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Journal articleQiao S, Harrison SP, Prentice IC, et al., 2023,
Optimality-based modelling of wheat sowing dates globally
, Agricultural Systems, Vol: 206, Pages: 1-11, ISSN: 0308-521XCONTEXTSowing dates are currently an essential input for crop models. However, in the future, the optimal sowing time will be affected by climate changes and human adaptations to these changes. A better understanding of what determines the choice of wheat type and sowing dates is required to be able to predict future crop yields reliably.OBJECTIVEThis study was conducted to understand how climate conditions affect the choice of wheat types and sowing dates globally.METHODSWe develop a model integrating optimality concepts for simulating gross primary production (GPP) with climate constraints on wheat phenology to predict sowing dates. We assume that wheat could be sown at any time with suitable climate conditions and farmers would select a sowing date that maximises yields. The model is run starting on every possible climatically suitable day, determined by climate constraints associated with low temperature and intense precipitation. The optimal sowing date is the day which gives the highest yield in each location. We evaluate the simulated optimal sowing dates with data on observed sowing dates created by merging census-based datasets and local agronomic information, then predict their changes under future climate scenarios to gain insight into the impacts of climate change.RESULTS AND CONCLUSIONSCold-season temperatures are the major determinant of sowing dates in the extra-tropics, whereas the seasonal cycle of monsoon rainfall is important in the tropics. Our model captures the timing of reported sowing dates, with differences of less than one month over much of the world; maximum errors of up to two months occur in tropical regions with large altitudinal gradients. Discrepancies between predictions and observations are larger in tropical regions than temperate and cold regions. Slight warming is shown to promote earlier sowing in wet areas but later in dry areas; larger warming leads to delayed sowing in most regions. These predictions arise due to the interac
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Journal articleCampana SE, Smolinski S, Black BA, et al., 2023,
Growth portfolios buffer climate-linked environmental change in marine systems
, ECOLOGY, Vol: 104, ISSN: 0012-9658- Author Web Link
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- Citations: 1
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Journal articleKotidis P, Donini R, Arnsdorf J, et al., 2023,
CHOGlycoNET: comprehensive glycosylation reaction network for CHO cells
, Metabolic Engineering, Vol: 76, Pages: 87-96, ISSN: 1096-7176Chinese hamster ovary (CHO) cells are extensively used for the production of glycoprotein therapeutics proteins, for which N-linked glycans are a critical quality attribute due to their influence on activity and immunogenicity. Manipulation of protein glycosylation is commonly achieved through cell or process engineering, which are often guided by mathematical models. However, each study considers a unique glycosylation reaction network that is tailored around the cell line and product at hand. Herein, we use 200 glycan datasets for both recombinantly produced and native proteins from different CHO cell lines to reconstruct a comprehensive reaction network, CHOGlycoNET, based on the individual minimal reaction networks describing each dataset. CHOGlycoNET is used to investigate the distribution of mannosidase and glycosyltransferase enzymes in the Golgi apparatus and identify key network reactions using machine learning and dimensionality reduction techniques. CHOGlycoNET can be used for accelerating glycomodel development and predicting the effect of glycoengineering strategies. Finally, CHOGlycoNET is wrapped in a SBML file to be used as a standalone model or in combination with CHO cell genome scale models.
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Journal articleGumbs R, Gray C, Böhm M, et al., 2023,
The EDGE2 protocol: advancing the prioritisation of Evolutionarily Distinct and Globally Endangered species for practical conservation action
, PLoS Biology, Vol: 21, Pages: 1-22, ISSN: 1544-9173The conservation of evolutionary history has been linked to increased benefits for humanity and can be captured by phylogenetic diversity (PD). The Evolutionarily Distinct and Globally Endangered (EDGE) metric has, since 2007, been used to prioritise threatened species for practical conservation that embody large amounts of evolutionary history. While there have been important research advances since 2007, they have not been adopted in practice because of a lack of consensus in the conservation community. Here, building from an interdisciplinary workshop to update the existing EDGE approach, we present an “EDGE2” protocol that draws on a decade of research and innovation to develop an improved, consistent methodology for prioritising species conservation efforts. Key advances include methods for dealing with uncertainty and accounting for the extinction risk of closely related species. We describe EDGE2 in terms of distinct components to facilitate future revisions to its constituent parts without needing to reconsider the whole. We illustrate EDGE2 by applying it to the world’s mammals. As we approach a crossroads for global biodiversity policy, this Consensus View shows how collaboration between academic and applied conservation biologists can guide effective and practical priority-setting to conserve biodiversity.
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Journal articleTravin DYY, Jouan R, Vigouroux A, et al., 2023,
Dual-Uptake Mode of the Antibiotic Phazolicin Prevents Resistance Acquisition by Gram-Negative Bacteria
, MBIO, ISSN: 2150-7511- Author Web Link
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- Citations: 1
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Journal articleChen T, Riaz S, Davey P, et al., 2023,
Producing fast and active Rubisco in tobacco to enhance photosynthesis.
, Plant Cell, Vol: 35, Pages: 795-807Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) performs most of the carbon fixation on Earth. However, plant Rubisco is an intrinsically inefficient enzyme given its low carboxylation rate, representing a major limitation to photosynthesis. Replacing endogenous plant Rubisco with a faster Rubisco is anticipated to enhance crop photosynthesis and productivity. However, the requirement of chaperones for Rubisco expression and assembly has obstructed the efficient production of functional foreign Rubisco in chloroplasts. Here, we report the engineering of a Form 1A Rubisco from the proteobacterium Halothiobacillus neapolitanus in Escherichia coli and tobacco (Nicotiana tabacum) chloroplasts without any cognate chaperones. The native tobacco gene encoding Rubisco large subunit was genetically replaced with H. neapolitanus Rubisco (HnRubisco) large and small subunit genes. We show that HnRubisco subunits can form functional L8S8 hexadecamers in tobacco chloroplasts at high efficiency, accounting for ∼40% of the wild-type tobacco Rubisco content. The chloroplast-expressed HnRubisco displayed a ∼2-fold greater carboxylation rate and supported a similar autotrophic growth rate of transgenic plants to that of wild-type in air supplemented with 1% CO2. This study represents a step toward the engineering of a fast and highly active Rubisco in chloroplasts to improve crop photosynthesis and growth.
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Journal articleBubeck D, Couves E, Gardner S, et al., 2023,
Structural basis for membrane attack complex inhibition by CD59
, Nature Communications, Vol: 14, Pages: 1-13, ISSN: 2041-1723CD59 is an abundant immuno-regulatory receptor that protects human cells from damage during complement activation. Here we show how the receptor binds complement proteins C8 and C9 at the membrane to prevent insertion and polymerization of membrane attack complex (MAC) pores. We present cryo-electron microscopy structures of two inhibited MAC precursors known as C5b8 and C5b9. We discover that in both complexes, CD59 binds the pore-forming β-hairpins of C8 to form an intermolecular β-sheet that prevents membrane perforation. While bound to C8, CD59 deflects the cascading C9 β-hairpins, rerouting their trajectory into the membrane. Preventing insertion of C9 restricts structural transitions of subsequent monomers and indirectly halts MAC polymerization. We combine our structural data with cellular assays and molecular dynamics simulations to explain how the membrane environment impacts the dual roles of CD59 in controlling pore formation of MAC, and as a target of bacterial virulence factors which hijack CD59 to lyse human cells.
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Journal articleGermain RR, Feng S, Buffan L, et al., 2023,
Changes in the functional diversity of modern bird species over the last million years.
, Proc Natl Acad Sci U S A, Vol: 120, Pages: e2201945119-e2201945119Despite evidence of declining biosphere integrity, we currently lack understanding of how the functional diversity associated with changes in abundance among ecological communities has varied over time and before widespread human disturbances. We combine morphological, ecological, and life-history trait data for >260 extant bird species with genomic-based estimates of changing effective population size (Ne) to quantify demographic-based shifts in avian functional diversity over the past million years and under pre-anthropogenic climate warming. We show that functional diversity was relatively stable over this period, but underwent significant changes in some key areas of trait space due to changing species abundances. Our results suggest that patterns of population decline over the Pleistocene have been concentrated in particular regions of trait space associated with extreme reproductive strategies and low dispersal ability, consistent with an overall erosion of functional diversity. Further, species most sensitive to climate warming occupied a relatively narrow region of functional space, indicating that the largest potential population increases and decreases under climate change will occur among species with relatively similar trait sets. Overall, our results identify fluctuations in functional space of extant species over evolutionary timescales and represent the demographic-based vulnerability of different regions of functional space among these taxa. The integration of paleodemographic dynamics with functional trait data enhances our ability to quantify losses of biosphere integrity before anthropogenic disturbances and attribute contemporary biodiversity loss to different drivers over time.
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Journal articlePawar S, 2023,
Another step towards a unifying theory for ecosystems?
, JOURNAL OF BIOSCIENCES, Vol: 48, ISSN: 0250-5991 -
Conference paperHamburg S, Franks K, Rouse SL, 2023,
Impact of bioscience DAOs on research and innovation
, Publisher: CELL PRESS, Pages: 286A-286A, ISSN: 0006-3495 -
Journal articleIbrahim T, Khandare V, Mirkin FG, et al., 2023,
AlphaFold2-multimer guided high-accuracy prediction of typical and atypical ATG8-binding motifs
, PLoS Biology, Vol: 21, Pages: 1-19, ISSN: 1544-9173Macroautophagy/autophagy is an intracellular degradation process central to cellular homeostasis and defense against pathogens in eukaryotic cells. Regulation of autophagy relies on hierarchical binding of autophagy cargo receptors and adaptors to ATG8/LC3 protein family members. Interactions with ATG8/LC3 are typically facilitated by a conserved, short linear sequence, referred to as the ATG8/LC3 interacting motif/region (AIM/LIR), present in autophagy adaptors and receptors as well as pathogen virulence factors targeting host autophagy machinery. Since the canonical AIM/LIR sequence can be found in many proteins, identifying functional AIM/LIR motifs has proven challenging. Here, we show that protein modelling using Alphafold-Multimer (AF2-multimer) identifies both canonical and atypical AIM/LIR motifs with a high level of accuracy. AF2-multimer can be modified to detect additional functional AIM/LIR motifs by using protein sequences with mutations in primary AIM/LIR residues. By combining protein modelling data from AF2-multimer with phylogenetic analysis of protein sequences and protein-protein interaction assays, we demonstrate that AF2-multimer predicts the physiologically relevant AIM motif in the ATG8-interacting protein 2 (ATI-2) as well as the previously uncharacterized noncanonical AIM motif in ATG3 from potato (Solanum tuberosum). AF2-multimer also identified the AIM/LIR motifs in pathogen-encoded virulence factors that target ATG8 members in their plant and human hosts, revealing that cross-kingdom ATG8-LIR/AIM associations can also be predicted by AF2-multimer. We conclude that the AF2-guided discovery of autophagy adaptors/receptors will substantially accelerate our understanding of the molecular basis of autophagy in all biological kingdoms.
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Journal articleBeltran LC, Cvirkaite-Krupovic V, Miller J, et al., 2023,
Archaeal DNA-import apparatus is homologous to bacterial conjugation machinery
, Nature Communications, Vol: 14, ISSN: 2041-1723Conjugation is a major mechanism of horizontal gene transfer promoting the spread of antibiotic resistance among human pathogens. It involves establishing a junction between a donor and a recipient cell via an extracellular appendage known as the mating pilus. In bacteria, the conjugation machinery is encoded by plasmids or transposons and typically mediates the transfer of cognate mobile genetic elements. Much less is known about conjugation in archaea. Here, we determine atomic structures by cryo-electron microscopy of three conjugative pili, two from hyperthermophilic archaea (Aeropyrum pernix and Pyrobaculum calidifontis) and one encoded by the Ti plasmid of the bacterium Agrobacterium tumefaciens, and show that the archaeal pili are homologous to bacterial mating pili. However, the archaeal conjugation machinery, known as Ced, has been 'domesticated', that is, the genes for the conjugation machinery are encoded on the chromosome rather than on mobile genetic elements, and mediates the transfer of cellular DNA.
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Journal articleArce A, Cantwell-Jones A, Tansley M, et al., 2023,
Signatures of increasing environmental stress in bumblebee wings over the past century: Insights from museum specimens
, Journal of Animal Ecology, Vol: 92, Pages: 297-309, ISSN: 0021-87901. Determining when animal populations have experienced stress in the past is fundamental to understanding how risk factors drive contemporary and future species’ responses to environmental change. For insects, quantifying stress and associating it with environmental factors has been challenging due to a paucity of time-series data and because detectable population-level responses can show varying lag effects. One solution is to leverage historic entomological specimens to detect morphological proxies of stress experienced at the time stressors emerged, allowing us to more accurately determine population responses.2. Here we studied specimens of four bumblebee species, an invaluable group of insect pollinators, from five museums collected across Britain over the 20th century. We calculated the degree of fluctuating asymmetry (FA; random deviations from bilateral symmetry) between the right and left forewings as a potential proxy of developmental stress.3. We: i) investigated whether baseline FA levels vary between species, and how this compares between the first and second half of the century; ii) determined the extent of FA change over the century in the four bumblebee species, and whether this followed a linear or non-linear trend; iii) tested which annual climatic conditions correlated with increased FA in bumblebees.4. Species differed in their baseline FA, with FA being higher in the two species that have recently expanded their ranges in Britain. Overall, FA significantly increased over the century but followed a non-linear trend, with the increase starting c. 1925. We found relatively warm and wet years were associated with higher FA. 5. Collectively our findings show that FA in bumblebees increased over the 20th century and under weather conditions that will likely increase in frequency with climate change. By plotting FA trends and quantifying the contribution of annual climate conditions on past populations, we provide an important step towards impro
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Journal articleRansome E, Hobbs F, Jones S, et al., 2023,
Evaluating the transmission risk of SARS-CoV-2 from sewage pollution
, Science of the Total Environment, Vol: 858, Pages: 1-8, ISSN: 0048-9697The presence of SARS-CoV-2 in untreated sewage has been confirmed in many countries but its incidence and infection risk in contaminated waters is poorly understood. The River Thames in the UK receives untreated sewage from 57 Combined Sewer Overflows (CSOs), with many discharging dozens of times per year. This study investigated if such discharges provide a pathway for environmental transmission of SARS-CoV-2. Samples of wastewater, surface water, and sediment collected close to six CSOs on the River Thames were assayed over eight months for SARS-CoV-2 RNA and infectious virus. Bivalves were also sampled as an indicator species of viral bioaccumulation. Sediment and water samples from the Danube and Sava rivers in Serbia, where raw sewage is also discharged in high volumes, were assayed as a positive control. No evidence of SARS-CoV-2 RNA or infectious virus was found in UK samples, in contrast to RNA positive samples from Serbia. Furthermore, this study shows that infectious SARS-CoV-2 inoculum is stable in Thames water and sediment for <3 days, while SARS-CoV-2 RNA is detectable for at least seven days. This indicates that dilution of wastewater likely limits environmental transmission, and that detection of viral RNA alone is not an indication of pathogen spillover.
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Journal articleMullin VE, Stephen W, Arce AN, et al., 2023,
First large-scale quantification study of DNA preservation in insects from natural history collections using genome-wide sequencing
, Methods in Ecology and Evolution, Vol: 14, Pages: 360-371, ISSN: 2041-210X1. Insect declines are a global issue with significant ecological and economic ramifications. Yet we have a poor understanding of the genomic impact these losses can have. Genome-wide data from historical specimens has the potential to provide baselines of population genetic measures to study population change, with natural history collections representing large repositories of such specimens. However, an initial challenge in conducting historical DNA data analyses, is to understand how molecular preservation varies between specimens.2. Here, we highlight how Next Generation Sequencing methods developed for studying archaeological samples can be applied to determine DNA preservation from only a single leg taken from entomological museum specimens, some of which are more than a century old. An analysis of genome-wide data from a set of 113 red-tailed bumblebee (Bombus lapidarius) specimens, from five British museum collections, was used to quantify DNA preservation over time. Additionally, to improve our analysis and further enable future research we generated a novel assembly of the red-tailed bumblebee genome. 3. Our approach shows that museum entomological specimens are comprised of short DNA fragments with mean lengths below 100 base pairs (BP), suggesting a rapid and large-scale post-mortem reduction in DNA fragment size. After this initial decline, however, we find a relatively consistent rate of DNA decay in our dataset, and estimate a mean reduction in fragment length of 1.9bp per decade. The proportion of quality filtered reads mapping to our assembled reference genome was around 50%, and decreased by 1.1 % per decade. 4. We demonstrate that historical insects have significant potential to act as sources of DNA to create valuable genetic baselines. The relatively consistent rate of DNA degradation, both across collections and through time, mean that population level analyses - for example for conservation or evolutionary studies - are entirely feasible, a
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Journal articleWesterband AC, Wright IJ, Maire V, et al., 2023,
Coordination of photosynthetic traits across soil and climate gradients
, Global Change Biology, Vol: 29, Pages: 856-873, ISSN: 1354-1013"Least-cost theory" posits that C3 plants should balance rates of photosynthetic water loss and carboxylation in relation to the relative acquisition and maintenance costs of resources required for these activities. Here we investigated the dependency of photosynthetic traits on climate and soil properties using a new Australia-wide trait dataset spanning 528 species from 67 sites. We tested the hypotheses that plants on relatively cold or dry sites, or on relatively more fertile sites, would typically operate at greater CO2 drawdown (lower ratio of leaf internal to ambient CO2 , Ci :Ca ) during light-saturated photosynthesis, and at higher leaf N per area (Narea ) and higher carboxylation capacity (Vcmax 25 ) for a given rate of stomatal conductance to water vapour, gsw . These results would be indicative of plants having relatively higher water costs than nutrient costs. In general, our hypotheses were supported. Soil total phosphorus (P) concentration and (more weakly) soil pH exerted positive effects on the Narea -gsw and Vcmax 25 -gsw slopes, and negative effects on Ci :Ca . The P effect strengthened when the effect of climate was removed via partial regression. We observed similar trends with increasing soil cation exchange capacity and clay content, which affect soil nutrient availability, and found that soil properties explained similar amounts of variation in the focal traits as climate did. Although climate typically explained more trait variation than soil did, together they explained up to 52% of variation in the slope relationships and soil properties explained up to 30% of the variation in individual traits. Soils influenced photosynthetic traits as well as their coordination. In particular, the influence of soil P likely reflects the Australia's geologically ancient low-relief landscapes with highly leached soils. Least-cost theory provides a valuable framework for understanding trade-offs between resource costs and use in plants, including
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Journal articleBloomfield KJ, Stocker BD, Keenan TF, et al., 2023,
Environmental controls on the light use efficiency of terrestrial gross primary production
, Global Change Biology, Vol: 29, Pages: 1037-1053, ISSN: 1354-1013Gross primary production (GPP) by terrestrial ecosystems is a key quantity in the global carbon cycle. The instantaneous controls of leaf-level photosynthesis are well established, but there is still no consensus on the mechanisms by which canopy-level GPP depends on spatial and temporal variation in the environment. The standard model of photosynthesis provides a robust mechanistic representation for C3 species; however, additional assumptions are required to “scale up” from leaf to canopy. As a consequence, competing models make inconsistent predictions about how GPP will respond to continuing environmental change. This problem is addressed here by means of an empirical analysis of the light use efficiency (LUE) of GPP inferred from eddy covariance carbon dioxide flux measurements, in situ measurements of photosynthetically active radiation (PAR), and remotely sensed estimates of the fraction of PAR (fAPAR) absorbed by the vegetation canopy. Focusing on LUE allows potential drivers of GPP to be separated from its overriding dependence on light. GPP data from over 100 sites, collated over 20 years and located in a range of biomes and climate zones, were extracted from the FLUXNET2015 database and combined with remotely sensed fAPAR data to estimate daily LUE. Daytime air temperature, vapor pressure deficit, diffuse fraction of solar radiation, and soil moisture were shown to be salient predictors of LUE in a generalized linear mixed-effects model. The same model design was fitted to site-based LUE estimates generated by 16 terrestrial ecosystem models. The published models showed wide variation in the shape, the strength, and even the sign of the environmental effects on modeled LUE. These findings highlight important model deficiencies and suggest a need to progress beyond simple “goodness of fit” comparisons of inferred and predicted carbon fluxes toward an approach focused on the functional responses of the underlying dependencies.
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Journal articleGarcia FC, Clegg T, O'Neill DB, et al., 2023,
The temperature dependence of microbial community respiration is amplified by changes in species interactions
, NATURE MICROBIOLOGY, Vol: 8, Pages: 272-283, ISSN: 2058-5276- Author Web Link
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- Citations: 3
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Journal articleBrazeau MDD, Yuan H, Giles S, et al., 2023,
A well-preserved 'placoderm' (stem-group Gnathostomata) upper jaw from the Early Devonian of Mongolia clarifies jaw evolution
, Royal Society Open Science, Vol: 10, ISSN: 2054-5703The origin of jaws and teeth remains contentious in vertebrate evolution. ‘Placoderms’ (Silurian-Devonian armoured jawed fishes) are central to debates on the origins of these anatomical structures. ‘Acanthothoracids’ are generally considered the most primitive ‘placoderms’. However, they are so far known mainly from disarticulated skeletal elements that are typically incomplete. The structure of the jaws—particularly the jaw hinge—is poorly known, leaving open questions about their jaw function and comparison with other placoderms and modern gnathostomes. Here we describe a near-complete ‘acanthothoracid’ upper jaw, allowing us to reconstruct the likely orientation and angle of the bite and compare its morphology with that of other known ‘placoderm’ groups. We clarify that the bite position is located on the upper jaw cartilage rather than on the dermal cheek and thus show that there is a highly conserved bite morphology among most groups of ‘placoderms’, regardless of their overall cranial geometry. Incorporation of the dermal skeleton appears to provide a sound biomechanical basis for jaw origins. It appears that ‘acanthothoracid’ dentitions were fundamentally similar in location to that of arthrodire ‘placoderms’, rather than resembling bony fishes. Irrespective of current phylogenetic uncertainty, the new data here resolve the likely general condition for ‘placoderms’ as a whole, and as such, ancestral morphology of known jawed vertebrates.
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Journal articleRasmussen HO, Kumar A, Shin B, et al., 2023,
FapA is an Intrinsically Disordered Chaperone for<i> Pseudomonas</i> Functional Amyloid FapC
, JOURNAL OF MOLECULAR BIOLOGY, Vol: 435, ISSN: 0022-2836- Author Web Link
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- Citations: 4
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Journal articleYamamoto H, Cheuk A, Shearman J, et al., 2023,
Impact of engineering the ATP synthase rotor ring on photosynthesis in tobacco chloroplasts
, Plant Physiology, ISSN: 0032-0889 -
Journal articleQureshi A, Keen E, Brown G, et al., 2023,
The size of larval rearing container modulates the effects of diet amount and larval density on larval development in Aedes aegypti
, PLoS One, Vol: 18, Pages: 1-18, ISSN: 1932-6203Mass-rearing of mosquitoes under laboratory conditions is an important part of several new control techniques that rely on the release of males to control mosquito populations. While previous work has investigated the effect of larval density and diet amount on colony productivity, the role of the size of the container in which larval development takes place has been relatively ignored. We investigated the role of container size in shaping life history and how this varied with density and food availability in Aedes aegypti, an important disease vector and target of mass-rearing operations. For each treatment combination, immature development time and survival and adult body size and fecundity were measured, and then combined into a measure of productivity. We additionally investigated how larval aggregation behaviour varied with container size. Container size had important effects on life history traits and overall productivity. In particular, increasing container size intensified density and diet effects on immature development time. Productivity was also impacted by container size when larvae were reared at high densities (1.4 larva/ml). In these treatments, the productivity metric of large containers was estimated to be significantly lower than medium or small containers. Regardless of container size, larvae were more likely to be observed at the outer edges of containers, even when this led to extremely high localized densities. We discuss how container size and larval aggregation responses may alter the balance of energy input and output to shape development and productivity.
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Journal articlePennica C, Hanna G, Islam SA, et al., 2023,
A new web resource to predict the impact of missense variants at protein interfaces using 3D structural data: Missense3D-PPI
<jats:title>ABSTRACT</jats:title><jats:p>In 2019, we released Missense3D which identifies stereochemical features that are disrupted by a missense variant, such as introducing a buried charge. Missense3D analyses the effect of a missense variant on a single structure and thus may fail to identify as damaging surface variants disrupting a protein interface i.e., a protein-protein interaction (PPI) site. Here we present Missense3D-PPI designed to predict missense variants at PPI interfaces.</jats:p><jats:p>Our development dataset comprised of 1,279 missense variants (pathogenic n=733, benign n=546) in 434 proteins and 545 experimental structures of PPI complexes. Benchmarking of Missense3D-PPI was performed after dividing the dataset in training (320 benign and 320 pathogenic variants) and testing (226 benign and 413 pathogenic). Structural features affecting PPI, such as disruption of interchain bonds and introduction of unbalanced charged interface residues, were analysed to assess the impact of the variant at PPI.</jats:p><jats:p>Missense3D-PPI’s performance was superior to that of Missense3D: sensitivity 42% versus 8% and accuracy 58% versus 40%, p=4.23×10<jats:sup>−16</jats:sup>However, the specificity of Missense3D-PPI was slightly lower compared to Missense3D (84% versus 98%). On our dataset, Missense3D-PPI’s accuracy was superior to BeAtMuSiC (p=2.3×10<jats:sup>−5</jats:sup>), mCSM-PPI2 (p=3.2×10<jats:sup>−12</jats:sup>) and MutaBind2 (p=0.003).</jats:p><jats:p>Missense3D-PPI represents a valuable tool for predicting the structural effect of missense variants on biological protein networks and is available at the Missense3D web portal (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://missense3d.bc.ic.ac.uk/missense3d/indexppi.html">http://mis
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Journal articleYung HW, Zhao X, Glover L, et al., 2023,
Perturbation of placental protein glycosylation by endoplasmic reticulum stress promotes maladaptation of maternal hepatic glucose metabolism
, iScience, Vol: 26, ISSN: 2589-0042Placental hormones orchestrate maternal metabolic adaptations to support pregnancy. We hypothesized that placental ER stress, which characterizes early-onset pre-eclampsia (ePE), compromises glycosylation, reducing hormone bioactivity and these maladaptations predispose the mother to metabolic disease in later life. We demonstrate ER stress reduces the complexity and sialylation of trophoblast protein N-glycosylation, while aberrant glycosylation of vascular endothelial growth factor reduced its bioactivity. ER stress alters the expression of 66 of the 146 genes annotated with “protein glycosylation” and reduces the expression of sialyltransferases. Using mouse placental explants, we show ER stress promotes the secretion of mis-glycosylated glycoproteins. Pregnant mice carrying placentas with junctional zone-specific ER stress have reduced blood glucose, anomalous hepatic glucose metabolism, increased cellular stress and elevated DNA methyltransferase 3A. Using pregnancy-specific glycoproteins as a readout, we also demonstrate aberrant glycosylation of placental proteins in women with ePE, thus providing a mechanistic link between ePE and subsequent maternal metabolic disorders.
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Journal articleSugihara Y, Abe Y, Takagi H, et al., 2023,
Disentangling the complex gene interaction networks between rice and the blast fungus identifies a new pathogen effector
, PLoS Biology, Vol: 21, ISSN: 1544-9173Studies focused solely on single organisms can fail to identify the networks underlying host-pathogen gene-for-gene interactions. Here, we integrate genetic analyses of rice (Oryza sativa, host) and rice blast fungus (Magnaporthe oryzae, pathogen) and uncover a new pathogen recognition specificity of the rice nucleotide-binding domain and leucine-rich repeat protein (NLR) immune receptor Pik, which mediates resistance to M. oryzae expressing the avirulence effector gene AVR-Pik. Rice Piks-1, encoded by an allele of Pik-1, recognizes a previously unidentified effector encoded by the M. oryzae avirulence gene AVR-Mgk1, which is found on a mini-chromosome. AVR-Mgk1 has no sequence similarity to known AVR-Pik effectors and is prone to deletion from the mini-chromosome mediated by repeated Inago2 retrotransposon sequences. AVR-Mgk1 is detected by Piks-1 and by other Pik-1 alleles known to recognize AVR-Pik effectors; recognition is mediated by AVR-Mgk1 binding to the integrated heavy metal-associated (HMA) domain of Piks-1 and other Pik-1 alleles. Our findings highlight how complex gene-for-gene interaction networks can be disentangled by applying forward genetics approaches simultaneously to the host and pathogen. We demonstrate dynamic coevolution between an NLR integrated domain and multiple families of effector proteins.
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Journal articleShen DY, Ferguson-Gow H, Groner V, et al., 2023,
Potential decline in the distribution and food provisioning services of the mopane worm (Gonimbrasia belina) in southern Africa
, Frontiers of Biogeography, Vol: 15, Pages: 1-15, ISSN: 1948-6596The mopane worm (Gonimbrasia belina) is an edible insect distributed across southern Africa. As a culturally important source of food, the mopane worm provides nutrition, livelihoods and improves wellbeing for rural communities across its range. However, this is strong evidence that insect populations are declining worldwide, and climate change is likely to cause many insect species to shift in their distributions. For these reasons, we aimed to model how the ecosystem service benefits of the mopane worm are likely to change in the coming decades. We modelled the distribution of the mopane worm under two contrasting climate change scenarios (RCPs 4.5 and 8.5). Moreover, given that the mopane worm shows strong interactions with other species, particularly trees, we incorporated biotic interactions in our models using a Bayesian network. Our models project significant contraction across the species’ range, with up to 70% decline in habitat by the 2080s. Botswana and Zimbabwe are predicted to be the most severely impacted countries, with almost all habitat in Botswana and Zimbabwe modelled to be lost by the 2080s. Decline of mopane worm habitat would likely have negative implications for the health of people in rural communities due to loss of an important source of protein as well as household income provided by their harvest. Biogeographic shifts therefore have potential to exacerbate food insecurity, socio-economic inequalities, and gender imbalance (women are the main harvesters), with cascading effects that most negatively impact poor rural communities dependent on natural resource
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Journal articleMills MB, Malhi Y, Ewers RM, et al., 2023,
Tropical forests post-logging are a persistent net carbon source to the atmosphere.
, Proceedings of the National Academy of Sciences of USA, Vol: 120, Pages: 1-7, ISSN: 0027-8424Logged and structurally degraded tropical forests are fast becoming one of the most prevalent land-use types throughout the tropics and are routinely assumed to be a net carbon sink because they experience rapid rates of tree regrowth. Yet this assumption is based on forest biomass inventories that record carbon stock recovery but fail to account for the simultaneous losses of carbon from soil and necromass. Here, we used forest plots and an eddy covariance tower to quantify and partition net ecosystem CO2 exchange in Malaysian Borneo, a region that is a hot spot for deforestation and forest degradation. Our data represent the complete carbon budget for tropical forests measured throughout a logging event and subsequent recovery and found that they constitute a substantial and persistent net carbon source. Consistent with existing literature, our study showed a significantly greater woody biomass gain across moderately and heavily logged forests compared with unlogged forests, but this was counteracted by much larger carbon losses from soil organic matter and deadwood in logged forests. We estimate an average carbon source of 1.75 ± 0.94 Mg C ha-1 yr-1 within moderately logged plots and 5.23 ± 1.23 Mg C ha-1 yr-1 in unsustainably logged and severely degraded plots, with emissions continuing at these rates for at least one-decade post-logging. Our data directly contradict the default assumption that recovering logged and degraded tropical forests are net carbon sinks, implying the amount of carbon being sequestered across the world's tropical forests may be considerably lower than currently estimated.
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Journal articleHanna G, Khanna T, Islam S, et al., 2023,
Missense3D-TM: predicting the effect of missense variants in helical transmembrane protein regions using 3D protein structures
, Journal of Molecular Biology, Vol: 436, ISSN: 0022-2836Variant effect predictors assess if a substitution is pathogenic or benign. Most predictors, including those that are structure-based, are designed for globular proteins in aqueous environments and do not consider that the variant residue is located within the membrane. We report Missense3D-TM that provides a structure-based assessment of the impact of a missense variant located within a membrane. On a dataset of 2,078 pathogenic and 1,060 benign variants, spanning 711 proteins from 706 structures, Missense3D-TM achieved an accuracy of 66%, Mathews correlation coefficient of 0.37, sensitivity of 58% and specificity of 81%. Missense3D-TM performed similarly to mCSM-membrane: accuracy 66% vs 61% (p=0.02) on an unbalanced test set and 70% vs 67% (p=0.20) on a balanced test set. The Missense3D-TM website provides an analysis of the structural effects of the variant along with its predicted position within the membrane. The web server is available at http://missense3d.bc.ic.ac.uk/.
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Journal articleCopland A, Mackie GM, Scarfe L, et al., 2023,
<i>Salmonella</i>cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity
<jats:title>Summary</jats:title><jats:p>Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours.<jats:italic>Salmonella enterica</jats:italic>Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) reporter mice (<jats:italic>Nr4a3-Tocky-Ifng-YFP</jats:italic>) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic TILs exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced T<jats:sub>CM</jats:sub>formation. Modelling of T-cell–tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase<jats:italic>ansB</jats:italic>reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.</jats:p>
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Journal articleLucaci D, Yu X, Chadderton P, et al., 2023,
Histamine release in the prefrontal cortex excites fast-spiking interneurons while GABA released from the same axons inhibits pyramidal cells
, The Journal of Neuroscience, Vol: 43, Pages: 187-198, ISSN: 0270-6474We studied how histamine and GABA release from axons originating from the hypothalamic tuberomammillary nucleus (TMN) and projecting to the prefrontal cortex (PFC) influence circuit processing. We optostimulated histamine/GABA from genetically defined TMN axons that express the histidine decarboxylase gene (TMNHDC axons). Whole-cell recordings from PFC neurons in layer 2/3 of prelimbic, anterior cingulate, and infralimbic regions were used to monitor excitability before and after optostimulated histamine/GABA release in male and female mice. We found that histamine-GABA release influences the PFC through actions on distinct neuronal types: the histamine stimulates fast-spiking interneurons; and the released GABA enhances tonic (extrasynaptic) inhibition on pyramidal cells (PyrNs). For fast-spiking nonaccommodating interneurons, histamine released from TMNHDC axons induced additive gain changes, which were blocked by histamine H1 and H2 receptor antagonists. The excitability of other fast-spiking interneurons in the PFC was not altered. In contrast, the GABA released from TMNHDC axons predominantly produced divisive gain changes in PyrNs, increasing their resting input conductance, and decreasing the slope of the input–output relationship. This inhibitory effect on PyrNs was not blocked by histamine receptor antagonists but was blocked by GABAA receptor antagonists. Across the adult life span (from 3 to 18 months of age), the GABA released from TMNHDC axons in the PFC inhibited PyrN excitability significantly more in older mice. For individuals who maintain cognitive performance into later life, the increases in TMNHDC GABA modulation of PyrNs during aging could enhance information processing and be an adaptive mechanism to buttress cognition.
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