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Frank, M.

Publications and source records attributed to Frank, M..

At least 37 records · Page 2Linked to original sources

Re-analysis of mobile mRNA datasets highlights challenges in the detection of mobile transcripts from short-read RNA-Seq data

Short-read RNA-Seq analyses of grafted plants have led to the proposal that large numbers of mRNAs move over long distances between plant tissues, acting as potential signals. The detection of transported transcripts by RNA-Seq is both experimentally and computationally challenging, requiring successful grafting, delicate harvesting, rigorous contamination controls and data processing approaches that can identify rare events in inherently noisy data. Here, we perform a meta-analysis of existing datasets and examine the associated bioinformatic pipelines. Our analysis reveals that technological noise, biological variation and incomplete genome assemblies give rise to features in the data that can distort the interpretation. Taking these considerations into account, we find that a substantial number of transcripts that are currently annotated as mobile are left without support from the available RNA-Seq data. Whilst several annotated mobile mRNAs have been validated, we cannot exclude that others may be false positives. The identified issues may also impact other RNA-Seq studies, in particular those using single nucleotide polymorphisms (SNPs) to detect variants.

plant biology↗

TransfoRNA: Navigating the Uncertainties of Small RNA Annotation with an Adaptive Machine Learning Strategy

Small RNAs hold crucial biological information and have immense diagnostic and therapeutic value. While many established annotation tools focus on microRNAs, there are myriads of other small RNAs that are currently underutilized. These small RNAs can be difficult to annotate, as ground truth is limited and well-established mapping and mismatch rules are lacking. TransfoRNA is a machine learning framework based on Transformers that explores an alternative strategy. It uses common annotation tools to generate a small seed of high-confidence training labels, while then expanding upon those labels iteratively. TransfoRNA learns sequence-specific representations of all RNAs to construct a similarity network which can be interrogated as new RNAs are annotated, allowing to rank RNAs based on their familiarity. While models can be flexibly trained on any RNA dataset, we here present a version trained on TCGA (The Cancer Genome Atlas) small RNA sequences and demonstrate its ability to add annotation confidence to an unrelated dataset, where 21% of previously unannotated RNAs could be annotated. Relative to its training data, TransfoRNA could boost high-confidence annotations in TCGA by [~]50% while providing transparent explanations even for low-confidence ones. It could learn to annotate 97% of isomiRs from just single examples and confidently identify new members of other familiar classes with high accuracy, while reliably rejecting false RNAs. All source code is available at https://github.com/gitHBDX/TransfoRNA and can be executed at Code Ocean (https://codeocean.com/capsule/5415298/). An interactive website is available at www.transforna.com. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/599329v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@11bc3d9org.highwire.dtl.DTLVardef@1d6ff01org.highwire.dtl.DTLVardef@1ffac02org.highwire.dtl.DTLVardef@75ccd8_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

Lateral olivocochlear neurons modulate cochlear responses to noise exposure

The sense of hearing originates in the cochlea, which detects sounds across dynamic sensory environments. Like other peripheral organs, the cochlea is subjected to environmental insults, including loud, damage-inducing sounds. In response to internal and external stimuli, the central nervous system directly modulates cochlear function through olivocochlear neurons (OCNs), which are located in the brainstem and innervate the cochlear sensory epithelium. One population of OCNs, the lateral olivocochlear (LOC) neurons, target spiral ganglion neurons (SGNs), the primary sensory neurons of the ear. LOCs alter their transmitter expression for days to weeks in response to noise exposure (NE), suggesting that they are well-positioned to tune SGN excitability over long time periods in response to auditory experience. To examine how LOCs affect auditory function after NE, we characterized the transcriptional profiles of OCNs and found that LOCs exhibit transient changes in gene expression after NE, including upregulation of multiple neuropeptide-encoding genes. Next, by generating intersectional mouse lines that selectively target LOCs, we chemogenetically ablated LOC neurons and assayed auditory responses at baseline and after NE. Compared to controls, mice lacking LOCs showed stronger NE-induced functional deficits one day later and had worse auditory function after a two-week recovery period. The number of remaining presynaptic puncta at the SGN synapse with inner hair cells did not differ between control and LOC-ablated animals, suggesting that the primary role of LOCs after NE is likely not one of protection, but one of compensation, ensuring that SGN function is enhanced during periods of need.

neuroscience↗

chronODE: A framework to integrate time-series multi-omics data based on ordinary differential equations combined with machine learning

Most functional genomic studies are conducted in steady-state conditions, therefore providing a description of molecular processes at a particular moment of cell differentiation or organismal development. Longitudinal studies can offer a deeper understanding of the kinetics underlying epigenetic events and their contribution to defining cell-type-specific transcriptional programs. Here we develop chronODE, a mathematical framework based on ordinary differential equations that uniformly models the kinetics of temporal changes in gene expression and chromatin features. chronODE employs biologically interpretable parameters that capture tissue-specific kinetics of genes and regulatory elements. We further integrate this framework with a neural-network architecture that can link and predict changes across different data modalities by solving multivariate time-series regressions. Next, we apply this framework to investigate region-specific kinetics of epigenome rewiring in the developing mouse brain, and we demonstrate that changes in chromatin accessibility within regulatory elements can accurately predict changes in the expression of putative target genes over the same time period. Finally, by integrating single-cell ATAC-seq data generated during the same time course, we show that regulatory elements characterized by fast activation kinetics in bulk measurements are active in early-appearing cell types, such as radial glial and other neural progenitors, whereas elements characterized by slow activation kinetics are specific to more differentiated cell types that emerge at later stages of brain development.

bioinformatics↗

Leveraging a large language model to predict protein phase transition: a physical, multiscale and interpretable approach

Protein phase transitions (PPTs) from the soluble state to a dense liquid phase (forming droplets via liquid-liquid phase separation) or to solid aggregates (such as amyloids) play key roles in pathological processes associated with age-related diseases such as Alzheimers disease. Several computational frameworks are capable of separately predicting the formation of droplets or amyloid aggregates based on protein sequences, yet none have tackled the prediction of both within a unified framework. Recently, large language models (LLMs) have exhibited great success in protein structure prediction; however, they have not yet been used for PPTs. Here, we fine-tune a LLM for predicting PPTs and demonstrate its usage in evaluating how sequence variants affect PPTs, an operation useful for protein design. In addition, we show its superior performance compared to suitable classical benchmarks. Due to the "black-box" nature of the LLM, we also employ a classical random forest model along with biophysical features to facilitate interpretation. Finally, focusing on Alzheimers disease-related proteins, we demonstrate that greater aggregation is associated with reduced gene expression in AD, suggesting a natural defense mechanism. Significance StatementProtein phase transition (PPT) is a physical mechanism associated with both physiological processes and age-related diseases. We present a modeling approach for predicting the protein propensity to undergo PPT, forming droplets or amyloids, directly from its sequence. We utilize a large language model (LLM) and demonstrate how variants within the protein sequence affect PPT. Because the LLM is naturally domain-agnostic, to enhance interpretability, we compare it with a classical knowledge-based model. Furthermore, our findings suggest the possible regulation of PPT by gene expression and transcription factors, hinting at potential targets for drug development. Our approach demonstrates the usefulness of fine-tuning a LLM for downstream tasks where only small datasets are available.

biophysics↗

Sialoglycan binding triggers spike opening in a human coronavirus

Coronavirus (CoV) spikes mediate receptor binding and membrane fusion, making them prime targets for neutralising antibodies. In the cases of SARS-CoV, SARS-CoV-2, and MERS-CoV, spikes transition freely between open and closed conformations to balance host cell attachment and immune evasion. The open conformation exposes domain S1B, allowing it to bind to proteinaceous cell surface receptors. It also facilitates protein refolding during spike-mediated membrane fusion. However, with a single exception, the pre-fusion spikes of all other CoVs studied so far have been observed exclusively in the closed state. This raises the possibility of regulation, where spikes more commonly transition to open states in response to specific cues, rather than spontaneously. In our study, using cryo-EM and molecular dynamics simulations, we show that the spike protein of the common cold human coronavirus HKU1 undergoes local and long-range conformational changes upon binding a sialoglycan-based primary receptor to domain S1A. This binding triggers the transition of S1B domains to the open state via allosteric inter-domain cross-talk. Our findings paint a more elaborate picture of CoV attachment, with possibilities of dual receptor usage and priming of entry as a means of immune escape.

microbiology↗

Single-cell analysis maps distinct cellular responses to rhizobia and identifies the novel infection regulator SYMRKL1 in Lotus japonicus

Legume-rhizobium signaling during establishment of symbiotic nitrogen fixation restricts rhizobium colonization to specific cells. A limited number of root hair cells allow infection threads to form, and only a fraction of the epidermal infection threads progress to cortical layers to establish functional nodules. Here we use single-cell analysis to define the epidermal and cortical cell populations that respond to and facilitate rhizobium infection. We then identify high-confidence nodulation gene candidates based on their specific expression in these populations, pinpointing genes stably associated with infection across genotypes and time points. We show that one of these, which we name SYMRKL1, encodes a protein with an ectodomain predicted to be nearly identical to that of SYMRK and is required for normal infection thread formation. Our work disentangles cellular processes and transcriptional modules that were previously confounded due to lack of cellular resolution, providing a more detailed understanding of symbiotic interactions.

plant biology↗

Integrated PET and confocal imaging informs a functional timeline for the dynamic process of vascular reconnection during grafting.

Grafting is a widely used agricultural technique that involves the physical joining of separate plant parts so they form a unified vascular system, enabling beneficial traits from independent genotypes to be captured in a single plant. This simple, yet powerful tool has been used for thousands of years to improve abiotic and biotic stress tolerance, enhance yield, and alter plant architecture in diverse crop systems. Despite the global importance and ancient history of grafting, our understanding of the fundamental biological processes that make this technique successful remains limited, making it difficult to efficiently expand on new genotypic graft combinations. One of the key determinants of successful grafting is the formation of the graft junction, an anatomically unique region where xylem and phloem strands connect between newly joined plant parts to form a unified vascular system. Here, we use an integrated imaging approach to establish a spatiotemporal framework for graft junction formation in the model crop Solanum lycopersicum (tomato), a plant that is commonly grafted worldwide to boost yield and improve abiotic and biotic stress resistance. By combining Positron Emission Tomography (PET), a technique that enables the spatio-temporal tracking of radiolabeled molecules, with high-resolution laser scanning confocal microscopy (LSCM), we are able to merge detailed, anatomical differentiation of the graft junction with a quantitative timeline for when xylem and phloem connections are functionally re-established. In this timeline, we identify a 72-hour window when anatomically connected xylem and phloem strands regain functional capacity, with phloem restoration typically preceding xylem restoration by about 24-hours. Furthermore, we identify heterogeneity in this developmental and physiological timeline that corresponds with microvariability in the physical contact between newly joined rootstock-scion tissues. Our integration of PET and confocal imaging technologies provides a spatio-temporal timeline that will enable future investigations into cellular and tissue patterning events that underlie successful versus failed vascular restoration across the graft junction.

plant biology↗

Chromosome-level genome assembly of Euphorbia peplus, a model system for plant latex, reveals that relative lack of Ty3 transposons contributed to its small genome size

Euphorbia peplus (petty spurge) is a small, fast-growing plant that is native to Eurasia and has become a naturalized weed in North America and Australia. E. peplus is not only medicinally valuable, serving as a source for the skin cancer drug ingenol mebutate, but also has great potential as a model for latex production owing to its small size, ease of manipulation in the laboratory, and rapid reproductive cycle. To help establish E. peplus as a new model, we generated a 267.2 Mb HiC-anchored PacBio HiFi nuclear genome assembly with an embryophyta BUSCO score of 98.5%, a genome annotation based on RNA-seq data from six tissues, and publicly accessible tools including a genome browser and an interactive organ-specific expression atlas. Chromosome number is highly variable across Euphorbia species. Using a comparative analysis of our newly sequenced E. peplus genome with other Euphorbiaceae genomes, we show that variation in Euphorbia chromosome number is likely due to fragmentation and rearrangement rather than aneuploidy. Moreover, we found that the E. peplus genome is relatively compact compared to related members of the genus in part due to restricted expansion of the Ty3 transposon family. Finally, we identify a large gene cluster that contains many previously identified enzymes in the putative ingenol mebutate biosynthesis pathway, along with additional gene candidates for this biosynthetic pathway. The genomic resources we have created for E. peplus will help advance research on latex production and ingenol mebutate biosynthesis in the commercially important Euphorbiaceae family. Significance statementEuphorbia is one of the five largest genera in the plant kingdom. Despite an impressive phenotypic and metabolic diversity in this genus, only one Euphorbia genome has been sequenced so far, restricting insights into Euphorbia biology. Euphorbia peplus has excellent potential as a model species due to its latex production, fast growth rate and production of the anticancer drug ingenol mebutate. Here, we present a chromosome-level E. peplus genome assembly and publicly accessible resources to support molecular research for this unique species and the broader genus. We also provide an explanation of one reason the genome is so small, and identify more candidate genes for the anticancer drug and related compounds.

plant biology↗

Experience-dependent flexibility in a molecularly diverse central-to-peripheral auditory feedback system

Brainstem olivocochlear neurons (OCNs) modulate the earliest stages of auditory processing through feedback projections to the cochlea and have been shown to influence hearing and protect the ear from sound-induced damage through unclear mechanisms. Here, we used single-nucleus sequencing, anatomical reconstructions, and electrophysiology to characterize OCNs during postnatal development and after sound exposure. We identified markers for known OCN subtypes, medial (MOC) and lateral (LOC) OCNs, and show that they express distinct cohorts of physiologically relevant genes that change over development. In addition, we discovered a neuropeptide-enriched LOC subtype that produces Neuropeptide Y along with other neurotransmitters. Throughout the cochlea, both LOC subtypes extend arborizations over wide frequency domains. Moreover, LOC neuropeptide expression is strongly upregulated days after acoustic trauma, potentially providing a sustained protective signal to the cochlea. OCNs are therefore poised to have diffuse, dynamic effects on early auditory processing over timescales ranging from milliseconds to days.

neuroscience↗

Revisiting the bad luck hypothesis: Cancer risk and aging are linked to replication-driven changes to the epigenome

Aging is the leading risk factor for cancer. While its been proposed that the age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. Here, we show that both aging and cancer share a common epigenetic replication signature, which we modeled from DNA methylation data in extensively passaged immortalized human cells in vitro and tested on clinical tissues. This epigenetic signature of replication - termed CellDRIFT - increased with age across multiple tissues, distinguished tumor from normal tissue, and was escalated in normal breast tissue from cancer patients. Additionally, within-person tissue differences were correlated with both predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Overall, our findings suggest that age-related replication drives epigenetic changes in cells, pushing them towards a more tumorigenic state. One sentence summaryCellular replication leaves an epigenetic fingerprint that may partially underly the age-associated increase in cancer risk.

cancer biology↗

CEP peptide and cytokinin pathways converge on CEPD glutaredoxins to inhibit root growth

C-TERMINALLY ENCODED PEPTIDE (CEP) and cytokinin hormones act over short and long distances to control plant responses to environmental cues. CEP and cytokinin pathway mutants share phenotypes, however, it is not known if these pathways intersect. We show that CEP and cytokinin signalling converge on CEP DOWNSTREAM (CEPD) glutaredoxins to inhibit primary root growth. CEP inhibition of root growth was impaired in mutants defective in trans-zeatin (tZ)-type cytokinin biosynthesis, transport, perception, and output. Concordantly, mutants affected in CEP RECEPTOR 1 showed reduced root growth inhibition in response to tZ, and altered levels of tZ-type cytokinins. Grafting and organ-specific hormone treatments showed that tZ-mediated root growth inhibition required CEPD activity in roots. By contrast, root growth inhibition by CEP depended on shoot CEPD function. The results demonstrate that CEP and cytokinin pathways intersect, and utilise signalling circuits in separate organs involving common glutaredoxin genes to coordinate root growth.

plant biology↗

Anatomical and biophysical characterization of intergenic graft-incompatibility within the Solanoideae

Interspecies grafting is a technique that allows beneficial shoot and root combinations from separate species to be combined into a single organism. Despite its relevance to agricultural production, little is known about the determinants of graft compatibility. One hypothesis for compatibility revolves around the taxonomic degree of relatedness between the two plants. To test how phylogenetic distance affects interspecific graft compatibility within the economically important Solanaceae sub-family, Solanoideae, we characterized the anatomical and biophysical integrity of graft junctions for graft combinations made between four species: tomato (Solanum lycopersicum), eggplant (Solanum melongena), pepper (Capsicum annuum), and groundcherry (Physalis pubescens). We analyzed the survival, growth, and junction integrity via bend tests, and imaged the cellular composition of the graft junctions in order to deduce the status of vascular connectivity across the junction. Utilizing these techniques, we were able to quantitatively assess the degree to which each interspecific combination exhibits compatibility. Despite the fact that most of our graft combinations exhibited high survival rates, we show that only tomato and eggplant heterografts are truly compatible. Unlike incompatible grafts, the formation of reconnected vascular tissue within the tomato and eggplant heterografts contributed to biophysically stable grafts that were resistant to snapping. Furthermore, we identified 10 graft combinations that show delayed incompatibility, providing a useful, economically relevant system to pursue deeper work into genetic and genomic determinants of graft compatibility. This work provides new evidence indicating that graft compatibility may be limited to intrageneric combinations within the Solanoideae subfamily. Further research using more extensive graft combinations amongst Solanaceous species can be used to test whether our hypothesis broadly applies to this family.

plant biology↗

GlycoVHH: Introducing N-glycans on the camelid VHH antibody scaffold - Optimal sites and use for macrophage delivery

As small and stable high-affinity antigen binders, VHHs boast attractive characteristics both for therapeutic use in various disease indications, and as versatile reagents in research and diagnostics. To further increase the versatility of VHHs, we explored the VHH scaffold in a structure-guided approach to select regions where the introduction of an N-glycosylation N-X-T sequon and its associated glycan should not interfere with protein folding or epitope recognition. We expressed variants of such glycoengineered VHHs in the Pichia pastoris GlycoSwitchM5 strain, allowing us to pinpoint preferred sites at which Man5GlcNAc2-glycans can be introduced at high site occupancy without affecting antigen binding. A VHH carrying predominantly a Man5GlcNAc2 N-glycan at one of these preferred sites showed highly efficient, glycan-dependent uptake by Mf4/4 macrophages in vitro and by alveolar lung macrophages in vivo, illustrating one potential application of glyco-engineered VHHs: a glycan-based targeting approach for lung macrophage endolysosomal system delivery. The set of optimal artificial VHH N-glycosylation sites identified in this study can serve as a blueprint for targeted glyco-engineering of other VHHs, enabling site-specific functionalization through the rapidly expanding toolbox of synthetic glycobiology.

molecular biology↗

The Free Fatty Acid-Binding Pocket is a Conserved Hallmark in Pathogenic β-Coronavirus Spike Proteins from SARS-CoV to Omicron

As COVID-19 persists, severe acquired respiratory syndrome coronavirus-2 (SARS-CoV-2) Variants of Concern (VOCs) emerge, accumulating spike (S) glycoprotein mutations. S receptor-binding domain (RBD) comprises a free fatty acid (FFA)-binding pocket. FFA-binding stabilizes a locked S conformation, interfering with virus infectivity. We provide evidence that the pocket is conserved in pathogenic {beta}-coronaviruses ({beta}-CoVs) infecting humans. SARS-CoV, MERS-CoV, SARS-CoV-2 and VOCs bind the essential FFA linoleic acid (LA), while binding is abolished by one mutation in common cold-causing HCoV-HKU1. In the SARS-CoV S structure, LA stabilizes the locked conformation while the open, infectious conformation is LA-free. Electron tomography of SARS-CoV-2 infected cells reveals that LA-treatment inhibits viral replication, resulting in fewer, deformed virions. Our results establish FFA-binding as a hallmark of pathogenic {beta}-CoV infection and replication, highlighting potential antiviral strategies. One-Sentence SummaryFree fatty acid-binding is conserved in pathogenic {beta}-coronavirus S proteins and suppresses viral infection and replication.

biochemistry↗

A bacterial pan-genome makes gene essentiality strain-dependent and evolvable

Many bacterial species are represented by a pan-genome, whose genetic repertoire far outstrips that of any single bacterial genome. Here we investigate how a bacterial pan-genome might influence gene essentiality, and whether essential genes that are initially critical for the survival of an organism can evolve to become non-essential. By using Tn-Seq, whole-genome sequencing, and RNA-Seq on a set of 36 clinical Streptococcus pneumoniae strains representative of >68% of the species pan-genome, we identify a species-wide essentialome that can be subdivided into universal, strain-specific and accessory essential genes. By employing forced-evolution experiments we show that specific genetic changes allow bacteria to bypass essentiality. Moreover, by untangling several genetic mechanisms we show that gene-essentiality can be highly influenced and/or dependent on: 1) the composition of the accessory genome; 2) the accumulation of toxic intermediates; 3) functional redundancy; 4) efficient recycling of critical metabolites; and 5) pathway rewiring. While this functional characterization underscores the evolvability-potential of many essential genes, we also show that genes with differential essentiality remain important antimicrobial drug target candidates, as their inactivation almost always has a severe fitness cost in vivo.

microbiology↗

The mycotoxin Beauvericin exhibits immunostimulatory effects on dendritic cells via activating the TLR4 signaling pathway

Beauvericin (BEA), a mycotoxin of the enniatin family produced by various toxigenic fungi, has been attributed multiple biological activities such as anti-cancer, anti-inflammatory, and anti-microbial functions. However, effects of BEA on dendritic cells remain unknown so far. Here, we identified effects of BEA on murine granulocyte-macrophage colony-stimulating factor (GM-CSF)-cultured bone marrow derived dendritic cells (BMDCs) and the underlying molecular mechanisms. BEA potently activates BMDCs as signified by elevated IL-12 and CD86 expression. Multiplex immunoassays performed on myeloid differentiation primary response 88 (MyD88) and toll/interleukin-1 receptor (TIR) domain containing adaptor inducing interferon beta (TRIF) single or double deficient BMDCs indicate that BEA induces inflammatory cytokine and chemokine production in a MyD88/TRIF dependent manner. Furthermore, we found that BEA was not able to induce IL-12 or IFN{beta} production in Toll-like receptor 4 (Tlr4)-deficient BMDCs, whereas induction of these cytokines was not compromised in Tlr3/7/9 deficient BMDCs. This suggests that TLR4 might be the functional target of BEA on BMDCs. Consistently, in luciferase reporter assays BEA stimulation significantly promotes NF-{kappa}B activation in mTLR4/CD14/MD2 overexpressing but not control HEK-293 cells. RNA-sequencing analyses further confirmed that BEA induces transcriptional changes associated with the TLR4 signaling pathway. Together, these results identify TLR4 as a cellular BEA sensor and define BEA as a potent activator of BMDCs, implying that this compound can be exploited as a promising candidate structure for vaccine adjuvants or cancer immunotherapies.

immunology↗

A genome-wide atlas of antibiotic susceptibility targets and pathways to tolerance.

Detailed knowledge on how bacteria evade antibiotics and eventually develop resistance could open avenues for novel therapeutics and diagnostics. It is thereby key to develop a comprehensive genome-wide understanding of how bacteria process antibiotic stress, and how modulation of the involved processes affects their ability to overcome said stress. Here we undertake a comprehensive genetic analysis of how the major human pathogen Streptococcus pneumoniae responds to 20 antibiotics. We built a genome-wide atlas of drug susceptibility determinants and generate a genetic interaction network that connects cellular processes and genes of unknown function, which we show can be used as therapeutic targets. Pathway analysis reveals a genome-wide "tolerome", defined by cellular processes that can make a bacterium less susceptible, and often tolerant, in an antibiotic specific manner. Importantly, modulation of these processes confers fitness benefits during active infections under antibiotic selection. Moreover, screening of sequenced clinical isolates demonstrates that mutations in tolerome genes readily evolve and are frequently associated with resistant strains, indicating such mutations may be an important harbinger for the emergence of antibiotic resistance.

microbiology↗