Biology subjects

Gibson, L.

Publications and source records attributed to Gibson, L..

10 recordsLinked to original sources

bioRxiv2026

Pre-existing levels of pro-survival proteins and induction of BCL-XL dictate cell fate after p53 activation

TP53 (also called TRP53 or p53) is a critical tumour suppressor that prevents cancer development by inducing a transcriptional program which can lead to diverse cellular responses, most prominently, cell proliferation arrest/senescence with survival of cells or cell death by apoptosis. Why distinct cell types undergo different outcomes after p53 activation remains unclear. Using integrated RNA-sequencing, proteomic and functional analyses across a diverse range of murine primary cell types, we demonstrate that cell fate is governed by the balance between pro-survival BCL-2 and pro-apoptotic BH3-only proteins. Cells resistant to apoptosis displays a higher starting ratio of pro-survival BCL-2 to pro-apoptotic BH3-only proteins, along with transcriptional upregulation of the pro-survival gene Bcl2l1, encoding BCL-XL. This control of cell fate is also seen in human wild-type p53 cancer cell lines. These findings reveal the mechanism for understanding p53-driven cell fate decisions, suggest therapeutic strategies to shift p53-induced cell proliferation arrest/senescence toward apoptotic cell death and allowed generation of an RNAseq data-based predictor of outcome for cancer cells after p53 activation.

cancer biology↗

bioRxiv2026

The compounding costs of being female in academia: Individual-based modelling of career progression and interventions

We develop a novel individual-based population dynamics model of academic career progression, using 15 years of data from over 1,000 academics from one university. Our model improves on previous models, which, by homogenising career progression, may underestimate the costs of being female. We find multiple effects that compound to slow career progression for women. Women are hired at lower ranks than men, then face the sticky floor problem of getting stuck at the bottom for longer. Further, individuals in STEM fields are promoted more quickly; this disproportionately affects women who are more prevalent in non-STEM fields. Our model reveals age is more complicated than others have found with ODE-based models. Women are older when hired, and promotions favour the young; hence age costs women more. Finally, the probability of attrition rises with years spent at the same rank, regardless of gender. Since women are promoted slower, they experience higher attrition rates. We also deploy our model to test possible interventions. We find just hiring more women will not work. A more nuanced set of interventions is required. Gender parity will only be achieved at the highest ranks if hiring rates are jointly equalised across gender, academic rank, and discipline.

scientific communication and education↗

bioRxiv2024

Female-dominated disciplines have lower evaluated research quality and funding success rates, for men and women

We use data from 30 countries and find that the more women in a discipline, the lower quality the research in that discipline is evaluated to be and the lower the funding success rate is. This affects men and women, and is robust to age, number of research outputs, and bibliometric measures where such data are available. Our work builds on others findings that womens work is valued less, regardless of who performs that work.

scientific communication and education↗

bioRxiv2024

Indirect effects of habitat amount mediated by habitat configuration determine bat diversity at the landscape-scale in Peninsular Malaysia

The impacts of fragmentation are often overlooked in landscape studies investigating how habitat loss impacts biodiversity, despite the casual relationship linking both processes. As habitat loss is the primary cause of fragmentation, understanding the inter-related effects of these twin processes on biodiversity is key to minimise biodiversity loss. Here we assess how habitat amount and configuration influence insectivorous bat assemblages, considering both the direct effects of these processes, as well as the indirect effects of habitat amount mediated through configuration. Bats were acoustically surveyed along independent gradients of habitat amount (forest cover) and configuration (number of patches and edge density) across 28 insular landscapes embedded within a Malaysian hydroelectric reservoir. Using Structural Equation Modelling, the direct and indirect effects of habitat amount were examined on bat sonotype richness, total, and guild-specific activity (forest, edge and open-space foragers). Forest cover had a direct and positive effect on sonotype richness and forest forager activity. The quadratic relationship linking edge density and forest cover was strong and overall positive, but while below 30% of forest cover, increasingly forested landscapes had increasingly high edge densities, the opposite pattern was observed in more forested landscapes. On the other hand, increasingly forested landscapes consistently harboured less patches. Owing to the overall low habitat amount in our landscapes and negative edge effects, the indirect effects of forest cover (mediated through edge density) were therefore negative on sonotype richness, outweighing any positive direct effect. The number of patches had little effect on the bat assemblage, except on total activity which was higher in landscapes harbouring more forest patches. As a result, negative indirect effects of forest cover mediated through number of patches were only observed on total activity. Our results highlight that, in natural settings, habitat amount can hardly be altered without influencing habitat configuration, thereby preventing any independent management of these threats. Minimising habitat loss is therefore essential to balance the associated prevailing negative effects of fragmentation on insectivorous bats across tropical forests.

ecology↗

bioRxiv2023

Relative importance of MCL-1's Anti-Apoptotic versus Non-Apoptotic Functions in vivo

MCL-1 is an anti-apoptotic member of the BCL-2 protein family that ensures cell survival by blocking the intrinsic apoptotic cell death pathway1. MCL-1 is unique in being essential for early embryonic development and the survival of many cell types, including many cancer cells, which are not affected by the loss of the other anti-apoptotic BCL-2 family members1-4. Non-apoptotic functions of MCL-1 controlling mitochondrial ATP production and dynamics have been proposed to underlie this unique requirement for MCL-15-9. The relative contributions of the anti-apoptotic versus the non-apoptotic functions of MCL-1 in normal physiology have not been addressed. Here we replaced the coding sequence for MCL-1 with those for the anti-apoptotic proteins BCL-XL, BCL-2 or A1. We hypothesised that BCL-XL, BCL-2 and A1 may substitute for MCL-1 in the inhibition of apoptosis, but that they will not be able to replace MCL-1s non-apoptotic function. Strikingly, Mcl-1Bcl-xL/Bcl-xL and Mcl-1Bcl-2/Bcl-2 embryos survived to embryonic day 14.5, greatly surpassing the pre-implantation lethality of Mcl-1-/- embryos at E3.5. This demonstrates that the non-apoptotic functions of MCL-1 are dispensable for early development. However, at later stages of development and life after birth many cell types, particularly ones with high energy demand, were found to require both the anti-apoptotic and the non-apoptotic functions of MCL-1. These findings reveal the relative importance of these distinct functions of MCL-1 in physiology, providing important information for basic biology and the advancement of MCL-1 inhibitors in cancer therapy.

cell biology↗

bioRxiv2023

Foraging guild modulates insectivorous bat responses to habitat loss and insular fragmentation in peninsular Malaysia

Despite mounting evidence on the ecological impacts of damming for biodiversity, little is known regarding its consequences in the hyper-diverse Southeast Asian tropical forests. Here we assess the effects of habitat loss and fragmentation on the diversity and activity of insectivorous bats within the hydroelectric Kenyir Lake in peninsular Malaysia. We surveyed bat assemblages on 26 islands and two mainland continuous forest sites using passive acoustic monitoring. Echolocation calls were classified into sonotypes, each corresponding to either one or multiple species, and grouped into foraging guilds. We then examined bat overall assemblage (sonotype richness, activity, and composition), guild- and sonotype-specific activity. From 9360 hours of recordings, we identified 16 bat sonotypes, including 10 forest (2854 bat passes), three edge (13 703) and three open-space foragers (3651). Sonotype richness increased towards denser forest structures (higher Normalized Difference Vegetation Index - NDVI), while species composition varied across the gradient of forest area. Forest foragers were positively affected by NDVI and negatively affected by distance to the closest neighbour, whereas edge foragers activity increased in smaller islands. Of the six sonotypes analysed, the activity of one forest sonotype increased with forest area, while that of one edge sonotype decreased. Ensuring habitat quality within insular forest remnants, in addition to their functional connectivity, maximises bat diversity, including the persistence of forest foraging species. Future hydropower development should therefore avoid the creation of a myriad of small, isolated, and habitat-degraded islands further characterised by altered levels of bat diversity and guild-level activity. HighlightsO_LIWe assessed the diversity of insectivorous bats in dam-induced islands in Malaysia C_LIO_LISpecies persistence was modulated by island size and habitat quality C_LIO_LIForest foragers were negatively affected by island isolation and degradation C_LIO_LIEdge foragers benefited from fragmentation, increasing in activity on smaller islands C_LIO_LIBy creating multiple small, isolated, degraded islands, damming erodes bat diversity C_LI

ecology↗

bioRxiv2021

Visual, delay and oculomotor timing and tuning in macaque dorsal pulvinar during instructed and free choice memory saccades

Causal perturbations suggest that the primate dorsal pulvinar (dPul) plays a crucial role in target selection and saccade planning, but its basic visuomotor neuronal properties are unclear. While some functional aspects of dPul and interconnected frontoparietal areas - e.g. ipsilesional choice bias after inactivation - are similar, it is unknown if dPul shares oculomotor properties of the cortical circuitry, in particular the delay and choice-related activity. We investigated such properties in macaque dPul during instructed and free-choice memory saccades. Most recorded units showed visual (16%), visuomotor (29%) or motor-related (35%) responses. Visual responses were mainly contralateral; motor-related responses were predominantly post-saccadic (64%) and showed weak contralateral bias. Pre-saccadic enhancement was infrequent (9-15%) - instead, activity was often suppressed during saccade planning (30%) and execution (19%). Surprisingly, only few units exhibited classical visuomotor patterns combining cue and continuous delay activity until the saccade or pre-saccadic ramping, and most spatially-selective neurons did not encode the upcoming decision during free-choice delay. Thus, in absence of a visible goal, the dorsal pulvinar has a limited role in prospective saccade planning, with patterns partially complementing its frontoparietal partners. Conversely, prevalent cue and post-saccadic responses imply the participation in integrating spatial goals with processing across saccades.

neuroscience↗

bioRxiv2020

Effective connectivity and spatial selectivity-dependent fMRI changes elicited by microstimulation of pulvinar and LIP

The thalamic pulvinar and the lateral intraparietal area (LIP) share reciprocal anatomical connections and are part of an extensive cortical and subcortical network involved in spatial attention and oculomotor processing. The goal of this study was to compare the effective connectivity of dorsal pulvinar (dPul) and LIP and to probe the dependency of microstimulation effects on task demands and spatial tuning properties of a given brain region. To this end, we applied unilateral electrical microstimulation in the dPul (mainly medial pulvinar) and LIP in combination with event-related BOLD fMRI in monkeys performing fixation and memory-guided saccade tasks. Microstimulation in both dPul and LIP enhanced task-related activity in monosynaptically-connected fronto-parietal cortex and along the superior temporal sulcus (STS) including putative face patch locations, as well as in extrastriate cortex. LIP microstimulation elicited strong activity in the opposite homotopic LIP while no homotopic activation was found with dPul stimulation. Both dPul and LIP stimulation also elicited activity in several heterotopic cortical areas in the opposite hemisphere, implying polysynaptic propagation of excitation. Despite extensive activation along the intraparietal sulcus evoked by LIP stimulation, there was a difference in frontal and occipital connectivity elicited by posterior and anterior LIP stimulation sites. Comparison of dPul stimulation with the adjacent but functionally dissimilar ventral pulvinar also showed distinct connectivity. On the level of single trial timecourses within each region of interest (ROI), most ROIs did not show task-dependence of stimulation-elicited response modulation. Across ROIs, however, there was an interaction between task and stimulation, and task-specific correlations between the initial spatial selectivity and the magnitude of stimulation effect were observed. Consequently, stimulation-elicited modulation of task-related activity was best fitted by an additive model scaled down by the initial response amplitude. In summary, we identified overlapping and distinct patterns of thalamocortical and corticocortical connectivity of pulvinar and LIP, highlighting the dorsal bank and fundus of STS as a prominent node of shared circuitry. Spatial task-specific and partly polysynaptic modulations of cue and saccade planning delay period activity in both hemispheres exerted by unilateral pulvinar and parietal stimulation provide insight into the distributed interhemispheric processing underlying spatial behavior. HighlightsO_LIElectrical stimulation of pulvinar and LIP was used to study fMRI effective connectivity C_LIO_LIBoth regions activated prefrontal cortex and the dorsal bank of superior temporal sulcus C_LIO_LIActivations within and across hemispheres suggest polysynaptic propagation C_LIO_LIStimulation effects show interactions between task- and spatial selectivity C_LIO_LIStimulation effects are best fitted by an additive model scaled by the initial response C_LI

neuroscience↗

bioRxiv2019

Eye position signals in the dorsal pulvinar during fixation and goal-directed saccades

Most sensorimotor cortical areas contain eye position information thought to ensure perceptual stability across saccades and underlie spatial transformations supporting goal-directed actions. One pathway by which eye position signals could be relayed to and across cortical areas is via the dorsal pulvinar. Several studies demonstrated saccade-related activity in the dorsal pulvinar and we have recently shown that many neurons exhibit post-saccadic spatial preference long after the saccade execution. In addition, dorsal pulvinar lesions lead to gaze-holding deficits expressed as nystagmus or ipsilesional gaze bias, prompting us to investigate the effects of eye position. We tested three starting eye positions (-15{degrees}/0{degrees}/15{degrees}) in monkeys performing a visually-cued memory saccade task. We found two main types of gaze dependence. First, [~]50% of neurons showed an effect of static gaze direction during initial and post-saccadic fixation. Eccentric gaze preference was more common than straight ahead. Some of these neurons were not visually-responsive and might be primarily signaling the position of the eyes in the orbit, or coding foveal targets in a head/body/world-centered reference frame. Second, many neurons showed a combination of eye-centered and gaze-dependent modulation of visual, memory and saccadic responses to a peripheral target. A small subset showed effects consistent with eye position-dependent gain modulation. Analysis of reference frames across task epochs from visual cue to post-saccadic target fixation indicated a transition from predominantly eye-centered encoding to representation of final gaze or foveated locations in non-retinocentric coordinates. These results show that dorsal pulvinar neurons carry information about eye position, which could contribute to steady gaze during postural changes and to reference frame transformations for visually-guided eye and limb movements.\n\nNew & NoteworthyWork on the pulvinar focused on eye-centered visuospatial representations, but position of the eyes in the orbit is also an important factor that needs to be taken into account during spatial orienting and goal-directed reaching. Here we show that dorsal pulvinar neurons are influenced by eye position. Gaze direction modulated ongoing firing during stable fixation, as well as visual and saccade responses to peripheral targets, suggesting involvement of the dorsal pulvinar in spatial coordinate transformations.

neuroscience↗

bioRxiv2019

Targeting the dysfunctional mitochondrial respiration in drug resistant B-cell acute lymphoblastic leukemia

Reprogramming of cellular pathways is a crucial mechanism of drug resistance and survival in refractory acute lymphoblastic leukemia (ALL) cells. In the present study, we performed an unbiased gene expression analysis and identified a dysfunctional mitochondrial respiration program in drug-resistant ALL cells grown in a co-culture system with bone marrow stromal cells (BMSC). Specifically, the activity of the complexes within the electron transport chain was significantly downregulated, correlated with decreased mitochondrial mass and ATP production in drug-resistant ALL cells. To validate mitochondrial respiration as a druggable target, we utilized pyrvinium pamoate (PP), a known inhibitor of mitochondrial respiration and documented its anti-leukemic activity in several ALL cell lines grown alone or in co-culture with BMSC. To increase the bioavailability profile of PP, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. PP anti-leukemic activity was decreased by the addition of sodium pyruvate, and furthermore, PP was found to have an additive anti-leukemic effect when used in combination with rotenone, a mitochondrial complex I inhibitor with activity similar to PP on the mitochondrial respiration. Importantly, PPs cell death activity was found to be specific for leukemic cells as primary normal immune cells were resistant to PP-mediated cell death. In conclusion, we have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells.

cancer biology↗