Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic ...evidence in mouse and
models suggests a gain-of-function mechanism. In this study, we used in vivo, cell type–specific transcriptional and translational profiling to show that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2 (general control nonderepressible 2). The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of
alleviated the peripheral neuropathy. The activation of GCN2 suggests that the aberrant activity of the mutant tRNA synthetases is still related to translation and that inhibiting GCN2 or the ISR may represent a therapeutic strategy in CMT.
Summary Background A serogroup A meningococcal polysaccharide–tetanus toxoid conjugate vaccine (PsA–TT, MenAfriVac) was licensed in India in 2009, and pre-qualified by WHO in 2010, on the basis of ...its safety and immunogenicity. This vaccine is now being deployed across the African meningitis belt. We studied the effect of PsA–TT on meningococcal meningitis and carriage in Chad during a serogroup A meningococcal meningitis epidemic. Methods We obtained data for the incidence of meningitis before and after vaccination from national records between January, 2009, and June, 2012. In 2012, surveillance was enhanced in regions where vaccination with PsA–TT had been undertaken in 2011, and in one district where a reactive vaccination campaign in response to an outbreak of meningitis was undertaken. Meningococcal carriage was studied in an age-stratified sample of residents aged 1–29 years of a rural area roughly 13–15 and 2–4 months before and 4–6 months after vaccination. Meningococci obtained from cerebrospinal fluid or oropharyngeal swabs were characterised by conventional microbiological and molecular methods. Findings Roughly 1·8 million individuals aged 1–29 years received one dose of PsA–TT during a vaccination campaign in three regions of Chad in and around the capital N'Djamena during 10 days in December, 2011. The incidence of meningitis during the 2012 meningitis season in these three regions was 2·48 per 100 000 (57 cases in the 2·3 million population), whereas in regions without mass vaccination, incidence was 43·8 per 100 000 (3809 cases per 8·7 million population), a 94% difference in crude incidence (p<0·0001), and an incidence rate ratio of 0·096 (95% CI 0·046–0·198). Despite enhanced surveillance, no case of serogroup A meningococcal meningitis was reported in the three vaccinated regions. 32 serogroup A carriers were identified in 4278 age-stratified individuals (0·75%) living in a rural area near the capital 2–4 months before vaccination, whereas only one serogroup A meningococcus was isolated in 5001 people living in the same community 4–6 months after vaccination (adjusted odds ratio 0·019, 95% CI 0·002–0·138; p<0·0001). Interpretation PSA–TT was highly effective at prevention of serogroup A invasive meningococcal disease and carriage in Chad. How long this protection will persist needs to be established. Funding The Bill & Melinda Gates Foundation, the Wellcome Trust, and Médecins Sans Frontères.
We present a time‐of‐flight mass spectrometer design for the measurement of ions in the ~30 keV to 10 MeV range for protons (up to ~40 MeV and ~150 MeV for He and heavy ions, respectively) and ~30 ...keV to 1 MeV range for electrons, covering half of the sky with 80 apertures. The instrument, known as the “Mushroom,” owing to its shape, solves the field of view problem for magnetospheric and heliospheric missions that employ three‐axis stabilized spacecraft, yet still require extended angular coverage; the Mushroom is also compatible with a spinning spacecraft. The most important new feature of the Mushroom is the method through which uncomplicated electrostatic optics and clean position sensing combine to permit many apertures to fit into a compact, low‐mass sensor head (or wedge), several of which (ideally eight) compose a full instrument. Most of the sensor head's volume is an empty, equipotential region, resulting in the modest 250 g mass of each 10‐aperture wedge. The Mushroom is capable of separating ion species across most of its energy range and angular field of view. For example, separation of the neighboring 3He and 4He isotopes is excellent; the full width at half maximum mass resolution has been measured to be 0.24 amu to 0.32 amu, respectively. Converting this to a Gaussian width σm in mass m, this represents a σm/m mass resolution better than 0.04. This separation is highly desirable for the flight program for which the first Mushroom was built, the Solar Probe Plus mission. More generally, we estimate the mass resolution to be σm/m ≈ 0.1, but this is energy, mass, and angularly dependent. We also discuss the solid‐state detector stack capability, which extends the energy range of protons and helium, with composition, to ~100 MeV.
Key Points
Anisotropy, pitch angle distributions, and large field of view are important for energetic ion and electron science
The “Mushroom” instrument has been developed by JHU/APL to provide needed large FOV and angular resolution
The first Mushroom, EPI‐Lo, part of the ISʘIS investigation on Solar Probe Plus, has achieved excellent composition and spatial separation
Abstract
The Mouse Genome Database (MGD; http://www.informatics.jax.org) is the community model organism genetic and genome resource for the laboratory mouse. MGD is the authoritative source for ...biological reference data sets related to mouse genes, gene functions, phenotypes, and mouse models of human disease. MGD is the primary outlet for official gene, allele and mouse strain nomenclature based on the guidelines set by the International Committee on Standardized Nomenclature for Mice. In this report we describe significant enhancements to MGD, including two new graphical user interfaces: (i) the Multi Genome Viewer for exploring the genomes of multiple mouse strains and (ii) the Phenotype-Gene Expression matrix which was developed in collaboration with the Gene Expression Database (GXD) and allows researchers to compare gene expression and phenotype annotations for mouse genes. Other recent improvements include enhanced efficiency of our literature curation processes and the incorporation of Transcriptional Start Site (TSS) annotations from RIKEN’s FANTOM 5 initiative.
Parker Solar Probe (PSP) observations of a small dispersive event on 2022 February 27 and 28 indicate scatter-free propagation as the dominant transport mechanism between the low corona and greater ...than 35 solar radii. The event occurred during unique orbital conditions that prevailed along specific flux tubes that PSP encountered repeatedly between 25 and 35 Rs during outbound orbit 11. This segment of the PSP orbit exhibits almost stationary angular motion relative to the rotating solar surface, such that in the rotating frame, PSP’s motion is essentially radial. The time dispersion often observed in impulsive solar energetic particle (SEP) events continues in this case down to velocities including the core solar-wind ion velocities. Especially at the onset of this event, the 3He content is much larger than the usual SEP abundances seen in the energy range from ∼100 keV to several MeV for helium. Later in the event, iron is enhanced. The compositional signatures suggest this to be an example of an acceleration mechanism for generating the seed energetic particles required by shock (or compression) acceleration models in SEP events to account for the enrichment of various species above solar abundances in such events. A preliminary search of similar orbital conditions over the PSP mission has not revealed additional such events, although favorable conditions (isolated impulsive acceleration and well-ordered magnetic field connection with minimal magnetic field fluctuation) that would be required are infrequently realized, given the small fraction of the PSP trajectory that meets these observation conditions.
Abstract High-energy neutral solar radiation in the form of γ -rays and neutrons is produced as secondary products in solar flares. The characteristics of this emission can provide key information ...regarding the energization of charged particles, particularly when primary particles remain trapped in the corona. The Integrated Science Investigation of the Sun (IS⊙IS) suite on Parker Solar Probe is composed of instruments primarily intended to measure energetic charged particles. However, the High Energy Telescope (HET) in IS⊙IS was also designed with a supplementary neutral mode intended to measure γ -rays and neutrons. HET observed its first clear solar γ -ray event in connection with a hard X-ray flare, the eruption of a coronal mass ejection, and a solar energetic particle event on 2022 September 5. The X-ray spectral shape was observed to harden over the course of the event, culminating with the observation of γ -rays by HET. A coincident enhancement in the lower-energy Energetic Particle Instrument (EPI-Lo) was also observed, likely produced by incident solar γ -rays despite the EPI-Lo instrument not having any special neutral measurement capabilities. We use Monte Carlo modeling to reconstruct the incident γ -ray spectrum based on the measured spectrum to demonstrate that the combination of IS⊙IS instruments can measure hard X-rays and γ -rays from ∼60 keV–7 MeV. Despite the fact that this is a supplemental science goal of the mission, the capability of the IS⊙IS instruments to measure γ -rays is important for the study of this population due to the very limited instruments currently observing the Sun in γ -rays.
The therapeutic utility of antibodies and their derivatives is achieved by various means. The FDA has approved several targeted antibodies that disrupt signaling of various growth factor receptors ...for the treatment of a number of cancers. Rituximab, and other anti-CD20 monoclonal antibodies are active in B cell malignancies. As more experience has been gained with anti-CD20 monoclonal antibodies, the multifactorial nature of their anti-tumor mechanisms has emerged. Other targeted antibodies function to dampen inhibitory checkpoints. These checkpoint inhibitors have recently achieved dramatic results in several cancers, including melanoma. These and related antibodies continue to be investigated in the clinical and pre-clinical settings. Novel antibody structures that target two or more antigens have also made their way into clinical use. Tumor targeted antibodies can also be conjugated to chemo- or radiotherapeutic agents, or catalytic toxins, as a means to deliver toxic payloads to cancer cells. Here we provide a review of these mechanisms and a discussion of their relevance to current and future clinical applications.
Considerable research has documented that exposure to traumatic events has negative effects on physical and mental health. Much less research has examined the predictors of traumatic event exposure. ...Increased understanding of risk factors for exposure to traumatic events could be of considerable value in targeting preventive interventions and anticipating service needs.
General population surveys in 24 countries with a combined sample of 68 894 adult respondents across six continents assessed exposure to 29 traumatic event types. Differences in prevalence were examined with cross-tabulations. Exploratory factor analysis was conducted to determine whether traumatic event types clustered into interpretable factors. Survival analysis was carried out to examine associations of sociodemographic characteristics and prior traumatic events with subsequent exposure.
Over 70% of respondents reported a traumatic event; 30.5% were exposed to four or more. Five types - witnessing death or serious injury, the unexpected death of a loved one, being mugged, being in a life-threatening automobile accident, and experiencing a life-threatening illness or injury - accounted for over half of all exposures. Exposure varied by country, sociodemographics and history of prior traumatic events. Being married was the most consistent protective factor. Exposure to interpersonal violence had the strongest associations with subsequent traumatic events.
Given the near ubiquity of exposure, limited resources may best be dedicated to those that are more likely to be further exposed such as victims of interpersonal violence. Identifying mechanisms that account for the associations of prior interpersonal violence with subsequent trauma is critical to develop interventions to prevent revictimization.
Voyager 1 (V1) began measuring precursor energetic ions and electrons from the heliospheric termination shock (TS) in July 2002. During the ensuing 2.5 years, average particle intensities rose as V1 ...penetrated deeper into the energetic particle foreshock of the TS. Throughout 2004, V1 observed even larger, fluctuating intensities of ions from 40 kiloelectron volts (keV) to >/=50 megaelectron volts per nucleon and of electrons from >26 keV to >/=350 keV. On day 350 of 2004 (2004/350), V1 observed an intensity spike of ions and electrons that was followed by a sustained factor of 10 increase at the lowest energies and lesser increases at higher energies, larger than any intensities since V1 was at 15 astronomical units in 1982. The estimated solar wind radial flow speed was positive (outward) at approximately+100 kilometers per second (km s⁻¹) from 2004/352 until 2005/018, when the radial flows became predominantly negative (sunward) and fluctuated between approximately-50 and 0 km s⁻¹ until about 2005/110; they then became more positive, with recent values (2005/179) of approximately+50 km s⁻¹. The energetic proton spectrum averaged over the postshock period is apparently dominated by strongly heated interstellar pickup ions. We interpret these observations as evidence that V1 was crossed by the TS on 2004/351 (during a tracking gap) at 94.0 astronomical units, evidently as the shock was moving radially inward in response to decreasing solar wind ram pressure, and that V1 has remained in the heliosheath until at least mid-2005.
Broad regions on both sides of the solar wind termination shock are populated by high intensities of non-thermal ions and electrons. The pre-shock particles in the solar wind have been measured by ...the spacecraft Voyager 1 (refs 1-5) and Voyager 2 (refs 3, 6). The post-shock particles in the heliosheath have also been measured by Voyager 1 (refs 3-5). It was not clear, however, what effect these particles might have on the physics of the shock transition until Voyager 2 crossed the shock on 31 August-1 September 2007 (refs 7-9). Unlike Voyager 1, Voyager 2 is making plasma measurements. Data from the plasma and magnetic field instruments on Voyager 2 indicate that non-thermal ion distributions probably have key roles in mediating dynamical processes at the termination shock and in the heliosheath. Here we report that intensities of low-energy ions measured by Voyager 2 produce non-thermal partial ion pressures in the heliosheath that are comparable to (or exceed) both the thermal plasma pressures and the scalar magnetic field pressures. We conclude that these ions are the >0.028 MeV portion of the non-thermal ion distribution that determines the termination shock structure and the acceleration of which extracts a large fraction of bulk-flow kinetic energy from the incident solar wind.
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