Interchange reconnection as the source of the fast solar wind within coronal holes.

The fast solar wind that fills the heliosphere originates from deep within regions of open magnetic field on the Sun called 'coronal holes'. The energy source responsible for accelerating the plasma is widely debated; however, there is evidence that it is ultimately magnetic in nature, with candidate mechanisms including wave heating1,2 and interchange reconnection3-5. The coronal magnetic field near the solar surface is structured on scales associated with 'supergranulation' convection cells, whereby descending flows create intense fields. The energy density in these 'network' magnetic field bundles is a candidate energy source for the wind. Here we report measurements of fast solar wind streams from the Parker Solar Probe (PSP) spacecraft6 that provide strong evidence for the interchange reconnection mechanism. We show that the supergranulation structure at the coronal base remains imprinted in the near-Sun solar wind, resulting in asymmetric patches of magnetic 'switchbacks'7,8 and bursty wind streams with power-law-like energetic ion spectra to beyond 100 keV. Computer simulations of interchange reconnection support key features of the observations, including the ion spectra. Important characteristics of interchange reconnection in the low corona are inferred from the data, including that the reconnection is collisionless and that the energy release rate is sufficient to power the fast wind. In this scenario, magnetic reconnection is continuous and the wind is driven by both the resulting plasma pressure and the radial Alfvénic flow bursts.

Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus.

BACKGROUND: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. METHODS: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. RESULTS: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. CONCLUSIONS: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).

Probing the energetic particle environment near the Sun.

NASA's Parker Solar Probe mission1 recently plunged through the inner heliosphere of the Sun to its perihelia, about 24 million kilometres from the Sun. Previous studies farther from the Sun (performed mostly at a distance of 1 astronomical unit) indicate that solar energetic particles are accelerated from a few kiloelectronvolts up to near-relativistic energies via at least two processes: 'impulsive' events, which are usually associated with magnetic reconnection in solar flares and are typically enriched in electrons, helium-3 and heavier ions2, and 'gradual' events3,4, which are typically associated with large coronal-mass-ejection-driven shocks and compressions moving through the corona and inner solar wind and are the dominant source of protons with energies between 1 and 10 megaelectronvolts. However, some events show aspects of both processes and the electron-proton ratio is not bimodally distributed, as would be expected if there were only two possible processes5. These processes have been very difficult to resolve from prior observations, owing to the various transport effects that affect the energetic particle population en route to more distant spacecraft6. Here we report observations of the near-Sun energetic particle radiation environment over the first two orbits of the probe. We find a variety of energetic particle events accelerated both locally and remotely including by corotating interaction regions, impulsive events driven by acceleration near the Sun, and an event related to a coronal mass ejection. We provide direct observations of the energetic particle radiation environment in the region just above the corona of the Sun and directly explore the physics of particle acceleration and transport.

Alfvénic velocity spikes and rotational flows in the near-Sun solar wind.

The prediction of a supersonic solar wind1 was first confirmed by spacecraft near Earth2,3 and later by spacecraft at heliocentric distances as small as 62 solar radii4. These missions showed that plasma accelerates as it emerges from the corona, aided by unidentified processes that transport energy outwards from the Sun before depositing it in the wind. Alfvénic fluctuations are a promising candidate for such a process because they are seen in the corona and solar wind and contain considerable energy5-7. Magnetic tension forces the corona to co-rotate with the Sun, but any residual rotation far from the Sun reported until now has been much smaller than the amplitude of waves and deflections from interacting wind streams8. Here we report observations of solar-wind plasma at heliocentric distances of about 35 solar radii9-11, well within the distance at which stream interactions become important. We find that Alfvén waves organize into structured velocity spikes with duration of up to minutes, which are associated with propagating S-like bends in the magnetic-field lines. We detect an increasing rotational component to the flow velocity of the solar wind around the Sun, peaking at 35 to 50 kilometres per second-considerably above the amplitude of the waves. These flows exceed classical velocity predictions of a few kilometres per second, challenging models of circulation in the corona and calling into question our understanding of how stars lose angular momentum and spin down as they age12-14.

Highly structured slow solar wind emerging from an equatorial coronal hole.

During the solar minimum, when the Sun is at its least active, the solar wind1,2 is observed at high latitudes as a predominantly fast (more than 500 kilometres per second), highly Alfvénic rarefied stream of plasma originating from deep within coronal holes. Closer to the ecliptic plane, the solar wind is interspersed with a more variable slow wind3 of less than 500 kilometres per second. The precise origins of the slow wind streams are less certain4; theories and observations suggest that they may originate at the tips of helmet streamers5,6, from interchange reconnection near coronal hole boundaries7,8, or within coronal holes with highly diverging magnetic fields9,10. The heating mechanism required to drive the solar wind is also unresolved, although candidate mechanisms include Alfvén-wave turbulence11,12, heating by reconnection in nanoflares13, ion cyclotron wave heating14 and acceleration by thermal gradients1. At a distance of one astronomical unit, the wind is mixed and evolved, and therefore much of the diagnostic structure of these sources and processes has been lost. Here we present observations from the Parker Solar Probe15 at 36 to 54 solar radii that show evidence of slow Alfvénic solar wind emerging from a small equatorial coronal hole. The measured magnetic field exhibits patches of large, intermittent reversals that are associated with jets of plasma and enhanced Poynting flux and that are interspersed in a smoother and less turbulent flow with a near-radial magnetic field. Furthermore, plasma-wave measurements suggest the existence of electron and ion velocity-space micro-instabilities10,16 that are associated with plasma heating and thermalization processes. Our measurements suggest that there is an impulsive mechanism associated with solar-wind energization and that micro-instabilities play a part in heating, and we provide evidence that low-latitude coronal holes are a key source of the slow solar wind.

Hyperpolarized 13C magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: First investigations in a large animal model.

Early biomarkers of cerebral damage are essential for accurate prognosis, timely intervention, and evaluation of new treatment modalities in newborn infants with hypoxia and ischemia at birth. Hyperpolarized 13C magnetic resonance imaging (MRI) is a novel method with which to quantify metabolism in vivo with unprecedented sensitivity. We aimed to investigate the applicability of hyperpolarized 13C MRI in a newborn piglet model and whether this method may identify early changes in cerebral metabolism after a standardized hypoxic-ischemic (HI) insult. Six piglets were anesthetized and subjected to a standardized HI insult. Imaging was performed prior to and 2 h after the insult on a 3-T MR scanner. For 13C studies, [1-13C]pyruvate was hyperpolarized in a commercial polarizer. Following intravenous injection, images were acquired using metabolic-specific imaging. HI resulted in a metabolic shift with a decrease in pyruvate to bicarbonate metabolism and an increase in pyruvate to lactate metabolism (lactate/bicarbonate ratio, mean [SD]; 2.28 [0.36] vs. 3.96 [0.91]). This is the first study to show that hyperpolarized 13C MRI can be used in newborn piglets and applied to evaluate early changes in cerebral metabolism after an HI insult.

ADAM12-Generated Basigin Ectodomain Binds ß1 Integrin and Enhances the Expression of Cancer-Related Extracellular Matrix Proteins.

Desmoplasia is a common feature of aggressive cancers, driven by a complex interplay of protein production and degradation. Basigin is a type 1 integral membrane receptor secreted in exosomes or released by ectodomain shedding from the cell surface. Given that soluble basigin is increased in the circulation of patients with a poor cancer prognosis, we explored the putative role of the ADAM12-generated basigin ectodomain in cancer progression. We show that recombinant basigin ectodomain binds ß1 integrin and stimulates gelatin degradation and the migration of cancer cells in a matrix metalloproteinase (MMP)- and ß1-integrin-dependent manner. Subsequent in vitro and in vivo experiments demonstrated the altered expression of extracellular matrix proteins, including fibronectin and collagen type 5. Thus, we found increased deposits of collagen type 5 in the stroma of nude mice tumors of the human tumor cell line MCF7 expressing ADAM12-mimicking the desmoplastic response seen in human cancer. Our findings indicate a feedback loop between ADAM12 expression, basigin shedding, TGFß signaling, and extracellular matrix (ECM) remodeling, which could be a mechanism by which ADAM12-generated basigin ectodomain contributes to the regulation of desmoplasia, a key feature in human cancer progression.

Epinephrine vs placebo in neonatal resuscitation: ROSC and brain MRS/MRI in term piglets.

BACKGROUND: We aimed to investigate the effect of epinephrine vs placebo on return of spontaneous circulation (ROSC) and brain magnetic resonance spectroscopy and imaging (MRS/MRI) in newborn piglets with hypoxic cardiac arrest (CA). METHODS: Twenty-five piglets underwent hypoxia induced by endotracheal tube clamping until CA. The animals were randomized to CPR + intravenous epinephrine or CPR + placebo (normal saline). The primary outcome was ROSC, and secondary outcomes included time-to-ROSC, brain MRS/MRI, and composite endpoint of death or severe brain MRS/MRI abnormality. RESULTS: ROSC was more frequent in animals treated with epinephrine than placebo; 10/13 vs 4/12, RR = 2.31 (95% CI: 1.09-5.77). We found no difference in time-to-ROSC (120 (113-211) vs 153 (116-503) seconds, p = 0.7) or 6-h survival (7/13 vs 3/12, p = 0.2). Among survivors, there was no difference between groups in brain MRS/MRI. We found no difference in the composite endpoint of death or severe brain MRS/MRI abnormality; RR = 0.7 (95% CI: 0.37-1.19). CONCLUSIONS: Resuscitation with epinephrine compared to placebo improved ROSC frequency after hypoxic CA in newborn piglets. We found no difference in time-to-ROSC or the composite endpoint of death or severe brain MRS/MRI abnormality. IMPACT: In a newborn piglet model of hypoxic cardiac arrest, resuscitation with epinephrine compared to placebo improved the rate of return of spontaneous circulation and more than doubled the 6-h survival. Brain MRS/MRI biomarkers were used to evaluate the effect of epinephrine vs placebo. We found no difference between groups in the composite endpoint of death or severe brain MRS/MRI abnormality. This study adds to the limited evidence regarding the effect and safety of epinephrine; the lack of high-quality evidence from randomized clinical trials was highlighted in the latest ILCOR 2020 guidelines, and newborn animal studies were specifically requested.

Effects of different drainage conditions on nitrogen losses of an agricultural sandy loam soil.

Prolonged waterlogging in agricultural fields has severe consequences for the crop development and growth, and could potentially lead to higher N losses. In this study, a 3.93 ha agricultural field in Denmark was separated into two parts of well-drained (WD) and poorly-drained (PD) based on the installation depth of the tile drains. The field was continuously monitored for drainage, soil water dynamics, nitrogen leaching through the drains, and grain dry matter and nitrogen yields in a 4-year period (2017-2020). Furthermore, denitrification potential of the top 1 m of the soil at both parts of the field was measured through the denitrifying enzyme activity assay, and a 1D Daisy model was utilized to capture the differences between water and nitrogen balances at WD and PD. Results indicated that on average over the 4 years, annual harvested nitrogen in the crops at PD was 14% lower compared to WD, with a significant reduction of 33% in 2017-2018, that coincided with the longest period of waterlogging at PD. Moreover, greater losses of nitrogen through leaching from drainage and other pathways were measured at the PD (109 kg N ha-1 ya-1) compared to the WD (95 kg N ha-1 ya-1). Based on the simulations, losses through preferential flow pathways to the drains dominated at PD and most of the denitrification is expected to occur within the topsoil. Future studies could significantly benefit from monitoring the redox dynamics in the top 30 cm of the PD soils, and increasing the depth of tiles drains by redrainage could reduce the N losses of poorly drained agricultural soils.

Remote ischemic postconditioning for neuroprotection after newborn hypoxia-ischemia: systematic review of preclinical studies.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a major contributor to death and disability worldwide. Remote ischemic postconditioning (RIPC) may offer neuroprotection but has only been tested in preclinical models. Various preclinical models with different assessments of outcomes complicate interpretation. The objective of this systematic review was to determine the neuroprotective effect of RIPC in animal models of HIE. METHODS: The protocol was preregistered at The International Prospective Register of Systematic Reviews (PROSPERO) (CRD42020205944). Literature was searched in PubMed, Embase, and Web of Science (April 2020). A formal meta-analysis was impossible due to heterogeneity and a descriptive synthesis was performed. RESULTS: Thirty-two papers were screened, and five papers were included in the analysis. These included three piglet studies and two rat studies. A broad range of outcome measures was assessed, with inconsistent results. RIPC improved brain lactate/N-acetylaspartate ratios in two piglet studies, suggesting a limited metabolic effect, while most other outcomes assessed were equally likely to improve or not. CONCLUSIONS: There is a lack of evidence to evaluate the neuroprotective effect of RIPC in HIE. Additional studies should aim to standardize methodology and outcome acquisition focusing on clinically relevant outcomes. Future studies should address the optimal timing and duration of RIPC and the combination with therapeutic hypothermia. IMPACT: This systematic review summarizes five preclinical studies that reported inconsistent effects of RIPC as a neuroprotective intervention after hypoxia-ischemia. The heterogeneity of hypoxia-ischemia animal models employed, mode of postconditioning, and diverse outcomes assessed at varying times means the key message is that no clear conclusions on effect can be drawn. This review highlights the need for future studies to be designed with standardized methodology and common clinically relevant outcomes in models with documented translatability to the human condition.

Parker Solar Probe Observations of Solar Wind Energetic Proton Beams Produced by Magnetic Reconnection in the Near-Sun Heliospheric Current Sheet.

We report observations of reconnection exhausts in the Heliospheric Current Sheet (HCS) during Parker Solar Probe Encounters 08 and 07, at 16 R s and 20 R s , respectively. Heliospheric current sheet (HCS) reconnection accelerated protons to almost twice the solar wind speed and increased the proton core energy by a factor of ∼3, due to the Alfvén speed being comparable to the solar wind flow speed at these near-Sun distances. Furthermore, protons were energized to super-thermal energies. During E08, energized protons were found to have leaked out of the exhaust along separatrix field lines, appearing as field-aligned energetic proton beams in a broad region outside the HCS. Concurrent dropouts of strahl electrons, indicating disconnection from the Sun, provide further evidence for the HCS being the source of the beams. Around the HCS in E07, there were also proton beams but without electron strahl dropouts, indicating that their origin was not the local HCS reconnection exhaust.

No Differences in Cerebral Immunohistochemical Markers following Remote Ischemic Postconditioning in Newborn Piglets with Hypoxia-Ischemia.

BACKGROUND: Despite therapeutic hypothermia, neonates with hypoxic-ischemic encephalopathy still develop neurological disabilities. We have previously investigated neuroprotection by remote ischemic postconditioning (RIPC) in newborn piglets following hypoxia-ischemia (HI). The aim of this study was to further investigate potential effects of RIPC on cerebral immunohistochemical markers related to edema, apoptosis, and angiogenesis. METHODS: Brain expression of aquaporin 4, caspase-3, B-cell lymphoma 2, and vascular endothelial growth factor was analyzed by immunohistochemistry in 23 piglets, randomly selected from a larger study of RIPC after HI. Twenty animals were subjected to 45 minutes of HI and randomized to treatment with and without RIPC, while three animals were randomized to sham procedures. RIPC was conducted by four conditioning cycles of 5-minute ischemia and reperfusion. Piglets were euthanized 72 hours after the HI insult. RESULTS: Piglets subjected to HI treated with and without RIPC were similar at baseline and following the HI insult. However, piglets randomized to HI alone had longer duration of low blood pressure during the insult. We found no differences in the brain expression of the immunohistochemical markers in any regions of interest or the whole brain between the two HI groups. CONCLUSION: RIPC did not influence brain expression of markers related to edema, apoptosis, or angiogenesis in newborn piglets at 72 hours after HI. These results support previous findings of limited neuroprotective effect by this RIPC protocol. Our results may have been affected by the time of assessment, use of fentanyl as anesthetic, or limitations related to our immunohistochemical methods.

Parker Solar Probe Enters the Magnetically Dominated Solar Corona.

The high temperatures and strong magnetic fields of the solar corona form streams of solar wind that expand through the Solar System into interstellar space. At 09:33 UT on 28 April 2021 Parker Solar Probe entered the magnetized atmosphere of the Sun 13 million km above the photosphere, crossing below the Alfvén critical surface for five hours into plasma in casual contact with the Sun with an Alfvén Mach number of 0.79 and magnetic pressure dominating both ion and electron pressure. The spectrum of turbulence below the Alfvén critical surface is reported. Magnetic mapping suggests the region was a steady flow emerging on rapidly expanding coronal magnetic field lines lying above a pseudostreamer. The sub-Alfvénic nature of the flow may be due to suppressed magnetic reconnection at the base of the pseudostreamer, as evidenced by unusually low densities in this region and the magnetic mapping.

Short-term outcomes of remote ischemic postconditioning 1 h after perinatal hypoxia-ischemia in term piglets.

BACKGROUND: We aimed to assess remote ischemic postconditioning (RIPC) as a neuroprotective strategy after perinatal hypoxia-ischemia (HI) in a piglet model. METHODS: Fifty-four newborn piglets were subjected to global HI for 45 min. One hour after HI, piglets were randomized to four cycles of 5 min of RIPC or supportive treatment only. The primary outcome was brain lactate/N-acetylaspartate (Lac/NAA) ratios measured by magnetic resonance spectroscopy at 72 h. Secondary outcomes included diffusion-weighted imaging and neuropathology. RESULTS: RIPC was associated with a reduction in overall and basal ganglia Lac/NAA ratios at 72 h after HI, but no effect on diffusion-weighted imaging, neuropathology scores, neurological recovery, or mortality. CONCLUSIONS: The selective effect of RIPC on Lac/NAA ratios may suggest that the metabolic effect is greater than the structural and functional improvement at 72 h after HI. Further studies are needed to address whether there is an add-on effect of RIPC to hypothermia, together with the optimal timing, number of cycles, and duration of RIPC. IMPACT: RIPC after HI was associated with a reduction in overall and basal ganglia Lac/NAA ratios at 72 h, but had no effect on diffusion-weighted imaging, neuropathology scores, neurological recovery, or mortality. RIPC may have a selective metabolic effect, ameliorating lactate accumulation without improving other short-term outcomes assessed at 72 h after HI. We applied four cycles of 5 min RIPC, complementing existing data on other durations of RIPC. This study adds to the limited data on RIPC after perinatal HI and highlights that knowledge gaps, including timing and duration of RIPC, must be addressed together with exploring the combined effects with hypothermia.

Loss of ADAM9 expression impairs ß1 integrin endocytosis, focal adhesion formation and cancer cell migration.

The transmembrane protease ADAM9 is frequently upregulated in human cancers, and it promotes tumour progression in mice. In vitro, ADAM9 regulates cancer cell adhesion and migration by interacting with integrins. However, how ADAM9 modulates integrin functions is not known. We here show that ADAM9 knockdown increases ß1 integrin levels through mechanisms that are independent of its protease activity. In ADAM9-silenced cells, adhesion to collagen and fibronectin is reduced, suggesting an altered function of the accumulated integrins. Mechanistically, ADAM9 co-immunoprecipitates with ß1 integrin, and both internalization and subsequent degradation of ß1 integrin are significantly decreased in ADAM9-silenced cells, with no effect on ß1 integrin recycling. Accordingly, the formation of focal adhesions and actin stress fibres in ADAM9-silenced cells is altered, possibly explaining the reduction in cell adhesion and migration in these cells. Taken together, our data provide mechanistic insight into the ADAM9-integrin interaction, demonstrating that ADAM9 regulates ß1 integrin endocytosis. Moreover, our findings indicate that the reduced migration of ADAM9-silenced cells is, at least in part, caused by the accumulation and altered activity of ß1 integrin at the cell surface.

Constraining Ion-Scale Heating and Spectral Energy Transfer in Observations of Plasma Turbulence.

We perform a statistical study of the turbulent power spectrum at inertial and kinetic scales observed during the first perihelion encounter of the Parker Solar Probe. We find that often there is an extremely steep scaling range of the power spectrum just above the ion-kinetic scales, similar to prior observations at 1 A.U., with a power-law index of around -4. Based on our measurements, we demonstrate that either a significant (>50%) fraction of the total turbulent energy flux is dissipated in this range of scales, or the characteristic nonlinear interaction time of the turbulence decreases dramatically from the expectation based solely on the dispersive nature of nonlinearly interacting kinetic Alfvén waves.

Plasma Double Layers at the Boundary Between Venus and the Solar Wind.

The solar wind is slowed, deflected, and heated as it encounters Venus's induced magnetosphere. The importance of kinetic plasma processes to these interactions has not been examined in detail, due to a lack of constraining observations. In this study, kinetic-scale electric field structures are identified in the Venusian magnetosheath, including plasma double layers. The double layers may be driven by currents or mixing of inhomogeneous plasmas near the edge of the magnetosheath. Estimated double-layer spatial scales are consistent with those reported at Earth. Estimated potential drops are similar to electron temperature gradients across the bow shock. Many double layers are found in few high cadence data captures, suggesting that their amplitudes are high relative to other magnetosheath plasma waves. These are the first direct observations of plasma double layers beyond near-Earth space, supporting the idea that kinetic plasma processes are active in many space plasma environments.

Dutch genome diagnostic laboratories accelerated and improved variant interpretation and increased accuracy by sharing data.

Each year diagnostic laboratories in the Netherlands profile thousands of individuals for heritable disease using next-generation sequencing (NGS). This requires pathogenicity classification of millions of DNA variants on the standard 5-tier scale. To reduce time spent on data interpretation and increase data quality and reliability, the nine Dutch labs decided to publicly share their classifications. Variant classifications of nearly 100,000 unique variants were catalogued and compared in a centralized MOLGENIS database. Variants classified by more than one center were labeled as "consensus" when classifications agreed, and shared internationally with LOVD and ClinVar. When classifications opposed (LB/B vs. LP/P), they were labeled "conflicting", while other nonconsensus observations were labeled "no consensus". We assessed our classifications using the InterVar software to compare to ACMG 2015 guidelines, showing 99.7% overall consistency with only 0.3% discrepancies. Differences in classifications between Dutch labs or between Dutch labs and ACMG were mainly present in genes with low penetrance or for late onset disorders and highlight limitations of the current 5-tier classification system. The data sharing boosted the quality of DNA diagnostics in Dutch labs, an initiative we hope will be followed internationally. Recently, a positive match with a case from outside our consortium resulted in a more definite disease diagnosis.

Sorting nexin 9 (SNX9) regulates levels of the transmembrane ADAM9 at the cell surface.

ADAM9 is an active member of the family of transmembrane ADAMs (a disintegrin and metalloproteases). It plays a role in processes such as bone formation and retinal neovascularization, and importantly, its expression in human cancers correlates with disease stage and poor prognosis. Functionally, ADAM9 can cleave several transmembrane proteins, thereby shedding their ectodomains from the cell surface. Moreover, ADAM9 regulates cell behavior by binding cell-surface receptors such as integrin and membrane-type matrix metalloproteases. Because these functions are mainly restricted to the cell surface, understanding the mechanisms regulating ADAM9 localization and activity at this site is highly important. To this end, we here investigated how intracellular trafficking regulates ADAM9 availability at the cell surface. We found that ADAM9 undergoes constitutive clathrin-dependent internalization and subsequent degradation or recycling to the plasma membrane. We confirmed previous findings of an interaction between ADAM9 and the intracellular sorting protein, sorting nexin 9 (SNX9), as well as its close homolog SNX18. Knockdown of either SNX9 or SNX18 had no apparent effects on ADAM9 internalization or recycling. However, double knockdown of SNX9 and SNX18 decreased ADAM9 internalization significantly, demonstrating a redundant role in this process. Moreover, SNX9 knockdown revealed a nonredundant effect on overall ADAM9 protein levels, resulting in increased ADAM9 levels at the cell surface, and a corresponding increase in the shedding of Ephrin receptor B4, a well-known ADAM9 substrate. Together, our findings demonstrate that intracellular SNX9-mediated trafficking constitutes an important ADAM9 regulatory pathway.

Severity of hypoxic ischemic encephalopathy and heart rate variability in neonates: a systematic review.

BACKGROUND: Several studies have investigated heart rate variability (HRV) as a biomarker for acute brain injury in hypoxic ischemic encephalopathy (HIE). However, the current evidence is heterogeneous and needs further reviewing to direct future studies. We aimed to systematically review whether HIE severity is associated with HRV. METHODS: This systematic review was conducted according to the preferred reporting items for systematic review and meta analyses (PRISMA). We included studies comparing neonates with severe or moderate HIE with neonates with mild or no HIE with respect to different HRV measures within 7 days of birth. Article selection and quality assessment was independently performed by two reviewers. Risk of bias and strength of evidence was evaluated by the Newcastle-Ottawa scale (NOS) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We screened 1187 studies. From these, four observational studies with 248 neonates were included. For all HRV measures, the strength of evidence was very low. Neonates with severe or moderate HIE showed a reduction in most HRV measures compared to neonates with mild or no HIE with a greater reduction in those with severe HIE. CONCLUSIONS: Moderate and severe HIE was associated with a reduction in most HRV measures. Accordingly, HRV is a potential biomarker for HIE severity during the first week of life. However, the uncertainty calls for more studies.