Biology subjects

Martin, K.

Publications and source records attributed to Martin, K..

At least 19 recordsLinked to original sources

bioRxiv2026

BRET-Based Ligand Binding at Recombinant and Endogenous Dopamine D2 Receptors

Dopamine D2 receptor (D2R) regulates diverse biological processes and is an important therapeutic target, underscoring the need for robust methods to quantify ligand binding at this receptor. Bioluminescence resonance energy transfer (BRET)-based ligand binding assays have emerged as a powerful platform for quantifying binding in living cells, but their application to D2R has been limited by the availability of suitable fluorescent tracers. Here, we developed three far-red fluorescent antagonists (CELT-240, CELT-383, and CELT-385) as BRET tracers for D2R. All three compounds produced specific, saturable D2R binding with nanomolar affinity. Further characterization of CELT-385 demonstrated its utility for kinetic and competition binding measurements and revealed high affinity binding at the closely related dopamine D3 receptor (D3R). We also extended BRET-based ligand binding beyond genetically-modified receptors using bystander BRET, enabling measurements at unmodified recombinant and endogenously expressed D2R. Together, these findings provide new tools for quantitative D2R/D3R ligand binding and a template for extending BRET-based ligand binding to endogenously expressed GPCRs.

pharmacology and toxicology↗

bioRxiv2026

Rhomboid protease Rhbdl2 regulates macrophage recruitment and wound regeneration in zebrafish

Tissue regeneration requires tight control of immune cell behavior, yet the mechanisms that restrain immune-driven regenerative responses remain poorly defined. Here, we identify the rhomboid intramembrane serine protease Rhbdl2 as a critical regulator of regeneration in zebrafish. We generated rhbdl2 mutants by CRISPR Cas9 and found that it does not affect normal development, but triggers enhanced regenerative growth following injury, accompanied by increased macrophage accumulation at the wound site, which is accompanied by increased early apoptosis and proliferation. Proteomic analyses reveal increased Rac2 protein levels in rhbdl2 mutants, indicating dysregulated immune signaling. Functionally, Rac2 morpholino oligonucleotides mediated knockdown in rhbdl2 mutant larvae suppresses the elevated macrophage recruitment and enhanced tissue regenerative phenotype. Together, these findings uncover Rhbdl2 as an immune checkpoint that constrains macrophage driven enhanced regeneration, with vast implications for inflammatory disease, fibrosis, and tumor immune interactions.

immunology↗

bioRxiv2025

Optimization of AAV tools to target Muller glial cells for retinal gene therapy

Reprogramming of Muller glial (MG) cells into retinal neurons has the potential to treat vision loss by regenerating the retina. Development of efficient gene delivery systems to target the MG cells is critical. Adeno-associated virus (AAV) serotypes and promoter specificity are important factors that influence AAV transduction profile in the retina. However, studies that optimize these parameters to specifically target MG cells are limited, in particular in rats which are commonly used for eye research. Here we tested 4 AAV serotypes and 14 promoters to optimize gene delivery to human MG cells in vitro and/or rat MG cells in vivo. We showed that the combinatorial use of MG-specific serotypes and promoters achieved high specificity for MG cell targeting, with ShH10Y serotype and the GFAP (gfaABC1D) promoter as the best performing tool to target rat MG cells in vivo. We developed new AAV vectors using known and novel MG-specific promoters and engineered short promoter variants to improve the cargo capacity of AAV delivery. Our results highlighted a number of promoters that can target MG cells in vitro or in vivo. This study further expands the AAV toolbox to target MG cells, which has important implications for retinal gene therapy development.

molecular biology↗

bioRxiv2025

The germline-restricted chromosome orchestrates germ cell development in passerine birds

While the definition of germ cell fate has been extensively studied in model organisms, evolutionary innovations and mechanistic novelties may remain hidden in understudied systems. The phenomenon of programmed DNA elimination allows germ cells to acquire germline-restricted genes, offering a novel paradigm of germ cell specificity. In passerine birds, the germline-restricted chromosome (GRC) is eliminated from somatic cells in early embryogenesis, yet the role and consequences of its maintenance in the germ cells remain poorly understood. Here, using the zebra finch Taeniopygia guttata as a model, we combined RNA-seq and Spatial Transcriptomics to construct a high-resolution spatiotemporal expression map to understand the role of the GRC across germ cell development. We found a GRC-linked integrin-BMP signaling in maturing oocytes and tfebGRC upregulation at blastoderm embryos, suggesting the involvement of the GRC in oocyte maturation and germ cell determination. We also identified developmental specialization of GRC-linked gene expression relative to their paralogs on the autosomes and sex chromosomes, revealing a gene repertoire which promotes germline stemness and germline/soma distinction. Together, the passerine GRC constitutes a unique system that manifests germ cell complexity, whilst allowing pinpointing the effects on gene expression that may elucidate vertebrate germ cell fate.

developmental biology↗

bioRxiv2025

Sex differences in development alter the fledgling sex ratio in a lekking bird with strong sexual size dimorphism

Sex ratio variation is of fundamental importance for population ecology, and the evolution of sex roles and life-histories. Yet, the ecological mechanisms underlying such variation remain often unknown. Using a multiyear dataset from captive and wild precocial Ruffs Calidris pugnax, we show that poorer survival and later fledging of males relative to females result in a female biased sex ratio of the fledgling population. Both sex-specific survival and maturation time contributed equally to an increasing sex ratio bias from hatching to fledging in this sexually dimorphic bird. On average, juvenile females fledged three days earlier than males due to expedited wing development, despite the higher absolute rate of wing growth in males. We argue that sex differences in growth, maturation, and offspring survival are likely the result of strong pre-sexual selection on males to achieve dominance and may help to enforce the Darwinian sex roles observed in this species.

ecology↗

bioRxiv2025

Benchmarking antigen-aware inverse folding methods for antibody design.

Computational antibody design has seen many recent advances pioneered via the use of language models and advanced structure prediction tools. Developing a de novo antibody against a specific antigen requires structural awareness that most language models lack. A prominent class of machine learning methods combining the best of language model and structural worlds is inverse folding. This approach aims to predict a sequence that would fit a given structure. Such methods are now increasingly used to predict alternate sequences given a structure of a binder. It is known that, just like language models, such methods have certain predictive power in identifying binders. Here we performed a set of tests to reveal where, if at all, such methods provide value in the realistic setting of antibody discovery.

bioinformatics↗

bioRxiv2025

Effect of combined Respiratory Muscle Training on Sleep and Cardiovascular Biometrics in a non-clinical cohort

Study objectivesSleep disruption is a growing health problem, affecting a significant portion of the adult population worldwide. Insufficient sleep has various short- and long-term consequences, including an elevated risk of cardiovascular and metabolic diseases. Previous research has demonstrated that resistive respiratory muscle training (RMT) can enhance both sleep quality and cardiovascular health in individuals diagnosed with obstructive sleep apnea, underscoring its efficacy as a non-pharmacological therapeutic strategy for this patient group. However, the effects of RMT on sleep and cardiovascular parameters have not been investigated in non-clinical populations. MethodsThis prospective study investigated the effects of combined inspiratory and expiratory RMT (cRMT) on sleep parameters and cardiovascular biometrics, specifically heart rate variability (HRV), in a non-clinical adult cohort. Utilizing a wearable device for remote data collection, this randomized controlled trial included 67 participants divided into good and poor sleeper groups based on historical sleep data. During a five-week intervention period, participants in the intervention group underwent cRMT using a Breather Fit device, while control group participants did not receive the intervention. ResultsStudy findings demonstrate a significant increase in overnight HRV metrics during the intervention period compared to the baseline, indicating improved autonomic cardiac function. However, no significant changes were observed in any parameters of sleep quality. ConclusionThese results suggest that cRMT may enhance cardiovascular health by improving autonomic function in non-clinical populations without directly affecting sleep quality. This study underscores the potential of RMT as a non-pharmacological intervention to improve cardiovascular health, warranting further investigation in future studies. Brief summaryO_LICurrent Knowledge/Study Rationale: Insufficient, disrupted, or ineffective sleep is prevalent and can increase the risk of developing cardiovascular disease (CVD). While respiratory muscle training has been found effective in improving sleep and cardiovascular parameters in sleep apnea, its effect in healthy people with or without sleep issues is unknown. C_LIO_LIStudy Impact: This study demonstrates significant benefits of RMT on CVD metrics including HR and HRV, indicating improved autonomic cardiac function. These findings highlight the potential of RMT as a non-pharmacological intervention to improve cardiovascular health. C_LI

physiology↗

bioRxiv2025

Elp3 uses a conserved molecular tunnel to transport acetate between distant active sites and catalyze tRNA wobble base modification

The radical SAM enzyme Elp3 and eukaryotic Elongator complex catalyze formation of a key intermediate transfer RNA (tRNA) modification, 5-carboxymethyluridine (cm5U), in the anticodons of tRNAs across all domains of life. cm5U-derived modifications are important for fine tuning codon-anticodon interactions and efficient protein translation, and defects in this modification are linked to development of neurodegenerative disease in humans. Here we reconstitute tRNA modification activity with a model Elp3 enzyme and combine structural analyses, enzymology, and isotope incorporation experiments to show Elp3 harbors a conserved molecular tunnel that shuttles free acetate molecules from the acetyl-CoA binding domain to the radical SAM active site over 20 [A] away, where acetate undergoes radical-mediated reaction and addition to tRNA U34. Our model explains how Elp3 and Elongator bridge a large distance between active sites to catalyze tRNA carboxymethylation and illustrate a unique mechanism for intermediate transport in radical SAM enzymes. Graphical AbstractThe radical SAM enzyme Elp3 installs a critical tRNA wobble base modification in organisms across all domains of life. Here, the authors show how Elp3 uses a conserved molecular tunnel to transport acetate between distant Elp3 active sites to catalyze tRNA carboxymethylation, revealing a new mechanism for Elp3 and Elongator-mediated tRNA modification and the first example of acetate transport through an enzyme tunnel. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/652618v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@b3c25eorg.highwire.dtl.DTLVardef@19dd2b6org.highwire.dtl.DTLVardef@74d07corg.highwire.dtl.DTLVardef@123896f_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

nanoFOLD : sequence design of nanobodies via inverse folding

Antibodies devoid of light chains are a promising class of biotherapeutics. Computational methods that address these molecules are crucially needed to accelerate the traditional, long and expensive experimental process of their discovery. Inverse folding, wherein one is tasked to predict a sequence given molecular coordinates, is an established method in scaffold-based protein design. Here we develop an inverse folding method speci[fi]c to nanobodies. We demonstrate its application in nanobody-engineering scenarios of enriching binders from next-generation sequencing experiments and novel binder design.

bioinformatics↗

bioRxiv2025

Shear stress targeted delivery of nitroglycerin to brain collaterals improves ischaemic stroke outcome

In patients with ischaemic stroke, retrograde perfusion of the penumbra by the leptomeningeal collateral vessels (LMCs) is a strong predictor of clinical outcome, thus raising the possibility that enhancing LMC flow could offer a novel therapeutic approach. Here, using computational modelling we show that LMCs experience elevated fluid shear stress that is significantly higher than that in other blood vessels during ischaemic stroke in animals and humans. We take advantage of this to selectively enhance flow in LMCs using shear-activated nanoparticle aggregates carrying the vasodilator nitroglycerin (NG-NPAs) that specifically release drug in regions of vessels with high shear stress ([≥]100 dyne/cm2). The NG-NPAs significantly increased LMC-mediated penumbral perfusion, decreased infarct volume, and reduced neurological deficit without altering systemic blood pressure in a rat ischaemic stroke model. The NG-NPAs also did not cause known common side effects of systemic nitrate administration, such as systemic hypotension, cerebral vascular steal, cortical vein dilation, or intracranial pressure elevation. Systemic administration of free NG at the maximal tolerated dose, which was ten times higher than the dose of NG used in the NG-NPAs, did not enhance LMC perfusion and dropped blood pressure. Thus, packaging NG within shear-activated NPAs can potentially enable this widely available vasodilator to become a highly effective therapeutic for ischaemic stroke.

physiology↗

bioRxiv2024

Neutrophils drive sexual dimorphism in experimental periodontitis

The motivating premise of this study is to improve the treatment of periodontal disease by elucidating sex-specific mechanisms of periodontal disease progression. Men and women experience inflammation in fundamentally different ways and understanding the sex-specific biology leading to inflammation and bone loss in the periodontium will inevitably improve patient outcomes. We therefore examined clinical and immunological differences in the progression of periodontal disease using the ligature-induced periodontitis model. Periodontitis was induced in male and female C57BL/6j mice by tying a 5-0 silk suture around the left maxillary second molar. The ligature was left on for 7 or 21 days at which point maxillae were characterized for bone loss by CT or immune infiltrate by flow cytometry. Neutrophil depletion was accomplished through systemic administration of a Ly6G antibody. Conditions were compared using two-way ANOVA with Tukeys multiple comparison correction from n[≥]5 animals. Ligature-induced periodontitis led to alveolar bone loss at both 7 and 21 days in both female and male mice. Males and females had approximately the same amount of linear bone loss 7 days post-ligature placement, while male mice had significantly more linear bone loss by day 21. Male mice had significantly more immune cells in their maxillae 7 days post ligature placement compared to female mice. Both male and female mice showed a shift in immune populations towards neutrophils, with no significant difference between males and females. Neutrophil counts were significantly elevated in male mice on day 7 but not day 21, while female mice did not have any statistically significant changes in neutrophil counts. Neutrophil depletion using a Ly6G antibody limited bone loss in male but not female mice relative to isotype antibody-treated controls. Analysis of single-cell sequencing data from human patients with periodontitis showed differences in neutrophil phenotypes that were also observed in a mouse model of periodontitis. Together, these data suggest a mechanistic role for neutrophil inflammation in sexual dimorphism in periodontitis.

pathology↗

bioRxiv2024

Ethanol drinking sex-dependently alters cortical IL-1β synaptic signaling and cognitive behavior in mice

Individuals with alcohol use disorder (AUD) struggle with inhibitory control, decision making, and emotional processing. These cognitive symptoms reduce treatment adherence, worsen clinical outcomes, and promote relapse. Neuroimmune activation is a key factor in the pathophysiology of AUD, and targeting this modulatory system is less likely to produce unwanted side effects compared to directly targeting neurotransmitter dysfunction. Notably, the cytokine interleukin-1{beta} (IL-1{beta}) has been broadly associated with the cognitive symptoms of AUD, though the underlying mechanisms are not well understood. Here we investigated how chronic intermittent 24-hour access two bottle choice ethanol drinking affects medial prefrontal cortex (mPFC)-related cognitive function and IL-1 synaptic signaling in male and female C57BL/6J mice. In both sexes, ethanol drinking decreased reference memory and increased mPFC IL-1 receptor 1 (IL-1R1) mRNA levels. In neurons, IL-1{beta} can activate either pro-inflammatory or neuroprotective intracellular pathways depending on the isoform of the accessory protein (IL-1RAcP) recruited to the IL-1R1 complex. Moreover, ethanol drinking sex-dependently shifted mPFC IL-1RAcP isoform gene expression and IL-1{beta} regulation of mPFC GABA synapses, both of which may contribute to female mPFC resiliency and male mPFC susceptibility. This type of signaling bias has become a recent focus of rational drug development. Therefore, in addition to increasing our understanding of how IL-1{beta} sex-dependently contributes to mPFC dysfunction in AUD, our current findings also support the development of a new class of pharmacotherapeutics based on biased IL-1 signaling. Highlights- Female mice consumed more ethanol, but were less cognitively impaired than males - Ethanol altered IL-1{beta} effects at mPFC GABA synapses, with females less sensitive than males - Ethanol altered mPFC Il1rap mRNA to promote female neuroprotection and male neuroinflammation

neuroscience↗

bioRxiv2024

Sex and morph variation in activity from early ontogeny to maturity in ruffs (Calidris pugnax)

Intraspecific variation provides the substrate for the evolution of organisms. Ruffs show exceptional phenotypic variation in physiology, appearance and behaviour linked to variation between sexes and male alternative reproductive tactics (ARTs). The male ARTs are associated with the evolution of separate morphs, which are encoded by an autosomal supergene. However, the effects of the supergene on females and chicks are much less well understood. In particular, it is still unknown, whether females also show morph-specific behavioural variation, when behavioural differences emerge during ontogeny, and whether behavioural differences can be detected outside of the breeding context. To address these knowledge gaps, we repeatedly measured the activity in an unfamiliar environment, also known as exploration behaviour, of 109 hand-raised young ruffs throughout their first two years of life. We used automated tracking in an open field arena, and quantified the distance moved within 10 minutes to examine behavioural differences between sexes, morphs and individuals. The activity of young ruffs rapidly increased during the first month after their crouching reflex, a response to potential threats, subsided. Repeatability of individual activity was initially low but increased throughout juvenile ontogeny and was high (R = 0.5) from day 21 onwards. Variation in activity was clearly sex-linked with females moving more than males, indicating potential energetic trade-offs accompanying the strong sexual size dimorphism. In contrast, morph differences in activity remained inconsistent and elusive, both in females and in males. Our results indicate that in species where much of the known behavioural variation is linked to mating tactics, a non-reproductive behaviour can show between-individual variation and clear sex differences, whereas morph differences appear less pronounced.

animal behavior and cognition↗

bioRxiv2024

Can we trace the social affiliation of rooks (Corvusfrugilegus) through their vocal signature?

Inter-individual recognition is crucial for stable social relationships and it is frequently mediated through vocal signatures. In socially complex species, recognition may additionally require additional levels corresponding to other layers of social organisation such as the pair, family, social group or colony. Additional vocal signatures may encode these different levels of social organisations for recognition. We investigated this hypothesis in the calls of the rook (Corvus frugilegus), a highly social corvid. Rooks form large breeding colonies where multiple pairs nest in clusters. We recorded the calls of five colonies located in France and in Great Britain, including both wild and captive colonies. To exclude variations due to different call types, we focused on the loud nest call produced exclusively by nesting females during the breeding season. We compared the acoustic distance of calls from each individual and between individuals at various levels of nest proximity, i.e. from the same nest cluster, from different nest clusters, from colonies within the same country, and from colonies in different countries. The only vocal signatures we found were at the individual level, but not at the nest cluster or colony level. This suggests a lack of vocal convergence in this species, at least for the nest call, which may be important for pair recognition in large colonies. Further studies should now evaluate if types of calls other than the nest call better carry vocal signatures as markers of different layers of sociality in this species, or if vocal divergence is a more general vocal phenomenon. In that case, applying new methods of monitoring vocal signatures in wild individuals should help understand the cognitive, social and environmental mechanisms underlying this vocal singularisation. 1. Significance statementInter-individual recognition is crucial for social relationships in animals, and is often mediated by individual-specific acoustic characteristics in vocalisations, called a vocal signature. High levels of social organisations, such as a social group of familiar conspecifics or a breeding colony, may likewise be signalled by vocal signatures shared by multiple individuals. We used machine-learning techniques to investigate vocal signatures at multiple social levels in the nest call of brooding female rooks, a corvid species that breeds colonially but lives year-round in social groups. We find evidence of a strong individual vocal signature, but no common vocal signature even in females that nest close together, or in the same colony. A strong individual vocal signature may be a potent tool to monitor populations in this species with minimal disturbance and minimal material, especially as corvids are frequently targeted by human-fauna conflicts in continental Europe.

animal behavior and cognition↗

bioRxiv2023

Validation of cell-free protein synthesis aboard the International Space Station

Cell-free protein synthesis (CFPS) is a rapidly maturing in vitro gene expression platform that can be used to transcribe and translate nucleic acids at the point of need, enabling on-demand synthesis of peptide-based vaccines and biotherapeutics, as well as the development of diagnostic tests for environmental contaminants and infectious agents. Unlike traditional cell-based systems, CFPS platforms do not require the maintenance of living cells and can be deployed with minimal equipment; therefore, they hold promise for applications in low-resource contexts, including spaceflight. Here we evaluate the performance of cell-free BioBits(R) platform aboard the International Space Station by expressing RNA-based aptamers and fluorescent proteins that can serve as biological indicators. We validate two classes of biological sensors that detect either the small molecule DFHBI or a specific RNA sequence. Upon detection of their respective analytes, both biological sensors produce fluorescent readouts that are visually confirmed using a handheld fluorescence viewer and imaged for quantitative analysis. Our findings provide insight into the kinetics of cell-free transcription and translation in a microgravity environment and reveal that both biosensors perform robustly in space. Our findings lay the groundwork for portable, low-cost applications ranging from point-of-care health monitoring to on-demand detection of environmental hazards in low-resource communities both on Earth and beyond. Visual graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/570403v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@140f8f2org.highwire.dtl.DTLVardef@97dda3org.highwire.dtl.DTLVardef@5824bforg.highwire.dtl.DTLVardef@d47ded_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2023

A fluorescence viewer for rapid molecular assay readout in space and low-resource terrestrial environments

Fluorescence-based assays provide sensitive and adaptable methods for point of care testing, environmental monitoring, studies of protein abundance and activity, and a wide variety of additional applications. Currently, their utility in remote and low-resource environments is limited by the need for technically complicated or expensive instruments to read out fluorescence signal. Here we describe the Genes in Space Fluorescence Viewer (GiS Viewer), a portable, durable viewer for rapid molecular assay readout that can be used to visualize fluorescence in the red and green ranges. The GiS Viewer can be used to visualize any assay run in standard PCR tubes and contains a heating element. Results are visible by eye or can be imaged with a smartphone or tablet for downstream quantification. We demonstrate the capabilities of the GiS Viewer using two case studies - detection of SARS-CoV-2 RNA using RT-LAMP and quantification of drug-induced changes in gene expression via qRT-PCR on Earth and aboard the International Space Station. We show that the GiS Viewer provides a reliable method to visualize fluorescence in space without the need to return samples to Earth and can further be used to assess the results of RT-LAMP and qRT-PCR assays on Earth.

molecular biology↗

bioRxiv2023

Sperm traits of the three genetic morphs in the ruff sandpiper

BackgroundThe ruff sandpiper Calidris pugnax is a Palearctic lekking shorebird with three genetic morphs determined by an autosomal inversion. Male morphs differ strikingly in body size, ornaments, endocrinology and mating behavior. Aggressive Independents represent the ancestral haplotype, while female-mimicking Faeders and semi-cooperative Satellites are the inverted haplotypes. Because one inversion breakpoint is homozygous lethal, the inverted haplotypes cannot recombine and are expected to accumulate deleterious mutations. The inversion regions also harbor genes involved in spermatogenesis. However, it remains unknown whether the genetic differences between the morphs also translate into differences in sperm traits. Here, we use a captive-bred population of ruffs to compare sperm swimming speed and morphology among the morphs. ResultsRuff sperm morphologically resembled those of passerines, but moved differently, vibrating from side to side while slowly moving forward, rather than rotating while moving forward. Faeder sperm moved the slowest, which is consistent with the prediction of genetic deterioration over time. However, against expectation, sperm of Independents did not seem to be of the highest quality, i.e., their sperm were not the fastest nor the least variable, and they had sperm with the shortest tail and midpiece. Although the midpiece contains the energy-producing mitochondria, sperm midpiece length was not associated with sperm swimming speed. Instead, two of three velocity metrics weakly positively correlated with head length (absolute and relative). ConclusionsThe three genetically determined ruff morphs showed subtle differences in swimming speed and in the length of some sperm components. However, the between-morph differences in sperm swimming speed were not linked to the differences in morphology. We conclude that there is at best limited evidence for lower-quality sperm in the morphs that carry the inversion, and suggest that the potential for the evolution of morph-specific sperm adaptations may be limited in this system. Lay SummaryThe ruff sandpiper is a shorebird that exhibits three genetically distinct types of males, which differ markedly in body size, ornaments, hormones, and mating behavior. Aggressive Independents represent the type that evolved first. Semi-cooperative Satellites and female-mimicking Faeders evolved later through a specific type of genetic rearrangement called an inversion, in which a segment of a chromosome reversed in orientation. Due to the nature of this inversion, Satellite and Faeder chromosomes are expected to deteriorate over time. However, it remains unclear whether the genetic differences between these morphs, which affect physiological and behavioral traits, also translate into differences in sperm traits. We used a captive population of ruffs to compare sperm swimming speed and length measurements between the three types of males. Faeder sperm was the slowest, which is consistent with expectations based on genetic deterioration over time. However, against our expectations, the sperm of Independents does not appear to have better performance characteristics. Although the midpiece of a sperm is responsible for energy production, the length of the midpiece did not relate to sperm swimming speed.

evolutionary biology↗

bioRxiv2023

Emergent epileptiform activity drives spinal sensory circuits to generate ectopic bursting in intraspinal afferent axons after cord injury

Spinal cord injury (SCI) leads to hyperexcitability and dysfunction in spinal sensory processing. As hyperexcitable circuits can become epileptiform elsewhere, we explored whether such activity emerges in spinal sensory circuits in a thoracic SCI contusion model of neuropathic pain. Recordings from spinal sensory axons in multiple below-lesion segmental dorsal roots (DRs) demonstrated that SCI facilitated the emergence of spontaneous ectopic burst spiking in afferent axons, which synchronized across multiple adjacent DRs. Burst frequency correlated with behavioral mechanosensitivity. The same bursting events were recruited by afferent stimulation, and timing interactions with ongoing spontaneous bursts revealed that recruitment was limited by a prolonged post-burst refractory period. Ectopic bursting in afferent axons was driven by GABAA receptor activation, presumably via shifting subthreshold GABAergic interneuronal presynaptic axoaxonic inhibitory actions to suprathreshold spiking. Collectively, the emergence of stereotyped bursting circuitry with hypersynchrony, sensory input activation, post-burst refractory period, and reorganization of connectivity represent defining features of epileptiform networks. Indeed, these same features were reproduced in naive animals with the convulsant 4-aminopyridine (4-AP). We conclude that SCI promotes the emergence of epileptiform activity in spinal sensory networks that promotes profound corruption of sensory signaling. This corruption includes downstream actions driven by ectopic afferent bursts that propagate via reentrant central and peripheral projections and GABAergic presynaptic circuit hypoexcitability during the refractory period.

neuroscience↗