Biology subjects

Jackson, M.

Publications and source records attributed to Jackson, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

GplR1, an unusual TetR-like transcription factor in Mycobacterium abscessus, controls the production of cell wall glycopeptidolipids, colony morphology, and virulence

Mycobacterium abscessus is a major human pathogen, mostly infecting people with pre-existing lung conditions such as cystic fibrosis. The production of glycopeptidolipids (GPL) is a major determinant of virulence of this bacterium, with clinical isolates that lack GPL generally exhibiting more aggressive clinical behavior. The current paradigm is that GPL production is abolished in vivo via irreversible, spontaneous mutations taking place as part of in-host evolution. Little is known about the mechanisms or extent to which GPL production may be regulated. Here we describe an unusual TetR-like transcription factor of M. abscessus, MAB_1638, that appears to be a strong positive regulator of the entire GPL biosynthesis and export gene cluster through a combination of direct and indirect mechanisms. The inactivation of mab_1638 abolished GPL production and thus led to stable rough colony morphology, as well as increased virulence in infection models, characteristic of rough, non-GPL-producers. Transcriptome analysis found the mab_1638 mutant had 118 differentially expressed genes, including the GPL locus and a second, recently described GPL-like locus that produces a related glycosylated lipopeptide called GP8L. Chromatin Immunoprecipitation and sequencing revealed a consensus inverted-repeat DNA sequence motif characteristic of genes regulated by mab_1638. Together, mab_1638 appears to encode a transcription factor required for production of GPL and therefore having a profound effect on virulence traits. We propose naming this gene GPL regulator 1 (gplR1). This finding raises the important possibility that M. abscessus strains appearing smooth in laboratory growth conditions may nonetheless downregulate GPL-cluster genes in other conditions, including in-patient conditions, and thus acquire the phenotypic characteristics of rough strains. ImportanceMycobacterium abscessus is an important human pathogen, causing disease that is difficult to treat. M. abscessus strains have been observed to have two distinct colony morphologies, smooth and rough, which substantially impact clinical presentation. Rough strains are associated with later-stage, more severe disease and are more virulent in animal models. Smooth morphology is conferred by a molecule called glycopeptidolipid in the outer cell envelope, and rough morphology is known to occur when mutations inactivate genes required for glycopeptidolipid biosynthesis. Little is known about the possibility that glycopeptidolipid production could be regulated. Here we have identified a transcription factor that is required for glycopeptidolipid biosynthesis, indicating that glycopeptidolipid production is indeed a regulated process, and raising the important possibility that strains exhibiting smooth morphology in the lab may down-regulated GPL production in the human host and thereby acquire the virulence properties of rough strains.

microbiology↗

bioRxiv2025

Improving wearable-based seizure prediction by feature fusion using growing network

AO_SCPLOWBSTRACTC_SCPLOWThe unpredictability of seizures is one of the most compromising features reported by people with epilepsy. Non-stigmatizing and easy-to-use wearable devices may provide information to predict seizures based on physiological data. We propose a patient-agnostic seizure prediction method that identifies group-level patterns across data from multiple patients. We employ supervised long-short-term networks (LSTMs) and add unsupervised deep canonically correlated autoencoders (DCCAE) and 24-hour patterns using time-of-day information. We fuse features from these three techniques using a growing neural network, allowing incremental learning. Our method with all three features improves prediction accuracy over the baseline LSTM by 7.3%, from 74.4% to 81.7%, averaged across all patients, and outperforms the LSTM in 84% of patients. Compared to the all-at-once fusion, the growing network improves the accuracy by 9.5%. We analyze the impact of preictal data duration, wearable data quality, and clinical variables on the prediction performance.

bioinformatics↗

bioRxiv2024

Targeting eIF4G1-dependent translation in melanoma

Expression of components of the translation initiation complex (eIF4F) is frequently elevated in cancer, resulting in enhanced synthesis of oncogenic proteins. We thus set out to limit eIF4F pro-oncogenic activity, a notable challenge given its essential role in normal tissues. CRISPR-Cas9-based functional screen using tiling sgRNAs identified the eIF4G1 MA3 domain, a subunit of the eIF4F complex, as a target for developing small molecule inhibitors. Combination of structure-guided in silico modeling and chemical library screening led to the identification of small molecule candidates M19 and its analog M19-6 that binds to the MA3 domain of eIF4G1 and disrupts eIF4F complex. M19-6 treatment reprograms the melanoma translatome, limiting synthesis of factors that promote cell proliferation and neoplastic growth, as well as reducing translation of mRNAs encoding ferroptosis suppressors. Whole genome CRISPR screen indentified ferroptosis activators to augment M19-6 activity, which was confirmed in cultured melanoma cells. M19-6 alleviates melanoma resistance to BRAF and MEK inhibitors, while eliciting anti-tumor and anti-metastatic effects in preclinical mouse models. Among several biomarkers found in M19-6 sensitive cell lines, THBS1 and TGF{beta}I expression were elevated in patients who are non-responders to PD-1 therapy as in patients with metastasis. Our studies identify M19-6 as a therapeutic candidate, offering a novel insights into targeting the eIF4F complex to overcome melanoma resistance to therapy and metastasis. SignificanceWe identify M19-6 as a small molecule that disrupts the eIF4F, translation initiation complex, by targeting the MA3 domain of eIF4G1, resulting in elimination of melanoma cells in culture, overcoming therapy resistance while inhibiting melanoma growth and metastasis in vivo. As M19-6 causes minimal toxicity to melanocytes, it offers a therapeutic modality for melanoma.

cancer biology↗

bioRxiv2024

The level of endothelial glycocalyx maturity modulates interactions with charged nano-materials

Nanomaterials have been extensively investigated for their potential in delivering therapeutics to target tissues, but few have advanced to clinical application. The luminal surface of endothelial cells that line blood vessels are covered by a glycocalyx, a complex extracellular matrix rich in anionic glycans. However, the role of this glycocalyx in governing nanomaterial-cell interactions is often overlooked. In this study, we demonstrate that gold nanoparticles functionalized with branched polyethyleneimine (AuNP+) bind to primary human endothelial cells expressing either a developing or mature glycocalyx, with the interaction involving hyaluronan and heparan sulfate. Notably, the mature glycocalyx decreases the toxicity of AuNP+. In contrast, lipoic acid-functionalized gold nanoparticles (AuNP-) bind to endothelial cells with a developing glycocalyx, but not a mature glycocalyx. To further investigate this phenomenon, we studied charged polymers, including poly(arginine) (polyR) and poly(glutamic acid) (polyE). PolyE does not associate with endothelial cells regardless of glycocalyx maturity, but when glycans are enzymatically degraded, it can bind to the cells. Conversely, polyR associates with endothelial cells irrespective of glycocalyx maturity or glycan degradation. These findings highlight the intricate relationship between nanomaterial charge and presentation in interactions with endothelial cells, offering insights for modulating nanomaterial interactions with the blood vessel wall.

bioengineering↗

bioRxiv2024

Terrestrial 3D Laser Scanning for Ecosystem and Fire Effects Monitoring

Long-term terrestrial ecosystem monitoring is a critical component of documenting outcomes of land management actions, assessing progress towards management objectives, and guiding realistic long-term ecological goals, all through repeated observation and measurement. Traditional monitoring methods have evolved for specific applications in forestry, ecology, and fire and fuels management. While successful monitoring programs have clear goals, trained expertise, and rigorous sampling protocols, new advances in technology and data management can help overcome the most common pitfalls in data quality and repeatability. This paper presents Terrestrial Laser Scanning (TLS), a specific form of LiDAR (Light Detection and Ranging), as an emerging sampling method that can complement and enhance existing monitoring methods. TLS captures in high resolution the 3D structure of a terrestrial ecosystem (forest, grassland, etc.), and is increasingly efficient and affordable (<$30,000). Integrating TLS into ecosystem monitoring can standardize data collection, improve efficiency, and reduce bias and error. Streamlined data processing pipelines can rigorously analyze TLS data and incorporate constant improvements to inform management decisions and planning. The approach described in this paper utilizes portable, push-button TLS equipment that, when calibrated with initial transect sampling, captures detailed forestry, fuels, and ecological features in less than 5 minutes per plot. We also introduce an interagency automated processing pipeline and dashboard viewer for instant, user-friendly analysis, and data retrieval of hundreds of metrics. Forest metrics and inventories produced with these methods offer effective decision-support data for managers to quantify landscape-scale conditions and respond with efficient action. This protocol further supports interagency compatibility for efficient natural resource monitoring across jurisdictional boundaries with uniform data, language, methods, and data analysis. With continued improvement of scanner capabilities and affordability, these data will shape the future of terrestrial ecosystem monitoring as an important means to address the increasingly fast pace of ecological change facing natural resource managers.

ecology↗

bioRxiv2024

Body size is a better predictor of intra- than interspecific variation of animal stoichiometry across realms

Animal stoichiometry affects fundamental processes ranging from organismal physiology to global element cycles. However, it is unknown whether animal stoichiometry follows predictable scaling relationships with body mass and whether adaptation to life on land or water constrains patterns of elemental allocation. To test both interspecific and intraspecific body-size scaling relationships of the nitrogen (N), phosphorus (P), and N:P content of animals, we used a subset of the StoichLife database encompassing 9,933 individual animals (vertebrates and invertebrates) belonging to 1,543 species spanning 10 orders of magnitude of body size from terrestrial, freshwater, and marine realms. Across species, body mass did not explain much variation in %N and %P composition, although the %P of invertebrates decreased with size. The effects of body size on species elemental content were small in comparison to the effects of taxonomy. Body size was a better predictor of intraspecific than interspecific elemental patterns. Between 42 to 45% in intraspecific stoichiometric variation was explained by body size for 27% of vertebrate species and 35% of invertebrate species. Further, differences between organisms inhabiting aquatic and terrestrial realms were observed only in invertebrate interspecific %N, suggesting that the realm does not play an important role in determining elemental allocation of animals. Based on our analysis of the most comprehensive animal stoichiometry database, we conclude that (i) both body size and realm are relatively weak predictors of animal stoichiometry across taxa, and (ii) body size is a good predictor of intraspecific variation in animal elemental content, which is consistent with tissue-scaling relationships that hold broadly across large groups of animals. This research reveals a lack of general scaling patterns in the elemental content across animals and instead points to a large variation in scaling relationships within and among lineages.

ecology↗

bioRxiv2023

Mutation of NOTCH1 is selected within normal esophageal tissues, yet leads to selective epistasis suppressive of further evolution into cancer

BackgroundSomatic mutations commonly accumulate in histologically normal tissues and contribute to cancer development. However, many mutations that are common in normal tissue are also found in cancers from the same organ, making their role in malignant progression unclear. To address this, we asked whether such mutations increase cell proliferation and survival to different degrees at different steps of esophageal tumor development, and whether they alter selection for other driver mutations. MethodsWe used a quantitative evolutionary framework to distinguish underlying mutation rate from selection across two steps of esophageal development: from organogenesis to clonal histologically normal esophageal epithelium, and from that tissue to esophageal squamous-cell carcinoma. Analyzing sequence data from 2171 samples, we estimated step-specific selection on recurrent somatic mutations, corresponding to increased cellular division and survival, and tested whether mutations in one gene earlier in the trajectory changed selection for mutations on another. We additionally examined somatic copy-number alterations and single-cell transcriptomic profiles to contextualize these evolutionary patterns within broader genomic and cellular changes during progression. ResultsNOTCH1 mutations were strongly selected during the clonal expansion of histologically normal esophageal epithelium, explaining their high prevalence in that tissue. However, for the first time, we show that there is little to no positive selection for NOTCH1, NOTCH2, and FAT1 mutations during progression from clonal histologically normal esophageal tissue to esophageal squamous-cell carcinoma in humans, leading to a conclusion that these alterations promote clonal expansion in normal tissue, but do not drive malignant progression from established normal clones. Moreover, we provide a somatic genetic basis for this step-specific effect: we demonstrate for the first time that mutations in NOTCH1 exhibit antagonistic epistasis with mutations of TP53 and RB1, reducing selection for these key tumor suppressor alterations during tumor development. Consistent with this model, copy-number alterations associated with later ESCC progression were more strongly selected in TP53-mutant samples, supporting the idea that TP53 disruption promotes a genomic context more permissive for malignant evolution. ConclusionsEarly somatic mutations can promote clonal expansion in normal tissue without promoting cancer, and in some cases may limit progression by reducing selection for later driver events. NOTCH1 and other genes can shape evolutionary trajectories in ways that ultimately constrain malignant progression. By separating mutation rate from selection, quantifying step-specific genetic interactions, and considering broader changes in genomic and cellular context, our study shows that the effects of recurrent mutations depend strongly on disease stage and mutational context--what promotes clonal expansion in normal tissue may later impede growth or survival in tumors. These insights underscore the need for precision strategies that account for the shifting fitness landscape across premalignant and malignant stages, informing early detection, prevention, and therapeutic prioritization.

cancer biology↗

bioRxiv2023

Immune Responses in Checkpoint Myocarditis Across Heart, Blood, and Tumor

Immune checkpoint inhibitors (ICIs) are widely used anti-cancer therapies that can cause morbid and potentially fatal immune-related adverse events (irAEs). ICI-related myocarditis (irMyocarditis) is uncommon but has the highest mortality of any irAE. The pathogenesis of irMyocarditis and its relationship to anti-tumor immunity remain poorly understood. We sought to define immune responses in heart, tumor, and blood during irMyocarditis and identify biomarkers of clinical severity by leveraging single-cell (sc)RNA-seq coupled with T cell receptor (TCR) sequencing, microscopy, and proteomics analysis of 28 irMyocarditis patients and 23 controls. Our analysis of 284,360 cells from heart and blood specimens identified cytotoxic T cells, inflammatory macrophages, conventional dendritic cells (cDCs), and fibroblasts enriched in irMyocarditis heart tissue. Additionally, potentially targetable, pro-inflammatory transcriptional programs were upregulated across multiple cell types. TCR clones enriched in heart and paired tumor tissue were largely non-overlapping, suggesting distinct T cell responses within these tissues. We also identify the presence of cardiac-expanded TCRs in a circulating, cycling CD8 T cell population as a novel peripheral biomarker of fatality. Collectively, these findings highlight critical biology driving irMyocarditis and putative biomarkers for therapeutic intervention.

immunology↗

bioRxiv2023

Insights into Digit Evolution from a Fate Map Study of the Forearm

The cellular and genetic networks which contribute to the development of the zeugopod, (radius and ulna of the forearm, tibia and fibula of the leg) are not well understood, although these bones are susceptible to loss in congenital human syndromes and to the action of teratogens such as thalidomide. Using a new fate mapping approach in transgenic chickens, we show that there is a small contribution of SHH expressing cells to the posterior ulna, posterior carpals and digit 3. We establish that while the majority of the ulna develops in response to paracrine SHH signaling in both the chicken and mouse, there are differences in the contribution of SHH expressing cells to other tissues of the zeugopod between these two species as well as between the chicken ulna and fibula. This is evidence that although zeugopod bones are clearly homologous according to the fossil record, the zeugopod bones of the wing and leg are formed by subtly different signalling and patterning events during embryonic development, which can be used to understand the shaping of the bird wing skeleton during the evolution of powered flight.

developmental biology↗

bioRxiv2023

Non-invasive canine electroencephalography (EEG): a systematic review

AO_SCPLOWBSTRACTC_SCPLOWThe emerging field of canine cognitive neuroscience uses neuroimaging tools such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to map the cognitive processes of dogs to neural substrates in their brain. Within the past decade, the non-invasive use of EEG has provided real-time, accessible, and portable neuroimaging insight into canine cognitive processes. To promote systematization and create an overview of framings, methods and findings for future work, we provide a systematic review of non-invasive canine EEG studies (N=22), dissecting their study makeup, technical setup, and analysis frameworks and highlighting emerging trends. We further propose new directions of development, such as the standardization of data structures and integrating predictive modeling with descriptive statistical approaches. Our review ends by underscoring the advances and advantages of EEG-based canine cognitive neuroscience and the potential for accessible canine neuroimaging to inform both fundamental sciences as well as practical applications for cognitive neuroscience, working dogs, and human-canine interactions.

animal behavior and cognition↗

bioRxiv2023

Trade-offs in a reef-building coral after six years of thermal acclimation

Evidence is growing that reef-building corals have the capacity to acclimate to new and challenging thermal conditions by increasing their thermal resistance. This raises hopes for their future persistence in a warming world. However, potential trade-offs that accompany such resistance gains, have remained largely unexplored. We provide the first report on the physiological trade-offs in a globally abundant and ecologically relevant coral species (Pocillopora acuta), after a long-term exposure to an elevated temperature of 31 {degrees}C in comparison to conspecifics cultivated under a cooler control thermal regime. At both temperatures, corals consistently appeared to be visually healthy throughout a six-year period. At 31 {degrees}C, corals had increased metabolic rates (both respiration and photosynthesis) that resulted in higher biomass accumulation and total energy reserves compared to the corals from the ambient regime. Further, the composition of coral host tissues shifted in favor of lipid build-up, suggesting an altered mechanism of energy storage. The increase in biomass growth came at the cost of declining skeletal growth rates and the formation of higher density skeletons. In the long-term, this trade-off will result in lower extension rates that can entail major ramifications for future reef building processes and reef community composition. Moreover, symbionts at 31 {degrees}C were physiologically more compromised with overall lower energy reserves, possibly indicating a stronger exploitation by the host and potentially a lower stress resilience. Our study provides first insights into a successful thermal acclimation mechanism that involved the prioritization of energy storage over skeletal growth, entailing higher demands on the symbionts. Our observation in this 6-year study does not align with observations of short-term studies, where elevated temperatures caused a depletion of tissue lipids in corals, which highlights the importance of studying acclimation of organisms over their relevant biological scales. Further investigations into trade-offs at biologically relevant scales and how they unfold under an acute heat stress will help to provide a more comprehensive picture of the future coral reef trajectory. Importantly, these insights will also help improve interventions aimed at increasing the thermal resilience of corals which anticipate to use thermal preconditioning treatments for stress-hardening. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/549699v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@139b33corg.highwire.dtl.DTLVardef@1264477org.highwire.dtl.DTLVardef@158f7c9org.highwire.dtl.DTLVardef@1f3c35a_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗

bioRxiv2022

Discovery, Synthesis, and Optimization of 1,2,4-Triazolyl Pyridines Targeting Mycobacterium tuberculosis

Tuberculosis (TB) results in 1.5 million deaths every year. The rise in multi-drug resistant TB underscores the urgent need to develop new antibacterials, particularly those with new chemical entities and/or novel mechanisms of action that can be used in combination therapy with existing drugs to prevent the rapid emergence of resistance. Herein, we report the discovery and synthesis of a new series of compounds containing a 3-thio-1,2,4-triazole moiety that show inhibition of Mycobacterium tuberculosis (Mtb) growth and survival. Structure-activity relationship studies led us to identify potent analogs displaying nanomolar inhibitor activity, specifically against Mtb. These potent analogs exhibit a promising ADME/pharmacokinetic profile and no cytotoxicity in mammalian cells at over 100 times the effective dose in Mtb. Our preliminary investigations into the mechanism of action suggest this series is not engaging promiscuous targets and, thereby, could be acting on a novel target. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/516356v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1fd7a78org.highwire.dtl.DTLVardef@738c7dorg.highwire.dtl.DTLVardef@c7957org.highwire.dtl.DTLVardef@f26ae3_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

A Multivalent Polyomavirus Vaccine Elicits Durable Neutralizing Antibody Responses in Macaques

In 2019, there were about 100,000 kidney transplants globally, with more than a quarter of them performed in the United States. Unfortunately, some engrafted organs are lost to polyomavirus-associated nephropathy (PyVAN) caused by BK and JC viruses (BKPyV and JCPyV). Transplant patients are routinely monitored for BKPyV viremia, which is an accepted hallmark of nascent nephropathy. If viremia is detected, a reduction in immunosuppressive therapy is standard care, but the intervention comes with increased risk of immune rejection of the engrafted organ. Recent reports have suggested that transplant recipients with high levels of polyomavirus-neutralizing antibodies are protected against PyVAN. Virus-like particle (VLP) vaccines, similar to approved human papillomaviruses vaccines, have an excellent safety record and are known to induce high levels of neutralizing antibodies associated and long-lasting protection from infection. In this study, we demonstrate that VLPs representing BKPyV genotypes I, II, and IV, as well as JCPyV genotype 2 produced in insect cells elicit robust antibody titers. In rhesus macaques, all monkeys developed neutralizing antibody titers above a previously proposed protective threshold of 10,000. A second inoculation, administered 19 weeks after priming, boosted titers to a plateau of [≥]25,000 that was maintained for almost two years. No vaccine-related adverse events were observed in any macaques. A multivalent BK/JC VLP immunogen did not show inferiority compared to the single-genotype VLP immunogens. Considering these encouraging results, we believe a clinical trial administering the multivalent VLP vaccine in patients waiting to receive a kidney transplant is warranted to evaluate its ability to reduce or eliminate PyVAN. HIGHLIGHTSO_LIRecombinant virus-like particle vaccine was safely administered to rhesus macaques C_LIO_LIVaccination generated high-titer neutralizing antibody responses C_LIO_LIMultivalent BK/JC polyomavirus vaccine was as effective as monovalent vaccines C_LIO_LIHigh neutralizing titers were sustained for 92 weeks without appreciable decline C_LI

immunology↗

bioRxiv2022

Mechanical morphotype switching as an adaptive response in mycobacteria

Invading microbes face a myriad of cidal mechanisms of phagocytes that inflict physical damage to microbial structures. How intracellular bacterial pathogens adapt to these stresses is not fully understood. Here, we report a new virulence mechanism by which mycobacteria alter the mechanical stiffness of their cell surface to become refractory to killing during infection. Long-Term Time-Lapse Atomic Force Microscopy was used to reveal a process of "mechanical morphotype switching" in mycobacteria exposed to host intracellular stress. A "soft" mechanical morphotype switch enhances tolerance to intracellular macrophage stress, including cathelicidin. Genetic manipulation, by deletion of uvrA, or pharmacological treatment, with bedaquiline, locked mycobacteria into a "soft" mechanical morphotype state, enhancing survival in macrophages. Our study proposes microbial mechanical adaptation as a new axis for surviving host-mediated stressors. One-Sentence SummaryBacteria alter their cell surface mechanical properties to increase survival during macrophage infection.

microbiology↗

bioRxiv2021

Melanoma Addiction to GCDH is Mediated by NRF2 Tumor Suppressor Function

Tumor dependency on specific metabolic signals has guided numerous therapeutic approaches. Here we identify melanoma addiction to the mitochondrial protein Glutaryl-CoA dehydrogenase (GCDH), a component in lysine metabolism which controls protein glutarylation. GCDH knockdown promoted apoptotic Unfolded Protein Response signaling and cell death in melanoma cells, an activity blocked by knockdown of the upstream lysine catabolism enzyme DHTKD1. Correspondingly, reduced GCDH expression correlated with improved survival of melanoma patients. A key mediator of GCDH-dependent melanoma cell death programs is the transcription factor NRF2, which induces ATF3, CHOP, and CHAC1 transcription linking lysine catabolism with the UPR signaling. NRF2 glutarylation upon GCDH KD increased its stability and DNA binding activity, which coincided with increased transcriptional activity, promoting apoptotic UPR signaling and tumor suppression. In vivo, genetic GCDH inhibition effectively inhibited melanoma tumor growth. Overall, these findings demonstrate an addiction of melanoma cells to GCDH, which by controlling NRF2 glutarylation limits apoptotic UPR signaling. Inhibiting the GCDH pathway could represent a novel therapeutic modality to treat melanoma.

cancer biology↗

bioRxiv2021

Increased apoptotic priming of glioblastoma enables therapeutic targeting by BH3-mimetics

IDH wild-type glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. Tackling this, we investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of anti- apoptotic BCL-xL and MCL-1 were consistently increased in GBM compared with non- malignant cells and tissue. Moreover, we found that relative to their differentiated counterparts, patient-derived GBM stem-like cells also displayed higher expression of anti- apoptotic BCL-2 family members. Surprisingly, high anti-apoptotic BCL-xL and MCL-1 expression correlated with heightened susceptibility of GBM to BCL-2 family protein- targeting BH3-mimetics. This is indicative of increased apoptotic priming. Indeed, GBM displayed an obligate requirement for MCL-1 expression in both tumour development and maintenance. Investigating this apoptotic sensitivity, we found that sequential inhibition of BCL-xL and MCL-1 led to robust anti-tumour responses in vivo, in the absence of overt toxicity. These data demonstrate that BCL-xL and MCL-1 pro-survival function is a fundamental prerequisite for GBM survival that can be therapeutically exploited by BH3- mimetics.

cancer biology↗

bioRxiv2021

riboviz 2: A flexible and robust ribosome profiling data analysis and visualization workflow

MotivationRibosome profiling, or Ribo-seq, is the state of the art method for quantifying protein synthesis in living cells. Computational analysis of Ribo-seq data remains challenging due to the complexity of the procedure, as well as variations introduced for specific organisms or specialized analyses. Many bioinformatic pipelines have been developed, but these pipelines have key limitations in terms of functionality or usability. ResultsWe present riboviz 2, an updated riboviz package, for the comprehensive transcript-centric analysis and visualization of Ribo-seq data. riboviz 2 includes an analysis workflow built on the Nextflow workflow management system, combining freely available software with custom code. The package is extensively documented and provides example configuration files for organisms spanning the domains of life. riboviz 2 is distinguished by clear separation of concerns between annotation and analysis: prior to a run, the user chooses a transcriptome in FASTA format, paired with annotation for the CDS locations in GFF3 format. The user is empowered to choose the relevant transcriptome for their biological question, or to run alternative analyses that address distinct questions. riboviz 2 has been extensively tested on various library preparation strategies, including multiplexed samples. riboviz 2 is flexible and uses open, documented file formats, allowing users to integrate new analyses with the pipeline. Availabilityriboviz 2 is freely available at github.com/riboviz/riboviz. Supplementary information

bioinformatics↗

bioRxiv2021

Beyond coral-algal regimes: high taxonomic resolution surveys and trait-based analyses reveal multiple benthic regimes

As coral reef communities change and reorganise in response to anthropogenic and climate disturbances, there is a growing need of detecting and understanding the different emerging species regimes and their contribution to key ecosystem processes. Using a case study on coral reefs at the epicentre of tropical marine biodiversity (North Sulawesi), we explored how application of different biodiversity approaches (i.e. use of major taxonomic categories, high taxonomic resolution categories and trait-based approaches) affects the detection of distinct fish and benthic community assemblages. Our results show that using major categories (family level or above) to study coral reef communities fails to identify distinct regimes. We also show that for detection of different benthic regimes, especially communities dominated by non-coral organisms, monitoring of only scleractinian coral communities is insufficient, and that all types of benthic organisms (e.g. sponges, ascidians, soft corals, algae etc.) need to be considered. We have implemented for the first time, the use of a trait-based approach to study the functional diversity of whole coral reef benthic assemblages, which allowed us to detect five different community regimes, only one of which was dominated by scleractinian corals. We circumvented the challenge that for some benthic groups (e.g. sponges, ascidians or some soft corals) visual identification up to the species level is not possible, by identifying and categorising traits that can be applied to groups of similar organisms instead of specific species. Furthermore, by the parallel study of benthic and fish communities we provide new insights into key processes and functions that might dominate or be compromised in the different community regimes.

ecology↗