- by Vande Velde, S., Engelbeen, C., Pagani, I. S., Ross, D. M., Hautphenne, S.Chronic myeloid leukemia (CML) arises from the BCR::ABL1 fusion gene, but the exact stage of cellular differentiation at which the first leukemic cell emerges remains uncertain. We develop a stochastic 27-compartment model of hematopoiesis (blood cell development) using a continuous-time multitype branching process to capture the dynamics of both healthy and cancer cells. To infer the origin of CML, we develop a discrete-parameter Approximate Bayesian Computation – Population Monte Carlo (ABC-PMC) algorithm, tailored to estimate the posterior distribution for the […]
- by Cary, G. A., Li, Q., Wiley, J. C., Paisie, C. A., Du, Y., Zoeller, E. L., Duong, D., Fu, H., Seyfried, N. T., Levey, A. I., Betarbet, R., Carter, G. W.IntroductionAlzheimers disease (AD) is a complex neurodegenerative disorder. Hundreds of therapeutic targets have been nominated through genetic and multi-omic studies, but effective prioritization remains a major bottleneck. MethodsWe applied an integrative screening framework to assess 29 candidate targets from risk-enriched biological domains. Using disease-relevant murine BV2 microglial cell lines with stable Psen2 knockdown, we performed siRNA-mediated perturbations followed by cellular phenotypic assays and quantitative proteomics. ResultsTwenty-five candidate targets significantly altered at least one phenotype, with stronger effects in Psen2 knockdown […]
- by Zwartjes, M. S. Z., de Jonge, P., van de Laar, A. W., Bruin, S. C., Meijnikman, A. S., Groen, B., Gerdes, V. E. A., Nieuwdorp, M.BackgroundObesity is an important risk factor for cardiometabolic disease including dyslipidemia and atherosclerotic cardiovascular disease. While the role of the liver in dyslipidemia is established, the contribution of adipose tissue is less clear. This study aims to clarify the role of adipose tissue in lipid metabolism and its impact on dyslipidemia development. MethodsWe conducted a cross-sectional analysis of 125 patients from the BARIA longitudinal cohort study, consisting of patients with obesity undergoing bariatric surgery. Comprehensive phenotyping with fasting untargeted plasma […]
- by Adigwe, S., Harshavardhan, B., Jolly, M. K., Gedeon, T.Gene regulatory networks (GRN) control the expression levels of proteins in cells, and understanding their dynamics is key to potentially controlling disease processes. Steady states of GRNs are interpreted as cellular phenotypes, and the first step in understanding GRN dynamics is describing the collection of steady states the network can support in different conditions. We consider a collection of all monotone Boolean function models compatible with a given GRN, and ask which steady states are supported by most models. We […]
- by Gasparyan, M., Bhalla, U. S., Radulescu, O., Rao, S.We present a method for modeling the dynamics of enzymatic chemical reaction networks using species-reaction graphs. These bipartite graphs contain two sets of vertices, one representing species and the other representing reactions, connected by directed edges that indicate relationships between them. Our approach starts by assigning appropriate edge weights to the bipartite graph, which are then used to compute the weighted graph Laplacian. This Laplacian allows us to reformulate the standard system of ordinary differential equations governing the network dynamics, […]
- by Cary, G. A., Keegan, S., Wiley, J. C., Gockley, J., Longo, F. M., Levey, A. I., Greenwood, A. K., Leal, K., Carter, G. W.IntroductionAlzheimers Disease (AD) is a complex neurodegenerative disorder with numerous known risk factors. Identification of which genetic factors are causal drivers is difficult due to the long disease prodrome in an inaccessible organ. The application of integrative, systems-level approaches are crucial for addressing this complexity. MethodsSixteen biological domain specific interaction networks were derived from the top AD risk- enriched proteins within each domain. Weighted key driver analysis identified influential hub nodes within each network. ResultsDistinct processes and drivers were identified […]
- by Serdiuk, T., Redeker, V., Savistchenko, J., Neupane, S., Haenseler, W., Fleischmann, Y., Reber, V., Keller, S., Tiberi, C., Bachmann-Gagescu, R., Gstaiger, M., Braun, T., Riek, R., Gentleman, S., Aguzzi, A., de Souza, N., Melki, R., Picotti, P.The aggregation of the protein alpha-synuclein (Syn) is a common feature of multiple neurodegenerative diseases collectively called synucleinopathies, for which the pathobiology is not well understood. The different phenotypic characteristics of the synucleinopathies Parkinsons disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) have been proposed to originate from the distinct structures adopted by Syn in its amyloid forms. Here, using covalent labeling and limited proteolysis coupled to mass spectrometry (LiP-MS) in vitro and in situ within […]
- by Nashebi, R., Vera-Sigüenza, E., Lyu, Y., A. Tennant, D., Spill, F.1The mitochondrial dicarboxylate carrier SLC25A10 exchanges phosphate with dicarboxylates such as succinate and malate, playing a central role in metabolic regulation. Structural studies establish a ping-pong mechanism, but most mathematical models still assume sequential binding, lacking mechanistic justification and overlooking the alternation of a single binding site. Here, we present the first mechanistically derived and thermodynamically consistent model of SLC25A10 based on the ping-pong framework. The model incorporates competitive dicarboxylate binding, phosphate exchange, heteroexchange, reversibility, and electroneutrality, and is validated […]
- by Morishita, S., Uda, S., Kubota, H.Insulin resistance is a deficiency in insulin-mediated regulation of glucose metabolism and is considered a cause of multiple diseases such as diabetes and hypertension. The insulin signaling pathways contribution to insulin resistance remains incompletely understood. Insulin receptor (IR) mutations can cause insulin resistance; however, reduced IR expression in obesity may still permit sufficient signaling due to the characteristics of IR, known as the spare receptor hypothesis. Selective insulin resistance, in which glucose metabolism is impaired while other pathways remain intact, […]
- by Danan, D., Grosskopf, Y., Hayut, Y., Toledano, Y., Doenyas-Barak, K., Mayo, A., Alon, U.Post-traumatic Stress Disorder (PTSD) is a debilitating psychiatric condition characterized by intrusive memories, hyperarousal, avoidance, and cognitive and mood disturbances. A longstanding biological paradox in PTSD is the observation of low basal cortisol levels, despite the expectation of elevated cortisol under chronic stress. This "low cortisol paradox" challenges traditional hypothalamic-pituitary-adrenal (HPA) axis regulation models. Individuals with PTSD also exhibit normal or near-normal adrenocorticotropic hormone (ACTH) levels despite reduced cortisol and blunted hormonal responses to acute stress. In this paper, we […]
- by Fusar Bassini, L., Schede, H. H., Capolupo, L., Haj Abdullah Alieh, L., Venturi, F., Valente, A., Droin, C., Trejo Banos, D., Khven, I., Asirim, E. Z., Nasrallah, A., Kaysudu, I., Krymova, E., D'Angelo, G., La Manno, G.Lipids are fundamental components of the brain, crucial for synaptic transmission and signal propagation. Altered brain lipid composition is associated with common and rare neuropathologies, yet, the spatial organization of the mammalian brain lipidome remains insufficiently characterized compared to other modalities1-8. Here, we mapped the membrane lipid architecture of the adult mouse brain at micrometric scale, across sexes, and during pregnancy. This Lipid Brain Atlas reveals that lipids define a fine-grained biochemical structure that aligns with functional anatomy. Membrane lipid […]
- by Jiao, F., Yuan, B.Understanding extinction probabilities in branching processes is pivotal for epidemiology and population dynamics. Traditional models often assume a fixed generation time, resulting in extinction probabilities determined solely by offspring distributions and remaining unchanged over time. By contrast, our study incorporates the generation time into the analysis, considering how the timing of each generation influences extinction dynamics. By focusing on the finite-time risk of extinction, our approach reveals that shorter generation times can lead to a temporary increase in the risk […]
- by Ham, L., Jackson, M., Sukys, A., Stumpf, M. P. H.Cells do not act in isolation; they communicate with each other through a complex network of signals. In multicellular organisms, cell signaling buffers against fluctuations in gene expression. Its effect, however, on multistability–the ability of genetically identical cells to take on and maintain diverse stable states or phenotypes–is unclear. We develop spatially explicit stochastic models that couple fine-grained gene regulatory dynamics with intercellular signaling to study cell fate control in multicellular tissues. We show that intercellular signaling acts as a […]
- by Buljan, I., Bago-Horvath, Z., Rendeiro, A. F.Aging disrupts tissue structure at various scales, from cellular alterations to tissue and organ-level integrity. Microanatomical domains – recurrent cellular arrangements essential to organ-specific function, provide a highly physiologically relevant perspective on tissue homeostasis but are severely understudied in human aging. To address this gap, we developed H&E-UTAG, an unsupervised algorithm to detect microanatomical domains in whole slide histopathological images, which enables large-scale, label-free analysis of human microanatomy. Applying it to 24,945 whole-slide images from 40 human tissues of 983 […]
- by Duddu, A. S., Jolly, M. K., Raju, A.Geometrical models have been recently used to construct landscapes for cell-fate decisions, inferred directly from experimental data. However, such quantitative cell-fate data is available for a few systems only; instead, gene regulatory networks dynamics have been studied for a broader set of biological decision-making scenarios. Thus, connecting the geometry of cell-fate decisions to their underlying regulatory networks remains an open question. Recently, two regulatory networks have been shown to exhibit tristability – a toggle switch with self-activation, and a toggle […]
- by Jung, W. J., Acharya, S., Ruskin, D. P., Liao, S., Akbary Moghaddam, V., Erdenebaatar, Z., Brent, M. R.Transcription factor (TF) network maps link TFs to their direct, functional gene targets whose transcription they regulate by binding cis-regulatory elements (CREs). Existing methods to reconstruct these networks typically rely either on TF motifs in CREs or gene expression data alone, limiting their accuracy. Motif data alone often fail to identify actual TF binding sites, while expression data cannot distinguish direct from indirect regulatory relationships. Additionally, accurate TF networks must be tissue-specific due to varied TF activities and expression patterns […]
- by Rice, S., Grond, K., Gering, S. M., Reisz, J., Bailey-Parsons, T. R. M., Buck, C. L., Duddleston, K.Hibernators rely on endogenous supplies of amino acids (AAs) and other nutrients to sustain organ function and skeletal muscle mass. Gut microbiota-mediated recycling of urea-nitrogen into AAs has long been considered a mechanism to assist in conserving nitrogen; however, the relevance of urea nitrogen salvage (UNS) to overall host physiology and metabolism is debated. We hypothesized that incorporation of microbially-liberated urea-nitrogen (MLUN) into AAs would be higher in host tissues of hibernating arctic ground squirrels compared to those of summer […]
- by Qin, D., Das, R., Schallenberg, S., Riecken, K., Tinhofer, I., Coscia, F.Drug resistance in cancer therapy continues to significantly contribute to treatment failure and disease progression, and is linked to intratumoral heterogeneity. Mass spectrometry (MS)-based single-cell proteomics (SCP) provides a unique opportunity to uncover the mechanisms underlying drug-resistant phenotypes; however, current methods lack clonal resolution and are often confounded by cell cycle and cell size differences. Here, we introduce PhenoSCoP, a microscopy-guided discovery proteomics concept for mapping clonal proteomic heterogeneity. By distinguishing between transient and long-lived protein level changes, our approach […]
- by Mallick, H., Nirmalkar, K., Adams, J. B., Krajmalnik-Brown, R.BackgroundMicrobiota transplant therapy (MTT) is a promising avenue for the substantial improvement of gastrointestinal and behavioral symptoms in children with autism spectrum disorder (ASD). Previous work has demonstrated that microbiome and metabolite profiles of children with ASD become more similar to those of their typically developing (TD) peers following MTT. MethodsTo enhance a systems-level understanding of MTT in ASD children that extends beyond previously reported findings, we present a multi-omics analysis of an ASD cohort spanning 10 weeks and 2 […]
- by Gribkova, A. K., Armeev, G. A., Kirpichnikov, M. P., Shaytan, A. K.The full complement of chromatin-associated proteins–collectively referred to as the chromatome–enables genome functioning in eukaryotes by participating in a wide range of physico-chemical processes. These include mediating diverse specific and non-specific intermolecular interactions, catalyzing in situ synthesis and modification of macromolecules, facilitating ATP-dependent chromatin remodeling, etc. Despite considerable progress in epigenomics and the structural characterization of many nuclear proteins and their complexes, our understanding of chromatin organization at the proteome scale remains incomplete. This gap hinders the development of a […]
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