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Administration of a Novel Reprogramming Formula Improves Cardiac Function and Decreases Cardiac Fibrosis in a Myocardial Infarction Model
No full textBackground: The reprogramming of fibroblasts into (induced) cardiomyocytes offers a direct myocardial regeneration strategy for improving postinfarction myocardial function. Compared to lower-order species, human cells are relatively resistant to such reprogramming. We previously found that p63-transactivation inhibitory domain (TID; the portion of p63 that physical interacts and interferes with its activation of the epigenetic repressor HDAC1) combined with the cardio-differentiation factors Hand2 and Myocardin (HM) enhanced rat and human cell transdifferentiation. The present study sought to determine the in vivo effects of this reprogramming strategy in a rat myocardial infarction model.
Methods: Adult male and female rats underwent left anterior descending coronary artery ligation, followed 3 weeks later by direct myocardial injection of adenovectors encoding vascular endothelial growth factor (VEGF)+TID/HM, VEGF+GATA4+MEF2C+TBX5 (GMT), or green fluorescent protein (GFP) (n = 12/group). After serial echocardiography over a 4-week period, the animals were euthanized, and histologic analysis was performed.
Results: Animals treated with VEGF+GMT or VEGF+TID/HM demonstrated an increase in ejection fraction (EF) of 8% ± 17% and 7% ± 15%, respectively, at 4 weeks after vector administration, while EF decreased by 3% ± 7% in GFP-treated animals (P \u3c .05). Systolic left ventricular posterior wall thickness also was increased in the treated groups but decreased in the control group (P \u3c .05). Fibrosis likewise was reduced in treated animals compared with those receiving GFP (P \u3c .01).
Conclusions: Adenoviral mediated administration of VEGF+TID/HM to the rat heart induced improvements in cardiac function and decreased fibrosis after myocardial infarction equivalent to that observed with VEGF+GMT administration. Given the efficacy of VEGF+TID/HM versus VEGF+GMT in cardio-differentiating human cells, these findings suggest the use of VEGF+TID/HM as a potential human myocardial regeneration strategy
Touch&Play Wood Typification by the MasSpec Pen
No full textWe have investigated the ability of a MasSpec Pen (MSPen) three-in-one (extraction, transfer, and ionization) device coupled to a mass spectrometer to provide instantaneous chemical profiles that could promptly characterize wood samples from the mahogany (Meliaceae) family. For that, we selected a set of five representative wood species, that is, Brazilian mahogany (Swietenia macrophylla, also known as Honduran mahogany), two African mahoganies (Khaya ivorensis and Khaya senegalensis), and two nongenuine ( fake ) mahogany woods: cedar (Cedrela odorata) and andiroba (Carapa guianensis). By simply touching the superficially polished wood surface and after 3 s of automatic extraction, profiles of highly characteristic markers that effectively discriminated all five mahoganies were detected. The superficial surface of a wood Brazilian mahogany sample as compared with internal wood accessed via deep sanding showed minor profile changes mainly by shifts in the relative abundances of the wood markers, indicating that aging only marginally changes MSPen wood signatures. The direct touch&play analysis offered by MSPen was therefore found to provide nondestructive, fast, sample-preparation-free, and reliable typification of woods. This spatially free device also allows broad screening because multiple points on the whole surface of any small or large-size intricate wood sample can be rapidly analyzed, demonstrating its high potential for forensic investigations, particularly for endangered species such as the Brazilian mahogany
Genetic and Embryonic Transcriptome Analyses Reveal the Molecular and Developmental Basis of Mayer-Rokitansky-Küster-Hauser Syndrome
No full textBackground: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterised by aplasia of the uterus, cervix and upper part of the vagina. The genetic aetiology remains incompletely understood.
Methods: We performed gene-level and gene set-level burden analyses based on exome sequencing/genome sequencing data from 727 probands with MRKHS and 2504 female control individuals. Single-cell RNA sequencing (scRNA-seq) was performed on human and mouse embryonic metanephros at different developmental stages. Genetic and transcriptomic data were integrated to prioritise suboptimal genetic signals, identify relevant cell types and determine key developmental stages. Potential digenic inheritance was assessed and prioritised using coexpression patterns from scRNA-seq data.
Results: We identified known MRKHS genes (PAX8, BMP7, GREB1L) and novel candidates (PAN2, AGPAT2) with exome-wide significance. Enriched biological processes included cell apoptosis and mesenchymal-to-epithelial transition. In human embryos, MRKHS-associated genes were enriched in the uterine epithelium at eight gestational weeks (w8) and Wolffian duct epithelium at w11, supporting the biological relevance of burden signals. We detected 992 digenic combinations in MRKHS, with three achieving exome-wide significance (CPSF3L/CYP2A7, AICDA/NOS1, EVC2/KANK1).
Conclusion: Our study reveals both established and novel genetic contributors to MRKHS, links them to specific embryonic cell types and stages, and highlights potential digenic inheritance patterns. Integrating genetic burden and single-cell transcriptomic data provides new insights into the complex molecular mechanisms underlying MRKHS
NF1-Depleted Er+ Breast Cancers Are Differentially Sensitive to CDK4/6 Inhibitors
No full textNeurofibromin/NF1 is a RAS (rat sarcoma virus) GTPase activating protein and estrogen receptor (ER) transcriptional corepressor. NF1low status, identified by copy number loss or low mRNA/protein expression is associated with endocrine therapy resistance in approximately 20% of ER+/HER2− (human epidermal growth factor receptor 2) early-stage breast cancers. The identification of targeted treatments for NF1low ER+/HER2− breast cancer is therefore a priority. In this study proteogenomic analysis of ER+/HER2− breast cancer demonstrated that NF1low tumors exhibited elevated cyclin-dependent kinase 4/6 (CDK4/6) activity. In cell lines, NF1-deletion had a dual effect on CDK4 activity. First, by promoting ER recruitment to CCND1 (cyclin D1), thereby increasing CDK4-cyclin D1 complex formation and second, through C-RAF (rapidly accelerated fibrosarcoma) activation which drove phosphorylation of the CDK4 activation-loop. Preclinical modelling demonstrated that NF1low ER+ cancer cells were more sensitive to fulvestrant combined with a CDK4/6 inhibitor (CDK4/6i) versus fulvestrant alone, with the induction of cell-death in vitro, and durable tumor regressions in ER+ NF1low patient-derived xenograft models in vivo. Furthermore, NF1low ER+/HER2− tumors were more sensitive to neoadjuvant aromatase inhibitor (AI) plus palbociclib compared to neoadjuvant AI alone, as indicated by suppression of mRNA-based proliferation scores. These data are consistent with a model whereby that ER and RAS co-activation upon NF1-loss can drive CDK4/6 activity and endocrine therapy resistance but renders NF1low ER+ tumors susceptible to CDK4/6 inhibition. Development of clinical-grade NF1 diagnostics should be prioritized to determine whether NF1low ER+ breast cancers should receive adjusted adjuvant treatment recommendations that reflect increased responsiveness to CDK4/6i inhibition
Designing and Implementing Solution-Oriented Team Science Initiatives-A Chronic Pain Example
No full textLarge, collaborative projects that combine researchers from multiple scientific disciplines have become an integral part of the scientific endeavor. While transdisciplinary team science projects hold great potential, they also come with a unique set of challenges compared to monodisciplinary projects. The Science of Team Science (SciTS) field has developed multiple conceptual models and frameworks that guide the design, implementation, and evaluation of team science initiatives to maximize their potential for making breakthrough discoveries and creating solutions for complex problems. While these conceptual models contain a trove of valuable information for successful team science, guidance on how to effectively implement them is lacking. Here, we describe our experiences with implementing conceptual SciTS models to design and establish the REstoring JOINt health and function to reduce pain (RE-JOIN) consortium, a transdisciplinary team science project aimed at elucidating the mechanisms underlying chronic joint pain, with a solution-oriented focus. We highlight our experiences and challenges with implementing existing conceptual models and provide practical tips and guidance for designing and implementing solution-oriented team science initiatives
YAP Overcomes Mechanical Barriers to Induce Mitotic Rounding and Adult Cardiomyocyte Division
No full textBackground: Many specialized cells in adult organs acquire a state of cell cycle arrest and quiescence through unknown mechanisms. Our limited understanding of mammalian cell cycle arrest is derived primarily from cell culture models. Adult mammalian cardiomyocytes, a classic example of cell cycle arrested cells, exit the cell cycle postnatally and remain in an arrested state for the life of the organism. Cardiomyocytes can be induced to re-enter the cell cycle by YAP5SA, an active form of the Hippo signaling pathway effector YAP.
Methods: We performed clonal analyses to determine the cell cycle kinetics of YAP5SA cardiomyocytes. We also performed single-cell RNA sequencing, marker gene analysis, and functional studies to examine how YAP5SA cardiomyocytes progress through the cell cycle.
Results: We discovered that YAP5SA-expressing cardiomyocytes divided efficiently, with \u3e20% of YAP5SA cardiomyocyte clones containing ≥2 cardiomyocytes. YAP5SA cardiomyocytes re-entered cell cycle at the G1/S transition and had an S phase lasting ≈48 hours. Sarcomere disassembly is required for cardiomyocyte progression from S to G2 phase and the induction of mitotic rounding. Although oscillatory Cdk expression was induced in YAP5SA cardiomyocytes, these cells inefficiently progressed through G2 phase. This is improved by inhibiting P21 function, implicating checkpoint activity as an additional barrier to YAP5SA-induced cardiomyocyte division.
Conclusions: Our data reveal that YAP5SA overcomes the mechanically constrained myocardial microenvironment to induce mitotic rounding with cardiomyocyte division, thus providing new insights into the in vivo mechanisms that maintain cell cycle quiescence in adult mammals
Functional Assays in Drosophila Facilitate Classification of Variants of Uncertain Significance Associated With Rare Diseases
No full textIndividuals living with rare diseases often undergo a frustrating and expensive diagnostic odyssey. Clinical geneticists who analyze exome or genome sequencing data from rare disease patients often encounter a list of variants of uncertain significance (VUS) in known disease-causing genes or rare variants in genes of uncertain significance (GUS) that are difficult to interpret, even with the integration of the latest bioinformatic tools. In this Perspective, we review how studies using the fruit fly Drosophila melanogaster have facilitated rare disease diagnosis by uncovering the clinical relevance of GUS and classifying rare variants into specific allelic categories (loss-of-function or gain-of-function, Muller\u27s morphs). We showcase how fly researchers have been collaboratively studying the loss-of-function of orthologous fly genes, assessing the ability of the human genes to rescue the fly mutant phenotypes, determining the effect of overexpressing human proteins, and testing functional consequences of rare variants of interest by generating analogous fly mutants to contribute to rare disease diagnosis. We argue that data obtained using Drosophila can be leveraged to design effective multiplexed assays for variant effects (MAVEs) to decipher the vast human variome
Hypertriglyceridemia in New-Onset Type 1 Pediatric Diabetes
No full textHypertriglyceridemia (HTG) in the setting of newly diagnosed diabetes is common in both adult and pediatric populations, as insulin deficiency promotes lipolysis and impairs triglyceride (TG) clearance. Severe HTG (defined as TG levels above 1000 mg/dL) in pediatric patients with new-onset type 1 diabetes mellitus (T1D) is rare; the true incidence and sequela of this phenomenon have not been well characterized. We present a single-center experience on severe HTG in pediatric patients with new-onset T1D between 2013 and 2022 and summarize the cases previously reported in the literature. Our cases display variability in their presentation and in their association with high-risk complications, such as acute pancreatitis. We discuss suggestions of early screening for HTG and pancreatitis in patients with protracted abdominal pain, and close monitoring of those identified to have significant HTG
Severe Gastrointestinal Manifestations in Childhood-Onset Lupus: A Single-Center Cohort and Review of the Literature
No full textObjective
Systemic lupus erythematosus (SLE) is a complex autoimmune condition with diverse manifestations. Childhood-onset SLE (cSLE) presents more severely than adult-onset disease with a higher incidence of severe neurologic or renal manifestations and lower estimated survival rates. There is limited literature on the range of severe gastrointestinal manifestations at presentation in cSLE, and this lack of information results in underappreciation of these potentially life-threatening complications and little guidance regarding management of these patients. Methods
We reviewed cases of patients with cSLE and severe GI manifestations at presentation diagnosed at our institution and additionally provide a comprehensive review of existing cases in the literature to discuss presenting symptoms, other clinical features, longitudinal course, treatment, and long-term outcomes. Results
We identified six cases of cSLE with primary, severe GI symptoms at time of diagnosis at our institution and an additional 25 patients who presented similarly in the literature. Severe GI manifestations included protein-losing enteropathy, thoracoabdominal aortitis, severe pancreatitis, lupus enteritis or mesenteric vasculitis, and intestinal pseudo-obstruction. Delays in diagnosis affected several patients, and 26% of patients required surgical intervention. Many patients required intensive immunomodulatory treatment in addition to prolonged bowel rest and parenteral nutrition. Long-term outcomes of GI manifestations varied overall, however, most patients at our institution achieved clinical remission. Conclusions
Understanding these rare cases of severe GI manifestations in cSLE can aid clinicians in prompt diagnosis and collaborative management, improving clinical outcomes for this vulnerable population
Intracranial Rhizomucor Pusillus Mucormycosis in an Adolescent Triggering a Stroke Alert: A Case Report and a Systematic Review of Pediatric Cases
No full textMucormycosis is a rare, life-threatening opportunistic infection primarily affecting immunocompromised patients. The available literature on Rhizomucor pusillus (R pusillus) infections of the central nervous system (CNS) in children is very limited. We present the case of an immunocompromised adolescent with intracranial mucormycosis due to R pusillus manifesting with stroke-like symptoms. This case highlights this rare condition\u27s diagnostic complexity and management challenges. We include a review of the available literature on pediatric R pusillus CNS infections to increase awareness among health care providers