Biology subjects

Martin, R. A.

Publications and source records attributed to Martin, R. A..

13 recordsLinked to original sources

bioRxiv2026

Fibroblast signaling influences macrophage-dependent, biomaterial-induced tissue remodeling

The ability to induce tissue regeneration on demand using biomaterials remains a major goal in biomedical research, yet significant challenges persist. Among the most advanced biomaterial models, the nanofiber-hydrogel composite has demonstrated a striking ability to induce soft adipose tissue remodeling at the injection site without incorporating exogenous biological cues.1,2 However, the underlying mechanisms that drive such a tissue response remain unclear. Here, we show that biomaterial-induced tissue remodeling is driven by sustained and controlled inflammation mediated by macrophages in strong communication with fibroblasts. Notably, both pro-inflammatory and anti-inflammatory signals remained elevated during this process in the long-term, challenging the prevailing notion that inflammation opposes remodeling. Using macrophage depletion in mice, we demonstrate that macrophages are essential for this process. Single-cell RNA sequencing further revealed robust fibroblast-to-macrophage signaling, contrasting with the conventional macrophage-to-fibroblast paradigm, and identified unique Spp1 macrophages and Ctla2a fibroblasts within the remodeling niche. These findings provide a comprehensive view of the immune landscape in biomaterial-induced tissue remodeling, highlighting key cellular interactions, prolonged kinetics, and unexpected signaling pathways. By defining key targets and fundamental principles, this work has broad implications for advancing biomaterial-induced tissue regeneration.

bioengineering↗

bioRxiv2026

Signatures of selection in pleiotropic genes involved in insect neuronal and immune systems

Pleiotropy, where a single gene contributes to multiple biological functions, plays a central role in shaping evolutionary constraints. The nervous and immune systems are tightly integrated both functionally and genetically, but it is not clear whether pleiotropy constrains adaptation in each system or contributes to disease. Building on evidence that genes that are pleiotropic between development and immunity in Drosophila melanogaster evolve slower than immune-specific genes, we tested whether pleiotropic neuro-immune genes likewise exhibit reduced evolutionary rates compared to genes functioning solely in neuronal or immune processes, and whether such evolutionary constraint is associated with human neurological disease. We identified immune, neuronal, and neuro-immune genes in D. melanogaster using Gene Ontology annotations, estimated their evolutionary rates across 12 Drosophila species, and investigated the breadth of their expression across developmental stages as a complementary proxy for pleiotropy. We further curated associations between the human orthologs for these genes and neurological disease and tested whether their evolutionary rates and pleiotropic status predicted disease involvement. We found that pleiotropic genes exhibited significantly lower dN/dS values and were less stage-specific than non-pleiotropic immune genes. Slower-evolving genes were more likely to be associated with human neurological diseases but this pattern was strongest for non-pleiotropic neuronal genes, suggesting that pleiotropy alone is not the strongest predictor of disease. Our results therefore indicate that dN/dS could be a stronger predictor of disease association than pleiotropy, raising new questions about the maintenance of pleiotropy in evolutionarily dynamic physiological systems.

evolutionary biology↗

bioRxiv2025

The evolution of investment in innate-like and diversified T cell receptors across development

New insights into the diversity of lymphocyte functions challenges previous dogma about the rigid divide between innate and adaptive immunity. While T cells with canonically diversified receptors are crucial for recognizing novel antigens, other T cell lineages express innate-like receptors that recognize conserved molecular patterns. The relative frequency of innate-like to diversifying T cell receptors (iTCRs: dTCRs) varies greatly across vertebrate species and across ontogeny within species. These within-species dynamics can potentially be explained by developmental constraints on immunity, pathogen diversity and exposure, or by trade-offs associated with specificity. To better understand how these factors shape T cell repertoires, we constructed an agent-based model of TCR evolution inspired by the diversity of ontogenic life histories in amphibians but applicable to an array of vertebrate species. Our model features two life stages with distinct parasite populations and life history costs. The model predicts that changes in ontogeny (stage duration, T cell maturation time) and environmental factors (parasite diversity, parasite complexity) exert drastic effects on the stage structure of T cell investment strategies. A better understanding of the evolutionary pressures that shape TCR diversity will provide new insights into lymphocyte evolution and immune investment across organismal development.

evolutionary biology↗

bioRxiv2024

Pleiotropy increases with gene age in six model multicellular eukaryotes

Fundamental traits of genes, including function, length and GC content, all vary with gene age. Pleiotropy, where a single gene affects multiple traits, arises through selection for novel traits and is expected to be removed from the genome through subfunctionalization following duplication events. It is unclear, however, how these opposing forces shape the prevalence of pleiotropy through time. We hypothesized that the prevalence of pleiotropy would be lowest in young genes, peak in middle aged genes, and then either decrease to a middling level in ancient genes or stay near the middle-aged peak, depending on the balance between exaptation and subfunctionalization. To address this question, we have calculated gene age and pleiotropic status for several model multicellular eukaryotes, including Homo sapiens, Mus musculus, Danio rerio, Drosophila melanogaster, Caenorhabditis elegans, and Arabidopsis thaliana. Gene age was determined by finding the most distantly related species that shared an ortholog using the Open Tree of Life and the Orthologous Matrix Database (OMAdb). Pleiotropic status was determined using both protein-protein interactions (STRINGdb) and associated biological processes (Gene Ontology). We found that middle-aged and ancient genes tend to be more pleiotropic than young genes, and that this relationship holds across all species evaluated and across both modalities of measuring pleiotropy. We also found absolute differences in the degree of pleiotropy based on gene functional class, but only when looking at biological process count. From these results we propose that there is a fundamental relationship between pleiotropy and gene age and further study of this relationship may shed light on the mechanism behind the functional changes genes undergo as they age. Impact statementPleiotropy, the phenomenon where a single gene acts on multiple traits, is fundamental to genomic organization and has profound consequences for fitness. This work identifies a previously unknown relationship between pleiotropy and gene age, highlighting the dynamism of pleiotropy across time. This relationship holds across six distantly related model organisms, suggesting that it could be a highly generalizable finding, at least among multicellular eukaryotes. Following from this work, future investigation into mechanisms dictating the prevalence of pleiotropy at the gene or cellular level could provide fundamental insight into the maintenance of pleiotropy despite the potential for constraining rapid adaptation.

evolutionary biology↗

bioRxiv2024

How do body size and habitat fragmentation influence extinction in lizards? A long-term case study on artificial islands in the Brazilian Cerrado

Habitat fragmentation is known to cause extinctions and species turnover, but the factors that allow some species to persist while others become locally extinct are not well understood. Landscape flooding following the construction of hydroelectric dams causes a particularly dramatic form of fragmentation disturbance, where former terrestrial habitats become aquatic and former hilltops become land-bridge islands. As such, reservoir land-bridge islands have become a successful model for accessing the impacts of fragmentation on biodiversity. We used the lizard community, to assess species sensitivity to habitat structural change during land-bridge island formation. We monitored the lizard community for 23 years before, during, and after the flooding of the Serra da Mesa Dam reservoir. Over the course of our study, the diversity of the lizard community on land-bridge islands and mainland sites along the shores of the newly formed reservoir declined from 19 to six species. We found that in Serra da Mesa islands, lizards with large body sizes (e.g., Teiidae and Tropiduridae) decreased in abundance along the flooding process, thereby increasing their extinction risk. In contrast, we found a high abundance of small-bodied lizards (Gekkonidae, Gymnophthalmidae, Scincidae, and Sphaerodactylidae) on Serra da Mesa islands. Richness on the islands declined dramatically, resulting in communities currently with one highly abundant species, Gymnodactylus amarali. For the sake of biodiversity conservation, island or fragment sizes must be considered for maintaining a reasonable number of species and our characterization of the local extinction patterns may provide relevant information to mitigate wildlife depletion due to habitat fragmentation.

ecology↗

bioRxiv2024

Widespread brain activity increases in frontal lobe seizures with impaired consciousness

Impaired consciousness is a serious clinical manifestation of epilepsy with negative consequences on quality of life. Little work has investigated impaired consciousness in frontal lobe seizures, a common form of focal epilepsy. In temporal lobe seizures, previous studies showed widespread cortical slow waves associated with depressed subcortical arousal and impaired consciousness. However, in frontal lobe epilepsy, it is not known whether cortical slow waves are present, or whether a very different cortical activity pattern may be related to impaired consciousness. We used intracranial EEG recordings of 65 frontal lobe seizures in 30 patients for quantitative analysis of ictal cortical activity and its relationship to impaired consciousness. Behavioral changes based on blinded review of seizure videos were used to classify focal aware, focal impaired awareness, and focal to bilateral tonic-clonic seizures. Changes in intracranial EEG power from preictal baseline were analyzed in different cortical regions and across frequency ranges in these three categories. We found that frontal lobe focal aware seizures showed approximately 40% increases in intracranial EEG power localized to the frontal lobe of seizure onset across frequency ranges, with relatively smaller changes in other cortical regions. Frontal lobe focal impaired awareness seizures showed approximately 50% increases in intracranial EEG power, not significantly different from focal aware seizures in the frontal lobe of seizure onset (P = 1.038), but significantly greater than focal aware seizures in other broad cortical regions (P < 0.001). Importantly, the widespread cortical increases in EEG power observed in focal impaired awareness versus focal aware seizures were seen not just in the frequency range of slow waves, but were also observed across other frequencies including fast activity. However, the widespread cortical increases in focal impaired awareness seizures differed from focal to bilateral tonic-clonic seizures where intracranial EEG power increased to a much higher level by approximately 600%. The large power increases in focal to bilateral tonic-clonic were significantly greater than in focal impaired awareness seizures both in the frontal lobe of seizure onset and in other cortical regions (P < 0.001). Our findings contrast with focal temporal lobe epilepsy, where impaired consciousness is associated with cortical slow waves. We can speculate that different focal seizure types produce impaired consciousness by impacting widespread cortical regions but through different physiological mechanisms. Insights gained by studying mechanisms of impaired consciousness may be the first step towards developing novel treatments to prevent this important negative consequence of epilepsy.

neuroscience↗

bioRxiv2024

Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a post-transcriptional influence.

Exercise is firmly established as a key contributor to overall well-being and is frequently employed as a therapeutic approach to mitigate various health conditions. One pivotal aspect of the impact of exercise lies in the systemic transcriptional response, which underpins its beneficial adaptations. While extensive research has been devoted to understanding the transcriptional response to exercise, our knowledge of the protein constituents of nuclear processes that accompany gene expression in skeletal muscle remains largely elusive. We hypothesize that alterations in the nuclear proteome following exercise hold vital clues for comprehending the transcriptional regulation and other related nuclear functions. We isolated skeletal muscle nuclei from C57BL/6 mice both sedentary control and one-hour post 30-minute treadmill running, to gain insights into the nuclear proteome after exercise. A substantial number of the 2,323 proteins identified, were related to nuclear functions. For instance, we found 59 proteins linked to nucleocytoplasmic transport were higher in sedentary mice compared to exercise, hinting at an exercise-induced modulation to nuclear trafficking. Furthermore, 135 proteins exhibited increased abundance after exercise (FDR < 0.1) while 89 proteins decreased, with the most prominent changes in proteins linked to mRNA processing and splicing. Super resolution microscopy further highlights potential localization change in mRNA processing proteins post-exercise, further suggesting changes in nuclear transport dynamics. Nonetheless, our data provide important considerations for the study of the nuclear proteome and supports a paradigm through which exercise downregulated mRNA processing and splicing, offering valuable insights into the broader landscape of the impact from acute exercise. New & NoteworthyExercise plays a crucial role in promoting muscle health, but our understanding of nuclear proteins orchestrating exercise responses is limited. Isolation of skeletal muscle nuclei coupled with mass spectrometry enhanced the identification of nuclear proteins. This approach was used to investigate the effects of acute exercise, revealing changes in the muscle nuclear proteome 1-hour post-exercise, including proteins linked to post-transcriptional processing and splicing. Our findings offer insights into the exercise-induced changes within muscle nuclear proteins.

physiology↗

bioRxiv2023

Muscle Bmal1 is necessary for normal transcriptomic and metabolomic adaptation to endurance exercise training.

ObjectivesIn this investigation, we addressed the contribution of the core circadian clock factor, BMAL1, in skeletal muscle to both acute transcriptional responses to exercise and transcriptional remodelling in response to exercise training. Additionally, we adopted a systems biology approach to investigate how loss of skeletal muscle BMAL1 altered peripheral tissue homeostasis as well as exercise training adaptations in iWAT, liver, heart, and lung of male mice. MethodsCombining inducible skeletal muscle specific BMAL1 knockout mice, physiological testing and standardized exercise protocols, we performed a multi-omic analysis (transcriptomics, chromatin accessibility and metabolomics) to explore loss of muscle BMAL1 on muscle and peripheral tissue responses to exercise. ResultsMuscle-specific BMAL1 knockout mice demonstrated a blunted transcriptional response to acute exercise, characterized by the lack of upregulation of well-established exercise responsive transcription factors including Nr4a3 and Ppargc1a. Six weeks of exercise training in muscle-specific BMAL1 knockout mice induced significantly greater and divergent transcriptomic and metabolomic changes in muscle. Surprisingly, liver, lung, inguinal white adipose and heart showed divergent exercise training transcriptomes with less than 5% of exercise-training responsive genes shared for each tissue between genotypes. ConclusionOur investigation has uncovered the critical role that BMAL1 plays in skeletal muscle as a key regulator of gene expression programs for both acute exercise and training adaptations. In addition, our work has uncovered the significant impact that altered exercise response in muscle plays in the peripheral tissue adaptation to exercise training. We also note that the transcriptome adaptations to steady state training suggest that without BMAL1, skeletal muscle does not achieve the expected homeostatic program. Our work also demonstrates that if the muscle adaptations diverge to a more maladaptive state this is linked to increased inflammation across many tissues. Understanding the molecular targets and pathways contributing to health vs. maladaptive exercise adaptations will be critical for the next stage of therapeutic design for exercise mimetics.

physiology↗

bioRxiv2023

Single-fly assemblies fill major phylogenomic gaps across the Drosophilidae Tree of Life

Long-read sequencing is driving rapid progress in genome assembly across all major groups of life, including species of the family Drosophilidae, a longtime model system for genetics, genomics, and evolution. We previously developed a cost-effective hybrid Oxford Nanopore (ONT) long-read and Illumina short-read sequencing approach and used it to assemble 101 drosophilid genomes from laboratory cultures, greatly increasing the number of genome assemblies for this taxonomic group. The next major challenge is to address the laboratory culture bias in taxon sampling by sequencing genomes of species that cannot easily be reared in the lab. Here, we build upon our previous methods to perform amplification-free ONT sequencing of single wild flies obtained either directly from the field or from ethanol-preserved specimens in museum collections, greatly improving the representation of lesser studied drosophilid taxa in whole-genome data. Using Illumina Novaseq X Plus and ONT P2 sequencers with R10.4.1 chemistry, we set a new benchmark for inexpensive hybrid genome assembly at US $150 per genome while assembling genomes from as little as 35 ng of genomic DNA from a single fly. We present 183 new genome assemblies for 179 species as a resource for drosophilid systematics, phylogenetics, and comparative genomics. Of these genomes, 62 are from pooled lab strains and 121 from single adult flies. Despite the sample limitations of working with small insects, most single-fly diploid assemblies are comparable in contiguity (>1Mb contig N50), completeness (>98% complete dipteran BUSCOs), and accuracy (>QV40 genome-wide with ONT R10.4.1) to assemblies from inbred lines. We present a well-resolved multi-locus phylogeny for 360 drosophilid and 4 outgroup species encompassing all publicly available (as of August 2023) genomes for this group. Finally, we present a Progressive Cactus whole-genome, reference-free alignment built from a subset of 298 suitably high-quality drosophilid genomes. The new assemblies and alignment, along with updated laboratory protocols and computational pipelines, are released as an open resource and as a tool for studying evolution at the scale of an entire insect family.

evolutionary biology↗

bioRxiv2022

An alternative mechanism for skeletal muscle dysfunction in long-term post-viral lung disease

Chronic lung disease is often accompanied by disabling extrapulmonary symptoms, notably skeletal muscle dysfunction and atrophy. Moreover, the severity of respiratory symptoms correlates with decreased muscle mass and in turn lowered physical activity and survival rates. Previous models of muscle atrophy in chronic lung disease often modeled COPD and relied on cigarette smoke exposure and LPS-stimulation, but these conditions independently affect skeletal muscle even without accompanying lung disease. Moreover, there is an emerging and pressing need to understand the extrapulmonary manifestations of long-term post-viral lung disease (PVLD) as found in Covid-19. Here, we examine the development of skeletal muscle dysfunction in the setting of chronic pulmonary disease using a mouse model of PVLD caused by infection due to the natural pathogen Sendai virus. We identify a significant decrease in myofiber size when PVLD is maximal at 49 d after infection. We find no change in the relative types of myofibers, but the greatest decrease in fiber size is localized to fast-twitch type IIB myofibers based on myosin heavy chain immunostaining. Remarkably, all biomarkers of myocyte protein synthesis and degradation (total RNA, ribosomal abundance, and ubiquitin-proteasome expression) were stable throughout the acute infectious illness and chronic post-viral disease process. Together, the results demonstrate a distinct pattern of skeletal muscle dysfunction in a mouse model of long-term PVLD. The findings thereby provide new insight into prolonged limitations in exercise capacity in patients with chronic lung disease after viral infections and perhaps other types of lung injury.

physiology↗

bioRxiv2022

Pleiotropy promotes the evolution of inducible immune responses in a model of host-pathogen coevolution

Components of immune systems face significant selective pressure to efficiently use organismal resources, mitigate infection, and resist parasitic manipulation. A theoretically optimal immune defense balances investment in constitutive and inducible immune components depending on the kinds of parasites encountered, but genetic and dynamic constraints can force deviation away from theoretical optima. One such potential constraint is pleiotropy, the phenomenon where a single gene affects multiple phenotypes. Although pleiotropy can prevent or dramatically slow adaptive evolution, it is prevalent in the signaling networks that compose metazoan immune systems. We hypothesized that pleiotropy is maintained in immune signaling networks despite slowed adaptive evolution because it provides some other advantage, such as forcing network evolution to compensate in ways that increase host fitness during infection. To study the effects of pleiotropy on the evolution of immune signaling networks, we used an agent-based modeling approach to evolve a population of host immune systems infected by simultaneously co-evolving parasites. Four kinds of pleiotropic restrictions on evolvability were incorporated into the networks, and their evolutionary outcomes were compared to, and competed against, non-pleiotropic networks. As the networks evolved, we tracked several metrics of immune network complexity, relative investment in inducible and constitutive defenses, and features associated with the winners and losers of competitive simulations. Our results suggest non-pleiotropic networks evolve to deploy highly constitutive immune responses regardless of parasite prevalence, but some implementations of pleiotropy favor the evolution of highly inducible immunity. These inducible pleiotropic networks are no less fit than non-pleiotropic networks and can out-compete non-pleiotropic networks in competitive simulations. These provide a theoretical explanation for the prevalence of pleiotropic genes in immune systems and highlight a mechanism that could facilitate the evolution of inducible immune responses. Author SummaryGenes involved in immune defense are hotspots of adaptive evolution as they resist rapidly evolving parasites and pathogens. Pleiotropic genes, which affect multiple discrete traits, have been shown to evolve at a much slower rate than non-pleiotropic genes but are highly represented in the immune system. The evolutionary effects of pleiotropic signaling genes on immune evolution are poorly understood, so we developed a model of pleiotropic signaling network evolution to address this gap in knowledge. Our results show that pleiotropy may be an important genomic feature in the development of inducible immunity.

evolutionary biology↗

bioRxiv2020

In a nutshell, a reciprocal transplant experiment reveals local adaptation and fitness trade-offs in response to urban evolution in an acorn-dwelling ant

Urban-driven evolution is widely evident, but whether these changes confer fitness benefits and thus represent cases of adaptive urban evolution is less clear. We performed a multi-year field reciprocal transplant experiment of acorn-dwelling ants across urban and rural environments. Fitness trade-offs via survival were consistent with local adaptation: we found a survival advantage of the home treatments compared to the away treatments. Seasonal bias in survival was consistent with evolutionary patterns of gains and losses in thermal tolerance traits across the urbanization gradient, such that rural ants in the urban environment were more vulnerable in the summer, putatively due to low heat tolerance and urban ants in the rural environment were more vulnerable in winter, putatively due to an evolved loss of cold tolerance. The results for fitness via fecundity were more complex. Fecundity differences were present in the rural environment, but not the urban environment, and could reflect mismatched cues for the seasonal production of reproductives. To broadly contextualize our results, we performed a multi-species meta-analysis of urban adaptive evolution studies and found general support for local adaptation. The rural adaptation signal was stronger than for urban adaptation, consistent with the relative differences in time for adaptation to occur.

evolutionary biology↗

bioRxiv2019

Evolution, not transgenerational plasticity, explains the divergence of acorn ant thermal tolerance across an urban-rural temperature cline

Disentangling the mechanisms of phenotypic shifts in response to environmental change is critical, and although studies increasingly disentangle phenotypic plasticity from evolutionary change, few explore the potential role for transgenerational plasticity in this context. Here, we evaluate the potential role that transgenerational plasticity plays in phenotypic divergence of acorn ants in response to urbanization. F2 generation worker ants (offspring of lab-born queens) exhibited similar divergence among urban and rural populations as F1 generation worker ants (offspring of field-born queens) indicating that evolutionary differentiation rather than transgenerational plasticity was responsible for shifts towards higher heat tolerance and diminished cold tolerance in urban acorn ants. Hybrid matings between urban and rural populations provided further insight into the genetic architecture of thermal adaptation. Heat tolerance of hybrids more resembled the urban-urban pure type, whereas cold tolerance of hybrids more resembled the rural-rural pure type. As a consequence, thermal tolerance traits in this system appear to be influenced by dominance rather than being purely additive traits, and heat and cold tolerance might be determined by separate genes. Though transgenerational plasticity does not explain divergence of acorn ant thermal tolerance, its role in divergence of other traits and across other urbanization gradients merits further study.

evolutionary biology↗