Biology subjects

Muller, M.

Publications and source records attributed to Muller, M..

At least 19 recordsLinked to original sources

bioRxiv2026

RAPTOR-targeted Antisense Oligonucleotides Restrict Pathological mTORC1 Activity in GATOR1-dependent Disease

Loss-of-function mutations in the GATOR1 complex (NPRL2, NPRL3, and DEPDC5) are among the most common genetic causes of epilepsy. These mutations impair amino acid-dependent regulation of mTORC1 and cause hyperactive signaling, neuronal hyperexcitability, astrocytic metabolic remodeling, seizures, and early mortality. Here, we report the development of antisense oligonucleotides (ASOs) targeting RAPTOR, an mTORC1 scaffolding subunit, to correct pathological mTORC1 hyperactivity caused by defective upstream regulation. RAPTOR-targeted ASO treatment reduced RAPTOR expression in mouse and human systems and dampened mTORC1 signaling in GATOR1-deficient models. ASO-mediated RAPTOR reduction rescued neuronal hyperexcitability, corrected astrocytic mitochondrial dysfunction, and suppressed spontaneous seizures in vivo. A single treatment significantly extended longevity across neuronal and astrocytic models of GATOR1 deficiency. Collectively, these findings establish RAPTOR-targeted ASOs as a mechanism-based therapeutic approach that durably corrects cellular and circuit-level consequences of GATOR1 deficiency. By tuning RAPTOR abundance, this strategy provides a therapeutic framework for mTORC1-driven epilepsies and related diseases.

neuroscience↗

bioRxiv2026

Linking live-cell imaging to single-cell sequencing using genetic barcoding

Linking cellular phenotype to genotype and gene expression is a central goal in biomedical research. Live-cell imaging captures dynamic cellular phenotypes, whereas single-cell sequencing measures genome-wide molecular states, but pairing these readouts for the same cell remains challenging. Here we present Waldo, a genetically encoded single-cell barcoding strategy that can be read out by both live-cell imaging and single-cell sequencing to connect single cells across both modalities. Waldo barcodes are generated by combinatorial expression of synthetic cell-surface receptors, each detected by a cognate peptide probe coupled either to a fluorescent dye or a DNA barcode. Iterative fluorescent probe staining achieves large barcode diversity, while preserving fluorescence channels for phenotypic reporters. As a proof-of-principle, we use Waldo to link cell division phenotypes after chromosome missegregation to the karyotype and transcriptome of the same cells. Waldo provides a general strategy for connecting imaging phenotypes to genome-wide sequencing readouts in single cells.

cell biology↗

bioRxiv2026

Novel native serum peptidomics workflow enables the discovery of circulating subtype-specific peptide biomarkers in acute ischemic and haemorrhagic stroke

Novel serum peptidomics offers a direct insight into proteolytic activity, tissue injury, and systemic signaling. Nevertheless, existing workflows suffer from low peptide yields, low throughput, and limited recovery of low-abundance species. Here we present a native serum peptidomics protocol that integrates mild acid treatment, solid-phase extraction with molecular weight cutoff filtration and data-independent acquisition mass spectrometry (DIA-MS). The protocol requires less than 100 {micro}l of serum or plasma, is completed within hours, time-cost-effective and compatible with 96-well formats without specialized equipment. Applied to a proof-of-concept cohort of patients with acute ischemic stroke (AIS), intracranial haemorrhage (ICH), and healthy controls, the workflow identified over 12,000 peptides, exceeding the three-fold threshold of existing peptidomics approaches. DIA-MS analysis across independent batches demonstrated 78-83% peptide overlap and consistent fold-change directionality. We further introduce peptide locus analysis, which aggregates overlapping peptides within defined protein regions. This approach revealed bidirectional regulation within individual precursor proteins such as the fibrinogen alpha chain (FIBA), resolving intraprotein proteolytic dynamics. Three candidate peptides from TYB4, CO4B, and ITIH4 proteins accurately distinguished stroke subtypes and controls, while characteristic shifts in peptide physicochemical properties were observed across strokes. This workflow substantially advances the sensitivity, throughput, and biological resolution of serum peptidomics for quantitative multi-biomarker discovery, validation and its output promises effective implementation of AI/ML models aiming for new dimensions in diagnostics, prognostics, prediction and monitoring.

neuroscience↗

bioRxiv2026

PlantMetWiki: a FAIR knowledge graph for plant metabolic pathway cross-species representation and integration

Plants produce a vast diversity of specialized metabolites with extensive potential ecological, agro-industrial, and pharmaceutical applications. Discovery of novel plant natural products relies on combining multi-omics evidence with biochemical transformations. However, pathway-level annotations are fragmented across individual species, databases, and publications, limiting comparative cross-species pathway analyses and systematic generation of hypotheses. To support integration and reuse of plant metabolic knowledge, we developed PlantMetWiki, a FAIR Linked Open Data semantically enriched knowledge graph built on infrastructure adapted from WikiPathways. Our approach extends on the highly curated pathway information from Plant Metabolic Network with crosslinks to biosynthetic gene clusters resources (MIBiG and plantiSMASH), metabolite annotations, and cross-species modelling. This way, our resource captures pathway genomic context, increases metabolomics data interoperability via federated queries, and supports cross-species analysis to identify annotation gaps. PlantMetWiki represents 1,162 plant metabolic pathways as Resource Description Framework (RDF) graphs, preserving pathway structure, literature provenance, annotations, and taxonomic information from PlantCyc 17.0. PlantMetWiki is distributed through a public SPARQL endpoint with open-source reproducible data transformation and validation workflows. By modelling pathways as a multispecies graph, PlantMetWiki enables comparative analyses across taxa, integration with external chemical knowledge resources through federated queries, and identification of metabolic, genomic, and chemical annotation gaps. As a result, PlantMetWiki provides a foundation for FAIR reuse and integration of plant pathway knowledge.

bioinformatics↗

bioRxiv2026

Decoding the Sequence Requirements for Translation Initiation

Accurate selection of start codons by ribosomes is a fundamental determinant of proteome composition. Although the Kozak sequence--an 8-nucleotide sequence flanking the start codon--has long been viewed as the primary determinant of initiation in eukaryotes, it fails to explain the large diversity of start codon usage across transcripts. Here we combine massively parallel reporter assays, bioinformatics, machine learning, single-molecule imaging and cryo-electron microscopy to define the extended translation initiation sequence (eTIS), an [~]80-nucleotide sequence surrounding the start codon that governs initiation efficiency. A deep-learning model trained on eTIS features accurately predicts translation initiation across transcripts. Unexpectedly, we find that the Kozak sequence is not optimal for initiation as is widely presumed, and we identify the origin of this discrepancy. eTIS nucleotides that promote efficient initiation are enriched in the human transcriptome and are evolutionarily conserved, underscoring their functional importance. Biophysical and structural analyses reveal that specific eTIS residues--including the key +6 position and residues in the mRNA entry and exit channel--engage ribosomal proteins, rRNA and initiation factors to promote start codon recognition by stabilizing the ribosome at the start codon and facilitating the structural transitions required for initiation. Finally, optimization of the eTIS markedly enhances translational fidelity and protein output from therapeutic mRNAs, highlighting its practical utility. Together, these findings redefine the sequence logic of translation initiation and establish a framework for precise control of protein expression.

molecular biology↗

bioRxiv2026

Cell surface remodeling caused by the loss of TMEM30A in immune cells

Plasma membrane lipid asymmetry is tightly regulated and fundamental to mammalian cell physiology. TMEM30A is the {beta}-subunit of P4-ATPases, flippase enzymes that maintain strict phosphatidylserine (PS) asymmetry by pumping it from the outer to the cytosolic leaflet. Loss of TMEM30A function causes constitutive PS externalization and has been implicated in diseases such as diffuse large B-cell lymphoma and tumour immune evasion. Here, we systematically define the biophysical and molecular consequences of TMEM30A deletion in immune cells. Using a live-cell lipid reporter, membrane order probe, and surface proteome mapping, we show that TMEM30A-knockout cells display robust PS externalization accompanied by faster lateral diffusion of membrane constituents and decreased plasma membrane order. Surface proteome reorganization includes increased abundance of tetraspanins and CD47. Further, TMEM30A loss triggers glycocalyx remodeling via ADAM10-dependent shedding that removes major transmembrane mucins, including CD43 and CD162. Together, these data reveal a coordinated reorganization of lipids, glycans, and proteins upon TMEM30A loss, suggesting mechanistic links between flippase dysfunction and increased plasma membrane dynamics and potential sensitization to immune therapy. Furthermore, our study provides an integrated surfaceome framework that might shed light on the relationship between TMEM30A expression and clinical outcomes in cancer.

immunology↗

bioRxiv2025

NDNF+ interneurons have a privileged role in regulating cortical excitability

Cortical processing depends critically on the precise modulation of excitatory activity by a diverse population of GABAergic interneurons. Among these, neuron-derived neurotrophic factor-expressing (NDNF+) interneurons have been proposed to be "master regulators" of cortical microcircuits. While their role in coordinating physiological cortical activity is beginning to be understood, their contribution to restraining hyperexcitability during epileptiform activity remains unexplored. To address this, we employed calcium imaging, optogenetics, and chemogenetics in an NDNF-Cre mouse line to investigate how NDNF+ interneurons influence cortical hyperactivity and spontaneous seizures. Our results demonstrate that NDNF+ interneurons are actively recruited during interictal spikes and focal seizures, although more slowly than parvalbumin-positive interneurons. Optogenetic hyperpolarization of NDNF+ interneurons exacerbates epileptic discharges, whereas their depolarization suppresses focal seizures, even when the optogenetic stimulus is delayed by several seconds from seizure onset. This effect is largely mediated by GABAB receptor signalling. Additionally, chemogenetic depolarization of NDNF+ interneurons has robust antiepileptic effects both ex vivo and in vivo. Collectively, these findings establish NDNF+ neurons as key regulators of cortical excitability and identify them as promising cellular targets for the development of anti-epileptic therapies.

neuroscience↗

bioRxiv2025

Virally encoded interleukin-6 (vIL-6) coordinates with human IL-6 to modulate cytokine expression during KSHV infection

Kaposi Sarcoma-Associated Herpesvirus (KSHV) is characterized by its ability to establish lifelong infections that can lead to disease in immunocompromised individuals. Understanding the complex interactions between KSHV, the host cellular machinery, and the immune response is essential for unraveling the mechanisms underlying viral persistence and pathogenesis. KSHV extensively remodels the host gene expression landscape by inducing widespread RNA decay via the viral endoribonuclease SOX. While the vast majority of cellular mRNAs are degraded by SOX, select transcripts including Interleukin 6 (IL-6) escape degradation. Interestingly, KSHV encodes a viral homolog of IL-6, known as viral interleukin-6 (vIL-6). Given the importance of IL-6 for KSHV biology and its ability to escape SOX-mediated decay, we explored how vIL-6 expression is regulated upon KSHV infection. Our data demonstrate that unlike IL-6, vIL-6 3UTR does not provide protection from SOX degradation, yet vIL-6 mRNA steady state levels remain high throughout KSHV lytic cycle, suggesting a distinct transcriptional regulation. To assess the contributions of vIL-6 and IL-6 in modulating host gene expression, inflammatory signaling and KSHV-driven pathogenesis, we used a vIL-6 null viral mutant combined with an IL-6 knock down to perform transcriptomic analyses. This analysis revealed that depletion of IL-6, vIL-6 or both results in distinct alterations of the host gene expression environment, with differential effects on chemokine signaling and related pathways as well as a synergistic effect when both IL-6 and vIL-6 are present. Furthermore, functional assays confirmed vIL-6 alone is sufficient to activate key signaling pathways and pro-inflammatory responses, including the JAK/STAT pathway. Collectively, our findings suggest a mechanistic synergy between vIL-6 and IL-6 that may enhance KSHV-mediated immune modulation and contribute to viral persistence and tumorigenesis.

microbiology↗

bioRxiv2025

Obesogenic Diet Impairs Social Memory Through Alterations of Hippocampal CA2 Excitability and Oxytocin Signaling

While obesity induces cardio-metabolic disorders and cognitive deficits, the underlying neural mechanisms remain unexplored. In mice, exposure to an obesogenic high-fat and sugar diet (HFD) resulted in social recognition memory deficits in both males and females, a process that is dependent upon hippocampal area CA2 and oxytocin signaling. HFD-fed mice had stronger inputs onto CA2 pyramidal neurons that led to increased action potential firing, without altering intrinsic properties or inhibitory transmission. Chemogenetic CA2 pyramidal neuron inhibition in HFD-fed mice rescued social novelty discrimination, with novelty preference in males and familiarity preference in females. We also observed that HFD in both males and females impaired the ability of oxytocin receptor activation to be permissive for endocannabinoid-mediated plasticity. Furthermore, chemogenetic inhibition of CA2 pyramidal neurons rescued oxytocin-induced endocannabinoid plasticity in both HFD-fed male and female mice, whereas it prevented endocannabinoid plasticity in control diet-fed mice. In a concentration-dependent manner, oxytocin restored potentiation of excitatory responses, allowed for endocannabinoid plasticity at CA2 inhibitory synapses, and rescued social novelty discrimination in HFD-fed mice. This study uncovers mechanisms linking neuromodulation and endocannabinoid-mediated plasticity in social memory processes and reveals the deleterious consequences of an obesogenic diet on this process.

neuroscience↗

bioRxiv2025

Spatiotemporal dynamics of tumor microenvironment remodelling

During tumorigenesis, interactions between tumor and stromal cells progressively remodel the tumor microenvironment (TME) towards pro-tumoral functions. Understanding early TME remodeling dynamics is therefore crucial for developing interceptive therapies. However, clinical samples typically provide isolated, late tumorigenesis snapshots. To overcome this limitation, we generated triple-negative breast cancer mice that develop multifocal, asynchronous tumors along a continuous luminal-to-basal transdifferentiation trajectory. Ordering spatial transcriptomes from 100+ ducts along this trajectory reveals the spatiotemporal dynamics of TME remodeling and underlying molecular mechanisms. Cancer-associated myofibroblasts (myCAFs) emerge as key players in advanced tumors, where they orchestrate pro-invasive remodeling of the tumor-stromal interface. myCAFs are conserved in patient-derived xenograft models and steer tumor trajectories towards invasive phenotypes when co-injected with tumor cells in syngeneic mice. Our study shows that temporal ordering of spatially-resolved disease snapshots unravels some of the molecular "forces" that, starting from the cell-of-origin, propel cells/microenvironments along a disease trajectory.

cancer biology↗

bioRxiv2025

Q1020R in the spike proteins of MERS-CoV from Arabian camels and recent human cases confers resistance against soluble human DPP4

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a pre-pandemic coronavirus that is transmitted from camels, the natural reservoir, to humans and can cause severe disease. MERS cases have been documented in Arabia but not Africa, although the virus is circulating in both Arabian and African camels. Further, evidence has been provided that viruses in African camels might have a reduced capacity to cause disease. However, the underlying determinants are incompletely understood. Here, employing pseudotyped particles as model systems for MERS-CoV entry into cells, we compared cell entry of viruses from African and Arabian camels and its inhibition. We show that viruses found in Arabian camels and recent human cases are less susceptible to inhibition by human soluble DPP4 (sDPP4) than viruses from African camels, although both enter human cells efficiently and are comparably sensitive to inhibition by IFITM proteins and neutralizing antibodies. Furthermore, relative resistance to soluble DPP4 was linked to mutation Q1020R, present in the spike proteins of recent Arabian but not African viruses. These results support the concept that soluble DPP4 might constitute a natural barrier against human infection that is more efficiently overcome by viruses currently circulating in Arabian camels than those in African camels. IMPORTANCEMERS-CoV is an emerging virus that can cause severe lung disease, MERS, and is transmitted from camels to humans. Although MERS-CoV infects camels in both Africa and Arabia, MERS cases have only been documented in Arabia for reasons that remain incompletely understood. Here, we provide evidence that viruses recently circulating in Arabian camels and causing human infections are less susceptible to inhibition by human sDPP4 - a secreted version of the viral receptor that is present in various bodily fluids. Furthermore, we link sDPP4 resistance to mutation Q1020R in the spike protein of these viruses. These results suggest that viruses currently circulating in Arabian camels are better equipped to overcome a natural barrier to infection, sDPP4, than those circulating in African camels.

microbiology↗

bioRxiv2025

IL-6 Evades KSHV-Mediated Hyperadenylation repression via CRM1-Dependent Nuclear Export.

RNA turnover is critical for regulating cellular homeostasis, with nuclear export representing a key step in mRNA fate. During infection by Kaposis Sarcoma-associated Herpesvirus (KSHV), widespread mRNA decay is mediated by the viral endonuclease SOX, which depletes cytoplasmic transcripts and induces secondary nuclear RNA processing defects. One such defect includes transcript hyperadenylation, which promotes nuclear retention and decay. However, a subset of mRNAs escapes both SOX degradation and nuclear retention, raising questions about their export mechanisms. Here, we investigate how KSHV infection impacts mRNA poly(A) tail length and nuclear export dynamics using poly(A)-sequencing in KSHV-positive cells. Our data confirm a global increase in poly(A) tail length during KSHV infection, yet we identified a group of hyperadenylated transcripts that remain localized in the cytoplasm, suggesting active evasion of nuclear retention. Notably, we focused on interleukin-6 (IL-6), an mRNA known to escape SOX-mediated decay. Using G/I tailing and sPAT assays, we show that IL-6 is hyperadenylated yet, exported. We demonstrate that its export is dependent upon the CRM1 nuclear export pathway, rather than through the canonical NXF1-NXT1 pathway. Inhibition of CRM1 impairs IL-6 nuclear export and reduces steady-state mRNA levels, implicating CRM1 export in the stabilization of this transcript. Our findings reveal a previously unrecognized mechanism by which select host mRNAs like IL-6, bypass KSHV-imposed nuclear export block, thereby preserving their cytoplasmic function during infection. This study highlights viral manipulation of RNA processing and export pathways as a critical determinant of transcript fate and identifies CRM1 as a key mediator of selective transcript preservation during KSHV infection. SIGNIFICANCE STATEMENTKaposis sarcoma-associated herpesvirus (KSHV) globally disrupts host gene expression by inducing host shutoff which triggers a global repression of the host transcriptome via widespread RNA decay, RNA, nascent transcript hyperadenylation and nuclear export blocks, yet a subset of transcripts escape this repression. This study reveals that despite acquiring long poly(A) tails, select host mRNAs such as IL-6 evade nuclear retention by using the alternative CRM1-dependent export pathway and remain stable in the cytoplasm. These findings challenge the prevailing model that hyperadenylation alone dictates nuclear decay and uncover a selective mechanism by which crucial host transcripts bypass KSHV-mediated gene repression. Understanding this selective escape provides new insights into host-virus interactions and highlights CRM1 as a potential therapeutic target in KSHV-associated diseases.

microbiology↗

bioRxiv2025

Genomic and Immunogenomic Profiling of Extramedullary Acute Myeloid Leukemia Reveals Actionable Clonal Branching and Frequent Immune Editing

Extramedullary acute myeloid leukemia (eAML) is a rare form of myeloid neoplasm characterized by leukemic infiltration outside the bone marrow (BM). Despite its prognostic significance, eAML is often underdiagnosed and poorly characterized at molecular level. We performed a comprehensive genomic and immunogenomic profiling on paired BM and extramedullary specimens from 26 eAML patients, alongside over 400 AML cases without extramedullary involvement and 97 healthy controls. Clonal branching from BM was observed in 38.5% of extramedullary sites, frequently involving actionable mutations in FLT3, IDH2 and NPM1 genes. Both compartments were enriched in RAS pathway mutations and class II HLA losses, suggesting active immunoediting mechanisms driving eAML development. Strikingly all relapsed cases acquired FLT3 aberrations, highlighting therapeutic opportunities. These findings underpin the need for improved detection and routine genomic profiling, including targeted sequencing of suspected extramedullary lesions.

genomics↗

bioRxiv2024

Circuit-Level Dynamics of Slow Wave Activity and Propagation During the Awakening Process

Slow-wave activity (SWA) is a hallmark of the loss of consciousness in non-REM sleep and anesthesia. The mechanistic underpinnings of SWA, and its evolution when transitioning towards the conscious brain state is poorly understood. We address this topic by recording multi-area and laminar activity in posterior parietal (PPC) and primary visual (V1) cortices of mice spontaneously awakening from isoflurane anesthesia. Spectral power is stronger in PPC (especially in superficial layers) during deep unconsciousness, but stronger in V1 when awakening. Rostro-caudal (feedback-like) propagation of SWA also shows state-dependent modulation, particularly in layer 5. The excitability of layer 2/3 neurons, hindered at high isoflurane, recovers during awakening, when V1 and the feedforward pathway reacquire a strong role. Detailing the hierarchical and laminar properties of spontaneous traveling oscillations, we provide evidence that SWA is a multiscale phenomenon. Explicating the functional role of these processes is critical to understand the neuronal mechanisms of consciousness.

neuroscience↗

bioRxiv2024

Predicting Immunogenic CD4+ T Cell Epitopes in Bacteria Using Antigen and Peptide Features

BackgroundT cell epitope prediction methods have been broadly utilized to facilitate epitope discovery in infectious agents and help design reagents, diagnostics, and vaccines. Current prediction methods are mainly focused on peptide presentation by MHC molecules, which is a necessary but not sufficient requirement for an epitope. For complex pathogens such as bacteria, it would be desirable to make such predictions more specific to limit the number of candidates that have to be experimentally tested. ObjectiveTo develop a machine learning-based prediction model that integrates both peptide-level and antigen-level features to improve the specificity of CD4+ T cell epitope predictions for bacteria. MethodsWe used a dataset of 20,216 peptides from Mycobacterium tuberculosis (Mtb), tested for T cell recognition in Mtb-infected participants, that led to the discovery of n = 144 peptide epitopes. For each peptide, we calculated six peptide-level features (e.g. MHC class II binding predictions and conservation scores) and six antigen-level features (e.g. including RNA expression levels and subcellular localization scores). Three machine learning algorithms--Random Forest, Gradient Boosting, and XGBoost--were trained using stratified, 5-fold cross-validation and combined into an ensemble model. Experimental validation was performed on Streptococcus pneumoniae peptides, using ex vivo IFN{gamma} assays to confirm the predictive performance. ResultsThe ensemble model achieved an ROC-AUC of 0.91 in predicting immunogenic peptides in the Mycobacterium tuberculosis (Mtb) dataset. Gene expression and conservation were identified as the most impactful features, followed by MHC class II binding predictions. When validated on an independent Bordetella pertussis dataset, the model demonstrated accurate predictive capability, especially for peptides with broad recognition in the participant cohort (ROC-AUC up to 0.82). Prospectively applying the model to Streptococcus pneumoniae, we synthesized peptides predicted by our ensemble model to be immunogenic or non-immunogenic. Ex vivo testing with PBMCs from healthy participants showed that peptides predicted to be immunogenic elicited significantly higher IFN{gamma} responses than non-immunogenic peptides, validating the model. ConclusionsOur machine learning approach, integrating both peptide and antigen features, effectively predicts immunogenic CD4+ T cell epitopes across different bacterial pathogens. This method enhances epitope selection efficiency, aiding vaccine development and immunological research by reducing the need for extensive experimental screening.

immunology↗

bioRxiv2024

Predicted mechanistic impacts of human protein missense variants

Genome sequencing efforts have led to the discovery of tens of millions of protein missense variants found in the human population with the majority of these having no annotated role and some likely contributing to trait variation and disease. Sequence-based artificial intelligence approaches have become highly accurate at predicting variants that are detrimental to the function of proteins but they do not inform on mechanisms of disruption. Here we combined sequence and structure-based methods to perform proteome-wide prediction of deleterious variants with information on their impact on protein stability, protein-protein interactions and small-molecule binding pockets. AlphaFold2 structures were used to predict approximately 100,000 small-molecule binding pockets and stability changes for over 200 million variants. To inform on protein-protein interfaces we used AlphaFold2 to predict structures for nearly 500,000 protein complexes. We illustrate the value of mechanism-aware variant effect predictions to study the relation between protein stability and abundance and the structural properties of interfaces underlying trans protein quantitative trait loci (pQTLs). We characterised the distribution of mechanistic impacts of protein variants found in patients and experimentally studied example disease linked variants in FGFR1.

bioinformatics↗

bioRxiv2024

Population genomics of Plasmodium ovale species in sub-Saharan Africa

Plasmodium ovale curtisi (Poc) and Plasmodium ovale wallikeri (Pow) are relapsing malaria parasites endemic to Africa and Asia that were previously thought to represent a single species. Amid increasing detection of ovale malaria in sub-Saharan Africa, we performed a population genomic study of both species across the continent. We conducted whole-genome sequencing of 25 isolates from Central and East Africa and analyzed them alongside 20 previously published African genomes. Isolates were predominantly monoclonal (43/45), with their genetic similarity aligning with geography. Pow showed lower average nucleotide diversity (1.8x10-4) across the genome compared to Poc (3.0x10-4) (p < 0.0001). Signatures of selective sweeps involving the dihydrofolate reductase gene were found in both species, as were signs of balancing selection at the merozoite surface protein 1 gene. Differences in the nucleotide diversity of Poc and Pow may reflect unique demographic history, even as similar selective forces facilitate their resilience to malaria control interventions.

genomics↗

bioRxiv2023

The antiviral protein Shiftless blocks p-body formation during KSHV infection.

P-bodies (PB) are non-membranous foci involved in determining mRNA fate by affecting translation and mRNA decay. In this study, we identify the anti-viral factor SHFL as a potent disassembly factor of PB. We show that PBs remain sparse in the presence of SHFL even in the context of oxidative stress, a major trigger for PB induction. Mutational approaches revealed that SHFL RNA binding activity is not required for its PB disassembly function. However, we have identified a new region of SHFL which bridges two distant domains as responsible for PB disassembly. Furthermore, we show that SHFL ability to disrupt PB formation is directly linked to its anti-viral activity during KSHV infection. While WT SHFL efficiently restricts KSHV lytic cycle, PB disruption defective mutants no longer lead to reactivation defects. SHFL-mediated PB disassembly also leads to increased expression of key anti-viral cytokines, further expanding SHFL dependent anti-viral state. Taken together, our observations suggest a role of SHFL in PB disassembly, which could have important anti-viral consequences during infection.

microbiology↗