Methods of Reducing Myocardial Injury Following Myocardial Infarction

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Tissue Salvage in the Non-reperfused Myocardium Mediated by (the absence of the circadian rhythm gene) mPer2 and (the receptor tyrosine kinase) EphrinA1

Alterations in circadian rhythm have been associated with numerous cardiovascular pathologies. In project 1, we tested the hypothesis that functional mutation of the Per2 circadian clock gene would provide cardioprotection to mice that had undergone permanent coronary ligation to induce myocardial infarction (MI). mPer2-M mice had a 43% smaller infarct size compared to wild type (WT), along with reduced leukocyte infiltration, increased capillary density, increased myocyte hypertrophy, and reduced myocyte apoptosis. This suggests that mutation of mPer2 is cardioprotective.  The heart lacks a sufficient capacity for endogenous repair after injury. We tested the hypothesis that intramyocardial administration of ephrinA1-Fc at the time of MI would promote cardiomyocyte survival, subsequently reducing infarct size and inflammatory cell infiltrate. The ephrinA1 ligand has been predominantly characterized as a pro-angiogenic factor in development and tumor progression, but is also involved in apoptosis and inflammation. The ephrinA1 ligand has not been studied in the adult myocardium or in the context of acute MI.   Intramyocardial injection of EphrinA1-Fc reduced infarct size, necrosis, chamber dilation, and left ventricular free wall thinning four days after MI. Inflammation was also substantially reduced, with reductions in neutrophil and leukocyte density. We measured reductions in serum cTnI, and cleaved PARP, and increased bag-1 protein expression, suggesting reduced cell death. Phosphorylated AKT/total AKT protein was increased, indicating improved cellular survival. Our analysis of gene expression revealed that Eph receptors A1-A4, A6, and A7 were expressed in the uninjured adult myocardium. Expression of EphA1-A3 and EphA7 was significantly increased following MI while EphA6 expression was decreased. Treatment with ephrinA1-Fc further increased EphA1 and EphA2 gene expression, and also increased EphA4 expression.   To date, only reperfusion has been shown to reduce injury and improve long-term remodeling. We have discovered two new mechanisms by which this can be effected: 1) we have observed a dramatic reduction in cardiac injury in mice lacking a functional circadian gene product mPer2; and 2) we are the first to identify a role for ephrinA1/EphA signaling in the repair process following MI, and have identified a novel, protective role for ephrinA1-Fc administration at the time of MI.  Ph.D

Moving biochemistry and molecular biology courses online in times of disruption: Recommended practices and resources ‐ a collaboration with the faculty community and ASBMB

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163423/2/bmb21354_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163423/1/bmb21354.pd

Deconstructing complexity: A comparative study of government collaboration in national digital platforms and smart city networks in Europe

This research deconstructs complexity as a key challenge of intergovernmental digitalisation projects. While much of the literature acknowledges that the fundamental restructuring coupled with technical capacity that these joint projects require leads to increased complexity, little is known about how different types of complexity interact within the collaborative process. Using Klijn and Koppenjan’s (2014) work on substantive, strategic, and institutional complexity, we apply complexity theory in collaborative digital environments. To do so, eight digital projects are analysed that differ by state structure and government level. Using a cross-case design with 50 semi-structured expert interviews, we find that each digitalisation project exhibits all types of complexity and that these complexities overlap. However, clear differences emerge between national and local level projects, suggesting that complexity in digitalisation processes presents different challenges for collaborative digitalisation projects across contexts

Ephrin–Eph signaling as a potential therapeutic target for the treatment of myocardial infarction

Although numerous strategies have been developed to reduce the initial ischemic insult and cellular injury that occurs during myocardial infarction (MI), few have progressed into the clinical arena. The epidemiologic and economic impact of MI necessitates the development of innovative therapies to rapidly and effectively reduce the initial injury and subsequent cardiac dysfunction. The Eph receptors and their cognate ligands, the ephrins, are the largest family of receptor tyrosine kinases, and their signaling has been shown to play a diverse role in various cellular processes. The recent advances in the study of ephrin– Eph signaling have shown promising progress in many fields of medicine. They have been implicated in the pathophysiology of various cancers and in the regulation of inflammation and apoptosis. Recent studies have shown that manipulation of ephrin–Eph cell signaling can favorably influence cardiomyocyte viability and ultimately preserve cardiac function post-MI. In this article, we explore the hypothesis that manipulation of ephrin–Eph signaling may potentially be a novel therapeutic target in the treatment of MI through alteration of the cellular processes that govern injury and wound healing

Genotype–phenotype correlations in individuals with pathogenic RERE variants

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7

Genotype–phenotype correlations in individuals with pathogenic RERE variants

Heterozygous variants in the arginine‐glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin‐1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss‐of‐function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine‐rich region in the Atrophin‐1 domain. We have also identified a recurrent two‐amino‐acid duplication in this region that is associated with the development of a CHARGE syndrome‐like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.We describe nine unrelated individuals who carry partial deletions or putatively deleterious sequence variants in RERE. An analysis of clinical and molecular data from individuals with mutations affecting RERE suggests the existence of novel genotype‐phenotype correlations and demonstrates that a high percentage of RERE pathogenic variants affect a histidine‐rich region in the Atrophin‐1 domain. We have also identified a recurrent two‐amino‐acid duplication in this region that is associated with the development of a CHARGE syndrome‐like phenotype.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143789/1/humu23400_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143789/2/humu23400.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143789/3/humu23400-sup-0001-SuppMat.pd

Clinical experience with severe acute respiratory syndrome Coronavirus 2-related illness in children : hospital experience in Cape Town, South Africa

CITATION: van der Zalm, M. M. et al. 2021. Clinical Experience With Severe Acute Respiratory Syndrome Coronavirus 2-Related Illness in Children: Hospital Experience in Cape Town, South Africa. Clinical infectious diseases, 72(12):e938–e944. doi:10.1093/cid/ciaa1666The original publication is available at https://academic.oup.com/cid/Background: Children seem relatively protected from serious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease, but little is known about children living in settings with high tuberculosis and human immunodeficiency virus (HIV) burden. This study reflects clinical data on South African children with SARS-CoV-2. Methods: We collected clinical data of children aged <13 years with laboratory-confirmed SARS-CoV-2 presenting to Tygerberg Hospital, Cape Town, between 17 April and 24 July 2020. Results: One hundred fifty-nine children (median age, 48.0 months [interquartile range {IQR}, 12.0-106.0 months]) were included. Hospitalized children (n = 62), with a median age of 13.5 months (IQR, 1.8-43.5 months) were younger than children not admitted (n = 97; median age, 81.0 months [IQR, 34.5-120.5 months]; P < .01.). Thirty-three of 159 (20.8%) children had preexisting medical conditions. Fifty-one of 62 (82.3%) hospitalized children were symptomatic; lower respiratory tract infection was diagnosed in 21 of 51 (41.2%) children, and in 11 of 16 (68.8%) children <3 months of age. Respiratory support was required in 25 of 51 (49.0%) children; 13 of these (52.0%) were <3 months of age. One child was HIV infected and 11 of 51 (21.2%) were HIV exposed but uninfected, and 7 of 51 (13.7%) children had a recent or new diagnosis of tuberculosis. Conclusions: Children <1 year of age hospitalized with SARS-CoV-2 in Cape Town frequently required respiratory support. Access to oxygen may be limited in some low- and middle-income countries, which could potentially drive morbidity and mortality. HIV infection was uncommon but a relationship between HIV exposure, tuberculosis, and SARS-CoV-2 should be explored.https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac266/6591403Publishers versio