- by Caddeo, A., BARRET, M., PEYRAUD, R.Pathogens rely on multiple pathogenicity traits, such as proliferation, adhesion, motility and the production of virulence factors, to successfully colonize their host. The expression of virulence functions is often finely regulated to mitigate resource allocation trade-offs due to their cost for the cell. The ways in which constraints encountered inside the host shape strategies for mitigating the trade-off between pathogenicity traits remain poorly understood. Xanthomonas campestris pv. campestris (Xcc) and Ralstonia solanacearum (Rs) are two bacterial phytopathogens that can colonize […]
- by Hayashi, S., Takeuchi, M., Nakano, T., Setoyama, D., Singh, S. A., Sonawane, A. R., Iwamoto, T., Kishimoto, H., Tsuchimoto, A., Yamada, S., Kang, D., Ago, T., Kitazono, T., Aikawa, M., Kunisaki, Y.Focal segmental glomerulosclerosis (FSGS) is a major cause of glucocorticoid-resistant nephrosis, yet its pathogenesis remains unclear. To define the molecular and cellular landscape of FSGS, we employed multi-omics approaches on independent human kidney biopsy cohorts. Proteomics revealed enhanced immune and complement activation. Spatial transcriptomics using a target gene panel constructed from the proteomics highlighted alternative pathway activation driven by complement factor D as a prominent feature. Complement activation emerged in glomeruli alongside altered signaling in podocytes and parietal epithelial cells […]
- by Collins, K., Stanley, C. E., Ouldridge, T. E.Microfluidic devices with surface-bound biomolecular patterns enable localised detection arrays, enzymatic catalysis, and gene expression. Photolithography is a contactless patterning method with high spatial control. However, while patterning open surfaces by photolithography is well-established, patterning enclosed microfluidic channels remains technically challenging. Such capability would enable in situ surface modification and precise pattern alignment to channel geometries. Here, we present a photolithographic method using commercially available reagents to pattern sealed microfluidic devices. We first coat surfaces with (3-Aminopropyl)triethoxysilane (APTES) to bond […]
- by Feng, Z., Chen, F., Xiao, J., Du, A., Deng, J., Zhang, Y., Li, X., Zheng, A., Li, H.Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent condition that progresses from simple steatosis to advanced fibrosis, significantly affecting liver function and systemic health. Despite its widespread impact, therapeutic options are limited, highlighting the urgent need for comprehensive exploration to identify potential therapeutic targets. In this study, we created an analysis pipeline anchored on liver gene expression, integrating differential meta-analysis of transcriptomic data across three MASLD stages, transcriptome-wide Mendelian randomization (MR), and transcriptome-wide association studies (TWAS), to identify 39 […]
- by Higashitani, A., Moon, J.-H., Hwang, J.-I., Higashitani, N., Hashizume, T., Abu, A. A., Ooizumi, K., Sazuka, I., Hashizume, Y., Umehara, M., Alcantara, A. V., Kim, B.-s., Etheridge, T., Szewczyk, N. J., Abe, T., Lee, J. I., Higashibata, A.Space travel is becoming accessible, yet our understanding of how space environment and microgravity (uG) affect biology, physiology, and health remains incomplete. We investigated uG effects on neuromuscular development and aging in Caenorhabditis elegans. Nematodes in uG showed downregulation of genes related to synaptic signaling, dopamine response, locomotion, and cuticle development, with impaired synaptic vesicle dynamics, reduced motility, and shorter body lengths. Aged worms in uG showed decreased collagen gene expression, increased motor neuron defects, synaptic vesicle accumulation and decreased […]
- by Breuil, L., Doumic, M., Kaakaï, S., Rera, M.Ageing is traditionally conceived as a continuous process of progressive physiological decline. Recent evidence across multiple species challenges this view, suggesting ageing may proceed through distinct phases. Here we present a rigorous statistical framework to test and refine the two-phase ageing model using longitudinal survival data from Drosophila melanogaster. We analyzed 1,159 individually tracked female flies from the Smurf assay, which identifies a transition from a non-Smurf state to a Smurf state characterized by increased intestinal permeability that precedes death. […]
- by Vega, A. G., Bennett, N. E., Beadle, E. P., Alshafeay, S., Chitturi, R., Nagarimadugu, A., Villur, H., Jaiswal, A., Rhoades, J. A., Harris, L. A.Tumor-induced bone disease (TIBD) arises from a complex interplay between metastatic cancer cells and the bone microenvironment, creating a self-reinforcing "vicious cycle" of bone destruction and tumor growth. Experimental evidence from our group (Buenrostro et al., Bone 113:77-88, 2018) suggests that tumor cells in the bone microenvironment early in disease rely more heavily on bone-derived growth factors, such as transforming growth factor-{beta} (TGF-{beta}), to sustain proliferation than tumor cells late in disease, which may grow independently of these factors. Here, […]
- by Neirynck, R. E., Chirinos, J. A., Van Damme, M., Coussement, L., Segers, P., De Buyzere, M., Rietzschel, E. R., De Meyer, T.Organ-specific proteomic clocks are promising tools for quantifying heterogeneity in biological aging, but their longitudinal behavior remains largely unexplored. Here, we analyzed paired plasma proteomic profiles with 10-year follow-up in middle-aged adults (n= 1,250) to evaluate their longitudinal properties. Cross-sectional associations of protein concentrations with age mirrored average longitudinal trajectories, validating the common cross-sectional training of clocks. Organ-specific age acceleration was moderately stable over the decade, and aging across organs progressed in parallel, with the immune and adipose systems acting […]
- by Barkai, T., Frieman-Sharabi, R., Bahar Halpern, K., Novoselsky, R., Korem Kohanim, Y., Shir, S., Golani, O., Goliand, I., Addadi, Y., Kedmi, M., Keren-Shaul, H., Prichislov, L., Guz-Mark, A., Nissim, H., Shamir, R., Shouval, D., Itzkovitz, S.Enterocytes in the human small intestine exhibit distinct functional states in different zones along the crypt-villus axis, a feature that is thought to convey optimal absorption. In celiac disease (CeD), autoimmune destruction of enterocytes leads to villus blunting, but how this altered tissue morphology affects enterocyte states is unclear. Using spatial and single-cell transcriptomics, we show that in patients with CeD, enterocytes acquire a novel identity characterized by co-expression of multiple zonal programs. This aberrant zonal co-expression results from reduced […]
- by Fachareldeen, R., Brenner, N.Degeneracy – the multiplicity of phenotypes with equivalent fitness – is a prevalent feature of biological systems. Such degeneracy is often associated with neutral evolution, under the assumption that adaptive dynamics on degenerate fitness manifolds lacks direction. Here we show that this is not generally the case. Using a minimal model of evolutionary dynamics on smooth degenerate fitness landscapes, we demonstrate that stochastic mutation-selection dynamics induce a directional drift on manifolds of optimal fitness toward regions of reduced curvature. This […]
- by Kidder, B. L.Understanding how gene function emerges across molecular, cellular, and pharmacologic contexts remains a central challenge in systems biology and drug discovery. Conventional computational models typically operate within a single modality, such as expression, ontology, or interaction networks, limiting their ability to capture the multidimensional nature of gene function. Here, we present NEWT (Neural Embeddings for Wide-spectrum Targeting), a multimodal deep learning framework that integrates heterogeneous biological knowledge into a unified and interpretable representation space. By combining functional annotations, large-scale co-expression […]
- by Leung, G. H. D., Chen, J., Ergun, I. A., Izumchenko, E., Aliper, A., Ren, F., Pun, F. W., Zhavoronkov, A.Aging is increasingly viewed as a pathologic process and a principal driver of diverse age-related diseases (ARDs). Framing aging as a disease offers an opportunity to identify therapeutic targets capable of modifying multiple chronic disorders simultaneously. Here, we developed an AI-driven target discovery framework that integrates large-scale multi-omic datasets to prioritise therapeutic targets shared between aging and 12 ARDs across four major disease areas: neurological, inflammatory, metabolic, and fibrotic disorders. We identified 29 high-confidence and 16 previously unrecognized aging-associated targets […]
- by Basirattalab, A., Wallis, D. C., Hartel, N. G., Jalalifarahani, M., Phillips, C. M., Graham, N. A.Although protein arginine methylation regulates diverse biological processes, it remains understudied relative to other post-translational modifications. Here, we analyzed C. elegans prmt-1 and prmt-5 null mutants using LC-MS proteomics to map PRMT methylation substrates and to quantify the effects of PRMT knockout on global protein abundance. High-pH strong cation exchange fractionation was used to enrich methylated peptides, and parallel analysis of whole cell lysates was used to measure global protein abundance. Quantitative methyl-proteomics identified 31 PRMT-1-dependent methyl-arginine peptides from 15 […]
- by Joca, H., Silva, P. A., Santos, J., Dias, E., Barbosa, T. P., Degaki, K., Morales, R., Terra, M., Rabelo, R. S., Cardoso, M. B., Saito, A., Avelino, T. M.Conventional two-dimensional (2D) histology relies upon destructive sample preparation and stereological estimation, frequently leading to sampling bias and loss of critical spatial context required for understanding renal structure relationships. Here, we detail a novel pipeline for high-resolution 3D histology of ex vivo murine kidneys using X-ray micro-computed tomography (micro-CT) at the high flux of a synchrotron light source, the architecture of the nephron and associated microvasculature necessitates three-dimensional (3D) analysis to accurately characterize its complexity. Soft-tissue contrast was optimized through […]
- by Horecka, I., Rost, H.SummaryHierarchical clustering organizes high-dimensional biological matrices and is commonly used for visualization rather than statistical inference. Most enrichment-based analyses of such matrices are confined to gene expression data and fixed workflows. We introduce Hierarchical Matrix Layout and Annotation Software (HiMaLAYAS), a framework for post hoc enrichment-based annotation of hierarchically clustered matrices. HiMaLAYAS treats clusters as statistical units, evaluates annotation enrichment, and renders significant annotations alongside the matrix. HiMaLAYAS supports biological and non-biological domains. Availability and ImplementationHiMaLAYAS is a Python package […]
- by Lakrisenko, P., Isensee, J., Hucho, T., Weindl, D., Hasenauer, J.Protein kinase A (PKA) is a central integrator of nociceptive signaling, yet a quantitative account of how pro- and anti-nociceptive inputs shape its dynamics remains incomplete. Here, we develop a mechanistic model of PKA activity in nociceptive neurons that explicitly links receptor activation to downstream kinase regulation. Using time-course and dose-response measurements, we infer unknown process parameters and quantify parameter and prediction uncertainties to ensure robust conclusions. The model captures the activation of PKA by serotonin and forskolin and its […]
- by Zylstra, A. J., Rovetta, M., Vedelaar, S., Bleischwitz, C., Fülleborn, J. A., van Oppen, Y. B., Markus, H. P., Korbeld, K. T., Milias-Argeitis, A., Buczak, K., Schmidt, A., Heinemann, M.The cell division cycle is characterised by oscillatory dynamics in regulatory mechanisms and biosynthesis, coordinated with genome replication and segregation. To understand these dynamics, quantitative cell cycle-dependent protein concentration data is essential. Unfortunately, accurate resolution of cell cycle-dependent protein dynamics is challenging because single-cell proteomics is currently infeasible and bulk proteomics requires inherently imperfect cell synchronisation. Here, we developed a computational method to deconvolve cell cycle-dependent protein concentration dynamics and applied it to new budding yeast bulk proteome data. Key […]
- by Mishra, D., Agrawal, S., Malik, D., Pathak, E., Mishra, R.TFE3-rearranged papillary renal cell carcinoma (pRCC) remains poorly understood due to its rarity and complex biology. By integrating matched mRNA and miRNA sequencing from the TCGA-KIRP cohort, this study reveals a fusion-specific post-transcriptional program orchestrating ferroptosis resistance, metabolic adaptation, adhesion loss, immune remodeling, and dormancy-associated signaling. Fusion-positive tumors exhibited coordinated upregulation of antioxidant and mTORC1 components (SOD2, GPX4, G6PD, NQO1, FNIP2, RRAGC), reinforced by loss of miRNA-mediated repression. In parallel, elevated miRNAs (miR-185, miR-148a, miR-130b, miR-342) suppressed MAPK, Wnt, and […]
- Machine learning-guided spatial omics for tissue-scale discovery of cell-type-specific architecturesby Lian, Y., Adjavon, D., Kawase, T., Kim, J., Fleishman, G., Preibisch, S., Funke, J., Liu, Z. J.Multiplexed protein imaging enables spatially resolved analysis of molecular organization in tissues, but existing spatial proteomics platforms remain constrained in scalability, throughput, and integration with RNA measurements and interpretable computational analysis. Here, we present an integrated spatial omics framework that combines highly multiplexed protein and RNA imaging with explainable machine learning to map cell-type-specific molecular and structural architectures at tissue scale. Using this platform, we simultaneously profiled up to 46 proteins and 79 RNA species across [~]370,000 cells in intact […]
- by Song, J., deng, l., Royer, L., Kalafut, B., DeBord, D., Meyer, J.Parallel Accumulation with Mobility-Aligned Fragmentation (PAMAF) achieves near-complete ion utilization and high spectral specificity by fragmenting all mobility-separated precursors without quadrupole isolation. Leveraging the ultrahigh mobility resolution of SLIM, this quadrupole-free strategy maximizes ion utilization efficiency and offers a promising approach in mass spectrometry-based proteomics, particularly for low-abundance peptides or low-input samples. However, the unique data structure of PAMAF where precursor-fragment relationships are encoded along the mobility dimension renders it incompatible with existing peptide identification tools. Here, we present xTracer, […]
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