Humanit Soc Sci Commun. 2024;11(1):351. doi: 10.1057/s41599-024-02797-w. Epub 2024 Mar 2.

ABSTRACT

Consequential STEM experiences in informal settings can address issues of equity by fully engaging historically marginalized high school students in complex socio-scientific issues. However, inclusive and effective programs are in high demand, and there is little research on what specific aspects, context, and timeframes are most important when scaling these experiences. Using a mixed method approach, this study demonstrates that students make significant gains, in the short and long term, through in-person and remote informal programs ranging between 22-h and 320-h. Progress across STEM learning constructs is attributed to authentic research experiences, students' connections to STEM professionals, direct hands-on participation in projects, and group work. Relative to formal education settings, research-based informal STEM programs can be implemented with minimal resources, can maintain effectiveness while scaling, and work towards addressing the societal challenge of improving STEM learning and outcomes for high school students from historically marginalized communities.

PMID:39035098 | PMC:PMC11259043 | DOI:10.1057/s41599-024-02797-w

Sci Total Environ. 2024 Jul 19:174868. doi: 10.1016/j.scitotenv.2024.174868. Online ahead of print.

ABSTRACT

Passive Acoustic Monitoring (PAM), which involves using autonomous record units for studying wildlife behaviour and distribution, often requires handling big acoustic datasets collected over extended periods. While these data offer invaluable insights about wildlife, their analysis can present challenges in dealing with geophonic sources. A major issue in the process of detection of target sounds is represented by wind-induced noise. This can lead to false positive detections, i.e., energy peaks due to wind gusts misclassified as biological sounds, or false negative, i.e., the wind noise masks the presence of biological sounds. Acoustic data dominated by wind noise makes the analysis of vocal activity unreliable, thus compromising the detection of target sounds and, subsequently, the interpretation of the results. Our work introduces a straightforward approach for detecting recordings affected by windy events using a pre-trained convolutional neural network. This process facilitates identifying wind-compromised data. We consider this dataset pre-processing crucial for ensuring the reliable use of PAM data. We implemented this preprocessing by leveraging YAMNet, a deep learning model for sound classification tasks. We evaluated YAMNet as-is ability to detect wind-induced noise and tested its performance in a Transfer Learning scenario by using our annotated data from the Stony Point Penguin Colony in South Africa. While the classification of YAMNet as-is achieved a precision of 0.71, and recall of 0.66, those metrics strongly improved after the training on our annotated dataset, reaching a precision of 0.91, and recall of 0.92, corresponding to a relative increment of >28 %. Our study demonstrates the promising application of YAMNet in the bioacoustics and ecoacoustics fields, addressing the need for wind-noise-free acoustic data. We released an open-access code that, combined with the efficiency and peak performance of YAMNet, can be used on standard laptops for a broad user base.

PMID:39034006 | DOI:10.1016/j.scitotenv.2024.174868

Biosystems. 2024 Jul 19:105272. doi: 10.1016/j.biosystems.2024.105272. Online ahead of print.

ABSTRACT

As development varies greatly across the tree of life, it may seem difficult to suggest a model that proposes a single mechanism for understanding collective cell behaviors and the coordination of tissue formation. Here we propose a mechanism called differentiation waves, which unify many disparate results involving developmental systems from across the tree of life. We demonstrate how a relatively simple model of differentiation proceeds not from function-related molecular mechanisms, but from so-called differentiation waves. A phenotypic model of differentiation waves is introduced, and its relation to molecular mechanisms is proposed. These waves contribute to a differentiation tree, which is an alternate way of viewing cell lineage and local action of the molecular factors. We construct a model of differentiation wave-related molecular mechanisms (genome, epigenome, and proteome) based on bioinformatic data from the nematode Caenorhabditis elegans. To validate this approach across different modes of development, we evaluate protein expression across different types of development by comparing Caenorhabditis elegans with several model organisms: fruit flies (Drosophila melanogaster), yeast (Saccharomyces cerevisiae), and mouse (Mus musculus). Inspired by gene regulatory networks, two Models of Interactive Contributions (fully-connected MICs and ordered MICs) are used to suggest potential genomic contributions to differentiation wave-related proteins. This, in turn, provides a framework for understanding differentiation and development.

PMID:39033973 | DOI:10.1016/j.biosystems.2024.105272

Ticks Tick Borne Dis. 2024 Jul 20;15(6):102379. doi: 10.1016/j.ttbdis.2024.102379. Online ahead of print.

ABSTRACT

Ixodes scapularis, the black-legged tick, is a major arthropod vector that transmits the causative agents of Lyme disease and several other pathogens of human significance. The tick midgut is the main tissue involved in blood acquisition and digestion and the first organ to have contact with pathogens ingested through the blood meal. Gene expression in the midgut before, during, and after a blood meal may vary in response to the physiological changes due to blood feeding. A systems biology approach based on RNA and protein sequencing was used to gain insight into the changes in tick midgut transcripts and proteins during blood ingestion (unfed and partially fed) and digestion (1-, 2-, 7-, and 14 days post detachment from the host) by the Ixodes scapularis female ticks. A total of 2,726 differentially expressed transcripts, and 449 proteins were identified across the time points. Genes involved in detoxification of xenobiotics, proteases, protease inhibitors, metabolism, and immunity were differentially expressed in response to blood feeding. Similarly, proteins corresponding to the same groups were also differentially expressed. Nine genes from major gene categories were chosen as potential vaccine candidates, and, using RNA interference, the effect of these gene knockdowns on tick biology was investigated. Knockdown of these genes had variable negative impacts on tick physiology, such as the inability to engorge fully and to produce eggs and increased mortality. These and additional gene targets provide opportunities to explore novel tick control strategies.

PMID:39033644 | DOI:10.1016/j.ttbdis.2024.102379

Am J Reprod Immunol. 2024 Jul;92(1):e13905. doi: 10.1111/aji.13905.

ABSTRACT

PROBLEM: The vaginal microbiome has a substantial role in the occurrence of preterm birth (PTB), which contributes substantially to neonatal mortality worldwide. However, current bioinformatics approaches mostly concentrate on the taxonomic classification and functional profiling of the microbiome, limiting their abilities to elucidate the complex factors that contribute to PTB.

METHOD OF STUDY: A total of 3757 vaginal microbiome 16S rRNA samples were obtained from five publicly available datasets. The samples were divided into two categories based on pregnancy outcome: preterm birth (PTB) (N = 966) and term birth (N = 2791). Additionally, the samples were further categorized based on the participants' race and trimester. The 16S rRNA reads were subjected to taxonomic classification and functional profiling using the Parallel-META 3 software in Ubuntu environment. The obtained abundances were analyzed using an integrated systems biology and machine learning approach to determine the key microbes, pathways, and genes that contribute to PTB. The resulting features were further subjected to statistical analysis to identify the top nine features with the greatest effect sizes.

RESULTS: We identified nine significant features, namely Shuttleworthia, Megasphaera, Sneathia, proximal tubule bicarbonate reclamation pathway, systemic lupus erythematosus pathway, transcription machinery pathway, lepA gene, pepX gene, and rpoD gene. Their abundance variations were observed through the trimesters.

CONCLUSIONS: Vaginal infections caused by Shuttleworthia, Megasphaera, and Sneathia and altered small metabolite biosynthesis pathways such as lipopolysaccharide folate and retinal may increase the susceptibility to PTB. The identified organisms, genes, pathways, and their networks may be specifically targeted for the treatment of bacterial infections that increase PTB risk.

PMID:39033501 | DOI:10.1111/aji.13905

Gastric Cancer. 2024 Jul 20. doi: 10.1007/s10120-024-01537-y. Online ahead of print.

ABSTRACT

BACKGROUND: Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy.

METHODS: We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments.

RESULTS: Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib's off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR.

CONCLUSION: In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy.

PMID:39033209 | DOI:10.1007/s10120-024-01537-y

Sci Total Environ. 2024 Jul 18:174754. doi: 10.1016/j.scitotenv.2024.174754. Online ahead of print.

ABSTRACT

OBJECTIVE: Improved understanding of metabolic obesity phenotypes holds great promise for personalized strategies to combat obesity and its co-morbidities. Such investigation is however lacking in Tibetans with unique living environments and lifestyle in the highlands. Effects of altitude on heterogeneous metabolic obesity phenotypes remain unexplored.

METHODS: We defined metabolic obesity phenotypes i.e., metabolically healthy/unhealthy and obesity/normal weight in Tibetans (n = 1204) living at 2800 m in the suburb or over 4000 m in pastoral areas. 129 lipoprotein parameters and 25 low-molecular-weight metabolites were quantified and their associations with each phenotype were assessed using logistic regression models adjusting for potential confounders. The metabolic BMI (mBMI) was generated using a machine learning strategy and its relationship with prevalence of obesity co-morbidities and dietary exposures were investigated.

RESULTS: Ultrahigh altitude positively associated with the metabolically healthy and non-obese phenotype and had a tendency towards a negative association with metabolically unhealthy phenotype. Phenotype-specific associations were found for 107 metabolites (e.g., lipoprotein subclasses, N-acetyl-glycoproteins, amino acids, fatty acids and lactate, p < 0.05), among which 55 were manipulated by altitude. The mBMI showed consistent yet more pronounced associations with cardiometabolic outcomes than BMI. The ORs for diabetes, prediabetes and hypertriglyceridemia were reduced in individuals residing at ultrahigh altitude compared to those residing at high altitude. The mBMI mediated the negative association between pastoral diet and prevalence of prediabetes, hypertension and hypertriglyceridemia, respectively.

CONCLUSIONS: We found metabolite markers representing distinct obesity phenotypes associated with obesity co-morbidities and the modification effect of altitude, deciphering mechanisms underlying protective effect of ultrahigh altitude and the pastoral diet on metabolic health.

PMID:39032745 | DOI:10.1016/j.scitotenv.2024.174754

Chemosphere. 2024 Jul 18:142888. doi: 10.1016/j.chemosphere.2024.142888. Online ahead of print.

ABSTRACT

Glyphosate is the most widely used systemic herbicide. There is ample scientific literature on the effects of this compound and its metabolite aminomethylphosphonic acid (AMPA), whereas their possible combined genotoxic action has not yet been studied. With the present study, we aimed to determine the level of genomic damage caused by glyphosate and AMPA in cultured human lymphocytes and to investigate the possible genotoxic action when both compounds were present at the same concentrations in the cultures. We used a micronuclei assay to test the genotoxicity of glyphosate and AMPA at six concentrations (0.0125, 0.025, 0.050, 0.100, 0.250, 0.500 μg/mL), which are more realistic than the highest concentrations used in previous published studies. Our data showed an increase in micronuclei frequency after treatment with both glyphosate and AMPA starting from 0.050 μg/mL up to 0.500 μg/mL. Similarly, a genomic damage was observed also in the cultures treated with the same concentrations of both compounds, except for exposure to 0.0065 and 0.0125 μg/mL. No synergistic action was observed. Finally, a significant increase in apoptotic cells was observed in cultures treated with the highest concentration of tested xenobiotics, while a significant increase in necrotic cells was observed also at the concentration of 0.250 μg/mL of both glyphosate and AMPA alone and in combination (0.125+0.125 μg/mL). Results of our study indicate that both glyphosate and its metabolite AMPA are able to cause genomic damage in human lymphocyte cultures, both alone and when present in equal concentrations.

PMID:39032731 | DOI:10.1016/j.chemosphere.2024.142888

Am J Pathol. 2024 Jul 18:S0002-9440(24)00237-2. doi: 10.1016/j.ajpath.2024.06.006. Online ahead of print.

ABSTRACT

Hyponatremia and salt wasting is a common occurance in patients with HIV/AIDS, however, the understanding of its contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the distal tubules and on the expression level of the Slc12a3 gene, encoding the Na-Cl cotransporter, which is responsible for sodium reabsorption in distal nephron segments, single-nucleus RNA sequencing was performed on kidney cortices from three wild-type (WT) and three Vpr-transgenic (Vpr Tg) mice. The results showed that the percentage of distal convoluted tubule (DCT) cells was significantly lower in Vpr Tg mice compared with WT mice (P < 0.05), and that in Vpr Tg mice, Slc12a3 expression was not significantly different in DCT cells. The Pvalb+ DCT1 subcluster had fewer cells in Vpr Tg mice compared with WT mice (P < 0.01). Immunohistochemistry demonstrated fewer Slc12a3+Pvalb+ DCT1 segments in Vpr Tg mice. Differential gene expression analysis between Vpr Tg and WT in the DCT cluster showed downregulation of Ier3 gene, which is an inhibitor of apoptosis. The in vitro knockdown of Ier3 by siRNA transfection induced apoptosis in mouse DCT cells. These observations suggest that the salt-wasting effect of Vpr in Vpr Tg mice is likely mediated by Ier3 downregulation in DCT1 cells and loss of Slc12a3+Pvalb+ DCT1 segments.

PMID:39032602 | DOI:10.1016/j.ajpath.2024.06.006

Mol Cells. 2024 Jul 18:100095. doi: 10.1016/j.mocell.2024.100095. Online ahead of print.

ABSTRACT

Metabolic networks are fundamental to cellular processes, driving energy production, biosynthesis, redox regulation, and cellular signaling. Recent advancements in metabolic research tools have provided unprecedented insights into cellular metabolism. Among these tools, the extracellular flux analyzer stands out for its real-time measurement of key metabolic parameters: glycolysis, mitochondrial respiration, and fatty acid oxidation (FAO), leading to its widespread use. This review provides a comprehensive summary of the basic principles and workflow of the extracellular flux assay (the Seahorse assay) and its diverse applications. We highlight the assay's versatility across various biological models, including cancer cells, immunocytes, C. elegans, tissues, isolated mitochondria, and 3D structures like organoids, and summarize key considerations for using extracellular flux assay in these models. Additionally, we discuss the limitations of the Seahorse assay and propose future directions for its development. This review aims to enhance the understanding of extracellular flux assay and its significance in biological studies.

PMID:39032561 | DOI:10.1016/j.mocell.2024.100095

Phytomedicine. 2024 Jul 14;132:155879. doi: 10.1016/j.phymed.2024.155879. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary arterial hypertension (PAH) and the consequent right heart dysfunction persist with high morbidity and mortality, and the mechanisms and pharmacologic interventions for chronic right-sided heart failure (RHF) have not been adequately investigated. Research has shown that prolonged inflammation is critical in precipitating the progression of PAH-associated right heart pathology. Some research demonstrated that Lingguizhugan decoction (LGZGD), as a classical Chinese medicine formula, had beneficial effects in alleviating PAH and RHF, while its underlying mechanisms involved are not fully elucidated.

PURPOSE: Based on that, this study aims to investigate the effects and underlying mechanisms of LGZGD on PAH-induced RHF.

STUDY DESIGN: In this study, we identified the serum constituents and deciphered the potential anti-inflammatory mechanism and crucial components of LGZGD using combined approaches of UPLC-HRMS, transcriptomic analysis, and molecular docking techniques. Finally, we used in vivo experiments to verify the expression of key targets in the monocrotaline (MCT)-induced RHF model and the intervene effect of LGZGD.

RESULTS: Integrated strategies based on UPLC-HRMS and systems biology approach combined with in vivo experimental validation showed that LGZGD could improve right heart fibrosis and dysfunction via regulating diverse inflammatory signaling pathways and the activity of immune cells, including chemokine family CCL2, CXCR4, leukocyte integrins family ITGAL, ITGB2, and M2 macrophage infiltration, as well as lipid peroxidation-associated HMOX1, NOX4, and 4-HNE.

CONCLUSION: The present research demonstrated for the first time that LGZGD might improve PAH-induced RHF through multiple anti-inflammatory signaling and inhibition of ferroptosis, which could provide certain directions for future research in related fields.

PMID:39032277 | DOI:10.1016/j.phymed.2024.155879

Clin Transl Med. 2024 Jul;14(7):e1760. doi: 10.1002/ctm2.1760.

ABSTRACT

BACKGROUND: Cell-free long RNAs in human plasma and extracellular vesicles (EVs) have shown promise as biomarkers in liquid biopsy, despite their fragmented nature.

METHODS: To investigate these fragmented cell-free RNAs (cfRNAs), we developed a cost-effective cfRNA sequencing method called DETECTOR-seq (depletion-assisted multiplexed cell-free total RNA sequencing). DETECTOR-seq utilised a meticulously tailored set of customised guide RNAs to remove large amounts of unwanted RNAs (i.e., fragmented ribosomal and mitochondrial RNAs) in human plasma. Early barcoding strategy was implemented to reduce costs and minimise plasma requirements.

RESULTS: Using DETECTOR-seq, we conducted a comprehensive analysis of cell-free transcriptomes in both whole human plasma and EVs. Our analysis revealed discernible distributions of RNA types in plasma and EVs. Plasma exhibited pronounced enrichment in structured circular RNAs, tRNAs, Y RNAs and viral RNAs, while EVs showed enrichment in messenger RNAs (mRNAs) and signal recognition particle RNAs (srpRNAs). Functional pathway analysis highlighted RNA splicing-related ribonucleoproteins (RNPs) and antimicrobial humoral response genes in plasma, while EVs demonstrated enrichment in transcriptional activity, cell migration and antigen receptor-mediated immune signals. Our study indicates the comparable potential of cfRNAs from whole plasma and EVs in distinguishing cancer patients (i.e., colorectal and lung cancer) from healthy donors. And microbial cfRNAs in plasma showed potential in classifying specific cancer types.

CONCLUSIONS: Our comprehensive analysis of total and EV cfRNAs in paired plasma samples provides valuable insights for determining the need for EV purification in cfRNA-based studies. We envision the cost effectiveness and efficiency of DETECTOR-seq will empower transcriptome-wide investigations in the fields of cfRNAs and liquid biopsy.

KEYPOINTS: DETECTOR-seq (depletion-assisted multiplexed cell-free total RNA sequencing) enabled efficient and specific depletion of sequences derived from fragmented ribosomal and mitochondrial RNAs in plasma. Distinct human and microbial cell-free RNA (cfRNA) signatures in whole Plasma versus extracellular vesicles (EVs) were revealed. Both Plasma and EV cfRNAs were capable of distinguishing cancer patients from normal individuals, while microbial RNAs in Plasma cfRNAs enabled better classification of cancer types than EV cfRNAs.

PMID:39031987 | DOI:10.1002/ctm2.1760

Appl Microbiol Biotechnol. 2024 Jul 20;108(1):422. doi: 10.1007/s00253-024-13250-y.

ABSTRACT

Identifying the nutritional requirements and growth conditions of microorganisms is crucial for determining their applicability in industry and understanding their role in clinical ecology. Predatory bacteria such as Bdellovibrio bacteriovorus have emerged as promising tools for combating infections by human bacterial pathogens due to their natural killing features. Bdellovibrio's lifecycle occurs inside prey cells, using the cytoplasm as a source of nutrients and energy. However, this lifecycle supposes a challenge when determining the specific uptake of metabolites from the prey to complete the growth inside cells, a process that has not been completely elucidated. Here, following a model-based approach, we illuminate the ability of B. bacteriovorus to replicate DNA, increase biomass, and generate adenosine triphosphate (ATP) in an amino acid-based rich media in the absence of prey, keeping intact its predatory capacity. In this culture, we determined the main carbon sources used and their preference, being glutamate, serine, aspartate, isoleucine, and threonine. This study offers new insights into the role of predatory bacteria in natural environments and establishes the basis for developing new Bdellovibrio applications using appropriate metabolic and physiological methodologies. KEY POINTS: • Amino acids support axenic lifestyle of Bdellovibrio bacteriovorus. • B. bacteriovorus preserves its predatory ability when growing in the absence of prey.

PMID:39031211 | DOI:10.1007/s00253-024-13250-y

FEBS Open Bio. 2024 Jul 19. doi: 10.1002/2211-5463.13860. Online ahead of print.

ABSTRACT

Epithelial-to-mesenchymal transition (EMT) contributes to the poor prognosis of patients with cancer by promoting distant metastasis and anti-cancer drug resistance. Several distinct metabolic alterations have been identified as key EMT phenotypes. In the present study, we further characterize the role of transforming growth factor-β (TGF-β)-induced EMT in non-small-cell lung cancer. Our study revealed that TGF-β plays a role in EMT functions by upregulation of cytidine 5'-triphosphate synthetase 1 (CTPS), a vital enzyme for CTP biosynthesis in the pyrimidine metabolic pathway. Both knockdown and enzymatic inhibition of CTPS reduced TGF-β-induced changes in EMT marker expression, chemoresistance and migration in vitro. Moreover, CTPS knockdown counteracted the TGF-β-mediated downregulation of UDP-glucuronate, glutarate, creatine, taurine and nicotinamide. These findings indicate that CTPS plays a multifaceted role in EMT metabolism, which is crucial for the malignant transformation of cancer through EMT, and underline its potential as a promising therapeutic target for preventing drug resistance and metastasis in non-small-cell lung cancer.

PMID:39030877 | DOI:10.1002/2211-5463.13860

New Phytol. 2024 Jul 18. doi: 10.1111/nph.19986. Online ahead of print.

ABSTRACT

Viroids are pathogenic noncoding RNAs that completely rely on their host molecular machinery to accomplish their life cycle. Several interactions between viroids and their host molecular machinery have been identified, including interference with epigenetic mechanisms such as DNA methylation. Despite this, whether viroids influence changes in other epigenetic marks such as histone modifications remained unknown. Epigenetic regulation is particularly important during pathogenesis processes because it might be a key regulator of the dynamism of the defense response. Here we have analyzed the changes taking place in Cucumis sativus (cucumber) facultative and constitutive heterochromatin during hop stunt viroid (HSVd) infection using chromatin immunoprecipitation (ChIP) of the two main heterochromatic marks: H3K9me2 and H3K27me3. We find that HSVd infection is associated with changes in both H3K27me3 and H3K9me2, with a tendency to decrease the levels of repressive epigenetic marks through infection progression. These epigenetic changes are connected to the transcriptional regulation of their expected targets, genes, and transposable elements. Indeed, several genes related to the defense response are targets of both epigenetic marks. Our results highlight another host regulatory mechanism affected by viroid infection, providing further information about the complexity of the multiple layers of interactions between pathogens/viroids and hosts/plants.

PMID:39030826 | DOI:10.1111/nph.19986

Stem Cells Dev. 2024 Jul 20. doi: 10.1089/scd.2024.0088. Online ahead of print.

ABSTRACT

Endothelial cells (ECs) are a multifaceted component of the vascular system with roles in immunity, maintaining tissue-fluid balance, and vascular tone. Dysregulation or dysfunction of ECs can have far-reaching implications, leading pathologies ranging from cardiovascular diseases, like hypertension and atherosclerosis, ischemia, chronic kidney disease, blood-brain barrier integrity, dementia, and tumor metastasis. Recent advancements in regenerative medicine have highlighted the potential of stem cell-derived ECs, particularly from induced-pluripotent stem cells (iPSCs), to treat ischemic tissues, as well as models of vascular integrity. This review will summarize what is known in the generation of ECs with an emphasis on tissue-specific ECs and EC subphenotypes important in development of targeted cell-based therapies for patient treatment.

PMID:39030822 | DOI:10.1089/scd.2024.0088

BMC Bioinformatics. 2024 Jul 19;25(1):245. doi: 10.1186/s12859-024-05855-x.

ABSTRACT

BACKGROUND: Inference of Gene Regulatory Networks (GRNs) is a difficult and long-standing question in Systems Biology. Numerous approaches have been proposed with the latest methods exploring the richness of single-cell data. One of the current difficulties lies in the fact that many methods of GRN inference do not result in one proposed GRN but in a collection of plausible networks that need to be further refined. In this work, we present a Design of Experiment strategy to use as a second stage after the inference process. It is specifically fitted for identifying the next most informative experiment to perform for deciding between multiple network topologies, in the case where proposed GRNs are executable models. This strategy first performs a topological analysis to reduce the number of perturbations that need to be tested, then predicts the outcome of the retained perturbations by simulation of the GRNs and finally compares predictions with novel experimental data.

RESULTS: We apply this method to the results of our divide-and-conquer algorithm called WASABI, adapt its gene expression model to produce perturbations and compare our predictions with experimental results. We show that our networks were able to produce in silico predictions on the outcome of a gene knock-out, which were qualitatively validated for 48 out of 49 genes. Finally, we eliminate as many as two thirds of the candidate networks for which we could identify an incorrect topology, thus greatly improving the accuracy of our predictions.

CONCLUSION: These results both confirm the inference accuracy of WASABI and show how executable gene expression models can be leveraged to further refine the topology of inferred GRNs. We hope this strategy will help systems biologists further explore their data and encourage the development of more executable GRN models.

PMID:39030497 | DOI:10.1186/s12859-024-05855-x

Nat Commun. 2024 Jul 20;15(1):6113. doi: 10.1038/s41467-024-50471-1.

ABSTRACT

Aberrant DNA methylation patterns have been used for cancer detection. However, DNA hemi-methylation, present at about 10% CpG dinucleotides, has been less well studied. Here we show that a majority of differentially hemi-methylated regions (DHMRs) in liver tumor DNA or plasma cells free (cf) DNA do not overlap with differentially methylated regions (DMRs) of the same samples, indicating that DHMRs could serve as independent biomarkers. Furthermore, we analyzed the cfDNA methylomes of 215 samples from individuals with liver or brain cancer and individuals without cancer (controls), and trained machine learning models using DMRs, DHMRs or both. The models incorporated with both DMRs and DHMRs show a superior performance compared to models trained with DMRs or DHMRs, with AUROC being 0.978, 0.990, and 0.983 in distinguishing control, liver and brain cancer, respectively, in a validation cohort. This study supports the potential of utilizing both DMRs and DHMRs for multi-cancer detection.

PMID:39030196 | DOI:10.1038/s41467-024-50471-1

Ann Allergy Asthma Immunol. 2024 Jul 17:S1081-1206(24)00452-6. doi: 10.1016/j.anai.2024.07.014. Online ahead of print.

NO ABSTRACT

PMID:39029557 | DOI:10.1016/j.anai.2024.07.014

Structure. 2024 Jul 11:S0969-2126(24)00235-1. doi: 10.1016/j.str.2024.06.017. Online ahead of print.

ABSTRACT

Complex associating with SET1 (COMPASS) is a histone H3K4 tri-methyltransferase controlled by several regulatory subunits including CXXC zinc finger protein 1 (Cfp1). Prior studies established the structural underpinnings controlling H3K4me3 recognition by the PHD domain of Cfp1's yeast homolog (Spp1). However, metazoans Cfp1PHD lacks structural elements important for H3K4me3 stabilization in Spp1, suggesting that in metazoans, Cfp1PHD domain binds H3K4me3 differently. The structure of Cfp1PHD in complex with H3K4me3 shows unique features such as non-canonical coordination of the first zinc atom and a disulfide bond forcing the reorientation of Cfp1PHD N-terminus, thereby leading to an atypical H3K4me3 binding pocket. This configuration minimizes Cfp1PHD reliance on canonical residues important for histone binding functions of other PHD domains. Cancer-related mutations in Cfp1PHD impair H3K4me3 binding, implying a potential impact on epigenetic signaling. Our work highlights a potential diversification of PHD histone binding modes and the impact of cancer mutations on Cfp1 functions.

PMID:39029460 | DOI:10.1016/j.str.2024.06.017