Biology subjects

Elliott, M.

Publications and source records attributed to Elliott, M..

10 recordsLinked to original sources

bioRxiv2025

Gut microbiota of dogs with cancer receiving anti-EGFR/HER2 immunization reveals potential biomarkers of patient survival

BackgroundCanine cancer remains a leading cause of death in dogs, yet advances in veterinary oncology lag behind human medicine, particularly in immunotherapy. While immune checkpoint inhibitors are just entering clinical trials in dogs, other immunotherapies, such as anti-EGFR/HER2 vaccines, have shown promise. In parallel, mounting evidence in human oncology links gut microbiota composition to immunotherapy response. However, this relationship remains unexplored in canine patients. In this pilot study, we analyzed the gut microbiome of dogs enrolled in a clinical trial of anti-EGFR/HER2 immunotherapy to identify microbial biomarkers associated with survival outcomes. MethodsRectal swab samples of 51 dogs were collected at the time of first vaccine administration (baseline microbiota) and underwent 16S rRNA gene sequencing according to standard protocols. ResultsMicrobiome composition showed no significant differences by cancer type, sex, or breed, suggesting no inherent microbiome bias in the cohort. However, Cox regression analysis revealed 11 bacterial taxa whose abundances were significantly associated with overall survival (FDR < 0.1), independently of cancer type. Seven taxa were linked to increased mortality risk, while four were associated with prolonged survival. These associations remained significant after adjusting for confounders such as hemangiosarcoma diagnosis and advanced age. ConclusionsTo our knowledge, this is the first study to identify gut microbial signatures associated with survival in dogs undergoing cancer immunotherapy. These findings suggest that specific bacterial taxa may serve as prognostic biomarkers for immunotherapy outcomes in canine cancer, laying the groundwork for microbiota-targeted strategies to improve therapeutic efficacy in veterinary oncology.

cancer biology↗

bioRxiv2024

Pathological microcircuits initiate epileptiform events in patient hippocampal slices

How seizures begin at the level of microscopic neuronal circuits remains unknown. Advancements in high-density CMOS-based microelectrode arrays can be harnessed to study neuronal network activity with unprecedented spatial and temporal resolution. We use high-density electrophysiology recordings to probe the network activity of human hippocampal brain slices from six patients with mesial temporal lobe epilepsy. Two slices from the dentate gyrus exhibited epileptiform activity in the presence of low magnesium media with kainic acid. Both slices exhibit network oscillations indicative of a reciprocally connected circuit, which is unexpected under normal physiological conditions. Future studies may apply this approach to elucidate the network signals that underlie seizure initiation.

neuroscience↗

bioRxiv2024

Changes in brain connectivity and neurovascular dynamics during dexmedetomidine-induced loss of consciousness

Understanding the neurophysiological changes that occur during loss and recovery of consciousness is a fundamental aim in neuroscience and has marked clinical relevance. Here, we utilize multimodal magnetic resonance neuroimaging to investigate changes in regional network connectivity and neurovascular dynamics as the brain transitions from wakefulness to dexmedetomidine-induced unconsciousness, and finally into early-stage recovery of consciousness. We observed widespread decreases in functional connectivity strength across the whole brain, and targeted increases in structure-function coupling (SFC) across select networks-- especially the cerebellum--as individuals transitioned from wakefulness to hypnosis. We also observed robust decreases in cerebral blood flow (CBF) across the whole brain--especially within the brainstem, thalamus, and cerebellum. Moreover, hypnosis was characterized by significant increases in the amplitude of low-frequency fluctuations (ALFF) of the resting-state blood oxygen level-dependent signal, localized within visual and somatomotor regions. Critically, when transitioning from hypnosis to the early stages of recovery, functional connectivity strength and SFC--but not CBF--started reverting towards their awake levels, even before behavioral arousal. By further testing for a relationship between connectivity and neurovascular alterations, we observed that during wakefulness, brain regions with higher ALFF displayed lower functional connectivity with the rest of the brain. During hypnosis, brain regions with higher ALFF displayed weaker coupling between structural and functional connectivity. Correspondingly, brain regions with stronger functional connectivity strength during wakefulness showed greater reductions in CBF with the onset of hypnosis. Earlier recovery of consciousness was associated with higher baseline (awake) levels of functional connectivity strength, CBF, and ALFF, as well as female sex. Across our findings, we also highlight the role of the cerebellum as a recurrent marker of connectivity and neurovascular changes between states of consciousness. Collectively, these results demonstrate that induction of, and emergence from dexmedetomidine-induced unconsciousness are characterized by widespread changes in connectivity and neurovascular dynamics.

neuroscience↗

bioRxiv2023

Evidence for deliberate burial of the dead by Homo naledi

In this study we describe new results of excavations in the Dinaledi Subsystem of the Rising Star cave system, South Africa. In two areas within the Hill Antechamber and the Dinaledi Chamber this work uncovered concentrations of abundant Homo naledi fossils including articulated, matrix-supported skeletal regions consistent with rapid covering by sediment prior to the decomposition of soft tissue. We additionally re-examine the spatial positioning of skeletal material and associated sediments within the Puzzle Box area, from which abundant H. naledi remains representing a minimum of six individuals were recovered in 2013 and 2014. Multiple lines of evidence exclude the hypothesis that skeletal remains from these three areas come from bodies that decomposed on the floor of the chamber or within a shallow depression prior to burial by sediments. The spatial positioning of skeletal material, the topography of the subsystem, and observations on sediments within and surrounding features exclude the hypothesis that rapid burial by sediment was a result of gravity-driven slumping or spontaneous movement of sediments. We present a minimal hypothesis of hominin cultural burial and test the evidence from all three areas, finding that this hypothesis is most compatible with the pattern of evidence. These results suggest that mortuary behavior including cultural burial was part of the repertoire of Homo naledi.

paleontology↗

bioRxiv2023

Structure and activity of botulinum neurotoxin X

Botulinum neurotoxins (BoNTs) are the most potent toxins known and are used to treat an increasing number of medical disorders. All BoNTs are naturally co-expressed with a protective partner protein (NTNH) with which they form a 300 kDa complex, to resist acidic and proteolytic attack from the digestive tract. We have previously identified a new botulinum neurotoxin serotype, BoNT/X, that has unique and therapeutically attractive properties. We present the cryo-EM structure of the BoNT/X-NTNH/X complex at 3.1 [A] resolution. Unexpectedly, the BoNT/X complex is stable and protease resistant at both neutral and acidic pH and disassembles only in alkaline conditions. Using the stabilizing effect of NTNH, we isolated BoNT/X and showed that it has very low potency both in vitro and in vivo. Given the high catalytic activity and translocation efficacy of BoNT/X, low activity of the full toxin is likely due to the receptor-binding domain, which presents weak ganglioside binding and exposed hydrophobic surfaces.

biochemistry↗

bioRxiv2021

Prenatal cadmium exposure does not induce greater incidence or earlier onset of autoimmunity in the offspring

We previously demonstrated that exposure of adult mice to environmental levels of cadmium (Cd) alters the immune cell development and function with increases in anti-streptococcal antibody levels, as well as decreases in splenic natural regulatory T cells (nTreg) in the adult female offspring. Based on these data, we hypothesized that prenatal Cd exposure could predispose an individual to developing autoimmunity as adults. To test this hypothesis, the effects of prenatal Cd on the development of autoimmune diabetes and arthritis were investigated. Non-obese diabetic (NOD) mice were exposed to Cd in a manner identical to our previous studies, and the onset of diabetes was assessed in the offspring. Our results showed a similar time-to-onset and severity of disease to historical data, and there were no statistical differences between Cd-exposed and control offspring. Numerous other immune parameters were measured and none of these parameters showed biologically relevant differences between Cd-exposed and control animals. To test whether prenatal Cd-exposure affected development of autoimmune arthritis, we used SKG mice. While the levels of arthritis were similar between Cd-exposed and control offspring of both sexes, the pathology of arthritis determined by micro-computed tomography (CT) between Cd-exposed and control animals, showed some statistically different values, especially in the female offspring. However, the differences were small and thus, the biological significance of these changes is open to speculation. Overall, based on the results from two autoimmune models, we conclude that prenatal exposure to Cd did not lead to a measurable propensity to develop autoimmune disease later in life.

immunology↗

bioRxiv2021

Differential impact of transdiagnostic, dimensional psychopathology on multiple scales of functional connectivity

IntroductionDimensional psychopathology strives to associate different domains of cognitive dysfunction with brain circuitry. Connectivity patterns as measured by functional magnetic resonance imaging (fMRI) exist at multiple scales, with global networks of connectivity composed of microscale interactions between individual nodes. It remains unclear how separate dimensions of psychopathology might differentially impact these different scales of organization. MethodsPatients experiencing anxious misery symptomology (depression, anxiety and trauma; n = 192) were assessed for symptomology and received resting-state fMRI scans. Three modeling approaches (seed-based correlation analysis [SCA], support vector regression [SVR] and Brain Basis Set Modeling [BSS]), each relying on increasingly dense representations of functional connectivity patterns, were used to associate connectivity patterns with six different dimensions of psychopathology: anxiety sensitivity, anxious arousal, rumination, anhedonia, insomnia and negative affect. Importantly, a full 50 patients were held-out in a testing dataset, leaving 142 patients as training data. ResultsDifferent symptom dimensions were best modeled by different scales of brain connectivity: anhedonia and anxiety sensitivity were best modeled with single connections (SCA), insomnia and anxious arousal by mesoscale patterns (SVR) and negative affect and ruminative thought by broad, cortex-spanning patterns (BBS). Dysfunction within the default mode network was implicated in all symptom dimensions that were best modeled by multivariate models. ConclusionThese results suggest that symptom dimensions differ in the degree to which they impact different scales of brain organization. In addition to advancing our basic understanding of transdiagnostic psychopathology, this has implications for the translation of basic research paradigms to human disorders.

neuroscience↗

bioRxiv2020

Decision value signals in the ventromedial prefrontal cortex and anhedonia across mood and psychotic disorders

Deficits in motivation and pleasure are common across many psychiatric disorders, and manifest as symptoms of amotivation and anhedonia, which are prominent features of both mood and psychotic disorders. Here we provide evidence for a shared transdiagnostic mechanism underlying impairments in motivation and pleasure across major depression, bipolar disorder, and schizophrenia. We found that value signals in the ventromedial prefrontal cortex (vmPFC) during decision-making were dampened in individuals with greater motivational and hedonic deficits, regardless of the primary diagnosis. This relationship remained significant while controlling for diagnosis-specific symptoms of mood and psychosis, such as depression as well as positive and negative symptoms. Our results demonstrate that dysfunction in the vmPFC during value-based decision-making is specifically linked to motivational and hedonic impairments across various psychiatric conditions. These findings provide a quantitative neural target for the potential development of novel treatments for amotivation and anhedonia.

neuroscience↗

bioRxiv2018

Individualized non-invasive brain stimulation engages the subgenual anterior cingulate and amygdala

Brain stimulation is used clinically to treat a variety of neurological and psychiatric conditions. The mechanisms of the clinical effects of these brain-based therapies are presumably dependent on their effects on brain networks. It has been hypothesized that using individualized brain network maps is an optimal strategy for defining network boundaries and topologies. Traditional non-invasive imaging can determine correlations between structural or functional time series. However, they cannot easily establish hierarchies in communication flow as done in non-human animals using invasive methods. In the present study, we interleaved functional MRI recordings with non-invasive transcranial magnetic stimulation in the attempt to map causal communication between the prefrontal cortex and two subcortical structures thought to contribute to affective dysregulation: the subgenual anterior cingulate cortex (sgACC) and the amygdala. In both cases, we found evidence that these brain areas were engaged when TMS was applied to prefrontal sites determined from each participants previous fMRI scan. Specifically, after transforming individual participant images to within-scan quantiles of evoked TMS response, we modeled the average quantile response within a given region across stimulation sites and individuals to demonstrate that the targets were differentially influenced by TMS. Furthermore, we found that the sgACC distributed brain network, estimated in a separate cohort, was engaged in response to sgACC focused TMS and was partially separable from the proximal default mode network response. The amygdala, but not its distributed network, responded to TMS. Our findings indicate that individual targeting and brain response measurements usefully capture causal circuit mapping to the sgACC and amygdala in humans, setting the stage for approaches to noninvasively modulate subcortical nodes of distributed brain networks in clinical interventions and mechanistic human neuroscience studies.

neuroscience↗

bioRxiv2017

Root grooves on two adjacent anterior teeth of Australopithecus africanus

Tooth root grooves and other ante-mortem dental tissue loss not associated with caries found on or near the cementoenamel junction (CEJ) are commonly termed non-carious cervical lesions. Three main processes are implicated in forming these lesions: abrasion, dental erosion, and abfraction. As yet, these lesions have not been described in non-Homo hominins. In this study South African fossil hominin collections were examined for evidence of any type of non-carious cervical lesion. Only one individual shows ante-mortem root grooves consistent with non-carious cervical lesions. Two teeth, a mandibular right permanent lateral incisor (STW 270) and canine (STW 213), belonging to the same Australopithecus africanus individual, show clear ante-mortem grooves on the labial root surface. These lesions start below the CEJ, extend over a third of the way toward the apex, and taper to a point towards the lingual side. Microscopic examination revealed no clear directional striations. The shape of these grooves is extremely similar to clinical examples of dental erosion, with the lack of striations supporting this diagnosis. These are the oldest hominin examples of non-carious cervical lesions and first described in a genus other than Homo; further, the lesions suggest that this individual regularly consumed or processed acidic food items.

paleontology↗