Biology subjects

Collins, S.

Publications and source records attributed to Collins, S..

49 records · Page 3Linked to original sources

bioRxiv2021

PDE9 Inhibition Activates PPARa to Stimulate Mitochondrial Fat Metabolism and Reduce Cardiometabolic Syndrome

Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show inhibiting cyclic-GMP selective phosphodiesterase-9A (PDE9-I) suppresses established diet-induced obesity and CMS in ovariectomized female and male mice. PDE9-I reduces abdominal, hepatic, and myocardial fat accumulation, stimulates mitochondrial activity in brown and white fat, and improves CMS, without altering activity or food intake. PDE9 localizes to mitochondria, and its inhibition stimulates lipolysis and mitochondrial respiration coupled to PPAR-dependent gene regulation. PPAR upregulation is required for PDE9-I metabolic efficacy and is absent in non-ovariectomized females that also display no metabolic benefits from PDE9-I. The latter is compatible with estrogen receptor- altering PPAR chromatin binding identified by ChIPSeq. In humans with heart failure and preserved ejection fraction, myocardial expression of PPARA and its regulated genes is reduced versus control. These findings support testing PDE9-I to treat obesity/CMS in men and postmenopausal women. SummaryOral inhibition of phosphodiesterase type 9 stimulates mitochondrial fat metabolism and lipolysis, reducing central obesity without changing appetite

physiology↗

bioRxiv2020

The role of changes in environmental quality in multitrait plastic responses to environmental and social change in the model microalga Chlamydomonas reinhardtii.

Intraspecific variation plays a key role in species responses to environmental change; however, little is known about the role of changes in environmental quality (the population growth rate an environment supports) on intraspecific trait variation. Here, we hypothesize that intraspecific trait variation will be higher in ameliorated environments than in degraded ones. We first measure the range of multitrait phenotypes over a range of environmental qualities for three strains and two evolutionary histories of Chlamydomonas reinhardtii in laboratory conditions. We then explore how environmental quality and trait variation affect the predictability of lineage frequencies when lineage pairs are grown in indirect co-culture. Our results show that environmental quality has the potential to affect intraspecific variability both in terms of the variation in expressed trait values, and in terms of the genotype composition of rapidly growing populations. We found low phenotypic variability in degraded or same-quality environments and high phenotypic variability in ameliorated conditions. This variation can affect population composition, as monoculture growth rate is a less reliable predictor of lineage frequencies in ameliorated environments. Our study highlights that understanding whether populations experience environmental change as an increase or a decrease in quality relative to their recent history affects the changes in trait variation during plastic responses, including growth responses to the presence of conspecifics. This points towards a fundamental role for changes in overall environmental quality in driving phenotypic variation within closely-related populations, with implications for microevolution.

evolutionary biology↗

bioRxiv2020

Surviving heatwaves: thermal experience predicts life and death in a Southern Ocean diatom

Extreme environmental fluctuations such as marine heatwaves (MHWs) can have devastating effects on ecosystem health and functioning through rapid population declines and destabilisation of trophic interactions. However, recent studies have highlighted that population tolerance to MHWs is variable, with some populations even benefitting from MHWs. A number of factors can explain variation in responses between populations including their genetic variation, previous thermal experience and the intensity and duration of the heatwave itself. We disentangle the contributions of these factors on population survival and post-heatwave growth rates by experimentally simulating heatwaves (7.5 or 9.2 {degrees}C, for up to nine days) for three genotypes of the Southern Ocean diatom Actinocyclus actinochilus. The effects of simulated heatwaves on mortality and population growth varied with both genotype and thermal experience. Firstly, hotter and longer heatwaves increased mortality and decreased post-heatwave growth rates relative to milder, shorter heatwaves. Secondly, growth above the thermal optimum before heatwaves exacerbated heatwave-associated negative effects, leading to higher mortality during heatwaves and slower growth after heatwaves. Thirdly, hotter and longer heatwaves resulted in more pronounced changes to thermal optima (Topt) immediately following heatwaves. Finally, there is substantial intraspecific variation in mortality during heatwaves and in post-heatwave growth. Our findings shed light on the potential of Southern Ocean diatoms to tolerate MHWs, which will increase both in frequency and in intensity under future climate change.

ecology↗

bioRxiv2020

Evolving trait correlations underlie multi-trait adaptation in a eukaryotic alga

Microbes form the base of food webs and drive biogeochemical cycling. Predicting the effects of microbial evolution on global elemental cycles remains a significant challenge due to the sheer number of interacting environmental and trait combinations. Here we present an approach for integrating multivariate trait data into a predictive model of trait evolution. We investigated the outcome of thousands of possible adaptive walks parameterized using empirical evolution data from the alga Chlamydomonas exposed to high CO2. We found that the direction of historical bias (existing trait correlations) influenced both the rate of adaptation and the evolved phenotypes (trait combinations). Critically, we use fitness landscapes derived directly from empirical trait values to capture known evolutionary phenomena. This work demonstrates that ecological models need to represent both changes in traits and changes in the correlation between traits in order to accurately capture phytoplankton evolution and predict future shifts in elemental cycling.

microbiology↗

bioRxiv2020

Impairment of the Gβγ-SNAP25 brake on exocytosis enhances insulin action, protects against diet-induced obesity, and promotes adipocyte browning

Negative regulation of exocytosis from secretory cells throughout the body is accomplished through inhibitory signals from Gi/o G protein-coupled receptors by G{beta}{gamma} subunit inhibition of two common mechanisms: (i) decreased calcium entry and (ii) direct interaction of G{beta}{gamma} with the Soluble N-ethylmaleimide-sensitive factor Attachment Protein (SNAP) Receptor (SNARE) plasma membrane fusion machinery. We have previously shown that disabling the second mechanism with a truncation of SNAP25 (SNAP25{Delta}3/{Delta}3) decreases the affinity of G{beta}{gamma} for the SNARE complex, leaving exocytotic fusion as well as modulation of calcium entry intact but disabling GPCR inhibition of exocytosis. Here we report significant beneficial metabolic remodeling in mice carrying this mutation. Chow-fed SNAP25{Delta}3/{Delta}3 mice exhibit enhanced insulin sensitivity and increased beiging of white fat. In response to a high fat diet, the metabolic protection was amplified in SNAP25{Delta}3/{Delta}3 mice. Glucose homeostasis, whole body insulin action, and insulin-mediated glucose uptake into white adipose tissue were improved along with resistance to diet-induced obesity. This metabolic protection in SNAP25{Delta}3/{Delta}3 mice occurred without compromising the physiological response to fasting or cold. All metabolic phenotypes were reversed at thermoneutrality, suggesting basal autonomic activity is required. Direct electrode stimulation of sympathetic neurons exocytosis from SNAP25{Delta}3/{Delta}3 inguinal adipose depot resulted in enhanced and prolonged norepinephrine release. Thus, the G{beta}{gamma}-SNARE interaction represents a cellular mechanism that deserves further exploration as a new avenue for combatting metabolic disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/069138v4_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@2c1fa0org.highwire.dtl.DTLVardef@d076ceorg.highwire.dtl.DTLVardef@27e351org.highwire.dtl.DTLVardef@bce219_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2019

Quality-quantity tradeoffs drive functional trait evolution in a model microalgal climate change winner

Phytoplankton are the unicellular photosynthetic microbes that form the base of aquatic ecosystems, and their responses to global change will impact everything from food web dynamics to global nutrient cycles. Some taxa respond to environmental change by increasing population growth rates in the short-term, and, based on this, are projected to increase in frequency over decades. To gain insight into how functional traits in these projected \"climate change winners\" change over different timescales, we evolved populations of microalgae in ameliorated environments for several hundred generations. While populations initially responded to environmental amelioration by increasing photosynthesis and population growth rates as expected, this response was not sustained. Instead, most populations evolved to allocate a smaller proportion of carbon to growth while increasing their ability to tolerate and metabolise reactive oxygen species (ROS). This diversion of fixed carbon from growth to catabolism underlies a quality-quantity tradeoff in daughter cell production which drives the evolution of population growth rates and of functional traits that underlie the ecological and biogeochemical roles of phytoplankton. There is intraspecific variation in the trait combinations that evolve, but all are consistent with mitigating ROS production and accumulation in ameliorated environments over hundreds of generations. This offers both an evolutionary and a metabolic framework for understanding how functional traits can change in primary producers projected to be \"climate change winners\", and suggests that short-term population booms and associated trait shifts have the potential to be dampened or reversed if environmental amelioration persists.

evolutionary biology↗

bioRxiv2019

Whole-chromosome hitchhiking driven by a male-killing endosymbiont

Neo-sex chromosomes are found in many taxa, but the forces driving their emergence and spread are poorly understood. The female-specific neo-W chromosome of the African monarch (or queen) butterfly Danaus chrysippus presents an intriguing case study because it is restricted to a single contact zone population, involves a putative colour patterning supergene, and co-occurs with infection by the the male-killing endosymbiont Spiroplasma. We investigated the origin and evolution of this system using whole genome sequencing. We first identify the BC supergene, a broad region of suppressed recombination across nearly half a chromosome, which links two colour patterning loci. Association analysis suggests that the genes yellow and arrow in this region control the forewing colour pattern differences between D. chrysippus subspecies. We then show that the same chromosome has recently formed a neo-W that has spread through the contact zone within [~]2200 years. We also assembled the genome of the male-killing Spiroplasma, and find that it shows perfect genealogical congruence with the neo-W, suggesting that the neo-W has hitchhiked to high frequency as the male killer has spread through the population. The complete absence of female crossing-over in the Lepidoptera causes whole-chromosome hitchhiking of a single neo-W haplotype, carrying a single allele of the BC supergene, and dragging multiple non-synonymous mutations to high frequency. This has created a population of infected females that all carry the same recessive colour patterning allele, making the phenotypes of each successive generation highly dependent on uninfected male immigrants. Our findings show how hitchhiking can occur between the unlinked genomes of host and endosymbiont, with dramatic consequences.

evolutionary biology↗

bioRxiv2019

Individual variation of the masticatory system dominates 3D skull shape in the herbivory-adapted marsupial wombats

BackgroundWithin-species skull shape variation of marsupial mammals is widely considered low and strongly size-dependent (allometric), possibly due to developmental constraints arising from the altricial birth of marsupials. However, species whose skulls are impacted by strong muscular stresses - particularly those produced through mastication of tough food items - may not display such intrinsic patterns very clearly because of the known plastic response of bone to muscle activity of the individual. In such cases, shape variation should not be dominated by allometry; ordination of shape in a geometric morphometric context through principal component analysis (PCA) should reveal main variation in areas under masticatory stress (incisor region/zygomatic arches/mandibular ramus); but this main variation should emerge from high individual variability and thus have low eigenvalues.\n\nResultsWe assessed the evidence for high individual variation through 3D geometric morphometric shape analysis of crania and mandibles of thre species of grazing-specialized wombats, whose diet of tough grasses puts considerable strain on their masticatory system. As expected, we found little allometry and low Principal Component 1 (PC1) eigenvalues within crania and mandibles of all three species. Also as expected, the main variation was in the muzzle, zygomatic arches, and masticatory muscle attachments of the mandibular ramus. We then implemented a new test to ask if the landmark variation reflected on PC1 was reflected in individuals with opposite PC1 scores and with opposite shapes in Procrustes space. This showed that correspondence between individual and ordinated shape variation was limited, indicating high levels of individual variability in the masticatory apparatus.\n\nDiscussionOur results are inconsistent with hypotheses that skull shape variation within marsupial species reflects a constraint pattern. Rather, they support suggestions that individual plasticity can be an important determinant of within-species shape variation in marsupials (and possibly other mammals) with high masticatory stresses, making it difficult to understand the degree to which intrinsic constraint act on shape variation at the within-species level. We conclude that studies that link micro- and macroevolutionary patterns of shape variation might benefit from a focus on species with low-impact mastication, such as carnivorous or frugivorous species.

evolutionary biology↗

bioRxiv2019

Diverse strategies link growth rate and competitive ability in phytoplankton responses to changes in CO2 levels

Aquatic microbial primary producers exist in genetically variable populations, but are often studied as single lineages. However, the properties of lineages grown alone often fail to predict the composition of microbial assemblages. We demonstrate that different lineages of a marine picoplankter have unique growth strategies, and that they modulate their lineage growth rate in the presence of other lineages. This explains why growth rates of lineages in isolation do not reliably predict the lineage composition of assemblages. The diversity of growth strategies observed are consistent with lineage-specific energy-allocation that depends on social milieu. Since lineage growth is only one of many traits determining fitness in natural assemblages, we propose that in all but the poorest quality environments where allocating maximum energy to growth is the only viable strategy, we should expect intraspecific variation in growth strategies, with more strategies possible in ameliorated environments, such as high CO2 for many marine picoplankton. This emphasizes the importance of understanding and accounting for basic organismal biology in our models of aquatic primary producers.\n\nData archivingShould this manuscript be accepted, data will be archived at Pangea, and the DOI be included at the end of the article

evolutionary biology↗

bioRxiv2019

Hitting a moving target: Microbial evolutionary strategies in a dynamic ocean

Marine microbes form the base of ocean food webs and drive ocean biogeochemical cycling. Yet little is known about how microbial populations will evolve due to global change-driven shifts in ocean dynamics. Understanding adaptive timescales is critical where long-term trends (e.g. warming) are coupled to shorter-term advection dynamics that move organisms rapidly between ecoregions. Here we investigated the interplay between physical and biological timescales using a model of adaptation and an eddy-resolving ocean circulation climate model. Two criteria ( and {beta}) were identified that relate physical and biological timescales and determine the timing and nature of adaptation. Genetic adaptation was impeded in highly variable regimes (<1) but promoted in more stable environments (>1). An evolutionary trade-off emerged where greater short-term transgenerational effects (low-{beta}-strategy) enabled rapid responses to environmental fluctuations but delayed genetic adaptation, while fewer short-term transgenerational effects (high-{beta}-strategy) allowed faster genetic adaptation but inhibited short-term responses. Our results suggest that organisms with faster growth rates are better positioned to adapt to rapidly changing ocean conditions and that more variable environments will favor a bet-hedging, low-{beta}-strategy. Understanding the relationship between evolutionary and physical timescales is critical for robust predictions of future microbial dynamics.

evolutionary biology↗

bioRxiv2018

Connecting the legs with a spring improves human running economy

Spring-like tissues attached to the swinging legs of animals are thought to improve running economy by simply reducing the effort of leg swing. Here we show that a spring, or exotendon, connecting the legs of a human runner improves economy instead through a more complex mechanism that produces savings during both swing and stance. The spring increases the energy optimal stride frequency; when runners adopt this new gait pattern, savings occur in both phases of gait. Remarkably, the simple device improves running economy by 6.4 {+/-} 2.8%, comparable to savings achieved by motorized assistive robotics that directly target the costlier stance phase of gait. Our results highlight the importance of considering both the dynamics of the body and the adaptive strategies of the user when designing systems that couple human and machine.

physiology↗

bioRxiv2018

HDAC11 Suppresses the Thermogenic Program of Adipose Tissue via BRD2

Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit dramatically enhanced thermogenic potential and, in response to high fat feeding, attenuated obesity, insulin resistance, and hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to {beta}-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone binding protein. These findings define a novel epigenetic pathway for the regulation of energy homeostasis, and suggest potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.

molecular biology↗

bioRxiv2017

A map of gene expression in neutrophil-like cell lines

BackgroundHuman neutrophils are central players in innate immunity, a major component of inflammatory responses, and a leading model for cell motility and chemotaxis. However, primary neutrophils are remarkably short-lived, limiting their experimental usefulness in the laboratory. Thus, human myeloid cell lines have been established and characterized for their ability to undergo neutrophil-like differentiation in vitro. The HL-60 cell line and its PLB-985 sub-line are commonly used as a model for human neutrophil behavior, but how closely gene expression in differentiated cells resembles that of primary neutrophils has remained unclear.\n\nResultsIn the present study, we compared the effectiveness of differentiation protocols and used RNA sequencing (RNA-seq) to compare the transcriptomes of HL-60 and PLB-985 cells with published data for human and mouse primary neutrophils. Among commonly used differentiation protocols for neutrophil like cell lines, addition of dimethyl sulfoxide (DMSO) gave the best combination of cell viability and expression of markers for differentiation. However, combining DMSO with the serum-free-supplement Nutridoma resulted in an increased chemotactic response and cell surface expression of the neutrophil markers FPR1 and CD11b without a cost in viability. RNA-seq analysis of HL-60 and PLB-985 cells before and after differentiation showed that differentiation broadly increases the similarity in gene expression between the cell lines and primary neutrophils. Furthermore, the gene expression pattern of the differentiated cell lines correlated slightly better with that of human neutrophils than the mouse neutrophil pattern did. Finally, we created a publicly available gene expression database that is searchable by gene name and by protein domain content, where users can compare gene expression in HL-60, PLB-985 and primary human and mouse neutrophils.\n\nConclusionsOur study verifies that a DMSO-based differentiation protocol for HL-60 and PLB-985 cell lines gives superior differentiation and cell viability relative to other common protocols, and indicates that addition of Nutridoma may be preferable for studies of chemotaxis. Our neutrophil gene expression database will be a valuable tool to identify similarities and differences in gene expression between the cell lines and primary neutrophils, to compare expression levels for genes of interest, and to improve the design of tools for genetic perturbations.

genomics↗