Biology subjects

Graham, C. H.

Publications and source records attributed to Graham, C. H..

12 recordsLinked to original sources

bioRxiv2026

Failure of Bacillus Calmette-Guerin Therapy in Patients with Bladder Cancer is Characterized by Immune Dysfunction Associated with Activator Protein 1

The standard-of-care for patients with higher-risk non-muscle invasive bladder cancer (NMIBC) after tumour resection is intravesical administration of Bacillus Calmette-Guerin (BCG). While this form of adjuvant immunotherapy has improved recurrence-free and progression-free survival, a large proportion of patients experience recurrences within a year of diagnosis. The reasons for this high rate of early recurrence following BCG therapy remain unclear; however, inadequate activation of systemic immunity may be a contributing factor. To address this, we analysed the transcriptomic and chromatin accessibility profiles of peripheral blood mononuclear cells obtained from patients with NMIBC at single-cell resolution before BCG immunotherapy and after five induction doses of BCG. Monocytes from patients who experienced disease recurrence within a year of initiation of BCG therapy (BCG non-responders) exhibited a pro-inflammatory phenotype consistent with age-related immunosenescence prior to BCG immunotherapy. Moreover, inflammation-associated pathways that were active before initiation of BCG therapy in the BCG non-responders were down-regulated after five instillations of BCG. In contrast, these pathways were quiescent before BCG therapy in patients who remained disease-free for at least a year but were markedly up-regulated after five doses of BCG. Genomic regions with accessible chromatin were enriched in activator protein 1 (AP-1) binding sequences in monocytes from BCG-non-responders prior to BCG therapy. AP-1 is a central regulator of the inflammatory phenotype associated with immunosenescence. Our findings indicate that a pre-existing state of innate immunosenescence underlies early disease recurrence following BCG. Patients unlikely to benefit from BCG may be offered alternative therapies early in their disease journey. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/723215v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@55b065org.highwire.dtl.DTLVardef@1afcea6org.highwire.dtl.DTLVardef@12833baorg.highwire.dtl.DTLVardef@5c22fc_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Differential effects of BCG-Russia and BCG-TICE on trained immunity: potential implications for bladder cancer immunotherapy

In recent years, immunotherapy of patients with higher-risk non-muscle invasive bladder cancer (NMIBC) in North America has relied on the use of the TICE strain of BCG. However, limitations in the supply chain have warranted investigation of the therapeutic benefit of other strains of BCG, such as BCG-Russia. Trained immunity, a form of innate immune memory, is now widely believed to be an important component of the therapeutic benefit of BCG. Therefore, in the present study we compared the effects of BCG-TICE and BCG-Russia on the acquisition of trained immunity and related secondary immune responses. C57BL/6 mice received a single intravenous injection of BCG-Russia or BCG-TICE. Four weeks later, bone marrow was collected for flow cytometric analysis of hematopoietic stem and progenitor cell (HSPC) populations, generation of bone marrow-derived macrophages, functional assessment of trained immunity, and transcriptomic profiling. Compared with BCG-Russia, BCG-TICE elicited stronger levels of trained immunity, characterized by higher production of several proinflammatory cytokines upon secondary activation. BCG promoted the expansion of HSPCs independent of strain. BCG-TICE was linked to upregulation of key inflammation-related genes and enrichment of functionally relevant pathways. The results of this study reveal strain-dependent differences in the ability of BCG to induce innate immune memory and inflammatory pathways that could ultimately determine efficacy of immunotherapy of patients with NMIBC.

immunology↗

bioRxiv2024

A probabilistic view of forbidden links: their prevalence and their consequences for the robustness of mutualistic networks

The presence in ecological communities of unfeasible species interactions, termed forbidden links, due to physiological or morphological exploitation barriers has been long debated, but little direct evidence has been found. Forbidden links are likely to make ecological communities less robust to species extinctions, stressing the need to assess their prevalence. Here, we used a dataset of plant-hummingbird interactions, coupled with a Bayesian hierarchical model, to assess the importance of exploitation barriers in determining species interactions. We found evidence for exploitation barriers between flowers and hummingbirds across the 32 studied communities, however, the proportion of forbidden links changed drastically among communities, because of changes in trait distributions. The higher the proportion of forbidden links, the more they decreased network robustness, because of constraints on interaction rewiring. Our results suggest that exploitation barriers are not rare in plant-hummingbird communities and have the potential to limit the rescue of species experiencing partner extinction.

ecology↗

bioRxiv2023

When cheating turns into a stabilizing mechanism of mutualistic networks

Mutualistic interactions, such as plant-mycorrhizal or plant-pollinator interactions, are widespread in ecological communities and frequently exploited by cheaters, species that profit from interactions without providing benefits in return. Cheating usually negatively affects the fitness of the individuals that are cheated on, but the effects of cheating at the community level remains poorly understood. Here we describe two different kinds of cheating in mutualistic networks and use a generalized Lotka-Volterra model to show that they have very different consequences for the persistence of the community. Conservative cheating, where a species cheats on its mutualistic partners to escape the cost of mutualistic interactions, negatively affects community persistence. In contrast, innovative cheating occurs with species with whom legitimate interactions are not possible, because of a physiological or morphological barrier. Innovative cheating can enhance community persistence under some conditions: when cheaters have few mutualistic partners, cheat at low or intermediate frequency and the cost associated with mutualism is not too high. In this case, the negative effects of cheating on partner persistence are over-compensated at the community level by the positive feedback loops that arise in mutualistic networks. Using an empirical dataset of plant-bird interactions, we found that observed cheating patterns are highly consistent with theoretical cheating patterns found to increase community persistence. This result suggests that the cheating patterns observed in nature could contribute to promote species coexistence in mutualistic communities, instead of necessarily destabilizing them.

ecology↗

bioRxiv2023

Autophagy mediates cancer cell resistance to doxorubicin induced by the Programmed Death 1/Programmed Death Ligand 1 immune checkpoint axis

BackgroundWhile the Programmed Death 1/Programmed Death Ligand 1 (PD-1/PD-L1) immune checkpoint is an important mechanism of immune evasion in cancer, recent studies have shown that it can also lead to resistance to chemotherapy in cancer cells via reverse signaling. Here we describe a novel mechanism by which autophagy mediates cancer cell drug resistance induced by PD-1/PD-L1 signaling. MethodsHuman and mouse breast cancer cells were treated with recombinant PD-1 (rPD-1) to stimulate PD-1/PD-L1 signaling. Activation of autophagy was assessed by immunoblot analysis of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II and Beclin 1 protein levels, two important markers of autophagy. Moreover, autophagosome formation was assessed in human breast cancer cells using green fluorescence protein (GFP)-tagged LC3. Cells were either treated with Beclin 1 or Atg7 shRNA to assess the role of autophagy on resistance to doxorubicin mediated by PD-1/PD-L1 signalling. We then investigated signaling mechanisms upstream of PD-1/PD-L1 induced autophagy by assessing phosphorylation of extracellular signal-related kinase (ERK). ResultsTreatment of cells with rPD-1 resulted in a time-dependent increase in LC3-II as well as Beclin 1, and an increase in autophagosome formation. Knockdown of Beclin 1 or Atg7 prevented drug resistance induced by PD-1/PD-L1 signaling. Exposure of breast cancer cells to rPD-1 resulted in increased ERK phosphorylation and inhibition of ERK activation abolished autophagy induced by PD-1/PD-L1 signaling. ConclusionsThese studies provide a rationale for the use of PD-1/PD-L1 immune checkpoint blockers and autophagy inhibitors as potential chemosensitizers in cancer therapy.

cancer biology↗

bioRxiv2021

Blue and green food webs respond differently to elevation and land use

While aquatic (blue) and terrestrial (green) food webs are parts of the same landscape, it remains unclear whether they respond similarly to shared environmental gradients. We use empirical community data from hundreds of sites across Switzerland, and show that blue and green food webs have different structural and ecological properties along elevation as a temperature proxy, and among various land-use types. Specifically, in green food webs, their modular structure increases with elevation and the overlap of consumers diet niche decreases, while the opposite pattern is observed in blue food webs. Such differences between blue and green food webs are particularly pronounced in farmland-dominated habitats, indicating that anthropogenic habitat modification moderates the climatic effects on food webs but differently in blue versus green systems. These findings indicate general structural differences between blue and green food webs and suggest their potential divergent future alterations through land use or climatic changes.

ecology↗

bioRxiv2021

Global plant-frugivore trait matching is shaped by climate and biogeographic history

Species interactions are influenced by the trait structure of local multi-trophic communities. However, it remains unclear whether mutualistic interactions in particular can drive trait patterns at the global scale, where climatic constraints and biogeographic processes gain importance. Here we evaluate global relationships between traits of frugivorous birds and palms (Arecaceae), and how these relationships are affected, directly or indirectly, by assemblage richness, climate and biogeographic history. We leverage a new and expanded gape size dataset for nearly all avian frugivores, and find a positive relationship between gape size and fruit size, i.e., trait matching, which is influenced indirectly by palm richness and climate. We also uncover a latitudinal gradient in trait matching strength, which increases towards the tropics and varies among zoogeographic realms. Taken together, our results suggest trophic interactions have consistent influences on trait structure, but that abiotic, biogeographic and richness effects also play important, though sometimes indirect, roles in shaping the functional biogeography of mutualisms.

ecology↗

bioRxiv2021

Landscape dynamics promoted the evolution of mega-diversity in South American freshwater fishes

Landscape dynamics and river network rearrangements are widely thought to shape the diversity of Neotropical freshwater fishes, the most species-rich continental vertebrate fauna on Earth. Yet the effects of hydrogeographic changes on fish dispersal and diversification remain poorly understood. Here we integrate an unprecedented occurrence dataset of 4,967 South American freshwater fish species with a species-dense phylogeny to track the evolutionary processes associated with hydrogeographic events over 100 Ma. Net lineage diversification was heterogeneous through time, across space, and among clades. Three abrupt shifts in diversification rates occurred during the Paleogene (between 63 and 23 Ma) in association with major landscape evolution events, and net diversification accelerated from the Miocene to the Recent (c. 20 - 0 Ma). The Western Amazon exhibited the highest rates of in situ diversification and was also the most important source of species dispersing to other regions. All regional biotic interchanges were associated with documented hydrogeographic events and the formation of biogeographic corridors, including Early Miocene (c. 20 Ma) uplift of the Serra do Mar, and Late Miocene (c. 10 Ma) uplift of the Northern Andes and formation of the modern transcontinental Amazon River. Reciprocal mass dispersal of fishes between the Western and Eastern Amazon coincided with this phase of Andean uplift. The Western Amazon has the highest contemporary levels of species richness and phylogenetic endemism. Our results support the hypothesis that landscape dynamics were constrained by the history of drainage basin connections, strongly affecting the assembly and diversification of basin-wide fish faunas. Significance StatementDespite progress in mapping geographic distributions and genealogical relationships, scientists have few clear answers about the origins of South American freshwater fishes, the most diverse vertebrate fauna on Earth. Here we used the most complete dataset of geographic distributions and evolutionary relationships of South American fishes to track how the geological history of river dynamics influenced the origin, extinction, and interchange of species over the past 100 Ma. We found abrupt increases of species origination between 66 and 23 Ma, coinciding with repeated uplifts of the Andes. The Western Amazon region served as source of freshwater fishes to other regions, as a place where species tended to persist over longer historical periods, and where species originations occurred with higher frequency.

ecology↗

bioRxiv2021

Transgenerational impact of aberrant inflammation in rat pregnancy

Children of women with pre-eclampsia have increased risk of cardiovascular (CV) and metabolic disease in adult life. Furthermore, the risk of pregnancy complications is higher in daughters born to women affected by pre-eclampsia than in daughters born after uncomplicated pregnancies. While aberrant inflammation contributes to the pathophysiology of pregnancy complications, including pre-eclampsia, the contribution of maternal inflammation to subsequent risk of CV and metabolic disease as well as pregnancy complications in the offspring remains unclear. Here we demonstrate that 24-week-old female rats (F1) born to dams (F0) exposed to lipopolysaccharide (LPS) during pregnancy (to induce inflammation) exhibited mild systolic dysfunction, increased cardiac growth-related gene expression, abnormal glucose tolerance and coagulopathy; whereas male F1 offspring exhibited abnormal glucose tolerance and increased visceral fat accumulation compared with F1 sex-matched offspring born to saline-treated dams. Both male and female F1 offspring born to LPS-treated dams had evidence of anemia. Fetuses (F2) from F1 females born to LPS-treated dams were growth restricted, and this reduction in fetal growth was associated with increased CD68 positivity and decreased expression of glucose transporter-1 in their utero-placental units. These results indicate that abnormal maternal inflammation can contribute to increased risk of CV and metabolic disease in offspring, and that the effects of inflammation may be transgenerational. This study provides evidence in support of early screening for CV and metabolic disease, as well as pregnancy complications in offspring affected by pre-eclampsia or other pregnancy complications associated with aberrant inflammation.

developmental biology↗

bioRxiv2021

Interannual climate variability data improves niche estimates in species distribution models

AimClimate is an essential element of species niche estimates in many current ecological applications such as species distribution models (SDMs). Climate predictors are often used in the form of long-term mean values. Yet, climate can also be described as spatial or temporal variability for variables like temperature or precipitation. Such variability, spatial or temporal, offers additional insights into niche properties. Here, we test to what degree spatial variability and long-term temporal variability in temperature and precipitation improve SDM predictions globally. LocationGlobal. Time period1979-2013 Major taxa studiesMammal, Amphibians, Reptiles MethodsWe use three different SDM algorithms, and a set of 833 amphibian, 779 reptile, and 2211 mammal species to quantify the effect of spatial and temporal climate variability in SDMs. All SDMs were cross-validated and accessed for their performance using the Area under the Curve (AUC) and the True Skill Statistic (TSS). ResultsMean performance of SDMs with climatic means as predictors was TSS=0.71 and AUC=0.90. The inclusion of spatial variability offers a significant gain in SDM performance (mean TSS=0.74, mean AUC=0.92), as does the inclusion of temporal variability (mean TSS=0.80, mean AUC=0.94). Including both spatial and temporal variability in SDMs shows similarly high TSS and AUC scores. Main conclusionsAccounting for temporal rather than spatial variability in climate improved the SDM prediction especially in exotherm groups such as amphibians and reptiles, while for endotermic mammals no such improvement was observed. These results indicate that more detailed information about temporal climate variability offers a highly promising avenue for improving niche estimates and calls for a new set of standard bioclimatic predictors in SDM research.

ecology↗

bioRxiv2021

Facultative variation across a shallow to deep torpor spectrum in hummingbirds

Many small endotherms use torpor, saving energy by a controlled reduction of their body temperature and metabolic rate. Some species (e.g. arctic ground squirrels, hummingbirds) enter deep torpor, dropping their body temperatures by 23-37 {degrees}C, while others can only enter shallow torpor (e.g., pigeons, 3-10 {degrees}C reductions). However, deep torpor in mammals can increase predation risk (unless animals are in burrows or caves), inhibit immune function, and result in sleep deprivation, so even for species that can enter deep torpor, facultative shallow torpor might help balance energy savings with these potential costs. Deep torpor occurs in three avian orders. Although the literature hints that some bird species can use both shallow and deep torpor, little empirical evidence of such an avian torpor spectrum exists. We infrared imaged three hummingbird species that are known to use deep torpor, under natural temperature and light cycles, to test if they were also capable of shallow torpor. All three species used both deep and shallow torpor, often on the same night. Depending on the species, they used shallow torpor for 5-35% of the night. The presence of a bird torpor spectrum indicates a capacity for fine-scale physiological and genetic regulation of avian torpid metabolism.

ecology↗

bioRxiv2018

Torpor duration, more than temperature, is key to hummingbird nighttime energy savings

O_LITorpor is an important energy saving strategy in small endotherms, but it has been insufficiently studied in natural field conditions. Building on what we know from laboratory studies, we compared torpor use across hummingbird species and different natural temperature regimes to explore predominant hypotheses about torpor use and evaluate the possible effects of environmental variation on energy management.\nC_LIO_LIWe found that the probability of an individual entering torpor was correlated with mass and unrelated to nighttime temperature, and that hummingbirds at both warm tropical and cooler temperate sites used torpor.\nC_LIO_LIEnergy savings in torpor were maximized as ambient temperatures approached a species minimum body temperature consistent with laboratory studies; energy savings ranged between 65-92% of energy per hour in torpor compared to normothermy.\nC_LIO_LIHowever, variation in total nighttime energy expenditure was more significantly influenced by torpor bout duration than by the variation in energy savings in torpor.\nC_LIO_LIOur results show that a small endotherms nighttime energy management in its natural habitat is more affected by torpor bout duration, which is linked to photoperiod, than by temperature. This result suggests that in their natural environments, hummingbirds are able to save energy in torpor across a range nighttime temperature, indicating that they may have sufficient physiological flexibility to tolerate climatic variation.\nC_LI

ecology↗