Taylor and Ogilvie, 1994). However, little attention has been given to supporting and preparing individuals for permanent and temporary transfers in football. This is particularly important to explore given the introduction, yet lack of evaluation, of the Elite Player Performance Plan (EPPP) in 2012, which intended to increase holistic development and home grown talent development in England (Horrocks et al., 2016). To address this research gap, this thesis adopts a qualitative case study, drawing on interviews and document analysis, to gain in-depth insight to the experiences of an elite, high quality sample of players and staff across a range of Premier League and Championship clubs with regards to the loan process. The objectives of the research were to: a) explore the role of the Loan Managers (LMs) and their responsibilities in supporting loan players and processes; b) understand the perspectives of wider club staff, LMs and players to explore the loan process as a novel temporary transition; and c) develop recommendations regarding the LM role and broader loans process for individuals, clubs and policy-makers. There were a range of significant insights and novel contributions when addressing the objectives, including the lack of clarity for LMs and their day to day responsibilities. Similarly, consideration of wider perspectives allowed understanding of multi-disciplinary team (MDT) involvement as well as wider support and decision-making processes surrounding loan processes. Additionally, the current research recommends that professional football clubs ensure that a support structure is provided for LMs, whereby National Governing Bodies (NGBs) and organisations (e.g. Football Association; FA, English Premier League; EPL) could provide more formal support networks across clubs and leagues to ensure that sharing of best practice is in place. This may also help clubs and wider organisations place greater value on the loan transfer process, especially in line with the EPPP’s prioritisation of holistic development of homegrown talent, along with continued developments implemented by Fédération Internationale de Football Association (FIFA, 2022) regarding loan regulations

    The deubiquitinating enzyme MINDY2 promotes pancreatic cancer proliferation and metastasis by stabilizing ACTN4 expression and activating the PI3K/AKT/mTOR signaling pathway

    Get PDF
    The pathogenic mechanisms of pancreatic cancer (PC) are still not fully understood. Ubiquitination modifications have a crucial role in tumorigenesis and progression. Yet, the role of MINDY2, a member of the motif interacting with Ub-containing novel DUB family (MINDY), as a newly identified deubiquitinating enzyme, in PC is still unclear. In this study, we found that MINDY2 expression is elevated in PC tissue (clinical samples) and was associated with poor prognosis. We also found that MINDY2 is associated with pro-carcinogenic factors such as epithelial-mesenchymal transition (EMT), inflammatory response, and angiogenesis; the ROC curve suggested that MINDY2 has a high diagnostic value in PC. Immunological correlation analysis suggested that MINDY2 is deeply involved in immune cell infiltration in PC and is associated with immune checkpoint-related genes. In vivo and in vitro experiments further suggested that elevated MINDY2 promotes PC proliferation, invasive metastasis, and EMT. Meanwhile, actinin alpha 4 (ACTN4) was identified as a MINDY2-interacting protein by mass spectrometry and other experiments, and ACTN4 protein levels were significantly correlated with MINDY2 expression. The ubiquitination assay confirmed that MINDY2 stabilizes the ACTN4 protein level by deubiquitination. The pro-oncogenic effect of MINDY2 was significantly inhibited by silencing ACTN4. Bioinformatics Analysis and Western blot experiments further confirmed that MINDY2 stabilizes ACTN4 through deubiquitination and thus activates the PI3K/AKT/mTOR signaling pathway. In conclusion, we identified the oncogenic role and mechanism of MINDY2 in PC, suggesting that MINDY2 is a viable candidate gene for PC and may be a therapeutic target and critical prognostic indicator
    corecore