Nature. 2024 Aug 13. doi: 10.1038/s41586-024-07907-x. Online ahead of print.

ABSTRACT

In systemic lupus erythematosus (SLE) loss of immune tolerance, autoantibody production and immune complex deposition are required but not sufficient for organ damage1. How inflammatory signals are initiated and amplified in the setting of autoimmunity remains elusive. Here, we set out to dissect layers and hierarchies of autoimmune kidney inflammation in order to identify tissue-specific cellular hubs that amplify auto-inflammatory responses. Using high-resolution single-cell profiling of kidney immune and parenchymal cells, in combination with antibody blocking and genetic deficiency, we show that tissue-resident NKp46+ innate lymphoid cells (ILC) are crucial signal amplifiers of disease-associated macrophage expansion and epithelial cell injury in lupus nephritis, downstream of autoantibody production. NKp46 signaling in a distinct subset of ILC1 instructed an unconventional immune-regulatory transcriptional program, which included the expression of the myeloid cell growth factor CSF2. CSF2 production by NKp46+ ILC promoted the population expansion of monocyte-derived macrophages. Blockade of the NKp46 receptor (using the antibody mNCR1.152) or genetic deficiency of NKp46 abrogated epithelial cell injury. The same cellular and molecular patterns were operative in human lupus nephritis. Our data support that NKp46+ ILC1 promote parenchymal cell injury by granting monocyte-derived macrophages access to epithelial cell niches. NKp46 activation in ILC1 thus constitutes a previously unrecognized, critical tissue rheostat that amplifies organ damage in autoimmune hosts, with broad implications for inflammatory pathologies and therapies.

PMID:39137897 | DOI:10.1038/s41586-024-07907-x

Dev Cell. 2024 Aug 8:S1534-5807(24)00456-8. doi: 10.1016/j.devcel.2024.07.016. Online ahead of print.

ABSTRACT

Formation of fluid-filled lumina by epithelial tissues is essential for organ development. How cells control the hydraulic and cortical forces to control lumen morphology is not well understood. Here, we quantified the mechanical role of tight junctions in lumen formation using MDCK-II cysts. We found that the paracellular ion barrier formed by claudin receptors is not required for the hydraulic inflation of a lumen. However, the depletion of the zonula occludens scaffold resulted in lumen collapse and folding of apical membranes. Combining quantitative measurements of hydrostatic lumen pressure and junctional tension with modeling enabled us to explain lumen morphologies from the pressure-tension force balance. Tight junctions promote lumen inflation by decreasing cortical tension via the inhibition of myosin. In addition, our results suggest that excess apical area contributes to lumen opening. Overall, we provide a mechanical understanding of how epithelial cells use tight junctions to modulate tissue and lumen shape.

PMID:39137775 | DOI:10.1016/j.devcel.2024.07.016

Am J Physiol Lung Cell Mol Physiol. 2024 Aug 13. doi: 10.1152/ajplung.00166.2024. Online ahead of print.

ABSTRACT

Integrative multiomics can help elucidate the pathophysiology of pulmonary fibrosis (PF) associated pulmonary hypertension (PH) (PF-PH). Weighted gene co-expression network analysis (WGCNA) was performed on a transcriptomic dataset of explanted lung tissue from 116 patients with PF. Patients were stratified by pulmonary vascular resistance (PVR) and differential gene expression analysis was conducted. Gene modules were correlated with hemodynamics at the time of transplantation and tested for enrichment in the lung transcriptomics signature of an independent pulmonary arterial hypertension (PAH) cohort. We found 1,250 differentially expressed genes between high and low PVR groups. WGCNA identified that black and yellowgreen modules negatively correlated with PVR, while the tan and darkgrey modules positively correlated with PVR. Additionally, the tan module showed the strongest enrichment for an independent PAH gene signature, suggesting shared gene expression patterns between PAH and PF-PH. Pharmacotranscriptomic analysis using the Connectivity Map implicated the tan and darkgrey modules as potentially pathogenic in PF-PH, given their combined module signature demonstrated a high negative connectivity score for Treprostinil, a medication used in the treatment of PF-PH, and a high positive connectivity score for Bone morphogenetic protein loss of function. Pathway enrichment analysis revealed that inflammatory pathways and oxidative phosphorylation were downregulated, whereas epithelial mesenchymal transition was upregulated in modules associated with increased PVR. Our integrative systems biology approach to the lung transcriptome of PF with and without PH identified several PH-associated co-expression modules and gene targets with shared molecular features with PAH warranting further investigation to uncover potential new therapies for PF-PH.

PMID:39137526 | DOI:10.1152/ajplung.00166.2024

Arch Toxicol. 2024 Aug 13. doi: 10.1007/s00204-024-03836-w. Online ahead of print.

ABSTRACT

Despite extensive research on the metabolism of polychlorinated biphenyls (PCBs), knowledge gaps persist regarding their isoform-specific biotransformation pathways. This study aimed to elucidate the role of different cytochrome P450 enzymes in PCB metabolism, focusing on WHO-congeners 2,4,4'-trichlorobiphenyl (PCB28), 2,2',5,5'-tetrachlorobiphenyl (PCB52), and 2,2',4,5,5'-pentachlorobiphenyl (PCB101). Utilizing engineered HEK293 cell lines, we investigated the in vitro metabolism of these PCBs by CYP1A2, CYP2C8, CYP2C9, CYP3A4, CYP2A6, and CYP2E1, revealing robust production of hydroxylated metabolites. Our results show that CYP2A6 plays a major role in the metabolism of these congeners responsible for predominant formation of para-position hydroxylated metabolites, with concentrations reaching up to 1.61 µg/L (5,89 nM) for PCB28, 316.98 µg/L (1,03 µM) for PCB52, and 151.1 µg/L (441 nM) for PCB101 from a 20 µM parent PCB concentration. Moreover, concentration-dependent cytotoxic and cytostatic effects induced by reactive intermediates of the PCB hydroxylation pathway were observed in HEK293CYP2A6 cells, for all three congeners tested. CYP2A6 was specifically capable of activating PCBs 28 and 101 to genotoxic metabolites which produced genetic defects which were propagated to subsequent generations, potentially contributing to carcinogenesis. In a clinical study examining CYP2A6 enzyme activity in formerly exposed individuals with elevated internal PCB levels, a participant with increased enzyme activity showed a direct association between the phenotypic activity of CYP2A6 and the metabolism of PCB28, confirming the role of CYP2A6 in the in vivo metabolism of PCB28 also in humans. These results altogether reinforce the concept that CYP2A6 plays a pivotal role in PCB congener metabolism and suggest its significance in human health, particularly in the metabolism of lower chlorinated, volatile PCB congeners.

PMID:39136732 | DOI:10.1007/s00204-024-03836-w

Front Immunol. 2024 Jul 29;15:1408173. doi: 10.3389/fimmu.2024.1408173. eCollection 2024.

ABSTRACT

INTRODUCTION: The human leukocyte antigen complex (HLA) is essential for inducing specific immune responses to cancer by presenting tumor-associated peptides (TAP) to T cells. Overexpressed tumor associated antigens, mainly cancer-testis antigens (CTA), are outlined as essential targets for immunotherapy in oropharyngeal squamous cell carcinoma (OPSCC). This study assessed the degree to which presentation, gene expression, and antibody response (AR) of TAP, mainly CTA, are correlated in OPSCC patients to evaluate their potential as immunotherapy targets.

MATERIALS AND METHODS: Snap-frozen tumor (NLigand/RNA=40), healthy mucosa (NRNA=6), and healthy tonsils (NLigand=5) samples were obtained. RNA-Seq was performed using Illumina HiSeq 2500/NovaSeq 6000 and whole exome sequencing (WES) utilizing NextSeq500. HLA ligands were isolated from tumor tissue using immunoaffinity purification, UHPLC, and analyzed by tandem MS. Antibodies were measured in serum (NAb=27) utilizing the KREX™ CT262 protein array. Data analysis focused on 312 proteins (KREX™ CT262 panel + overexpressed self-proteins).

RESULTS: 183 and 94 of HLA class I and II TAP were identified by comparative profiling with healthy tonsils. Genes from 26 TAP were overexpressed in tumors compared to healthy mucosa (LFC>1; FDR<0.05). Low concordance (r=0.25; p<0.0001) was found between upregulated mRNA and class I TAP. The specific mode of correlation of TAP was found to be dependent on clinical parameters. A lack of correlation was observed both between mRNA and class II TAP, as well as between class II tumor-unique TAP (TAP-U) presentation and antibody response (AR) levels.

DISCUSSION: This study demonstrates that focusing exclusively on gene transcript levels fails to capture the full extent of TAP presentation in OPSCC. Furthermore, our findings reveal that although CTA are presented at relatively low levels, a few CTA TAP-U show potential as targets for immunotherapy.

PMID:39136024 | PMC:PMC11317303 | DOI:10.3389/fimmu.2024.1408173

Front Immunol. 2024 Jul 29;15:1425906. doi: 10.3389/fimmu.2024.1425906. eCollection 2024.

ABSTRACT

BACKGROUND AND AIMS: Allergic asthma has a considerable burden on the quality of life. A significant portion of moderate-to-severe allergic asthma patients need omalizumab, an anti-immunoglobulin-E monoclonal antibody, as an add-on therapy. In this phase III clinical trial P043 (Zerafil®, CinnaGen, Iran) efficacy, safety, and immunogenicity were compared with Xolair® (the originator omalizumab). The primary outcome was the rate of protocol-defined asthma exacerbations.

METHODS: Exacerbation rates, Asthma Control Test (ACT) results, spirometry measurements, immunogenicity, and safety were evaluated. Each subject received either medication with a dose ranging from 150 to 375 mg based on pre-treatment serum total IgE level (IU/mL) and body weight (kg) every two or four weeks for a duration of 28 weeks.

RESULTS: Exacerbation rates were 0.150 (CI: 0.079-0.220) in the P043 group, and 0.190 (CI: 0.110-0.270) in the omalizumab group (per-protocol). The least squares mean differences of predicted Forced Expiratory Volume in the First second (FEV1) were -2.51% (CI: -7.17-2.15, P=0.29) and -3.87% (CI: -8.79-1.04, P=0.12), pre- and post-bronchodilator use. The mean ± SD of ACT scores at the screening and the last visit were 10.62 ± 2.93 and 20.93 ± 4.26 in P043 and 11.09 ± 2.75 and 20.46 ± 5.11 in the omalizumab group. A total of 288 adverse events were reported for the 256 enrolled participants. Among all, "dyspnea" and "headache" were the most reported ones. The overall incidence of adverse events (P=0.62) and serious adverse events (P=0.07) had no significant differences between the two groups. None of the samples were positive for anti-drug antibodies.

CONCLUSION: P043 was equivalent to omalizumab in the management of asthma in reduction of exacerbations. There was no significant difference in other efficacy and safety parameters.

CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (NCT05813470) and www.IRCT.ir (IRCT20150303021315N20).

PMID:39136011 | PMC:PMC11317399 | DOI:10.3389/fimmu.2024.1425906

Ecol Evol. 2024 Aug 12;14(8):e70123. doi: 10.1002/ece3.70123. eCollection 2024 Aug.

ABSTRACT

The equilibrium of sex ratios in sexually reproducing species is often disrupted by various environmental and genetic factors, including endosymbionts like Wolbachia. In this study, we explore the highly female-biased sex ratio observed in the flea beetle, Altica lythri, and its underlying mechanisms. Ancient hybridization events between Altica species have led to mitochondrial DNA introgression, resulting in distinct mitochondrial haplotypes that go along with different Wolbachia infections (HT1-wLytA1, HT1*- uninfected, HT2-wLytA2, and HT3-wLytB). Notably, beetles with some haplotypes exclusively produce female offspring, suggesting potential Wolbachia-induced phenomena such as feminization of genetic males. However, the observed female bias could also be a consequence of the ancient hybridization resulting in nuclear-cytoplasmic conflicts between introgressed mtDNA and nuclear genes. Through transcriptomic analysis and the program SEX-DETector, we established markers for genotypic sex differentiation for A. lythri, enabling genetic sexing via qPCR. Our findings suggest that feminization of genetic males is contributing to the skewed sex ratios, highlighting the intricate dynamics of sex determination and reproductive strategies in this flea beetle. This study provides valuable insights into the dynamics of genetic conflicts, endosymbionts, and sex ratios, revealing the novel phenomenon of genetic male feminization in the flea beetle A. lythri.

PMID:39135725 | PMC:PMC11318108 | DOI:10.1002/ece3.70123

Imeta. 2024 Jun 25;3(4):e218. doi: 10.1002/imt2.218. eCollection 2024 Aug.

ABSTRACT

The MASS cohort comprises 2000 ICU patients with severe pneumonia, covering community-acquired pneumonia, hospital-acquired pneumonia, and ventilator-associated pneumonia, sourced from 19 hospitals across 10 cities in three provinces. A wide array of samples including bronchoalveolar lavage fluid, sputum, feces, and whole blood are longitudinally collected throughout patients' ICU stays. The cohort study seeks to uncover the dynamics of lung and gut microbiomes and their associations with severe pneumonia and host susceptibility, integrating deep metagenomics and transcriptomics with detailed clinical data.

PMID:39135692 | PMC:PMC11316923 | DOI:10.1002/imt2.218

Imeta. 2024 Jun 12;3(4):e211. doi: 10.1002/imt2.211. eCollection 2024 Aug.

ABSTRACT

The life cycle of genome builds spans interlocking pillars of assembly, annotation, and comparative genomics to drive biological insights. While tools exist to address each pillar separately, there is a growing need for tools to integrate different pillars of a genome project holistically. For example, comparative approaches can provide quality control of assembly or annotation; genome assembly, in turn, can help to identify artifacts that may complicate the interpretation of genome comparisons. The JCVI library is a versatile Python-based library that offers a suite of tools that excel across these pillars. Featuring a modular design, the JCVI library provides high-level utilities for tasks such as format parsing, graphics generation, and manipulation of genome assemblies and annotations. Supporting genomics algorithms like MCscan and ALLMAPS are widely employed in building genome releases, producing publication-ready figures for quality assessment and evolutionary inference. Developed and maintained collaboratively, the JCVI library emphasizes quality and reusability.

PMID:39135687 | PMC:PMC11316928 | DOI:10.1002/imt2.211

Imeta. 2024 Jun 12;3(4):e212. doi: 10.1002/imt2.212. eCollection 2024 Aug.

ABSTRACT

We analyzed eight oral microbiota shotgun metagenomic sequencing cohorts from five countries and three continents, identifying 54 species biomarkers and 26 metabolic biomarkers consistently altered in health and disease states across three or more cohorts. Additionally, machine learning models based on taxonomic profiles achieved high accuracy in distinguishing periodontitis patients from controls (internal and external areas under the receiver operating characteristic curves of 0.86 and 0.85, respectively). These results support metagenome-based diagnosis of periodontitis and provide a foundation for further research and effective treatment strategies.

PMID:39135686 | PMC:PMC11316925 | DOI:10.1002/imt2.212

Am J Primatol. 2024 Aug 12:e23673. doi: 10.1002/ajp.23673. Online ahead of print.

ABSTRACT

The study of how animals adapt their behaviors depending on weather variables has gained particular significance in the context of climate change. This exploration offers insights into endangered species' potential threats and provides information on the direction to take in conservation activities. In this context, noninvasive, cost-effective, and potentially long-term monitoring systems, such as Passive Acoustic Monitoring (PAM), become particularly appropriate. Our study investigates the relationship between weather variables and the vocal behavior of Indri indri, the sole singing lemur species, within Madagascar's Maromizaha New Protected Area. Using PAM, we explore the factors shaping the vocalization patterns of this primate species in response to some environmental factors in their natural habitat. Analysis of an extensive audio data set collected across different years revealed the differential influence of temperature and precipitation on Indri indri vocal activity. We found that rainfall negatively influenced the emission of the vocalizations while warmer temperatures correlated with a greater emission of songs. The various environmental factors we considered also affected the timing of vocal emissions, showing the same pattern. Furthermore, our study confirms, once again, the strength of PAM as a valuable tool for studying vocal animal communication quickly, giving us information about long-term behavioral patterns that would be difficult to get in other ways. This research gives us further valuable information about how indris use vocalizations in their environment and how they adjust to environmental changes.

PMID:39135345 | DOI:10.1002/ajp.23673

bioRxiv [Preprint]. 2024 Jul 29:2024.07.28.604841. doi: 10.1101/2024.07.28.604841.

ABSTRACT

Cellular desiccation - the loss of nearly all water from the cell - is a recurring stress in an increasing number of ecosystems that can drive proteome-wide protein unfolding and aggregation. For cells to survive this stress, at least some of the proteome must disaggregate and resume function upon rehydration. The molecular determinants that underlie the ability of proteins to do this remain largely unknown. Here, we apply quantitative and structural proteomic mass spectrometry to desiccated and rehydrated yeast extracts to show that some proteins possess an innate capacity to survive extreme water loss. Structural analysis correlates the ability of proteins to resist desiccation with their surface chemistry. Remarkably, highly resistant proteins are responsible for the production of the cell's building blocks - amino acids, metabolites, and sugars. Conversely, those proteins that are most desiccation-sensitive are involved in ribosome biogenesis and other energy consuming processes. As a result, the rehydrated proteome is preferentially enriched with metabolite and small molecule producers and depleted of some of the cell's heaviest consumers. We propose this functional bias enables cells to kickstart their metabolism and promote cell survival following desiccation and rehydration.

PMID:39131385 | PMC:PMC11312438 | DOI:10.1101/2024.07.28.604841

bioRxiv [Preprint]. 2024 Jul 29:2024.07.28.605011. doi: 10.1101/2024.07.28.605011.

ABSTRACT

The three-dimensional structure of chromatin has emerged as an important feature of eukaryotic gene regulation. Recent technological advances in DNA sequencing-based assays have revealed locus- and chromatin state-specific structural patterns at the length scale of a few nucleosomes (~1 kb). However, interpreting these data sets remains challenging. Radiation-induced correlated cleavage of chromatin (RICC-seq) is one such chromatin structure assay that maps DNA-DNA-contacts at base pair resolution by sequencing single-stranded DNA fragments released from irradiated cells. Here, we develop a flexible modeling and simulation framework to enable the interpretation of RICC-seq data in terms of oligonucleosome structure ensembles. Nucleosomes are modeled as rigid bodies with excluded volume and adjustable DNA wrapping, connected by linker DNA modeled as a worm-like chain. We validate the model's parameters against cryo-electron microscopy and sedimentation data. Our results show that RICC-seq is sensitive to nucleosome spacing, nucleosomal DNA wrapping, and the strength of inter-nucleosome interactions. We show that nucleosome repeat lengths consistent with orthogonal assays can be extracted from experimental RICC-seq data using a 1D convolutional neural net trained on RICC-seq signal predicted from simulated ensembles. We thus provide a suite of analysis tools that add quantitative structural interpretability to RICC-seq experiments.

PMID:39131347 | PMC:PMC11312488 | DOI:10.1101/2024.07.28.605011

Mol Syst Biol. 2024 Aug 12. doi: 10.1038/s44320-024-00060-7. Online ahead of print.

ABSTRACT

Genome-scale metabolic models (GEMs) can facilitate metabolism-focused multi-omics integrative analysis. Since Yeast8, the yeast-GEM of Saccharomyces cerevisiae, published in 2019, has been continuously updated by the community. This has increased the quality and scope of the model, culminating now in Yeast9. To evaluate its predictive performance, we generated 163 condition-specific GEMs constrained by single-cell transcriptomics from osmotic pressure or reference conditions. Comparative flux analysis showed that yeast adapting to high osmotic pressure benefits from upregulating fluxes through central carbon metabolism. Furthermore, combining Yeast9 with proteomics revealed metabolic rewiring underlying its preference for nitrogen sources. Lastly, we created strain-specific GEMs (ssGEMs) constrained by transcriptomics for 1229 mutant strains. Well able to predict the strains' growth rates, fluxomics from those large-scale ssGEMs outperformed transcriptomics in predicting functional categories for all studied genes in machine learning models. Based on those findings we anticipate that Yeast9 will continue to empower systems biology studies of yeast metabolism.

PMID:39134886 | DOI:10.1038/s44320-024-00060-7

NPJ Digit Med. 2024 Aug 12;7(1):207. doi: 10.1038/s41746-024-01183-9.

ABSTRACT

In the United States, normal-risk pregnancies are monitored with the recommended average of 14 prenatal visits. Check-ins every few weeks are the standard of care. This low time resolution and reliance on subjective feedback instead of direct physiological measurement, could be augmented by remote monitoring. To date, continuous physiological measurements have not been characterized across all of pregnancy, so there is little basis of comparison to support the development of the specific monitoring capabilities. Wearables have been shown to enable the detection and prediction of acute illness, often faster than subjective symptom reporting. Wearables have also been used for years to monitor chronic conditions, such as continuous glucose monitors. Here we perform a retrospective analysis on multimodal wearable device data (Oura Ring) generated across pregnancy within 120 individuals. These data reveal clear trajectories of pregnancy from cycling to conception through postpartum recovery. We assessed individuals in whom pregnancy did not progress past the first trimester, and found associated deviations, corroborating that continuous monitoring adds new information that could support decision-making even in the early stages of pregnancy. By contrast, we did not find significant deviations between full-term pregnancies of people younger than 35 and of people with "advanced maternal age", suggesting that analysis of continuous data within individuals can augment risk assessment beyond standard population comparisons. Our findings demonstrate that low-cost, high-resolution monitoring at all stages of pregnancy in real-world settings is feasible and that many studies into specific demographics, risks, etc., could be carried out using this newer technology.

PMID:39134787 | DOI:10.1038/s41746-024-01183-9

Nat Plants. 2024 Aug 12. doi: 10.1038/s41477-024-01742-8. Online ahead of print.

ABSTRACT

Biological membranes play a crucial role in actively hosting, modulating and coordinating a wide range of molecular events essential for cellular function. Membranes are organized into diverse domains giving rise to dynamic molecular patchworks. However, the very definition of membrane domains has been the subject of continuous debate. For example, in the plant field, membrane domains are often referred to as nanodomains, nanoclusters, microdomains, lipid rafts, membrane rafts, signalling platforms, foci or liquid-ordered membranes without any clear rationale. In the context of plant-microbe interactions, microdomains have sometimes been used to refer to the large area at the plant-microbe interface. Some of these terms have partially overlapping meanings at best, but they are often used interchangeably in the literature. This situation generates much confusion and limits conceptual progress. There is thus an urgent need for us as a scientific community to resolve these semantic and conceptual controversies by defining an unambiguous nomenclature of membrane domains. In this Review, experts in the field get together to provide explicit definitions of plasma membrane domains in plant systems and experimental guidelines for their study. We propose that plasma membrane domains should not be considered on the basis of their size alone but rather according to the biological system being considered, such as the local membrane environment or the entire cell.

PMID:39134664 | DOI:10.1038/s41477-024-01742-8

Nat Mater. 2024 Aug 12. doi: 10.1038/s41563-024-01972-3. Online ahead of print.

ABSTRACT

Jamming of cell collectives and associated rigidity transitions have been shown to play a key role in tissue dynamics, structure and morphogenesis. Cellular jamming is controlled by cellular density and the mechanics of cell-cell contacts. However, the contribution of subcellular organelles to the physical state of the emergent tissue is unclear. Here we report a nuclear jamming transition in zebrafish retina and brain tissues, where physical interactions between highly packed nuclei restrict cellular movements and control tissue mechanics and architecture. Computational modelling suggests that the nuclear volume fraction and anisotropy of cells control the emerging tissue physical state. Analysis of tissue architecture, mechanics and nuclear movements during eye development show that retina tissues undergo a nuclear jamming transition as they form, with increasing nuclear packing leading to more ordered cellular arrangements, reminiscent of the crystalline cellular packings in the functional adult eye. Our results reveal an important role of the cell nucleus in tissue mechanics and architecture.

PMID:39134649 | DOI:10.1038/s41563-024-01972-3

Commun Biol. 2024 Aug 12;7(1):977. doi: 10.1038/s42003-024-06564-0.

ABSTRACT

A universal coordinate system that can ensemble the huge number of cells and capture their heterogeneities is of vital importance for constructing large-scale cell atlases as references for molecular and cellular studies. Studies have shown that cells exhibit multifaceted heterogeneities in their transcriptomic features at multiple resolutions. This nature of complexity makes it hard to design a fixed coordinate system through a combination of known features. It is desirable to build a learnable universal coordinate model that can capture major heterogeneities and serve as a controlled generative model for data augmentation. We developed UniCoord, a specially-tuned joint-VAE model to represent single-cell transcriptomic data in a lower-dimensional latent space with high interpretability. Each latent dimension can represent either discrete or continuous feature, and either supervised by prior knowledge or unsupervised. The latent dimensions can be easily reconfigured to generate pseudo transcriptomic profiles with desired properties. UniCoord can also be used as a pre-trained model to analyze new data with unseen cell types and thus can serve as a feasible framework for cell annotation and comparison. UniCoord provides a prototype for a learnable universal coordinate framework to enable better analysis and generation of cells with highly orchestrated functions and heterogeneities.

PMID:39134617 | DOI:10.1038/s42003-024-06564-0

Sci Rep. 2024 Aug 12;14(1):18666. doi: 10.1038/s41598-024-69705-9.

ABSTRACT

Brain cancer is one of the deadliest diseases, although many efforts have been made to treat it, there is no comprehensive and effective treatment approach yet. In recent years, the use of network-based analysis to identify important biological genes and pathways involved in various complex diseases, including brain cancer, has attracted the attention of researchers. The goal of this manuscript is to perform a comprehensive analysis of the various results presented related to brain cancer. For this purpose, firstly, based on the CORMINE medical database, collected all the genes related to brain cancer with a valid P-value. Then the structural and functional relationships between the above gene sets have been identified based on the STRING database. Next, in the PPI network, hub centrality analysis was performed to determine the proteins that have many connections with other proteins. After the modularization of the network, the module with the most hub vertices is considered as the most relevant module to the formation and progression of brain cancer. Since the driver vertices play an important role in biological systems, the edges of the selected module were oriented, and by analyzing the controllability of complex networks, a set of five proteins with the highest control power has been identified. Finally, based on the drug-gene interaction, a set of drugs effective on each of the driver genes has been obtained, which can potentially be used as new combination drugs. Validation of the hub and driver proteins shows that they are mainly essential proteins in the biological processes related to the various cancers and therefore the drugs that affect them can be considered as new combination therapy. The presented procedure can be used for any other complex disease.

PMID:39134610 | DOI:10.1038/s41598-024-69705-9

NPJ Syst Biol Appl. 2024 Aug 12;10(1):87. doi: 10.1038/s41540-024-00411-y.

ABSTRACT

Network controllability is unifying the traditional control theory with the structural network information rooted in many large-scale biological systems of interest, from intracellular networks in molecular biology to brain neuronal networks. In controllability approaches, the set of minimum driver nodes is not unique, and critical nodes are the most important control elements because they appear in all possible solution sets. On the other hand, a common but largely unexplored feature in network control approaches is the probabilistic failure of edges or the uncertainty in the determination of interactions between molecules. This is particularly true when directed probabilistic interactions are considered. Until now, no efficient algorithm existed to determine critical nodes in probabilistic directed networks. Here we present a probabilistic control model based on a minimum dominating set framework that integrates the probabilistic nature of directed edges between molecules and determines the critical control nodes that drive the entire network functionality. The proposed algorithm, combined with the developed mathematical tools, offers practical efficiency in determining critical control nodes in large probabilistic networks. The method is then applied to the human intracellular signal transduction network revealing that critical control nodes are associated with important biological features and perturbed sets of genes in human diseases, including SARS-CoV-2 target proteins and rare disorders. We believe that the proposed methodology can be useful to investigate multiple biological systems in which directed edges are probabilistic in nature, both in natural systems or when determined with large uncertainties in-silico.

PMID:39134558 | DOI:10.1038/s41540-024-00411-y