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Ferroptosis is a regulated, non-apoptotic form of cell death, characterized by hydroxy-peroxidation of discrete phospholipid hydroperoxides, particularly hydroperoxyl (Hp) forms of arachidonoyl- and adrenoyl-phosphatidylethanolamine, with a downstream cascade of oxidative damage to membrane lipids, proteins and DNA, culminating in cell death. We recently showed that human trophoblasts are particularly sensitive to ferroptosis caused by depletion or inhibition of glutathione peroxidase 4 (GPX4) or the lipase PLA2G6. Here, we show that trophoblastic ferroptosis is accompanied by a dramatic change in the trophoblast plasma membrane, with macro-blebbing and vesiculation. Immunofluorescence revealed that ferroptotic cell-derived blebs stained positive for F-actin, but negative for cytoplasmic organelle markers. Transfer of conditioned medium that contained detached macrovesicles or co-culture of wild-type target cells with blebbing cells did not stimulate ferroptosis in target cells. Molecular modeling showed that the presence of Hp-phosphatidylethanolamine in the cell membrane promoted its cell ability to be stretched. Together, our data establish that membrane macro-blebbing is characteristic of trophoblast ferroptosis and can serve as a useful marker of this process. Whether or not these blebs are physiologically functional remains to be established. [ABSTRACT FROM AUTHOR]

BACKGROUNDThe 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 the BNT162b2 mRNA vaccine versus native infection on maternal humoral, as well as transplacentally acquired fetal immune response, potentially providing newborn protection.METHODSA multicenter study where parturients presenting for delivery were recruited at 8 medical centers across Israel and assigned to 3 study groups: vaccinated (n = 86); PCR-confirmed SARS-CoV-2 infected during pregnancy (n = 65), and unvaccinated noninfected 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 the Milliplex MAP SARS-CoV-2 Antigen Panel (for S1, S2, RBD, and N).RESULTSThe 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 with second trimester infection. Lastly, fetal IgM response was detected in 5 neonates, all in the infected group.CONCLUSIONAntenatal BNT162b2 mRNA vaccination induces a robust maternal humoral response that effectively transfers to the fetus, supporting the role of vaccination during pregnancy.FUNDINGIsrael Science Foundation and the Weizmann Institute Fondazione Henry Krenter. [ABSTRACT FROM AUTHOR]

The recently identified ferroptotic cell death is characterized by excessive accumulation of hydroperoxy-arachidonoyl (C20:4)- or adrenoyl (C22:4)- phosphatidylethanolamine (Hp-PE). The seleniumdependent glutathione peroxidase 4 (GPX4) inhibits ferroptosis, converting unstable ferroptotic lipid hydroperoxides to nontoxic lipid alcohols in a tissue-specificmanner. 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. [ABSTRACT FROM AUTHOR]

Objective  Animal studies indicate a possible intrauterine immunological imprinting in pregnancies complicated by hypothyroidism. We aimed to evaluate whether exposure to maternal hypothyroidism during pregnancy increases the risk of long-term infectious morbidity of the offspring. Study Design  A retrospective cohort study compared the long-term risk of hospitalization associated with infectious morbidity in children exposed and unexposed in utero to maternal hypothyroidism. Outcome measures included infectious diagnoses obtained during any hospitalization of the offspring (up to the age of 18 years). Results  The study included 224,950 deliveries. Of them, 1.1% (n  = 2,481) were diagnosed with maternal hypothyroidism. Children exposed to maternal hypothyroidism had a significantly higher rate of hospitalizations related to infectious morbidity (13.2 vs. 11.2% for control; odds ratio: 1.2; 95% confidence interval: 1.08–1.36; p  = 0.002). Specifically, incidences of ear, nose, and throat; respiratory; and ophthalmic infections were significantly higher among the exposed group. The Kaplan–Meier curve indicated that children exposed to maternal hypothyroidism had higher cumulative rates of long-term infectious morbidity. In the Cox proportional hazards model, maternal hypothyroidism remained independently associated with an increased risk of infectious morbidity in the offspring while adjusting for confounders. Conclusion  Maternal hypothyroidism during pregnancy is associated with significant pediatric infectious morbidity of the offspring. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether children born with isolated single umbilical artery (iSUA) at term are at an increased risk for long-term pediatric hospitalizations due to respiratory morbidity.Methods: Design: a population-based cohort study compared the incidence of long-term, pediatric hospitalizations due to respiratory morbidity in children born with and without iSUA at term.Setting: Soroka University Medical Center.Participants: all singleton pregnancies of women who delivered between 1991 and 2013.Main Outcome Measure(s): hospitalization due to respiratory morbidity.Analyses: Kaplan-Meier survival curves were used to estimate cumulative incidence of respiratory morbidity. A Cox hazards model analysis was used to establish an independent association between iSUA and pediatric respiratory morbidity of the offspring while controlling for clinically relevant confounders.Results: The study included 232,281 deliveries. 0.3% were of newborns with iSUA (n = 766). Newborns with iSUA had a significantly higher rate of long-term respiratory morbidity compared to newborns without iSUA (7.6 vs 5.5%, p = 0.01). Using a Kaplan-Meier survival curve, newborns with iSUA had a significantly higher cumulative incidence of respiratory hospitalizations (log rank = 0.006). In the Cox model, while controlling for the maternal age, gestational age, and birthweight, iSUA at term was found to be an independent risk factor for long-term respiratory morbidity (adjusted HR = 1.39, 95% CI 1.08-1.81; p = 0.012).Conclusion: Newborns with iSUA are at an increased risk for long-term respiratory morbidity. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether patients with a history of gestational diabetes mellitus (GDM) have an increased risk for long-term ophthalmic morbidity.Methods: Design a population-based study compared the incidence of long-term maternal ophthalmic morbidity in a cohort of women with and without a history of GDM. Setting Soroka University Medical Center.Participants: All singleton pregnancies of women who delivered between 1988 and 2013. Main outcome measure(s) Diagnosis of ophthalmic morbidity. Analyses A Kaplan-Meier survival curve was used to estimate cumulative incidence of ophthalmic morbidity. Cox proportional hazards models were used to estimate the adjusted hazard ratios (HR) for ophthalmic morbidity.Results: During the study period, 104,751 deliveries met the inclusion criteria; 9.4% (n = 9888) of which occurred in patients with a diagnosis of GDM during at least one of their pregnancies. Patients with GDM had a significantly higher incidence of ophthalmic morbidity such as glaucoma, diabetic retinopathy, and retinal detachment compared with controls (0.1 vs. 0.02%, p < 0.001; 0.2 vs. 0.04%, p < 0.001; 0.2 vs. 0.1%, p < 0.001, respectively). Patients with concurrent GDM and preeclampsia had a significantly higher incidence of total ophthalmic complications compared to patients with GDM only (1 vs. 0.6%, respectively, p < 0.001). Using Kaplan-Meier survival curve, patients with a previous diagnosis of GDM had significantly higher cumulative incidence of ophthalmic morbidity (p < 0.001, log-rank test). In the Cox proportional hazards model, a history of GDM remained independently associated with ophthalmic morbidity (adjusted HR 2.0; 95% CI 1.5-2.8; p < 0.001).Conclusions: GDM is an independent risk factor for long-term maternal ophthalmic morbidity. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether patients with a history of obesity during pregnancy have an increased risk for subsequent long-term ophthalmic complications, after controlling for diabetes and preeclampsia.Methods: A population-based study compared the incidence of long-term maternal ophthalmic complications in a cohort of women with and without a history of obesity during pregnancy. Deliveries occurred between the years 1988 and 2013, with a mean follow-up duration of 12 years.Results: During the study period 106 220 deliveries met the inclusion criteria; 2.2% (n = 2353) occurred in patients with a diagnosis of obesity during at least one of their pregnancies. These patients had a significantly higher incidence of ophthalmic complications in total and specifically of diabetic retinopathy. Using a Kaplan-Meier survival curve, we found that patients with a history of obesity during pregnancy had a significantly higher cumulative incidence of ophthalmic complications. Using a Cox proportional hazards model, adjusted for confounders such as maternal age, preeclampsia and diabetes mellitus, we found obesity during pregnancy remained independently associated with ophthalmic complications (adjusted HR, 2.4; 95% CI, 1.4-4.2; p = 0.003).Conclusion: Obesity during pregnancy is an independent risk factor for long-term ophthalmic complications, and specifically diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Objective: The long-term impact of placenta previa on term infants is unknown. We aimed to investigate whether abnormal placentation increases the risk for long-term morbidity of the term offspring.Study Design: A population-based cohort study compared the incidence of long-term hospitalizations up to the age of 18 due to cardiovascular, endocrine, neurological, hematological, respiratory and urinary morbidity of children born at term in pregnancies diagnosed with placenta previa and those without. Deliveries occurred between the years 1991-2013 in a tertiary medical center. Multiple pregnancies, and fetal congenital malformations were excluded. Kaplan-Meier survival curves were used to compare cumulative morbidity incidence over time. A multivariable generalized estimating equation (GEE) logistic regression model analysis was used to control for confounders and for maternal clusters.Results: During the study period 233,123 term deliveries met the inclusion criteria; 0.2% (n=502) of the children were born to mothers with placenta previa. During the follow-up period, children born to mothers with placenta previa did not have an increased risk for long-term cardiovascular, endocrine, hematological, neurological, respiratory, and urinary morbidity.Conclusion: Term offsprings of mothers diagnosed with placenta previa do not appear to be at an increased risk for long-term morbidity up to the age of 18. [ABSTRACT FROM AUTHOR]

Objective To investigate whether patients with a history of preeclampsia have an increased risk of long-term ophthalmic complications. Study Design A population-based study comparing the incidence of long-term maternal ophthalmic complications in a cohort of women with and without a history of preeclampsia. Results During the study period, a total of 103,183 deliveries met the inclusion criteria; 8.1% (n = 8,324) occurred in patients with a diagnosis of preeclampsia during at least one of their pregnancies. Patients with preeclampsia had a significantly higher incidence of long-term ophthalmic morbidity such as diabetic retinopathy and retinal detachment. In addition, a positive linear correlation was found between the severity of preeclampsia and the prevalence of future ophthalmic morbidities (0.3 vs. 0.5 vs. 2.2%, respectively). Kaplan-Meier survival curve indicated that women with preeclampsia had higher rates of total ophthalmic morbidity (0.2 vs. 0.4%, for no preeclampsia and with preeclampsia, respectively; odds ratio = 2.06, 95% confidence interval: 1.42-2.99; p < 0.001). In a Cox proportional hazards model, adjusted for confounders, a history of preeclampsia remained independently associated with ophthalmic complications. Conclusion Preeclampsia is an independent risk factor for long-term maternal ophthalmic morbidity, specifically diabetic retinopathy and retinal detachment. This risk is more substantial depending on the severity of the disease. [ABSTRACT FROM AUTHOR]

Purpose: Placental growth factor (PlGF) has been suggested as a possible biomarker for major placenta-related disorders such as preeclampsia and intrauterine growth restriction. However, experimental findings suggest that PlGF concentrations may be influenced by other factors besides the placenta. In the present study, we examined how acute fetal injury affects PlGF concentrations in maternal circulation. We therefore monitored PlGF concentrations in maternal circulation before and after feticide. Methods: A prospective comparative study was performed. Blood samples were drawn prospectively between January and July 2012, before and after feticide at predetermined time points in relation to the procedure (0, 30, 60, and 120 min). The levels of lactate dehydrogenase (LDH) in the maternal circulation were measured to detect acute tissue damage. PlGF concentrations were measured by standard human ELISA. Results: Following feticide (60 and 120 min), PlGF concentrations decreased significantly compared to the concentrations before feticide. LDH concentrations did not change before and after feticide. Conclusions: Our finding, along with the detailed review of the literature described in our work, supports a new concept in which primary fetal distress can affect PlGF concentration in maternal circulation. A large-scale study is required to strengthen our finding. [ABSTRACT FROM AUTHOR]

Birth asphyxia results in a significant percentage of neonatal morbidity and mortality. A key factor in the management of this complication is the early and accurate detection of brain damage following asphyxia. Currently, reliable tools for such diagnosis are absent. Extensive research has focused on biomarkers in an attempt to solve this matter. Recent data marked serum and urine elevation of the S100B protein as an established peripheral biomarker for detection of brain injury including traumatic head injuries and brain damage following cardiac arrest and stroke. In the past decade, a substantial number of studies illustrated the potential use of S100B testing in order to detect brain damage in asphyxiated newborns. This review summarizes the available data regarding the use of S100B as a biomarker of brain damage following birth asphyxia. [ABSTRACT FROM AUTHOR]

Zinc transporter-1 (ZnT-1) is a putative zinc transporter that confers cellular resistance from zinc toxicity. In addition, ZnT-1 has important regulatory functions, including inhibition of L-type calcium channels and activation of Raf-1 kinase. Here we studied the effects of ZnT-1 on the expression and function of T-type calcium channels. In Xenopus oocytes expressing voltage-gated calcium channel (CaV) 3.1 or CaV3.2, ZnT-1 enhanced the low-threshold calcium currents (IcaT) to 182 ± 15 and 167.95 ± 9.27% of control, respectively (P < 0.005 for both channels). As expected, ZnT-1 also enhanced ERK phosphorylation. Coexpression of ZnT-1 and nonactive Raf-1 blocked the ZnT-1-mediated ERK phosphorylation and abolished the ZnT-1-induced augmentation of IcaT. In mammalian cells (Chinese hamster ovary), coexpression of CaV3.1 and ZnT-1 increased the IcaT to 166.37 ± 6.37% compared with cells expressing CaV3.1 alone (P < 0.01). Interestingly, surface expression measurements using biotinylation or total internal reflection fluorescence microscopy indicated marked ZnT-1-induced enhancement of CaV3.1 surface expression. The MEK inhibitor PD- 98059 abolished the ZnT-1-induced augmentation of surface expression of CaV3.1. In cultured murine cardiomyocytes (HL-1 cells), transient exposure to zinc, leading to enhanced ZnT-1 expression, also enhanced the surface expression of endogenous CaV3.1 channels. Consistently, in these cells, endothelin-1, a potent activator of Ras- ERK signaling, enhanced the surface expression of CaV3.1 channels in a PD-98059-sensitive manner. Our findings indicate that ZnT-1 enhances the activity of CaV3.1 and CaV3.2 through activation of Ras-ERK signaling. The augmentation of CaV3.1 currents by Ras- ERK activation is associated with enhanced trafficking of the channel to the plasma membrane. [ABSTRACT FROM AUTHOR]

Activation of ERK signaling may promote cardioprotection from ischemia-reperfusion (I/R) injury. ZnT-1, a protein that confers resistance from zinc toxicity, was found to interact with Raf-1 kinase through its C-terminal domain, leading to downstream activation of ERK. In the present study, we evaluated the effects of ZnT-1 in cultured murine cardiomyocytes (HL-1 cells) that were exposed to simulated-I/R. Cellular injury was evaluated by lactate dehydrogenase (LDH) release and by staining for pro-apoptotic caspase activation. Overexpression of ZnT-1 markedly reduced LDH release and caspase activation following I/R. Knockdown of endogenous ZnT-1 augmented the I/R-induced release of LDH and increased caspase activation following I/R. Phospho-ERK levels were significantly increased following I/R in cells overexpressing ZnT-1, while knockdown of ZnT-1 reduced phospho-ERK levels. Pretreatment of cells with the MEK inhibitor PD98059 abolished the protective effect of ZnT-1 following I/R. Accordingly, a truncated form of ZnT-1 lacking the C-terminal domain failed to induce ERK activation and did not protect the cells from I/R injury. In contrast, expression of the C-terminal domain by itself was sufficient to induce ERK activation and I/R protection. Interestingly, the C-terminal of the ZnT-1 did not have protective effect against the toxicity of zinc. In the isolated rat heart, global ischemic injury rapidly increased the endogenous levels of ZnT-1. However, following reperfusion ZnT-1 levels were found to be decreased. Our findings indicate that ZnT-1 may have important role in the ischemic myocardium through its ability to interact with Raf-1 kinase. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF), the highest occurring cardiac arrhythmia in the Western world, is associated with substantial morbidity and increased mortality. In spite of extensive research, the cause of atrial electrical remodeling, a major factor in the self-perpetuating nature of AF, is still unknown. Downregulation of L-type Ca2+ channel (LTCC) activity is the hallmark of atrial electrical remodeling. ZnT-1 is a ubiquitous membrane protein that was recently suggested to inhibit the LTCC. We have studied and shown that ZnT-1 expression inhibits LTCC function in an oocyte expression system as well as in isolated cardiomyocytes. Our data also show that rapid electrical pacing can augment ZnT-1 expression in culture as well as in the atria of rats in vivo. Finally, in a pilot study, ZnT-1 expression was found to be augmented in the atria of AF patients. These findings position ZnT-1 as a probable missing link in the mechanism underlying atrial tachycardia remodeling. [ABSTRACT FROM AUTHOR]

The L-type calcium channel (LTCC) has a variety of physiological roles that are critical for the proper function of many cell types and organs. Recently, a member of the zinc-regulating family of proteins, ZnT-1, was recognized as an endogenous inhibitor of the LTCC, but its mechanism of action has not been elucidated. In the present study, using two-electrode voltage clamp recordings in Xenopus oocytes, we demonstrate that ZnT1-mediated inhibition of the LTCC critically depends on the presence of the LTCC regulatory β-subunit. Moreover, the ZnT-1-induced inhibition of the LTCC current is also abolished by excess levels of the β-subunit. An interaction between ZnT-1 and the β-subunit, as demonstrated by co-immunoprecipitation and by fluorescence resonance energy transfer, is consistent with this result. Using surface biotinylation and total internal reflection fluorescence microscopy in HEK293 cells, we show a ZnT-1-dependent decrease in the surface expression of the pore-forming α1-subunit of the LTCC. Similarly, a decrease in the surface expression of the α1-subunit is observed following up-regulation of the expression of endogenous ZnT-1 in rapidly paced cultured cardiomyocytes. We conclude that ZnT-1-mediated inhibition of the LTCC is mediated through a functional interaction of ZnT-1 with the LTCC β-subunit and that it involves a decrease in the trafficking of the LTCC α1-subunit to the surface membrane. [ABSTRACT FROM AUTHOR]

The article presents the discussion on providing substantial evidence for the effect of the BNT162b2 mRNA vaccine versus native infection on maternal humoral. Topics include demonstrating the pregnant women with COVID-19 infection being at increased risk for intensive care unit (ICU) admission; and COVID-19 infection being the rapid resolution of infection by neutralizing immune response and transfer of immunity to the newborn.

Objective Our objective was to determine whether maternal blood angiogenic factors in suspected-small-for-gestational-age (sSGA) fetuses can predict critical adverse perinatal outcomes (CAPO) and improve risk assessment. Methods Women with singleton pregnancies diagnosed with sSGA, between 24 and 35 6/7 weeks' gestation, were included. Clinical and sonographic comprehensive evaluations were performed at enrolment. Plasma angiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), were obtained at diagnosis. In parallel, three attending maternal-fetal-medicine specialists predicted the risk (1–5 scale) of these pregnancies to develop CAPO, based on the clinical presentation. CAPOs were defined as prolonged neonatal intensive care unit hospitalization, fetal or neonatal death, and major neonatal morbidity. Statistical analysis included sensitivity, specificity, positive and negative predictive values, and receiver-operating characteristic (ROC) curve analyses. Results Of the 79 cases included, 32 were complicated by CAPO (40.5%). In SGA fetuses with CAPO, the sFlt-1/PlGF ratio was higher (p < 0.001) and PlGF was lower (p < 0.001) as compared with uncomplicated pregnancies. The areas under the ROC curves for specialists were 0.913, 0.824, and 0.811 and for PlGF and sFlt-1/PlGF ratio 0.926 and 0.900, respectively. CAPO was more common in pregnancies with absent end-diastolic flow or reversed end-diastolic flow (AEDF or REDF) in the umbilical artery upon enrolment (91.6%). Yet, 65.6% of cases involving CAPO occurred in patients without AEDF or REDF, and 66.6% of these cases were not identified by one or more of the experts. The sFlt-1/PlGF ratio identified 92.9% of the experts' errors in this group and 100% of the errors in cases with AEDF or REDF. Conclusion Among sSGA pregnancies prior to 36 weeks' gestation, angiogenic factors testing can identify most cases later complicated with CAPO. Our data demonstrate for the first time that these markers can reduce clinician judgment errors. Incorporation of these measures into decision-making algorithms could potentially improve management, outcomes, and even health care costs. Key Points Angiogenic factors at diagnosis of sSGA can be used to predict CAPO. The sFlt-1/PlGF ratio can flag sSGA pregnancies at increased risk. The sFlt-1/PlGF ratio at admission of sSGA adds to clinical assessment. [ABSTRACT FROM AUTHOR]

The vast majority of membrane phospholipids (PLs) include two asymmetrically positioned fatty acyls: oxidizable polyunsaturated fatty acids (PUFA) attached predominantly at the sn2 position, and non‐oxidizable saturated/monounsaturated acids (SFA/MUFA) localized at the sn1 position. The peroxidation of PUFA‐PLs, particularly sn2‐arachidonoyl(AA)‐ and sn2‐adrenoyl(AdA)‐containing phosphatidylethanolamines (PE), has been associated with the execution of ferroptosis, a program of regulated cell death. There is a minor subpopulation (≈1–2 mol %) of doubly PUFA‐acylated phospholipids (di‐PUFA‐PLs) whose role in ferroptosis remains enigmatic. Here we report that 15‐lipoxygenase (15LOX) exhibits unexpectedly high pro‐ferroptotic peroxidation activity towards di‐PUFA‐PEs. We revealed that peroxidation of several molecular species of di‐PUFA‐PEs occurred early in ferroptosis. Ferrostatin‐1, a typical ferroptosis inhibitor, effectively prevented peroxidation of di‐PUFA‐PEs. Furthermore, co‐incubation of cells with di‐AA‐PE and 15LOX produced PUFA‐PE peroxidation and induced ferroptotic death. The decreased contents of di‐PUFA‐PEs in ACSL4 KO A375 cells was associated with lower levels of di‐PUFA‐PE peroxidation and enhanced resistance to ferroptosis. Thus, di‐PUFA‐PE species are newly identified phospholipid peroxidation substrates and regulators of ferroptosis, representing a promising therapeutic target for many diseases related to ferroptotic death. [ABSTRACT FROM AUTHOR]

The vast majority of membrane phospholipids (PLs) include two asymmetrically positioned fatty acyls: oxidizable polyunsaturated fatty acids (PUFA) attached predominantly at the sn2 position, and non‐oxidizable saturated/monounsaturated acids (SFA/MUFA) localized at the sn1 position. The peroxidation of PUFA‐PLs, particularly sn2‐arachidonoyl(AA)‐ and sn2‐adrenoyl(AdA)‐containing phosphatidylethanolamines (PE), has been associated with the execution of ferroptosis, a program of regulated cell death. There is a minor subpopulation (≈1–2 mol %) of doubly PUFA‐acylated phospholipids (di‐PUFA‐PLs) whose role in ferroptosis remains enigmatic. Here we report that 15‐lipoxygenase (15LOX) exhibits unexpectedly high pro‐ferroptotic peroxidation activity towards di‐PUFA‐PEs. We revealed that peroxidation of several molecular species of di‐PUFA‐PEs occurred early in ferroptosis. Ferrostatin‐1, a typical ferroptosis inhibitor, effectively prevented peroxidation of di‐PUFA‐PEs. Furthermore, co‐incubation of cells with di‐AA‐PE and 15LOX produced PUFA‐PE peroxidation and induced ferroptotic death. The decreased contents of di‐PUFA‐PEs in ACSL4 KO A375 cells was associated with lower levels of di‐PUFA‐PE peroxidation and enhanced resistance to ferroptosis. Thus, di‐PUFA‐PE species are newly identified phospholipid peroxidation substrates and regulators of ferroptosis, representing a promising therapeutic target for many diseases related to ferroptotic death. [ABSTRACT FROM AUTHOR]

Natural killer cells (NKs) found during pregnancy at the maternal-fetal interface named decidual (d)NKs, show signs of education following first pregnancy, resulting in better placentation and fetus-growth, hence termed pregnancy trained dNKs (PTdNKs). Here we show that PTdNKs provide increased protection of the fetus from Fusobacterium nucleatum (FN) infection. We demonstrate that PTdNKs secrete elevated amounts of the bacteriocidal protein granulysin (GNLY) upon incubation with FN compared to dNKs derived from first pregnancies, which leads to increased killing of FN. Furthermore, we showed mechanistically that the GNLY secretion is mediated through the interaction of the FN's Fap2 protein with Gal-GalNAc present on PTdNKs. Finally, we show in vivo, using GNLY-tg mice that enhanced protection of the fetuses from FN infection is observed, as compared to wild type and that this enhance protection is NK cell dependent. Altogether, we show a new function for PTdNKs as protectors of the fetus from bacterial infection. Author summary: During this project, we aimed to elucidate the influence of natural killer (NK) cells in the protection of fetuses during pregnancy. At the maternal-fetal interface a special subset of NK cells can be found, the decidual NK (dNK) cells, which have been shown to be rather nurturing, in contrast to the cytotoxic peripheral blood NK cells. These cells are thought to be essential for the healthy development of placenta and fetus in the uterus. Bacterial and viral infections are quite common during pregnancy and pose a significant risk for the fetus and its development. In this manuscript, we describe how the dNK cells primed through first pregnancy show specific antibacterial properties against the bacterium Fusobacterium nucleatum via the lytic protein granulysin in contrast to the peripheral blood NK cells. Additionally, we showed that NK cells expressing granulysin in mice protect the developing fetuses from the effects of a maternal infection with the bacterium. [ABSTRACT FROM AUTHOR]

Optimal clinical outcomes in cancer treatments could be achieved through the development of reliable, precise ex vivo tumor models that function as drug screening platforms for patient-targeted therapies. Microfluidic tumor-on-chip technology is emerging as a preferred tool since it enables the complex set-ups and recapitulation of the physiologically relevant physical microenvironment of tumors. In order to overcome the common hindrances encountered while using this technology, a fully 3D-printed device was developed that sustains patient-derived multicellular spheroids long enough to conduct multiple drug screening tests. This tool is both cost effective and possesses four necessary characteristics of effective microfluidic devices: transparency, biocompatibility, versatility, and sample accessibility. Compelling correlations which demonstrate a clinical proof of concept were found after testing and comparing different chemotherapies on tumor spheroids, derived from ten patients, to their clinical outcomes. This platform offers a potential solution for personalized medicine by functioning as a predictive drug-performance tool.A unique 3D-printed device made of sustainable materials was developed to produce 3D spheroids from primary cells and perform drug screening assays in a biomimetic environment. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether patients with a history of recurrent pregnancy loss (RPL) have an increased risk for future female malignancies.Methods: A retrospective population-based study compared the incidence of long-term female malignancies in a cohort of women with and without a history of RPL (2 or more consecutive pregnancy losses). Deliveries occurred between the years 1988 and 2013, with a mean follow-up duration of 12 years. Women with known malignancies before the index pregnancy were excluded from the analysis. Female malignancies were divided according to specific type including ovary, breast, uterine and uterine cervix. Kaplan-Meier survival curve was used to estimate the cumulative incidence of malignancies. Cox proportional hazards model was used to determine the adjusted hazard ratios (HR) for female malignancy after controlling for confounders.Results: During the study period, 106,265 patients met the inclusion criteria; 6.6% (n = 7052) of patients had a diagnosis of RPL. During the follow-up period, patients with RPL had a significantly increased risk of being diagnosed with female malignancies as a group, while individually there was an increased risk of breast and uterine cervix cancer. Using a Kaplan-Meier survival curve, patients with a history of RPL had a significantly higher cumulative incidence of female malignancies. Using a Cox proportional hazards model, adjusted for confounders such as smoking, parity, and diabetes mellitus, a history of RPL remained independently associated with female malignancies (adjusted HR 1.4; P = 0.003).Conclusions: RPL is independently associated with long-term female malignancies. Patients with a history of RPL may benefit from counseling and screening for breast and uterine cervix cancer in particular. [ABSTRACT FROM AUTHOR]

Background: Preterm delivery may affect the development of the upper airways resulting in a higher risk of obstructive sleep apnoea (OSA). We investigated whether children born at early term (37-38 6/7 weeks' gestation) are at an increased risk for childhood OSA as compared with those born later.Methods: In this population-based cohort analysis all singleton deliveries occurring between 1991-2013 at a single regional tertiary medical centre were included. Gestational age upon delivery was sub-divided into: early preterm (<33 6/7 weeks' gestation), late preterm (34-36 6/7), early term, full term (39-40 6/7), late term (41-41 6/7), and post term (>42 0/7). Incidence of OSA related hospitalizations of the offspring, up to the age of 18 years, was evaluated. A survival curve and a Cox model were used to assess the association.Results: During the study period 240 953 deliveries met the inclusion criteria. OSA hospitalization (n = 1320) rates decreased as gestational age increased from 1.1% in the early preterm group, 0.8% in late preterm, 0.7% at early term, 0.5% in full term, 0.4% in late term, to 0.3% in post term born children. In the Cox regression, early term delivery exhibited an increased risk for paediatric OSA (adjusted hazard ratio (HR) 1.3 95% Confidence interval (CI) 1.2, 1.5) while late and post term deliveries were associated with significantly lower OSA risk when compared with full term (HR 0.8 95% CI 0.6, 0.9 and HR 0.6 95% CI 0.4, 0.8, respectively).Conclusions: Early term deliveries are associated with higher rates of paediatric OSA, which decrease gradually as gestational age advances. [ABSTRACT FROM AUTHOR]

Objective: To determine whether an isolated single umbilical artery (iSUA) is an independent risk factor for perinatal mortality in term neonates with normal estimated fetal weight (EFW) prior to delivery.Method: A population-based study was conducted, including all deliveries occurring between 1993 and 2013, in a tertiary medical center. Pregnancies with and without iSUA were compared. Multiple gestations, chromosomal, and structural abnormalities were excluded from the cohort. Only pregnancies delivered at term with normal EFW evaluated prior to delivery were included. Stratified analysis was performed using multiple logistic regression models to evaluate the risk of adverse outcomes and perinatal mortality for iSUA fetuses.Results: During the study period, 233,123 deliveries occurred at "Soroka" University Medical Center, out of which 786 (0.3 %) were diagnosed with iSUA. Different pregnancy complications were more common with iSUA fetuses including: placental abruption (OR = 3.4), true knot of cord (OR = 3.5) and cord prolapse (OR = 2.8). Induction of labor and cesarean delivery were also more common in these pregnancies (OR = 1.5 and OR = 1.9, respectively). iSUA neonates had lower Apgar scores at 1 and 5 min (OR = 1.8, OR = 1.9, respectively) compared to the control group and perinatal mortality rates were higher both antenatally (IUFD, OR = 8.1) and postnatally (PPD, OR = 6.1).Conclusion: iSUA appears to be an independent predictor of adverse perinatal outcomes in term neonates. [ABSTRACT FROM AUTHOR]

Background: Since the introduction of anti-COVID-19 mRNA vaccination, few studies have shown that reproductive outcomes in artificial reproductive technology (ART) treatments are not impaired, after receiving the two-dose regimen. Our aim was to investigate whether a boosting dose of the Pfizer–BioNtech mRNA vaccine affects reproductive outcomes in ART patients. Materials and Methods: This is a prospective observational study, including 157 consecutive in-vitro fertilization (IVF) cycles between October 1, 2021, and November 24, 2021, in a single university affiliated IVF unit. We included female patients going through an ART procedure and male partners in cases of utilization of a fresh sperm sample. The study population was divided into four groups according to exposure status: vaccinated and boosted patients (three total doses of Pfizer–BioNtech mRNA vaccine), patients who were vaccinated without the booster dose (one or two vaccine doses), PCR-confirmed convalescent COVID-19 patients, and unvaccinated nonconvalescent patients. Main outcome measure was clinical pregnancy rate. Results: In total, 99 (63%) female patients were vaccinated three times, 24 (15.3%) were vaccinated without the booster dose, 21 (13.4%) were convalescent, and 13 were (8.3%) unexposed. Although age differed between study groups, vaccination exposure status did not affect treatment outcome: clinical pregnancy rates, maximal estradiol levels, and number of oocytes retrieved did not differ significantly between study groups (p = 0.78, 0.50, and 0.97, respectively). Vaccinated patients who received a boosting vaccine dose were treated within 43.3 ± 30.9 days after receiving the last dose, whereas vaccinated, nonboosted, or convalescent patients were treated 168.7 ± 53 and 209.6 ± 85.1 days after their last exposure, respectively. We stratified the male cohort according to boosting vaccine dose status. Sperm concentration and motility did not differ significantly after boosting (p = 0.49 and 0.49, respectively). Conclusions: Our results provide further reassurance that IVF outcomes are not affected by the anti-SARS-CoV-2 Pfizer–BioNtech mRNA vaccine, in particular the three-dose regimen. [ABSTRACT FROM AUTHOR]

Data collection regarding the effects of COVID-19 on reproduction is ongoing. This study examined the effect of COVID-19 on IVF cycle parameters and early pregnancy outcomes. It included two arms: the first compared non-exposed cycles to post-SARS-CoV-2 IVF cycles. Sperm parameters were also compared. The second, prospective arm compared pregnancy outcomes among IVF patients who contracted COVID-19 during early pregnancy to those who did not. None of the patients were vaccinated against SARS-CoV-2. The first arm included 60 treatment cycles of women with confirmed COVID-19, compared to 60 non-exposed cycles (either the same patient before exposure or matched non-exposed patients). The outcomes of the treatment cycles did not differ significantly between exposed and non-exposed groups, including number of oocytes, endometrial thickness, fertilization rate and number of top-quality embryos. In 11 cycles, the male partner had also recently recovered: sperm concentration was lower post-exposure: 6.27 million/mL vs. 16.5 pre-exposure (p = 0.008). In 189 patients with IVF-achieved pregnancies, pregnancy loss and hospital admissions did not differ between exposed and non-exposed groups. IVF treatment outcomes and the rate of early pregnancy loss appears to be unaffected by SARS-CoV-2 disease, despite a minor decline in sperm concentration among recent recoverees. [ABSTRACT FROM AUTHOR]

Background: Until recently, the membrane protein ZnT-1 was studied mainly in the context of zinc homeostasis. However, new findings indicate that it acts as an inhibitor of L-type calcium channels. We recently found that acute rapid pacing of the rat atria in vivo augments the expression of ZnT-1, while knockdown of ZnT-1 in culture can oppose the inhibition of L-type calcium channels following rapid pacing. This pilot study, the first to assess cardiac ZnT-1 in humans, was designed to look for possible correlation between the atrial expression of ZnT-1 and atrial fibrillation. Methods: Right atrial appendage tissue was collected from 39 patients (27 with sinus rhythm and 12 with atrial fibrillation; 6-permanent, 6- paroxysmal or persistent) undergoing open-heart surgery. The expression of ZnT-1 was analyzed by Western blot utilizing β-actin as an internal loading control and a standard rat heart sample (STD) for inter-blot comparison. Results: Overall atrial fibrillation patients (n = 12) had median ZnT-1/β-actin of 1.80 STD (inter-quartile range 1.26 to 2.85) versus 0.73 STD (0.24 to 1.64) in the sinus rhythm group (P = 0.002). No association was found between ZnT-1 level and most other clinical parameters tested. Multivariate analysis determined that atrial fibrillation and increased body mass index were the only independent variables clearly associated with higher ZnT-1 levels (Standardized coefficients Beta = 0.62, 0.31; P = 0.002, P = 0.04, respectively). Conclusions: This pilot study provides evidence for increased ZnT-1 expression in the atria of patients with atrial fibrillation. [ABSTRACT FROM AUTHOR]

Objective  This study aimed to determine whether isolated single umbilical artery (iSUA), even absent identifiable genitourinary (GU) abnormalities, increases the risk of GU infection during childhood. Study Design  Retrospective population-based comparison of fetuses with iSUA versus normal three-vessel cords. Fetuses with growth restriction, prematurity, multiple gestations, and anatomical or chromosomal anomalies were excluded. The primary outcome was hospital-associated GU infection during the first 18 years of life. Kaplan–Meier's survival curves were used to assess cumulative risk; Cox's multivariable models were used to adjust for confounders. Results  Among 227,599 term singleton deliveries, children with iSUA (n  = 729) had a higher incidence (1.8 vs. 0.6%, p  < 0.001) and cumulative incidence (log-rank test, p  < 0.001) of hospital-associated GU infection. The Cox's models confirmed these findings (hazard ratio: >2.82, confidence interval: 1.63–4.87 in composite models). Conclusion  iSUA represents an independent risk factor for GU infection. Urinary tract imaging may be warranted. [ABSTRACT FROM AUTHOR]

Objective  Previous studies suggested maternal hypothyroidism during pregnancy to be associated with cognitive impairment of the offspring. Scarce data exist regarding long-term endocrine health of the offspring. This study was aimed to assess whether children born to mothers with hypothyroidism during pregnancy are at an increased risk for long-term endocrine morbidity. Study Design  A retrospective population-based cohort study compared long-term endocrine morbidity of children born between the years 1991 and 2014 to mothers with and without hypothyroidism. Multiple gestations, fetuses with congenital malformations, and women lacking prenatal care were excluded. Hospitalizations of the offspring up to the age of 18 years involving endocrine morbidity were evaluated according to a predefined set of ICD-9 codes. Kaplan–Meier's survival curves were used to compare the cumulative risk and a Cox multivariable model was used to adjust for confounders. Results  During the study period, 217,910 deliveries met the inclusion criteria; 1.1% of which were with maternal hypothyroidism (n  = 2,403). During the follow-up period, the cumulative incidence of endocrine morbidity among children born to mothers with hypothyroidism was 27 per 1,000 person-years and 0.47 per 1,000 person-years in the comparison group (relative risk: 2.14; 95% confidence interval [CI]: 1.21–3.79). The Kaplan–Meier's survival curve demonstrated a significantly higher cumulative endocrine morbidity in children born to mothers with hypothyroidism (log-rank test, p  = 0.007). In the Cox regression model controlled for maternal age, birth weight, preterm birth, maternal diabetes, hypertensive disorders of pregnancy, induction of labor, and mode of delivery, maternal hypothyroidism was found to be independently associated with pediatric endocrine morbidity in the offspring (adjusted hazard ratio = 1.92, 95% CI: 1.08–3.4, p  = 0.025). Conclusion  Maternal hypothyroidism appears to be independently associated with long-term pediatric endocrine morbidity of the offspring. [ABSTRACT FROM AUTHOR]

We recently found that ferroptosis, a unique form of programmed cell death, causes human trophoblast injury and is associated with pregnancy complications. Hence, the development and repurposing of pregnancysafe drugs that inhibit ferroptosis may ofer novel, promising treatment approach and significantly advance the field of obstetrics. Here we study the link between placental ferroptosis and soluble fms-like tyrosine kinase-1 (sFlt-1) secretion, a key player in the pathophysiology of preeclampsia. We use PMZ and DPY drugs found in our high throughput screening as pregnancy-safe drugs that inhibit ferroptosis. Placental explants of normal term pregnancies, were treated with Vehicle (DMSO), RSL3 (0.4-0.8uM, ferroptosis specific inducer), Ferrostatin-1 (Fer-1, ferroptosis specific inhibitor) and PMZ and DPY for 24h. We monitored the secretion of sFlt-1 and LDH using Human VEGFR1/Flt-1 ELISA (R&D) and LDHCytotoxicity Assay (R&D), respectively. Induction of ferroptosis in human placental explants, n=7 (A) results in excess secretion of sFLT-1, n=5 (B). Inhibition of ferroptotic signaling attenuates sFLT-1 secretion in placental explant of normal term, n=7 (C), and early preeclampsia, n= 3(D). Preeclamptic placental tissues were obtained from two patients with early PE (31, 30, and 28 weeks) with severe features (severe hypertension or HELLP). We provide the first direct evidence linking placental ferroptosis and sFlt-1 secretion. These findings mark anti-ferroptotic treatment as a potential novel treatment or preventive tool for preeclampsia. [ABSTRACT FROM AUTHOR]

Introduction: Research in animal models and preliminary clinical studies in humans support the use of pravastatin for the prevention of preeclampsia. However, its use during pregnancy is still controversial due to limited data about its effect on the human placenta and fetus. Methods: In the present study, human placental cotyledons were perfused in the absence or presence of pravastatin in the maternal reservoir (PraM). In addition, placental explants were treated with pravastatin for 5, 24 and 72 h under normoxia and hypoxia. We monitored the secretion of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), endothelial nitric oxide synthase (eNOS) expression and activation and the fetal vasoconstriction response to angiotensin-II. Results: The concentrations of PlGF, sFlt-1 and sEng were not significantly altered by pravastatin in PraM cotyledons and in placental explants compared to control. Under hypoxic conditions, pravastatin decreased sFlt-1 concentrations. eNOS expression was significantly increased in PraM cotyledons but not in pravastatin-treated placental explants cultured under normoxia or hypoxia. eNOS phosphorylation was not significantly affected by pravastatin. The feto-placental vascular tone and the fetal vasoconstriction response to angiotensin-II, did not change following exposure of the maternal circulation to pravastatin. Conclusion: We found that pravastatin does not alter the essential physiological functions of the placenta investigated in the study. The relevance of the study lays in the fact that it expands the current knowledge obtained thus far regarding the effect of the drug on the normal human placenta. This data is reassuring and important for clinicians that consider the treatment of high-risk patients with pravastatin, a treatment that exposes some normal pregnancies to the drug. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether there is an association between a history of fertility treatments and future risk for long-term maternal ophthalmic complications.Study Design: A population-based study compared the incidence of long-term maternal ophthalmic complications in a cohort of women with and without a prior history of fertility treatments, including in vitro fertilization (IVF) and ovulation induction (OI). Deliveries occurred between the years 1988-2013, with a mean follow-up duration of 12 years. Women with known ophthalmic diseases prior to the index pregnancy were excluded from the analysis. Ophthalmic complications were further divided to glaucoma, diabetic retinopathy, macular degeneration and retinal detachment. Kaplan-Meier survival curve was used to estimate cumulative incidence of ophthalmic complications. Cox proportional hazards model was used to estimate the adjusted hazard ratios (HR) for ophthalmic complications.Results: During the study period, 106 004 deliveries met the inclusion criteria; 4.1% (n = 4364) occurred in patients with a history of fertility treatments. Patients with a history of fertility treatments, as a group, did not have a significantly higher incidence of ophthalmic complications. However, the subgroup of patients with a history of IVF (but not OI) had a higher incidence of retinal detachment (0.3% versus 0.1%; p = 0.02). Using a Kaplan-Meier survival curve, patients following IVF had a significantly higher cumulative incidence of retinal detachment. Using Cox proportional hazards models, controlling for maternal age, obesity and parity, IVF was noted as an independent risk factor for retinal detachment (adjusted HR 3.4; 95% 1.2-9.3; p = 0.011).Conclusion: Patients following IVF treatments have a significant higher long-term risk for retinal detachment. OI treatments do not pose a risk for long-term maternal ophthalmic complications. [ABSTRACT FROM AUTHOR]

Objective Spontaneous preterm deliveries (PTDs) have been consistently associated with maternal vascular complications. We aimed to investigate an association between PTD and subsequent maternal ophthalmic morbidity. Study Design In this population-based cohort study, we included all singleton deliveries occurring between 1988 and 2013. We excluded women with known ophthalmic disease. The exposure was at least one pregnancy with PTD. Outcomes included different maternal ophthalmic morbidity. The cumulative incidence and adjusted hazard ratios were assessed using a Kaplan-Meier survival curve and Cox hazards models. Results Of the 105,018 patients included, 17,600 (16.7%) delivered preterm. Patients with a history of PTD (both induced and spontaneous) had higher rates of ophthalmic complications (odds ratio [OR]: 2.12; confidence interval [CI]: 1.6-2.7; p < 0.001), specifically diabetic retinopathy and glaucoma (OR: 4.79 and 2.48, respectively). A linear association was found between the number of previous PTDs and ophthalmic complications (0.2% for no PTD; 0.4% for one PTD; 0.6% for two or more PTDs; p < 0.001) and for early and late PTD (p < 0.001). A Cox model revealed an independent association between PTD and ophthalmic complications (adjusted hazard ratio: 2.2; 95% CI: 1.6-2.9). Conclusion A history of PTD is an independent risk factor for ophthalmic morbidity. [ABSTRACT FROM AUTHOR]

Studies of atrial electrophysiology (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 ± 2.3% in rats (P <0.0001; n = 35), 31.7 ± 8.3% in ICR mice (P = 0.0001; n = 13), and 57.7 ± 13.7% in C57BL6 mice (P = 0.015; n = 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 tachy-pacing 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 remodeling-reverse 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. [ABSTRACT FROM AUTHOR]

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+/Ca2+ 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+/Ca2+ 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 Ca2+ flux at a rate comparable with NCX1 but without promoting Na+/Ba2+ 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 Ca2+ exchange whereas the known exchangers are inert to Li+ ions? Identification of this novel member of the Na+/ Ca2+ superfamily, with distinct characteristics, including the ability to transport Li+, may provide an explanation for this phenomenon. [ABSTRACT FROM AUTHOR]