Biology subjects

Rose, C.

Publications and source records attributed to Rose, C..

16 recordsLinked to original sources

bioRxiv2026

A Weight Loss Fibrotic Response in Visceral Fat Is Driven by Defective Lysosome-Dependent Collagenolysis

Obesity induces pathological remodeling of white adipose tissue (WAT), including chronic inflammation and fibrosis, which drive metabolic dysfunction. Although weight loss (WL) is the cornerstone of obesity treatment and improves systemic metabolic health, its impact on WAT remodeling remains incompletely understood. Using a mouse model of diet-induced obesity followed by nutritional weight loss, we show that visceral WAT (vWAT) fails to fully recover despite normalization of body weight and marked metabolic improvment. Notably, vWAT fibrosis persists and continues to progress after WL. This occurs while extracellular matrix (ECM) production by adipose progenitor cells is markedly reduced following WL, explaining why pharmacological inhibition of ECM synthesis fails to prevent fibrosis during WL. Instead, we observed impaired collagen degradation by both progenitor cells and macrophages, along with lysosomal dysfunction, during WL. This suggests that defective ECM degradation, rather than continued ECM production, underlies fibrosis persistence and aggravation during WL. Together, these findings identify impaired collagenolysis as a critical barrier to adipose tissue recovery after WL and suggest that enhancing ECM clearance, rather than inhibiting ECM synthesis, may represent a more effective therapeutic strategy to restore adipose tissue function.

pathology↗

bioRxiv2026

Click alginate cryogel for real-time gastric pH monitoring

Gastric acidity shapes mucosal injury in reflux disease, peptic ulcer, and gastritis, yet is almost never measured. Acid-suppressive therapy, taken by approximately 40% of elderly adults, is therefore titrated on symptoms alone. A gastric sensor must hold onto its reporter in a highly acidic protease-rich environment, conditions that destabilize ionically crosslinked hydrogels and leach physically entrapped dyes. Click alginates, established in biomechanics and drug delivery but not as sensors, meet this requirement with a single chemistry: bioorthogonal tetrazine-norbornene crosslinks are inert to acid and proteases, and excess norbornene from crosslinking become the anchoring site for the pH-sensitive reporter, so network and reporter are installed by the same mechanism. Cryogelation adds macroporosity for rapid gastric fluid influx. A screen identifies IRDye 680RD as the only near-infrared dye responsive across the targeted pH 2-5. Dye release stays below 1.5% in simulated gastric and intestinal fluids, and the pH response remains active after nine months of storage. In rats, the orally administered NIR fluorescent cryogel resolves pH 2.0 from pH 5.0 transabdominally, and discriminates esomeprazole- from saline-treated animals, without plasma fluorescence. Photoacoustic imaging points toward detection at translationally relevant depths, establishing covalently functionalized cryogels as a general sensing platform for hostile physiological environments.

bioengineering↗

bioRxiv2026

A Multimodal Single-Cell Epigenomic and 3D Genome Atlas of the Human Basal Ganglia

The basal ganglia (BG) underlie motor control, reward processing, and many neurological and psychiatric disorders, but a comprehensive epigenomic and 3D-genome atlas of the human BG is lacking. Here we present a multimodal single-cell atlas profiling DNA methylation and 3D chromatin conformation in 261,331 nuclei (snm3C-seq) across eight subregions, resolving 12 classes, 31 subclasses, and 59 groups. Harmonized under the HMBA basal-ganglia consensus taxonomy, this atlas integrates with matched RNA, ATAC-seq, and histone-modification data across five regulatory layers. We identify millions of cell-type- and region-specific differentially methylated regions enriched for distinct transcription factor motifs and link them to disease-associated heritability. Neuron-specific loops dominate cell-type-specific 3D contact remodeling, while most non-neuron-specific loops are constitutive. Among spiny projection neurons (SPNs), chromatin loops, rather than TAD boundaries, distinguish D1, D2, and eccentric SPN subclasses, with eccentric SPNs showing the most loop-level reorganization among the three. We characterize STR D2 SMYD2-HTR7 SPN, a newly recognized POU6F2 D2-SPN subtype, and reveal region-specific methylation and contact gradients of disease-associated genes, including CADM1 and PDE8B. Integrative gene-regulatory networks reconstruct cell-type-resolved enhancer-promoter links to interpret Parkinsons disease risk variants at SNCA. Finally, MERFISH spatial profiling combined with cross-species Patch-seq identifies non-SPN neuronal subtypes, including a MOXD1 striosomal STR FS PTHLH-PVALB GABA subtype with distinct electrophysiology, partitioning across the striatal matrix-striosome boundary. HighlightsO_LIA multimodal single-cell atlas maps DNA methylation and 3D genome architecture across human basal ganglia cell types and subregions. C_LIO_LINeuron-specific loops dominate cell-type-specific 3D contact remodeling in the human BG, whereas most non-neuron-specific loops are constitutive. C_LIO_LISpiny Projection Neuron (SPN) subtypes exhibit regionally organized epigenomic and 3D genome signatures that align with dorsal-ventral identities. C_LIO_LIChromatin loops are the primary distinguishing feature among D1, D2, and eccentric SPN subclasses, with eccentric SPNs being the most 3D-reorganized. C_LIO_LIIntegrated regulatory maps link cell-type-specific enhancers to disease-associated genetic risk in the human basal ganglia. C_LIO_LINon-SPN interneurons differ in distribution and in transcriptional and epigenetic identity across the matrix-striosome boundary. C_LI

neuroscience↗

bioRxiv2026

Single-cell Multiome Analysis of Chromatin State and Transcriptome in the Human Basal Ganglia

The basal ganglia play essential roles in motor control, emotion, learning and reward processing. Their dysfunction contributes to many neurological and psychiatric disorders. However, the gene regulatory programs defining basal ganglia cell-type identity and function remain poorly understood, limiting interpretation of disease-associated non-coding variants. Here, we present the first single-cell multiome atlas of histone modifications and transcriptomes across eight basal ganglia regions from neurotypical adult human donors. Joint profiling reveals cell-type-specific deployment of active and repressive cis-regulatory elements and gene regulatory networks, and suggests a combinatorial homeobox transcription factor code underlying cell identity. Integration with matched spatial transcriptomic MERFISH data uncovers regional heterogeneity of epigenomic landscapes. Comparative analysis between human and mouse medium spiny neurons uncovers conservation of core gene regulatory features. This atlas interprets non-coding risk variants of neuropsychiatric disorders and supports the development of a deep learning model to predict gene regulation and functional effects of disease-associated variants. HIGHLIGHTSO_LIJoint single-cell profiling of transcriptomes and three histone modifications across eight human basal ganglia regions characterizes active and repressive chromatin states at cell-type resolution. C_LIO_LICell-type-specific gene regulatory programs decode combinatorial homeobox TF grammar governing the identity and diversification of basal ganglia neurons. C_LIO_LIIntergrative analyses link noncoding neuropsychiatric risk variants to specific cell types, regulatory elements, and candidate target genes. C_LIO_LIA sequence-to-function deep-learning model predicts gene regulation from DNA sequence and prioritizes functional disease-associated variants. C_LI

genomics↗

bioRxiv2026

Single-Cell Atlas of Transcription and Chromatin States Reveals Regulatory Programs in the Human Brain

Directly measuring chromatin states alongside transcription is essential for understanding how cell-type-specific regulatory programs are established and maintained in the adult human brain. We present a large-scale single-cell multimodal atlas generated by jointly profiling transcriptome with active (H3K27ac) and repressive (H3K27me3) histone modifications across 18 brain regions. We profile >750,000 nuclei spanning 160 cell types and integrate these data with chromatin accessibility, DNA methylation, 3D genome architecture, and spatial transcriptome. This framework annotates >500,000 regulatory elements and resolves cell-type-specific chromatin states. We link enhancers to target genes, infer gene regulatory networks, and classify chromatin interactions, revealing neuron-enriched long-range Polycomb repression of developmental genes. Integrating these maps with GWAS data and sequence-based model prioritizes noncoding variants, effector genes, and vulnerable cell types for neuropsychiatric disorders. Finally, cross-species comparisons show conserved activation but more divergent repression. Together, this study provides a functional reference for interpreting noncoding variants, epigenetic memory, and brain organization. HIGHLIGHTSO_LIJoint single-cell profiling of transcriptomes with active or repressive histone modification in >750,000 nuclei across adult human brain. C_LIO_LIChromatin state annotation of >500,000 candidate cis-regulatory elements distinguishes active enhancers from accessible and Polycomb-repressed regions. C_LIO_LICell-type-resolved regulatory networks and sequence-based deep learning model prioritize functional neuropsychiatric risk variants. C_LIO_LISpatial epigenomic imputation reveals laminar layer-specific Polycomb repression programs. C_LIO_LIIntegration with 3D genome architecture reveals neuron-specific super long-range chromatin loops silencing early developmental genes. C_LIO_LIEvolutionary analysis uncovers conserved active regulatory grammar but divergent repressive landscape. C_LI

genomics↗

bioRxiv2025

The beta-triketone, nitisinone, kills insecticide-resistant mosquitoes through cuticular uptake

The efficacy of numerous vector control initiatives is compromised by growing insecticide resistance among disease-transmitting arthropods of agricultural, veterinary, and public health significance. Previous investigations on hematophagous (blood-feeding) arthropod vectors, including mosquitoes, have indicated that ingesting blood containing inhibitors of the second enzyme in the tyrosine metabolism pathway, 4-hydroxyphenylpyruvate dioxygenase (HPPD), results in high insect mortality. Building upon this foundation, we evaluated the insecticidal efficacy of the HPPD inhibitor, nitisinone, against susceptible and pyrethroid-resistant strains of three mosquito species: Anopheles gambiae, Aedes aegypti and Culex quinquefasciatus. These mosquitoes are vectors of historical diseases such as malaria, emerged diseases such as Dengue and Zika and emerging viral diseases such as the Oropouche and Usutu viruses. We demonstrate, by employing standard screening assays designed to assess the cuticular uptake of mosquitocidal agents, that nitisinone has mosquitocidal activity when blood-fed mosquitoes contact a nitisinone-coated surface. Notably, there is no discernible disparity in susceptibility to nitisinone between an insecticide-susceptible strain of Anopheles gambiae and two strains carrying multiple insecticide-resistance mechanisms. We conclude that the mosquitocidal mode of action of nitisinone differs from any of the current 37 classes of insecticides as none have a mode of action that specifically interferes with blood digestion. By highlighting the efficacy of nitisinone as a contact-based insecticide, our findings support the potential expansion of vector control strategies where nitisinone is incorporated into classic interventions like treated bednets and indoor residual spraying.

zoology↗

bioRxiv2024

Deep learning-driven neuromorphogenesis screenings identify repurposable drugs for mitochondrial disease

Mitochondrial disease encompasses untreatable conditions affecting tissues with high energy demands. A severe manifestation of mitochondrial disease is Leigh syndrome (Leigh), which causes defects in basal ganglia and midbrain regions, psychomotor regression, lactic acidosis, and early death. We previously generated isogenic pairs of Leigh cerebral organoids and uncovered defects in neuromorphogenesis. Here, we leveraged on this disease feature to devise drug discovery pipelines. We developed a deep learning algorithm tailored for cell type-specific drug repurposing to identify drugs capable of promoting neuronal commitment. In parallel, we performed a survival drug screen in yeast and validated the repurposable hits on branching capacity in Leigh neurons. The two approaches independently highlighted azole compounds, Talarozole and Sertaconazole, both of which lowered lactate release and improved neurogenesis and neurite organization in Leigh midbrain organoids. Hence, targeting neuromorphogenesis has led to identify potential new drugs for mitochondrial disease and could prove an effective strategy for further drug discovery.

neuroscience↗

bioRxiv2023

Graph-pMHC: Graph Neural Network Approach to MHC Class II Peptide Presentation and Antibody Immunogenicity

Antigen presentation on MHC Class II (pMHCII presentation) plays an essential role in the adaptive immune response to extracellular pathogens and cancerous cells. But it can also reduce the efficacy of large-molecule drugs by triggering an anti-drug response. Significant progress has been made in pMHCII presentation modeling due to the collection of large-scale pMHC mass spectrometry datasets (ligandomes) and advances in deep machine learning. Here, we develop graph-pMHC, a graph neural network approach to predict pMHCII presentation. We derive adjacency matrices for pMHCII using Alphafold2-multimer, and address the peptide-MHC binding groove alignment problem with a simple graph enumeration strategy. We demonstrate that graph-pMHC dramatically outperforms methods with suboptimal inductive biases, such as the multilayer-perceptron-based NetMHCIIan-4.0 (+22.84% average precision). Finally, we create an antibody drug immunogenicity dataset from clinical trial data, and develop a method for measuring anti-antibody immunogenicity risk using pMHCII presentation models. In comparison with BioPhis Sapiens score, a deep learning based measure of the humanness of an antibody drug, our strategy achieves a 7.14% ROC AUC improvement in predicting antibody drug immunogenicity.

immunology↗

bioRxiv2020

Tsetse salivary glycoproteins are modified with paucimannosidic N-glycans, are recognised by C-type lectins and bind to trypanosomes

African sleeping sickness is caused by Trypanosoma brucei, a parasite transmitted by the bite of a tsetse fly. Trypanosome infection induces a severe transcriptional downregulation of tsetse genes encoding for salivary proteins, which reduces its anti-hemostatic and anti-clotting properties. To better understand trypanosome transmission and the possible role of glycans in insect bloodfeeding, we characterized the N-glycome of tsetse saliva glycoproteins. Tsetse salivary N-glycans were enzymatically released, tagged with either 2-aminobenzamide (2-AB) or procainamide, and analyzed by HILIC-UHPLC-FLR coupled online with positive-ion ESI-LC-MS/MS. We found that the N-glycan profiles of T. brucei-infected and naive tsetse salivary glycoproteins are almost identical, consisting mainly (>50%) of highly processed Man3GlcNAc2 in addition to several other paucimannose, high mannose, and few hybrid-type glycans. In overlay assays, these sugars were differentially recognized by the C-type lectins mannose receptor and DC-SIGN. We also show that salivary glycoproteins bind strongly to the surface of transmissible metacyclic trypanosomes. We suggest that although the repertoire of tsetse salivary N-glycans does not change during a trypanosome infection, the interactions with mannosylated glycoproteins may influence parasite transmission into the vertebrate host.

biochemistry↗

bioRxiv2020

Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis

Tsetse transmit African trypanosomiasis, which is a disease fatal to both humans and animals. A vaccine to protect against this disease does not exist so transmission control relies on eliminating tsetse populations. Although neurotoxic insecticides are the gold standard for insect control, they negatively impact the environment and reduce insect pollinator species. Here we present a promising, environment-friendly alternative that targets insect tyrosine metabolism pathway. A bloodmeal contains high levels of tyrosine, which is toxic to haematophagous insects if it is not degraded. RNAi silencing of either the first two enzymes in the tyrosine degradation pathway (TAT and HPPD) was lethal to tsetse. Furthermore, nitisinone (NTBC), an FDA-approved tyrosine catabolism inhibitor, killed tsetse regardless if the drug was orally or topically applied. However, it did not affect bumblebee survival. A mathematical model shows that NTBC could reduce the transmission of African trypanosomiasis in sub-Saharan Africa, thus accelerating current elimination programmes.

biochemistry↗

bioRxiv2019

Encoding information in synthetic metabolomes

Biomolecular information systems offer numerous potential advantages over conventional semiconductor technologies. Downstream from DNA, the metabolome is an information-rich molecular system with diverse chemical dimensions which could be harnessed for information storage and processing. As a proof of principle of postgenomic data storage, here we demonstrate a workflow for representing abstract data in synthetic metabolomes. Our approach leverages robotic liquid handling for writing digital information into chemical mixtures, and mass spectrometry for extracting the data. We present several kilobyte-scale image datasets stored in synthetic metabolomes, which are decoded with accuracy exceeding 98-99% using multi-mass logistic regression. Cumulatively, >100,000 bits of digital image data was written into metabolomes. These early demonstrations provide insight into the benefits and limitations of postgenomic chemical information systems.

synthetic biology↗

bioRxiv2019

The Glossina Genome Cluster: Comparative Genomic Analysis of the Vectors of African Trypanosomes

BackgroundTsetse flies (Glossina sp.) are the sole vectors of human and animal trypanosomiasis throughout sub-Saharan Africa. Tsetse are distinguished from other Diptera by unique adaptations, including lactation and the birthing of live young (obligate viviparity), a vertebrate blood specific diet by both sexes and obligate bacterial symbiosis. This work describes comparative analysis of six Glossina genomes representing three sub-genera: Morsitans (G. morsitans morsitans (G.m. morsitans), G. pallidipes, G. austeni), Palpalis (G. palpalis, G. fuscipes) and Fusca (G. brevipalpis) which represent different habitats, host preferences and vectorial capacity. ResultsGenomic analyses validate established evolutionary relationships and sub-genera. Syntenic analysis of Glossina relative to Drosophila melanogaster shows reduced structural conservation across the sex-linked X chromosome. Sex linked scaffolds show increased rates of female specific gene expression and lower evolutionary rates relative to autosome associated genes. Tsetse specific genes are enriched in protease, odorant binding and helicase activities. Lactation associated genes are conserved across all Glossina species while male seminal proteins are rapidly evolving. Olfactory and gustatory genes are reduced across the genus relative to other characterized insects. Vision associated Rhodopsin genes show conservation of motion detection/tracking functions and significant variance in the Rhodopsin detecting colors in the blue wavelength ranges. ConclusionsExpanded genomic discoveries reveal the genetics underlying Glossina biology and provide a rich body of knowledge for basic science and disease control. They also provide insight into the evolutionary biology underlying novel adaptations and are relevant to applied aspects of vector control such as trap design and discovery of novel pest and disease control strategies.

genomics↗

bioRxiv2019

Trypanosoma brucei colonises the tsetse gut via an immature peritrophic matrix in the proventriculus

The peritrophic matrix (PM) of haematophagus insects is a chitinous structure that surrounds the bloodmeal, forming a protective barrier against oral pathogens and abrasive particles. To establish an infection in the tsetse midgut, Trypanosoma brucei must colonise the ectoperitrophic space (ES), located between the PM and gut epithelium. Although unproven, it is generally accepted that trypanosomes reach the ES by directly penetrating the PM in the anterior midgut. Here we revisited this event by employing novel fluorescence and electron microscopy methodologies and found that instead, trypanosomes reach the ES via the newly secreted PM in the tsetse proventriculus. Within this model, parasites colonising the proventriculus can either migrate to the ES or become trapped within PM layers forming cysts that move along the entire gut as the PM gets remodelled. Early proventricular colonisation appears to be promoted by unidentified factors in trypanosome-infected blood, resulting in higher salivary gland infections and potentially increasing parasite transmission.

microbiology↗

bioRxiv2018

The crystal structure and localization of Trypanosoma brucei invariant surface glycoproteins suggest a more permissive VSG coat in the tsetse-transmitted metacyclic stage

Trypanosoma brucei spp. develop into mammalian-infectious metacyclic trypomastigotes inside the tsetse salivary glands. Besides acquiring a variant surface glycoprotein (VSG) coat, nothing is known about expression of invariant surface antigens by the metacyclic stage. Proteomic analysis of saliva from T. brucei-infected flies revealed a novel family of hypothetical GPI-anchored surface proteins herein named Metacyclic Invariant Surface Proteins (MISP). MISP are encoded by five homolog genes and share ~80% protein identity. The crystal structure of MISP N-terminus at 1.82 [A] resolution revealed a triple helical bundle that shares key features with other trypanosome surface proteins. However, molecular modelling combined with live fluorescent microscopy suggest that MISP N-termini are extended above the metacyclic VSG coat, exposing immunogenic epitopes. Collectively, we suggest that the metacyclic cell surface architecture appears more permissive than bloodstream forms in terms of expression of invariant GPI-anchored glycoproteins, which could be exploited for the development of novel vaccines against African trypanosomiases.

microbiology↗

bioRxiv2018

Transposable Element Expression In Tumors Is Associated With Immune Infiltration And Increased Antigenicity

Profound loss of DNA methylation is a well-recognized hallmark of cancer. Given its role in silencing transposable elements (TEs), we hypothesized that extensive TE expression occurs in tumors with highly demethylated DNA. We developed REdiscoverTE, a computational method for quantifying genome-wide TE expression in RNA sequencing data. Using The Cancer Genome Atlas database, we observed increased expression of over 400 TE subfamilies, of which 262 appeared to result from a proximal loss of DNA methylation. The most recurrent TEs were among the evolutionarily youngest in the genome, predominantly expressed from intergenic loci, and associated with antiviral or DNA damage responses. Treatment of glioblastoma cells with a demethylation agent resulted in both increased TE expression and de novo presentation of TE-derived peptides on MHC class I molecules. Therapeutic reactivation of tumor-specific TEs may synergize with immunotherapy by inducing both inflammation and the display of potentially immunogenic neoantigens.\n\nOne Sentence SummaryTransposable element expression in tumors is associated with increased immune response and provides tumor-associated antigens

cancer biology↗

bioRxiv2017

Bacterial Biofilm Formation On Soil Fungi: A Widespread Ability Under Controls

In natural environments, bacteria preferentially live in biofilms that they build on abiotic surfaces but also on living tissues. Although fungi form extensive networks of hyphae within soils and thus could provide immense surfaces for bacteria to build biofilms and to proliferate, the extent on such phenomenon and the consequences for the fitness of both microorganisms is poorly known in soils. Here, we analyzed the process of formation of biofilms by various bacteria on hyphae of soil fungi in an in vitro setting using confocal and electron microscopy. We showed that the ability to form biofilms on fungal hyphae is widely shared among soil bacteria. In contrast, some fungi, mainly belonging to the Ascomycete class, did not allow for the formation of bacterial biofilms on their surfaces. The formation of biofilms was also strongly modulated by the presence of tree roots and by the development of the ectomycorrhizal symbiosis, suggesting that biofilm formation does not occur randomly in soil but that it is highly regulated by several biotic factors. Finally, our study led to the unexpected finding that networks of filaments made of extracellular DNA were used to build the skeleton of biofilms by a large array of bacteria.

microbiology↗