Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A HLA-A, -B, and -C genes) may affect susceptibility to and severity of the disease ...caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive
analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.
Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.
Muscle power declines earlier and more precipitously with advancing age compared with muscle strength. Peak muscle power also has emerged as an important predictor of functional limitations in older ...adults. Our current working hypothesis is focused on examining lower extremity muscle power as a more discriminant variable for understanding the relationships between impairments, functional limitations, and resultant disability with aging.
Summary
This 3-year longitudinal study among older adults showed that declining muscle mass, strength, power, and physical performance are independent contributing factors to increased fear of ...falling, while declines of muscle mass and physical performance contribute to deterioration of quality of life. Our findings reinforce the importance of preserving muscle health with advancing age.
Introduction
The age-associated loss of skeletal muscle quantity and function are critical determinants of independent physical functioning in later life. Longitudinal studies investigating how decrements in muscle components of sarcopenia impact fear of falling (FoF) and quality of life (QoL) in older adults are lacking.
Methods
Twenty-six healthy older subjects (age, 74.1 ± 3.7; Short Physical Performance Battery (SPPB) score ≥10) and 22 mobility-limited older subjects (age, 77.2 ± 4.4; SPPB score ≤9) underwent evaluations of lower extremity muscle size and composition by computed tomography, strength and power, and physical performance at baseline and after 3-year follow-up. The Falls Efficacy Scale (FES) and Short Form-36 questionnaire (SF-36) were also administered at both timepoints to assess FoF and QoL, respectively.
Results
At 3-year follow-up, muscle cross-sectional area (CSA) (
p
< 0.013) and power decreased (
p
< 0.001), while intermuscular fat infiltration increased (
p
< 0.001). These decrements were accompanied with a longer time to complete 400 m by 22 ± 46 s (
p
< 0.002). Using linear mixed-effects regression models, declines of muscle CSA, strength and power, and SPPB score were associated with increased FES score (
p
< 0.05 for each model). Reduced physical component summary score of SF-36 over follow-up was independently associated with decreased SPPB score (
p
< 0.020), muscle CSA (
p
< 0.046), and increased 400 m walk time (
p
< 0.003).
Conclusions
In older adults with and without mobility limitations, declining muscle mass, strength, power, and physical performance contribute independently to increase FoF, while declines of muscle mass and physical performance contribute to deterioration of QoL. These findings provide further rationale for developing interventions to improve aging muscle health.
•Our experiments on deforming ice show dissipation greater than predicted by viscoelastic models.•The attenuation is modestly nonlinear (strain-amplitude dependent) and independent of grain ...size.•Grain size-independent attenuation represents a paradigm shift in how lab data are extrapolated.•When creep involves dislocations, the substructure and spatial interactions control attenuation.
The thermal and mechanical evolution of Europa and comparable icy satellites—the physics behind creating and sustaining a subsurface water ocean—depends almost entirely on the mechanical dissipation of tidal energy in ice to produce heat, the mechanism(s) of which remain poorly understood. In deformation experiments, we combine steady–state creep and low-frequency, small-strain periodic loading, similar conditions in which tectonics and tidal flexing are occurring simultaneously. The data reveal that the relevant, power-law attenuation in ice (i) is non-linear, depending on strain amplitude, (ii) is independent of grain size, and (iii) exceeds in absorption the prediction of the Maxwell solid model by an order of magnitude. The Maxwell solid model is widely used to model the dynamics of planetary ice shells, so this discrepancy is important. The prevalent understanding of damping in the geophysical context is that it is controlled by chemical diffusion on grain boundaries, which renders attenuation strongly dependent on grain size. In sharp contrast, our results indicate instead the importance of intracrystalline dislocations and their spatial interactions as the critical structural variable affecting dissipation. These dislocation structures are controlled by stress and realized by accumulated plastic strain. Thus, tectonics and attenuation are coupled, which, beyond the icy satellite/subsurface ocean problem, has implications also for understanding the attenuation of seismic waves in deforming regions of the Earth's upper mantle.
Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have ...largely failed
. Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance.
Tumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad ...acceptance as a result. However, TMB harbors intrinsic variability across cancer types, and its assessment and interpretation are poorly standardized.
Using a standardized approach, we quantify the robustness of TMB as a metric and its potential as a predictor of immunotherapy response and survival among a diverse cohort of cancer patients. We also explore the additive predictive potential of RNA-derived variants and neoepitope burden, incorporating several novel metrics of immunogenic potential.
We find that TMB is a partial predictor of immunotherapy response in melanoma and non-small cell lung cancer, but not renal cell carcinoma. We find that TMB is predictive of overall survival in melanoma patients receiving immunotherapy, but not in an immunotherapy-naive population. We also find that it is an unstable metric with potentially problematic repercussions for clinical cohort classification. We finally note minimal additional predictive benefit to assessing neoepitope burden or its bulk derivatives, including RNA-derived sources of neoepitopes.
We find sufficient cause to suggest that the predictive clinical value of TMB should not be overstated or oversimplified. While it is readily quantified, TMB is at best a limited surrogate biomarker of immunotherapy response. The data do not support isolated use of TMB in renal cell carcinoma.
Experimental deformation experiments have been conducted on fine‐grained, two‐phase aggregates of olivine and orthopyroxene to investigate the role of grain and phase boundary sliding on rheology and ...fabric development. A suite of large‐strain (γ ≥ 1) general shear experiments conducted at T = 1200°C and P = 1.6 GPa on aggregates ranging from 65 to 0 vol % orthopyroxene, to characterize the evolution of fabric, were complemented by small‐strain axial compression experiments at T = 1200°C and P = 0.3 GPa, to better constrain the rheology. Microstructural and rheological data suggest that deformation of these two‐phase aggregates in the diffusion creep regime occurs via interface‐reaction‐controlled diffusion creep that is accompanied by extensive migration of olivine‐orthopyroxene phase boundaries. The resulting rheologies suggest that olivine + orthopyroxene composites are weaker than the olivine end‐member at the conditions tested. Physically, this behavior arises because long‐range, i.e., grain‐scale, diffusion of Si4+ is unnecessary in these pseudobinary two‐phase aggregates. We further demonstrate that interface‐controlled diffusion creep leads to strong crystallographic preferred orientations (CPO) of the component minerals, which develops in the near absence of dislocation activity. The CPO formed in these anhydrous, low‐stress experiments has the olivine a axis aligned perpendicular to the flow direction (“type B” fabric) argued by some to be the unique result of deformation under conditions of high differential stress and high water fugacity. Phase boundary dynamics, thus, are argued as a significant factor in the accumulation of strain in polyphase aggregates.
There is growing interest in retained introns in a variety of disease contexts including cancer and aging. Many software tools have been developed to detect retained introns from short RNA-seq reads, ...but reliable detection is complicated by overlapping genes and transcripts as well as the presence of unprocessed or partially processed RNAs.
We compared introns detected by 8 tools using short RNA-seq reads with introns observed in long RNA-seq reads from the same biological specimens. We found significant disagreement among tools (Fleiss' Formula: see text) such that 47.7% of all detected intron retentions were not called by more than one tool. We also observed poor performance of all tools, with none achieving an F1-score greater than 0.26, and qualitatively different behaviors between general-purpose alternative splicing detection tools and tools confined to retained intron detection.
Short-read tools detect intron retention with poor recall and precision, calling into question the completeness and validity of a large percentage of putatively retained introns called by commonly used methods.
The Moon is generally thought to have formed and evolved through a single or a series of catastrophic heating events, during which most of the highly volatile elements were lost. Hydrogen, being the ...lightest element, is believed to have been completely lost during this period. Here we make use of considerable advances in secondary ion mass spectrometry to obtain improved limits on the indigenous volatile (CO2, H2O, F, S and Cl) contents of the most primitive basalts in the Moon-the lunar volcanic glasses. Although the pre-eruptive water content of the lunar volcanic glasses cannot be precisely constrained, numerical modelling of diffusive degassing of the very-low-Ti glasses provides a best estimate of 745 p.p.m. water, with a minimum of 260 p.p.m. at the 95 per cent confidence level. Our results indicate that, contrary to prevailing ideas, the bulk Moon might not be entirely depleted in highly volatile elements, including water. Thus, the presence of water must be considered in models constraining the Moon's formation and its thermal and chemical evolution.
Artificial intelligence (AI) is emerging as a technology with the power to transform established industries, and with applications from automated manufacturing to advertising and facial recognition ...to fully autonomous transportation. Advances in each of these domains have led some to call AI the “fourth” industrial revolution 1. In healthcare, AI is emerging as both a productive and disruptive force across many disciplines. This is perhaps most evident in Diagnostic Radiology and Pathology, specialties largely built around the processing and complex interpretation of medical images, where the role of AI is increasingly seen as both a boon and a threat. In Radiation Oncology as well, AI seems poised to reshape the specialty in significant ways, though the impact of AI has been relatively limited at present, and may rightly seem more distant to many, given the predominantly interpersonal and complex interventional nature of the specialty. In this overview, we will explore the current state and anticipated future impact of AI on Radiation Oncology, in detail, focusing on key topics from multiple stakeholder perspectives, as well as the role our specialty may play in helping to shape the future of AI within the larger spectrum of medicine.
PDF
