Biology subjects

Vogel, H.

Publications and source records attributed to Vogel, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Rapid Host Plant Adaptation via Ectopic Gene Conversion in Plutellid Moths

Herbivorous insects face an extraordinary challenge: the chemical defenses of their host plants are highly diverse, rapidly evolving, and largely unpredictable. How insects meet this challenge remains poorly understood. Here we show that ectopic gene conversion (EGC) has repeatedly driven the evolutionary diversification of glucosinolate sulfatases (GSSs), the key larval counteradaptation in plutellid moths to glucosinolate based defenses in cruciferous plants. Across seven plutellid species, enzyme assays with heterologously expressed GSSs and 21 glucosinolates revealed distinct activity profiles: GSSs from species with broad host ranges within glucosinolate-containing plants showed balanced activity across substrates, whereas GSSs from specialists displayed profiles biased toward the glucosinolate composition of their host plants. Comparative genomic analyses identified extensive conversion among duplicated genes, both historically across the clade and in contemporary Plutella armoraciae. In this originally monophagous species, EGC-mediated diversification of GSS enzymes coincides with the rapid inclusion of a new cruciferous host within <200 years, demonstrating the potential of EGC to drive host-range expansion on strikingly short evolutionary timescales. Structural modelling and molecular dynamics simulations further support functional shifts in GSS enzymes arising from EGC-derived sequence alterations. Together, these results demonstrate that EGC provides a powerful mechanism for fine tuning detoxification enzymes, enabling herbivorous insects to adapt to chemically diverse host plants despite constrained enzymatic toolkits.

evolutionary biology↗

bioRxiv2026

Reversible Opto-Chemical activation of KRASG12V signaling with near single-cell precision

KRAS mutations drive some of the most lethal carcinomas, and genomic and inducible systems have established many of the cellular and tissue-level consequences. However, these approaches operate at the level of oncogene expression, allowing for cellular adaptation that masks the individual role of KRAS oncoprotein signaling. Here, we developed a reversible Opto-Chemical system to activate KRAS signaling by chemically translocating a cytosolic mutant KRASG12V G-domain to the plasma membrane upon light or small-molecule input. In MDCK cells, the G-domain plasma membrane recruitment activated downstream signaling and reduced collective migration. In mouse small Intestinal Organoids, G-domain recruitment promoted increased crypt size and number under Epidermal Growth Factor-deprived conditions. We further showed that the increased number of crypts depended on continuous KRASG12V signaling. Finally, under the same deprived conditions, localized activation in just one budding crypt promoted crypt formation compared to controls. This system decouples oncoprotein activity from oncogene expression, allowing to investigate the KRAS signaling contribution to early epithelial transformation.

Systems Biology↗

bioRxiv2026

Somatic mutations reveal the ontogeny of human microglia

Microglia are the resident hematopoietic cells of the central nervous system1. In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult hematopoiesis2-4. The origins of human microglia are less clear, but recent evidence suggests that marrow-derived cells may be able to supplement the human microglial pool in certain individuals5,6. Here, to investigate the ontogeny of human microglia, we develop a method that uses the collection of accumulated somatic mutations which uniquely labels each clone of cells to track the infiltration of marrow-derived cells into the human brain. Applying this method to 20 aged individuals, we find evidence of an influx of marrow-derived cells into the brain in all examined individuals. Single cell analysis, including single cell lineage tracing using mitochondrial DNA variants, demonstrates that these infiltrating cells are nearly identical to microglia and can comprise a large fraction of the microglial pool. Analysis of large-scale sequencing cohorts demonstrates a protective association between most types of clonal hematopoiesis and Alzheimers disease. In sum, this work uncovers a widespread influx of myeloid cells into the healthy human brain which serves to reinforce the pool of human microglia and becomes common with aging.

immunology↗

bioRxiv2026

Characterization of the urinary DNA virome of hematopoietic stem cell transplant recipient and healthy cynomolgus macaques

BK polyomavirus (BKPyV) and chronic latent DNA virus infections frequently reactivate after hematopoietic stem cell transplantation (HSCT), where they contribute to major complications in humans with limited options for prevention or treatment. Mauritian cynomolgus macaques (MCM; Macaca fascicularis) serve as an important animal model for transplantation research due to their limited major histocompatibility complex (MHC) diversity. Similar viral reactivations and disease complications occur in MCMs and humans post-transplantation, including polyomavirus-associated hemorrhagic cystitis and nephropathy. To define the polyomaviruses associated with these outcomes and characterize the broader urinary DNA virome, we sequenced rolling circle-amplified urine DNA from HSCT recipient and healthy cynomolgus macaques, allowing for comprehensive genomic characterization of the detected polyomaviruses. De novo assembly and annotation identified three polyomaviruses with apparent specific host tropism to cynomolgus macaques: Macaca fascicularis polyomavirus 2 (MafaPyV2) and Macaca fascicularis polyomavirus 3 (MafaPyV3), which are closely related to human polyomaviruses, and a newly identified strain of simian virus 40 (SV40 type IIB). All three viruses were detected in both HSCT recipients and healthy animals but were shed at significantly higher relative loads in HSCT recipients. Multiple polyomaviruses were frequently detected within individual hosts, and all three were identified in HSCT recipients that developed urologic disease. Together, these findings further characterize polyomavirus diversity, shedding, and disease associations in hematopoietic stem cell-transplanted Mauritian cynomolgus macaques. ImportanceReactivation of latent viruses after hematopoietic stem cell transplantation is a major cause of illness in transplant recipients, yet options for prevention and treatment remain limited. Progress has been hindered by the lack of animal models that accurately reflect human disease. In this study, we show that Mauritian cynomolgus macaques harbor multiple polyomaviruses that reactivate at high levels following transplantation and are associated with urinary tract disease, closely paralleling complications seen in humans. We define the genetic identity of these viruses and demonstrate that immunosuppression strongly enhances viral shedding and disease severity. By establishing clear similarities between viral reactivation in macaques and humans, this work validates the Mauritian cynomolgus macaque transplantation model as a powerful platform for studying virus-driven disease mechanisms and testing antiviral therapies and vaccines relevant to human transplantation.

microbiology↗

bioRxiv2026

Damage sensing recruitment of a lipid phosphatase couples lysosomal membrane repair to proteostatic adaptation

Restoration of organellar membrane integrity is critical for maintaining cellular homeostasis. Lysosomal membrane damage activates local repair machineries and global stress responses, but how signaling lipid metabolism is engaged by damage sensors to support and mechanistically link these processes remains poorly understood. Here we show that the phosphoinositide 3-phosphatase MTMR14 is recruited to damaged lysosomes through calcium-dependent binding to sphingomyelin. At these sites, MTMR14 promotes local PI(3)P hydrolysis and supports PI(4)P accumulation, thereby facilitating formation of ER-lysosome contact sites associated with membrane repair, without affecting ESCRT recruitment. MTMR14-dependent lipid remodelling causes reduced mTORC1 signalling and a decrease in global protein synthesis, consistent with an acute proteostatic adaptation to lysosomal injury. Cells lacking MTMR14 display impaired damage-induced lipid remodelling, altered repair-associated structures, sustained protein synthesis, and increased sensitivity to lysosomal injury, all of which can be mitigated by mTORC1/S6K inhibition. Our findings identify damage-sensing recruitment of MTMR14 and local PI(3)P turnover on damaged lysosomes as a phosphoinositide module that promotes lysosomal membrane integrity and homeostasis while functionally linking nutrient signalling to proteostasis under membrane stress.

cell biology↗

bioRxiv2026

The floral illusion: A parasitic beetle mimics the scent of flowers to attract bees

Animals are not known to biosynthesize floral signals to manipulate pollinators, although such mimicry could profoundly shape plant-pollinator interactions. Larvae of the poisonous European blister beetle Meloe proscarabaeus parasitize multiple solitary bee species, yet the mechanism enabling host attraction has remained unresolved. Here we show that these larvae lure bees by emitting a bouquet of volatile compounds that closely resembles floral scent. Chemical analyses reveal a complex blend of monoterpenoids derived from (S)-linalool, a ubiquitous floral volatile. Behavioral assays demonstrate that these compounds function as floral cues, eliciting attraction in bees. Transcriptomic and functional analyses identify cytochrome P450 enzymes that oxidize (S)-linalool, demonstrating that larvae biosynthesize these plant-like volatiles de novo. Together, these findings broaden the scope of interkingdom chemical mimicry and uncover a striking form of sensory deception in which an insect chemically assumes the signal identity of a flower, revealing that animals can evolve biosynthetic pathways to exploit plant-pollinator communication.

ecology↗

bioRxiv2025

Colorectal cancer relies on an immunosuppressive cellular topography and genomic adaptations for establishing brain metastases

Colorectal cancer (CRC) brain metastases have a poor prognosis and limited treatment options, including resistance to radiation therapy. Little is known about the molecular and cellular mechanisms that enable CRC tumor cells to adapt to the brain and establish a supportive tumor microenvironment. To address this gap we used spatial transcriptomics to analyze 51 CRC brain metastases. A subset had matched primary colon tumors and longitudinally paired metastatic resections before and after radiation treatment. We identified the critical spatial cellular features of the tumor epithelium and the surrounding tumor microenvironment that support metastatic growth in the brain. CRC brain metastases developed a stromal microenvironment with abundant fibroblasts and tumor-associated macrophages. A fibroblast-macrophage cellular neighborhood promoted angiogenesis, extracellular matrix remodeling, and immune suppression. Tumor cells showed local adaptations. In endothelial-rich regions, they were proliferative whereas in macrophage-rich regions, they were more differentiated and immune evasive. Compared with paired primary tumors, CRC brain metastases showed increased chromosomal instability, with activation of RNA-processing, stress response, and junctional remodeling pathways. After radiation treatment, resistant clones had increased epithelial-mesenchymal transition, while the immunosuppressive stroma remained intact. We identified tumor-derived MIF, GDF15, PRSS3 and SEMA3C ligands and macrophage-derived SPP1 that have the potential to affect multiple cell types in the metastatic niche. These ligand-receptor interactions drive angiogenesis, stromal activation and immune suppression. In a macrophage-tumor-fibroblast co-culture model, knockout of SPP1 in macrophages led to reduced expression of lipid-metabolism related genes and disrupted tumor-promoting interactions. Together, these results indicate that CRC growth in the brain is sustained by a specific cellular organization with immunosuppressive multicellular interactions.

cancer biology↗

bioRxiv2025

Long vs. short read sequencing for microbial ecology of sedimentary environments: a case study from Lake Arnon, Switzerland

The subsurface biosphere remains poorly characterized, with many resident microorganisms uncultured and lacking genomic references. Despite the growing accessibility of shotgun metagenomics, 16S rRNA gene sequencing remains a standard tool for microbial community profiling, often relying on sequence similarity to reference databases such as SILVA to infer taxonomy and potential function. However, in environments with low biomass and high proportions of unknown lineages, such as deeper sedimentary environments, the accuracy of these inferences and our ability to capture rare taxa remain uncertain. A better inference of these rare taxa may now be possible with the advent of accurate long-read applications that have recently become available. Here we provide a comparison of long-read (PacBio) and short-read (Illumina NextSeq) 16S rRNA approaches for microbial communities from a sediment core of Lake Arnon (Switzerland). We compared community composition in environmental samples and mock controls to evaluate the strengths and limitations of each method. While sequencing technology significantly influenced observed community structure, sediment depth had an even stronger effect. Taxonomic profiles were broadly consistent across methods for most bacterial groups, but archaeal diversity was underrepresented in the long-read data, likely due to primer mismatch. When detected, long-read sequencing offered more accurate taxonomic resolution, often down to the species level, enabling better inference of metabolic potential. Beta diversity patterns were similar at broad taxonomic levels between methods, though more detailed metrics such as species contributions to beta diversity (SCBD) and co-occurrence networks showed enhanced resolution and specificity in long-read datasets. Our results highlight the critical importance of primer design, in particular for capturing archaeal taxa that play important roles in the deep biosphere. With improved primer coverage and continued cost reductions, long-read sequencing holds strong potential for advancing our understanding of subsurface microbial identity, structure and function.

ecology↗

bioRxiv2025

A multi-partner symbiotic community inhabits the emerging pest Pentastiridius leporinus

The planthopper Pentastiridius leporinus has emerged as a severe crop pest, rapidly expanding both its host plant range and the affected areas in central Europe. Originating as a monophagous herbivore of reed grass, P. leporinus recently adopted polyphagous feeding and is now a pest of sugar beet, potato, carrot, and onion, suggesting rapid ecological niche expansion. P. leporinus vectors two bacterial pathogens, the {gamma}-proteobacterium Candidatus Arsenophonus phytopathogenicus (CAP) and the stolbur phytoplasma Candidatus Phytoplasma solani (CPS), which are responsible for a range of disease syndromes, including syndrome basses richesses (SBR) in sugar beet. We used long-read metagenomic sequencing to characterize the genomes of microbes associated with P. leporinus, resulting in the complete sequences of CAP and CPS, as well as primary symbionts of the genera Purcelliella, Sulcia and Vidania, and facultative symbionts Rickettsia and Wolbachia. The primary symbionts are inferred to provide all ten essential amino acids and contribute to B vitamin biosynthesis. The genomes of CPS and CAP encode numerous pathogenicity factors, enabling the colonization of different hosts. Bacterial fluorescence in situ hybridization revealed the tissue distribution, cellular localization, relative abundance and transmission patterns of these bacteria. The intracellular presence of all primary symbionts in bacteriomes, the intracellular presence of Wolbachia, and the intranuclear localization of Rickettsia, suggest vertical transmission. CPS was restricted to salivary glands, suggesting strict horizontal, plant-mediated transmission, whereas CAP colonized all tissue types, allowing for horizontal and vertical transmission. Our data suggest that P. leporinus hosts an exceptionally broad range of symbionts, encompassing mutualistic, commensal and pathogenic interactions. ImportanceThe planthopper Pentastiridius leporinus has recently expanded its host plant range and emerged as severe pest of sugar beet and potato crops in central Europe, which is exacerbated by its capacity to vector bacterial pathogens to its host plants. Because microbial symbionts may play an important role for both the host plant shifts and the transmission of pathogens, we used metagenomic sequencing and fluorescence in situ hybridization to characterize the microbial community associated with P. leporinus. We detected three bacteriome-localized primary symbionts that together provision all essential amino acids and several B-vitamins to the host, as well as two intracellular bacteria with a broader tissue distribution. In addition, we infer localization, transmission, and putative pathogenicity factors for the two major phytopathogens that are vectored by P. leporinus. Our results reveal a complex community of symbiotic bacteria that likely shapes the interaction of this emerging pest with its host plants.

systems biology↗

bioRxiv2025

Spatial Profiling Reveals Equivalence-Derived Molecular Signatures of Brain Mimicry and Adaptation in Breast Cancer Brain Metastases

Brain metastases (BrMets), common for advanced-stage breast cancer patients, are associated with poor median survival and accompanied by severe neurologic decline. Halting the progression of breast cancer brain metastases (BCBMs) may require modulation of the tumor microenvironment (TME), yet little is known about the impact of the primary breast TME on brain tropism, or how, once there, metastatic breast cancer cells coexist with brain-resident cells (e.g., neurons and glia). Traditionally, studies in this space have focused on differential expression analysis, overlooking potential insights gained from investigating genes with equivalent expression between groups. This is particularly crucial in distant metastasis, where tumor cells may co-opt the transcriptional programs of the host organ (e.g., brain) to facilitate successful seeding and outgrowth. Prior to our work, no computational framework existed to determine biologically-relevant equivalent gene expression. To resolve molecular mechanisms of BCBM enabled by metastatic cancer cells and/or resident brain cells, we leveraged Nanostring GeoMx to perform spatially-resolved transcriptomic profiling on 235 patient-derived tissue cores from BCBM (including adjacent normal brain), primary invasive breast cancers, and normal (non-cancer) brain; analyzing 18,677 RNAs in 450 areas of interest (AOIs). We introduce the "Equivalent Expression Index" a highly specific and accurate algorithm that identifies statistically significant "Equivalently-Expressed Genes". This method facilitated the identification of molecular remodeling and mimicry genes within tissue-specific TMEs. By integrating differential expression analysis with the Equivalent Expression Index, we discovered multiple novel gene signatures associated with BCBM and primary tumor brain-metastatic potential. We demonstrate that the Equivalent Expression Index is a powerful tool to uncover shared gene expression programs representing the adaptation of metastatic cells and brain-resident cells to the BCBM microenvironment.

cancer biology↗

bioRxiv2025

Ptpn14 Knockout Mice Reveal Critical Female-Specific Roles for the Hippo Pathway

The Hippo pathway regulates many physiological processes, including development, tumor suppression, and wound healing. One understudied Hippo pathway component is PTPN14, an evolutionarily conserved tyrosine-phosphatase that inhibits YAP/TAZ. While an established tumor suppressor, PTPN14s role in tissue homeostasis has remained unclear. We thus generated Ptpn14-deficient mice and found that only [~]60% of Ptpn14-/- mice survived postnatally, highlighting the importance of PTPN14 for viability, while also enabling the discovery of PTPN14 physiological functions. Ptpn14-/-mice developed debilitating corneal lesions and the uterus defect, hydrometra, as well as heart and kidney abnormalities. Ptpn14-deficiency precipitated an impaired injury response in the cornea and dysregulated YAP signaling in the uterus. Notably, these phenotypes were female-specific, revealing sexually-dimorphic Hippo pathway function through PTPN14. Finally, analysis of human PTPN14 variants suggested that PTPN14s essential roles are conserved in humans, underscoring the importance of our insights for designing therapies to improve womens health.

developmental biology↗

bioRxiv2024

Phylogenomic reconstruction of Cryptosporidium spp. captured directly from clinical samples reveals extensive genetic diversity

Cryptosporidium is a leading cause of severe diarrhea and mortality in young children and infants in Africa and southern Asia. More than twenty Cryptosporidium species infect humans, of which C. parvum and C. hominis are the major agents causing moderate to severe diarrhea. Relatively few genetic markers are typically applied to genotype and/or diagnose Cryptosporidium. Most infections produce limited oocysts making it difficult to perform whole genome sequencing (WGS) directly from stool samples. Hence, there is an immediate need to apply WGS strategies to 1) develop high-resolution genetic markers to genotype these parasites more precisely, 2) to investigate endemic regions and detect the prevalence of different genotypes, and the role of mixed infections in generating genetic diversity, and 3) to investigate zoonotic transmission and evolution. To understand Cryptosporidium global population genetic structure, we applied Capture Enrichment Sequencing (CES-Seq) using 74,973 RNA-based 120 nucleotide baits that cover [~]92% of the genome of C. parvum. CES-Seq is sensitive and successfully sequenced Cryptosporidium genomic DNA diluted up to 0.005% in human stool DNA. It also resolved mixed strain infections and captured new species of Cryptosporidium directly from clinical/field samples to promote genome-wide phylogenomic analyses and prospective GWAS studies.

genomics↗

bioRxiv2024

Repeated horizontal acquisition of lagriamide-producing symbionts in Lagriinae beetles

Microbial symbionts associate with multicellular organisms on a continuum from facultative associations to mutual codependency. In some of the oldest intracellular symbioses there is exclusive vertical symbiont transmission, and co-diversification of symbiotic partners over millions of years. Such symbionts often undergo genome reduction due to low effective population sizes, frequent population bottlenecks, and reduced purifying selection. Here, we describe multiple independent acquisition events of closely related defensive symbionts followed by genome erosion in a group of Lagriinae beetles. Previous work in Lagria villosa revealed the dominant genome-eroded symbiont of the genus Burkholderia produces the antifungal compound lagriamide and protects the beetles eggs and larvae from antagonistic fungi. Here, we use metagenomics to assemble 11 additional genomes of lagriamide-producing symbionts from seven different host species within Lagriinae from five countries, to unravel the evolutionary history of this symbiotic relationship. In each host species, we detected one dominant genome-eroded Burkholderia symbiont encoding the lagriamide biosynthetic gene cluster (BGC). Surprisingly, however, we did not find evidence for host-symbiont co-diversification, or for a monophyly of the lagriamide-producing symbionts. Instead, our analyses support at least four independent acquisition events of lagriamide-encoding symbionts and subsequent genome erosion in each of these lineages. By contrast, a clade of plant-associated relatives retained large genomes but secondarily lost the lagriamide BGC. In conclusion, our results reveal a dynamic evolutionary history with multiple independent symbiont acquisitions characterized by high degree of specificity. They highlight the importance of the specialized metabolite lagriamide for the establishment and maintenance of this defensive symbiosis.

genomics↗

bioRxiv2023

A novel mouse model of cerebral adrenoleukodystrophy highlights NLRP3 activity in lesion pathogenesis

ObjectiveWe sought to create and characterize a mouse model of the inflammatory, cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD) that would facilitate the study of disease pathogenesis and therapy development. We also sought to cross-validate potential therapeutic targets such as fibrin, oxidative stress, and the NLRP3 inflammasome, in post-mortem human and murine brain tissues. BackgroundALD is caused by mutations in the gene ABCD1 encoding a peroxisomal transporter. More than half of males with an ABCD1 mutation develop the cerebral phenotype (cALD). Incomplete penetrance and absence of a genotype-phenotype correlation imply a role for environmental triggers. Mechanistic studies have been limited by the absence of a cALD phenotype in the Abcd1-null mouse. MethodsWe generated a cALD phenotype in 8-week-old, male Abcd1-null mice by deploying a two-hit method that combines cuprizone (CPZ) and experimental autoimmune encephalomyelitis (EAE) models. We employed in vivo MRI and post-mortem immunohistochemistry to evaluate myelin loss, astrogliosis, blood-brain barrier (BBB) disruption, immune cell infiltration, fibrin deposition, oxidative stress, and Nlrp3 inflammasome activation in mice. We used bead-based immunoassay and immunohistochemistry to evaluate IL-18 in CSF and post-mortem human cALD brain tissue. ResultsMRI studies revealed T2 hyperintensities and post-gadolinium enhancement in the medial corpus callosum of cALD mice, similar to human cALD lesions. Both human and mouse cALD lesions shared common histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-null mice had more severe cerebral inflammation, demyelination, fibrin deposition, oxidative stress, and IL-18 activation. IL-18 immunoreactivity co-localized with macrophages/microglia in the perivascular region of both human and mouse brain tissue. InterpretationThis novel mouse model of cALD suggests loss of Abcd1 function predisposes to more severe cerebral inflammation, oxidative stress, fibrin deposition, and Nlrp3 pathway activation, which parallels the findings seen in humans with cALD. We expect this model to enable long-sought investigations into cALD mechanisms and accelerate development of candidate therapies for lesion prevention, cessation, and remyelination. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/564025v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1fbfebforg.highwire.dtl.DTLVardef@111e1e8org.highwire.dtl.DTLVardef@10647eborg.highwire.dtl.DTLVardef@15b9af4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Clinically relevant concurrent BRAF and MEK inhibition alters differentiation states and sensitizes BRAF V600E-mutated high-grade gliomas to immune checkpoint blockade

Resistance to BRAF plus MEK inhibition (BRAFi+MEKi) in BRAFV600E-mutant gliomas drives rebound, progression, and high mortality, yet it remains poorly understood. This study addresses the urgent need to develop treatments for BRAFi+MEKi-resistant glioma in novel mouse models and patient-derived materials. BRAFi+MEKi reveals glioma plasticity by heightening cell state transitions along glial differentiation trajectories, giving rise to astrocyte- and immunomodulatory oligodendrocyte (OL)-like states. PD-L1 upregulation in OL-like cells links cell state transitions to tumor evasion, possibly orchestrated by Galectin-3. BRAFi+MEKi induces interferon response signatures, tumor infiltration, and suppression of T cells. Combining BRAFi+MEKi with immune checkpoint inhibition enhances survival in a T cell-dependent manner, reinvigorates T cells, and outperforms individual or sequential therapies in mice. Elevated PD-L1 expression in BRAF-mutant versus BRAF-wildtype glioblastoma supports the rationale for PD-1 inhibition in patients. These findings underscore the potential of targeting glioma plasticity and highlight combination strategies to overcome therapy resistance in BRAFV600E-mutant HGG. In briefXing et al. show that combined BRAF and MEK inhibitor (BRAFi+MEKi) treatment induces cell state transitions in BRAFV600E-mutant high-grade glioma cells linked with programmed death-ligand (PD-L1) upregulation and T cell suppression, potentially orchestrated through the secretion of galectin-3. These tumor-intrinsic adaptations may be overcome by concurrent immune checkpoint inhibition (ICI), as demonstrated in murine studies, offering novel therapeutic opportunities. HighlightsO_LIBRAFV600E-mutant HGG exhibits cell plasticity induced by BRAFi+MEKi, which links cell state transitions towards glial differentiation with immune evasion C_LIO_LIBRAFi+MEKi enhances anti-tumor immunity and simultaneously suppresses T cells via PD-L1 upregulation C_LIO_LIBRAF-mutant glioblastoma has elevated PD-L1 expression compared to BRAF-wildtype counterparts, providing a criterion for PD-1 inhibition therapy C_LIO_LIConcurrent BRAFi+MEKi and immune checkpoint inhibition enhance T cell-mediated anti-tumor activity and boost survival more effectively than sequential treatment in mice, guiding clinical translation C_LI

cancer biology↗

bioRxiv2022

Synthetic whole-slide image tile generation with gene expression profiles infused deep generative models

The acquisition of multi-modal biological data for the same sample, such as RNA sequencing and whole slide imaging (WSI), has increased in recent years, enabling studying human biology from multiple angles. However, despite these emerging multi-modal efforts, for the majority of studies only one modality is typically available, mostly due to financial or logistical constraints. Given these difficulties, multi-modal data imputation and multi-modal synthetic data generation are appealing as a solution for the multi-modal data scarcity problem. Currently, most studies focus on generating a single modality (e.g. WSI), without leveraging the information provided by additional data modalities (e.g. gene expression profiles). In this work, we propose an approach to generate WSI tiles by using deep generative models infused with matched gene expression profiles. First, we train a variational autoencoder (VAE) that learns a latent, lower dimensional representation of multi-tissue gene expression profiles. Then, we use this representation to infuse generative adversarial networks (GAN) that generate lung and brain cortex tissue tiles, resulting in a new model that we call RNA-GAN. Tiles generated by RNA-GAN were preferred by expert pathologists in comparison to tiles generated using traditional GANs and in addition, RNA-GAN needs fewer training epochs to generate high-quality tiles. Finally, RNA-GAN was able to generalize to gene expression profiles outside of the training set, showing imputation capabilities. A web-based quiz is available for users to play a game distinguishing real and synthetic tiles: https://rna-gan.stanford.edu/ and the code for RNA-GAN is available here: https://github.com/gevaertlab/RNA-GAN.

bioinformatics↗

bioRxiv2021

Ancient and modern geochemical signatures in the 13,500-year sedimentary record of Lake Cadagno

Although lake sediments are globally important organic carbon sinks and therefore important habitats for deep microbial life, the deep lacustrine biosphere has thus far been little studied compared to its marine counterpart. To investigate the impact of the underexplored deep lacustrine biosphere on the sediment geochemical environment and vice versa, we performed a comprehensive microbiological and geochemical characterization of a sedimentary sequence from Lake Cadagno covering its entire environmental history since formation following glacial retreat. We found that both geochemical gradients and microbial community shifts across the [~]13.5 kyr subsurface sedimentary record reflect redox changes in the lake, going from oxic to anoxic and sulfidic. Most microbial activity occurs within the top 40 cm of sediment, where millimolar sulfate concentrations diffusing in from the bottom water are completely consumed. In deeper sediment layers, organic carbon remineralization is much slower but microorganisms nonetheless subsist on fermentation, sulfur cycling, metal reduction, and methanogenesis. The most surprising finding was the presence of a deep, oxidizing groundwater source. This water source generates an inverse redox gradient at the bottom of the sedimentary sequence and could contribute to the remineralization of organic matter sequestered in the energy-limited deep subsurface.

microbiology↗

bioRxiv2021

Microevolution of Pieris butterfly genes involved in host-plant adaptation along a host-plant community cline

Herbivorous insects have evolved counteradaptations to overcome the chemical defenses of their host plants. Several of these counteradaptations have been elucidated at the molecular level, in particular for insects specialized on cruciferous host plants. While the importance of these counteradaptations for host plant colonization is well established,little is known about their microevolutionary dynamics in the field. In this study, we examine patterns of host plant use and insect counteradaptation in three Pieris butterfly species across Japan. The larvae of these butterflies express nitrile-specifier protein (NSP) and its paralog major allergen (MA) in their gut to overcome the highly diversified glucosinolate-myrosinase defense system of their cruciferous host plants. Pieris napi and Pieris melete colonize wild Brassicaceae whereas Pieris rapae typically uses cultivated Brassica as a host, regardless of the local composition of wild crucifers. As expected, NSP and MA diversity was independent of the local composition of wild Brassicaceae in P. rapae. In contrast, NSP diversity correlated with local host plant diversity in both species that preferred wild Brassicaceae. P. melete and P. napi both revealed two distinct major NSP alleles, which shaped diversity among local populations, albeit with different evolutionary trajectories. In comparison, MA showed no indication for local adaptation. Altogether, MA appeared to be evolutionary more conserved than NSP, suggesting that both genes play different roles in diverting host plant chemical defense.

evolutionary biology↗