For clarity, the authors are updating Figure 1, the flow chart for this study, to better illustrate the excluded samples and criteria for exclusion. The HTML and PDF versions of the figure and its legend have been updated.
STUDY QUESTION Does the immune response to coronavirus disease 2019 (COVID-19) infection or the BNT162b2 mRNA vaccine involve the ovarian follicle, and does it affect its function? SUMMARY ANSWER We were able to demonstrate anti-severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) IgG in follicular fluid (FF) from both infected and vaccinated IVF patients, with no evidence for compromised follicular function. WHAT IS KNOWN ALREADY No research data are available yet. STUDY DESIGN, SIZE, DURATION This is a cohort study, composed of 32 consecutive IVF patients, either infected with COVID-19, vaccinated or non-exposed, conducted between 1 February and 10 March 2021 in a single university hospital-based IVF clinic. PARTICIPANTS/MATERIALS, SETTING, METHODS A consecutive sample of female consenting patients undergoing oocyte retrieval was recruited and assigned to one of the three study groups: recovering from confirmed COVID-19 (n = 9); vaccinated (n = 9); and uninfected, non-vaccinated controls (n = 14). Serum and FF samples were taken and analyzed for anti-COVID IgG as well as estrogen, progesterone and heparan sulfate proteoglycan 2 concentration, as well as the number and maturity of aspirated oocytes and day of trigger estrogen and progesterone measurements. Main outcome measures were follicular function, including steroidogenesis, follicular response to the LH/hCG trigger, and oocyte quality biomarkers. MAIN RESULTS AND THE ROLE OF CHANCE Both COVID-19 and the vaccine elicited anti-COVID IgG antibodies that were detected in the FF at levels proportional to the IgG serum concentration. No differences between the three groups were detected in any of the surrogate parameters for ovarian follicle quality. LIMITATIONS, REASONS FOR CAUTION This is a small study, comprising a mixed fertile and infertile population, and its conclusions should be supported and validated by larger studies. WIDER IMPLICATIONS OF THE FINDINGS This is the first study to examine the impact of SARS–Cov-2 infection and COVID-19 vaccination on ovarian function and these early findings suggest no measurable detrimental effect on function of the ovarian follicle. STUDY FUNDING/COMPETING INTEREST(S) The study was funded out of an internal budget. There are no conflicts of interest for any of the authors. TRIAL REGISTRATION NUMBER CinicalTrials.gov registry number NCT04822012.
Sodium-calcium exchangers have long been considered inert with respect to monovalent cations such as lithium, choline, and N-methyl-D-glucamine. A key question that has remained unsolved is how despite this, Li ؉ catalyzes calcium exchange in mammalian tissues. Here we report that a Na ؉ /Ca 2؉ exchanger, NCLX cloned from human cells (known as FLJ22233), is distinct from both known forms of the exchanger, NCX and NCKX in structure and kinetics. Surprisingly, NCLX catalyzes active Li ؉ /Ca 2؉ exchange, thereby explaining the exchange of these ions in mammalian tissues. The NCLX protein, detected as both 70-and 55-KDa polypeptides, is highly expressed in rat pancreas, skeletal muscle, and stomach. We demonstrate, moreover, that NCLX is a K ؉ -independent exchanger that catalyzes Ca 2؉ flux at a rate comparable with NCX1 but without promoting Na ؉ /Ba 2؉ exchange. The activity of NCLX is strongly inhibited by zinc, although it does not transport this cation. NCLX activity is only partially inhibited by the NCX inhibitor, KB-R7943. Our results provide a cogent explanation for a fundamental question. How can Li ؉ promote Ca 2؉ exchange whereas the known exchangers are inert to Li ؉ ions? Identification of this novel member of the Na ؉ / Ca 2؉ superfamily, with distinct characteristics, including the ability to transport Li ؉ , may provide an explanation for this phenomenon.Plasma membrane Na ϩ /Ca 2ϩ exchange is an important element in cellular Ca 2ϩ homeostasis. It has been extensively investigated in mammals, especially in cardiac and neuronal tissues (1), where this mechanism is essential for regulation of Ca 2ϩ homeostasis. Na ϩ /Ca 2ϩ exchange also plays a key role in many other organs and tissues by modulating the intracellular Ca 2ϩ response (2). The Na ϩ /Ca 2ϩ exchangers described to date are members of four major families (1). Of these, only NCX1-3 and NCKX1-4 are found in mammalian cells, whereas the other two are expressed in plants, yeast, and bacteria.The stoichiometry of NCX exchangers is based on 3-4Na ϩ / 1Ca 2ϩ , and the protein is structurally organized as nine transmembrane helixes divided by a large cytoplasmic loop (3). NCKX family proteins have a stoichiometry of 4Na/1Ca/1K, and their topology is thought to consist of two sets of five membrane helixes divided by a cytoplasmic loop and NH 2 -terminal extracellular domain (4). The two families share several important functional and structural motifs: a structural hallmark of the Na ϩ /Ca 2ϩ exchanger superfamily is the presence of two regions of sequence similarity, called ␣1 and ␣2, which are considered necessary and sufficient for generating exchange activity (1, 5). Functionally, these exchangers are considered catalytically inert to inorganic and organic monovalent cations such as Li ϩ , NMG ϩ , 1 and choline ϩ , which are often used in "sodium-free" solutions to reverse Na ϩ /Ca 2ϩ exchange activity (2).Although Li ϩ ions are not transported by either NCX or NCKX, numerous physiological studies have reported a significant effect of this ion ...
Background: The significant risks posed to mothers and fetuses by COVID-19 in pregnancy have sparked a worldwide debate surrounding the pros and cons of antenatal SARS-CoV-2 inoculation, as we lack sufficient evidence regarding vaccine effectiveness in pregnant women and their offspring. We aimed to provide substantial evidence for the effect of BNT162b2 mRNA vaccine versus native infection on maternal humoral, as well as transplacentally acquired fetal immune response, potentially providing newborn protection.Methods: A multicenter study where parturients presenting for delivery were recruited at 8 medical centers across Israel and assigned to three study groups: vaccinated (n=86); PCR-confirmed SARS-CoV-2 infected during pregnancy (n=65), and unvaccinated non-infected controls (n=62).Maternal and fetal blood samples were collected from parturients prior to delivery and from the umbilical cord following delivery, respectively. Sera IgG and IgM titers were measured using Milliplex MAP SARS-CoV-2 Antigen Panel (for S1, S2, RBD and N).Results: BNT162b2 mRNA vaccine elicits strong maternal humoral IgG response (Anti-S and RBD) that crosses the placenta barrier and approaches maternal titers in the fetus within 15 days following the first dose. Maternal to neonatal anti-COVID-19 antibodies ratio did not differ when comparing sensitization (vaccine vs. infection). IgG transfer ratio at birth was significantly lower for third-trimester as compared to second-trimester infection. Lastly, fetal IgM response was detected in 5 neonates, all in the infected group. Conclusions: Antenatal BNT162b2 mRNA vaccination induces a robust maternal humoral response that effectively transfers to the fetus, supporting the role of vaccination during pregnancy.
Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to accumulation of 15-hydroperoxy-arachidonoyl-PE (15-HpETE-PE) generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, PEBP1. As Ca 2+ -independent phospholipase PLA 2 (iPLA 2 β, PLA2G6/PNPLA9 gene), can preferentially hydrolyze peroxidized phospholipids, it may eliminate ferroptotic 15-HpETE-PE death signal. Here we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA 2 β averts ferroptosis whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6/PNPLA9 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson’s disease (PD)-associated mutation fPD R747W and found selectively decreased 15-HpETE-PE hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-CAS9-engineered PNPLA9 R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein mutant SNCA-A53T mice with decreased iPLA 2 β expression and PD-relevant phenotype. Thus, iPLA 2 β is a new ferroptosis regulator and its mutations may be implicated in PD pathogenesis.
(EP) in rodents are challenging, and available data are sparse. Herein, we utilized a novel type of bipolar electrode to evaluate the atrial EP of rodents through small lateral thoracotomy. In anesthetized rats and mice, we attached two bipolar electrodes to the right atrium and a third to the right ventricle. This standard setup enabled high-resolution EP studies. Moreover, a permanent implantation procedure enabled EP studies in conscious freely moving rats. Atrial EP was evaluated in anesthetized rats, anesthetized mice (ICR and C57BL6 strains), and conscious rats. Signal resolution enabled atrial effective refractory period (AERP) measurements and first time evaluation of the failed 1:1 atrial capture, which was unexpectedly longer than the AERP recorded at near normal cycle length by 27.2 Ϯ 2.3% in rats (P Ͻ 0.0001; n ϭ 35), 31.7 Ϯ 8.3% in ICR mice (P ϭ 0.0001; n ϭ 13), and 57.7 Ϯ 13.7% in C57BL6 mice (P ϭ 0.015; n ϭ 4). While AERP rate adaptation was noted when 10 S1s at near normal basic cycle lengths were followed by S2 at varying basic cycle length and S3 for AERP evaluation, such rate adaptation was absent using conventional S1S2 protocols. Atrial tachypacing in rats shortened the AERP values on a timescale of hours, but a reverse remodeling phase was noted thereafter. Comparison of left vs. right atrial pacing in rats was also feasible with the current technique, resulting in similar AERP values recorded in the low right atrium. In conclusion, our findings indicate that in vivo rate adaptation of the rodent atria is different than expected based on previous ex vivo recordings. In addition, atrial electrical remodeling of rats shows unique remodelingreverse remodeling characteristics that are described here for the first time. Further understanding of these properties should help to determine the clinical relevance as well as limitations of atrial arrhythmia models in rodents.atrial effective refractory period; rate adaptation; electrical remodeling MICE AND RATS ARE USED EXTENSIVELY in cardiac research, and reliable models of cardiac pathologies have been developed and applied in these species (4,19,31). Moreover, genetically altered mice have become invaluable tools for studying the molecular basis of cardiac pathologies including ventricular arrhythmias (7, 28). Use of rodents for studying atrial arrhythmias has been largely limited, but in recent years atrial tachyarrhythmias have been repeatedly produced in rats and mice, and rodents are increasingly used for studying various molecular, cellular, and pharmacological aspects of atrial function (1,5,8,24,36,37). In addition, mice with genetic alterations are providing important insights in this field as well (17,23,27,32).Due to the small size of the rodent heart and, more so, the rodent atria, electrode implantation for studies of functional electrophysiology is challenging. Several techniques were developed to increase the applicability of such studies (2, 23). The transesophageal approach, which is least invasive, necessitates the use of high e...
The recently identified ferroptotic cell death is characterized by excessive accumulation of hydroperoxy-arachidonoyl (C20:4)- or adrenoyl (C22:4)- phosphatidylethanolamine (Hp-PE). The selenium-dependent glutathione peroxidase 4 (GPX4) inhibits ferroptosis, converting unstable ferroptotic lipid hydroperoxides to nontoxic lipid alcohols in a tissue-specific manner. While placental oxidative stress and lipotoxicity are hallmarks of placental dysfunction, the possible role of ferroptosis in placental dysfunction is largely unknown. We found that spontaneous preterm birth is associated with ferroptosis and that inhibition of GPX4 causes ferroptotic injury in primary human trophoblasts and during mouse pregnancy. Importantly, we uncovered a role for the phospholipase PLA2G6 (PNPLA9, iPLA2beta), known to metabolize Hp-PE to lyso-PE and oxidized fatty acid, in mitigating ferroptosis induced by GPX4 inhibition in vitro or by hypoxia/reoxygenation injury in vivo. Together, we identified ferroptosis signaling in the human and mouse placenta, established a role for PLA2G6 in attenuating trophoblastic ferroptosis, and provided mechanistic insights into the ill-defined placental lipotoxicity that may inspire PLA2G6-targeted therapeutic strategies.
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