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Replacement Parts
In Replacement Parts, internationally renowned bioethicist Arthur L. Caplan and coeditors James J. McCartney and Daniel P. Reid assemble a collection of previously published writings from medicine, philosophy, economics, and religion that address the ethical challenges raised by organ transplantation.
eBook
Dietary methionine influences therapy in mouse cancer models and alters human metabolism
Nutrition exerts considerable effects on health, and dietary interventions are commonly used to treat diseases of metabolic aetiology. Although cancer has a substantial metabolic component
1
, the principles that define whether nutrition may be used to influence outcomes of cancer are unclear
2
. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. By contrast, whether specific dietary interventions can influence the metabolic pathways that are targeted in standard cancer therapies is not known. Here we show that dietary restriction of the essential amino acid methionine—the reduction of which has anti-ageing and anti-obesogenic properties—influences cancer outcome, through controlled and reproducible changes to one-carbon metabolism. This pathway metabolizes methionine and is the target of a variety of cancer interventions that involve chemotherapy and radiation. Methionine restriction produced therapeutic responses in two patient-derived xenograft models of chemotherapy-resistant RAS-driven colorectal cancer, and in a mouse model of autochthonous soft-tissue sarcoma driven by a G12D mutation in KRAS and knockout of p53 (
Kras
G12D
/+
;Trp53
−/−
) that is resistant to radiation. Metabolomics revealed that the therapeutic mechanisms operate via tumour-cell-autonomous effects on flux through one-carbon metabolism that affects redox and nucleotide metabolism—and thus interact with the antimetabolite or radiation intervention. In a controlled and tolerated feeding study in humans, methionine restriction resulted in effects on systemic metabolism that were similar to those obtained in mice. These findings provide evidence that a targeted dietary manipulation can specifically affect tumour-cell metabolism to mediate broad aspects of cancer outcome.
In two patient-derived xenograft models of colorectal cancer and a mouse model of autochthonous soft-tissue sarcoma, dietary restriction of methionine influences the outcome of cancer and interacts with antimetabolite and radiation therapies, through effects on one-carbon metabolism.
Journal Article
The dynamics of SARS-CoV-2 infectivity with changes in aerosol microenvironment
Understanding the factors that influence the airborne survival of viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in aerosols is important for identifying routes of transmission and the value of various mitigation strategies for preventing transmission. We present measurements of the stability of SARS-CoV-2 in aerosol droplets (∼5 to 10 μm equilibrated radius) over timescales spanning 5 s to 20 min using an instrument to probe survival in a small population of droplets (typically 5 to 10) containing ∼1 virus/droplet. Measurements of airborne infectivity change are coupled with a detailed physicochemical analysis of the airborne droplets containing the virus. A decrease in infectivity to ∼10% of the starting value was observable for SARS-CoV-2 over 20 min, with a large proportion of the loss occurring within the first 5 min after aerosolization. The initial rate of infectivity loss was found to correlate with physical transformation of the equilibrating droplet; salts within the droplets crystallize at relative humidities (RHs) below 50%, leading to a near-instant loss of infectivity in 50 to 60% of the virus. However, at 90% RH, the droplet remains homogenous and aqueous, and the viral stability is sustained for the first 2 min, beyond which it decays to only 10% remaining infectious after 10 min. The loss of infectivity at high RH is consistent with an elevation in the pH of the droplets, caused by volatilization of CO₂ from bicarbonate buffer within the droplet. Four different variants of SARS-CoV-2 were compared and found to have a similar degree of airborne stability at both high and low RH.
Journal Article
A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein
Respiratory syncytial virus (RSV) infection is the leading cause of hospitalization and infant mortality under six months of age worldwide; therefore, the prevention of RSV infection in all infants represents a significant unmet medical need. Here we report the isolation of a potent and broadly neutralizing RSV monoclonal antibody derived from a human memory B-cell. This antibody, RB1, is equipotent on RSV A and B subtypes, potently neutralizes a diverse panel of clinical isolates in vitro and demonstrates in vivo protection. It binds to a highly conserved epitope in antigenic site IV of the RSV fusion glycoprotein. RB1 is the parental antibody to MK-1654 which is currently in clinical development for the prevention of RSV infection in infants.
Respiratory syncytial virus (RSV) is a leading cause of infant hospitalization. Here, the authors isolate a human monoclonal antibody that binds to a highly conserved epitope on the RSV fusion protein, neutralizes RSV A and B subtypes equipotently and is protective in the cotton rat model.
Journal Article
Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations
Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample (
N
= 274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits’ PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.
The genetic underpinnings of alcohol use disorder and consumption are incompletely understood. Here, the authors perform GWAS for Alcohol Use Disorder (AUD) Identification Test-Consumption scores and AUD diagnosis from electronic health records of 274,424 individuals and identify a total of 18 associated loci.
Journal Article
A scalable and modular automated pipeline for stitching of large electron microscopy datasets
Serial-section electron microscopy (ssEM) is the method of choice for studying macroscopic biological samples at extremely high resolution in three dimensions. In the nervous system, nanometer-scale images are necessary to reconstruct dense neural wiring diagrams in the brain, so -called connectomes . The data that can comprise of up to 10 8 individual EM images must be assembled into a volume, requiring seamless 2D registration from physical section followed by 3D alignment of the stitched sections. The high throughput of ssEM necessitates 2D stitching to be done at the pace of imaging, which currently produces tens of terabytes per day. To achieve this, we present a modular volume assembly software pipeline ASAP (Assembly Stitching and Alignment Pipeline) that is scalable to datasets containing petabytes of data and parallelized to work in a distributed computational environment. The pipeline is built on top of the Render Trautman and Saalfeld (2019) services used in the volume assembly of the brain of adult Drosophila melanogaster (Zheng et al. 2018). It achieves high throughput by operating only on image meta-data and transformations. ASAP is modular, allowing for easy incorporation of new algorithms without significant changes in the workflow. The entire software pipeline includes a complete set of tools for stitching, automated quality control, 3D section alignment, and final rendering of the assembled volume to disk. ASAP has been deployed for continuous stitching of several large-scale datasets of the mouse visual cortex and human brain samples including one cubic millimeter of mouse visual cortex (Yin et al. 2020); Microns Consortium et al. (2021) at speeds that exceed imaging. The pipeline also has multi-channel processing capabilities and can be applied to fluorescence and multi-modal datasets like array tomography.
Journal Article
Comparing the mechanism of water condensation and evaporation in glassy aerosol
Atmospheric models generally assume that aerosol particles are in equilibrium with the surrounding gas phase. However, recent observations that secondary organic aerosols can exist in a glassy state have highlighted the need to more fully understand the kinetic limitations that may control water partitioning in ambient particles. Here, we explore the influence of slow water diffusion in the condensed aerosol phase on the rates of both condensation and evaporation, demonstrating that significant inhibition in mass transfer occurs for ultraviscous aerosol, not just for glassy aerosol. Using coarse mode (3–4 um radius) ternary sucrose/sodium chloride/aqueous droplets as a proxy for multicomponent ambient aerosol, we demonstrate that the timescale for particle equilibration correlates with bulk viscosity and can be ≫10 ³ s. Extrapolation of these timescales to particle sizes in the accumulation mode (e.g., approximately 100 nm) by applying the Stokes-Einstein equation suggests that the kinetic limitations imposed on mass transfer of water by slow bulk phase diffusion must be more fully investigated for atmospheric aerosol. Measurements have been made on particles covering a range in dynamic viscosity from < 0.1 to > 10 ¹³ Pa s. We also retrieve the radial inhomogeneities apparent in particle composition during condensation and evaporation and contrast the dynamics of slow dissolution of a viscous core into a labile shell during condensation with the slow percolation of water during evaporation through a more homogeneous viscous particle bulk.
Journal Article
The Contemporary Evolution of Fitness
The rate of evolution of population mean fitness informs how selection acting in contemporary populations can counteract environmental change and genetic degradation (mutation, gene flow, drift, recombination). This rate influences population increases (e.g., range expansion), population stability (e.g., cryptic eco-evolutionary dynamics), and population recovery (i.e., evolutionary rescue). We review approaches for estimating such rates, especially in wild populations. We then review empirical estimates derived from two approaches: mutation accumulation (MA) and additive genetic variance in fitness (I
Aw
). MA studies inform how selection counters genetic degradation arising from deleterious mutations, typically generating estimates of <1% per generation. I
Aw
studies provide an integrated prediction of proportional change per generation, nearly always generating estimates of <20% and, more typically, <10%. Overall, considerable, but not unlimited, evolutionary potential exists in populations facing detrimental environmental or genetic change. However, further studies with diverse methods and species are required for more robust and general insights.
Journal Article
An ultrafast symmetry switch in a Weyl semimetal
Topological quantum materials exhibit fascinating properties
1
–
3
, with important applications for dissipationless electronics and fault-tolerant quantum computers
4
,
5
. Manipulating the topological invariants in these materials would allow the development of topological switching applications analogous to switching of transistors
6
. Lattice strain provides the most natural means of tuning these topological invariants because it directly modifies the electron–ion interactions and potentially alters the underlying crystalline symmetry on which the topological properties depend
7
–
9
. However, conventional means of applying strain through heteroepitaxial lattice mismatch
10
and dislocations
11
are not extendable to controllable time-varying protocols, which are required in transistors. Integration into a functional device requires the ability to go beyond the robust, topologically protected properties of materials and to manipulate the topology at high speeds. Here we use crystallographic measurements by relativistic electron diffraction to demonstrate that terahertz light pulses can be used to induce terahertz-frequency interlayer shear strain with large strain amplitude in the Weyl semimetal WTe
2
, leading to a topologically distinct metastable phase. Separate nonlinear optical measurements indicate that this transition is associated with a symmetry change to a centrosymmetric, topologically trivial phase. We further show that such shear strain provides an ultrafast, energy-efficient way of inducing robust, well separated Weyl points or of annihilating all Weyl points of opposite chirality. This work demonstrates possibilities for ultrafast manipulation of the topological properties of solids and for the development of a topological switch operating at terahertz frequencies.
Terahertz light pulses induce transitions between a topological and a trivial phase in the Weyl semimetal WTe
2
through an interlayer shear strain.
Journal Article