Biology subjects

Giles, S.

Publications and source records attributed to Giles, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Encapsulated cell technology delivers ciliary neurotrophic factor to promote JAK/STAT-dependent photoreceptor survival in retinal degeneration

Sustained trophic factor delivery via Encapsulated Cell Technology (ECT) is a powerful new class of therapeutics with broad potential for targeted treatment. Intravitreal delivery of ciliary neurotrophic factor (CNTF) via the ECT, NT-501, is a first-in-class therapy that slows the progression of macular telangiectasia type 2 (MacTel). Despite its clinical efficacy, key questions remain regarding its mechanism of action, including whether other implant-derived factors contribute to therapeutic benefit and how optimal dosing should be determined. Resolving these issues is critical for optimizing NT-501 in MacTel and guiding the development of ECT-based therapies for other diseases. We evaluated the biological activity of implant-derived cytokines on retinal tissue, using long-term NT-501 intravitreal implants in rabbits alongside human retinal organoid (hRO) models treated with NT-501-conditioned medium (NT-501-CM). Then, using a MacTel-specific photoreceptor degeneration model in hROs, we showed NT-501-CM significantly reduced photoreceptor cell death, and this protective effect was abolished by either CNTF-neutralizing antibodies or JAK inhibitor. We also established a therapeutic dose-response relationship linking NT-501-derived CNTF levels to JAK/STAT3 activation and photoreceptor protection. These findings directly connect ECT-derived CNTF exposure with JAK/STAT3-mediated photoreceptor protection in human retinal tissue and suggest an optimal concentration range for efficacy.

pharmacology and toxicology↗

bioRxiv2026

An early CYP26A1/CRYAA progenitor-glial domain marks the presumptive macular region during human retinal development

The human macula, a high-acuity retinal region essential for central vision, emerges early in development, but the cellular basis of its regional specialisation remains incompletely resolved. Building on recent studies that identified CYP26A1-mediated retinoic acid (RA) suppression in the presumptive macula, we define a CRYAA-positive progenitor-glial compartment in the temporal human retina from post-conception week (pcw) 7 onward. Single-cell RNA sequencing, immunohistochemistry and spatial morphometry indicate that this compartment is linked to regional gliogenic maturation and later corresponds to a specialised macular Muller glial population, rather than simply reflecting uniform pan-retinal developmental timing. Spatial mapping shows that the CYP26A1-positive domain remains delimited as the surrounding retina expands. Adult tissue analysis shows that CYP26A1 expression is retained in primate macular Muller glia and in corresponding acute-zone regions of visual-streak species. These findings extend current models of CYP26A1-mediated RA modulation in human acute zone/macular development by linking the early CYP26A1 domain to a regionally specialised CRYAA-positive progenitor-glial compartment. We propose that early macular patterning includes a spatially restricted glial programme that may contribute to later regional architecture and disease vulnerability.

developmental biology↗

bioRxiv2025

The phylogenetic signal of extinction through the rise and fall of early vertebrates: field of bullets or clustered strike?

We investigate patterns of phylogenetic selectivity of extinction in early aquatic vertebrates from the Silurian to the Carboniferous, an interval punctuated by one of the Big Five mass extinctions and marked by many critical anatomical (e.g. jaws, limbs) and ecological (e.g. macrophagy, terrestrialization) vertebrate evolutionary innovations. Using a new >1300 taxon, formally inferred supertree, we show that phylogenetic extinction clustering in early vertebrates varied through time and between major ecomorphological divisions of the tree. At the end of the Silurian and into the Early Devonian, jawless fishes became marginalized components of vertebrate faunas and show more strongly clustered extinction than jawed fishes, which became ecologically dominant during this interval. Clustered extinction (contemporaneous extinction of close relatives) is typical of most stages of the Devonian, particularly during the Late Devonian extinctions. By contrast, the subsequent early Carboniferous interval of putative recovery is characterized by overdispersed extinction (contemporaneous extinction of distant relatives), consistent with widespread persistence of phylogenetically distinct lineages. This work shows how varying patterns of extinction selectivity pruned the vertebrate tree at the time when the first-order patterns of diversity apparent in modern aquatic vertebrate faunas were first established.

paleontology↗

bioRxiv2025

Erucamide regulates retinal neurovascular crosstalk

Neurovasculoglial crosstalk is critical in establishing and maintaining a functional neurovascular unit. Breakdown in the unit is central to many neurodegenerative disorders of the CNS of which the retina is a component. A growing literature indicated that primary fatty acid amides (PFAMs) can regulate this crosstalk between vasculature and neuronal tissues. In this study we describe a central role for erucamide, a 22:1 mono-unsaturated omega-9 fatty acid amide, in degenerating retinal tissues. Using high-resolution global mass spectrometry-based metabolomics, we cataloged metabolites in murine models of retinal degeneration and show that while PFAMs, in general, are highly dysregulated, erucamide is the one most significantly diminished during photoreceptor atrophy. Using rodent models of retinal degeneration and novel organosilane-modified porous silicon nanoparticles (pSiNPs) for the in vivo delivery of erucamide, we demonstrate that erucamide activates CD11b+ myeloid cells, leading to the upregulation of angiogenic and neurotrophic cytokines that stabilize retinal degeneration. We identified TMEM19 as a novel binding protein for erucamide that is crucial for human iPSC-derived macrophage precursor cells activation and subsequent neurotrophic and angiogenic factor production. These findings reveal a previously unknown PFAM pathway that is modulated during retinal degenerative diseases, demonstrating that erucamide or functional analogues and their action through TMEM19 may be useful as a therapeutic alternative to neuroprotective and stem cell-based approaches for the treatment of retinal degenerative diseases.

neuroscience↗

bioRxiv2025

Tongue bite apparatus highlights functional innovation in a 310-million-year-old ray-finned fish

Gill skeleton modifications for processing prey represent a major source of functional innovation in living ray-finned fishes. Here we present the oldest actinopterygian tongue bite, derived from the gill skeleton, in the Early Pennsylvanian ([~]310 Ma) {dagger}Platysomus parvulus. Unrelated to extant tongue biters, this deep-bodied taxon possesses a large, multipartite basibranchial tooth plate opposing an upper tooth field centered on the vomer. This branchial structure occurs in conjunction with toothed jaws, indicating a role for both in feeding. {dagger}P. parvulus illustrates the assembly of the tongue bite in the geologically younger {dagger}Bobasatraniidae: large opposing dorsal (vomerine) and ventral (basibranchial) crushing plates associated with toothless jaws. The origin of tongue bites falls within the Carboniferous actinopterygian radiation, although postdates the first signs of durophagy in other ray-finned lineages by several million years. This lends support to a protracted long-fuse model of actinopterygian diversification in the aftermath of the End-Devonian Mass Extinction.

paleontology↗

bioRxiv2025

Diversification dynamics of the Palaeozoic actinopterygian radiation

Ray-finned fish are the most speciose vertebrate group today, but the dynamics of their early diversification are contentious. Their fossil record suggests a first radiation in the Carboniferous following the Late Devonian mass extinction events. Conversely, recent phylogenetic hypotheses imply a radiation originating in the Late Devonian, but lack the taxonomic breadth required to robustly test this. This necessitates phylogeny-free inference of actinopterygian diversification rates from fossil occurrences, itself challenging due to complex systematics, incomplete occurrence databases, and severe spatiotemporal sampling biases. Here, we analyse a comprehensive dataset of Palaeozoic actinopterygian genera and species using approaches that accommodate spatial and temporal sampling variation. We detect elevated actinopterygian diversification in the Late Devonian, with substantially greater lineage survival across the Hangenberg extinction event than indicated by the raw fossil record. Surprisingly, we detect no positive shifts in origination across the event, refuting previous hypotheses of explosive actinopterygian radiation in its wake. Instead, cryptic survival of diversified lineages appears responsible for the robust signal of increased diversity across different geographic scales in the Carboniferous. Nonetheless, these trends are overwhelmingly driven by low palaeolatitude Euramerican fossil assemblages, highlighting the ongoing spatial limitations of the actinopterygian fossil record.

paleontology↗

bioRxiv2025

The lower jaw of Devonian ray-finned fishes (Actinopterygii): anatomy, relationships, and functional morphology

Actinopterygii is a major extant vertebrate group, but limited data are available for its earliest members. Here we investigate the morphology of Devonian actinopterygians, focusing on the lower jaw. We use X-Ray Computed Tomography (XCT) to provide comprehensive descriptions of the mandibles of 19 species, which span the whole of the Devonian and represent roughly two thirds of all taxa known from more than isolated or fragmentary material. Our findings corroborate previous reports in part but reveal considerable new anatomical data and represent the first detailed description for roughly half of these taxa. The mandibles display substantial variation in size, spanning more than an order of magnitude. Although most conform to a generalized pattern of a large dentary and one or two smaller infradentaries, XCT data reveal significant differences in the structure of the jaw and arrangement of teeth that may be of functional relevance. We report the presence of a rudimentary coronoid process in several taxa, contributed to by the dentary and/or infradentaries, as well a raised articular region, resulting in a mandible with an offset bite and that functions as a bent level arm. Among the most striking variation is that of tooth morphology: several taxa have heterodont dentary teeth that vary in size and orientation, and multiple variations on enlarged, whorl-like and posteriorly-oriented anterior coronoid dentition are observed. We use these new data to revise morphological characters that may be of phylogenetic significance and consider the possible functional implications of these traits. The observed variation in mandible form and structure suggests previously unappreciated functional diversity among otherwise morphologically homogenous Devonian ray-finned fishes.

paleontology↗

bioRxiv2025

Divergent morphologies with convergent performance in the mandible of pelagiarian fishes

Mandibles represent a key evolutionary innovation that enabled jawed vertebrates to adapt and diversify in response to a range of food sources. Using a phylogenetic comparative approach, we explore the phenotypic disparity and mechanical properties of the lower jaw in Pelagiaria, a morphologically diverse but relatively small clade of open-ocean fishes which are hypothesized to have radiated near the Cretaceous/Paleogene (K/Pg) mass extinction event. We found that body elongation and diet are not significantly correlated with jaw shape, but that habitat depth and tooth type are. Mechanical advantage (MA) is significantly correlated with mandible shape, with jaw-closing MA being most strongly correlated. Pelagiarian jaw shapes fall broadly into six morphotypes, of which two show significantly higher closing MA than other groups, despite differing substantially in shape. The high morphological disparity of pelagiarian mandible shape was established very early in their evolutionary history, and high levels of disparity have been maintained over tens of millions of years; this is consistent with the hypothesis that Pelagiaria represents an ancient adaptive radiation. Our results demonstrate both the mechanical and morphological diversity of the pelagiarian mandible and highlight the crucial role that morphological diversification has played in the trophic radiation of this clade.

evolutionary biology↗

bioRxiv2024

A Portrait of a Young Fish: Redescription of Pteronisculus gunnari (Nielsen, 1942) from a juvenile specimen from the Early Triassic of East Greenland, with implications for ontogenetic development in early actinopterygians

The Early-Middle Triassic actinopterygian genus Pteronisculus (White, 1933) is part of the Triassic Early Fish Fauna (TEFF), a cosmopolitan group of taxa that thrived in the aftermath of the end-Permian mass extinction. Pteronisculus is considered an important non-neopterygian outgroup taxon in many works dealing with the interrelationships of early crown actinopterygians, but the phylogenetic relationships of many of TEFF genera are debated, with the topology of the lineages giving rise to crown actinopterygians consequently unclear. This is despite exceptional, three-dimensionally preservation of an abundance of fossils associated with TEFF fishes. P. gunnari, from the Induan (Early Triassic) Kap Stosch Formation, East Greenland, is known in less detail than other species of the genus. Here, we use X-ray micro-computed tomography to comprehensively redescribe the three-dimensionally preserved holotype of P. gunnari, including a detailed description of the internal anatomy. The specimen shows morphological features previously undescribed for the genus, including paired premaxillae, medially-directed teeth on the palate, canals for the buccohypophysial canal and internal carotids piercing the parasphenoid, and numerous parotic toothplates. Scale covering is complete, but the braincase and palatoquadrate are ossified as multiple elements, indicating that the specimen was not fully mature and allowing new insights into ossification patterns and ontogenetic development of non-neopterygian actinopterygians. These new anatomical data enrich our understanding of both the morphological complexity and the interrelationships of actinopterygians from the Triassic Early Fish Fauna.

paleontology↗

bioRxiv2024

Investigating the impact of X-rays on decay: X-ray computed tomography as a non-invasive visualisation technique for sediment-based decay experiments

Decay experiments are ever increasing in complexity to better understand taphonomic processes. However, adding new variables, such as sediment, can create methodological biases, such as artificial anatomical character loss during exhumation. Non-invasive in situ imaging techniques such as X-ray computed tomography (XCT scanning) could mitigate this, but the consequences of exposing carcasses to X-rays are not fully understood, and evidence regarding the impact of X-rays on internal microbial faunas that drive decay is conflicting. Here, we test whether XCT scanning impacts the decay of Danio rerio carcasses within a substrate. Our control experiments show that quartz sand sediment physically stabilises the carcass throughout decay and the sequence of anatomical character loss remains constant, however, both the onset and rate of decay of soft tissues are initially accelerated. Our XCT data show that exposure to X-rays does not cause a deviation from the normal sequence of decay, validating XCT as a non-destructive visualisation method for decay experiments. Furthermore, when accompanied with traditional exhumation and dissection, XCT provides decay data with higher accuracy of character analysis than traditional methods, and allows novel quantitative techniques to monitor physical changes in the decaying carcass (e.g., total volume, build-up of gases, collapse of the body cavity etc.). We also underline limitations with the technique, but our experiment acts as an important stepping stone for progression toward non-invasive designs of decay experiments.

paleontology↗

bioRxiv2024

Micro-CT Based Description of Dorsetichthys bechei (Actinopterygii: Teleostei): Cranial Anatomy of an Iconic Early Teleost

Teleost fishes comprise more than 36,000 living vertebrate species and occupy a wide range of aquatic ecosystems. Despite their overwhelming success, extinct taxa outside of the living radiation--stem teleosts--remain poorly understood. Dorsetichthys bechei is an Early Jurassic stem teleost of historic importance. Although D. bechei is well described, its proximity to the teleost crown and relationships with other stem teleosts is challenging due to previous associations with the wastebasket assemblage known as "pholidophorids". Here we present a new, three-dimensionally preserved specimen of Dorsetichthys bechei from the Blue Lias Formation (Sinemurian) Lyme Regis, UK. High-resolution CT scanning of this specimen plus additional material reveals previously unknown internal morphological information, including of the jaw and palate, hyoid arch, and gill skeleton. Importantly, this previously undescribed articulated specimen permits description of the external dermal skeleton and internal endoskeleton for the same individual, clarifying past accounts drawing on composite descriptions of two- and three-dimensionally preserved specimens. We confirm the presence of important teleost synapomorphies such as a mobile premaxilla and quadratojugal process. However, contrasting previous accounts, we find no evidence for dorsal and ventral hypohyals or a postarticular process of the lower jaw. We also confirm the presence of a prearticular. The presence of a mobile upper jaw, elaborate gill rakers and reduced dentition also support a possible facultative filter feeding ecology. These new anatomical data support removal of D. bechei from Pholidophoridae and Pholidophoriformes as currently defined but indicate that finer-scale patterns of relationships among more crownward members of the teleost stem are some way from being resolved.

paleontology↗

bioRxiv2023

The three-dimensionally articulated oral apparatus of a Devonian heterostracan sheds light on feeding in Palaeozoic jawless fishes

Attempts to explain the origin and diversification of vertebrates have commonly invoked the evolution of feeding ecology, contrasting the passive suspension feeding of invertebrate chordates and larval lampreys with active predation in living jawed vertebrates. Of the extinct jawless vertebrates that phylogenetically intercalate these living groups, the feeding apparatus is preserved only in the early diverging stem-gnathostome heterostracans and its anatomy remains poorly understood. Here we use X-ray microtomography to characterise the feeding apparatus of the pteraspid heterostracan Rhinopteraspis dunensis (Roemer, 1855). We show that the apparatus is composed of thirteen plates arranged approximately bilaterally, the majority of which articulate from the postoral plate. Our reconstruction of the apparatus shows that the oral plates would have been capable of movement within the dorso-ventral plane, but their degree of movement was limited. The functional morphology of the apparatus in Rhinopteraspis precludes all proposed interpretations of feeding except for suspension/deposit feeding and we interpret the apparatus as having served primarily to moderate the oral gape. This is consistent with evidence that at least some early jawless gnathostomes were suspension feeders and runs contrary to macroecological scenarios that envisage early vertebrate evolution as characterised by a directional trend towards increasingly active food acquisition.

paleontology↗

bioRxiv2023

Three-dimensional anatomy of the early Eocene {dagger}Whitephippus (Teleostei: Lampriformes) documents parallel conquests of the pelagic environment by multiple teleost lineages

The early Eocene fossil assemblage of the London Clay (Southeastern England) is a key window to the early Paleogene diversification of teleost fishes in the open ocean. Despite their three-dimensional preservation that offers unique insight into skeletal anatomy, the London Clay fossils are still poorly described for the most part. {dagger}Whitephippus tamensis is a fossil teleost from this assemblage, known by several well-preserved specimens. Based on a complete description of the known material, including previously hidden structures (braincase, hyoid and branchial arches) revealed through 3D microtomography, we reinterpret {dagger}Whitephippus as an early member of the teleost group Lampriformes. More specifically, the anatomy of {dagger}Whitephippus indicates that it is likely a member of the so-called pelagic clade including modern opahs and oarfishes. This redescription of {dagger}Whitephippus provides the earliest definitive evidence of lampriforms conquering the pelagic environment, alongside numerous other teleost lineages.

paleontology↗

bioRxiv2023

Hagfish genome illuminates vertebrate whole genome duplications and their evolutionary consequences

Whole genome duplications (WGDs) are major events that drastically reshape genome architecture and are causally associated with organismal innovations and radiations1. The 2R Hypothesis suggests that two WGD events (1R and 2R) occurred during early vertebrate evolution2, 3. However, the veracity and timing of the 2R event relative to the divergence of gnathostomes (jawed vertebrates) and cyclostomes (jawless hagfishes and lampreys) is unresolved4-6 and whether these WGD events underlie vertebrate phenotypic diversification remains elusive7. Here we present the genome of the inshore hagfish, Eptatretus burgeri. Through comparative analysis with lamprey and gnathostome genomes, we reconstruct the early events in cyclostome genome evolution, leveraging insights into the ancestral vertebrate genome. Genome-wide synteny and phylogenetic analyses support a scenario in which 1R occurred in the vertebrate stem-lineage during the early Cambrian, and the 2R event occurred in the gnathostome stem-lineage in the late Cambrian after its divergence from cyclostomes. We find that the genome of stem-cyclostomes experienced two additional, independent genome duplications (herein CR1 and CR2). Functional genomic and morphospace analyses demonstrate that WGD events generally contribute to developmental evolution with similar changes in the regulatory genome of both vertebrate groups. However, appreciable morphological diversification occurred only after the 2R event, questioning the general expectation that WGDs lead to leaps of morphological complexity7.

genomics↗

bioRxiv2022

Integrating human iPSC-derived macrophage progenitors into retinal organoids to generate a mature retinal microglial niche

In the retina, microglia are resident immune cells that are essential for retinal development and function. Retinal microglia play a central role in mediating pathological degeneration in diseases such as glaucoma, retinitis pigmentosa, age-related neurodegeneration, ischemic retinopathy and diabetic retinopathy. Current models of mature human retinal organoids (ROs) derived from iPS cell (hiPSC) do not contain resident microglia integrated into retinal layers. Increasing cellular diversity in ROs by including resident microglia would more accurately represent the native retina and better model diseases in which microglia play a key role. In this study, we develop a new 3D in vitro tissue model of microglia-containing retinal organoids by co-culturing ROs and hiPSC-derived macrophage precursor cells (MPCs). We optimized the parameters for successful integration of MPCs into retinal organoids. We then reproducibly integrate MPCs into ROs where they develop into mature microglia (iMG) as seen by 1) migration to the appropriate anatomical locations; 2) development of a mature resting morphology; and 3) expression of mature microglial markers. We show that while in the ROs, MPCs migrate to the equivalent of the outer plexiform layer where retinal microglia cells reside in healthy retinal tissue. While there, they develop a mature morphology characterized by small cell bodies and long branching processes which is only observed in vivo. During this maturation process these microglia cycle through an activated phase followed by a stable mature phase characterized by cell-type specific microglia markers Tmem119 and P2ry12. This co-culture system may be useful for understanding the pathogenesis of retinal diseases involving retinal microglia and for drug discovery.

cell biology↗

bioRxiv2022

How to tuna fish: constraint, convergence and integration in the neurocranium of pelagiarian fishes.

Morphological evolution of the vertebrate skull has been explored across a wide range of tetrapod clades, but teleost fishes, accounting for roughly half of all vertebrate species, have largely been overlooked. Here we present the results of a study investigating three-dimensional morphological evolution across 114 species of Pelagiaria, a morphologically diverse clade of open-ocean teleost fishes that includes tuna and mackerel. Despite showing high shape disparity, the majority of taxa are concentrated in fairly restricted regions of morphospace, with taxa from all families falling into three distinct clusters. Phylogenetic signal in shape data is significant but low (Kmult = 0.27, p = 0.001) and a single-rate Ornstein-Uhlenbeck model of evolution is supported, revealing convergence in shape within and between families. Shape is significantly correlated with body elongation (R2 = 0.35, p =0.001), but correlation with size, diet, and habitat depth is weak. Integration of the neurocranium is high, supporting the hypothesis that high integration may promote the evolution of more extreme morphologies. Taken together, these results suggest that shape evolution in the pelagiarian neurocranium is constrained by a number of factors, resulting in the repeated evolution of a restricted range of morphologies.

evolutionary biology↗

bioRxiv2022

Imbalanced Unfolded Protein Response Signaling Contributes to 1-Deoxysphingolipid Retinal Toxicity

1-Deoxysphingolipids (1-dSLs) are atypical cytotoxic sphingolipids formed through the substitution of alanine for serine in de novo sphingolipid biosynthesis. Accumulation of 1-dSLs has been linked to diseases of the eye such as diabetic retinopathy and Macular Telangiectasia Type 2 (MacTel). However, the molecular mechanisms by which 1-dSLs induce toxicity in retinal cells remains poorly understood. Here, we integrate bulk and single-nucleus RNA-sequencing to define the biological pathways that contribute to toxicity caused by the 1-dSL species, 1-deoxysphinganine (1-dSA), in human retinal organoids. Our results demonstrate that 1-dSA preferentially and differentially activates signaling arms of the unfolded protein response (UPR) in photoreceptor cells and Muller glia within retinal organoids. Using a combination of pharmacologic inhibitors and activators, we define the roles for individual arms of the UPR in 1-dSL-mediated toxicity. We show that sustained PERK signaling through the integrated stress response (ISR) promotes 1-dSL-induced apoptosis in photoreceptors. In contrast, deficiencies in signaling through the ATF6 arm of the UPR contribute to photoreceptor toxicity. These results indicate that imbalanced signaling between the pro-apoptotic PERK/ISR and protective ATF6 arms of the UPR contributes to 1-dSL-induced photoreceptor toxicity. Further, our results identify new opportunities to intervene in 1-dSL linked diseases through targeting different signaling arms of the UPR.

cell biology↗

bioRxiv2022

Exceptional fossil preservation and evolution of the ray-finned fish brain

Brain anatomy provides key evidence for ray-finned fish relationships1, but two key limitations obscure our understanding of neuroanatomical evolution in this major vertebrate group. First, the deepest branching living lineages are separated from the groups common ancestor by hundreds of millions of years, with indications that aspects of their brain morphology-like other aspects of their anatomy2,3-are specialised relative to primitive conditions. Second, there are no direct constraints on brain morphology in the earliest ray-finned fishes beyond the coarse picture provided by cranial endocasts: natural or virtual infillings of void spaces within the skull4-8. Here we report brain and cranial nerve soft-tissue preservation in {dagger}Coccocephalichthys wildi, a [~]319-million-year-old (Myr) ray-finned fish. This oldest example of a well-preserved vertebrate brain provides a unique window into neural anatomy deep within ray-finned fish phylogeny. {dagger}Coccocephalichthys indicates a more complicated pattern of brain evolution than suggested by living species alone, highlighting cladistian apomorphies9 and providing temporal constraints on the origin of traits uniting all extant ray-finned fishes9-11. Our findings, along with a growing set of studies in other animal groups12-16, point to the significance of ancient soft tissue preservation in understanding the deep evolutionary assembly of major anatomical systems outside of the narrow subset of skeletal tissues17-20.

paleontology↗