Biology subjects

Burke, K.

Publications and source records attributed to Burke, K..

7 recordsLinked to original sources

bioRxiv2025

Pan-cancer analysis in the real-world setting uncovers immunogenomic drivers of acquired resistance post-immunotherapy

Immune checkpoint blockade (ICB) has revolutionised cancer therapy, yet resistance -- both primary and acquired -- remains a significant obstacle, affecting the majority of patients. Here, we leveraged a large-scale, real-world clinicogenomic dataset to systematically explore the molecular underpinnings of ICB resistance in the post-progression setting. Analysing over 5,000 pan-cancer patients with clinical and pre-/post-treatment genomic and transcriptomic data, we identify distinct immunogenomic drivers of acquired vs. primary ICB resistance. Post-ICB progression, acquired resistance showed extended survival compared to primary resistance across all cancer types. The acquired resistance clinical phenotype was paralleled by a universally immune-inflamed, albeit dysfunctional, tumour microenvironment (TME) at the onset of acquired resistance, with sustained or ICB-induced inflammatory and interferon responses. We confirm previously described mechanisms of acquired resistance, including B2M loss-of-function (LoF) in non-small cell lung cancer (NSCLC), and identify novel potential mediators, including LoF of TGFBR2 in NSCLC, CYLD in head and neck cancer, and RUNX1 in triple negative breast cancer. Further supporting their involvement in resistance, these acquired ICB alterations associated with immune-escaped TMEs, characterised by active immunomodulatory oncogenic signalling, hyperproliferation and invasiveness, or altered tumour metabolism. These findings emphasise the heterogeneity of molecular drivers of acquired resistance to ICB within and across cancers, and highlight the potential for personalised therapeutic interventions post-progression to improve patient outcomes.

cancer biology↗

bioRxiv2025

Increased vulnerability to noise exposure of low spontaneous rate type 1C spiral ganglion neuron synapses with inner hair cells (Pre-Print)

The inner hair cells (IHCs) in the inner ear form synapses with auditory nerve fibers (ANFs) that send sound signals to the brain. ANFs have been grouped by their level of spontaneous firing rates (SRs) into high-, medium-, and low-SR ANFs. Based on their molecular profiles evaluated by RNAseq experiments, ANFs have been divided into three groups (1A, 1B, and 1C) that likely correspond to high-, medium-, and low-SR ANFs, respectively. In guinea pigs, the synapses between IHCs and low-SR ANFs have been shown to be more vulnerable to noise exposure compared to other ANF subtypes, but not in a study performed in CBA/CaJ mice, questioning if these results can be generalized. Here, an LYPD1 reporter mouse model on a C57Bl/6J background with specifically labeled group 1C, low-SR ANFs was used to examine whether LYPD1 positive ANF synapses are more vulnerable to noise exposure. Six-week-old mice were exposed to an 8-16 kHz octave band noise presented at 100 dBA for 2 hours. One week later, cochlear tissue was harvested to quantify ANF synapses and compare the percentage of LYPD1 positive ANF synapses in noise-exposed and unexposed animals. Auditory brainstem response measurements were performed to assess hearing function after noise exposure. The number of all ANF synapses and the percentage of LYPD1-positive ANF synapses were reduced following noise exposure, concurrent with increased ABR thresholds and decreased ABR wave 1 amplitudes. The reduction in the percentage of LYPD1-positive ANF synapses specifically indicates greater vulnerability of LYPD1 positive ANF synapses to noise exposure compared to other ANFs in C57Bl/6J mice.

neuroscience↗

bioRxiv2025

Revealing hidden knowledge in amnestic mice

Alzheimers disease (AD) is a form of dementia in which memory and cognitive decline is thought to arise from underlying neurodegeneration. These cognitive impairments, however, are transient when they first appear and can fluctuate across disease progression. Here, we investigate the neural mechanisms underlying fluctuations of performance in amnestic mice. We trained APP/PS1+ mice on an auditory go/no-go task that dissociated learning of task contingencies (knowledge) from its more variable expression under reinforcement (performance). APP/PS1+ exhibited significant performance deficits compared to control mice. Using large-scale two-photon imaging of 6,216 excitatory neurons in 8 mice, we found that auditory cortical networks were more suppressed, less selective to the sensory cues, and exhibited aberrant higher-order encoding of reward prediction compared to control mice. A small sub-population of neurons, however, displayed the opposite phenotype, reflecting a potential compensatory mechanism. Volumetric analysis demonstrated that deficits were concentrated near A{beta} plaques. Strikingly, we found that these cortical deficits were reversed almost instantaneously on probe (non-reinforced) trials when APP/PS1+ performed as well as control mice, providing neural evidence for intact stimulus-action knowledge despite variable ongoing performance. A biologically-plausible reinforcement learning model recapitulated these results and showed that synaptic weights from sensory-to-decision neurons were preserved (i.e. intact stimulus-action knowledge) despite poor performance that was due to inadequate contextual scaling (i.e. impaired performance). Our results suggest that the amnestic phenotype is transient, contextual, and endogenously reversible, with the underlying neural circuits retaining the underlying stimulus-action associations. Thus, memory deficits commonly observed in amnestic mouse models, and potentially at early stages of dementia in humans, relate more to contextual drivers of performance rather than degeneration of the underlying memory traces.

neuroscience↗

bioRxiv2024

Effects of age on responses of principal cells of the mouse anteroventral cochlear nucleus in quiet and noise

Older listeners often report difficulties understanding speech in noisy environments. It is important to identify where in the auditory pathway hearing-in-noise deficits arise to develop appropriate therapies. We tested how encoding of sounds is affected by masking noise at early stages of the auditory pathway by recording responses of principal cells in the anteroventral cochlear nucleus (AVCN) of aging CBA/CaJ and C57BL/6J mice in vivo. Previous work indicated that masking noise shifts the dynamic range of single auditory nerve fibers (ANFs), leading to elevated tone thresholds. We hypothesized that such threshold shifts could contribute to increased hearing-in-noise deficits with age if susceptibility to masking increased in AVCN units. We tested this by recording the responses of AVCN principal neurons to tones in the presence and absence of masking noise. Surprisingly, we found that masker-induced threshold shifts decreased with age in primary-like units and did not change in choppers. In addition, spontaneous activity decreased in primary-like and chopper units of old mice, with no change in dynamic range or tuning precision. In C57 mice, which undergo early onset hearing loss, units showed similar changes in threshold and spontaneous rate at younger ages, suggesting they were related to hearing loss and not simply aging. These findings suggest that sound information carried by AVCN principal cells remains largely unchanged with age. Therefore, hearing-in-noise deficits may result from other changes during aging, such as distorted across-channel input from the cochlea and changes in sound coding at later stages of the auditory pathway. Significance StatementMiddle age and older listeners commonly experience hearing deficits in the presence of background noise. Central auditory areas have been implicated in hearing-in-noise deficits, but it is not known where these deficits arise. We performed in vivo recordings in mice of different ages at the first stage of the auditory pathway in the brain, the cochlear nucleus, to examine how encoding of sounds is perturbed by masking noise. We found that the responses of individual neurons remain largely intact with age, including the processing of tones in masking noise, despite previously documented structural and physiological degeneration of their auditory nerve inputs. This suggests that problems hearing in masking noise result from changes at other stages of the auditory pathway.

neuroscience↗

bioRxiv2023

Alpha9alpha10 knockout mice show altered physiological and behavioral responses to signals in masking noise

Medial olivocochlear (MOC) efferents modulate outer hair cell motility through specialized nicotinic acetylcholine receptors to support encoding of signals in noise. Transgenic mice lacking the alpha9 subunits of these receptors (9KOs) have normal hearing in quiet and noise, but lack classic cochlear suppression effects and show abnormal temporal, spectral, and spatial processing. Mice deficient for both the alpha9 and alpha10 receptor subunits (910KOs) may exhibit more severe MOC-related phenotypes. Like 9KOs, 910KOs have normal auditory brainstem response (ABR) thresholds and weak MOC reflexes. Here, we further characterized auditory function in 910KO mice. Wildtype and 910KO mice had similar ABR thresholds and acoustic startle response (ASR) amplitudes in quiet and noise, and similar frequency and intensity difference sensitivity. 910KO mice had larger ABR Wave I amplitudes than wildtypes in quiet and noise, but the noise:quiet amplitude ratio suggested 910KOs were more susceptible to masking effects for some stimuli. 910KO mice also had larger startle amplitudes in tone backgrounds than wildtypes. Overall, 910KO mice had grossly normal auditory function in quiet and noise, though their larger ABR amplitudes and hyperreactive startles suggest some auditory processing abnormalities. These findings contribute to the growing literature showing mixed effects of MOC dysfunction on hearing.

neuroscience↗

bioRxiv2020

Equine synovial fluid small non-coding RNA signatures in early osteoarthritis

BackgroundOsteoarthritis remains one of the greatest causes of morbidity and mortality in the equine population. The inability to detect pre-clinical changes in osteoarthritis has been a significant impediment to the development of effective therapies against this disease. Synovial fluid represents a potential source of disease-specific small non-coding RNAs (sncRNAs) that could aid in the understanding of the pathogenesis of osteoarthritis. We hypothesised that early stages of osteoarthritis would alter the expression of sncRNAs, facilitating the understanding of the underlying pathogenesis and potentially provide early biomarkers. MethodsSmall RNA sequencing was performed using synovial fluid from the metacarpophalangeal joints of both control and early osteoarthritic non-Thoroughbred horses. A group of differentially expressed sncRNAs was selected for further validation through qRT-PCR using an independent cohort of synovial fluid samples from control and early osteoarthritic horses. Bioinformatic analysis was performed in order to identify putative targets of the differentially expressed microRNAs and to explore potential associations with specific biological processes. ResultsResults revealed 22 differentially expressed sncRNAs including 13 microRNAs; miR-10a, miR-223, let7a, miR-99a, miR-23b, miR-378, miR-143 (and six novel microRNAs), four small nuclear RNAs; U2, U5, U11, U12, three small nucleolar RNAs; U13, snoR38, snord96, and one small cajal body-specific RNA; scarna3. Five sncRNAs were validated; miR-223 was significantly reduced in early OA and miR-23b, let-7a-2, snord96A and snord13 were significantly upregulated. Significant cellular functions deduced by the differentially expressed microRNAs included apoptosis (P < 0.0003), necrosis (P < 0.0009), autophagy (P < 0.0007) and inflammation (P < 0.00001). A conservatively filtered list of 57 messenger RNA targets was obtained; the top biological processes associated were regulation of cell population proliferation (P < 0.000001), cellular response to chemical stimulus (P < 0.000001) and cell surface receptor signalling pathway (P < 0.000001). ConclusionsSynovial fluid sncRNAs can be used as molecular biomarkers for early disease in equine osteoarthritic joints. The biological processes they regulate may play an important role in understanding early osteoarthritis pathogenesis. Characterising these dynamic molecular changes could provide novel insights on the process and mechanism of early osteoarthritis development and is critical for the development of new therapeutic approaches.

molecular biology↗

bioRxiv2018

The autism-associated gene Scn2a plays an essential role in synaptic stability and learning

Autism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein NaV1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here, we show NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons, in addition to regulating early developmental axonal excitability. NaV1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic stability, even when NaV1.2 expression was disrupted late in development. Furthermore, we identified behavioral impairments in learning and sociability, paralleling observations in children with SCN2A loss. These results reveal a novel dendritic function for NaV1.2, providing insight into cellular mechanisms likely underlying circuit and behavioral dysfunction in ASD.

neuroscience↗