Capturing uncertainty in magnetospheric ultra-low frequency wave models

We develop and test an empirical model predicting ground-based observations of ultra-low frequency (ULF, 1-20 mHz) wave power across a range of frequencies, latitudes and magnetic local time sectors. This is parameterized by instantaneous solar wind speed $v_{sw}$, variance in proton number density $var(Np)$ and interplanetary southward magnetic field $B_z$. A probabilistic model of ULF wave power will allow us to address uncertainty in radial diffusion coefficients and therefore improve diffusion modeling of radial transport in Earth's outer radiation belt. Our model can be used in two ways to reproduce wave power; by sampling from conditional probability distribution functions or by using the mean (expectation) values. We derive a method for testing the quality of the parameterization and test the ability of the model to reproduce ULF wave power time series. Sampling is a better method for reproducing power over an extended time period as it retains the same overall distribution while mean values are better for predicting the power in a time series. The model predicts each hour in a time series better than the assumption that power persists from the preceding hour. Finally, we review other sources of diffusion coefficient uncertainty. Although this wave model is designed principally for the goal of improved radial diffusion coefficients to include in outer radiation belt diffusion based modeling, we anticipate that our model can also be used to investigate the occurrence of ULF waves throughout the magnetosphere and hence the physics of ULF wave generation and propagation

Optical characterization of the growth and spatial structure of a substorm onset arc

We present a detailed case study of the characteristics of auroral forms that constitute the first ionospheric signatures of substorm expansion phase onset. Analysis of the optical frequency and along-arc (azimuthal) wave number spectra provides the strongest constraint to date on the potential mechanisms and instabilities in the near-Earth magnetosphere that accompany auroral onset and which precede poleward arc expansion and auroral breakup. We evaluate the frequency and growth rates of the auroral forms as a function of azimuthal wave number to determine whether these wave characteristics are consistent with current models of the substorm onset mechanism. We find that the frequency, spatial scales, and growth rates of the auroral forms are most consistent with the cross-field current instability or a ballooning instability, most likely triggered close to the inner edge of the ion plasma sheet. This result is supportive of a near-Earth plasma sheet initiation of the substorm expansion phase. We also present evidence that the frequency and phase characteristics of the auroral undulations may be generated via resonant processes operating along the geomagnetic field. Our observations provide the most powerful constraint to date on the ionospheric manifestation of the physical processes operating during the first few minutes around auroral substorm onset

Can we really say getting stronger makes your tendon feel better? No current evidence of a relationship between change in Achilles tendinopathy pain or disability and changes in Triceps Surae structure or function when completing rehabilitation: A systematic review

Objectives: Determine if improvements in pain and disability in patients with mid-portion Achilles tendinopathy relate to changes in muscle structure and function whilst completing exercise rehabilitation. Design: A systematic review exploring the relationship between changes in pain/disability and muscle structure/function over time, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Methods: Six online databases and the grey literature were searched from database inception to 16th December 2022 whereas clinical trial registries were searched from database inception to 11th February 2020. We included clinical studies where participants received exercise rehabilitation (± placebo interventions) for mid-portion Achilles tendinopathy if pain/disability and Triceps Surae structure/function were measured. We calculated Cohen\u27s d (95 % confidence intervals) for changes in muscle structure/function over time for individual studies. Data were not pooled due to heterogeneity. Study quality was assessed using a modified Newcastle–Ottawa Scale. Results: Seventeen studies were included for synthesis. No studies reported the relationship between muscle structure/function and pain/disability changes. Twelve studies reported muscle structure/function outcome measures at baseline and at least one follow-up time-point. Three studies reported improvements in force output after treatment; eight studies demonstrated no change in structure or function; one study did not provide a variation measure, precluding within group change over time calculation. All studies were low quality. Conclusions: No studies explored the relationship between changes in tendon pain and disability and changes in muscle structure and function. It is unclear whether current exercise-based rehabilitation protocols for mid-portion Achilles tendinopathy improve muscle structure or function. Systematic review registration: PROSPERO (registration number: CRD42020149970)

Dorsomorphin, a Selective Small Molecule Inhibitor of BMP Signaling, Promotes Cardiomyogenesis in Embryonic Stem Cells

Background: Pluripotent embryonic stem (ES) cells, which have the capacity to give rise to all tissue types in the body, show great promise as a versatile source of cells for regenerative therapy. However, the basic mechanisms of lineage specification of pluripotent stem cells are largely unknown, and generating sufficient quantities of desired cell types remains a formidable challenge. Small molecules, particularly those that modulate key developmental pathways like the bone morphogenetic protein (BMP) signaling cascade, hold promise as tools to study in vitro lineage specification and to direct differentiation of stem cells toward particular cell types. Methodology/Principal Findings: We describe the use of dorsomorphin, a selective small molecule inhibitor of BMP signaling, to induce myocardial differentiation in mouse ES cells. Cardiac induction is very robust, increasing the yield of spontaneously beating cardiomyocytes by at least 20 fold. Dorsomorphin, unlike the endogenous BMP antagonist Noggin, robustly induces cardiomyogenesis when treatment is limited to the initial 24-hours of ES cell differentiation. Quantitative-PCR analyses of differentiating ES cells indicate that pharmacological inhibition of BMP signaling during the early critical stage promotes the development of the cardiomyocyte lineage, but reduces the differentiation of endothelial, smooth muscle, and hematopoietic cells. Conclusions/Significance: Administration of a selective small molecule BMP inhibitor during the initial stages of ES cell differentiation substantially promotes the differentiation of primitive pluripotent cells toward the cardiomyocytic lineage, apparently at the expense of other mesodermal lineages. Small molecule modulators of developmental pathways like dorsomorphin could become versatile pharmacological tools for stem cell research and regenerative medicine

How Do Ultra‐Low Frequency Waves Access the Inner Magnetosphere During Geomagnetic Storms?

Wave‐particle interactions play a key role in radiation belt dynamics. Traditionally, ultra‐low frequency (ULF) wave‐particle interaction is parameterized statistically by a small number of controlling factors for given solar wind driving conditions or geomagnetic activity levels. Here we investigate solar wind driving of ULF wave power and the role of the magnetosphere in screening that power from penetrating deep into the inner magnetosphere. We demonstrate that during enhanced ring current intensity, the Alfvén continuum plummets, allowing lower frequency waves to penetrate deeper into the magnetosphere than during quiet periods. With this penetration, ULF wave power is able to accumulate closer to the Earth than characterized by statistical models. During periods of enhanced solar wind driving such as coronal mass ejection driven storms, where ring current intensities maximize, the observed penetration provides a simple physics‐based reason for why storm time ULF wave power is different compared to nonstorm time waves

Inner Magnetospheric ULF Waves: The Occurrence and Distribution of Broadband and Discrete Wave Activity

Ultralow frequency (ULF) waves are electromagnetic pulsations observed throughout the magnetosphere driven by processes both external and internal to the magnetosphere. Within the magnetosphere, discrete and broadband ULF wave activity can couple to the local plasma via coherent or stochastic wave-particle interactions. These wave-particle interactions can lead to dynamic changes in local plasma including rapid acceleration and transport of radiation belt electrons. Using observations from GOES-15 and the Automated Flare Inference of Oscillations algorithm we investigate the distribution and occurrence of broadband and discrete ULF waves to help understand the relative importance of coherent and stochastic wave-particle interactions. We find that intervals of discrete ULF waves are more commonly identified during slow and low-density solar wind and when Bz is near zero. Broadband waves are more commonly identified during periods of active solar wind, including periods of high solar wind speeds and large density perturbations, and large negative Bz. We also find that under all solar wind conditions the number of intervals of broadband ULF wave power exceeds that of discrete wave power; for example, ULF wave activity is more likely to be broadband. These results suggest that radial diffusion due to incoherent broadband waves is an important driver of wave-particle interactions, especially during active solar wind conditions. However, the presence of discrete waves during both active and quiet solar wind conditions suggests that these waves and the corresponding wave-particle interactions cannot be ignored, especially since discrete wave-particle interactions tend to be more efficient than radial diffusion

Diagnosing the Time‐Dependent Nature of Magnetosphere‐Ionosphere Coupling via ULF Waves at Substorm Onset

Azimuthal structuring is usually observed within the brightening auroral substorm onset arc; such structure has been linked to the exponential growth of electromagnetic ultralow‐frequency (ULF) waves. We present a case study investigating the timing and frequency dependence of such ULF waves on the ground and in the near‐Earth magnetotail. In the magnetotail, we observe an increase in broadband wave power across the 10‐ to 100‐s period range. On the ground, the arrival times spread from an epicenter. The onset of longer period waves occurs first and propagates fastest in latitude and longitude, while shorter periods appear to be more confined to the onset arc. The travel time from the spacecraft to the ground is inferred to be approximately 1–2 min for ULF wave periods between 15 and 60 s, with transit times of 60 s or less for longer period waves. This difference might be attributed to preferential damping of the shorter period waves, as their amplitude would take longer to rise above background levels. These results have important consequences for constraining the physics of substorm onset processes in the near‐Earth magnetotail and their communication to the ground

Glycolysis and the pentose phosphate pathway after human traumatic brain injury: microdialysis studies using 1,2-(13)C2 glucose.

Increased 'anaerobic' glucose metabolism is observed after traumatic brain injury (TBI) attributed to increased glycolysis. An alternative route is the pentose phosphate pathway (PPP), which generates putatively protective and reparative molecules. To compare pathways we employed microdialysis to perfuse 1,2-(13)C2 glucose into the brains of 15 TBI patients and macroscopically normal brain in six patients undergoing surgery for benign tumors, and to simultaneously collect products for nuclear magnetic resonance (NMR) analysis. (13)C enrichment for glycolytic 2,3-(13)C2 lactate was the median 5.4% (interquartile range (IQR) 4.6-7.5%) in TBI brain and 4.2% (2.4-4.4%) in 'normal' brain (P<0.01). The ratio of PPP-derived 3-(13)C lactate to glycolytic 2,3-(13)C2 lactate was median 4.9% (3.6-8.2%) in TBI brain and 6.7% (6.3-8.9%) in 'normal' brain. An inverse relationship was seen for PPP-glycolytic lactate ratio versus PbtO2 (r=-0.5, P=0.04) in TBI brain. Thus, glycolytic lactate production was significantly greater in TBI than 'normal' brain. Several TBI patients exhibited PPP-lactate elevation above the 'normal' range. There was proportionally greater PPP-derived lactate production with decreasing PbtO2. The study raises questions about the roles of the PPP and glycolysis after TBI, and whether they can be manipulated to achieve a better outcome. This study is the first direct comparison of glycolysis and PPP in human brain.We gratefully acknowledge financial support as follows. Study support: Medical Research Council (Grant Nos. G0600986 ID79068 and G1002277 ID98489) and National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). Authors’ support: I.J. – Medical Research Council (Grant no. G1002277 ID 98489) and National Institute for Health Research Biomedical Research Centre, Cambridge; K.L.H.C. – National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme); C.G. – the Canadian Institute of Health Research; A.H. – Medical Research Council/ Royal College of Surgeons of England Clinical Research Training Fellowship (Grant no. G0802251) and Raymond and Beverly Sackler Fellowship; D.K.M. and J.D.P. - National Institute for Health Research Senior Investigator Awards; P.J.H. – National Institute for Health Research Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship.This is the accepted manuscript version. The final version is available from the Nature Publishing Group http://www.nature.com/jcbfm/journal/v35/n1/full/jcbfm2014177a.html

Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice [preprint]

The outcome of an encounter with Mycobacterium tuberculosis (Mtb) depends on the pathogen’s ability to adapt to the heterogeneous immune response of the host. Understanding this interplay has proven difficult, largely because experimentally tractable small animal models do not recapitulate the heterogenous disease observed in natural infections. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to associate bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and represent reproducible models of qualitatively distinct immune states. Global analysis of Mtb mutant fitness across the CC panel revealed that a large fraction of the pathogen’s genome is necessary for adaptation to specific host microenvironments. Both immunological and bacterial traits were associated with genetic variants distributed across the mouse genome, elucidating the complex genetic landscape that underlies host-pathogen interactions in a diverse population