- by Gorstein, E., Aghdam, R., Solis-Lemus, C.High dimensional mixed-effect models are an increasingly important form of regression in modern biology, in which the number of variables often matches or exceeds the number of samples, which are collected in groups or clusters. The penalized likelihood approach to fitting these models relies on a coordinate gradient descent (CGD) algorithm that lacks guarantees of convergence to a global optimum. Here, we study empirically the behavior of the algorithm across a number of common study types in modern omics datatypes. […]
- by Malmstrom, E., Hauri, S., Mohanty, T., Scott, A. M., Karlsson, C. A. Q., Gueto Tettay, C. A., Ahrman, E., Nozohoor, S., Tingstedt, B., Regner, S., Elfving, P., Bjermer, L., Forsvall, A., Doyle, A., Magnusson, M., Hedenfalk, I., Kannisto, P., Brandt, C., Nilsson, E., Dahlin, L. B., Malm, J., Linder, A., Malmstrom, L., Nimeus, E., Malmstrom, J.The plasma proteome is maintained by the influx and efflux of proteins from surrounding organs and cells. To quantify the extent different organs and cells contribute to the plasma proteome composition, we developed a mass spectrometry-based proteomics strategy to infer the origin of proteins detected in human plasma in health and disease. First, we constructed an extensive human proteome atlas from 18 vascularized organs and the most abundant cell types in blood. Second, the atlas was interfaced with previous RNA/protein […]
- by Poyatos, J. F.Exploring the degree to which phenotypic variation, influenced by intrinsic nonlinear biological mechanisms, can be accurately captured using statistical methods is essential for advancing our comprehension of complex biological systems and predicting their functionality. Here, we examine this issue by combining a computational model of gene regulation networks with a linear additive prediction model, akin to polygenic scores utilized in genetic analyses. Inspired by the variational framework of quantitative genetics, we create a population of individual networks possessing identical topology […]
- by Corridori, C., Romeike, M., Nicoletti, G., Buecker, C., Suweis, S., Azaele, S., Martello, G.Physiological and pathological processes are governed by a network of genes called gene regulatory networks (GRNs). By reconstructing GRNs, we can accurately model how cells behave in their natural state and predict how genetic changes will affect them. Transcriptomic data of single cells are now available for a wide range of cellular processes in multiple species. Thus, a method building predictive GRNs from single-cell RNA sequencing (scRNA-seq) data, without any additional prior knowledge, could have a great impact on our […]
- by Bumbaca, B., Birtwistle, M. R., Gallo, J. M.Glioblastoma Multiforme (GBM) remains a particularly difficult cancer to treat, and survival outcomes remain poor. In addition to the lack of dedicated drug discovery programs for GBM, extensive intratumor heterogeneity and epigenetic plasticity related to cell-state transitions are major roadblocks to successful drug therapy in GBM. To study these phenomenon, publicly available snRNAseq and bulk RNAseq data from patient samples were used to categorize cells from patients into four cell states (i.e. phenotypes), namely: (i) neural progenitor-like (NPC-like), (ii) oligodendrocyte […]
- by Huang, J., Kwok, A. J., Li, J. C. Y., Chiu, C. L. H., Ip, B. Y. M., Tung, L. Y., Zheng, X., Chow, H. T., Lo, M. P. S., Li, Z., Chan, R. C. H., Lin, N., Wang, Z., Wang, M., Yan, L. Y. C., Chan, D. C. W., Wu, W. K. K., Chow, H.-M., Lin, W.-J., Tang, Y., Ng, B. W.-L., Wong, S. H., Leung, T. W., Mok, V. C. T., Ko, H.Identifying readily implementable methods that can effectively counteract aging is urgently needed for tackling age-related degenerative disorders. Here, we conducted functional assessments and deep molecular phenotyping in the aging mouse to demonstrate that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment attenuates body-wide age-related changes. Apart from improvements in physical and cognitive performance, the age-counteracting effects are prominently evident at multiple omic levels. These span the transcriptomes and DNA methylomes of various tissues, organs and circulating white blood cells, as well as […]
- by R. Moimenta, A., Troitino-Jordedo, D., Henriques, D., Contreras-Ruiz, A., Minebois, R., Morard, M., Barrio, E., Querol, A., Balsa-Canto, E.Batch fermentation is a biotechnological dynamic process that produces various products by employing microorganisms that undergo different growth phases: lag, exponential, growth-non-growth, stationary, and decay. Genome-scale constrained-based models are commonly used to explore the phenotypic potential of these microorganisms. Previous studies have primarily used dynamic Flux Balance Analysis (dFBA) to elucidate the metabolism during the exponential phase. However, this approach falls short in addressing the multi-phase nature of the process and secondary metabolism, posing significant challenges to our understanding of […]
- by Dunivant, T. S., Godinez-Vidal, D., Perkins, C., Lee, M. G., Ta, M., Groen, S. C.Like other plants, wild and domesticated rice species (Oryza nivara, O. rufipogon, and O. sativa) evolve in environments with various biotic and abiotic stresses that fluctuate in intensity through space and time. Microbial pathogens and invertebrate herbivores such as plant-parasitic nematodes and caterpillars show geographical and temporal variation in activity patterns and may respond differently to certain plant defensive mechanisms. As such, plant interactions with multiple community members may result in conflicting selection pressures on genetic polymorphisms. Here, through assays […]
- by Kumar, D., Budachetri, K., Rikihisa, Y., Karim, S.BackgroundMicroRNAs (miRNAs) represent a subset of small noncoding RNAs and carry tremendous potential for regulating gene expression at the post-transcriptional level. They play pivotal roles in distinct cellular mechanisms including inhibition of bacterial, parasitic, and viral infections via immune response pathways. Intriguingly, pathogens have developed strategies to manipulate the hosts miRNA profile, fostering environments conducive to successful infection. Therefore, changes in an arthropod hosts miRNA profile in response to pathogen invasion could be critical in understanding host-pathogen dynamics. Additionally, this […]
- by Lee, S., Kim, J., Baek, J., Jung, K.-Y., Lee, Y., Koh, A., Kim, H.-J.BackgroundParkinsons disease (PD) is characterized by diverse clinical presentations and etiological complexities, with rapid eye movement (REM) sleep behavior disorder (RBD) serving as a prodromal marker. While extensive unbiased metabolic profiling of plasma samples from PD subjects has been conducted to identify novel PD metabolic biomarkers, comprehensive metabolic profiling of PD subtypes based on RBD status remains limited. MethodsWe conducted a comprehensive metabolic profiling of PD subtypes at disease onset, considering the presence or absence of RBD, utilizing an untargeted […]
- by Kabus, D., Cloet, M., Zemlin, C., Bernus, O., Dierckx, H.Ithildin is an open-source library and framework for efficient parallelized simulations of excitable media, written in the C++ programming language. It uses parallelization on multiple CPU processors via the message passing interface (MPI). We demonstrate the librarys versatility through a series of simulations in the context of the mono-domain description of cardiac electrophysiology, including the S1S2 protocol, spiral break-up, and spiral waves in ventricular geometry. Our work demonstrates the power of Ithildin as a tool for studying complex wave patterns […]
- by Omelchenko, A. A., Siwek, J. C., Chhibbar, P., Arshad, S., Nazarali, I., Nazarali, K., Rosengart, A., Rahimikollu, J., Tilstra, J., Shlomchik, M. J., Koes, D. R., Joglekar, A. V., Das, J.The explosion of sequence data has allowed the rapid growth of protein language models (pLMs). pLMs have now been employed in many frameworks including variant-effect and peptide-specificity prediction. Traditionally, for protein-protein or peptide-protein interactions (PPIs), corresponding sequences are either co-embedded followed by post-hoc integration or the sequences are concatenated prior to embedding. Interestingly, no method utilizes a language representation of the interaction itself. We developed an interaction LM (iLM), which uses a novel language to represent interactions between protein/peptide sequences. […]
- by Cross, C. E., Mayeda, C., Medina, S., Hayes, M. J., Kaviany, S., Connelly, J. A., Rathmell, J. C., Weaver, K. D., Thompson, R. C., Chambless, L. B., Ihrie, R. A., Irish, J. M.A key challenge for single cell discovery analysis is to identify new cell types, describe them quantitatively, and seek these novel cells in new studies often using a different platform. Over the last decade, tools were developed to address identification and quantitative description of cells in human tissues and tumors. However, automated validation of populations at the single cell level has struggled due to the cytometry fields reliance on hierarchical, ordered use of features and on platform-specific rules for data […]
- by Yavuz, B. R., Sahin, U., Jang, H., Nussinov, R., Tuncbag, N.Interrogation of big genomic data and integration with large-scale protein-protein interaction networks and pathways, can provide deep patterns that are rare- yet can prompt dramatic phenotypic alterations and serve as clinical signatures. Mapping cancer-specific co-occurring mutation-pair signatures, in primary and metastatic tumors, is indispensable in precision oncology. The additivity of co-occurring driver mutations in different genes (in trans) can lead to powerful proliferation signals. Co-occurring rare in trans combinations can serve as metastasis markers; excluded combinations may indicate candidates for […]
- by Thirman, H. L., Hayes, M. J., Brown, L. E., Porco, J. A., Irish, J. M.A central challenge in chemical biology is to distinguish molecular families in which small structural changes trigger large changes in cell biology. Such families might be ideal scaffolds for developing cell-selective chemical effectors – for example, molecules that activate DNA damage responses in malignant cells while sparing healthy cells. Across closely related structural variants, subtle structural changes have the potential to result in contrasting bioactivity patterns across different cell types. Here, we tested a 600-compound Diversity Set of screening molecules […]
- by Li, C., Wei, Y., Lei, J.Patients diagnosed with advanced metastatic colorectal cancer (mCRC) often exhibit heterogeneous disease progression and face poor survival prospects. In order to comprehensively analyze the varied treatment responses among individuals and the challenge of tumor recurrence resistant to drugs in advanced mRCR, we developed a novel quantitative cancer-immunity cycle (QCIC) model. The proposed model was meticulously crafted utilizing a blend of differential equations and randomized modeling techniques to quantitatively elucidate the intricate mechanisms governing the cancer-immunity cycle and forecast tumor dynamics […]
- by Winner, T. S., Rosenberg, M. C., Berman, G. J., Kesar, T. M., Ting, L. H.Understanding individuals distinct movement patterns is crucial for health, rehabilitation, and sports. Recently, we developed a machine learning-based framework to show that "gait signatures" describing the neuromechanical dynamics governing able-bodied and post-stroke gait kinematics remain individual-specific across speeds. However, we only evaluated gait signatures within a limited speed range and number of participants, using only sagittal plane (i.e., 2D) joint angles. Here we characterized changes in gait signatures across a wide range of speeds, from very slow (0.3 m/s) to […]
- by Turner, B., Fiksel, G., Subbotin, V. M.Previously, we presented a hypothesis on the Darwinian evolution of liposomes that relies only on natural and ever-present phenomena: solar UV radiation, day/night cycle, gravity, and the formation of amphiphiles, e.g., fatty acids and phospholipids, in aqueous media. The hypothesis further suggests that liposomes, formed at the air-water interface, will be inevitably destroyed by Sun UV unless they are submerged and shielded by primordial water. The hypothesis makes two testable predictions. First, certain ingredients of the Archean waters, e.g., ferric […]
- by McCreery, C. V., Alessi, D., Mollo, K., Fasano, A., Zomorrodi, A. R.Celiac Disease (CeD) is an autoimmune condition characterized by an aberrant immune response triggered by the ingestion of gluten, which damages epithelial cells lining the small intestine. Small intestinal epithelial cells (sIECs) play a key role in various metabolic processes, including the enzymatic digestion and absorption of nutrients. Although nutritional malabsorption is widely recognized in CeD, the underlying disrupted metabolic processes remain largely undefined. To address this knowledge gap, we constructed personalized gender-specific genome-scale models of sIEC metabolism using transcriptional […]
- by Wang, Z., Zhu, J., Xu, M., Ma, X., Shen, M., Yan, J., Gan, G., Zhou, X.The incidence of post-cardiac arrest myocardial dysfunction (PAMD) is high, and there is currently no effective treatment available. This study aims to investigate the protective effects of exogenous mitochondrial transplantation. Exogenous mitochondrial transplantation can enhance myocardial function and improve the survival rate. Mechanistic studies suggest that mitochondrial transplantation can limit impairment in mitochondrial morphology, augment the activity of mitochondrial complexes II and IV, and raise ATP levels. As well, mitochondrial therapy ameliorated oxidative stress imbalance, reduced myocardial injury, and thus […]
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