Macrophage metabolic rewiring improves heme-suppressed efferocytosis and tissue damage in sickle cell disease.

Sickle cell disease (SCD) is hallmarked by an underlying chronic inflammatory condition, which is contributed by heme-activated proinflammatory macrophages. Although previous studies addressed heme ability to stimulate macrophage inflammatory skewing through Toll-like receptor4 (TLR4)/reactive oxygen species signaling, how heme alters cell functional properties remains unexplored. Macrophage-mediated immune cell recruitment and apoptotic cell (AC) clearance are relevant in the context of SCD, in which tissue damage, cell apoptosis, and inflammation occur owing to vaso-occlusive episodes, hypoxia, and ischemic injury. Here we show that heme strongly alters macrophage functional response to AC damage by exacerbating immune cell recruitment and impairing cell efferocytic capacity. In SCD, heme-driven excessive leukocyte influx and defective efferocytosis contribute to exacerbated tissue damage and sustained inflammation. Mechanistically, these events depend on heme-mediated activation of TLR4 signaling and suppression of the transcription factor proliferator-activated receptor γ (PPARγ) and its coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). These changes reduce efferocytic receptor expression and promote mitochondrial remodeling, resulting in a coordinated functional and metabolic reprogramming of macrophages. Overall, this results in limited AC engulfment, impaired metabolic shift to mitochondrial fatty acid ß-oxidation, and, ultimately, reduced secretion of the antiinflammatory cytokines interleukin-4 (IL-4) and IL-10, with consequent inhibition of continual efferocytosis, resolution of inflammation, and tissue repair. We further demonstrate that impaired phagocytic capacity is recapitulated by macrophage exposure to plasma of patients with SCD and improved by hemopexin-mediated heme scavenging, PPARγ agonists, or IL-4 exposure through functional and metabolic macrophage rewiring. Our data indicate that therapeutic improvement of heme-altered macrophage functional properties via heme scavenging or PGC1α/PPARγ modulation significantly ameliorates tissue damage associated with SCD pathophysiology.

Vasculo-toxic and pro-inflammatory action of unbound haemoglobin, haem and iron in transfusion-dependent patients with haemolytic anaemias.

Increasing evidence suggests that free haem and iron exert vasculo-toxic and pro-inflammatory effects by activating endothelial and immune cells. In the present retrospective study, we compared serum samples from transfusion-dependent patients with ß-thalassaemia major and intermedia, hereditary spherocytosis and sickle cell disease (SCD). Haemolysis, transfusions and ineffective erythropoiesis contribute to haem and iron overload in haemolytic patients. In all cohorts we observed increased systemic haem and iron levels associated with scavenger depletion and toxic 'free' species formation. Endothelial dysfunction, oxidative stress and inflammation markers were significantly increased compared to healthy donors. In multivariable logistic regression analysis, oxidative stress markers remained significantly associated with both haem- and iron-related parameters, while soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble endothelial selectin (sE-selectin) and tumour necrosis factor α (TNFα) showed the strongest association with haem-related parameters and soluble intercellular adhesion molecule 1 (sICAM-1), sVCAM-1, interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) with iron-related parameters. While hereditary spherocytosis was associated with the highest IL-6 and TNFα levels, ß-thalassaemia major showed limited inflammation compared to SCD. The sVCAM1 increase was significantly lower in patients with SCD receiving exchange compared to simple transfusions. The present results support the involvement of free haem/iron species in the pathogenesis of vascular dysfunction and sterile inflammation in haemolytic diseases, irrespective of the underlying haemolytic mechanism, and highlight the potential therapeutic benefit of iron/haem scavenging therapies in these conditions.

Serpentinite and the search for life beyond Earth.

Hydrogen from serpentinization is a source of chemical energy for some life forms on Earth. It is a potential fuel for life in the subsurface of Mars and in the icy ocean worlds in the outer solar system. Serpentinization is also implicated in life's origin. Planetary exploration offers a way to investigate such theories by characterizing and ultimately searching for life in geochemical settings that no longer exist on Earth. At present, much of the current context of serpentinization on other worlds relies on inference from modelling and studies on Earth. While there is evidence from orbital spectral imaging and martian meteorites that serpentinization has occurred on Mars, the extent and duration of that activity has not been constrained. Similarly, ongoing serpentinization might explain hydrogen found in the ocean of Saturn's tiny moon Enceladus, but this raises questions about how long such activity has persisted. Titan's hydrocarbon-rich atmosphere may derive from ancient or present-day serpentinization at the bottom of its ocean. In Europa, volcanism or serpentinization may provide hydrogen as a redox couple to oxygen generated at the moon's surface. We assess the potential extent of serpentinization in the solar system's wet and rocky worlds, assuming that microfracturing from thermal expansion anisotropy sets an upper limit on the percolation depth of surface water into the rocky interiors. In this bulk geophysical model, planetary cooling from radiogenic decay implies the infiltration of water to greater depths through time, continuing to the present. The serpentinization of this newly exposed rock is assessed as a significant source of global hydrogen. Comparing the computed hydrogen and surface-generated oxygen delivered to Europa's ocean reveals redox fluxes similar to Earth's. Planned robotic exploration missions to other worlds can aid in understanding the planetary context of serpentinization, testing the predictions herein. This article is part of a discussion meeting issue 'Serpentinite in the Earth System'.

Oxygen production from dissociation of Europa's water-ice surface.

Jupiter's moon Europa has a predominantly water-ice surface that is modified by exposure to its space environment. Charged particles break molecular bonds in surface ice, thus dissociating the water to ultimately produce H2 and O2, which provides a potential oxygenation mechanism for Europa's subsurface ocean. These species are understood to form Europa's primary atmospheric constituents. Although remote observations provide important global constraints on Europa's atmosphere, the molecular O2 abundance has been inferred from atomic O emissions. Europa's atmospheric composition had never been directly sampled and model-derived oxygen production estimates ranged over several orders of magnitude. Here, we report direct observations of H2+ and O2+ pickup ions from the dissociation of Europa's water-ice surface and confirm these species are primary atmospheric constituents. In contrast to expectations, we find the H2 neutral atmosphere is dominated by a non-thermal, escaping population. We find 12 ± 6 kg s-1 (2.2 ± 1.2 × 1026 s-1) O2 are produced within Europa's surface, less than previously thought, with a narrower range to support habitability in Europa's ocean. This process is found to be Europa's dominant exogenic surface erosion mechanism over meteoroid bombardment.

In Search of Subsurface Oceans Within the Uranian Moons.

The Galileo mission to Jupiter discovered magnetic signatures associated with hidden subsurface oceans at the moons Europa and Callisto using the phenomenon of magnetic induction. These induced magnetic fields originate from electrically conductive layers within the moons and are driven by Jupiter's strong time-varying magnetic field. The ice giants and their moons are also ideal laboratories for magnetic induction studies. Both Uranus and Neptune have a strongly tilted magnetic axis with respect to their spin axis, creating a dynamic and strongly variable magnetic field environment at the orbits of their major moons. Although Voyager 2 visited the ice giants in the 1980s, it did not pass close enough to any of the moons to detect magnetic induction signatures. However, Voyager 2 revealed that some of these moons exhibit surface features that hint at recent geologically activity, possibly associated with subsurface oceans. Future missions to the ice giants may therefore be capable of discovering subsurface oceans, thereby adding to the family of known "ocean worlds" in our Solar System. Here, we assess magnetic induction as a technique for investigating subsurface oceans within the major moons of Uranus. Furthermore, we establish the ability to distinguish induction responses created by different interior characteristics that tie into the induction response: ocean thickness, conductivity and depth, and ionospheric conductance. The results reported here demonstrate the possibility of single-pass ocean detection and constrained characterization within the moons of Miranda, Ariel, and Umbriel, and provide guidance for magnetometer selection and trajectory design for future missions to Uranus.

PFOS dominates PFAS composition in ambient fine particulate matter (PM2.5) collected across North Carolina nearly 20 years after the end of its US production.

Contamination of drinking water by per- and polyfluoroalkyl substances (PFASs) emitted from manufacturing plants, fire-fighting foams, and urban waste streams has received considerable attention due to concerns over toxicity and environmental persistence; however, PFASs in ambient air remain poorly understood, especially in the United States (US). We measured PFAS concentrations in ambient fine particulate matter (PM2.5) at 5 locations across North Carolina over a 1 year period in 2019. Thirty-four PFASs, including perfluoroalkyl carboxylic, perfluoroalkane sulfonic, perfluoroalkyl ether carboxylic and sulfonic acids were analyzed by UHPLC/ESI-MS/MS. Quarterly averaged concentrations ranged from <0.004-14.1 pg m-3. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) ranged from <0.18 to 14.1 pg m-3, comparable to previous PM2.5 measurements from Canada and Europe (<0.02-3.5 pg m-3). Concentrations above 1 pg m-3 were observed in July-September at Charlotte (14.1 pg m-3, PFOA), Wilmington (4.75 pg m-3, PFOS), and Research Triangle Park (1.37 pg m-3, PFOS). Notably, PM2.5 has a short atmospheric lifetime (<2 weeks), and thus, the presence of PFOS in these samples raises questions about their sources, since PFOS production was phased out in the US ∼20 years ago. This is the first US study to provide insights into ambient PFAS concentrations in PM2.5.

Synthesis and characterization of potassium metal/graphitic carbon nanofiber intercalates.

Direct reaction of herringbone, platelet, or narrow, tubular herringbone graphitic carbon nanofibers (GCNFs) with molten potassium gives K/GCNF intercalates with stoichiometric control of potassium loading. Intercalate formation is confirmed by powder X-ray diffraction and micro-Raman spectroscopy. K/GCNF intercalates act as radical-anion alkene polymerization catalysts and reduce water with stoichiometric formation of hydrogen gas. Stage-1 K/narrow, tubular GCNF intercalate exhibits thermionic emission at 300 degrees C. Stage-1 K/herringbone GCNF intercalate is an excellent thermionic emitter having high thermal stability up to 1000 degrees C. K/GCNF intercalates have much reduced work functions of ca. 2.2 eV with localized emission showing a work function of 1.6 eV.

The astrobiology primer: an outline of general knowledge--version 1, 2006.

The Astrobiology Primer has been created as a reference tool for those who are interested in the interdisciplinary field of astrobiology. The field incorporates many diverse research endeavors, but it is our hope that this slim volume will present the reader with all he or she needs to know to become involved and to understand, at least at a fundamental level, the state of the art. Each section includes a brief overview of a topic and a short list of readable and important literature for those interested in deeper knowledge. Because of the great diversity of material, each section was written by a different author with a different expertise. Contributors, authors, and editors are listed at the beginning, along with a list of those chapters and sections for which they were responsible. We are deeply indebted to the NASA Astrobiology Institute (NAI), in particular to Estelle Dodson, David Morrison, Ed Goolish, Krisstina Wilmoth, and Rose Grymes for their continued enthusiasm and support. The Primer came about in large part because of NAI support for graduate student research, collaboration, and inclusion as well as direct funding. We have entitled the Primer version 1 in hope that it will be only the first in a series, whose future volumes will be produced every 3-5 years. This way we can insure that the Primer keeps up with the current state of research. We hope that it will be a great resource for anyone trying to stay abreast of an ever-changing field.

Transthoracic defibrillation: effect of sternotomy on chest impedance.

The purpose of this study was to determine the effect of sternotomy on transthoracic impedance, a major determinant of current flow and defibrillation success. Transthoracic impedance was determined by using a validated test-pulse technique that does not require actual shocks. Seventeen patients undergoing median sternotomy were studied prospectively. Transthoracic impedance was determined before operation, 3 to 5 days after operation and (in eight patients) greater than or equal to 1 month after operation. When measured using paddle electrodes placed in the standard apex-right parasternal defibrillating position, transthoracic impedance declined after sternotomy in all patients, from 77 +/- 18 to 59 +/- 17 omega (p less than 0.01); smaller declines were demonstrated by using other electrode positions. Transthoracic impedance remained below the preoperative level in the eight patients who underwent a second set of measurements at least 1 month after operation. Six normal subjects not undergoing sternotomy underwent serial transthoracic impedance measurements at least 5 days apart; mean transthoracic impedance did not change. It is concluded that transthoracic impedance declines after sternotomy. At any operator-selected energy level a higher current flow will result after sternotomy; this may facilitate postoperative defibrillation.

Predicting posttraumatic epilepsy in penetrating head injury.

Using data derived from a 15-year follow-up study of 520 veterans surviving penetrating brain wounds received in the Vietnam war, we have developed a predictive formula and tables for posttraumatic epilepsy based on time elapsed postinjury and presence of specific clinical and computed tomographic scan risk factors. Such patients remain at some increased risk for epilepsy even ten to 15 years postinjury, although most can be 95% certain of avoiding epilepsy if they have been seizure free for three years posttrauma. Epilepsy onset latency was independent of any risk factors identified.

Isolated impairment of memory following a penetrating lesion of the fornix cerebri.

Persistent memory problems were reported by a 39-year-old man who suffered a penetrating brain wound while serving in Vietnam 15 years earlier. Neuropsychological testing indicated an unusually isolated memory impairment. Computed tomography revealed transection of the columns of the fornix cerebri with no temporal-lobe involvement and minimal thalamic damage. We suggest that the fornix cerebri has a role in the maintenance of information accessibility to both encoding and recall during post-working memory processing and in the organization of verbal information during encoding and/or retrieval for declarative (recall) purposes. These processes are not essential for verbal recognition but can result in decrements on specific laboratory tasks and in social adjustment.

Epilepsy after penetrating head injury. I. Clinical correlates: a report of the Vietnam Head Injury Study.

Of 421 veterans who had penetrating brain wounds in Vietnam 15 years ago, 53% had posttraumatic epilepsy, and one-half of those still had seizures 15 years after injury. The relative risk of developing epilepsy dropped from about 580 times higher than the general age-matched population in the first year to 25 times higher after 10 years. Patients with focal neurologic signs or large lesions had increased risk of epilepsy, and site of the lesion may have been more important than size in determining occurrence. Family history of epilepsy or preinjury intelligence had no effect on seizure occurrence. Seizure frequency in the first year predicted future severity of seizures. Phenytoin therapy in the first year after injury did not prevent later seizures.

Consciousness and amnesia after penetrating head injury: neurology and anatomy.

Among 342 men who survived severe penetrating brain wounds, only 15% had prolonged unconsciousness and 53% had no or momentary unconsciousness after injury, emphasizing the focal nature of these wounds. The left (or language-dominant) hemisphere was dominant for the "wakefulness" component of consciousness. The areas most associated with unconsciousness included the posterior limb of the left internal capsule, left basal forebrain, midbrain, and hypothalamus. Left dominance was not seen for posttraumatic amnesia after elimination of the wakefulness variable, suggesting that wakefulness may be linked to the role of the left hemisphere in verbal memory.

Penetrating war injuries of the basal forebrain: neurology and cognition.

We compared the neurologic and cognitive performance of 15 young veterans who suffered unilateral penetrating missile wounds to the basal forebrain 15 years ago in the Vietnam War with uninjured controls and patients with lesions elsewhere in the brain. The subjects performed worse on tests of episodic memory, reasoning, and arithmetic and had more prolonged unconsciousness after injury; but their performance usually compared favorably with that of uninjured controls on tests of intelligence, attention, and language and was not consistent with that of a demented patient. The data suggest that the basal forebrain is functionally related to the reticular formation and to the basal forebrain is functionally related to the reticular formation and to the limbic-hippocampal memory system.

Measurement of cochlear blood flow--new technique.

A newly-developed procedure which combines the microsphere method with surface preparation dissection was employed in an investigation of blood flow in cochleas of anesthetized gerbils. In these experiments, 10.1 +/- 0.9 microns carbon-coated microspheres were injected into the left auricle of the heart and a reference blood sample withdrawn at 0.165 ml/min from the iliac artery. The blood flow in the lateral portion (stria vascularis, ligamentum spirale, and suprastria) was calculated to be 337.20, 184.00 and 24.75 nl/min; in the spiral portion (basilar membrane, lamina spiralis ossea, and limbus spiralis) it was found to be 85.40, 39.55 and 6.10 nl/min; and in the central portion (modiolus) it was found to be 256.55, 43.60 and 2.45 nl/min in the first, second and third turns, respectively. The total blood flow in the left and right membranous cochleas was 1062.70 and 896.60 nl/min, respectively. Averaged total blood flow in both ears was 979.60 nl/min. This is a first attempt to measure blood flow in the very small, functionally different areas of the cochlea. This work has shown that it is possible to measure and compare blood flow between the turns and between different functional parts within the turns.

Cochlear blood flow. The effect of noise at 60 minutes' exposure.

The effect of 60 minutes of exposure to high-frequency (10- to 40-kHz), high-intensity (115-dB) noise on the cochlear blood flow (CoBF) was investigated in adult gerbils. The CoBF was measured with a newly improved microsphere method. The number of microspheres in cochlear tissue that had been dissected by the surface preparation technique was assessed by direct counting. Our experiments have indicated that the CoBF is elevated even after 60 minutes of noise exposure. This was true particularly in the areas where these frequencies stimulate the cochlea. The noise also increased CoBF in the opposite ear in areas not corresponding to the stimulation frequencies (second and third turn). This phenomenon is under further investigation.

Time course of cytokine release and complement activation after implantation of the HeartMate left ventricular assist device.

Pro-inflammatory mediators, including interleukin-6 (IL-6), IL-8, and complement C3a, are released after cardiac surgery as part of the inflammatory response related to blood-biomaterial interaction in the cardiopulmonary bypass circuit. Post operative time course data for these mediators are not fully defined in patients receiving left ventricular assist device (LVAD) support. The authors performed enzyme linked immunosorbent assays for concentrations of IL-6, IL-8, and C3a in plasma in six HeartMate LVAD recipients at the following times: pre operatively; 4, 8, 16, 24, 36, and 48 hr post operatively; daily through the first week; and weekly thereafter for 6 weeks. All patients survived without major complications during the study. Pre operative concentrations of IL-6 and C3a in plasma were significantly increased compared with age matched controls. Post operatively, the concentrations of IL-6 and IL-8 in plasma took longer to return to baseline values after insertion of the LVAD than the trends reported in the literature after routine cardiopulmonary bypass alone. Concentrations of IL-6 and complement C3a continued to decrease to lower than baseline post operatively, reaching statistical significance after 6 weeks of LVAD support. The authors conclude that the presence of the HeartMate LVAD delays the return of pro-inflammatory mediator concentrations back to baseline values compared with routine cardiopulmonary bypass alone, but the device does not appear to be an ongoing source of cytokine release or complement activation.

The effect of social support on adolescent mothers' styles of parent-child interaction as measured on three separate occasions.

The purpose of this study was to determine the effect of social support on parent-child interaction in a group of 19 adolescent mothers. The subjects participated in a 20-week model demonstration program in which they worked in a preschool classroom with skilled caregivers who modeled facilitative styles of interacting with young children. Each subject was videotaped while interacting with a 1- to 2-year-old child upon entering the program, midway through the program, and at the end. Results showed that girls who were 16 years or older significantly increased their frequency of using responsive, engaging, and elaborative styles of behavior. Those under age 16 did not show significant changes in these three behaviors. Overall, subjects significantly increased the duration of time they spent observing the child's play behavior.

Effects of left-hand preference on postinjury measures of distal motor ability.

The relationship of preinjury left-hand dominance for motor performance to postinjury distal motor skills following penetrating brain wounds in patients without overt hemiplegia was examined. We studied 13 controls, 13 right-hemisphere brain-damaged patients, and 11 left-hemisphere brain-damaged patients on motor tasks measuring reaction time, strength, and coordination. Our results indicated that no persistent deficits were seen on distal motor tasks in left-handed adults who suffered a penetrating brain wound. These findings are compatible with the relative sparing of persistent neuropsychological deficits in left-handers following brain damage.