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"Craig, Andrew (Andrew S.)"
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Motion of VAPB molecules reveals ER–mitochondria contact site subdomains
To coordinate cellular physiology, eukaryotic cells rely on the rapid exchange of molecules at specialized organelle–organelle contact sites
1
,
2
. Endoplasmic reticulum–mitochondrial contact sites (ERMCSs) are particularly vital communication hubs, playing key roles in the exchange of signalling molecules, lipids and metabolites
3
,
4
. ERMCSs are maintained by interactions between complementary tethering molecules on the surface of each organelle
5
,
6
. However, due to the extreme sensitivity of these membrane interfaces to experimental perturbation
7
,
8
, a clear understanding of their nanoscale organization and regulation is still lacking. Here we combine three-dimensional electron microscopy with high-speed molecular tracking of a model organelle tether, Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), to map the structure and diffusion landscape of ERMCSs. We uncovered dynamic subdomains within VAPB contact sites that correlate with ER membrane curvature and undergo rapid remodelling. We show that VAPB molecules enter and leave ERMCSs within seconds, despite the contact site itself remaining stable over much longer time scales. This metastability allows ERMCSs to remodel with changes in the physiological environment to accommodate metabolic needs of the cell. An amyotrophic lateral sclerosis-associated mutation in VAPB perturbs these subdomains, likely impairing their remodelling capacity and resulting in impaired interorganelle communication. These results establish high-speed single-molecule imaging as a new tool for mapping the structure of contact site interfaces and reveal that the diffusion landscape of VAPB at contact sites is a crucial component of ERMCS homeostasis.
High-speed molecular tracking is integrated with three-dimensional electron microscopy to map the diffusion distribution and ultrastructure of endoplasmic reticulum-mitochondria contact sites, revealing the ability of high-speed single-molecule imaging to map contact site interface structures and corresponding diffusion landscapes.
Journal Article
Advances in restoration ecology: rising to the challenges of the coming decades
Simultaneous environmental changes challenge biodiversity persistence and human wellbeing. The science and practice of restoration ecology, in collaboration with other disciplines, can contribute to overcoming these challenges. This endeavor requires a solid conceptual foundation based in empirical research which confronts, tests and influences theoretical developments. We review conceptual developments in restoration ecology over the last 30 years. We frame our review in the context of changing restoration goals which reflect increased societal awareness of the scale of environmental degradation and the recognition that inter-disciplinary approaches are needed to tackle environmental problems. Restoration ecology now encompasses facilitative interactions and network dynamics, trophic cascades, and above- and belowground linkages. It operates in a non-equilibrium, alternative states framework, at the landscape scale, and in response to changing environmental, economic and social conditions. Progress has been marked by conceptual advances in the fields of trait-environment relationships, community assembly, and understanding the links between biodiversity and ecosystem functioning. Conceptual and practical advances have been enhanced by applying evolving technologies, including treatments to increase seed germination and overcome recruitment bottlenecks, high throughput DNA sequencing to elucidate soil community structure and function, and advances in satellite technology and GPS tracking to monitor habitat use. The synthesis of these technologies with systematic reviews of context dependencies in restoration success, model based analyses and consideration of complex socio-ecological systems will allow generalizations to inform evidence based interventions. Ongoing challenges include setting realistic, socially acceptable goals for restoration under changing environmental conditions, and prioritizing actions in an increasingly space-competitive world. Ethical questions also surround the use of genetically modified material, translocations, taxon substitutions, and de-extinction, in restoration ecology. Addressing these issues, as the Ecological Society of America looks to its next century, will require current and future generations of researchers and practitioners, including economists, engineers, philosophers, landscape architects, social scientists and restoration ecologists, to work together with communities and governments to rise to the environmental challenges of the coming decades.
Journal Article
Bacterial community shifts of commercial apples, oranges, and peaches at different harvest points across multiple growing seasons
Assessing the microbes present on tree fruit carpospheres as the fruit enters postharvest processing could have useful applications, as these microbes could have a major influence on spoilage, food safety, verification of packing process controls, or other aspects of processing. The goal of this study was to establish a baseline profile of bacterial communities associated with apple (pome fruit), peach (stone fruit), and Navel orange (citrus fruit) at harvest. We found that commercial peaches had the greatest bacterial richness followed by oranges then apples. Time of harvest significantly changed bacterial diversity in oranges and peaches, but not apples. Shifts in diversity varied by fruit type, where 70% of the variability in beta diversity on the apple carposphere was driven by the gain and loss of species (i.e., nestedness). The peach and orange carposphere bacterial community shifts were driven by nearly an even split between turnover (species replacement) and nestedness. We identified a small core microbiome for apples across and between growing seasons that included only Methylobacteriaceae and Sphingomonadaceae among the samples, while peaches had a larger core microbiome composed of five bacterial families: Bacillaceae , Geodermtophilaceae , Nocardioidaceae , Micrococcaeceae , and Trueperaceae . There was a relatively diverse core microbiome for oranges that shared all the families present on apples and peaches, except for Trueperaceae , but also included an additional nine bacterial families not shared including Oxalobacteraceae , Cytophagaceae , and Comamonadaceae . Overall, our findings illustrate the important temporal dynamics of bacterial communities found on major commercial tree fruit, but also the core bacterial families that constantly remain with both implications being important entering postharvest packing and processing.
Journal Article
Myeloid EGFR deficiency accelerates recovery from AKI via macrophage efferocytosis and neutrophil apoptosis
Altered expression and activation of Epidermal Growth Factor Receptor (EGFR) is implicated in acute and chronic kidney injury. One of the important cellular sources of EGFR is the myeloid compartment, which plays roles in both acute kidney injury and subsequent fibrosis. Here we show in a murine ischemic acute kidney injury (AKI) model that myeloid deletion of EGFR promotes a pro-resolving, anti-inflammatory phenotype and increased efferocytotic capacity in macrophages. This leads to accelerated recovery in response to AKI and inhibited subsequent development of tubulointerstitial fibrosis. We find that selective EGFR deletion in neutrophils also accelerates recovery from ischemic kidney injury and reduces subsequent fibrosis. EGFR activation plays an essential role in increasing the life span of neutrophils in the injured kidney. Deletion of EGFR expression either in all murine myeloid cells or selectively in neutrophils decreases kidney neutrophil Mcl-1 expression and promotes neutrophil apoptosis, which is accompanied by accelerated recovery from organ injury and reduced subsequent fibrosis. These studies thus identify coordinated and complementary roles for EGFR activation in neutrophils and macrophages to exacerbate kidney injury.
Kidney-infiltrating myeloid cells play important roles in acute kidney injury and post-injury fibrosis. Here authors show that genomic deletion of Epidermal Growth Factor Receptor specifically in myeloid cells or in neutrophils alleviates acute kidney injury in a mouse model, via limiting the life span of these pro-inflammatory cells.
Journal Article
Orbital controls on eastern African hydroclimate in the Pleistocene
Understanding eastern African paleoclimate is critical for contextualizing early human evolution, adaptation, and dispersal, yet Pleistocene climate of this region and its governing mechanisms remain poorly understood due to the lack of long, orbitally-resolved, terrestrial paleoclimate records. Here we present leaf wax hydrogen isotope records of rainfall from paleolake sediment cores from key time windows that resolve long-term trends, variations, and high-latitude effects on tropical African precipitation. Eastern African rainfall was dominantly controlled by variations in low-latitude summer insolation during most of the early and middle Pleistocene, with little evidence that glacial–interglacial cycles impacted rainfall until the late Pleistocene. We observe the influence of high-latitude-driven climate processes emerging from the last interglacial (Marine Isotope Stage 5) to the present, an interval when glacial–interglacial cycles were strong and insolation forcing was weak. Our results demonstrate a variable response of eastern African rainfall to low-latitude insolation forcing and high-latitude-driven climate change, likely related to the relative strengths of these forcings through time and a threshold in monsoon sensitivity. We observe little difference in mean rainfall between the early, middle, and late Pleistocene, which suggests that orbitally-driven climate variations likely played a more significant role than gradual change in the relationship between early humans and their environment.
Journal Article
Cooperative adaptation to therapy (CAT) confers resistance in heterogeneous non-small cell lung cancer
Understanding intrinsic and acquired resistance is crucial to overcoming cancer chemotherapy failure. While it is well-established that intratumor, subclonal genetic and phenotypic heterogeneity significantly contribute to resistance, it is not fully understood how tumor sub-clones interact with each other to withstand therapy pressure. Here, we report a previously unrecognized behavior in heterogeneous tumors: cooperative adaptation to therapy (CAT), in which cancer cells induce co-resistant phenotypes in neighboring cancer cells when exposed to cancer therapy. Using a CRISPR/Cas9 toolkit we engineered phenotypically diverse non-small cell lung cancer (NSCLC) cells by conferring mutations in Dicer1, a type III cytoplasmic endoribonuclease involved in small non-coding RNA genesis. We monitored three-dimensional growth dynamics of fluorescently-labeled mutant and/or wild-type cells individually or in co-culture using a substrate-free NanoCulture system under unstimulated or drug pressure conditions. By integrating mathematical modeling with flow cytometry, we characterized the growth patterns of mono- and co-cultures using a mathematical model of intra- and interspecies competition. Leveraging the flow cytometry data, we estimated the model's parameters to reveal that the combination of WT and mutants in co-cultures allowed for beneficial growth in previously drug sensitive cells despite drug pressure via induction of cell state transitions described by a cooperative game theoretic change in the fitness values. Finally, we used an ex vivo human tumor model that predicts clinical response through drug sensitivity analyses and determined that cellular and morphologic heterogeneity correlates to prognostic failure of multiple clinically-approved and off-label drugs in individual NSCLC patient samples. Together, these findings present a new paradox in drug resistance implicating non-genetic cooperation among tumor cells to thwart drug pressure, suggesting that profiling for druggable targets (i.e. mutations) alone may be insufficient to assign effective therapy.
Journal Article
Population Viability of Sea Turtles in the Context of Global Warming
Sea turtles present a model for the potential impacts of climate change on imperiled species, with projected warming generating concern about their persistence. Various sea turtle life-history traits are affected by temperature; most strikingly, warmer egg incubation temperatures cause female-biased sex ratios and higher embryo mortality. Predictions of sea turtle resilience to climate change are often focused on how resulting male limitation or reduced offspring production may affect populations. In the present article, by reviewing research on sea turtles, we provide an overview of how temperature impacts on incubating eggs may cascade through life history to ultimately affect population viability. We explore how sex-specific patterns in survival and breeding periodicity determine the differences among offspring, adult, and operational sex ratios. We then discuss the implications of skewed sex ratios for male-limited reproduction, consider the negative correlation between sex ratio skew and genetic diversity, and examine consequences for adaptive potential. Our synthesis underscores the importance of considering the effects of climate throughout the life history of any species. Lethal effects (e.g., embryo mortality) are relatively direct impacts, but sublethal effects at immature life-history stages may not alter population growth rates until cohorts reach reproductive maturity. This leaves a lag during which some species transition through several stages subject to distinct biological circumstances and climate impacts. These perspectives will help managers conceptualize the drivers of emergent population dynamics and identify existing knowledge gaps under different scenarios of predicted environmental change.
Journal Article
Change in hydraulic properties of the rhizosphere of maize under different abiotic stresses
Background and aims
Root growth alters the rhizosphere thereby affecting root uptake of water and nutrients. However, the influence of abiotic stress on this process is poorly understood. In this study we investigated the effects of water and salinity stresses (both in isolation and combined) on maize (
Zea mays
L.).
Methods
Seedlings were grown in pots packed with a loamy sand soil for two weeks and then subjected to water and salinity stresses, together with an unstressed control. After an additional two weeks, plants were removed from the pots and the soil aggregates adhering to the roots were collected and scanned using X-ray Computed Tomography. The ability of the aggregates to conduct water was calculated from pore-scale simulation of water flow using the lattice Boltzmann method.
Results
It was found that both water and salinity stresses reduced the permeability of the rhizospheric aggregates, although the reduction under salinity stress was more significant than under water stress. Combining water and salinity stresses reduced the permeability of the rhizosphere by one order in magnitude compared to the unstressed rhizosphere.
Conclusions
Abiotic stresses work with root-induced activity to reshape the rhizosphere. As water and nutrients need to pass through the rhizosphere before being taken up by roots, understanding such rhizosphere changes has an important implication in plant acquisition of soil resources.
Journal Article
CD24 induces changes to the surface receptors of B cell microvesicles with variable effects on their RNA and protein cargo
The CD24 cell surface receptor promotes apoptosis in developing B cells, and we recently found that it induces B cells to release plasma membrane-derived, CD24-bearing microvesicles (MVs). Here we have performed a systematic characterization of B cell MVs released from WEHI-231 B lymphoma cells in response to CD24 stimulation. We found that B cells constitutively release MVs of approximately 120 nm, and that CD24 induces an increase in phosphatidylserine-positive MV release. RNA cargo is predominantly comprised of 5S rRNA, regardless of stimulation; however, CD24 causes a decrease in the incorporation of protein coding transcripts. The MV proteome is enriched with mitochondrial and metabolism-related proteins after CD24 stimulation; however, these changes were variable and could not be fully validated by Western blotting. CD24-bearing MVs carry Siglec-2, CD63, IgM, and, unexpectedly, Ter119, but not Siglec-G or MHC-II despite their presence on the cell surface. CD24 stimulation also induces changes in CD63 and IgM expression on MVs that is not mirrored by the changes in cell surface expression. Overall, the composition of these MVs suggests that they may be involved in releasing mitochondrial components in response to pro-apoptotic stress with changes to the surface receptors potentially altering the cell type(s) that interact with the MVs.
Journal Article