Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae.

By largely unknown mechanism(s), SARS-CoV-2 hijacks the host translation apparatus to promote COVID-19 pathogenesis. We report that the histone methyltransferase G9a noncanonically regulates viral hijacking of the translation machinery to bring about COVID-19 symptoms of hyperinflammation, lymphopenia, and blood coagulation. Chemoproteomic analysis of COVID-19 patient peripheral mononuclear blood cells (PBMC) identified enhanced interactions between SARS-CoV-2-upregulated G9a and distinct translation regulators, particularly the N -methyladenosine (m A) RNA methylase METTL3.

Nitric Oxide Affects Heme Oxygenase-1, Hepcidin, and Transferrin Receptor Expression in the Placenta.

Nitric oxide (NO) is a gasotransmitter that avidly binds both free and heme-bound iron, forming relatively stable iron nitrosyl compounds (FeNOs). We have previously demonstrated that FeNOs are present in the human placenta and are elevated in preeclampsia and intrauterine growth restriction. The ability of NO to sequester iron raises the possibility of the NO-mediated disruption of iron homeostasis in the placenta.

In utero Treatment of Congenital High Airway Obstruction Syndrome via Fetal Laryngoscopy and EXIT Procedure.

Introduction: Congenital high airway obstruction syndrome (CHAOS) is a rare condition that can progress to fetal hydrops and demise in utero or at birth unless interventions are undertaken to alleviate the tracheal obstruction. While the ex-utero intrapartum treatment (EXIT) procedure for airway stabilization is technically feasible, abnormal pulmonary development as a result of the antenatal obstructive process may result in severe postnatal respiratory complications.

Case Presentation: We describe a case of CHAOS with secondary hydrops treated in utero at 24 0/7 weeks' gestation by fetoscopic tracheal decompression via laser perforation of the airway obstruction.

Dual demise following laser surgery for twin-twin transfusion syndrome: Analysis of 52 cases at a single fetal surgery center.

Objective: To evaluate all individual cases of dual twin demise following laser surgery for twin-twin transfusion syndrome (TTTS).

Method: This is an analysis of all monochorionic diamniotic twin gestations with TTTS complicated by dual demise following laser surgery from 2006 to 2019. Cases were reviewed by (1) a fetal surgeon researcher and (2) a panel of independent experienced maternal-fetal medicine specialists to code an etiology of demise for the donor and recipient, and to assess for possible preventability.

A benchmarking study of SARS-CoV-2 whole-genome sequencing protocols using COVID-19 patient samples.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging new type of coronavirus that is responsible for the COVID-19 pandemic and the unprecedented global health emergency. Whole-genome sequencing (WGS) of SARS-CoV-2 plays a critical role in understanding the disease. Performance variation exists across SARS-CoV-2 viral WGS technologies, but there is currently no benchmarking study comparing different WGS sequencing protocols.

Initial clinical characteristics of gravid severe acute respiratory syndrome coronavirus 2-positive patients and the risk of progression to severe coronavirus disease 2019.

Background: Available data suggest that the obstetric population is particularly vulnerable to severe respiratory syndrome coronavirus 2 infection, with a variable clinical course leading to severe respiratory failure. However, established early warning scores designed to identify patients at risk of clinical deterioration were never validated in the obstetric population.

Objective: This retrospective cohort study sought to evaluate the initial clinical characteristics of pregnant patients diagnosed with severe acute respiratory syndrome coronavirus 2 infection and to develop a pregnancy-specific early warning score to identify patients at risk for clinical deterioration and requiring advanced respiratory support.

Novel gene-specific translation mechanism of dysregulated, chronic inflammation reveals promising, multifaceted COVID-19 therapeutics.

Hyperinflammation and lymphopenia provoked by SARS-CoV-2-activated macrophages contribute to the high mortality of Coronavirus Disease 2019 (COVID-19) patients. Thus, defining host pathways aberrantly activated in patient macrophages is critical for developing effective therapeutics. We discovered that G9a, a histone methyltransferase that is overexpressed in COVID-19 patients with high viral load, activates translation of specific genes that induce hyperinflammation and impairment of T cell function or lymphopenia.

Neonatal Outcomes and Maternal Characteristics in Monochorionic Diamniotic Twin Pregnancies: Uncomplicated versus Twin-to-Twin Transfusion Syndrome Survivors after Fetoscopic Laser Surgery.

Unlabelled: Preterm birth remains a major complication of fetal laser surgery (FLS) due to twin-to-twin transfusion syndrome (TTTS).

Objectives: We tested the hypothesis that neonatal outcomes in fetuses born at >24 weeks are worse in TTTS survivors compared to uncomplicated monochorionic diamniotic (MCDA) twins.

Methods: 196 patients with TTTS treated with laser therapy and 91 uncomplicated MCDA gestations were compared.

Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6.

Background: Mesenchymal stem cells (MSCs) are promising tools for the treatment of human lung disease and other pathologies relevant to newborn medicine. Recent studies have established MSC exosomes (EXO), as one of the main therapeutic vectors of MSCs in mouse models of multifactorial chronic lung disease of preterm infants, bronchopulmonary dysplasia (BPD). However, the mechanisms underlying MSC-EXO therapeutic action are not completely understood.

The Influence of Blood Pressure on Fetal Aortic Distensibility: An Animal Validation Study.

Background/aims: Aortic distension waveforms describe the change in diameter or cross-sectional area over the cardiac cycle. We aimed to validate the association of aortic fractional area change (AFAC) with blood pressure (BP) in a fetal lamb model.

Methods: Four pregnant ewes underwent open fetal surgery under general anesthesia at 107-120 gestational days.

Biomimetic Culture Reactor for Whole-Lung Engineering.

Decellularized organs are now established as promising scaffolds for whole-organ regeneration. For this work to reach therapeutic practice, techniques and apparatus are necessary for doing human-scale clinically applicable organ cultures. We have designed and constructed a bioreactor system capable of accommodating whole human or porcine lungs, and we describe in this study relevant technical details, means of assembly and operation, and validation.

Stem Cell Therapy in Neonatal Diseases.

Common complications in neonates occur in almost every organ system in the neonatal intensive care unit. While a number of them have short-term effects, a few of them also have long-term consequences. Among the latter are bronchopulmonary dysplasia and necrotizing enterocolitis in premature neonates, and hypoxic ischemic encephalopathy in borderline preterm and term neonates.

Antenatal maternal hypoxic stress: adaptations in fetal lung Renin-Angiotensin system.

Antenatal maternal hypoxia (AMH) can lead to intrauterine growth restriction (IUGR), as well as idiopathic pulmonary hypertension of newborn and adult, the latter of which may be a consequence of alterations in the local pulmonary renin-angiotensin system (RAS). Little is known of these adaptations, however. Thus, we tested the hypothesis that antenatal maternal hypoxia is associated with alterations in gene and protein expression of the pulmonary renin-angiotensin system, which may play an important role in pulmonary disorders in the offspring.

Tissue-specific dysregulation of DNA methylation in aging.

The normal aging process is a complex phenomenon associated with physiological alterations in the function of cells and organs over time. Although an attractive candidate for mediating transcriptional dysregulation, the contribution of epigenetic dysregulation to these progressive changes in cellular physiology remains unclear. In this study, we employed the genome-wide HpaII tiny fragment enrichment by ligation-mediated PCR assay to define patterns of cytosine methylation throughout the rat genome and the luminometric methylation analysis assay to measure global levels of DNA methylation in the same samples.

Brain renin-angiotensin system: fetal epigenetic programming by maternal protein restriction during pregnancy.

Objective: Maternal protein malnutrition during pregnancy can lead to significant alterations in the systemic renin-angiotensin system (RAS) in the fetus. All components of the RAS are present in brain and may be altered in many disease states. Importantly, these disorders are reported to be of higher incidence in prenatally malnourished individuals.

Gene expression in the placenta: maternal stress and epigenetic responses.

Successful placental development is crucial for optimal growth, development, maturation and survival of the embryo/fetus into adulthood. Numerous epidemiologic and experimental studies have demonstrated the profound influence of intrauterine environment on life, and the diseases to which one is subject as an adult. For the most part, these invidious influences, whether maternal hypoxia, protein or caloric deficiency or excess, and others, represent types of maternal stress.

Maternal protein deprivation: changes in systemic renin-angiotensin system of the mouse fetus.

We tested the hypothesis that maternal protein deprivation during gestation results in changes in expression of the systemic renin-angiotensin system in fetal mice. Fetal weight was decreased significantly as a consequence of 50% maternal protein deprivation during second half of gestation. In fetal liver, angiotensinogen protein expression was reduced significantly despite a significant increase in messenger RNA (mRNA).

Gene expression patterns in the hypoxic murine placenta: a role in epigenesis?

Hypoxia has been identified as a major stress or in placental and fetal development. To test the hypothesis that hypoxic stress responses are associated with gene expression changes, the authors measured gene expression in the mouse placenta in response to 48 hours of hypoxia. Embryonic day 15.

Gene expression patterns in the developing murine placenta.

Objective: Successful placental development is crucial for optimal growth, maturation, and survival of the embryo/fetus. To examine genetic aspects of placental development, we investigated gene expression patterns in the murine placenta at embryonic day 10.5 (E10.

Pre- and postjunctional alpha(2)-adrenergic receptors in fetal and adult ovine cerebral arteries.

In ovine cerebral arteries, adrenergic-mediated vasoconstrictor responses differ significantly with developmental age. We tested the hypothesis that, in part, these differences are a consequence of altered alpha(2)-adrenergic receptor (alpha(2)-AR) density and/or affinity. In fetal (approximately 140 days) and adult sheep, we measured alpha(2)-AR density and affinity with the antagonist [(3)H]idazoxan in main branch cerebral arteries and other vessels.