A Metabolic Basis for Endothelial-to-Mesenchymal Transition.

Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor ß (TGF-ß) family of ligands. Although required for normal heart valve development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in intracellular acetyl-CoA levels. Disruption of FAO via conditional deletion of endothelial carnitine palmitoyltransferase II (Cpt2E-KO) augments the magnitude of embryonic EndoMT, resulting in thickening of cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2E-KO mice demonstrate increased permeability in multiple vascular beds. Taken together, these results demonstrate that endothelial FAO is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.

Measuring In Vivo Mitophagy.

Alterations in mitophagy have been increasingly linked to aging and age-related diseases. There are, however, no convenient methods to analyze mitophagy in vivo. Here, we describe a transgenic mouse model in which we expressed a mitochondrial-targeted form of the fluorescent reporter Keima (mt-Keima). Keima is a coral-derived protein that exhibits both pH-dependent excitation and resistance to lysosomal proteases. Comparison of a wide range of primary cells and tissues generated from the mt-Keima mouse revealed significant variations in basal mitophagy. In addition, we have employed the mt-Keima mice to analyze how mitophagy is altered by conditions including diet, oxygen availability, Huntingtin transgene expression, the absence of macroautophagy (ATG5 or ATG7 expression), an increase in mitochondrial mutational load, the presence of metastatic tumors, and normal aging. The ability to assess mitophagy under a host of varying environmental and genetic perturbations suggests that the mt-Keima mouse should be a valuable resource.

Analytics and Lean Health Care to Address Nurse Care Management Challenges for Inpatients in Emerging Economies.

PURPOSE: Prescriptive and predictive analytics and artificial intelligence (AI) provide tools to analyze data with objectivity. In this paper, we provide an overview of how these techniques can improve nursing care, and we detail a quantitative model to afford managerial insights about care management in a Hospital in Colombia. Our main purpose is to provide tools to improve key performance indicators for the care management of inpatients which includes the nurse workload. METHODS: The optimal nurse-to-patient assignment problem is addressed using analytics, lean health care, and AI. Also, we propose a new mathematical model to optimize the nurse-to-patient assignment decisions considering several variables about the patient state such as the Barthel index, their risks, the complexity of the care, and the mental state. FINDINGS: Our results show that there are several processes inherent to compassionate nursing care that can be improved using technology. By using data analytics, we can also provide insights about the high variability of the care requirements and, by using models, find nurse-to-patient assignments that are nearly perfectly balanced. CONCLUSIONS: We illustrated this improvement with a pilot test that makes the equitable distribution of nursing workload the functionality of this strategy. The findings can be useful in highly complex hospitals in Latin America. CLINICAL RELEVANCE: The proposed model presents an opportunity to make near perfectly balanced nurse-to-patient assignments according to the number of patients and their health conditions using technology.

Apolipoprotein E Signals via TLR4 to Induce CXCL5 Secretion by Asthmatic Airway Epithelial Cells.

The primary function of APOE (apolipoprotein E) is to mediate the transport of cholesterol- and lipid-containing lipoprotein particles into cells by receptor-mediated endocytosis. APOE also has pro- and antiinflammatory effects, which are both context and concentration dependent. For example, Apoe-/- mice exhibit enhanced airway remodeling and hyperreactivity in experimental asthma, whereas increased APOE levels in lung epithelial lining fluid induce IL-1ß secretion from human asthmatic alveolar macrophages. However, APOE-mediated airway epithelial cell inflammatory responses and signaling pathways have not been defined. Here, RNA sequencing of human asthmatic bronchial brushing cells stimulated with APOE identified increased expression of mRNA transcripts encoding multiple proinflammatory genes, including CXCL5 (C-X-C motif chemokine ligand 5), an epithelial-derived chemokine that promotes neutrophil activation and chemotaxis. We subsequently characterized the APOE signaling pathway that induces CXCL5 secretion by human asthmatic small airway epithelial cells (SAECs). Neutralizing antibodies directed against TLR4 (Toll-like receptor 4), but not TLR2, attenuated APOE-mediated CXCL5 secretion by human asthmatic SAECs. Inhibition of TAK1 (transforming growth factor-ß-activated kinase 1), IκKß (inhibitor of nuclear factor κ B kinase subunit ß), TPL2 (tumor progression locus 2), and JNK (c-Jun N-terminal kinase), but not p38 MAPK (mitogen-activated protein kinase) or MEK1/2 (MAPK kinase 1/2), attenuated APOE-mediated CXCL5 secretion. The roles of TAK1, IκKß, TPL2, and JNK in APOE-mediated CXCL5 secretion were verified by RNA interference. Furthermore, RNA interference showed that after APOE stimulation, both NF-κB p65 and TPL2 were downstream of TAK1 and IκKß, whereas JNK was downstream of TPL2. In summary, elevated levels of APOE in the airway may activate a TLR4/TAK1/IκKß/NF-κB/TPL2/JNK signaling pathway that induces CXCL5 secretion by human asthmatic SAECs. These findings identify new roles for TLR4 and TPL2 in APOE-mediated proinflammatory responses in asthma.

Experience of Perinatal Death From the Father's Perspective.

BACKGROUND: Although perinatal deaths are still a common pregnancy outcome in developing countries, little is known about the effect perinatal death has on fathers. OBJECTIVE: The aim of the study was to understand and describe the meaning of perinatal death in a sample of fathers from northeastern Colombia. METHODS: Using purposive and snowball sampling approaches, we identified 15 participants from northeastern Colombia who agreed to participate. We used a descriptive phenomenological design. Data were collected through in-depth, semistructured interviews. RESULTS: Men suffer in solitude and hide their emotions as they feel the need to be the main supporters of their partners. Three major themes emerged: experience of loss, coming to terms with an irreparable loss, and overcoming the loss. DISCUSSION: While women are receiving care, health staff may neglect or forget men. Men suffer alone while seeking ways of attunement with their partners' emotions to support them during the grieving process. Fathers can overcome and adjust to the loss when they transcend it and find new meaning. Men felt neglected and marginalized at hospitals while their partners were receiving treatment. Health professionals should recognize and acknowledge the pain of fathers who face perinatal death and include them as much as possible in the standard of care. The results identify opportunities for healthcare providers in clinical and outpatient settings to acknowledge the importance of men within the context of pregnancy and to learn about their pain and suffering when they face a perinatal death.

The NAD-dependent deacetylase SIRT2 is required for programmed necrosis.

Although initially viewed as unregulated, increasing evidence suggests that cellular necrosis often proceeds through a specific molecular program. In particular, death ligands such as tumour necrosis factor (TNF)-α activate necrosis by stimulating the formation of a complex containing receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3). Relatively little is known regarding how this complex formation is regulated. Here, we show that the NAD-dependent deacetylase SIRT2 binds constitutively to RIP3 and that deletion or knockdown of SIRT2 prevents formation of the RIP1-RIP3 complex in mice. Furthermore, genetic or pharmacological inhibition of SIRT2 blocks cellular necrosis induced by TNF-α. We further demonstrate that RIP1 is a critical target of SIRT2-dependent deacetylation. Using gain- and loss-of-function mutants, we demonstrate that acetylation of RIP1 lysine 530 modulates RIP1-RIP3 complex formation and TNF-α-stimulated necrosis. In the setting of ischaemia-reperfusion injury, RIP1 is deacetylated in a SIRT2-dependent fashion. Furthermore, the hearts of Sirt2(-/-) mice, or wild-type mice treated with a specific pharmacological inhibitor of SIRT2, show marked protection from ischaemic injury. Taken together, these results implicate SIRT2 as an important regulator of programmed necrosis and indicate that inhibitors of this deacetylase may constitute a novel approach to protect against necrotic injuries, including ischaemic stroke and myocardial infarction.

Reciprocal regulation of acetyl-CoA carboxylase 1 and senescence in human fibroblasts involves oxidant mediated p38 MAPK activation.

We sought to explore the fate of the fatty acid synthesis pathway in human fibroblasts exposed to DNA damaging agents capable of inducing senescence, a state of irreversible growth arrest. Induction of premature senescence by doxorubicin or hydrogen peroxide led to a decrease in protein and mRNA levels of acetyl-CoA carboxylase 1 (ACC1), the enzyme that catalyzes the rate-limiting step in fatty-acid biosynthesis. ACC1 decay accompanied the activation of the DNA damage response (DDR), and resulted in decreased lipid synthesis. A reduction in protein and mRNA levels of ACC1 and in lipid synthesis was also observed in human primary fibroblasts that underwent replicative senescence. We also explored the consequences of inhibiting fatty acid synthesis in proliferating non-transformed cells. Using shRNA technology, we knocked down ACC1 in human fibroblasts. Interestingly, this metabolic perturbation was sufficient to arrest proliferation and trigger the appearance of several markers of the DDR and increase senescence associated ß-galactosidase activity. Reactive oxygen species and p38 mitogen activated protein kinase phosphorylation participated in the induction of senescence. Similar results were obtained upon silencing of fatty acid synthase (FAS) expression. Together our results point towards a tight coordination of fatty acid synthesis and cell proliferation in human fibroblasts.

Ethical Analysis of a Qualitative Researcher's Unease in Encountering a Participant's Existential Ambivalence.

Gaining in-depth understanding of the experiences of persons who have suffered traumatic events with physical and psychological sequelae is important for building effective interventions. However, qualitative research of this kind can be emotionally difficult for the researcher whose research interests derive from practice experiences with the population studied. It may be difficult for the researcher to separate the role of inquirer from that of practitioner. We explore this issue using ethical analysis to differentiate the responsibilities of the researcher from those of the clinician. In the first part of the chapter, we provide some background on the population studied and traumatic spinal cord injury and its aftermath as context for the issues raised by the narrative. Then, we describe briefly the first author's research exploring the meaning of bodily changes and embodiment in persons who have suffered a traumatic spinal cord injury. We provide the part of Jack's story that most troubled the researcher and led her to discuss the situation with an ethics colleague. Finally, we use the tools of moral reasoning, ethical analysis, and principles of research ethics to explore the pertinent excerpt of the narrative. The resulting clarifications are laid out for the reader with the intent of assisting other qualitative researchers in determining the extent and limits of their obligations to participants of qualitative studies, especially those that explore sensitive issues.

Feeding and Nutrition for People with Dementia in Gerontological Services: A Focus Group Study.

Purpose: This work sought to describe the experience of managers and caregivers with feeding and nutrition for older adults with dementia, in Colombian gerontological services. Participants and Methods: This is a qualitative focus group study with fourteen gerontological care centers for people with dementia. Results: The study reveals that care related to food and nutrition for people with dementia is organized based on the comprehensive assessment of the resident. Although there are basic support strategies, each caregiver requires specific knowledge, attitudes, behaviors, and institutional support, to generate a context that favors the health and quality of life of those involved. Conclusion: The experience of caring for people with dementia in aspects related to their food and nutrition, seen from the perspective of managers and caregivers of gerontological services in a developing country, strengthens specific strategies and public policies. This, in turn, reduces the burden on caregivers.

[Quality of life in institutionalized older adults with moderate to severe major neurocognitive disorder: Effect of Doll therapy]. / Calidad de vida en adultos mayores con trastorno neurocognitivo mayor moderado a grave institucionalizados: efecto de la Doll Therapy.

BACKGROUND AND OBJECTIVES: Major neurocognitive disorder is characterized by progressive cognitive impairment, a decrease in the person's ability to perform activities of daily living and the appearance of psychological and behavioral symptoms that lead to a deterioration in the quality of life and progression towards institutionalization. The most common management of major neurocognitive disorder is pharmacological therapy that mitigates or slow progressive deterioration and symptom control. The objective of this study was to establish the effect of a nursing intervention based on Doll therapy, compared to conventional care on the quality of life of older adults with moderate to severe major neurocognitive disorder institutionalized in nursing homes in the city of Medellín, Colombia. METHODS: Pilot experimental study with two groups and pretest post-test measurement. The sample consisted of 26 institutionalized elderly adults with advanced-stage major neurocognitive disorder, randomly assigned to each group. The experimental group received Doll therapy, based nursing therapy, while the comparison group continued to receive conventional therapy according to the institution's protocol. The QUALID instrument was used, which was evaluated by professionals external to the care centers. RESULTS: The comparison of the groups, before and after the intervention, indicates that the experimental group showed a positive effect on quality of life, supported by the statistical significance of the data, with a moderate effect. CONCLUSIONS: The Doll therapy as a non-pharmacological therapy has a positive effect on the quality of life of patients with moderate to severe major neurocognitive disorder, which constitutes a contribution to strengthen the knowledge associated with the effects or this intervention.

Nutritional Care for Institutionalized Persons with Dementia: An Integrative Review.

BACKGROUND: Older people are at risk of malnutrition, especially when they suffer from cognitive impairment. Guidelines that orient nursing care in this regard need to be updated. The aim of this review is to address the best available evidence on interventions that can benefit nutritional nursing care for institutionalized older adults with dementia. METHODS: Integrative review using the Dimensions and Eureka search engines, and the PubMed, Embase, Scielo, CINAHL, and ScienceDirect databases. We searched from the year 2015 through to 2021. We employed the MMAT guidelines for mixed, qualitative, and quantitative studies, and the PRISMA, CASP, and JBI guidelines to value the reviews. RESULTS: A total of 55 studies met the inclusion criteria. The best available evidence to support nutritional nursing care for institutionalized older adults with dementia highlights several aspects related to the assessment and caring interventions that are focused on people with dementia, their caregivers, and their context. CONCLUSIONS: Both the assessment and nutritional care interventions for older people with dementia should consider the patient-caregiver dyad as the subject of care and understand the context as a fundamental part of it. The analysis of the context should look further than the immediate environment.

SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling.

The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of IAP proteins to restore apoptotic pathways resulting in tumor death. We previously conducted a phase 2 clinical trial of the single-agent SMAC mimetic birinapant and observed minimal drug response in women with recurrent ovarian cancer despite demonstrating on-target activity. Accordingly, we performed a high-throughput screening matrix to identify synergistic drug combinations with birinapant. SMAC mimetics in combination with an HDAC inhibitor showed remarkable synergy and was, therefore, selected for further evaluation. We show here that this synergy observed both in vitro and in vivo results from multiple convergent pathways to include increased caspase activation, HDAC inhibitor-mediated TNF-α upregulation, and alternative NF-kB signaling. These findings provide a rationale for the integration of SMAC mimetics and HDAC inhibitors in clinical trials for recurrent ovarian cancer where treatment options are still limited.

Technological innovation for workload allocation in nursing care management: an integrative review.

Background: Technology reduces the nursing workload, improve the quality care processes, patient's safety, and avoid staff burnout. Innovative technologies are disrupting healthcare systems by improving the efficiency of processes and management. There is a discussion on the benefits, challenges, and barriers of these technologies and considering human factors of nursing management. The aim was to analyze the influence of technologies on the distribution of workload for nursing care management. Methods: An integrative literature review was performed. Four databases were searched: Scopus, Scielo, PUBMED, and CINALH following PRISMA guidelines. Articles published from January 2016 to December 2020, published in English, Spanish and Portuguese were included. Studies were excluded when they were not original research, did not met the quality criteria or they did not answer the research questions. Quality appraisal was performed using the Crowe Critical Appraisal Tool version 1.4 (CCAT). Two reviewers independently examined the title and abstract for eligibility according to the inclusion and exclusion criteria. Results: 2818 potentially relevant articles were found, but once the inclusion and exclusion criteria in the abstracts were analyzed, 177 remained for evaluation. After following the PRISMA Guidelines, 35 studies were included in the review. Three categories were identified: Nursing workload; Information technologies and technological means for management; Technology acceptance. Conclusions: Technology has the potential to improve care management by estimating nurse workload in ICUs and non-critical units, but scientific evidence is more detailed in the former type of services. The literature provides insights about the factors that factors and the barriers that promote the technology acceptance and usability. We did not find studies comparing technologies and no scientific evidence proving improvements in care.

First-in-human phase 1 clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors.

BACKGROUND: NEO201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens from patients with colorectal cancer. NEO-201 binds to core 1 or extended core 1 O-glycans expressed by its target cells. Here, we present outcomes from a phase I trial of NEO-201 in patients with advanced solid tumors that have not responded to standard treatments. METHODS: This was a single site, open label 3 + 3 dose escalation clinical trial. NEO-201 was administered intravenously every two weeks in a 28-day cycle at dose level (DL) 1 (1 mg/kg), DL 1.5 (1.5 mg/kg) and DL 2 (2 mg/kg) until dose limiting toxicity (DLT), disease progression, or patient withdrawal. Disease evaluations were conducted after every 2 cycles. The primary objective was to assess the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of NEO-201. The secondary objective was to assess the antitumor activity by RECIST v1.1. The exploratory objectives assessed pharmacokinetics and the effect of NEO-201 administration on immunologic parameters and their impact on clinical response. RESULTS: Seventeen patients (11 colorectal, 4 pancreatic and 2 breast cancers) were enrolled; 2 patients withdrew after the first dose and were not evaluable for DLT. Twelve of the 15 patients evaluable for safety discontinued due to disease progression and 3 patients discontinued due to DLT (grade 4 febrile neutropenia [1 patient] and prolonged neutropenia [1 patient] at DL 2, and grade 3 prolonged (> 72 h) febrile neutropenia [1 patient] at DL 1.5). A total of 69 doses of NEO-201 were administered (range 1-15, median 4). Common (> 10%) grade 3/4 toxicities occurred as follows: neutropenia (26/69 doses, 17/17 patients), white blood cell decrease (16/69 doses, 12/17 patients), lymphocyte decrease (8/69 doses, 6/17 patients). Thirteen patients were evaluable for disease response; the best response was stable disease (SD) in 4 patients with colorectal cancer. Analysis of soluble factors in serum revealed that a high level of soluble MICA at baseline was correlated with a downregulation of NK cell activation markers and progressive disease. Unexpectedly, flow cytometry showed that NEO-201 also binds to circulating regulatory T cells and reduction of the quantities of these cells was observed especially in patients with SD. CONCLUSIONS: NEO-201 was safe and well tolerated at the MTD of 1.5 mg/kg, with neutropenia being the most common adverse event. Furthermore, a reduction in the percentage of regulatory T cells following NEO-201 treatment supports our ongoing phase II clinical trial evaluating the efficiency of the combination of NEO-201 with the immune checkpoint inhibitor pembrolizumab in adults with treatment-resistant solid tumors. TRIAL REGISTRATION: NCT03476681 . Registered 03/26/2018.

Adaptation by Men to the Nurse Role. "Being Craftsmen in the Construction of their Professional Trajectory".

OBJECTIVES: This work sought to describe the adaptation process by men to the nurse role. METHODS: Secondary analysis of data from a collective case study that had as participants 12 male nurses working in the city of Medellín, with ages between 28 and 47 years and average time of professional experience of 11 years. Information collection was carried out through in-depth interviews. The analysis was conducted through Roy s Adaptation Model (RAM), reading of the interviews, identification of RAMs components, grouping of fragments, assignment of tags, construction of a matrix and classification. RESULTS: The analysis performed accounts for the coping processes and adaptation by male nurses and the ineffective responses (control of emotions and emotional silencing) when practicing a role considered feminine. CONCLUSIONS: In this study, it was possible to establish that, to achieve adaptation within nursing, men use strategies related with changes in bodily appearance, management of physical strength, and management of emotions.

From Being Caregiver to Being Cared for: The Experience of Adapting to Spinal Cord Injury, a Case Study.

This narrative case study portrays a young woman's life experience and adjustment process after suffering a traumatic spinal cord injury (SCI) 5 years ago. It is analyzed retrospectively from the perspective of the middle-range theory (MRT) of adapting to chronic health conditions by Buckner and Hayden (2014), and Ricoeur's narrative philosophy is expanded. Understanding Alice's narrative from this perspective allows us to understand the process of adaptation to a condition of disability due to a spinal cord injury, from the perspective of a nurse who was forced to change her role as a caregiver to a role of being cared for, due to the changes in her body and her corporality due to the consequences of the injury. In this narrative, the focal and contextual stimuli, the coping processes with special emphasis on the intrinsic and extrinsic adaptive processes, and the results of the process are identified.

Cysteine 202 of cyclophilin D is a site of multiple post-translational modifications and plays a role in cardioprotection.

AIMS: Cyclophilin-D is a well-known regulator of the mitochondrial permeability transition pore (PTP), the main effector of cardiac ischaemia/reperfusion injury. However, the binding of CypD to the PTP is poorly understood. Cysteine 202 (C202) of CypD is highly conserved among species and can undergo redox-sensitive post-translational modifications. We investigated whether C202 regulates the opening of PTP. METHODS AND RESULTS: We developed a knock-in mouse model using CRISPR where CypD-C202 was mutated to a serine (C202S). Infarct size is reduced in CypD-C202S Langendorff perfused hearts compared to wild type (WT). Cardiac mitochondria from CypD-C202S mice also have higher calcium retention capacity compared to WT. Therefore, we hypothesized that oxidation of C202 might target CypD to the PTP. Indeed, isolated cardiac mitochondria subjected to oxidative stress exhibit less binding of CypD-C202S to the proposed PTP component F1F0-ATP-synthase. We previously found C202 to be S-nitrosylated in ischaemic preconditioning. Cysteine residues can also undergo S-acylation, and C202 matched an S-acylation motif. S-acylation of CypD-C202 was assessed using a resin-assisted capture (Acyl-RAC). WT hearts are abundantly S-acylated on CypD C202 under baseline conditions indicating that S-acylation on C202 per se does not lead to PTP opening. CypD C202S knock-in hearts are protected from ischaemia/reperfusion injury suggesting further that lack of CypD S-acylation at C202 is not detrimental (when C is mutated to S) and does not induce PTP opening. However, we find that ischaemia leads to de-acylation of C202 and that calcium overload in isolated mitochondria promotes de-acylation of CypD. Furthermore, a high bolus of calcium in WT cardiac mitochondria displaces CypD from its physiological binding partners and possibly renders it available for interaction with the PTP. CONCLUSIONS: Taken together the data suggest that with ischaemia CypD is de-acylated at C202 allowing the free cysteine residue to undergo oxidation during the first minutes of reperfusion which in turn targets it to the PTP.

EMRE is essential for mitochondrial calcium uniporter activity in a mouse model.

The mitochondrial calcium uniporter is widely accepted as the primary route of rapid calcium entry into mitochondria, where increases in matrix calcium contribute to bioenergetics but also mitochondrial permeability and cell death. Hence, regulation of uniporter activity is critical to mitochondrial homeostasis. The uniporter subunit EMRE is known to be an essential regulator of the channel-forming protein MCU in cell culture, but EMRE's impact on organismal physiology is less understood. Here we characterize a mouse model of EMRE deletion and show that EMRE is indeed required for mitochondrial calcium uniporter function in vivo. EMRE-/- mice are born less frequently; however, the mice that are born are viable, healthy, and do not manifest overt metabolic impairment, at rest or with exercise. Finally, to investigate the role of EMRE in disease processes, we examine the effects of EMRE deletion in a muscular dystrophy model associated with mitochondrial calcium overload.

The ribosomal prolyl-hydroxylase OGFOD1 decreases during cardiac differentiation and modulates translation and splicing.

The mechanisms regulating translation and splicing are not well understood. We provide insight into a new regulator of translation, OGFOD1 (2-oxoglutarate and iron dependent oxygenase domain-containing protein 1), which is a prolyl-hydroxylase that catalyzes the posttranslational hydroxylation of Pro-62 in the small ribosomal protein S23. We show that deletion of OGFOD1 in an in vitro model of human cardiomyocytes decreases translation of specific proteins (e.g., RNA-binding proteins) and alters splicing. RNA sequencing showed poor correlation between changes in mRNA and protein synthesis, suggesting that posttranscriptional regulation was the primary cause for the observed differences. We found that loss of OGFOD1 and the resultant alterations in protein translation modulates the cardiac proteome, shifting it towards higher protein amounts of sarcomeric proteins such as cardiac troponins, titin and cardiac myosin binding protein C. Furthermore, we found a decrease of OGFOD1 during cardiomyocyte differentiation. These results suggest that loss of OGFOD1 modulates protein translation and splicing, thereby leading to alterations in the cardiac proteome and highlight the role of altered translation and splicing in regulating the proteome..