Microsatellite instability (MSI) is a biomarker for response to immune checkpoint inhibitors (ICPIs). PD-1 inhibitors in metastatic colorectal carcinoma (mCRC) with MSI-high (MSI-H) have demonstrated ...a high disease control rate and favorable progression-free survival (PFS); however, reported response rates to pembrolizumab and nivolumab are variable and often <50%, suggesting that additional predictive biomarkers are needed.
Clinicopathologic data were collected from patients with MSI-H mCRC confirmed by hybrid capture-based next-generation sequencing (NGS) treated with PD-1/L1 inhibitors at five institutes. Tumor mutational burden (TMB) was determined on 0.8–1.1Mb of sequenced DNA and reported as mutations/Mb. Potential biomarkers of response and time to progression were analyzed by univariate and multivariate analyses. Once TMB was confirmed as a predictive biomarker, a larger dataset of 18 140 unique CRC patients was analyzed to define the relevance of the identified TMB cut-point.
A total of 22 patients were treated with PD-1/L1 inhibitors including 19 with pembrolizumab monotherapy. Among tested variables, TMB showed the strongest association with objective response (OR; P<0.001) and PFS, by univariate (P<0.001) and multivariate analysis (P<0.01). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37 and 41 mutations/Mb. All 13 TMBhigh cases responded, while 6/9 TMBlow cases had progressive disease. The median PFS for TMBhigh has not been reached (median follow-up >18months) while the median PFS for TMBlow was 2months. A TMB of 37.4 mutations/Mb in a large MSI-H mCRC population (821/18, 140 cases; 4.5%) evaluated by NGS corresponded to the 35th percentile cut-point.
TMB appears to be an important independent biomarker within MSI-H mCRC to stratify patients for likelihood of response to ICPIs. If validated in prospective studies, TMB may play an important role in guiding the sequencing and/or combinations of ICPIs in MSI-H mCRC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) causes a highly contagious respiratory disease referred to as COVID‐19. However, emerging evidence indicates that a small but growing ...number of COVID‐19 patients also manifest neurological symptoms, suggesting that SARS‐CoV‐2 may infect the nervous system under some circumstances. SARS‐CoV‐2 primarily enters the body through the epithelial lining of the respiratory and gastrointestinal tracts, but under certain conditions this pleiotropic virus may also infect peripheral nerves and gain entry into the central nervous system (CNS). The brain is shielded by various anatomical and physiological barriers, most notably the blood–brain barrier (BBB) which functions to prevent harmful substances, including pathogens and pro‐inflammatory mediators, from entering the brain. The BBB is composed of highly specialized endothelial cells, pericytes, mast cells and astrocytes that form the neurovascular unit, which regulates BBB permeability and maintains the integrity of the CNS. In this review, potential routes of viral entry and the possible mechanisms utilized by SARS‐CoV‐2 to penetrate the CNS, either by disrupting the BBB or infecting the peripheral nerves and using the neuronal network to initiate neuroinflammation, are briefly discussed. Furthermore, the long‐term effects of SARS‐CoV‐2 infection on the brain and in the progression of neurodegenerative diseases known to be associated with other human coronaviruses are considered. Although the mechanisms of SARS‐CoV‐2 entry into the CNS and neurovirulence are currently unknown, the potential pathways described here might pave the way for future research in this area and enable the development of better therapeutic strategies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Chorus waves play a key role in outer Van Allen electron belt dynamics through cyclotron resonance. Here, we use Van Allen Probes data to reveal a new and distinct population of intense chorus waves ...excited in the heart of the radiation belt during the main phase of geomagnetic storms. The power of the waves is typically ~ 2-3 orders of magnitude greater than pre-storm levels, and are generated when fluxes of ~ 10-100 keV electrons approach or exceed the Kennel-Petschek limit. These intense chorus waves rapidly scatter electrons into the loss cone, capping the electron flux to a value close to the limit predicted by Kennel and Petschek over 50 years ago. Our results are crucial for understanding the limits to radiation belt fluxes, with accurate models likely requiring the inclusion of this chorus wave-driven flux-limiting process, that is independent of the acceleration mechanism or source responsible for enhancing the flux.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Loss mechanisms act independently or in unison to drive rapid loss of electrons in the radiation belts. Electrons may be lost by precipitation into the Earth's atmosphere, or through the magnetopause ...into interplanetary space—a process known as magnetopause shadowing. While magnetopause shadowing is known to produce dropouts in electron flux, it is unclear if shadowing continues to remove particles in tandem with electron acceleration processes, limiting the overall flux increase. We investigated the contribution of shadowing to overall radiation belt fluxes throughout a geomagnetic storm starting on the 7 September 2017. We use new, multimission phase space density calculations to decipher electron dynamics during each storm phase and identify features of magnetopause shadowing during both the net‐loss and the net‐acceleration storm phases on sub‐hour time scales. We also highlight two distinct types of shadowing; “direct,” where electrons are lost as their orbit intersects the magnetopause, and “indirect,” where electrons are lost through ULF wave driven radial transport toward the magnetopause boundary.
Plain Language Summary
Charged particles with extremely high energies are trapped by Earth's geomagnetic field. These particles form rings around Earth called the Van Allen radiation belts, which vary in intensity. This radiation poses a risk to satellites orbiting Earth, so it is important to understand how changes in geomagnetic conditions produce variations in the radiation belt intensity. In this work, we take measurements of electron radiation from many satellites to observe electron “dropouts,” where nearly the entire radiation belt is lost in a matter of hours. We found that it is necessary to use multimission measurements to make observations of dropouts because a dropout may occur quicker than a single satellite can traverse the radiation belt. In early September 2017, we observed that movements of the geomagnetic outer boundary, the magnetopause, were responsible for removing electrons, combined with diffusive processes. This agreed with the predictions by previous studies. We further observed that the magnetopause continued to remove electrons from the belt while electrons were simultaneously accelerated by fluctuations in the geomagnetic field. This is significant because electrons may be removed from the belt soon after they were created, limiting the overall growth of the radiation belt while the magnetopause was compressed.
Key Points
Multimission phase space density observations are necessary to resolve relativistic electron dynamics during September 2017 storm
Relativistic electron losses to the magnetopause were identified, which led to further diffusion of electrons toward the magnetopause
Electron loss to the magnetopause was observed simultaneous to prompt local energization in the heart of the radiation belt
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We analyzed the contribution of electromagnetic ion cyclotron (EMIC) wave driven electron loss to a flux dropout event in September 2017. The evolution of electron phase space density (PSD) through ...the dropout showed the formation of a radially peaked PSD profile as electrons were lost at high L*, resembling distributions created by magnetopause shadowing. By comparing 2D Fokker Planck simulations of pitch angle diffusion to the observed change in PSD, we found that the μ and K of electron loss aligned with maximum scattering rates at dropout onset. We conclude that, during this dropout event, EMIC waves produced substantial electron loss. Because pitch angle diffusion occurred on closed drift paths near the last closed drift shell, no radial PSD minimum was observed. Therefore, the radial PSD gradients resembled solely magnetopause shadowing loss, even though the local pitch angle scattering produced electron losses of several orders of magnitude of the PSD.
Plain Language Summary
Extremely energetic charged particles become trapped by Earth's geomagnetic field, forming the Van Allen radiation belts. The total amount of radiation trapped within these belts varies depending on the solar wind conditions, which can disturb the geomagnetic field to produce geomagnetic storms. At the beginning of a geomagnetic storm, there is a relative calm in the radiation belt, produced by the rapid drainage of electrons from the geomagnetic field. It is not fully understood if these electrons are primarily lost into the solar wind, or if they are lost into Earth's atmosphere. In this study, we analyze the remaining trapped electrons to reconstruct the mechanisms of electron escape at the beginning of a geomagnetic storm in September 2017. While previous work found that electrons were primarily lost into the solar wind, we found that loss into the atmosphere also played an important role. Furthermore, we showed that drainage of electrons into the atmosphere can be mistaken for loss into the solar wind if the energy and trajectory of lost electrons are not carefully considered.
Key Points
Characterizing electron loss through peaks and minima in radial phase space density can misrepresent simultaneous loss mechanisms
Analysis of electron loss across all adiabatic invariants μ, K, and L*, is necessary to correctly identify loss mechanisms
Observational analysis of phase space density data alone cannot be used to quantify individual contributions of simultaneous loss processes
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Fusarium wilt (FW; caused by
Fusarium oxysporum
f. sp.
ciceris
) and Ascochyta blight (AB; caused by
Ascochyta rabiei
) are two major biotic stresses that cause significant yield losses in chickpea (
...Cicer arietinum
L.). In order to identify the genomic regions responsible for resistance to FW and AB, 188 recombinant inbred lines derived from a cross JG 62 × ICCV 05530 were phenotyped for reaction to FW and AB under both controlled environment and field conditions. Significant variation in response to FW and AB was detected at all the locations. A genetic map comprising of 111 markers including 84 simple sequence repeats and 27 single nucleotide polymorphism (SNP) loci spanning 261.60 cM was constructed. Five quantitative trait loci (QTLs) were detected for resistance to FW with phenotypic variance explained from 6.63 to 31.55%. Of the five QTLs, three QTLs including a major QTL on CaLG02 and a minor QTL each on CaLG04 and CaLG06 were identified for resistance to race 1 of FW. For race 3, a major QTL each on CaLG02 and CaLG04 were identified. In the case of AB, one QTL for seedling resistance (SR) against ‘Hisar race’ and a minor QTL each for SR and adult plant resistance against isolate 8 of race 6 (3968) were identified. The QTLs and linked markers identified in this study can be utilized for enhancing the FW and AB resistance in elite cultivars using marker-assisted backcrossing.
Field Line Resonances (FLRs) are a critical component in Earth's magnetospheric dynamics, associated with the transfer of energy between Ultra Low Frequency waves and local plasma populations. In ...this study we investigate how the polarisation of FLRs are impacted by cold plasma density distributions during geomagnetic storms. We present an analysis of Van Allen Probe A observations, where the spacecraft traversed a storm time plasmaspheric plume. We show that the polarisation of the FLR is significantly altered at the sharp azimuthal density gradient of the plume boundary, where the polarisation is intermediate with significant poloidal and toroidal components. These signatures are consistent with magnetohydrodynamic modeling results, providing the first observational evidence of a 3D FLR associated with a plume in Earth's magnetosphere. These results demonstrate the importance of cold plasma in controlling wave dynamics in the magnetosphere, and have important implications for wave‐particle interactions at a range of energies.
Plain Language Summary
Earth's space environment is home to electrons and ions across a wide range of energies, trapped in the region by our global geomagnetic field. Energy can be transferred to and from the trapped particles through oscillations in the magnetic field, and these processes are responsible for the extreme energization of trapped electrons to hazardous levels for local spacecraft. In this paper we explore a type of magnetic field oscillation termed Field Line Resonances (FLRs): standing waves on a field line analogous to the oscillatory motion of guitar strings. We use spacecraft observations to show that the direction of the field line oscillations changes significantly depending on the density of the background plasma. The results confirm previous modeling work, and are the first observational evidence of 3D FLRs at a plume. The findings have important consequences for how FLRs transfer energy between the electrons and ions.
Key Points
We present the first observational evidence of a 3D Field Line Resonance at the sharp density gradient of a plume edge
The observed polarisation change confirms magnetohydrodynamic modeling results and predictions made by Elsden and Wright (2022)
The presence of 3D Field Line Resonances during storm times has impacts for how Ultra Low Frequency waves couple and interact with local plasma
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
An important technique for discovering and characterizing planets beyond our solar system relies upon measurement of weak Doppler shifts in the spectra of host stars induced by the influence of ...orbiting planets. A recent advance has been the introduction of optical frequency combs as frequency references. Frequency combs produce a series of equally spaced reference frequencies and they offer extreme accuracy and spectral grasp that can potentially revolutionize exoplanet detection. Here we demonstrate a laser frequency comb using an alternate comb generation method based on electro-optical modulation, with the comb centre wavelength stabilized to a molecular or atomic reference. In contrast to mode-locked combs, the line spacing is readily resolvable using typical astronomical grating spectrographs. Built using commercial off-the-shelf components, the instrument is relatively simple and reliable. Proof of concept experiments operated at near-infrared wavelengths were carried out at the NASA Infrared Telescope Facility and the Keck-II telescope.
A computational study has been carried out to assess the effectiveness of a porous medium as a passive control device suitable for reducing the drag in a normal-shock-wave/boundary-layer interaction ...at transonic speeds with a view toward application in aircraft wings. Reduction in overall drag is achieved via recirculation inside the porous medium, which primarily weakens the shock structure and hence reduces the wave drag. The study has been carried out for a Mach 1.3 normal-shock-wave/boundary-layer interaction on a flat plate in the presence of a porous medium beneath the region of interaction. The computations are performed as steady-state RANS calculations using Menter’s SST
k
-
ω
/
k
-
ϵ
model for turbulence closure. A parametric study that investigates the dependency of the effectiveness of control on dimensions of the cavity (length and depth), relative position of the cavity, and porosity of the medium has been carried out. It is observed that the change in overall drag is pronounced for parameters which result in significant changes to the size of the
lambda
-shock structure, such as the length of the cavity upstream of the inviscid shock location. Among the parameters investigated, porosity is seen to strongly affect the boundary-layer properties, with increase in porosity resulting in higher viscous drag.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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