Perpendicular Subcritical Shock Structure in a Collisional Plasma Experiment.

We present a study of perpendicular subcritical shocks in a collisional laboratory plasma. Shocks are produced by placing obstacles into the supermagnetosonic outflow from an inverse wire array z pinch. We demonstrate the existence of subcritical shocks in this regime and find that secondary shocks form in the downstream. Detailed measurements of the subcritical shock structure confirm the absence of a hydrodynamic jump. We calculate the classical (Spitzer) resistive diffusion length and show that it is approximately equal to the shock width. We measure little heating across the shock (<10% of the ion kinetic energy) which is consistent with an absence of viscous dissipation.

Investigating diagnostic sequencing techniques for CADASIL diagnosis.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Our laboratory has been undertaking genetic diagnostic testing for CADASIL since 1997. Work originally utilised Sanger sequencing methods targeting specific NOTCH3 exons. More recently, next-generation sequencing (NGS)-based technologies such as a targeted gene panel and whole exome sequencing (WES) have been used for improved genetic diagnostic testing. In this study, data from 680 patient samples was analysed for 764 tests utilising 3 different sequencing technologies. Sanger sequencing was performed for 407 tests, a targeted NGS gene panel which includes NOTCH3 exonic regions accounted for 354 tests, and WES with targeted analysis was performed for 3 tests. In total, 14.7% of patient samples (n = 100/680) were determined to have a mutation. Testing efficacy varied by method, with 10.8% (n = 44/407) of tests using Sanger sequencing able to identify mutations, with 15.8% (n = 56/354) of tests performed using the NGS custom panel successfully identifying mutations and a likely non-NOTCH3 pathogenic variant (n = 1/3) identified through WES. Further analysis was then performed through stratification of the number of mutations detected at our facility based on the number of exons, level of pathogenicity and the classification of mutations as known or novel. A systematic review of NOTCH3 mutation testing data from 1997 to 2017 determined the diagnostic rate of pathogenic findings and found the NGS-customised panel increases our ability to identify disease-causing mutations in NOTCH3.

Sources and space-time distribution of the electromagnetic pulses in experiments on inertial confinement fusion and laser-plasma acceleration.

When high-energy and high-power lasers interact with matter, a significant part of the incoming laser energy is transformed into transient electromagnetic pulses (EMPs) in the range of radiofrequencies and microwaves. These fields can reach high intensities and can potentially represent a significative danger for the electronic devices placed near the interaction point. Thus, the comprehension of the origin of these electromagnetic fields and of their distribution is of primary importance for the safe operation of high-power and high-energy laser facilities, but also for the possible use of these high fields in several promising applications. A recognized main source of EMPs is the target positive charging caused by the fast-electron emission due to laser-plasma interactions. The fast charging induces high neutralization currents from the conductive walls of the vacuum chamber through the target holder. However, other mechanisms related to the laser-target interaction are also capable of generating intense electromagnetic fields. Several possible sources of EMPs are discussed here and compared for high-energy and high-intensity laser-matter interactions, typical for inertial confinement fusion and laser-plasma acceleration. The possible effects on the electromagnetic field distribution within the experimental chamber, due to particle beams and plasma emitted from the target, are also described. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.

Complement-here, there and everywhere, but what about the transplanted organ?

The part of the innate immune system that communicates and effectively primes the adaptive immune system was termed "complement" by Ehrlich to reflect its complementarity to antibodies having previously been described as "alexine" (i.e protective component of serum) by Buchner and Bordet. It has been established that complement is not solely produced systemically but may have origin in different tissues where it can influence organ specific functions that may affect the outcome of transplanted organs. This review looks at the role of complement in particular to kidney transplantation. We look at current literature to determine whether blockade of the peripheral or central compartments of complement production may prevent ischaemic reperfusion injury or rejection in the transplanted organ. We also review new therapeutics that have been developed to inhibit components of the complement cascade with varying degrees of success leading to an increase in our understanding of the multiple triggers of this complex system. In addition, we consider whether biomarkers in this field are effective markers of disease or treatment.

Multiple deprivation and geographic distance to community physical activity events - achieving equitable access to parkrun in England.

OBJECTIVES: To evaluate geographic access to free weekly outdoor physical activity events ('parkrun') in England, with a particular focus on deprived communities, and to identify optimal locations for future events to further maximise access. STUDY DESIGN: This study is a cross-sectional ecological analysis of the socio-economic disparities in geographic access to parkrun events in England in late 2018. METHODS: We combined geolocation data on all English Lower Layer Super Output Areas and parkrun events to calculate geodesic distances to the nearest event for more than 32,000 communities in England. We use this measure of geographic access to summarise the relationship between access and socio-economic deprivation, measured using the index of multiple deprivation. We then used geographic coordinates of public green spaces in England to conduct a simple location-allocation analysis to identify 200 locations for future event locations that would maximise access. RESULTS: In England, 69% of the population live within 5 km of one of the 465 parkrun events. There is a small negative correlation between distance and deprivation, indicating that access is slightly better in more socio-economically deprived areas. Setting up an additional 200 events in optimal locations would improve access: the average distance to the nearest parkrun event would improve by 1.22 km, from 4.65 km to 3.43 km, and approximately 82% of the English population would live within 5 km of a parkrun event. CONCLUSION: Over two-thirds of the English population live within 5 km of a parkrun event, and contrary to our expectation, we find that geographic access is slightly better for those living in more deprived communities. Creating additional events may improve geographic access, but effective strategies will still be needed to increase engagement in new and existing events by those living in socio-economically deprived areas.

Infectious Disease Dynamics Inferred from Genetic Data via Sequential Monte Carlo.

Genetic sequences from pathogens can provide information about infectious disease dynamics that may supplement or replace information from other epidemiological observations. Most currently available methods first estimate phylogenetic trees from sequence data, then estimate a transmission model conditional on these phylogenies. Outside limited classes of models, existing methods are unable to enforce logical consistency between the model of transmission and that underlying the phylogenetic reconstruction. Such conflicts in assumptions can lead to bias in the resulting inferences. Here, we develop a general, statistically efficient, plug-and-play method to jointly estimate both disease transmission and phylogeny using genetic data and, if desired, other epidemiological observations. This method explicitly connects the model of transmission and the model of phylogeny so as to avoid the aforementioned inconsistency. We demonstrate the feasibility of our approach through simulation and apply it to estimate stage-specific infectiousness in a subepidemic of human immunodeficiency virus in Detroit, Michigan. In a supplement, we prove that our approach is a valid sequential Monte Carlo algorithm. While we focus on how these methods may be applied to population-level models of infectious disease, their scope is more general. These methods may be applied in other biological systems where one seeks to infer population dynamics from genetic sequences, and they may also find application for evolutionary models with phenotypic rather than genotypic data.

Assessment of bulbar function in amyotrophic lateral sclerosis: validation of a self-report scale (Center for Neurologic Study Bulbar Function Scale).

BACKGROUND AND PURPOSE: Impaired bulbar functions of speech and swallowing are among the most serious consequences of amyotrophic lateral sclerosis (ALS). Despite this, clinical trials in ALS have rarely emphasized bulbar function as an endpoint. The rater-administered Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) or various quality-of-life measures are commonly used to measure symptomatic benefit. Accordingly, we sought to evaluate the utility of measures specific to bulbar function in ALS. METHODS: We assessed bulbar functions in 120 patients with ALS, with clinicians first making direct observations of the degree of speech, swallowing and salivation impairment in these subjects. Clinical diagnosis of bulbar impairment was then compared with ALSFRS-R scores, speech rate, time to swallow liquids and solids, and scores obtained when patients completed visual analog scales (VASs) and the newly-developed 21-question self-administered Center for Neurologic Study Bulbar Function Scale (CNS-BFS). RESULTS: The CNS-BFS, ALSFRS-R, VAS and timed speech and swallowing were all concordant with clinician diagnosis. The self-report CNS-BFS and ALSFRS-R bulbar subscale best predicted clinician diagnosis with misclassification rates of 8% and 14% at the optimal cut-offs, respectively. In addition, the CNS-BFS speech and swallowing subscales outperformed both the bulbar component of the ALSFRS-R and speech and swallowing VASs when correlations were made between these scales and objective measures of timed reading and swallowing. CONCLUSIONS: Based on these findings and its relative ease of administration, we conclude that the CNS-BFS is a useful metric for assessing bulbar function in patients with ALS.

Thrombalexins: Cell-Localized Inhibition of Thrombin and Its Effects in a Model of High-Risk Renal Transplantation.

Allograft transplantation into sensitized recipients with antidonor antibodies results in accelerated antibody-mediated rejection (AMR), complement activation, and graft thrombosis. We have developed a membrane-localizing technology of wide applicability that enables therapeutic agents, including anticoagulants, to bind to cell surfaces and protect the donor endothelium. We describe here how this technology has been applied to thrombin inhibitors to generate a novel class of drugs termed thrombalexins (TLNs). Using a rat model of hyperacute rejection, we investigated the potential of one such inhibitor (thrombalexin-1 [TLN-1]) to prevent acute antibody-mediated thrombosis in the donor organ. TLN-1 alone was able to reduce intragraft thrombosis and significantly delay rejection. The results confirm a pivotal role for thrombin in AMR in vivo. This approach targets donor organs rather than the recipient and is intended to be directly translatable to clinical use.

Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation.

Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel "cytotopic" agent, thrombalexin (TLN), combines a cell-membrane-bound (myristoyl tail) anti-thrombin (hirudin-like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN versus HLL (without cytotopic tail) versus negative control. Both TLN- and HLL-treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells and neonatal porcine islets prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to 4 days after transplantation. There was no platelet deposition, and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis), were less in the TLN-treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated.

Human gestation-associated tissues express functional cytosolic nucleic acid sensing pattern recognition receptors.

The role of viral infections in adverse pregnancy outcomes has gained interest in recent years. Innate immune pattern recognition receptors (PRRs) and their signalling pathways, that yield a cytokine output in response to pathogenic stimuli, have been postulated to link infection at the maternal-fetal interface and adverse pregnancy outcomes. The objective of this study was to investigate the expression and functional response of nucleic acid ligand responsive Toll-like receptors (TLR-3, -7, -8 and -9), and retinoic acid-inducible gene 1 (RIG-I)-like receptors [RIG-I, melanoma differentiation-associated protein 5 (MDA5) and Laboratory of Genetics and Physiology 2(LGP2)] in human term gestation-associated tissues (placenta, choriodecidua and amnion) using an explant model. Immunohistochemistry revealed that these PRRs were expressed by the term placenta, choriodecidua and amnion. A statistically significant increase in interleukin (IL)-6 and/or IL-8 production in response to specific agonists for TLR-3 (Poly(I:C); low and high molecular weight), TLR-7 (imiquimod), TLR-8 (ssRNA40) and RIG-I/MDA5 (Poly(I:C)LyoVec) was observed; there was no response to a TLR-9 (ODN21798) agonist. A hierarchical clustering approach was used to compare the response of each tissue type to the ligands studied and revealed that the placenta and choriodecidua generate a more similar IL-8 response, while the choriodecidua and amnion generate a more similar IL-6 response to nucleic acid ligands. These findings demonstrate that responsiveness via TLR-3, TLR-7, TLR-8 and RIG-1/MDA5 is a broad feature of human term gestation-associated tissues with differential responses by tissue that might underpin adverse obstetric outcomes.

Anomalous Heating and Plasmoid Formation in a Driven Magnetic Reconnection Experiment.

We present a detailed study of magnetic reconnection in a quasi-two-dimensional pulsed-power driven laboratory experiment. Oppositely directed magnetic fields (B=3 T), advected by supersonic, sub-Alfvénic carbon plasma flows (V_{in}=50 km/s), are brought together and mutually annihilate inside a thin current layer (δ=0.6 mm). Temporally and spatially resolved optical diagnostics, including interferometry, Faraday rotation imaging, and Thomson scattering, allow us to determine the structure and dynamics of this layer, the nature of the inflows and outflows, and the detailed energy partition during the reconnection process. We measure high electron and ion temperatures (T_{e}=100 eV, T_{i}=600 eV), far in excess of what can be attributed to classical (Spitzer) resistive and viscous dissipation. We observe the repeated formation and ejection of plasmoids, consistent with the predictions from semicollisional plasmoid theory.

Absolute calibration of optical streak cameras on picosecond time scales using supercontinuum generation.

We report a new method using high-stability, laser-driven supercontinuum generation in a liquid cell to calibrate the absolute photon response of fast optical streak cameras as a function of wavelength when operating at fastest sweep speeds. A stable, pulsed white light source based around the use of self-phase modulation in a salt solution was developed to provide the required brightness on picosecond time scales, enabling streak camera calibration in fully dynamic operation. The measured spectral brightness allowed for absolute photon response calibration over a broad spectral range (425-650 nm). Calibrations performed with two Axis Photonique streak cameras using the Photonis P820PSU streak tube demonstrated responses that qualitatively follow the photocathode response. Peak sensitivities were one photon/count above background. The absolute dynamic sensitivity is less than the static by up to an order of magnitude. We attribute this to the dynamic response of the phosphor being lower.

Immunotoxin Against a Donor MHC Class II Molecule Induces Indefinite Survival of Murine Kidney Allografts.

Rejection of donor organs depends on the trafficking of donor passenger leukocytes to the secondary lymphoid organs of the recipient to elicit an immune response via the direct antigen presentation pathway. Therefore, the depletion of passenger leukocytes may be clinically applicable as a strategy to improve graft survival. Because major histocompatibility complex (MHC) class II(+) cells are most efficient at inducing immune responses, selective depletion of this population from donor grafts may dampen the alloimmune response and prolong graft survival. In a fully MHC mismatched mouse kidney allograft model, we describe the synthesis of an immunotoxin, consisting of the F(ab')2 fragment of a monoclonal antibody against the donor MHC class II molecule I-A(k) conjugated with the plant-derived ribosomal inactivating protein gelonin. This anti-I-A(k) gelonin immunotoxin depletes I-A(k) expressing cells specifically in vitro and in vivo. When given to recipients of kidney allografts, it resulted in indefinite graft survival with normal graft function, presence of Foxp3(+) cells within donor grafts, diminished donor-specific antibody formation, and delayed rejection of subsequent donor-type skin grafts. Strategies aimed at the donor arm of the immune system using agents such as immunotoxins may be a useful adjuvant to existing recipient-orientated immunosuppression.

Structure of a Magnetic Flux Annihilation Layer Formed by the Collision of Supersonic, Magnetized Plasma Flows.

We present experiments characterizing the detailed structure of a current layer, generated by the collision of two counterstreaming, supersonic and magnetized aluminum plasma flows. The antiparallel magnetic fields advected by the flows are found to be mutually annihilated inside the layer, giving rise to a bifurcated current structure-two narrow current sheets running along the outside surfaces of the layer. Measurements with Thomson scattering show a fast outflow of plasma along the layer and a high ion temperature (T_{i}∼Z[over ¯]T_{e}, with average ionization Z[over ¯]=7). Analysis of the spatially resolved plasma parameters indicates that the advection and subsequent annihilation of the inflowing magnetic flux determines the structure of the layer, while the ion heating could be due to the development of kinetic, current-driven instabilities.

Generation of high contrast and high spatial quality idler from a low-gain optical parametric amplifier.

The temporal contrast of a regeneratively amplified, sub-picosecond pulse is enhanced by employing a low-gain optical parametric amplification stage self-pumped by the second harmonic of the pulse. Through careful characterization of the two related nonlinear processes and optimization of the non-collinear geometry, a robust high-contrast idler pulse has been generated, with excellent spatial quality in both the near and far field. The overall energy conversion efficiency exceeds 14%, with 33% intensity conversion efficiency. The temporal cleaning is implemented without any bandwidth losses or spectral shift and produces approximately 20% temporal shortening. These experimental findings are in excellent agreement with numerical calculations.

Noninvasive Imaging of Activated Complement in Ischemia-Reperfusion Injury Post-Cardiac Transplant.

Ischemia-reperfusion injury (IRI) is inevitable in solid organ transplantation, due to the transplanted organ being ischemic for prolonged periods prior to transplantation followed by reperfusion. The complement molecule C3 is present in the circulation and is also synthesized by tissue parenchyma in early response to IRI and the final stable fragment of activated C3, C3d, can be detected on injured tissue for several days post-IRI. Complement activation post-IRI was monitored noninvasively by single photon emission computed tomography (SPECT) and CT using (99m) Tc-recombinant complement receptor 2 ((99m) Tc-rCR2) in murine models of cardiac transplantation following the induction of IRI and compared to (99m) Tc-rCR2 in C3(-/-) mice or with the irrelevant protein (99m) Tc-prostate-specific membrane antigen antibody fragment (PSMA). Significant uptake with (99m) Tc-rCR2 was observed as compared to C3(-/-) or (99m) Tc-PSMA. In addition, the transplanted heart to muscle ratio of (99m) Tc-rCR2 was significantly higher than (99m) Tc-PSMA or C3(-/-) . The results were confirmed by histology and autoradiography. (99m) Tc-rCR2 can be used for noninvasive detection of activated complement and in future may be used to quantify the severity of transplant damage due to complement activation postreperfusion.

Complotype affects the extent of down-regulation by Factor I of the C3b feedback cycle in vitro.

Sera from a large panel of normal subjects were typed for three common polymorphisms, one in C3 (R102G) and two in Factor H (V62I and Y402H), that influence predisposition to age-related macular degeneration and to some forms of kidney disease. Three groups of sera were tested; those that were homozygous for the three risk alleles; those that were heterozygous for all three; and those homozygous for the low-risk alleles. These groups vary in their response to the addition of exogenous Factor I when the alternative complement pathway is activated by zymosan. Both the reduction in the maximum amount of iC3b formed and the rate at which the iC3b is converted to C3dg are affected. For both reactions the at-risk complotype requires higher doses of Factor I to produce similar down-regulation. Because iC3b reacting with the complement receptor CR3 is a major mechanism by which complement activation gives rise to inflammation, the breakdown of iC3b to C3dg can be seen to have major significance for reducing complement-induced inflammation. These findings demonstrate for the first time that sera from subjects with different complement alleles behave as predicted in an in-vitro assay of the down-regulation of the alternative complement pathway by increasing the concentration of Factor I. These results support the hypothesis that exogenous Factor I may be a valuable therapeutic aid for down-regulating hyperactivity of the C3b feedback cycle, thereby providing a treatment for age-related macular degeneration and other inflammatory diseases of later life.

Multiwavelength interferometry system for the Orion laser facility.

We report on the design and testing of a multiwavelength interferometry system for the Orion laser facility based upon the use of self-path matching Wollaston prisms. The use of UV corrected achromatic optics allows for both easy alignment with an eye-safe light source and small (∼ millimeter) offsets to the focal lengths between different operational wavelengths. Interferograms are demonstrated at wavelengths corresponding to first, second, and fourth harmonics of a 1054 nm Nd:glass probe beam. Example data confirms the broadband achromatic capability of the imaging system with operation from the UV (263 nm) to visible (527 nm) and demonstrates that features as small as 5 µm can be resolved for object sizes of 15 by 10 mm. Results are also shown for an off-harmonic wavelength that will underpin a future capability. The primary optics package is accommodated inside the footprint of a ten-inch manipulator to allow the system to be deployed from a multitude of viewing angles inside the 4 m diameter Orion target chamber.

Interpenetration, deflection, and stagnation of cylindrically convergent magnetized supersonic tungsten plasma flows.

The interpenetration and interaction of supersonic, magnetized tungsten plasma flows has been directly observed via spatially and temporally resolved measurements of the Thomson scattering ion feature. A novel scattering geometry allows independent measurements of the axial and radial velocity components of the ions. The plasma flows are produced via the pulsed power driven ablation of fine tungsten wires in a cylindrical wire array z pinch. Fits of the data reveal the variations in radial velocity, axial velocity, and temperature of the ion streams as they interpenetrate and interact. A previously unobserved increase in axial velocity is measured near the array axis. This may be the result of v[over →]×B[over →] bending of the ion streams by a toroidal magnetic field, advected to and accumulated about the axis by the streams.

High-magnification Faraday rotation imaging and analysis of X-pinch implosion dynamics.

An X-pinch load driven by an intense current pulse (>100 kA in ∼100 ns) can result in the formation of a small radius, runaway compressional micro-pinch. A micro-pinch is characterized by a hot (>1 keV), current-driven (>100 kA), high-density plasma column (near solid density) with a small neck diameter (1-10 µm), a short axial extent (<1 mm), and a short duration (≲1 ns). With material pressures often well into the multi-Mbar regime, a micro-pinch plasma often radiates an intense, sub-ns burst of sub-keV to multi-keV x rays. A low-density coronal plasma immediately surrounding the dense plasma neck could potentially shunt current away from the neck and thus reduce the magnetic drive pressure applied to the neck. To study the current distribution in the coronal plasma, a Faraday rotation imaging diagnostic (1064 nm) capable of producing simultaneous high-magnification polarimetric and interferometric images has been developed for the MAIZE facility at the University of Michigan. Designed with a variable magnification (1-10×), this diagnostic achieves a spatial resolution of ∼35 µm, which is useful for resolving the ∼100-µm-scale coronal plasma immediately surrounding the dense core. This system has now been used on a reduced-output MAIZE (100-200 kA, 150 ns) to assess the radial distribution of drive current immediately surrounding the dense micro-pinch neck. The total current enclosed was found to increase as a function of radius, r, from a value of ≈50±25 kA at r ≈ 140 µm (at the edge of the dense neck) to a maximal value of ≈150±75 kA for r ≥ 225 µm. This corresponds to a peak magnetic drive pressure of ≈75±50 kbar at r ≈ 225 µm. The limitations of these measurements are discussed in the paper.