A census of baryons in the Universe from localized fast radio bursts.

More than three-quarters of the baryonic content of the Universe resides in a highly diffuse state that is difficult to detect, with only a small fraction directly observed in galaxies and galaxy clusters1,2. Censuses of the nearby Universe have used absorption line spectroscopy3,4 to observe the 'invisible' baryons, but these measurements rely on large and uncertain corrections and are insensitive to most of the Universe's volume and probably most of its mass. In particular, quasar spectroscopy is sensitive either to the very small amounts of hydrogen that exist in the atomic state, or to highly ionized and enriched gas4-6 in denser regions near galaxies7. Other techniques to observe these invisible baryons also have limitations; Sunyaev-Zel'dovich analyses8,9 can provide evidence from gas within filamentary structures, and studies of X-ray emission are most sensitive to gas near galaxy clusters9,10. Here we report a measurement of the baryon content of the Universe using the dispersion of a sample of localized fast radio bursts; this technique determines the electron column density along each line of sight and accounts for every ionized baryon11-13. We augment the sample of reported arcsecond-localized14-18 fast radio bursts with four new localizations in host galaxies that have measured redshifts of 0.291, 0.118, 0.378 and 0.522. This completes a sample sufficiently large to account for dispersion variations along the lines of sight and in the host-galaxy environments11, and we derive a cosmic baryon density of [Formula: see text] (95 per cent confidence; h70 = H0/(70 km s-1 Mpc-1) and H0 is Hubble's constant). This independent measurement is consistent with values derived from the cosmic microwave background and from Big Bang nucleosynthesis19,20.

A mildly relativistic wide-angle outflow in the neutron-star merger event GW170817.

GW170817 was the first gravitational-wave detection of a binary neutron-star merger. It was accompanied by radiation across the electromagnetic spectrum and localized to the galaxy NGC 4993 at a distance of 40 megaparsecs. It has been proposed that the observed γ-ray, X-ray and radio emission is due to an ultra-relativistic jet being launched during the merger (and successfully breaking out of the surrounding material), directed away from our line of sight (off-axis). The presence of such a jet is predicted from models that posit neutron-star mergers as the drivers of short hard-γ-ray bursts. Here we report that the radio light curve of GW170817 has no direct signature of the afterglow of an off-axis jet. Although we cannot completely rule out the existence of a jet directed away from the line of sight, the observed γ-ray emission could not have originated from such a jet. Instead, the radio data require the existence of a mildly relativistic wide-angle outflow moving towards us. This outflow could be the high-velocity tail of the neutron-rich material that was ejected dynamically during the merger, or a cocoon of material that breaks out when a jet launched during the merger transfers its energy to the dynamical ejecta. Because the cocoon model explains the radio light curve of GW170817, as well as the γ-ray and X-ray emission (and possibly also the ultraviolet and optical emission), it is the model that is most consistent with the observational data. Cocoons may be a ubiquitous phenomenon produced in neutron-star mergers, giving rise to a hitherto unidentified population of radio, ultraviolet, X-ray and γ-ray transients in the local Universe.

The dispersion-brightness relation for fast radio bursts from a wide-field survey.

Despite considerable efforts over the past decade, only 34 fast radio bursts-intense bursts of radio emission from beyond our Galaxy-have been reported1,2. Attempts to understand the population as a whole have been hindered by the highly heterogeneous nature of the searches, which have been conducted with telescopes of different sensitivities, at a range of radio frequencies, and in environments corrupted by different levels of radio-frequency interference from human activity. Searches have been further complicated by uncertain burst positions and brightnesses-a consequence of the transient nature of the sources and the poor angular resolution of the detecting instruments. The discovery of repeating bursts from one source3, and its subsequent localization4 to a dwarf galaxy at a distance of 3.7 billion light years, confirmed that the population of fast radio bursts is located at cosmological distances. However, the nature of the emission remains elusive. Here we report a well controlled, wide-field radio survey for these bursts. We found 20, none of which repeated during follow-up observations between 185-1,097 hours after the initial detections. The sample includes both the nearest and the most energetic bursts detected so far. The survey demonstrates that there is a relationship between burst dispersion and brightness and that the high-fluence bursts are the nearby analogues of the more distant events found in higher-sensitivity, narrower-field surveys5.

An investigation into the noradrenergic and serotonergic contributions of diffuse noxious inhibitory controls in a monoiodoacetate model of osteoarthritis.

Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play. Therefore, this study considers the central contributions of chronic pain, using a monoiodoacetate (MIA) model of OA. Particularly, this study explores the functionality of descending controls over the course of the model by assessing diffuse noxious inhibitory controls (DNIC). Early-phase MIA animals have a functional DNIC system, whereas DNIC are abolished in late-phase MIA animals, indicating a dysregulation in descending modulation over the course of the model. In early-phase animals, blocking the actions of spinal α2-adrenergic receptors completely abolishes DNIC, whereas blocking the actions of spinal 5-HT7 receptors only partially decreases the magnitude of DNIC. However, activating the spinal α2-adrenergic or 5-HT7 receptors in late-phase MIA animals restored DNIC-induced neuronal inhibition. This study confirms that descending noradrenergic signaling is crucial for DNIC expression. Furthermore, we suggest a compensatory increase in descending serotonergic inhibition acting at 5-HT7 receptors as the model progresses such that receptor activation is sufficient to override the imbalance in descending controls and mediate neuronal inhibition. NEW & NOTEWORTHY This study showed that there are both noradrenergic and serotonergic components contributing to the expression of diffuse noxious inhibitory controls (DNIC). Furthermore, although a tonic descending noradrenergic tone is always crucial for the expression of DNIC, variations in descending serotonergic signaling over the course of the model mean this component plays a more vital role in states of sensitization.

Engineering polyester monomer diversity through novel pathway design.

Polyesters composed of hydroxy acids (HAs) and diols serve many material niches and are invaluable to our daily lives. However, their traditional synthesis from petrochemicals creates many environmental concerns. Metabolically engineered microorganisms have been leveraged for the industrially competitive production of a few polyesters with properties that limit their application. Designing new metabolic pathways to polyester building blocks is essential to broadening material property diversity and improving carbon and energy usage of current bioproduction schemes. This review focuses on recently developed pathways to HAs and diols. Specifically, new pathways to 2,3- and ω-Hydroxy acids, as well as C3-C4 and medium-chain-length diols, are discussed. Pathways to the same compound are compared on the basis of criteria such as energy usage, number of pathway steps, and titer. Finally, suggestions for improvements and next steps for each pathway are also discussed.

A luminous fast radio burst that probes the Universe at redshift 1.

Fast radio bursts (FRBs) are millisecond-duration pulses of radio emission originating from extragalactic distances. Radio dispersion is imparted on each burst by intervening plasma, mostly located in the intergalactic medium. In this work, we observe the burst FRB 20220610A and localize it to a morphologically complex host galaxy system at redshift 1.016 ± 0.002. The burst redshift and dispersion measure are consistent with passage through a substantial column of plasma in the intergalactic medium and extend the relationship between those quantities measured at lower redshift. The burst shows evidence for passage through additional turbulent magnetized plasma, potentially associated with the host galaxy. We use the burst energy of 2 × 1042 erg to revise the empirical maximum energy of an FRB.

Central Nervous System Targets: Supraspinal Mechanisms of Analgesia.

While the acute sensation of pain is protective, signaling the presence of actual or potential bodily harm, its persistence is unpleasant. When pain becomes chronic, it has limited evolutionarily advantage. Despite the differing nature of acute and chronic pain, a common theme is that sufferers seek pain relief. The possibility to medicate pain types as varied as a toothache or postsurgical pain reflects the diverse range of mechanism(s) by which pain-relieving "analgesic" therapies may reduce, eliminate, or prevent pain. Systemic application of an analgesic able to cross the blood-brain barrier can result in pain modulation via interaction with targets at different sites in the central nervous system. A so-called supraspinal mechanism of action indicates manipulation of a brain-defined circuitry. Pre-clinical studies demonstrate that, according to the brain circuitry targeted, varying therapeutic pain-relieving effects may be observed that relate to an impact on, for example, sensory and/or affective qualities of pain. In many cases, this translates to the clinic. Regardless of the brain circuitry manipulated, modulation of brain processing often directly impacts multiple aspects of nociceptive transmission, including spinal neuronal signaling. Consideration of supraspinal mechanisms of analgesia and ensuing pain relief must take into account nonbrain-mediated effects; therefore, in this review, the supraspinally mediated analgesic actions of opioidergic, anti-convulsant, and anti-depressant drugs are discussed. The persistence of poor treatment outcomes and/or side effect profiles of currently used analgesics highlight the need for the development of novel therapeutics or more precise use of available agents. Fully uncovering the complex biology of nociception, as well as currently used analgesic mechanism(s) and site(s) of action, will expedite this process.

A single fast radio burst localized to a massive galaxy at cosmological distance.

Fast radio bursts (FRBs) are brief radio emissions from distant astronomical sources. Some are known to repeat, but most are single bursts. Nonrepeating FRB observations have had insufficient positional accuracy to localize them to an individual host galaxy. We report the interferometric localization of the single-pulse FRB 180924 to a position 4 kiloparsecs from the center of a luminous galaxy at redshift 0.3214. The burst has not been observed to repeat. The properties of the burst and its host are markedly different from those of the only other accurately localized FRB source. The integrated electron column density along the line of sight closely matches models of the intergalactic medium, indicating that some FRBs are clean probes of the baryonic component of the cosmic web.

An investigation into the inhibitory function of serotonin in diffuse noxious inhibitory controls in the neuropathic rat.

BACKGROUND: Following neuropathy α2-adrenoceptor-mediated diffuse noxious inhibitory controls (DNIC), whereby a noxious conditioning stimulus inhibits the activity of spinal wide dynamic range (WDR) neurons, are abolished, and spinal 5-HT7 receptor densities are increased. Here, we manipulate spinal 5-HT content in spinal nerve ligated (SNL) animals and investigate which 5-HT receptor mediated actions predominate. METHODS: Using in vivo electrophysiology we recorded WDR neuronal responses to von frey filaments applied to the hind paw before, and concurrent to, a noxious ear pinch (the conditioning stimulus) in isoflurane-anaesthetised rats. The expression of DNIC was quantified as a reduction in WDR neuronal firing in the presence of conditioning stimulus and was investigated in SNL rats following spinal application of (1) selective serotonin reuptake inhibitors (SSRIs) citalopram or fluoxetine, or dual application of (2) SSRI plus 5-HT7 receptor antagonist SB269970, or (3) SSRI plus α2 adrenoceptor antagonist atipamezole. RESULTS: DNIC were revealed in SNL animals following spinal application of SSRI, but this effect was abolished upon joint application of SSRI plus SB269970 or atipamezole. CONCLUSIONS: We propose that in SNL animals the inhibitory actions (quantified as the presence of DNIC) of excess spinal 5-HT (presumed present following application of SSRI) were mediated via 5-HT7 receptors. The anti-nociception depends upon an underlying tonic noradrenergic inhibitory tone via the α2-adrenoceptor. SIGNIFICANCE: Following neuropathy enhanced spinal serotonin availability switches the predominant spinal 5-HT receptor-mediated actions but also alters noradrenergic signalling. We highlight the therapeutic complexity of SSRIs and monoamine modulators for the treatment of neuropathic pain.

A radio counterpart to a neutron star merger.

Gravitational waves have been detected from a binary neutron star merger event, GW170817. The detection of electromagnetic radiation from the same source has shown that the merger occurred in the outskirts of the galaxy NGC 4993, at a distance of 40 megaparsecs from Earth. We report the detection of a counterpart radio source that appears 16 days after the event, allowing us to diagnose the energetics and environment of the merger. The observed radio emission can be explained by either a collimated ultrarelativistic jet, viewed off-axis, or a cocoon of mildly relativistic ejecta. Within 100 days of the merger, the radio light curves will enable observers to distinguish between these models, and the angular velocity and geometry of the debris will be directly measurable by very long baseline interferometry.

Illuminating gravitational waves: A concordant picture of photons from a neutron star merger.

Merging neutron stars offer an excellent laboratory for simultaneously studying strong-field gravity and matter in extreme environments. We establish the physical association of an electromagnetic counterpart (EM170817) with gravitational waves (GW170817) detected from merging neutron stars. By synthesizing a panchromatic data set, we demonstrate that merging neutron stars are a long-sought production site forging heavy elements by r-process nucleosynthesis. The weak gamma rays seen in EM170817 are dissimilar to classical short gamma-ray bursts with ultrarelativistic jets. Instead, we suggest that breakout of a wide-angle, mildly relativistic cocoon engulfing the jet explains the low-luminosity gamma rays, the high-luminosity ultraviolet-optical-infrared, and the delayed radio and x-ray emission. We posit that all neutron star mergers may lead to a wide-angle cocoon breakout, sometimes accompanied by a successful jet and sometimes by a choked jet.

Investigation into the impact of couch sag on delivered dose.

The effect of couch sag on treatment delivery accuracy has been investigated by modelling the variation of delivered dose from planned dose due to the difference between the treatment and simulation couches. The couch sag of the Siemens (Concord, USA) Primus linac was determined relative to the couch sag of the Siemens (Germany) Sensation 4 CT Scanner. A phantom planning study was then undertaken to evaluate the likely clinical impact of the couch sag through an evaluation of changes in dose distribution, dose volume histograms and monitor units. The couch sag was simulated by altering the angle of the CT gantry when obtaining image studysets. A second investigation into the effects of couch sag was undertaken using an existing patient CT studyset. For this investigation, the couch sag was simulated by appropriate rotation of the gantry and collimator angles. The effect of couch sag on calculated monitor units (MU) was found to be statistically insignificant. The small monitor unit changes observed were likely to result from differences in the average linear attenuation coefficient along the beam path to the isocentre. The major differences seen however were in the regions away from the central axis. The dose volume histograms showed that both the bladder and rectum were further spared with increasing tilt angle whilst the PTV dose was unchanged. The only issue at South West Sydney Cancer Services (SWSCS) in terms of patient position variation arises from the angle induced by the couch sag (or more precisely, the difference in couch sag angle between the CT and Linac couches). Due to the relatively uniform structures (of PTV, bladder and rectum), and the proximity of these critical structures to the isocentre, this angular rotation about the isocentre did not cause any major variations to the DVH, MU and isodoses for realistic levels of couch sag (i.e. less than 20mm).

The magnetic field and turbulence of the cosmic web measured using a brilliant fast radio burst.

Fast radio bursts (FRBs) are millisecond-duration events thought to originate beyond the Milky Way galaxy. Uncertainty surrounding the burst sources, and their propagation through intervening plasma, has limited their use as cosmological probes. We report on a mildly dispersed (dispersion measure 266.5 ± 0.1 parsecs per cubic centimeter), exceptionally intense (120 ± 30 janskys), linearly polarized, scintillating burst (FRB 150807) that we directly localize to 9 square arc minutes. On the basis of a low Faraday rotation (12.0 ± 0.7 radians per square meter), we infer negligible magnetization in the circum-burst plasma and constrain the net magnetization of the cosmic web along this sightline to <21 nanogauss, parallel to the line-of-sight. The burst scintillation suggests weak turbulence in the ionized intergalactic medium.

Circuitry and plasticity of the dorsal horn--toward a better understanding of neuropathic pain.

Maladaptive plasticity within the dorsal horn (DH) of the spinal cord is a key substrate for development of neuropathic pain following peripheral nerve injury. Advances in genetic engineering, tracing techniques and opto-genetics are leading to a much better understanding of the complex circuitry of the spinal DH and the radical changes evoked in such circuitry by nerve injury. These changes can be viewed at multiple levels including: synaptic remodeling including enhanced excitatory and reduced inhibitory drive, morphological and electrophysiological changes which are observed both to primary afferent inputs as well as DH neurons, and ultimately circuit-level rewiring which leads to altered connectivity and aberrant processing of sensory inputs in the DH. The DH should not be seen in isolation but is subject to important descending modulation from the brainstem, which is further dysregulated by nerve injury. Understanding which changes relate to specific disease-states is essential, and recent work has aimed to stratify patient populations in a mechanistic fashion. In this review we will discuss how such pathophysiological mechanisms may lead to the distressing sensory phenomena experienced by patients suffering neuropathic pain, and the relationship of such mechanisms to current and potential future treatment modalities.

Kit preparation of technetium-99m-mercaptoacetyltriglycine: analysis, biodistribution and comparison with technetium-99m-DTPA in patients with impaired renal function.

Technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) was prepared by a frozen solution method, enabling the preparation of kits yielding a product substantially free of lipophilic impurities (96% 99mTc-MAG3). However, biliary activity was not completely eliminated as HPLC-purified 99mTc-MAG3 was also excreted by that route. Sequential 99mTc-DTPA and 99mTc-MAG3 renal scans were performed in 15 patients with renal dysfunction, including renal transplant recipients. In all cases, the 99mTc-MAG3 kit preparation provided superior images to 99mTc-DTPA at all levels of renal function due to a higher target-to-background ratio and a plasma clearance twice as fast as 99mTc-DTPA. Interpretation of delayed 99mTc-MAG3 images, however, was complicated by biliary excretion which will limit quantitative estimates of renal clearance. A 99mTc-MAG3 kit is likely to be of value in renal transplant assessment and in cases of significant renal impairment but would not appear to offer major advantages over 99mTc-DTPA in routine renal imaging.

A technique of positive-pressure single-lung ventilation via a silicone T-Y stent.

Airway control and protection, in any operation, is the first priority. The presence of a T-Y stent in the proximal airway can complicate this fundamental principle. Here we describe an effective and safe technique for positive-pressure single-lung ventilation via a T-Y stent for a lung lobectomy.

Renal failure due to mesangiocapillary glomerulonephritis in pregnancy: use of plasma exchange therapy.

A 20-year-old female became pregnant 4 years after diagnosis of type I mesangiocapillary glomerulonephritis. Despite normal serum creatinine at conception renal function deteriorated during pregnancy. The use of plasmapheresis and albumin substitution as well as antihypertensive therapy enabled the continuation of the pregnancy from 27 weeks' gestation until a healthy infant could be delivered at 33 weeks. However, an abrupt decline in function at delivery did not reverse and the patient remains dialysis dependent. We conclude that plasma exchange therapy with albumin substitution may be of benefit in women with mesangiocapillary glomerulonephritis when renal function has deteriorated in pregnancy. Stabilization of renal function can allow continuation of the pregnancy until greater fetal maturity makes the delivery of a healthy infant more likely. Although plasma exchange is an experimental therapy, in our hands it appears safe for the fetus and maternal complications were limited to minor vascular access problems. The best prognostic marker in this case was the severity of the most recent renal biopsy rather than the level of renal function or hypertension at the start of pregnancy. This contrasts with most reported cases of pregnancy and primary glomerular disease where irreversible deterioration of renal function was uncommon when renal function at the start of pregnancy was only mildly impaired and hypertension well controlled.

Glomerular IgG subclass distribution in human glomerulonephritis.

IgG subclass distribution was determined in glomerular immune deposits found in patients with membranous, mesangiocapillary, lupus and antiglomerular basement membrane antibody induced glomerulonephritis. In each disease category IgG3 was the predominant subclass found. In membranous, lupus and anti-glomerular basement membrane antibody induced nephritis the other subclasses were detected in significant but lesser amounts although in anti-glomerular basement membrane antibody induced nephritis IgG2 deposition was minimal. Particularly striking was the excess of IgG3 compared with other subclasses in mesangiocapillary glomerulonephritis and the greater amount of IgG4 in membranous glomeruli compared to the other disease categories. These findings indicate a difference between the distribution of IgG subclasses in normal plasma and glomerular immune deposits and may be of importance in the pathogenesis of the types of glomerulonephritis studied.

The syndrome of IgA nephropathy.

A review is presented of the current knowledge concerning the syndrome of IgA nephropathy. Primary and secondary forms can now be delineated and this division has improved understanding of immunopathogenetic mechanisms giving rise to glomerular mesangial IgA deposits. Attention is paid to disorders of antigen exclusion at mucosal surfaces, defective reticulo-endothelial sequestration, and altered immunoglobulin A production and regulation. Particular reference is made to these mechanisms with respect to primary IgA nephropathy, Henoch-Schoenlein purpura and mesangial IgA nephritis associated with alcoholic cirrhosis.