Biology subjects

Burd, I.

Publications and source records attributed to Burd, I..

6 recordsLinked to original sources

bioRxiv2026

Ferroptosis of selective progenitor cell types during embryogenesis ensures proper organ morphogenesis

Ferroptosis, a form of non-apoptotic cell death, is induced by lipid peroxidation resulting from an intracellular accumulation of labile iron (1). While apoptosis is involved in embryonic development (2), the role of ferroptosis in embryogenesis is unknown. Here, we report that the ferroptosis process occurs in the embryonic lung and kidney at mid- and late-gestation. In these tissues, pro-ferroptotic cells include subpopulations of the Sox9+ distal lung epithelial cells and the Flk1+ vascular progenitors in the kidney glomeruli. Lipidomic analysis reveals mixed lipid peroxidation as the driver for ferroptosis. The role of ferroptosis in the morphogenesis of these organs was confirmed by triple positivity of TfR1, 4-HNE and TUNEL, mitochondrial defects, cell membrane breakage, dead cell remnants, single-cell RNA-sequencing of a ferroptosis gene signature. Genetic manipulation of Gpx4, an endogenous inhibitor of ferroptosis. Further, genetic knockout or transgenic overexpression of Gpx4 affects lung and kidney development and results in cystic lungs and kidneys. Notably, conditional deletion Gpx4 results in hypoplasia of the lung epithelia and of the renal glomeruli, while transgenic overexpression of Gpx4 resulted in atelectasis with collapsed lung alveoli and hypertrophic glomeruli. Together, these findings show that ferroptosis regulates lung and kidney morphogenesis by acting in key progenitor cell populations during gestation. Supplementation of iron or polyunsaturated fatty acid during pregnancy has implications for organogenesis.

developmental biology↗

bioRxiv2026

Early Insulin Signaling Defects and Oxidative Stress Kinase Activation Precede Tau Pathology in PS19 Tau Transgenic Mice

Pathological tau accumulation is a hallmark of Alzheimers disease (AD), yet its relationship with impaired insulin signaling remains unclear. Previously, we reported altered IRS1 phosphorylation reduced p IR beta, and GLUT3 expression in young AD transgenic mice prior to overt pathology. Here, we investigated insulin signaling and oxidative stress pathways in the Tau P301S (PS19) mouse model. We found that alterations in phospho IRS1, phospho IR beta, and the glucose transporters GLUT3 and GLUT4 occur before pathogenic tau deposition. In stable tau expressing human neuronal cell lines, tau expression was similarly associated with impaired insulin signaling. Concurrent dysregulation of insulin signaling and activation of oxidative stress responsive kinases, accompanied by increased microglial abundance, were evident in 2 month old PS19 mice and persisted into adulthood. Together, these findings demonstrate that insulin signaling abnormalities and oxidative stress kinase activation are early and sustained features of PS19 tauopathy, preceding the onset of overt neuropathology.

neuroscience↗

bioRxiv2025

Bacterial extracellular vesicles as a tunable platform for vaginal drug delivery

There is a critical gap in the development of new therapeutic platforms designed to treat gynecologic and obstetric diseases. Compared to systemic drug delivery, vaginal drug administration of nanoparticle formulations limits off-target side effects while increasing therapeutic concentration in target tissues, showing promise for clinical translation. However, these formulations suffer from limited scalability, high-cost reagents, and long optimization timelines. Recent work highlights the potential of bacterial extracellular vesicles (bEVs) as a low-cost, tunable platform for therapeutic applications. Here, we evaluate bEVs as a therapeutic carrier for vaginal drug delivery. We demonstrate the loading of the model protein moxNeonGreen into Escherichia coli Nissle 1917 bEVs. By optimizing growth parameters, we increase protein loading into bEVs. We evaluate the effect of bEVs on the vaginal microenvironment, and observe no negative impact on vaginal epithelial cells, endocervical cells, or vaginal bacteria in vitro. Additionally, we observe the retention of bEVs in the murine female reproductive tract for more than six hours. This study provides a framework for using genetically engineered bEVs to rapidly generate customizable therapies for a range of gynecologic and obstetric conditions, addressing longstanding challenges in womens health therapeutics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=50 SRC="FIGDIR/small/658669v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@e483d2org.highwire.dtl.DTLVardef@8a6d2corg.highwire.dtl.DTLVardef@5756borg.highwire.dtl.DTLVardef@5fdb67_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2023

Fetal Membrane Inflammasome Activation by Choriodecidual Ureaplasma parvum Infection without Intra-Amniotic Infection in an NHP Model

Intrauterine infection is a significant cause of preterm labor and neonatal morbidity and mortality. Ureaplasma parvum is the micro-organism most commonly isolated from cases of preterm birth and preterm premature rupture of membranes (pPROM). However, the mechanisms during the early stages of ascending reproductive tract infection that initiate maternal-fetal inflammatory pathways, preterm birth and pPROM remain poorly understood. To examine inflammation in fetal (chorioamnionic) membranes in response to Ureaplasma parvum infection, we utilized a novel in vivo non-human primate model of early choriodecidual infection. Eight chronically catheterized pregnant rhesus macaques underwent maternal-fetal catheterization surgery at 105-112 days gestation and choriodecidual inoculation with Ureaplasma parvum (105cfu/mL of a low passaged clinical isolate, serovar 1; n=4) or saline/sterile media (Controls; n=4) starting at 115-119 days gestation, repeated every 5 days until scheduled cesarean-section at 136-140d gestation (term=167d). The average inoculation to delivery interval was 21 days and Ureaplasma infection of the amniotic fluid was undetectable by culture and PCR in all animals. Inflammatory mediators in amniotic fluid (AF) were assessed by Luminex, ELISA and multiplex assays. RNA was extracted from the chorion and amnionic membranes for single gene analysis (qRT-PCR) and protein expression was determined by Western blot and immunohistochemistry. Our NHP model of choriodecidual Ureaplasma infection, representing an early-stage ascending reproductive tract infection without microbial invasion of the amniotic cavity, resulted in increased fetal membrane protein and gene expression of MMP-9 and PTGS2, but did not result in preterm labor (no increase in uterine contractility) or increased concentrations of amniotic fluid pro-inflammatory cytokines (IL-1{beta}, IL-6, IL-8, IL-18, TNF-). However, membrane expression of inflammasome sensor molecules, NLRP3, NLRC4, AIM2 and NOD2, and the adaptor protein ASC (PYCARD) gene expression were significantly increased in the Ureaplasma group when compared to non-infected controls. Gene expression of IL-1{beta}, IL-18, the IL-18R1 receptor, CASPASE-1 and pro-CASPASE-1 protein were also increased in the fetal membranes with Ureaplasma infection. Downstream inflammatory signaling genes MYD88 was also significantly upregulated in both the amnion and chorion, along with a significant increase in NFKB in the chorion. These results demonstrate that even at the early stages of ascending reproductive tract Ureaplasma infection, activation of inflammasome complexes and pathways associated with degradation of chorioamnionic membrane integrity are present. This study therefore provides experimental evidence for the importance of the early stages of ascending Ureaplasma infection in initiating processes of pPROM and preterm labor. These findings have implications for the identification of intrauterine inflammation before microbes are detectable in the amniotic fluid (sterile inflammation) and the timing of potential treatments for preterm labor and fetal injury caused by intrauterine infection.

physiology↗

bioRxiv2023

Suppression of progesterone by influenza A virus causes adverse maternal and fetal outcomes in mice

Influenza A virus infection during pregnancy can cause adverse maternal and fetal outcomes, but the mechanism responsible remains elusive. Infection of outbred mice with 2009 H1N1 at embryonic day (E) 10 resulted in significant maternal morbidity, placental tissue damage and inflammation, fetal growth restriction, and developmental delays that lasted through weaning. Restriction of pulmonary virus replication was not inhibited during pregnancy, but infected dams had suppressed circulating and placental progesterone (P4) concentrations that were caused by H1N1-induced upregulation of pulmonary cyclooxygenase (COX)-1, but not COX-2-, dependent synthesis and secretion of prostaglandin (PG) F2. Treatment with 17--hydroxyprogesterone caproate (17-OHPC), a synthetic progestin that is safe to use in pregnancy, ameliorated the adverse maternal and fetal outcomes from H1N1 infection and prevented placental cell death and inflammation. These findings highlight the therapeutic potential of progestin treatments for influenza during pregnancy. ImportancePregnant individuals are at risk of severe outcomes from both seasonal and pandemic influenza A viruses. Influenza infection during pregnancy is associated with adverse fetal outcomes at birth and adverse consequences for offspring into adulthood. We developed an outbred mouse model of 2009 H1N1 influenza virus infection during pregnancy, with semi-allogenic fetuses. When dams are infected with 2009 H1N1, in addition to pulmonary virus replication, tissue damage, and inflammation, the placenta shows evidence of transient damage and inflammation that is mediated by increased activity along the arachidonic acid pathway leading to suppression of circulating progesterone. Placental damage and suppressed progesterone are associated with long-term effects on perinatal growth and developmental delays in offspring. Treatment of H1N1-infected pregnant mice with 17-OHPC, a synthetic progestin treatment safe that is safe to use in pregnancy, prevents placental damage and inflammation and adverse fetal outcomes. This provided a novel therapeutic option for treatment of influenza during pregnancy that should be explored clinically.

microbiology↗

bioRxiv2023

Adverse outcomes in SARS-CoV-2 infected pregnant mice are gestational age-dependent and resolve with antiviral treatment

SARS-CoV-2 infection during pregnancy is associated with severe COVID-19 and adverse fetal outcomes, but the underlying mechanisms remain poorly understood. Moreover, clinical studies assessing therapeutics against SARS-CoV-2 in pregnancy are limited. To address these gaps, we developed a mouse model of SARS-CoV-2 infection during pregnancy. Outbred CD1 mice were infected at embryonic day (E) 6, E10, or E16 with a mouse adapted SARS-CoV-2 (maSCV2) virus. Outcomes were gestational age-dependent, with greater morbidity, reduced anti-viral immunity, greater viral titers, and more adverse fetal outcomes occurring with infection at E16 (3rd trimester-equivalent) than with infection at either E6 (1st trimester-equivalent) or E10 (2nd trimester-equivalent). To assess the efficacy of ritonavir-boosted nirmatrelvir (recommended for pregnant individuals with COVID-19), we treated E16-infected dams with mouse equivalent doses of nirmatrelvir and ritonavir. Treatment reduced pulmonary viral titers, decreased maternal morbidity, and prevented adverse offspring outcomes. Our results highlight that severe COVID-19 during pregnancy and adverse fetal outcomes are associated with heightened virus replication in maternal lungs. Ritonavir-boosted nirmatrelvir mitigated adverse maternal and fetal outcomes of SARS-CoV-2 infection. These findings prompt the need for further consideration of pregnancy in preclinical and clinical studies of therapeutics against viral infections.

microbiology↗