- by Flinkman, D., Deshpande, P., James, P., Coffey, E.Exposure to the environmental toxin rotenone increases risk for Parkinson's disease (PD). However, protein phosphorylation changes induced by rotenone in neural-derived cells have not been reported. We examined the effect of rotenone on the proteome and phosphoproteome of cortex-derived cultures from wild-type and Lrrk2-/- mouse brains. We also analyzed the phosphoproteome of the PD cadaver brain using a previously unanalyzed dataset. Rotenone alters phosphorylation at 904 sites, most of which are unchanged in Lrrk2-/- cultures. Common targets include proteins that […]
- by Ruoff, P.The term enantiostasis was introduced by Mangum and Towle to describe functional relationships between environmental changes and an organism's adaptation to them, and furthermore, to distinguish this kind of adaptation from homeostatic control. The defining example of enantiostasis is the blue crab's blood salinity response when exposed to different environmental salinities during the organism's move between the ocean and upriver freshwater conditions. In this paper an internal negative feedback loop in the Albers-Post mechanism of the sodium pump (Na,K-ATPase, NKA) […]
- by Lin, T.-S., Chen, Y., Li, X., Ji, X., Huang, S., Lyu, J., Li, L., Zuo, H., Li, S., Li, J., Huang, H.-Y., Zhuo, H., Zhang, X., Wang, Y.-F., Ning, S., Zhang, Z., Gu, Y., Zhang, T., Lin, Y.-C.-D., Huang, H.-D.The photoprotective efficacy of natural skin-active complexes is well recognized, yet their application is often hindered by the challenge of deciphering their complex, multi-component, and multi-target mechanisms. To bridge the gap between established phenotypes and molecular mechanisms, we developed an AI-driven integrated platform that combines phytochemical profiling, network pharmacology, and deep learning-based target prediction with rigorous biophysical validation. We applied this platform to investigate RRBE, a bioactive complex refined from red rice bran extract. In vivo clinical studies confirmed that […]
- by Shang, P., Hoang, J., Hong, E., Geng, Z., Ambrosino, H., Abnoosian, E., Zhu, X., Ma, M., Wei-Navarro, N. A., Webber, B. R., Qu, J., Montezuma, S. R., Agbaga, M.-P., Dutton, J. R., Ferrington, D. A.Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is associated with multiple risk factors and involves death of the retinal pigment epithelium (RPE). We investigated how the Y402H polymorphism of Complement Factor H (CFH) and cigarette smoke extract (CSE), major AMD genetic and environmental risks, affect lipid metabolism in RPE differentiated from induced pluripotent stem cells (iPSC-RPE) that were derived from human donors genotyped for low-risk (LR) or high-risk (HR) CFH. Results from discovery-based (lipidomics, proteomics) […]
- by Michael, C. T., Budak, M., Lin, P. L., Kirschner, D. E.Tuberculosis (TB) remains a global health concern, as Mycobacterium tuberculosis (Mtb) infects a quarter of the worlds population. Though many TB patients sterilize infection with treatment regimens including the current standard, incomplete sterilization leads to post-treatment relapse and development of drug resistance. Two mechanisms have been hypothesized as driving relapse: persistence, where treatment kills all replicating Mtb, and relapse follows once non-replicating Mtb return to a replicative niche; and threshold, where replicating Mtb remain alive, yet below detectable levels. Relapse […]
- by Sharma, S., Mehra, S.Multidrug-resistant efflux pumps play a critical role in antimicrobial resistance, yet the physiological limits of their overexpression remain poorly understood. While gene amplifications and regulatory mutations commonly drive this overexpression, these pumps remain transcriptionally inactive under normal cellular conditions due to their high energetic cost, making it challenging to assess their full impact on resistance evolution and the maximum attainable minimum inhibitory concentration (MIC). To delineate the extent and spectrum of efflux-based resistance, we subjected Mycobacterium smegmatis mc{superscript 2}155(Msm) wild-type […]
- by Muller, C., Audemard, J., Prigent, S., Frioux, C.MotivationMetabolic networks represent genome-derived information about the biochemical reactions that cells are capable of performing. Mapping omic data onto these networks is important to refine model simulations. However, metabolomic data mapping remains very challenging due to difficulties in identifier reconciliation between annotation profiles and metabolic networks. ResultsMetaNetMap is a Python package designed to automatise the process of mapping metabolomic data onto metabolic networks. It includes several layers of identifier matching, the use of customisable databases, and molecular ontology integration to […]
- by Krishnamurthy, M. B., P S, H., Subramanian, A.Genome-scale metabolic network (GSMN) models are rigorously curated, cellular-level representations of metabolism that enable flux-based metabolite fate discovery, metabolic engineering, drug target identification and context-specific multi-omics integration. However, the inherent complexity of model architectures, need for programming skills and limited visualization support restrict their broader applicability. Existing tools focus on visualization and analyses separately, necessitating tool-specific format conversions, offer either topology or flux analyses options exclusively, lack intuitive pathway-specific visualizations, database-integrated model refinement, pathway enrichment and large-scale perturbation analyses. Here, […]
- by Somparn, P., Sriswasdi, S., Wongkongkathep, P., Muanwien, P., Nanthawong, S., Apinan, T., Opanuraks, J., Shuangshoti, S., Hirankarn, N., Moonmuang, S., Kampoun, T., Chaiyawat, P., Pisitkun, T.This study profiles the personalized immunopeptidomes of 13 Thai patients with renal cell carcinoma (RCC), addressing a critical knowledge gap in Southeast Asian populations characterized by distinct HLA allele distributions. We combined whole-exome sequencing (WES)-based personalized proteome construction with liquid chromatography-tandem mass spectrometry (LC-MS/MS), using both database-driven searches and de novo peptide sequencing. HLA typing identified seven alleles not previously represented in major immunopeptidome databases, with HLA-A*11:01 being the most frequent (69%). Database-based analysis identified a single tumor-specific neoantigen derived […]
- by McLelland, L., Karki, D., Spratt, M., Burt, M., Zhao, J., Lane, K.Bacterial pathogens must balance rapid expression of virulence genes in host niches with tight repression when not needed to avoid fitness costs and ensure survival. Integration of virulence gene regulatory networks with the conserved global repressor H-NS was critical to achieve this balance. H-NS-mediated repression of virulence genes in non-inducing environments is essential for maintaining virulence genes and has shaped pathogen evolution. However, the role of H-NS-mediated repression in virulence gene activation and pathogen evolution in virulence-inducing conditions is less […]
- by Vanselow, D. J., Sugarman, A. L., Northover, D., Senft, S., Zaino, C. R., Yakovlev, M. A., Christ, J. M., Silverman, J., Chung, W.-S., La Riviere, P., Hanlon, R. T., Cheng, K. C., Ang, K. C., Ngu, M. S.Understanding how nervous systems mediate responses to sensation requires whole-body maps of periphery-to-brain connections. Octopuses exemplify this challenge with distributed control of eight arms and hundreds of suckers, yet their long-range microanatomical wiring remains elusive due to limitations in microscopy. We extend histotomography (Ding et al. 2019), a form of soft tissue microCT customized for volumetric characterization of cells and tissues, to centimeter range with a custom micro-CT imaging system (Ding et al., 2019). With its 10-mm field of view […]
- by Tarantino, R., Contino, S., Gugliotta, L., Indelicato, G., Panunzi, G., Bertolazzi, G., Romano, V.Actin polymerization is a critical cellular process involved in a wide range of activities, from cell motility to cytokinesis. The complex behavior of this molecular system, resulting in three different phases (i.e., nucleation, elongation, and steady state) is clear by looking at the way these dynamics emerge from a large number of interactions between different proteins, regulatory elements, and signaling pathways. In this article, we present an agent-based model of actin polymerization dynamics implemented with the NetLogo simulation platform and […]
- by Kscheschinski, B., Chauvin, D., Julou, T., van Nimwegen, E.Phenotypic heterogeneity is a universal feature in microbial life and has profound consequences for the behavior of single cells. However, dissecting and quantifying the sources of phenotypic noise is challenging as it requires precise quantification of the dynamics of gene expression fluctuations in vivo. Here, we analyze time-lapse microscopy data of single E. coli cells carrying fluorescent reporters for constitutive and ribosomal promoters to quantify how fluctuations in protein production, growth rate, and random sampling at division contribute to noise […]
- by Isaev, K., Knowles, D. A.Alternative splicing is a key gene regulatory process that diversifies the proteome and controls gene dosage. Previous studies have detected aging-associated splicing changes across various tissues. However, their use of bulk RNA-seq obfuscates the impacted cell-types and may confound cell-type proportion changes with cell-intrinsic ones. We present a framework that first assembles and maps alternative splicing events in appropriate single cell RNA-seq data (scRNA-seq), then applies LeafletFA, a probabilistic model that discovers coordinated splicing programs (SPs) without requiring prior knowledge […]
- by Emadi, A., Lipniacki, T., Levchenko, A., Abdi, A.Cells make hard calls under noise. When signaling is abnormal, those calls can go wrong and drive pathological conditions and diseases. In this research, we develop a Neyman-Pearson (NP) detection-theory framework that maximizes probability of detection (PD) for a chosen false alarm probability (PFA), without requiring prior probabilities, using experimental single-cell measurements of NF-{kappa}B responses to tumor necrosis factor (TNF), a critical pathway involved in cell survival, apoptosis, immune signaling, and stress response, in wild-type and A20-deficient fibroblasts. We model […]
- by Trifonova, K., Falk, M. J., Rouches, M., Vaikuntanathan, S., Elowitz, M. B., Murugan, A.Reports of learning in single cells without genetic change span decades yet remain controver-sial, in part because there is no accepted general molecular mechanism for training comparable to gradient-based training or Hebbian learning in neural circuits. Here we identify a minimal set of ingredients sufficient to realize non-genetic learning, drawing inspiration from Boltzmann neural networks. First, dense reversible interaction networks provide an expressive substrate in which modulating the concentrations of a small set of mediator species can reprogram function without […]
- by Stroock, A. D., Desai, S. A.Stomatal pores, formed by guard cells, govern the critical trade-off between carbon assimilation and water loss in plants. Their dynamic responses to environmental stresses, such as stomatal oscillations and drought "stress memory" (hysteresis), have lacked a unified mechanistic explanation. While abscisic acid (ABA) is believed to play key roles in water stress responses, no model has linked its core regulatory kinetics to these complex stomatal behaviors. Here, we introduce a coupled hydropassive-hydroactive (HP-HA) model that integrates leaf hydraulics with the […]
- by Joshi, A., Patel, D., Muralidharan, V., Mukerji, M.Meditation practices are often used as non-pharmacological adjunct therapy for managing stress and well-being benefits. We propose that beneath their non-pharmacological facade, meditation practices might operate via drug target modulation having profound neurophysiological effects. Firstly, we leverage the Connectivity Map (CMap) to investigate (a) the overlap between meditation-induced molecular signatures and established drug responses, and (b) the pathways and mechanisms contributing to meditation potential therapeutic effects. This was studied in a comprehensive temporal RNAseq dataset comprising premeditation, meditation, and follow-up […]
- by Moldakozhayev, A., Tyshkovskiy, A., Nigro, P., de Magalhaes, C. G., Ying, K., Eames, A. W., Poganik, J. R., Tskhay, A., Zhang, B., Tikhonov, S., Anekal, P. V., Carbone, N. P., Hirshman, M. F., Goodyear, L. J., Van Raamsdonk, J. M., Gladyshev, V. N.Exposure to a younger system can induce organismal rejuvenation, yet whether all tissues can be rejuvenated and by what mechanisms remains understudied. We performed heterochronic and isochronic transplantation of subcutaneous white adipose tissue (WAT) between young and old mice and longitudinally tracked changes in biological age. Transplantation accelerated tissue aging, and the molecular age of grafts shifted toward that of the host. Most importantly, old WAT was rejuvenated in a young body. Epigenetic and transcriptomic clocks revealed a reduction of […]
- by Honkala, A.Samples of closely related cells often contain substantial cell state heterogeneity, which traditional clustering-based analyses struggle to de-convolve. Archetype analysis is an alternative analysis approach that identifies a minimal convex hull enclosing all data points in a dimensionally-reduced space, such as PCA space. The points of this convex manifold, or hull, each represent theoretical extremal states specialized in a subset of functions that are mutually exclusive to the extremal states found at each other vertex. The transition between two points […]
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