Syk is a protein tyrosine kinase that couples B-cell receptor (BCR) activation with downstream signaling pathways, affecting cell survival and proliferation. Moreover, Syk is involved in ...BCR-independent functions, such as B-cell migration and adhesion. In chronic lymphocytic leukemia (CLL), Syk becomes activated by external signals from the tissue microenvironment, and was targeted in a first clinical trial with R788 (fostamatinib), a relatively nonspecific Syk inhibitor. Here, we characterize the activity of two novel, highly selective Syk inhibitors, PRT318 and P505-15, in assays that model CLL interactions with the microenvironment. PRT318 and P505-15 effectively antagonize CLL cell survival after BCR triggering and in nurse-like cell-co-cultures. Moreover, they inhibit BCR-dependent secretion of the chemokines CCL3 and CCL4 by CLL cells, and leukemia cell migration toward the tissue homing chemokines CXCL12, CXCL13, and beneath stromal cells. PRT318 and P505-15 furthermore inhibit Syk and extracellular signal-regulated kinase phosphorylation after BCR triggering. These findings demonstrate that the selective Syk inhibitors PRT318 and P505-15 are highly effective for inhibition of CLL survival and tissue homing circuits, and support the therapeutic development of these agents in patients with CLL, other B-cell malignancies and autoimmune disorders.
Diastolic dysfunction is increasingly identified as a key, early onset subclinical condition characterizing cardiopathologies of rising prevalence, including diabetic heart disease and heart failure ...with preserved ejection fraction (HFpEF). Diastolic dysfunction characterization has important prognostic value in management of disease outcomes. Validated tools for in vivo monitoring of diastolic function in rodent models of diabetes are required for progress in pre-clinical cardiology studies. 2D speckle tracking echocardiography has emerged as a powerful tool for evaluating cardiac wall deformation throughout the cardiac cycle. The aim of this study was to examine the applicability of 2D speckle tracking echocardiography for comprehensive global and regional assessment of diastolic function in a pre-clinical murine model of cardio-metabolic disease. Type 2 diabetes (T2D) was induced in C57Bl/6 male mice using a high fat high sugar dietary intervention for 20 weeks. Significant impairment in left ventricle peak diastolic strain rate was evident in longitudinal, radial and circumferential planes in T2D mice. Peak diastolic velocity was similarly impaired in the longitudinal and radial planes. Regional analysis of longitudinal peak diastolic strain rate revealed that the anterior free left ventricular wall is particularly susceptible to T2D-induced diastolic dysfunction. These findings provide a significant advance on characterization of diastolic dysfunction in a pre-clinical mouse model of cardiopathology and offer a comprehensive suite of benchmark values for future pre-clinical cardiology studies.
The occurrence of spatially and temporally variable reconnection at the Earth's magnetopause leads to the complex interaction of magnetic fields from the magnetosphere and magnetosheath. Flux ...transfer events (FTEs) constitute one such type of interaction. Their main characteristics are (1) an enhanced core magnetic field magnitude and (2) a bipolar magnetic field signature in the component normal to the magnetopause, reminiscent of a large‐scale helicoidal flux tube magnetic configuration. However, other geometrical configurations which do not fit this classical picture have also been observed. Using high‐resolution measurements from the Magnetospheric Multiscale mission, we investigate an event in the vicinity of the Earth's magnetopause on 7 November 2015. Despite signatures that, at first glance, appear consistent with a classic FTE, based on detailed geometrical and dynamical analyses as well as on topological signatures revealed by suprathermal electron properties, we demonstrate that this event is not consistent with a single, homogenous helicoidal structure. Our analysis rather suggests that it consists of the interaction of two separate sets of magnetic field lines with different connectivities. This complex three‐dimensional interaction constructively conspires to produce signatures partially consistent with that of an FTE. We also show that, at the interface between the two sets of field lines, where the observed magnetic pileup occurs, a thin and strong current sheet forms with a large ion jet, which may be consistent with magnetic flux dissipation through magnetic reconnection in the interaction region.
Key Points
We characterized the scale, geometry, and propagation of an ion scale current structure resulting from the interaction between interlaced flux tubes
Some signatures of magnetic reconnection are found at the interaction interface
The intrinsic properties of this event are inconsistent with a single, homogenous helicoidal magnetic structure as expected from a typical flux transfer event (FTE)
Objective
Glial cell line–derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm ...initial clinical benefits observed in a small, open‐label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin).
Methods
Thirty‐four PD patients were randomized 1 to 1 to receive bilateral continuous Ipu infusion of liatermin 15μg/putamen/day or placebo. The primary end point was the change in Unified Parkinson Disease Rating Scale (UPDRS) motor score in the practically defined off condition at 6 months. Secondary end points included other UPDRS scores, motor tests, dyskinesia ratings, patient diaries, and 18F‐dopa uptake.
Results
At 6 months, mean percentage changes in “off” UPDRS motor score were −10.0% and −4.5% in the liatermin and placebo groups, respectively. This treatment difference was not significant (95% confidence interval, −23.0 to 12.0, p = 0.53). Secondary end point results were similar between the groups. A 32.5% treatment difference favoring liatermin in mean 18F‐dopa influx constant (p = 0.019) was observed. Serious, device‐related adverse events required surgical repositioning of catheters in two patients and removal of devices in another. Neutralizing antiliatermin antibodies were detected in three patients (one on‐study and two in the open‐label extension).
Interpretation
Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased 18F‐dopa uptake. It is uncertain whether technical differences between this trial and positive open‐label studies contributed in any way this negative outcome. Ann Neurol 2006
Flux transfer events (FTEs) are transient phenomena frequently observed at the Earth's magnetopause. Their usual interpretation is a flux rope moving away from the reconnection region. However, the ...Magnetospheric Multiscale Mission revealed that magnetic reconnection sometimes occurs inside these structures, questioning their flux rope configuration. Here we investigate 229 FTE‐type structures and find reconnection signatures inside 19% of them. We analyze their large‐scale magnetic topology using electron heat flux and find that it is significantly different across the FTE reconnecting current sheets, demonstrating that they are constituted of two magnetically disconnected structures. We also find that the interplanetary magnetic field (IMF) associated with reconnecting FTEs presents a strong By component. We discuss several formation mechanisms to explain these observations. In particular, the maximum magnetic shear model predicts that for large IMF By, two spatially distinct X lines coexist at the magnetopause. They can generate separate magnetic flux tubes that may become interlaced.
Plain Language Summary
The solar wind and the Earth's magnetosphere are two gigantic magnetic structures that collide constantly over our heads, in the near‐space environment. At the boundary of their interaction (the magnetopause), the fundamental process of magnetic reconnection can occur. It is there that dynamic magnetic structures called “flux transfer events” are formed. They travel fast along the magnetopause and transport a lot of energy, from the solar wind into the magnetosphere. These structures are yet not well understood, as underlined by the recent observations made by the Magnetospheric Multiscale Mission (MMS), launched in 2015 by National Aeronautics and Space Administration. The four‐spacecraft mission, specifically designed to study the physics happening at the magnetopause, is capable of measuring right into these magnetic structures, collecting data on their particles and magnetic field properties. When analyzing MMS data, we found that 19% of the flux transfer events were not constituted of one, but two structures with very different properties. These dual magnetic structures tend to appear when the solar wind's magnetic field is oriented mainly toward the east or the west. From these observations and based on existing models of the magnetopause, we propose a scenario that allows such dual structures to form as interlaced magnetic tubes.
Key Points
Nineteen percent of FTE‐type structures observed by MMS during Phases 1A and 1B present signatures of magnetic reconnection in their core
They seem to be formed by two magnetically disconnected interlaced flux tubes and are typically observed for large IMF By
Several formation models are discussed, including a bifurcated X line scenario that results from the maximum shear angle model
Based on high-resolution measurements from NASA's Magnetospheric Multlscale mission, we present the dynamics of electrons associated with current systems observed near the diffusion region of ...magnetic reconnection at Earth's magnetopause. Using pitch angle distributions (PAD) and magnetic curvature analysis, we demonstrate the occurrence of electron scattering in the curved magnetic field of the diffusion region down to energies of 20eV. We show that scattering occurs closer to the current sheet as the electron energy decreases. The scattering of Inflowing electrons, associated with field-aligned electrostatic potentials and Hall currents, produces a new population of scattered electrons with broader PAD which bounce back and forth in the exhaust. Except at the center of the diffusion region the two populations are collocated and appear to behave adiabatically: the inflowing electron PAD focuses inward (toward lower magnetic field), while the bouncing population PAD gradually peaks at 90 degrees away from the center (where it mirrors owing to higher magnetic field and probable field-aligned potentials).
The Magnetospheric Multiscale mission has demonstrated the frequent presence of reconnection exhausts at thin current sheets within Kelvin‐Helmholtz (KH) waves at the flank magnetopause. Motivated by ...these recent observations, we performed a statistical analysis of the boundary layers on the magnetosheath side of all KH current sheets on 8 September 2015. We show 86% consistency between the exhaust flows and particle leakage in the magnetosheath boundary layers but further highlight the very frequent presence of additional boundary layer signatures that do not come from the locally observed reconnection exhausts. These additional electron and ion boundary layers, of various durations and at various positions with respect to the leading and trailing boundaries of the KH waves, signal connections to reconnection sites at other locations. Based on the directionality and extent of these layers, we provide an interpretation whereby complex magnetic topologies can arise within KH waves from the combination of reconnection in the equatorial plane and at midlatitudes in the Southern and Northern Hemispheres, where additional reconnection sites are expected to be triggered by the three‐dimensional field lines interweaving induced by the KH waves at the flanks (owing to differential flow and magnetic field shear with latitude). The present event demonstrates that the three‐dimensional development of KH waves can induce plasma entry (through reconnection at both midlatitude and equatorial regions) already sunward of the terminator where the instability remains in its linear stage.
Key Points
Statistical study of magnetosheath boundary layers at Kelvin‐Helmholtz wave boundaries
Particle leakage statistics consistent with local reconnection exhausts within KH waves
Additional signatures suggest complex topologies with reconnection sites at higher latitudes
The aim of this study was to comprehensively review the epidemiology of aortic sclerosis (ASc) and its association with cardiovascular events.
ASc, which is defined as thickening or calcification of ...the aortic valve without significant obstruction of blood flow, is a common finding on cardiac imaging.
We searched MEDLINE and EMBASE from inception to April 2013 for studies describing the epidemiology of ASc and performed a meta-analysis of the risk of adverse events using a random effects model.
Twenty-two studies were identified from the systematic review. The prevalence of ASc increased in proportion to the average age of study participants, ranging from 9% in a study in which the mean age was 54 years to 42% in a study in which the mean age was 81 years. In total, 1.8% to 1.9% of participants with ASc had progression to clinical aortic stenosis per year. There was a 68% increased risk of coronary events in subjects with ASc (hazard ratio HR: 1.68; 95% confidence interval CI: 1.31 to 2.15), a 27% increased risk of stroke (HR: 1.27; 95% CI: 1.01 to 1.60), a 69% increased risk of cardiovascular mortality (HR: 1.69; 95% CI: 1.32 to 2.15), and a 36% increased risk of all-cause mortality (HR: 1.36; 95% CI: 1.17 to 1.59).
ASc is a common finding that is more prevalent with older age. Despite low rates of progression to ASc, there is an independent increase in morbidity and mortality associated with the condition.
The impact of 9 single nucleotide polymorphisms (SNP) in the leptin (LEP), leptin receptor (LEPR), growth hormone receptor (GHR), and diacylglycerol acyltransferase (DGAT1) gene loci on daily milk ...production, feed intake, and feed conversion, and weekly measures of live weight, BCS, and body energy traits was evaluated using genetic and phenotypic data on 571 Holstein cows raised at the Langhill Dairy Cattle Research Center in Scotland. Six SNP were typed on the LEP gene and 1 on each of the other 3 loci. Of the 6 LEP SNP, 3 were in very high linkage disequilibrium, meaning there is little gain in typing all of them in the future. Seven LEP haplotypes were identified by parsimony-based analyses. Random-regression allele-substitution models were used to assess the impact of each SNP allele or haplotype on the traits of interest. Diacylglycerol acyltransferase had a significant effect on milk yield, whereas GHR significantly affected feed intake, feed conversion, and body energy traits. There was also evidence of dominance in allelic effects on milk yield and BCS. The LEP haplotype CCGTTT (corresponding to leptin SNP C207T, C528T, A1457G, C963T, A252T, and C305T, respectively) significantly affected milk yield and feed and dry matter intake. Animals carrying this haplotype produced 3.13kg more milk daily and consumed 4.64kg more feed. Furthermore, they tended to preserve more energy than average. Such results may be used to facilitate genetic selection in animal breeding programs.
The Fast Plasma Investigation (FPI) was developed for flight on the Magnetospheric Multiscale (MMS) mission to measure the differential directional flux of magnetospheric electrons and ions with ...unprecedented time resolution to resolve kinetic-scale plasma dynamics. This increased resolution has been accomplished by placing four dual 180-degree top hat spectrometers for electrons and four dual 180-degree top hat spectrometers for ions around the periphery of each of four MMS spacecraft. Using electrostatic field-of-view deflection, the eight spectrometers for each species together provide 4pi-sr-field-of-view with, at worst, 11.25-degree sample spacing. Energy/charge sampling is provided by swept electrostatic energy/charge selection over the range from 10 eVq to 30000 eVq. The eight dual spectrometers on each spacecraft are controlled and interrogated by a single block redundant Instrument Data Processing Unit, which in turn interfaces to the observatory's Instrument Suite Central Instrument Data processor. This paper described the design of FPI, its ground and in-flight calibration, its operational concept, and its data products.
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