Translational Pathway Research Articles

Accuracy of machine learning in predicting outcomes post-percutaneous coronary intervention: a systematic review.

Recent studies have shown potential in introducing machine learning (ML) algorithms to predict outcomes post-percutaneous coronary intervention (PCI). We aimed to critically appraise current ML models' effectiveness as clinical tools to predict outcomes post-PCI. Searches of four databases were conducted for articles published from the database inception date to 29 May 2021. Studies using ML to predict outcomes post-PCI were included. For individual post-PCI outcomes, measures of diagnostic accuracy were extracted. An adapted checklist comprising existing frameworks for new risk markers, diagnostic accuracy, prognostic tools and ML was used to critically appraise the included studies along the stages of the translational pathway: development, validation, and impact. Quality of training data and methods of dealing with missing data were evaluated. Twelve cohorts from 11 studies were included with a total of 4,943,425 patients. ML models performed with high diagnostic accuracy. However, there are concerns over the development of the ML models. Methods of dealing with missing data were problematic. Four studies did not discuss how missing data were handled. One study removed patients if any of the predictor variable data points were missing. Moreover, at the validation stage, only three studies externally validated the models presented. There could be concerns over the applicability of these models. None of the studies discussed the cost-effectiveness of implementing the models. ML models show promise as a useful clinical adjunct to traditional risk stratification scores in predicting outcomes post-PCI. However, significant challenges need to be addressed before ML can be integrated into clinical practice.

Stress granule formation helps to mitigate neurodegeneration.

Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and rodent neurons, reducing stress granule formation with nsP3 had modest impacts on lifespan even in the setting of serial stress pathway induction. In contrast, reducing stress granule formation in models of ataxia, amyotrophic lateral sclerosis and frontotemporal dementia largely exacerbated disease phenotypes. These data support a model whereby stress granules mitigate, rather than promote, neurodegenerative cascades.

Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting

ObjectiveCurrently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH). MethodsUnbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo. ResultsWe observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific Esrra knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and in vivo models of MASH. ConclusionsEsrra regulation of Rplp1-mediated translation of lysosome/autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.

Transcriptome profiling reveals dysregulation of inflammatory and protein synthesis genes in PCOS

To analyze the differential expression genes of polycystic ovary syndrome (PCOS), clarify their functions and pathways, as well as the protein–protein interaction network, identify HUB genes, and explore the pathological mechanism. PCOS microarray datasets were screened from the GEO database. Common differentially expressed genes (co-DEGs) were obtained using GEO2R and Venn analysis. Enrichment and pathway analyses were conducted using the DAVID online tool, with results presented in bubble charts. Protein–protein interaction analysis was performed using the STRING tool. HUB genes were identified using Cytoscape software and further interpreted with the assistance of the GeneCards database. A total of two sets of co-DEGs (108 and 102), key proteins (15 and 55), and hub genes (10 and 10) were obtained. The co-DEGs: (1) regulated inflammatory responses and extracellular matrix, TNF, and IL-17 signaling pathways; (2) regulated ribosomes and protein translation, ribosome and immune pathways. The key proteins: (1) regulated inflammation, immunity, transcription, matrix metabolism, proliferation/differentiation, energy, and repair; (2) regulated ubiquitination, enzymes, companion proteins, respiratory chain components, and fusion proteins. The Hub genes: (1) encoded transcription factors and cytokines, playing vital roles in development and proliferation; (2) encoded ribosomes and protein synthesis, influencing hormone and protein synthesis, associated with development and infertility. The dysregulated expression of inflammation and protein synthesis genes in PCOS may be the key mechanism underlying its onset and progression.

Lost in translation: How neurons cope with tRNA decoding.

Post-transcriptional tRNA modifications contribute to the decoding efficiency of tRNAs by supporting codon recognition and tRNA stability. Recent work shows that the molecular and cellular functions of tRNA modifications and tRNA-modifying-enzymes are linked to brain development and neurological disorders. Lack of these modifications affects codon recognition and decoding rate, promoting protein aggregation and translational stress response pathways with toxic consequences to the cell. In this review, we discuss the peculiarity of local translation in neurons, suggesting a role for fine-tuning of translation performed by tRNA modifications. We provide several examples of tRNA modifications involved in physiology and pathology of the nervous system, highlighting their effects on protein translation and discussing underlying mechanisms, like the unfolded protein response (UPR), ribosome quality control (RQC), and no-go mRNA decay (NGD), which could affect neuronal functions. We aim to deepen the understanding of the roles of tRNA modifications and the coordination of these modifications with the protein translation machinery in the nervous system.

Unveiling underlying mechanism of combined He–Ne laser and UV mutagenesis in Bacillus subtilis CICC 21927: A transcriptomic analysis

Conventional random mutation breeding remains the simplest and most cost-effective approach in enhancing strains in fermentation industry. Nonetheless, extensive research on compound mutagenesis are limited to screening target strains, and few studies on the interaction mechanism of compound mutagenesis factors. Herein, transcriptomic was employed to elucidate the molecular mechanism behind helium-neon (He–Ne) laser and ultraviolet (UV) compound mutagenesis in Bacillus subtilis. Transcriptomic sequencing analysis was conducted on five sample groups (control/CK, UV, laser/LA, UV-laser/UL, and laser-UV/LU), facilitating the statistical comparison of differentially expressed genes (DEGs) across 4 sample relationships (CK-vs-UV, CK-vs-LA, CK-vs-LU, and CK-vs-UL). The DEGs revealed that UV irradiation improved the biosynthesis of pyrimidine nucleotides by upregulating the activity of key enzymes (pyrimidine nucleotides synthetase, pyruvate dehydrogenase, phosphotransferase system (PTS) fructose-specific enzyme), while laser irradiation stimulated metabolism through the regulation of transmembrane transporter activity. Further KEGG enrichment analysis of 1891 DEGs in UV-vs-LU sample relationship unveiled 89 genes significantly enriched in the two-component system, which potentially linked to phytochrome. Moreover, analysis of 784 DEGs in UV-vs-UL sample relationship indicated up-regulation of genes associated with translation, replication, and genetic repair pathways, affirming the laser's induction of UV damage repair mechanisms. Subsequently, 9 pivotal genes (liaS, yvfT, yxdK, cheA, ykoW, uvrC, pcrA, recA, and ruvB) were selected for quantitative reverse transcriptional PCR (qRT-PCR) validation, demonstrating consistent trends with transcriptomic data. Conclusively, our findings unveiled interplay mechanism between UV and laser compound mutagenesis at molecular level, offered valuable insights for mutagenesis mode selection and further elucidation of mutagenesis mechanisms.

P-518 Differentially gene expression identified by RNA seq in aneuploid human blastocysts is more influenced by the phenomenon of aneuploidy than the involved chromosome

Abstract Study question What insights do RNA-Seq profiles provide about gene expression in aneuploid blastocysts with small and large chromosomes compared to euploid blastocysts? Summary answer The difference in gene expression is affected by aneuploidy and is more related to the presence of aneuploidy than the size of the aneuploid chromosomes. What is known already Embryonic aneuploidy is one of the main common causes of implantation failure and miscarriage. RNA-Seq investigations of the embryo in the early stages of preimplantation indicate that with the gradual replacement of the embryonic profile and the reduction of the oocyte residues, the gene expression profile in the blastocyst is more dependent on the embryo’s genome. A recent study by comparing the gene expression profile of euploid blastocysts and specific aneuploidies such as trisomy 21, trisomy 18, XXY and XO syndromes using RNA-Seq, showed how the type of aneuploidy might affect gene expression. Study design, size, duration This study was conducted on surplus embryos of the patients with history of recurrent implantation failure or recurrent miscarriage following PGT by Day-5 trophectoderm biopsy. Inclusion criteria involved maternal age ≤37, normal parental karyotypes, and ovulation by long stimulation protocol. As advanced maternal age and ovarian stimulation method can affect the aneuploidy rate and expression profile, embryos belonging to mothers > 37 years and included only patients with the long stimulation protocol were excluded. Participants/materials, setting, methods The normal embryos and those with single aneuploidy were selected for comparison of gene expression profiles using RNA sequencing. The single aneuploid embryos were classified in two groups: with defined aneuploidy(DA) of small chromosomes (including chromosomes 16, 20, 21, 22), and with undefined aneuploidy(UA) as single aneuploids for other chromosomes. To neutralize the effect of genomic content on gene expression profile in DA group, embryos were pooled reciprocally (trisomy and monosomy for the same chromosome). Main results and the role of chance Principal Component Analysis (PCA) validated embryos classification considering their differentially expressed genes (DEG) clustering into three distinct groups. To minimize the role of chance, only genes with significant adjusted P-values in both STAR and Hisat data analyses were included in consequent interpretations. In addition to comparison between and among the DA, UA and normal groups, the entire set of aneuploid groups was compared with the normal group. The DEG in both aneuploid groups compared to the normal group represented eminent upregulation rather than downregulation. Gene Ontology analyses indicated an upregulation of transcription, ubiquitination, autophagy, mitochondrial, chromosome segregation and DNA repair pathways in both DA and UA compared to normal group. Overexpression of the DNA repair pathway and other validated genes of interest in aneuploid embryos was in agreement with qPCR findings. Translation and protein synthesis pathways also showed overexpression as part of the functional response to aneuploidy. Upregulation of apoptotic process pathway was evident in the UA group. While comparison of gene expression between DA and UA showed overexpression of 143 genes, but cellular lipid synthesis was the only pathway with a significant difference. The distribution of DEG on chromosomes in the DA group was not associated with selected aneuploidies. Limitations, reasons for caution The number of biological replicates in each category was limited in order to provide more confident data by minimizing the time interval between providing the samples and RNA sequencing. Larger studies might change some affected pathways due to differences in identified DEG. Wider implications of the findings This study shed light on the black box of human preimplantation aneuploidy. Considering that the transcriptome is affected by the genomic status and some debates on genomic based current PGT approaches, this study is a step for selection of healthy and viable embryos by revealing the molecular mechanisms. Trial registration number not applicable

A dynamic in vitro model of Down syndrome neurogenesis with trisomy 21 gene dosage correction.

Excess gene dosage from chromosome 21 (chr21) causes Down syndrome (DS), spanning developmental and acute phenotypes in terminal cell types. Which phenotypes remain amenable to intervention after development is unknown. To address this question in a model of DS neurogenesis, we derived trisomy 21 (T21) human induced pluripotent stem cells (iPSCs) alongside, otherwise, isogenic euploid controls from mosaic DS fibroblasts and equipped one chr21 copy with an inducible XIST transgene. Monoallelic chr21 silencing by XIST is near-complete and irreversible in iPSCs. Differential expression reveals that T21 neural lineages and iPSCs share suppressed translation and mitochondrial pathways and activate cellular stress responses. When XIST is induced before the neural progenitor stage, T21 dosage correction suppresses a pronounced skew toward astrogenesis in neural differentiation. Because our transgene remains inducible in postmitotic T21 neurons and astrocytes, we demonstrate that XIST efficiently represses genes even after terminal differentiation, which will empower exploration of cell type-specific T21 phenotypes that remain responsive to chr21 dosage.

Spatial transcriptomic analysis of amelanotic acral melanoma versus pigmented acral melanoma reveals distinct molecular determinants.

Amelanotic acral melanoma (AAM) is a rare type of acral melanoma that has a poor prognosis. To investigate the transcriptomic differences between AAM and pigmented acral melanoma (PAM). Differences in the spatially resolved transcriptomic profiles of 9 patients with AAM with 29 regions of interest (ROIs) and 11 patients with PAM with 46 ROIs were investigated using S100b and CD3 morphology markers. In S100b+ tumour cell areas, we detected 11 upregulated differentially expressed genes (DEGs; including chaperone/ubiquitin--associated DEGs) and 82 downregulated DEGs (including human leucocyte antigen) in AAMs vs. PAMs. Protein-protein interaction network and pathway analyses revealed significant enrichment of dysregulated translational and nonsense-mediated decay pathways but significant decreases in antigen processing and presentation, interferon signalling and melanin biosynthesis pathways in S100b+ ROIs of AAMs compared with PAMs. In tumour-associated immune cell areas, the numbers of CD8 T cells (P = 0.04) and M1 macrophages (P = 0.01) were significantly decreased, whereas those of monocytes (P = 0.04) and endothelial cells (P = 0.04) were increased in AAMs compared with PAMs. These findings could widen our understanding of the biological differences between AAMs and PAMs, which might result in a different clinical course.

Altered Serum Proteins Suggest Inflammation, Fibrogenesis and Angiogenesis in Adult Patients with a Fontan Circulation.

Previous omics research in patients with complex congenital heart disease and single-ventricle circulation (irrespective of the stage of palliative repair) revealed alterations in cardiac and systemic metabolism, inter alia abnormalities in energy metabolism, and inflammation, oxidative stress or endothelial dysfunction. We employed an affinity-proteomics approach focused on cell surface markers, cytokines, and chemokines in the serum of 20 adult Fontan patients with a good functioning systemic left ventricle, and we 20 matched controls to reveal any specific processes on a cellular level. Analysis of 349 proteins revealed 4 altered protein levels related to chronic inflammation, with elevated levels of syndecan-1 and glycophorin-A, as well as decreased levels of leukemia inhibitory factor and nerve growth factor-ß in Fontan patients compared to controls. All in all, this means that Fontan circulation carries specific physiological and metabolic instabilities, including chronic inflammation, oxidative stress imbalance, and consequently, possible damage to cell structure and alterations in translational pathways. A combination of proteomics-based biomarkers and the traditional biomarkers (uric acid, γGT, and cholesterol) performed best in classification (patient vs. control). A metabolism- and signaling-based approach may be helpful for a better understanding of Fontan (patho-)physiology. Syndecan-1, glycophorin-A, leukemia inhibitory factor, and nerve growth factor-ß, especially in combination with uric acid, γGT, and cholesterol, might be interesting candidate parameters to complement traditional diagnostic imaging tools and the determination of traditional biomarkers, yielding a better understanding of the development of comorbidities in Fontan patients, and they may play a future role in the identification of targets to mitigate inflammation and comorbidities in Fontan patients.

Creative translation pathways for exploring gendered violence against Brazilian migrant women through a feminist translocational lens

ABSTRACT This paper explores how research on gendered violence among Brazilian migrant women in London has been translated through a range of creative engagements. It argues that these can challenge traditional forms of knowledge production, and advance intersectional feminist struggles through a logic of translocation. Yet it also challenges homogenous artistic encounters through developing ‘creative translation pathways’ which delineate different configurations of how researchers, artists, and participants using varied art forms . The paper focuses on two ‘creative translation pathways’ that capture different interpretative framings around the same research project. The first reflects a curatorial perspective through Gaël Le Cornec’s verbatim theatre play, Efêmera, which foregrounds her interpretation of Brazilian women’s stories adding a metatheatrical dimension to strengthen the narrative and connection with the audience. The second is a co-produced collaborative engagement, We Still Fight in the Dark, with community drama group, Migrants in Action, based around experimental workshops to produce an audio-visual film and installation where survivors’ perspectives and well-being are paramount. While both creative translation pathways reflected translocational feminist goals in raising awareness around gendered violence with a view to transform them, each had tensions around the individual, collective, artistic and therapeutic logics in the process of knowledge production.

Improved CAR-T cell activity associated with increased mitochondrial function primed by galactose.

CD19 CAR-T cells have led to durable remissions in patients with refractory B-cell malignancies; nevertheless, most patients eventually relapse in the long term. Many interventions aimed at improving current products have been reported, with a subset of them focusing on a direct or indirect link to the metabolic state of the CAR-T cells. We assessed clinical products from an ongoing clinical trial utilizing CD19-28z CAR-T cells from patients with acute lymphoblastic leukemia. CAR-T clinical products leading to a complete response had significantly higher mitochondrial function (by oxygen consumption rate) irrespective of mitochondrial content. Next, we replaced the carbon source of the media from glucose to galactose to impact cellular metabolism. Galactose-containing media increased mitochondrial activity in CAR-T cells, and improved in in-vitro efficacy, without any consistent phenotypic change in memory profile. Finally, CAR-T cells produced in galactose-based glucose-free media resulted in increased mitochondrial activity. Using anin-vivo model of Nalm6 injected mice, galactose-primed CAR-T cells significantly improved leukemia-free survival compared to standard glucose-cultured CAR-T cells. Our results prove the significance of mitochondrial metabolism on CAR-T cell efficacy and suggest a translational pathway to improve clinical products.

A novel bivalent interaction mode underlies a non-catalytic mechanism for Pin1-mediated protein kinase C regulation.

Regulated hydrolysis of the phosphoinositide phosphatidylinositol(4,5)-bis-phosphate to diacylglycerol and inositol-1,4,5-P3 defines a major eukaryotic pathway for translation of extracellular cues to intracellular signaling circuits. Members of the lipid-activated protein kinase C isoenzyme family (PKCs) play central roles in this signaling circuit. One of the regulatory mechanisms employed to downregulate stimulated PKC activity is via a proteasome-dependent degradation pathway that is potentiated by peptidyl-prolyl isomerase Pin1. Here, we show that contrary to prevailing models, Pin1 does not regulate conventional PKC isoforms α and βII via a canonical cis-trans isomerization of the peptidyl-prolyl bond. Rather, Pin1 acts as a PKC binding partner that controls PKC activity via sequestration of the C-terminal tail of the kinase. The high-resolution structure of full-length Pin1 complexed to the C-terminal tail of PKCβII reveals that a novel bivalent interaction mode underlies the non-catalytic mode of Pin1 action. Specifically, Pin1 adopts a conformation in which it uses the WW and PPIase domains to engage two conserved phosphorylated PKC motifs, the turn motif and hydrophobic motif, respectively. Hydrophobic motif is a non-canonical Pin1-interacting element. The structural information combined with the results of extensive binding studies and experiments in cultured cells suggest that non-catalytic mechanisms represent unappreciated modes of Pin1-mediated regulation of AGC kinases and other key enzymes/substrates.

Measurement of Adverse Events in Studies of Digital Health Interventions for Psychosis: Guidance and Recommendations Based on a Literature Search and Framework Analysis of Standard Operating Procedures.

Given the rapid expansion of research into digital health interventions (DHIs) for severe mental illness (SMI; eg, schizophrenia and other psychosis diagnoses), there is an emergent need for clear safety measures. Currently, measurement and reporting of adverse events (AEs) are inconsistent across studies. Therefore, an international network, iCharts, was assembled to systematically identify and refine a set of standard operating procedures (SOPs) for AE reporting in DHI studies for SMI. The iCharts network comprised experts on DHIs for SMI from seven countries (United Kingdom, Belgium, Germany, Pakistan, Australia, United States, and China) and various professional backgrounds. Following a literature search, SOPs of AEs were obtained from authors of relevant studies, and from grey literature. A thorough framework analysis of SOPs (n = 32) identified commonalities for best practice for certain domains, along with significant gaps in others; particularly around the classification of AEs during trials, and the provision of training/supervision for research staff in measuring and reporting AEs. Several areas which could lead to the observed inconsistencies in AE reporting and handling were also identified. The iCharts network developed best-practice guidelines and a practical resource for AE monitoring in DHI studies for psychosis, based on a systematic process which identified common features and evidence gaps. This work contributes to international efforts to standardize AE measurement and reporting in this emerging field, ensuring that safety aspects of DHIs for SMI are well-studied across the translational pathway, with monitoring systems set-up from the outset to support safe implementation in healthcare systems.

Translational pathway of a novel PFF2 respirator with chitosan nanotechnology: from the concept to the practical applications

Introduction:Translational Health Research (THR) is a tool aimed at assisting in the transformation of basic and/or applied scientific research into a health technology ready for commercialization. The aim of this study is to present the translational pathway in wich our research group developed a Personal Protective Equipment (PPE) called VESTA® Facial Respirator with chitosan nanotechnology for protection against viruses, bacteria, and fungi. The aim of this study is to present the process of THR applied to a health technology research.Methods:The theoretical-methodological process of THR was applied to the Research and Development (R&D) of the respirator. This method is characterized by subsequent phases, as follow: T (0)—Concept, T (1) Pre-Clinical, T (2) Clinical, T (3) Industrial Scale Production, and T (4) Characterized by subsequent phases, as follow: Technological Evaluation.Results:Applying the THR process in the development and production of the Particulate Filtering Facepiece class 2 (PFF2) respirator with chitosan nanotechnology, University of Brasilia was able to transform the research idea into a respirator approved by the National Regulatory Agency for industrial-scale production within 24 months. The THR process is not a linear action; this flexibility allows essential activities for transforming research into a marketable product.Discussion:The integration among various stakeholders right from the genesis of research is a driving force for the effective utilization of results. The maturity of the country’s industrial sector is crucial for converting university research into a marketable product, and governments need to prioritize these products in healthcare system incorporations. The academic culture of scientific research needs to intensify the technological transfer phase of its inventions. Conclusion: In less than 24 months, the University of Brasilia translated research on a new PPE into the market by applying the THR method.

Role of ribosomal pathways and comorbidity in COVID-19: Insight from SARS-CoV-2 proteins and host proteins interaction network analysis

The COVID-19 pandemic has become a significant global issue in terms of public health. While it is largely associated with respiratory complications, recent reports indicate that patients also experience neurological symptoms and other health issues. The objective of this study is to examine the network of protein-protein interactions (PPI) between SARS-CoV-2 proteins and human host proteins, pinpoint the central genes within this network implicated in disease pathology, and assess their viability as targets for drug development.The study adopts a network-based approach to construct a network of 29 SARS-CoV-2 proteins interacting with 2896 host proteins, with 176 host genes being identified as interacting genes with all the viral proteins. Gene ontology and pathway analysis of these host proteins revealed their role in biological processes such as translation, mRNA splicing, and ribosomal pathways. We further identified EEF2, RPS3, RPL9, RPS16, and RPL11 as the top 5 most connected hub genes in the disease-causing network, with significant interactions among each other. These hub genes were found to be involved in ribosomal pathways and cytoplasmic translation. Further a disease-gene interaction was also prepared to investigate the role of hub genes in other disorders and to understand the condition of comorbidity in COVID-19 patients. We also identified 13 drug molecules having interactions with all the hub genes, and estradiol emerged as the top potential drug target for the COVID-19 patients. Our study provides valuable insights using the protein-protein interaction network of SARS-CoV-2 proteins with host proteins and highlights the molecular basis of manifestation of COVID-19 and proposes drug for repurposing.As the pandemic continues to evolve, it is anticipated that investigating SARS-CoV-2 proteins will remain a critical area of focus for researchers globally, particularly in addressing potential challenges posed by specific SARS-CoV-2 variants in the future.

Combined Pharmacological Modulation of Translational and Transcriptional Activity Signaling Pathways as a Promising Therapeutic Approach in Children with Myocardial Changes.

Myocardial hypertrophy is the most common condition that accompanies heart development in children. Transcriptional gene expression regulating pathways play a critical role both in cardiac embryogenesis and in the pathogenesis of congenital hypertrophic cardiomyopathy, neonatal posthypoxic myocardial hypertrophy, and congenital heart diseases. This paper describes the state of cardiac gene expression and potential pharmacological modulators at different transcriptional levels. An experimental model of perinatal cardiac hypoxia showed the downregulated expression of genes responsible for cardiac muscle integrity and overexpressed genes associated with energy metabolism and apoptosis, which may provide a basis for a therapeutic approach. Current evidence suggests that RNA drugs, theaflavin, neuraminidase, proton pumps, and histone deacetylase inhibitors are promising pharmacological agents in progressive cardiac hypertrophy. The different points of application of the above drugs make combined use possible, potentiating the effects of inhibition in specific signaling pathways. The special role of N-acetyl cysteine in both the inhibition of several signaling pathways and the reduction of oxidative stress was emphasized.

Mitochondrial stress response and myogenic differentiation.

Regeneration and repair are prerequisites for maintaining effective function of skeletal muscle under high energy demands, and myogenic differentiation is one of the key steps in the regeneration and repair process. A striking feature of the process of myogenic differentiation is the alteration of mitochondria in number and function. Mitochondrial dysfunction can activate a number of transcriptional, translational and post-translational programmes and pathways to maintain cellular homeostasis under different types and degrees of stress, either through its own signaling or through constant signaling interactions with the nucleus and cytoplasm, a process known as the mitochondrial stress responses (MSRs). It is now believed that mitochondrial dysfunction is closely associated with a variety of muscle diseases caused by reduced levels of myogenic differentiation, suggesting the possibility that MSRs are involved in messaging during myogenic differentiation. Also, MSRs may be involved in myogenesis by promoting bioenergetic remodeling and assisting myoblast survival during myogenic differentiation. In this review, we will take MSRs as an entry point to explore its concrete regulatory mechanisms during myogenic differentiation, with a perspective to provide a theoretical basis for the treatment and repair of related muscle diseases.

374 Operationalization of a Translational Ethics Program

OBJECTIVES/GOALS: Within our CTSA hub, greater emphasis is on understanding innovation and human health impact of translational science writ large rather than focus on translational research projects. Our program is restructured to reflect distinguishing ethical features of translational science which are complimentary to traditional research ethics issues. METHODS/STUDY POPULATION: This descriptive analysis depicts the development of our ethics program as an exemplar of how to integrate into the research enterprise of an academic health science center that engages in translational research. Our relational approach is predicated on the embodiment of ethical values by all who are involved in research committed to proactive dialog, team building, and collaboration. This translational research culture is facilitated by a multidisciplinary ethics team who are embedded throughout the translational research enterprise. RESULTS/ANTICIPATED RESULTS: Our program is integrated into a translational science enterprise within a CTSA hub in four areas: relational structure (from leadership team to community engagement), education (from trainees to the research community to the public), support (through ethics consultation with multiple touchpoints in the translational science pathway), and team science (from team on-boarding and communication to D&I research of team science interventions). We have developed a research agenda examining research ethics topics that increase quality, applicability and downstream social impact of research; understanding translational science through historical and science & technologies studies lenses, and ethnographic and mixed-method approaches to understanding team science and the science of team science. DISCUSSION/SIGNIFICANCE: The integration of a translational ethics program provides attention to traditional research ethics issues regarding study conduct and integrity but also transcends those concerns to focus on the translational science enterprise itself through relationships, cultivating trust, team science, DEIA, and social responsibility.

494 Expert group decision making for pharmacogenomic testing in Ontario

OBJECTIVES/GOALS: There is a need to better understand how governments develop strategies to adopt, evaluate, and implement novel health technologies in a public healthcare system. The goal of this project is to understand this strategy development process for the translation of pharmacogenomic (PGx) testing in Ontario, Canada. METHODS/STUDY POPULATION: This observational case study of the Ontario Health PGx Working Group focused on developing recommendations for a PGx testing implementation strategy in the province. The group included 9 individuals affiliated with Ontario Health and 13 healthcare experts from multiple clinical fields. Ontario Health is the government agency that oversees provincial healthcare planning and service delivery. Guided by the Translational Thinking Framework and qualitative research methods, we observed the working group’s activities for eight months. We collected meeting recordings, slideshow decks, emails, and group characteristics. We used descriptive statistics and a nine-step inductive approach to analyze the data to create process maps, a case report, and key decision summaries. RESULTS/ANTICIPATED RESULTS: There were 19 meetings conducted remotely with videoconferencing technology. Throughout the working group’s activities, we identified 15 key decisions related to either administrative processes or PGx scientific content. We further stratified these two categories into four main themes relating to decisions about 1) membership involvement, 2) logistical management, 3) discussion and recommendation scope, and 4) information dissemination. These four decision themes represent tools by which Ontario Health guided the expert group activities and achieved their goal of generating a strategic roadmap for PGx testing implementation in Ontario. DISCUSSION/SIGNIFICANCE: The Ontario government makes decisions about how expert groups function by monitoring and controlling the group’s activities to ensure efficiency, standardization, and practicality. Describing expert group decision-making increases transparency and highlights the critical role they play in the translational pathway of health technologies.