Biology subjects

Stevens, M.

Publications and source records attributed to Stevens, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Viewing geometry and pattern type shape the detectability of snakes

Protective coloration can reduce predation risk by altering how prey are detected, recognised, or attacked. High-contrast markings may function as warning signals, camouflage, or both. In snakes, dorsal colour patterns are highly variable but the function remains debated, particularly because their appearance to an observer may change with viewing distance and angle. This study tested whether the function and efficacy of common snake pattern types (blotches, spots, diamonds, zig-zags and bands) is observer-view dependent, mediated by viewing distance and angle. Artificial snake models marked with these different pattern types that are broadly common across snake taxa, were placed in woodland habitat with a mixed shrub and grass understorey in Cornwall, UK, with photographs taken for evaluating levels of predicted camouflage and contrast against the background. Next, human volunteers searched for models, and we recorded detection distances and angles. Field results showed no significant difference in overall detection rates between pattern types; however, zigzag-patterned models were more likely to be detected at significantly shorter distances than blotch-patterned models, with a marginal trend towards shorter distances than diamond-patterned models, indicating effective longer-range camouflage. Detection risk did not alter gradually as volunteers approached but increased abruptly, correlating with image analyses showing that levels of predicted disruptive camouflage decreased with reduced distance. When detection was analysed using viewing angle, an advantage of zigzag patterns was robust to geometric scale, and observer height may further shape detection through viewing geometry. These findings suggest that snake dorsal patterns could potentially serve dual roles in reducing detection from afar, while being more conspicuous at close range. In addition, the results highlight the need to consider three-dimensional viewing geometry, including distance and visual angle, when evaluating the ecological function of animal coloration.

animal behavior and cognition↗

bioRxiv2026

Camouflage functions of juvenile giant panda colouration in forest environments

The contrasting black-and-white coloration of the giant panda (Ailuropoda melanoleuca) has long attracted attention. Recent works suggest this contrasting pattern may generate camouflage-relevant visual effects. However, most previous studies have focused on adult pandas, whereas juveniles may face greater predation risk and may therefore represent a more ecologically relevant life stage for testing concealment hypotheses. We investigated whether juvenile panda coloration provides the potential for camouflage through background matching or disruptive coloration, and how this potential is shaped by vegetation cover, illumination and background position. We used life-sized juvenile panda models with natural and experimentally modified coloration by adjusting the relative proportions and spatial arrangement of white, black, and grey patches. Models were photographed in temperate woodland environments at ground level and against canopy backgrounds, under sunny and cloudy conditions, with and without vegetation occlusion. We quantified colour and luminance contrast, as well as edge-disruption metrics, using dichromatic canid and felid visual models. Natural juvenile panda coloration influences target-background contrast and edge-disruption, although these effects varies with vegetation, lighting, background height and visual model. Vegetation cover significantly reduced contrast and increased edge disruption metrics, while bright light condition only increased the metrics of edge disruption. Background position affected camouflage-relevant metrics in a context- and observer-dependent manner: under vegetation occlusion, canopy placement reduced chromatic contrast under felid-like vision, whereas ground-level placement reduced luminance contrast under both visual models. Alterations to patch extent and boundary arrangement modified camouflage-relevant metrics under specific environmental conditions, suggesting that the natural arrangement of pelage boundaries may enhance concealment under specific conditions. Overall, our findings support the hypothesis that juvenile giant panda coloration can produce visual effects consistent with potential camouflage, while highlighting the importance of habitat structure and viewing context in shaping camouflage.

animal behavior and cognition↗

bioRxiv2026

Phenotype-environment matching in ground-nesting birds across and within large-scale biomes

Many animals have camouflage appearances that correspond to the habitat where they live, termed phenotype-environment matching. However, this has generally been tested in only a limited number of systems and natural settings, and often not to the relevant vision of key receivers (predators) across different spatial scales. Here, we measured the plumage attributes and putative camouflage used by ground-nesting bird species specialist to particular biomes, specifically tropical rainforest, taiga forest, dry forest, grassland, desert, and tundra from museum specimens. Digital photography and image analysis were used to quantify colour patterns to models of predator vision to understand how different colour patterns may correspond with biome type. With this information, we next created bird models that were photographed in situ in the Valdivian temperate rainforest and Patagonian grassland biomes of Chile to quantify the extent to which plumage coloration and pattern traits provide effective camouflage at different spatial scales. In general, we find that specialist ground-nesting birds express a phenotype that better matches the substrate composition and vegetation structure across large spatial scales of their own biome. This study reveals how animal camouflage works across biomes, relative to the visual system of raptor predators, and at the appropriate distance at which detection may occur.

ecology↗

bioRxiv2026

Toward a Random Background for Ligand Optimization

Ligand optimization is central to drug discovery as hundreds of analogs might be designed and synthesized between an initial hit and a therapeutic candidate. The efficiency of this process is unclear, at least partly because there is no random background for optimization against which to compare. Such a random background might emerge from synthetically accessible but otherwise systematic random small substitutions across starting ligands, measuring likelihood of achieving a substantial improvement in affinity/potency or other property by any single perturbation. Recent literature and ligand-affinity/potency databases suggest that perhaps 10% of analogs with minor modifications improve upon a parents potency substantially (by [≥]10-fold), but this number is clouded by reporting bias, intentional improvement, and inter-group reproducibility. To begin to establish a background expectation for ligand optimization, we comprehensively and systematically modified 18 lead molecules across six targets with single atom changes; 257 compounds were synthesized. Unexpectedly, 11.2% of these random small perturbation analogs improved potency by [≥]10-fold over their parents. Conversely, these more potent analogs typically had worse in vitro pharmacokinetics (e.g. reduced metabolic stability, lower plasma free fraction). While it was possible to find analogs where the potency increase compensated for inferior exposure and half-life, resulting in more potent compounds in vivo, overall a frustrated landscape for ligand optimization is revealed. This study begins to establish a background expectation for ligand potency optimization and offers a simple strategy to do so. It also begins to quantify the challenges confronting the field in moving beyond in vitro potency.

pharmacology and toxicology↗

bioRxiv2026

Unveiling key links between behaviour and appearance in the evolution of camouflage

Behaviour is a key yet often overlooked component of animal camouflage and how it evolves alongside colour and morphology remains poorly understood. The repeated evolution of stick-like postures in spiders offers a useful framework for investigating the importance of behaviour for concealment, since matching the environment should rely on specific body forms and postures, not just colouration. We hypothesised that when spiders behaviourally align their body with the background orientation it should influence the shape, posture and colouration that best enhances camouflage. To test this, we used a genetic algorithm and human observers to evolve digital spiders to be harder to find. We evaluated how selection under three behavioural orientation treatments (aligned, random, and evolvable orientation) influenced spider capture time, background match (lightness and colour), posture, and body (cephalothorax and abdomen) dimensions. We found that spiders that behaviourally aligned with the background took substantially longer to find through evolving a better background match, and a more elongated posture and body shape than randomly orientated spiders. Our spiders mirrored the shape and posture adopted by numerous clades, illustrating how behavioural camouflage represents a key concealment strategy in structurally complex habitats, part of an interacting suite of traits that encompass successful concealment.

evolutionary biology↗

bioRxiv2026

Prolyl hydroxylation is required for maturation and secretion of Zika virus non-structural protein 1

Mosquito-borne orthoflaviviruses such as Zika virus (ZIKV) and dengue virus (DENV) have a high epidemic potential and are associated with a wide range of possible outcomes, from asymptomatic infections to severe complications. The orthoflavivirus non-structural protein 1 (NS1), which can be membrane-bound as well as secreted from the cell, plays important roles in viral replication, immune evasion and pathogenesis. To describe the interactome of ZIKV NS1, we infected Huh7 and neural progenitor cells with a recombinant ZIKV expressing FLAG-tagged NS1 and identified interacting proteins by quantitative mass spectrometry. In both cell types, multiple prolyl hydroxylases, glycosylation enzymes, ER-associated degradation proteins, and proteins involved in immunity were identified as NS1 interactors. Mass spectrometry data showed that NS1 contains potential hydroxyproline residues, suggesting that prolyl hydroxylase enzymes are involved in post-translational modification of NS1. Chemical inhibition of prolyl hydroxylases impaired NS1 intracellular trafficking and plasma membrane localization and reduced ZIKV RNA levels and titers. Mutagenesis of the proline residue at position 281 impaired NS1 secretion, although viral replication was unaffected. Moreover, substituting proline at position 267 strongly dysregulated NS1 expression and reverted to the wild-type sequence already after a single passage, suggesting that this mutation leads to severe replication defects. Our results identify prolyl hydroxylation as an essential post-translational modification of ZIKV NS1.

microbiology↗

bioRxiv2025

Mechanistic analysis of compounds that modulate VEGF-A splicing in podocytes with therapeutic potential for diabetic nephropathy

Vascular endothelial growth factor A (VEGF-A) has an alternatively spliced variant, VEGF-A165b, formed when a distal 3 splice site in exon 8 is selected. The anti-angiogenic and anti-permeability VEGF-A165b has reno-protective properties and has been shown to rescue kidney function in diabetic nephropathy (DN) mouse models (PMID 25542969). We previously identified three new compounds that can increase the expression of the VEGF-A165b isoform. Two of these compounds, named ESSO1 and ESSO3, were discovered through a screen of synthetic compounds that alter VEGF-A splicing (PMID 33941763). A third compound, delphinidin, was found to be the key regulator of VEGF-A splicing in a natural blueberry and sea-buckthorn extract (DIAVIT) (PMID 30865689). This study aimed to investigate the signalling mechanism through which these three compounds regulate VEGF-A splicing and increase the protective VEGF-A165b isoform in renal podocytes. Human podocytes were exposed to a diabetic environment (glucose soup [GS]: 25 mM glucose, 1 ng/ml TNF-, 1 ng/ml IL-6, and 100 nM insulin), in comparison to a normal glucose (5.5 mM glucose) and an osmotic control (5.5 mM glucose + 19.5 mM mannitol) control, for 48 hours. RNA and protein were extracted for RT-PCR and Western blotting analysis of splice isoforms. Immunofluorescence and cell viability assays were also used. Immunofluorescence showed no significant difference in nephrin expression for all treatments compared to control, suggesting that normal podocyte function is not affected by these compounds. Trypan blue exclusion assay, used to assess the percentage cell viability of podocyte cells, showed that they do not affect podocyte cell viability. By using various inhibitor treatments, we have found several molecules involved in signalling, like JNK and splicing kinases SRPK1 and CLK1 for ESSO1, splicing factor hnRNPH and kinase CLK1 for ESSO3 and AMPK, splicing factor SRSF6 and kinase CLK1 for delphinidin. Other molecules, like ATM, E2F1, and hnRNPA1, were ruled out. Interestingly, all three compounds significantly increased expression of the splicing kinase CLK1, which has been involved in VEGF-A splicing regulation, suggesting that all three compounds may be increasing the VEGF-A165b/panVEGF-A165 ratio through signalling through this kinase. Studies of human biopsies showed that CLK1 is downregulated in DN patients compared to healthy volunteers. The development of a CLK1 activator as a DN therapy seems, therefore, a plausible opportunity.

pharmacology and toxicology↗

bioRxiv2025

The apoptosis gene BCL-X splice isoforms have opposing effects in diabetic kidney disease: potential treatment target and prognostic value

In recent years, the importance of alternative splicing (AS) of certain genes in the nature and progression of diabetic nephropathy (DN) has been studied. We report a novel AS event observed in the diabetic kidney - AS of the apoptosis gene BCL-X to increase the pro-apoptotic BCL-XS and decrease the anti-apoptotic BCL-XL. This study aimed to further investigate the role of this novel AS event in the pathogenesis of DN. To characterize important splicing events in progression of DN, human glomerular endothelial cells (GEnCs) were exposed to a diabetic environment for 1 week and RNAseq was performed. While several splicing changes have been discovered we have focused further on the apoptosis gene BCL-X isoforms. In GEnCs, an upregulation of the BCL-XS/BCL-XL ratio was observed which resulted in an increase in GEnC apoptosis. An upregulation of IL-6 was also observed; treatment with IL-6 alone induced a dose-dependent shift in BCL-X splicing to promote expression of the pro-apoptotic BCL-XS. Furthermore, we identified certain splicing factors, SF3B1 and PTBP1, involved in the BCL-X splicing regulation. A switch in expression of the anti-apoptotic BCL-XL isoform rescues apoptosis, suggesting a possible therapeutic avenue. In patients, an increase in the pro-apoptotic BCL-XS in urinary RNA correlated with a decline in the GFR, while in blood it correlated with the level of albuminuria. There is an increase in the pro-apoptotic BCL-XS isoform in the diabetic glomerular endothelium, resulting in increased GEnC apoptosis. Increased BCL-XS expression correlates with a markers of renal function decline, implicating this AS event as a potential biomarker for DN severity and suggesting that the switch of isoforms from BCL-XS to BCL-XL may for a novel therapeutic strategy.

molecular biology↗

bioRxiv2025

A novel combinatorial treatment for Neurofibromatosis type 1 tumours revealed through cross-species genetic analysis

Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder associated with a wide range of symptoms, including the formation of tumours along nerves. These tumours can affect nerve function, leading to pain and loss of sensory or motor capacity. Drug treatments are currently limited, and relatively few new targets have emerged for NF1 tumors despite intensive research. Therefore, new drugs to target NF1-deficient tumour cells are urgently required. Here, we have used a cross-species screening strategy combined with bioinformatic analysis to identify candidates with a high chance of successful translation to humans. First, we used data from a synthetic lethal screen performed in Drosophila cells to identify novel drug targets of NF1. Then, we performed statistical enrichment analysis of the screen results to identify further candidate targets that were not conserved between Drosophila and humans and could not have been found in the screen. We identified and validated hTERT as a synthetic lethal partner gene to NF1 with high potential as a therapeutic drug target, using the FDA-approved inhibitor azidothymidine (AZT). The lethal effect of AZT was validated in peripheral neurofibroma NF1-deficient human cell lines and NF1-deficient malignant peripheral nerve sheath tumour cells. The effect of AZT was also conserved in vivo, highlighting the translational potential; treatment of mice with AZT inhibited NF1 mutant xenograft growth to the same extent as the current clinically approved MEK inhibitor, selumetinib. Finally, we show that combined treatment with AZT and selumetinib resulted in a further synergistic reduction in NF1-deficient human cell viability. In conclusion, AZT represents a promising novel therapeutic for the treatment of NF1 tumours, either alone or in combination with selumetinib.

cancer biology↗

bioRxiv2024

Non-continuous neuromodulation in awake, unrestrained felines increases bladder capacity

ObjectiveNeuromodulation is a standard therapy for bladder symptoms such as overactive bladder. Previous studies have demonstrated that non-continuous stimulation (NCS) can increase bladder capacity and that bladder pressure can be estimated from dorsal root ganglia (DRG) neural activity in anesthetized animal models. Our goal is to determine if NCS elicits similar bladder capacity effects as continuous stimulation (CS) and if bladder pressure can be estimated from DRG signals in an awake, unrestrained animal model. ApproachWe performed aseptic, chronic implant surgeries with seven adult, male felines. Three animals were used to establish procedures, three for experimental testing, and one did not yield data. Bipolar stimulating electrodes were placed on the pudendal nerve and sacral nerve on the same side. Microelectrode arrays were inserted in two ipsilateral sacral DRG. Two single-lumen catheters were implanted in the bladder dome for recording bladder pressure and infusing saline. Fixed-sequence, repeated bladder fills were performed in four awake felines to evaluate the bladder capacity during no-stimulation (NS), NCS, and CS at either the pudendal or sacral nerve. NCS was performed based on increases in bladder pressure estimated from DRG recordings or when 50% of the average NS bladder capacity was reached. Main resultsWe observed similar bladder capacity increases for NCS (122 {+/-} 31% of NS control) as for CS (121 {+/-} 33%) in the four animals. NCS paradigms reduced stimulation time by 46% on average. Median correlation coefficients of 0.46 and 0.64 (maximum 0.93) between the predicted and measured bladder pressure were obtained for awake trials with DRG bladder units in two animals. SignificanceThis study demonstrated the feasibility of using NCS to increase bladder capacity in awake, unrestrained felines and for decoding bladder pressure from DRG recordings. Further studies are needed to optimize NCS timing for clinical translation.

bioengineering↗

bioRxiv2024

Determining the culturability of the bovine rumen bacterial and archaeal microbiota

Ruminants play an important part in global food security, but also emit methane which contributes to global warming. Microbes in the rumen strongly influence the energy retention efficiency from the hosts plant-based diet and produce methane as a by-product. While thousands of novel microbial genomes have been assembled from metagenome sequence data, their culturability is ill-defined. Here different media were used to isolate microbes from rumen fluid. 34 genera were grown, and the majority belonged to the phylum Bacillota (75.28% {+/-} 6.34), Bacteroidota (19.99% {+/-} 4.85), Pseudomonadota (2.46% {+/-} 2.01), and Actinomycetota (2.09% {+/-} 1.07). The most abundant genera were Selenomonas (28.08% {+/-} 11.71), Streptococcus (22.67% {+/-} 6.06), Prevotella (18.71% {+/-} 4.02), and unclassified Lachnospiraceae (11.50% {+/-} 2.54). When comparing the mean relative abundance of these genera between media, 31 were significantly enriched on at least one medium. The composition of the source rumen fluid was vastly different to those cultured. Bacteroidota (52.53% {+/-} 5.10) predominated, with by Bacillota (41.00% {+/-} 3.96), the archaeal Euryarchaeota (5.12% {+/-} 1.94), Pseudomonadota (1.22% {+/-} 0.78), and Actinomycetota (0.12% {+/-} 0.08) comprising the rest. The most abundant genera were Prevotella (29.13% {+/-} 4.16), Butyrivibrio (18.21% {+/-} 2.08), Succiniclasticum (15.57% {+/-} 5.03), unclassified Bacteroidetes (13.91% {+/-} 1.67), and unclassified Prevotellaceae (9.50% {+/-} 2.01). These data further emphasise the importance of using defined media to selectively enrich for different microbial taxa. This is essential to understand the complex workings of the rumen microbes to enhance digestion efficiency and reduce the loss of energy as methane.

microbiology↗

bioRxiv2024

Local photo-crosslinking of native tissue matrix regulates cell function

Within most tissues, the extracellular microenvironment provides mechanical cues that guide cell fate and function. Changes in the extracellular matrix such as aberrant deposition, densification and increased crosslinking are hallmarks of late-stage fibrotic diseases that often lead to organ dysfunction. Biomaterials have been widely used to mimic the mechanical properties of the fibrotic matrix and study cell function. However, the initiation of fibrosis has largely been overlooked, due to the challenges in recapitulating early fibrotic lesions within the native extracellular microenvironment. Using visible light mediated photochemistry, we induced local crosslinking and stiffening of extracellular matrix proteins within ex vivo murine and human tissue. In ex vivo lung tissue of epithelial cell lineage-traced mice, local matrix crosslinking mimicked early fibrotic lesions that increased alveolar epithelial cell spreading, differentiation and extracellular matrix remodeling. However, inhibition of cytoskeletal tension or integrin engagement reduced epithelial cell spreading and differentiation, resulting in alveolar epithelial cell dedifferentiation and reduced extracellular matrix deposition. Our findings emphasize the role of local extracellular matrix crosslinking and remodeling in early-stage tissue fibrosis and have implications for ex vivo disease modeling and applications to other tissues.

bioengineering↗

bioRxiv2024

Lymphostatin: Structure of a large multi-functional virulence factor

Enteropathogenic and Enterohaemorrhagic Escherichia coli are enteric pathogens of global importance and human infections can be life-threatening. Lymphostatin is a key virulence factor of these bacteria, being required for intestinal colonisation and a potent inhibitor of the mitogen- and antigen-activated proliferation of lymphocytes and proinflammatory responses. In some strains, it also mediates adherence to host cells and influences actin nucleation at sites of attachment. This 365 kDa protein requires glycosyltransferase and cysteine protease motifs for activity against lymphocytes, but high-resolution structural information has proven elusive and the molecular mechanisms by which it acts remain unclear. Here, we describe the structure of lymphostatin from the prototype O127:H6 enteropathogenic E. coli strain determined by electron cryo-microscopy. Our results reveal two glycosyltransferase domains, one PaTox-like protease domain, an ADP-ribosyltransferase domain, and a delivery domain. Long linkers act to hold these domains together. These linkers occlude the catalytic sites of the N-terminal glycosyltransferase and protease domains. In this dormant state, lymphostatin binds to HEK-293T cells, where it forms large clusters before being taken up and sequestered into cytosolic foci. With more functional domains than any other known large bacterial toxin, lymphostatin can be regarded as the multifunctional Swiss army knife of pathogenic Escherichia coli, enabling complex interactions with the host cells in different environments.

biophysics↗

bioRxiv2023

Disentangling the Innate Immune Responses of Intestinal Epithelial Cells and Lamina Propria Cells to Salmonella Typhimurium Infection in Chickens

Salmonella enterica serovar Typhimurium (STm) is a major foodborne pathogen and poultry are a key reservoir of human infections. To understand the host responses to early stages of Salmonella infection in poultry, we infected 2D and 3D enteroids, the latter of which contains leukocytes, neurons, and mesenchymal cells that are characteristic of the lamina propria. We infected these enteroids with wild-type (WT STm), a non-invasive mutant lacking the prgH gene ({Delta}prgH STm), or treated them with STm lipopolysaccharide (LPS) and analysed the expression of innate immune related genes by qPCR at 4 and 8 h. The localisation of ZO-1 expression was disrupted in WT STm infected enteroids but not{Delta} prgH STm or LPS treated enteroids, suggesting a loss of barrier integrity. The innate immune response to LPS was more pronounced in 2D enteroids compared to 3D enteroids and by 8 hpi, the response in 3D enteroids was almost negligible. However, when STm adhered to or invaded the enteroids, both 2D and 3D enteroids exhibited an upregulation of inflammatory responses. The presence of lamina propria cells in 3D enteroids resulted in the unique expression of genes associated with immune functions involved in regulating inflammation. Moreover, 2D and 3D enteroids showed temporal differences in response to bacterial invasion or adherence. At 8 hpi, innate responses in 3D but not 2D enteroids continued to increase after infection with WT STm, whereas the responses to the non-invasive strain decreased at 8 hpi in both 2D and 3D enteroids. In conclusion, STm infection of chicken enteroids recapitulated several observations from in vivo studies of Salmonella-infected chickens, including altered epithelial barrier integrity based on ZO-1 expression and inflammatory responses. Our findings provide evidence that Salmonella-infected enteroids serve as effective models for investigating host-pathogen interactions and exploring the molecular mechanisms of microbial virulence although the 3D model mimics the host more accurately due to the presence of a lamina propria.

immunology↗

bioRxiv2023

Overcoming the speed limit of four-way DNA branch migration with bulges in toeholds

Dynamic DNA nanotechnology involves the use of DNA strands to create programmable reaction networks and nanodevices. The key reaction in dynamic DNA nanotechnology is the exchange of DNA strands between different molecular species, which is achieved through three-way and four-way DNA exchange reactions. While both of these reactions have been widely used to build reaction circuits, the four-way exchange reaction has traditionally been slower and less efficient than the three-way reaction. In this paper, we describe a new mechanism to optimise the kinetics of the four-way DNA exchange reaction by adding bulges to the toeholds of the four-way DNA complexes involved in the reaction. These bulges facilitate an alternative branch migration mechanism and destabilise the four-way DNA junction, increasing the branch migration rate and unbinding rate of the four-way exchange reaction, bringing it closer to the kinetics of the three-way reaction. This new mechanism has the potential to expand the field of dynamic DNA nanotechnology by enabling efficient four-way DNA exchange reactions for in vivo applications.

biophysics↗

bioRxiv2022

Single particle profiler for measuring properties of nano-sized bioparticles

It is technically challenging to study the content and properties of nanoscale bioparticles in a high-throughput and single-molecule manner. We developed a high-throughput analysis method, called single particle profiler (SPP) that provides single-particle information on content and biophysical properties of thousands of particles. We applied SPP to measure the mRNA encapsulation efficiency of lipid nanoparticles, viral binding efficiency of different nanobodies and biophysical heterogeneity of liposomes, lipoproteins, exosomes and viruses.

biophysics↗

bioRxiv2021

Synthetic lethal screening identifies existing drugs with selective viability effects on Neurofibromatosis type-1 model systems

Neurofibromatosis type 1 (NF1) is a genetic disorder associated with various symptoms including the formation of benign tumors along nerves. Drug treatments are currently limited. The MEK inhibitor selumetinib is used for a subset of cases but is not always effective and can cause side effects. Therefore, there is a clear need to discover new drugs to target NF1-deficient tumor cells. Using a Drosophila cell model of NF1, we performed synthetic lethal screens to identify novel drug targets. We identified 54 candidates, which were validated with variable dose analysis as a secondary screen. Five candidates could be targeted using existing drugs, with autophagy inhibitors (chloroquine (CQ) and bafilomycin A1) showing the greatest potential for selectively killing NF1-deficient Drosophila cells. When further investigating autophagy-related genes, we found that 14 out of 30 genes tested had a synthetic lethal interaction with NF1. These 14 genes are involved in the regulation of all aspects of the autophagy pathway and can be targeted with additional autophagy drugs, although none were as effective as CQ. The lethal effect of autophagy inhibitors was conserved in a panel of human NF1-deficient Schwann cell lines, highlighting their translational potential. The effect of CQ was also conserved in a Drosophila NF1 in vivo model and in a xenografted NF1-deficient tumor cell line in mice, with CQ treatment resulting in a more significant reduction in tumor growth than selumetinib treatment. Furthermore, combined treatment with CQ and selumetinib resulted in a further reduction in NF1-deficient cell viability. In conclusion, NF1-deficient cells are vulnerable to disruption of the autophagy pathway. This pathway represents a promising therapeutic target for NF1-associated tumors, and CQ was identified as a promising candidate drug for the treatment of NF1 tumors.

cancer biology↗

bioRxiv2021

Antarctic biodiversity predictions through substrate qualities and environmental DNA

Antarctic conservation science is important to enhance Antarctic policy and to understand alterations of terrestrial Antarctic biodiversity. Antarctic conservation will have limited long term effect in the absence of large-scale biodiversity data, but if such data were available, it is likely to improve environmental protection regimes. To enable Antarctic biodiversity prediction across continental spatial scales through proxy variables, in the absence of baseline surveys, we link Antarctic substrate-derived environmental DNA (eDNA) sequence data from the remote Antarctic Prince Charles Mountains to a selected range of concomitantly collected measurements of substrate properties. We achieve this using a statistical method commonly used in machine learning. We find neutral substrate pH, low conductivity, and some substrate minerals to be important predictors of presence for basidiomycetes, chlorophytes, ciliophorans, nematodes, or tardigrades. Our bootstrapped regression reveals how variations of the identified substrate parameters influence probabilities of detecting eukaryote phyla across vast and remote areas of Antarctica. We believe that our work may improve future taxon distribution modelling and aid targeting logistically challenging biodiversity surveys.

ecology↗