Temporal effects of Sprouty on lung morphogenesis

AbstractParacrine signaling mediated by FGF-10 and the FGF-R2IIIb receptor is required for formation of the lung. To determine the temporal requirements for FGF signaling during pulmonary morphogenesis, Sprouty-4 (Spry-4), an intracellular FGF receptor antagonist, was expressed in epithelial cells of the fetal lung under control of a doxycycline-inducible system. Severe defects in lobulation and severe lung hypoplasia were observed when Spry-4 was expressed throughout fetal lung development (E6.5–E18.5) or from E6.5 until E13.5. Effects of Spry-4 on branching were substantially reversed by removal of doxycycline from the dam at E12.5, but not at E13.5. In contrast, when initiated late in development (E12.5 to birth), Spry-4 caused less severe pulmonary hypoplasia. Expression of Spry-4 from E16.5 to E18.5 reduced lung growth and resulted in perinatal death due to respiratory failure. Expression of Spry-4 during the saccular and alveolar stages, from E18.5 to postnatal day 21, caused mild emphysema. These findings demonstrate that the embryonic-pseudoglandular stage is a critical time period during which Spry-sensitive pathways are required for branching morphogenesis, lobulation, and formation of the peripheral lung parenchyma

AQUARIUS: The World\u27s First Water-Based Thruster Enabled 6U CubeSat to Complete Lunar Flyby

This paper presents the outcomes of the initial operations and on-orbit performance of AQUARIUS (AQUA ResIstojet propulsion System), a micro-propulsion system. AQUARIUS utilizes water as a propellant and is designed for trajectory control and reaction wheel desaturation of a 6U CubeSat, EQUULEUS (EQUilibriUm Lunar-Earth point 6U Spacecraft). The spacecraft was launched in November 2022 by SLS, following which the initial operations commenced. Both the spacecraft and the propulsion system were confirmed to be in good health during the checkout process. Performance evaluation of the propulsion system confirmed that it met the requirement to execute the first delta-V maneuver scheduled 38 hours after separation from the launch vehicle. The delta-V maneuver was successfully completed, achieving a total delta-V of 6.48 m/s. The propulsion system demonstrated an average thrust of 5.94 ± 0.21 mN. Subsequently, precise trajectory control maneuvers were carried out, resulting in a successful lunar flyby. As a result of these initial operations, AQUARIUS became the world\u27s first water propulsion system to successfully control its orbit in deep space

Thermal Operation for the 6U Deep Space CubeSat EQUULEUS in the Initial Critical Phase

EQUULEUS (EQUilibriUm Lunar-Earth point 6U Spacecraft) was launched to deep space by NASA\u27s SLS (Space Launch System) on November 16, 2022. It has an engineering mission to demonstrate low-energy orbit maneuvering to EML2, a libration orbit around the second Earth-Moon Lagrange Point using the water propulsion system “AQUARIUS” (AQUA ResIstojet propUlsion System). The initial critical phase in EQUULEUS refers to a series of operational procedures associated with the first delta-V(DV1), which generated the largest thrust throughout the entire mission, taking place about 38 hours after separation for entering the transfer orbit to EML2. Thisorbit control was followed by several Thrust Correction Maneuver (TCM) operations to compensate for thrust errors

Prospective assessment of inter-rater reliability of a neonatal adverse event severity scale

Introduction: To ensure the quality of clinical trial safety data, universal data standards are required. In 2019 the International Neonatal Consortium (INC) published a neonatal adverse event severity scale (NAESS) to standardize the reporting of adverse event (AE) severity. In this study the reliability of AE severity grading with INC NAESS was prospectively assessed in a real-world setting. Methods: Severity of AEs was assessed by two independent observers at each of four centers across the world. In each center two series of 30 neonatal adverse events were assessed by both observers: in a first phase with a generic (Common Terminology Criteria for Adverse Events, CTCAE) severity scale not specific to neonates, and in a second phase with INC NAESS (after a structured training). Intraclass correlation coefficients (ICC) were calculated to express inter-rater agreement in both phases, and bootstrap sampling was used to compare them. Results: 120 AEs were included in each of both phases. The ICC with the use of INC NAESS in phase 2 was 0.69. This represents a significant but modest improvement in comparison to the initial ICC of 0.66 in phase 1 (confidence interval of ratio of ICC in phase 2 to phase 1 = 1.005–1.146; excludes 1). The ICC was higher for those AEs for which a diagnosis specific AE severity table was available in INC NAESS (ICC 0.80). Discussion: Good inter-rater reliability of the INC NAESS was demonstrated in four neonatal intensive care units (NICUs) across the globe. The ICC is comparable to what is reported for scales with similar purposes in different populations. There is a modest, but significant, improvement in inter-rater agreement in comparison to the naïve phase without INC NAESS. The better performance when reviewers use AE-specific NAESS tables highlights the need to expand the number of AEs that are covered by specific criteria in the current version of INC NAESS.</p

Antenatal Glucocorticoid Administration Promotes Cardiac Structure and Energy Metabolism Maturation in Preterm Fetuses

Although the rate of preterm birth has increased in recent decades, a number of preterm infants have escaped death due to improvements in perinatal and neonatal care. Antenatal glucocorticoid (GC) therapy has significantly contributed to progression in lung maturation; however, its potential effects on other organs remain controversial. Furthermore, the effects of antenatal GC therapy on the fetal heart show both pros and cons. Translational research in animal models indicates that constant fetal exposure to antenatal GC administration is sufficient for lung maturation. We have established a premature fetal rat model to investigate immature cardiopulmonary functions in the lungs and heart, including the effects of antenatal GC administration. In this review, we explain the mechanisms of antenatal GC actions on the heart in the fetus compared to those in the neonate. Antenatal GCs may contribute to premature heart maturation by accelerating cardiomyocyte proliferation, angiogenesis, energy production, and sarcoplasmic reticulum function. Additionally, this review specifically focuses on fetal heart growth with antenatal GC administration in experimental animal models. Moreover, knowledge regarding antenatal GC administration in experimental animal models can be coupled with that from developmental biology, with the potential for the generation of functional cells and tissues that could be used for regenerative medical purposes in the future

Standardizing Safety Assessment and Reporting for Neonatal Clinical Trials

status: publishe

A Novel System for Spinal Muscular Atrophy Screening in Newborns: Japanese Pilot Study

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by SMN1 gene deletion/mutation. The drug nusinersen modifies SMN2 mRNA splicing, increasing the production of the full-length SMN protein. Recent studies have demonstrated the beneficial effects of nusinersen in patients with SMA, particularly when treated in early infancy. Because nusinersen treatment can alter disease trajectory, there is a strong rationale for newborn screening. In the current study, we validated the accuracy of a new system for detecting SMN1 deletion (Japanese patent application No. 2017-196967, PCT/JP2018/37732) using dried blood spots (DBS) from 50 patients with genetically confirmed SMA and 50 controls. Our system consists of two steps: (1) targeted pre-amplification of SMN genes by direct polymerase chain reaction (PCR) and (2) detection of SMN1 deletion by real-time modified competitive oligonucleotide priming-PCR (mCOP-PCR) using the pre-amplified products. Compared with PCR analysis results of freshly collected blood samples, our system exhibited a sensitivity of 1.00 (95% confidence interval [CI] 0.96&ndash;1.00) and a specificity of 1.00 (95% CI 0.96&ndash;1.00). We also conducted a prospective SMA screening study using DBS from 4157 Japanese newborns. All DBS tested negative, and there were no screening failures. Our results indicate that the new system can be reliably used in SMA newborn screening