Hybrid speciation driven by multilocus introgression of ecological traits.

Hybridization allows adaptations to be shared among lineages and may trigger the evolution of new species1,2. However, convincing examples of homoploid hybrid speciation remain rare because it is challenging to demonstrate that hybridization was crucial in generating reproductive isolation3. Here we combine population genomic analysis with quantitative trait locus mapping of species-specific traits to examine a case of hybrid speciation in Heliconius butterflies. We show that Heliconius elevatus is a hybrid species that is sympatric with both parents and has persisted as an independently evolving lineage for at least 180,000 years. This is despite pervasive and ongoing gene flow with one parent, Heliconius pardalinus, which homogenizes 99% of their genomes. The remaining 1% introgressed from the other parent, Heliconius melpomene, and is scattered widely across the H. elevatus genome in islands of divergence from H. pardalinus. These islands contain multiple traits that are under disruptive selection, including colour pattern, wing shape, host plant preference, sex pheromones and mate choice. Collectively, these traits place H. elevatus on its own adaptive peak and permit coexistence with both parents. Our results show that speciation was driven by introgression of ecological traits, and that speciation with gene flow is possible with a multilocus genetic architecture.

Transcriptome analysis reveals organ-specific effects of 2-deoxyglucose treatment in healthy mice.

OBJECTIVE: Glycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear. METHODS: This study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment. RESULTS: PCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways. CONCLUSIONS: These findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.

Algorithm vs. clinical experience: controlled ovarian stimulations with follitropin-delta and individualised doses of follitropin-alpha/beta.

In the registrational trials, follitropin delta was compared with a fixed dose of 150 UI of follitropin alpha/beta, finding higher chances to reach a target response of 8-14 oocytes compared to controls. For this reason, follitropin delta is marketed as particularly useful in expected hyper-responder patients. The main outcome of this study is to report if comparable results are reached in a real-life scenario with follitropin alpha/beta personalized doses, based on patients' characteristics. This is a retrospective study performed in two public fertility centres. All first cycles from January 2020 to June 2022 with either follitropin delta (cases) or alpha/beta (controls) in patients with antiMüllerian hormone >2.5 ng/ml were compared by an inverse probability weighting approach based on propensity score. The follitropin total dose was higher in controls (1179.06 ± 344.93 vs. 1668.67 ± 555.22 IU, p<0.001). The target response of 8-14 oocytes was reached by 40.2% of cases and 40.7% of controls (odds ratio (OR) 0.99, 95% confidence interval (CI) 0.65-1.53, p=0.98). Fewer than 8 oocytes were collected in 24.1% of cases and 22% of controls (OR 1.10, 95% CI 0.71-1.69, p=0.67); more than 14 oocytes in 35.7% of cases and 37.3% of controls (OR 0.83, 95% CI 0.54-1.28, p=0.40). Our experience did not find worse results in term of proportion of patients who reached the target response with an algorithm-chosen dose of follitropin delta compared to a personalised starting dose of follitropin alpha/beta, with follitropin delta having the advantage of objectivity. Larger numbers are needed to confirm these results.

The multi-lineage transcription factor ISL1 controls cardiomyocyte cell fate through interaction with NKX2.5.

Congenital heart disease often arises from perturbations of transcription factors (TFs) that guide cardiac development. ISLET1 (ISL1) is a TF that influences early cardiac cell fate, as well as differentiation of other cell types including motor neuron progenitors (MNPs) and pancreatic islet cells. While lineage specificity of ISL1 function is likely achieved through combinatorial interactions, its essential cardiac interacting partners are unknown. By assaying ISL1 genomic occupancy in human induced pluripotent stem cell-derived cardiac progenitors (CPs) or MNPs and leveraging the deep learning approach BPNet, we identified motifs of other TFs that predicted ISL1 occupancy in each lineage, with NKX2.5 and GATA motifs being most closely associated to ISL1 in CPs. Experimentally, nearly two-thirds of ISL1-bound loci were co-occupied by NKX2.5 and/or GATA4. Removal of NKX2.5 from CPs led to widespread ISL1 redistribution, and overexpression of NKX2.5 in MNPs led to ISL1 occupancy of CP-specific loci. These results reveal how ISL1 guides lineage choices through a combinatorial code that dictates genomic occupancy and transcription.

Surveillance of clinical research integrity in medically assisted reproduction: a systematic review of retracted publications.

Background and purpose: Retraction is a significant consequence of scientific research, resulting from various factors ranging from unintentional errors to intentional misconduct. Previous reviews on retracted publications in obstetrics and gynecology have identified "article duplication," "plagiarism," and "fabricated results" as the main reasons for retraction. However, the extent of retracted articles in the literature on medically assisted reproduction (MAR) remains unclear. This systematic review aimed to assess the number and characteristics of retracted articles in the field of MAR. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for this study. A comprehensive literature search was conducted on the PubMed database from 1993 to February 2023, limited to English articles and including all 283 terms from the International Glossary on Infertility and Fertility Care. To identify retracted studies, a specific query combining the 283 terms from the glossary with a retraction-related keyword was used. Only studies focused on MAR and involving human subjects were included. Results: The electronic search yielded a total of 523,067 records in the field of infertility and fertility care. Among these, a total of 2,458 records were identified as retracted. The citation retraction rate was found to be 0.47% (2,458/523,067; 95%CI 0.45-0.49), and the citation retraction rate for randomized controlled trials (RCTs) was 0.20% (93/45,616; 95%CI 0.16-0.25). A total of 39 retracted articles specifically related to MAR were identified. Among these, 41.0% were RCTs (n = 16), 15.4% were reviews (n = 6), and 10.3% were retrospective studies (n = 4) or prospective studies (n = 4). Most of the retractions occurred shortly after publication, with "plagiarism" being the most common reason for retraction, followed by "duplicate publication." Discussion: The issue of retraction exists within the field of infertility and fertility care, including MAR. Our findings indicate that scientific misconduct, particularly plagiarism and duplicate publication, are the primary causes of retraction in MAR. Despite finding that the proportion of retracted citations is low, promoting scientific integrity should be a priority. The consequences of article retractions have significant implications for patient care and the scientific community. Hence, it is crucial to prioritize thorough screening of manuscripts before publication to maintain research integrity. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=185769, PROSPERO, identifier: CRD42020185769.

Lessons from the genomic analysis of Hesperiidae (Lepidoptera) holotypes in the MIZA collection (Maracay, Venezuela).

Genomic sequencing and analysis of holotypes from the MIZA collection (Maracay, Venezuela) and their comparison with other species and their type specimens advances our understanding of their taxonomy. Jemadia demarmelsi Orellana, [2010] is confirmed as a species-level taxon and its female is genetically verified. The following are species-level taxa, not subspecies: Amenis pedro O. Mielke & Casagrande, 2022, stat. nov. (not Amenis pionia (Hewitson, 1857)) and Jemasonia sosia (Mabille, 1878), stat. rest. (not Jemasonia hewitsonii (Mabille, 1878)). Amenis ponina rogeri Orellana, [2010], stat. nov. and Jemasonia pater ortizi (Orellana, [2010]), stat. nov. are subspecies, not species. Jemadia pseudognetus imitator (Mabille, 1891), comb. nov. (not Jemadia hospita (Butler, 1877)) and Damas cervelina Orellana & Costa, 2019, comb. nov. (not Megaleas Godman, 1901) are new combinations.

Application of 4-D ultrasound-derived regional strain and proteomics analysis in Nkx2-5-deficient male mice.

The comprehensive characterization of cardiac structure and function is critical to better understanding various murine models of cardiac disease. We demonstrate here a multimodal analysis approach using high-frequency four-dimensional ultrasound (4DUS) imaging and proteomics to explore the relationship between regional function and tissue composition in a murine model of metabolic cardiomyopathy (Nkx2-5183P/+). The presented 4DUS analysis outlines a novel approach to mapping both circumferential and longitudinal strain profiles through a standardized framework. We then demonstrate how this approach allows for spatiotemporal comparisons of cardiac function and improved localization of regional left ventricular dysfunction. Guided by observed trends in regional dysfunction, our targeted Ingenuity Pathway Analysis (IPA) results highlight metabolic dysregulation in the Nkx2-5183P/+ model, including altered mitochondrial function and energy metabolism (i.e., oxidative phosphorylation and fatty acid/lipid handling). Finally, we present a combined 4DUS-proteomics z-score-based analysis that highlights IPA canonical pathways showing strong linear relationships with 4DUS biomarkers of regional cardiac dysfunction. The presented multimodal analysis methods aim to help future studies more comprehensively assess regional structure-function relationships in other preclinical models of cardiomyopathy.NEW & NOTEWORTHY A multimodal approach using both four-dimensional ultrasound (4DUS) and regional proteomics can help enhance our investigations of murine cardiomyopathy models. We present unique 4DUS-derived strain maps that provide a framework for both cross-sectional and longitudinal analysis of spatiotemporal cardiac function. We further detail and demonstrate an innovative 4DUS-proteomics z-score-based linear regression method, aimed at characterizing relationships between regional cardiac dysfunction and underlying mechanisms of disease.

Transcriptome Analysis Reveals Organ-Specific Effects of 2-Deoxyglucose Treatment in Healthy Mice.

OBJECTIVE: Glycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear. METHODS: This study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment. RESULTS: PCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways. CONCLUSIONS: These findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.

Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis.

Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction of lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activator Brd4 in Cx3cr1-positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1-positive cells identified a large enhancer proximal to Interleukin-1 beta (Il1b), and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression of Il1b in disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL1B neutralization prevented stress-induced expression of MEOX1, inhibited fibroblast activation, and improved cardiac function in heart failure. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides new therapeutic strategies for heart disease and other disorders of chronic inflammation and maladaptive tissue remodeling.

Mantle cell lymphoma involving the oral and maxillofacial region: a study of 20 cases.

OBJECTIVE: To investigate the clinicopathologic features of mantle cell lymphoma (MCL) involving the oral and maxillofacial region. METHODS: The MCL cases were retrieved from the pathosis database of 6 pathology laboratories. Original hematoxylin and eosin slides and immunohistochemical reactions were reviewed for confirmation of the initial diagnosis. Clinical data of the cases were obtained from the patients' pathosis and/or medical charts. RESULTS: Twenty cases were included in the study, showing a male predominance and a mean age of 66 years. The oral cavity (12 cases) and the oropharynx (5 cases) were the most commonly involved subsites. Most cases presented as asymptomatic swellings, with 2 cases showing bilateral involvement of the palate. The classic histologic variant predominated (12/20 cases). All cases expressed CD20 with nuclear cyclin D1 positivity. SOX11 was seen in 9/13 cases, CD5 in 6/16 cases, Bcl2 in 16/19 cases, CD10 in 2/20 cases, and Bcl6 in 4/16 cases. Ki67 showed a mean proliferation index of 40.6%. The Epstein-Barr virus (EBV) was negative in all cases investigated. Follow-up data was available for 7 patients, with 5 currently alive and 2 deceased. CONCLUSION: Mantle cell lymphoma, albeit rare, may manifest in the oral and maxillofacial region. Its histologic heterogeneity demands a high degree of diagnostic skill from pathologists.

Monozygotic twin rate among ART centers: a multicenter analysis of data from 18 Italian units.

PURPOSE: The risk of monozygotic twins (MZTs) is increased in couples undergoing assisted reproductive technology (ART) treatments. Several systematic reviews have investigated the possible determinants linked to ART, but results obtained have not been conclusive. The study aims to investigate whether the incidence of MZT differed among ART centers. METHODS: This is a multicenter retrospective cohort study using the Italian ART National Registry database and involving the centers reporting data from individual ART cycles from 2015 to 2019. To investigate the incidence of MZT, only single embryo transfer cycles were considered. Women who had sex-discordant deliveries were excluded. MZT rate was calculated as the number of multiple pregnancies (more than one gestational sac at first ultrasound) out of the total number of clinical pregnancies. A binomial distribution model was used to determine the 95% CI of the frequency of MZT. RESULTS: Eighteen centers were included, and they provided data on 10,433 pregnancies. The total number of MZT was 162, corresponding to an incidence of 1.5% (95% CI: 1.3-1.8%). The rate of MZT among centers varied between 0% (95% CI: 0.0-25.9%) and 3.2% (95% CI: 1.3-8.1%). All the 95% CIs included 1.5%, rejecting the hypothesis that the MZT rate may significantly differ among centers. CONCLUSIONS: The rate of MZT did not significantly vary among ART centers. Local factors are unlikely to explain the increased rate of MZT in ART pregnancies.

Transcription Factor GATA4 Regulates Cell Type-Specific Splicing Through Direct Interaction With RNA in Human Induced Pluripotent Stem Cell-Derived Cardiac Progenitors.

BACKGROUND: GATA4 (GATA-binding protein 4), a zinc finger-containing, DNA-binding transcription factor, is essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Defects in alternative splicing are associated with many heart diseases, yet relatively little is known about how cell type- or cell state-specific alternative splicing is achieved in the heart. Here, we show that GATA4 regulates cell type-specific splicing through direct interaction with RNA and the spliceosome in human induced pluripotent stem cell-derived cardiac progenitors. METHODS: We leveraged a combination of unbiased approaches including affinity purification of GATA4 and mass spectrometry, enhanced cross-linking with immunoprecipitation, electrophoretic mobility shift assays, in vitro splicing assays, and unbiased transcriptomic analysis to uncover GATA4's novel function as a splicing regulator in human induced pluripotent stem cell-derived cardiac progenitors. RESULTS: We found that GATA4 interacts with many members of the spliceosome complex in human induced pluripotent stem cell-derived cardiac progenitors. Enhanced cross-linking with immunoprecipitation demonstrated that GATA4 also directly binds to a large number of mRNAs through defined RNA motifs in a sequence-specific manner. In vitro splicing assays indicated that GATA4 regulates alternative splicing through direct RNA binding, resulting in functionally distinct protein products. Correspondingly, knockdown of GATA4 in human induced pluripotent stem cell-derived cardiac progenitors resulted in differential alternative splicing of genes involved in cytoskeleton organization and calcium ion import, with functional consequences associated with the protein isoforms. CONCLUSIONS: This study shows that in addition to its well described transcriptional function, GATA4 interacts with members of the spliceosome complex and regulates cell type-specific alternative splicing via sequence-specific interactions with RNA. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.

Adult mouse fibroblasts retain organ-specific transcriptomic identity.

Organ fibroblasts are essential components of homeostatic and diseased tissues. They participate in sculpting the extracellular matrix, sensing the microenvironment, and communicating with other resident cells. Recent studies have revealed transcriptomic heterogeneity among fibroblasts within and between organs. To dissect the basis of interorgan heterogeneity, we compare the gene expression of murine fibroblasts from different tissues (tail, skin, lung, liver, heart, kidney, and gonads) and show that they display distinct positional and organ-specific transcriptome signatures that reflect their embryonic origins. We demonstrate that expression of genes typically attributed to the surrounding parenchyma by fibroblasts is established in embryonic development and largely maintained in culture, bioengineered tissues and ectopic transplants. Targeted knockdown of key organ-specific transcription factors affects fibroblast functions, in particular genes involved in the modulation of fibrosis and inflammation. In conclusion, our data reveal that adult fibroblasts maintain an embryonic gene expression signature inherited from their organ of origin, thereby increasing our understanding of adult fibroblast heterogeneity. The knowledge of this tissue-specific gene signature may assist in targeting fibrotic diseases in a more precise, organ-specific manner.

Tailored support may reduce mental and relational impact of infertility on infertile patients and partners.

RESEARCH QUESTION: What is the psychological impact of infertility on infertile patients and partners of infertile patients? DESIGN: This online, international, quantitative survey assessed the impact of infertility on mental health, relationships and daily activities for 1944 respondents. Respondents were male or female infertile patients (n = 1037) or partners to infertile patients (n = 907; not necessarily partners of the patient sample) and were recruited at different stages of the treatment journey. RESULTS: The most common emotions were 'sadness' at infertility diagnosis and 'anxiety' during treatment. Emotions differed in nature and intensity throughout the journey. Envy of others who achieved pregnancy was frequently reported by women. More than half of respondents (60.4%; n = 1174) perceived the infertility journey to have impacted their mental health, and 44.1% (n = 857) of respondents sought mental health support. More patients reported mental health impacts (70.1%, n = 727) than partners (49.3%, n = 447). One in three respondents indicated that their relationship had suffered due to the infertility diagnosis. Of these respondents, 55.0% (n = 409) strongly agreed that infertility caused an emotional strain. Patients more often than partners reported a detrimental impact on daily activities. Respondents most commonly agreed with statements regarding an 'effect on work-life balance'. CONCLUSION: Treatment journey stages are defined by their impact profile, which differs between infertile patients and partners of infertile patients. Negative impacts are diverse (mental health, relational, daily activities). There was disparity between the number of respondents reporting mental health issues and the number seeking mental health support. This indicates the need for support services tailored to different treatment stages.

Transcription factor protein interactomes reveal genetic determinants in heart disease.

Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease.

3D-cardiomics: A spatial transcriptional atlas of the mammalian heart.

Understanding the spatial gene expression and regulation in the heart is key to uncovering its developmental and physiological processes, during homeostasis and disease. Numerous techniques exist to gain gene expression and regulation information in organs such as the heart, but few utilize intuitive true-to-life three-dimensional representations to analyze and visualise results. Here we combined transcriptomics with 3D-modelling to interrogate spatial gene expression in the mammalian heart. For this, we microdissected and sequenced transcriptome-wide 18 anatomical sections of the adult mouse heart. Our study has unveiled known and novel genes that display complex spatial expression in the heart sub-compartments. We have also created 3D-cardiomics, an interface for spatial transcriptome analysis and visualization that allows the easy exploration of these data in a 3D model of the heart. 3D-cardiomics is accessible from http://3d-cardiomics.erc.monash.edu/.

Barriers and factors associated with significant delays to initial consultation and treatment for infertile patients and partners of infertile patients.

RESEARCH QUESTION: What are the key drivers and barriers for infertile patients and their partners to see an infertility specialist and initiate treatment? DESIGN: An online, international, 30-minute quantitative survey collected data from 1944 respondents from nine countries. Respondents were infertile patients (n = 1037) or partners of infertile patients (n = 907; but not necessarily partners of the patient sample), at different stages of the treatment journey. RESULTS: The overall average times were 3.2 years to receiving a medical infertility diagnosis, 2.0 years attempting to achieve pregnancy without assistance before treatment, and 1.6 years of treatment before successful respondents achieved pregnancy. The most common driver for considering treatment after a consultation (n = 1025) was an equal desire within the couple to have a child (40.8%). Of the partners (n = 356), 29.8% reported that transparency of information from healthcare professionals about treatment expectations was important. A significantly higher proportion of respondents seeking treatment reported that healthcare professionals offered supportive services (61.2%) and mental health services (62.0%), than of the 207 respondents who did not seek treatment (32.4% and 36.7%, respectively; P < 0.001). Perceived cost was the most commonly reported barrier for respondents not seeking a consultation (37.5% of n = 352) or treatment (42.0% of n = 207). Of the 95 respondents who discontinued treatment, 34.7% discontinued due to the financial impact. CONCLUSIONS: Respondents reported significant delays to seeking treatment, probably negatively impacting the chances of achieving pregnancy. Motivational coherence within couples was a key driver and cost of treatment was the main barrier. Reported supportive service offerings by healthcare professionals were significantly associated with continuation of the treatment journey.

Learning from incidents in medically assisted reproduction: the Notify Library as a learning tool.

Biovigilance is the systematic monitoring of serious adverse reactions and events (SARE) that ensures the quality and safety of tissues and cells for human application in medically assisted reproduction (MAR). The Notify Library is an open access database launched by the World Health Organization and supported by the Italian National Transplant Centre (CNT) that has collected information on documented adverse occurrences in transplantation, transfusion and MAR. It is not a SARE register, but rather a collection of SARE types identified primarily by review of published articles and case reports from national or regional vigilance programmes. The Notify Library includes many well-documented records of adverse occurrences in MAR treatment, representing a useful tool for MAR operators in the evaluation of the risks associated with the clinical application of reproductive tissues and cells. It is updated with new records when a new type of incident is reported for the first time. All incident types described might have teaching value during the risk management carried out by a MAR centre. Sharing lessons learned from these incidents represents an important didactic opportunity that can help MAR centres to improve their processes and to achieve higher standards of quality and safety.

Dynamic Interstitial Cell Response during Myocardial Infarction Predicts Resilience to Rupture in Genetically Diverse Mice.

Cardiac ischemia leads to the loss of myocardial tissue and the activation of a repair process that culminates in the formation of a scar whose structural characteristics dictate propensity to favorable healing or detrimental cardiac wall rupture. To elucidate the cellular processes underlying scar formation, here we perform unbiased single-cell mRNA sequencing of interstitial cells isolated from infarcted mouse hearts carrying a genetic tracer that labels epicardial-derived cells. Sixteen interstitial cell clusters are revealed, five of which were of epicardial origin. Focusing on stromal cells, we define 11 sub-clusters, including diverse cell states of epicardial- and endocardial-derived fibroblasts. Comparing transcript profiles from post-infarction hearts in C57BL/6J and 129S1/SvImJ inbred mice, which displays a marked divergence in the frequency of cardiac rupture, uncovers an early increase in activated myofibroblasts, enhanced collagen deposition, and persistent acute phase response in 129S1/SvImJ mouse hearts, defining a crucial time window of pathological remodeling that predicts disease outcome.