Sci Total Environ. 2024 Aug 1:175054. doi: 10.1016/j.scitotenv.2024.175054. Online ahead of print.

ABSTRACT

Climate change, with its profound effects on stream sediment, hydrological, and temperature dynamics, will exacerbate impacts on habitat conditions for many species, particularly those with vulnerable early life stages relying on the hyporheic zone, such as gravel-spawning fishes. Due to the complex and interactive nature of multiple stressor effects, we employed large-scale outdoor mesocosms to systemically test how the reproductive success of three gravel-spawning fish species brown trout (Salmo trutta), nase, (Chrondrostoma nasus) and Danube salmon (Hucho hucho) was affected by individual and combined effects of warming (+3-4 °C), fine sediment (increase in <0.85 mm by 22 %) and low-flow (eightfold discharge-reduction). Fine sediment had the most detrimental effect on emergence rate and fry length in all three species, reducing the emergence rate to zero in brown trout, 9 % in nase, and 4 % in Danube salmon. The emergence mortality caused by fine sediment surpassed that of hatching distinctly, suggesting that negative effects due to hypoxia were considerably exacerbated by entombment. Warming had only minor effects as a single stressor, but low flow reduced emergence rates of the spring spawning species nase and Danube salmon by 8 and 50 %, respectively. In combined treatments including fine sediment, however, the emergence success of all three species responded strongly negatively, even in the cyprinid species nase, which showed little interactive effects between stressors regarding hatching success. Warming and fine sediment also led to the earlier emergence of fry, implying a risk of asynchrony with available food resources. This study dramatically shows that climate change can have deleterious impacts on the reproductive success of gravel-spawning fish species, irrespective of taxonomic or ecological traits.

PMID:39097014 | DOI:10.1016/j.scitotenv.2024.175054

STAR Protoc. 2024 Aug 2;5(3):103209. doi: 10.1016/j.xpro.2024.103209. Online ahead of print.

ABSTRACT

Seqtometry (sequencing-to-measurement) is an analytical platform for single-cell analysis based on direct profiling of gene expression and accessibility achieved by advanced scoring with gene signatures. Here, we present a protocol for single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) analysis using Seqtometry. We describe steps for preprocessing, imputation, scoring, and plotting, with extensions to large datasets and integration of multiple datasets. This protocol yields results in the form of biologically interpretable dimensions for direct identification and comprehensive characterization of specific cells. For complete details on the use and execution of this protocol, please refer to Kousnetsov et al.1.

PMID:39096493 | DOI:10.1016/j.xpro.2024.103209

bioRxiv [Preprint]. 2024 Jul 23:2024.07.22.604482. doi: 10.1101/2024.07.22.604482.

ABSTRACT

G protein-coupled receptors (GPCRs) are the largest class of membrane-bound receptors and transmit critical signals from the extracellular to the intracellular spaces. Transcriptomic data of resected breast tumors shows that low mRNA expression of the orphan GPCR GPR52 correlates with reduced overall survival in breast cancer patients, leading to the hypothesis that loss of GPR52 supports breast cancer progression. CRISPR-Cas9 was used to knockout GPR52 in human triple-negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231, and in the non-cancerous breast epithelial cell line, MCF10A. Loss of GPR52 was found to be associated with increased cell-cell interaction in 2D cultures, altered 3D spheroid morphology, and increased propensity to organize and invade collectively in Matrigel. Furthermore, GPR52 loss was associated with features of EMT in MDA-MB-468 cells. To determine the in vivo impact of GPR52 loss, MDA-MB-468 cells were injected into zebrafish and loss of GPR52 was associated with a greater total cancer area compared to control cells. RNA-sequencing and proteomic analyses of GPR52-null breast cancer cells reveal an increased cAMP signaling signature. Consistently, we found that treatment of wild-type (WT) cells with forskolin, which stimulates production of cAMP, induces some phenotypic changes associated with GPR52 loss, and inhibition of cAMP production rescued some of the GPR52 KO phenotypes. Overall, our results reveal GPR52 loss as a potential mechanism by which breast cancer progression may occur and support the investigation of GPR52 agonism as a therapeutic option in breast cancer.

PMID:39091857 | PMC:PMC11291042 | DOI:10.1101/2024.07.22.604482

Mol Cancer. 2024 Aug 2;23(1):156. doi: 10.1186/s12943-024-02060-5.

ABSTRACT

BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects.

METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs.

RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects.

CONCLUSIONS: This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

PMID:39095771 | DOI:10.1186/s12943-024-02060-5

Nat Med. 2024 Aug 2. doi: 10.1038/s41591-024-03183-4. Online ahead of print.

ABSTRACT

Breakthrough fungal infections in patients on antimicrobial prophylaxis during allogeneic hematopoietic cell transplantation (allo-HCT) represent a major and often unexplained cause of morbidity and mortality. Candida parapsilosis is a common cause of invasive candidiasis and has been classified as a high-priority fungal pathogen by the World Health Organization. In high-risk allo-HCT recipients on micafungin prophylaxis, we show that heteroresistance (the presence of a phenotypically unstable, low-frequency subpopulation of resistant cells (~1 in 10,000)) underlies breakthrough bloodstream infections by C. parapsilosis. By analyzing 219 clinical isolates from North America, Europe and Asia, we demonstrate widespread micafungin heteroresistance in C. parapsilosis. Standard antimicrobial susceptibility tests, such as broth microdilution or gradient diffusion assays, which guide drug selection for invasive infections, fail to detect micafungin heteroresistance in C. parapsilosis. To facilitate rapid detection of micafungin heteroresistance in C. parapsilosis, we constructed a predictive machine learning framework that classifies isolates as heteroresistant or susceptible using a maximum of ten genomic features. These results connect heteroresistance to unexplained antifungal prophylaxis failure in allo-HCT recipients and demonstrate a proof-of-principle diagnostic approach with the potential to guide clinical decisions and improve patient care.

PMID:39095599 | DOI:10.1038/s41591-024-03183-4

Nat Med. 2024 Aug 2. doi: 10.1038/s41591-024-03150-z. Online ahead of print.

ABSTRACT

While single-cell technologies have greatly advanced our comprehension of human brain cell types and functions, studies including large numbers of donors and multiple brain regions are needed to extend our understanding of brain cell heterogeneity. Integrating atlas-level single-cell data presents a chance to reveal rare cell types and cellular heterogeneity across brain regions. Here we present the Brain Cell Atlas, a comprehensive reference atlas of brain cells, by assembling single-cell data from 70 human and 103 mouse studies of the brain throughout major developmental stages across brain regions, covering over 26.3 million cells or nuclei from both healthy and diseased tissues. Using machine-learning based algorithms, the Brain Cell Atlas provides a consensus cell type annotation, and it showcases the identification of putative neural progenitor cells and a cell subpopulation of PCDH9high microglia in the human brain. We demonstrate the gene regulatory difference of PCDH9high microglia between hippocampus and prefrontal cortex and elucidate the cell-cell communication network. The Brain Cell Atlas presents an atlas-level integrative resource for comparing brain cells in different environments and conditions within the Human Cell Atlas.

PMID:39095595 | DOI:10.1038/s41591-024-03150-z

Nat Neurosci. 2024 Aug 2. doi: 10.1038/s41593-024-01724-1. Online ahead of print.

ABSTRACT

Hypothalamic gonadotropin-releasing hormone (GnRH) neurons regulate fertility and integrate hormonal status with environmental cues to ensure reproductive success. Here we show that GnRH neurons in the olfactory bulb (GnRHOB) of adult mice can mediate social recognition. Specifically, we show that GnRHOB neurons extend neurites into the vomeronasal organ and olfactory epithelium and project to the median eminence. GnRHOB neurons in males express vomeronasal and olfactory receptors, are activated by female odors and mediate gonadotropin release in response to female urine. Male preference for female odors required the presence and activation of GnRHOB neurons, was impaired after genetic inhibition or ablation of these cells and relied on GnRH signaling in the posterodorsal medial amygdala. GnRH receptor expression in amygdala kisspeptin neurons appear to be required for GnRHOB neurons' actions on male mounting behavior. Taken together, these results establish GnRHOB neurons as regulating fertility, sex recognition and mating in male mice.

PMID:39095587 | DOI:10.1038/s41593-024-01724-1

Sci Rep. 2024 Aug 2;14(1):17972. doi: 10.1038/s41598-024-66352-y.

ABSTRACT

This study is the first to investigate the presence and movement of the novel Liberibacter species 'Candidatus Liberibacter brunswickensis' (CLbr) in eggplant, Solanum melongena. The psyllid, Acizzia solanicola can transmit CLbr to eggplant and CLbr can be acquired by CLbr-negative A. solanicola individuals from CLbr-positive eggplants. In planta, CLbr can replicate, move and persist. Investigation into the early development of eggplants showed that CLbr titres had increased at the inoculation site at 14 days post inoculation access period (DPIAP). CLbr had become systemic in the majority of plants tested by 28 DPIAP. The highest bacterial titres were recorded at 35 DPIAP in all samples of the inoculated leaf, the roots, stems and the midrib and petiole samples of the newest leaf (the top leaf). This finding strongly suggests that CLbr movement in planta follows the source to sink relationship as previously described for 'Ca. Liberibacter asiaticus' (CLas) and 'Ca. Liberibacter solanacearum' (CLso). No symptoms consistent with Liberibacter-associated diseases were noted for plants colonised by CLbr during this study, consistent with the hypothesis that CLbr does not cause disease of eggplant during the early stages of host colonisation. In addition, no significant differences in biomass were found between eggplant colonised with CLbr, compared to those that were exposed to CLbr-negative A. solanicola, and to control plants.

PMID:39095446 | DOI:10.1038/s41598-024-66352-y

Nat Commun. 2024 Aug 3;15(1):6568. doi: 10.1038/s41467-024-51017-1.

ABSTRACT

Developing programmable bacterial cell-cell adhesion is of significant interest due to its versatile applications. Current methods that rely on presenting cell adhesion molecules (CAMs) on bacterial surfaces are limited by the lack of a generalizable strategy to identify such molecules targeting bacterial membrane proteins in their natural states. Here, we introduce a whole-cell screening platform designed to discover CAMs targeting bacterial membrane proteins within a synthetic bacteria-displayed nanobody library. Leveraging the potency of the bacterial type IV secretion system-a contact-dependent DNA delivery nanomachine-we have established a positive feedback mechanism to selectively enrich for bacteria displaying nanobodies that target antigen-expressing cells. Our platform successfully identified functional CAMs capable of recognizing three distinct outer membrane proteins (TraN, OmpA, OmpC), demonstrating its efficacy in CAM discovery. This approach holds promise for engineering bacterial cell-cell adhesion, such as directing the antibacterial activity of programmed inhibitor cells toward target bacteria in mixed populations.

PMID:39095377 | DOI:10.1038/s41467-024-51017-1

Nat Commun. 2024 Aug 2;15(1):6510. doi: 10.1038/s41467-024-50875-z.

ABSTRACT

Shotgun proteomics analysis presents multifaceted challenges, demanding diverse tool integration for insights. Addressing this complexity, OmicScope emerges as an innovative solution for quantitative proteomics data analysis. Engineered to handle various data formats, it performs data pre-processing - including joining replicates, normalization, data imputation - and conducts differential proteomics analysis for both static and longitudinal experimental designs. Empowered by Enrichr with over 224 databases, OmicScope performs Over Representation Analysis (ORA) and Gene Set Enrichment Analysis (GSEA). Additionally, its Nebula module facilitates meta-analysis from independent datasets, providing a systems biology approach for enriched insights. Complete with a data visualization toolkit and accessible as Python package and a web application, OmicScope democratizes proteomics analysis, offering an efficient and high-quality pipeline for researchers.

PMID:39095347 | DOI:10.1038/s41467-024-50875-z

Trends Biotechnol. 2024 Aug 1:S0167-7799(24)00184-7. doi: 10.1016/j.tibtech.2024.07.006. Online ahead of print.

ABSTRACT

Single cell sequencing technologies have become a fixture in the molecular profiling of cells due to their ease, flexibility, and commercial availability. In particular, partitioning individual cells inside oil droplets via microfluidic reactions enables transcriptomic or multi-omic measurements for thousands of cells in parallel. Complementing the multitude of biological discoveries from genomics analyses, the past decade has brought new capabilities from assay baselines to enable a deeper understanding of the complex data from single cell multi-omics. Here, we highlight four innovations that have improved the reliability and understanding of droplet microfluidic assays. We emphasize new developments that further orient principles of technology development and guidelines for the design, benchmarking, and implementation of new droplet-based methodologies.

PMID:39095258 | DOI:10.1016/j.tibtech.2024.07.006

Pharmacol Res. 2024 Jul 31:107336. doi: 10.1016/j.phrs.2024.107336. Online ahead of print.

ABSTRACT

G-Protein Pathway Suppressor 2 (GPS2) is an inhibitor of non-proteolytic K63 ubiquitination mediated by the E2 ubiquitin-conjugating enzyme Ubc13. Previous studies have associated GPS2-mediated restriction of ubiquitination with the regulation of insulin signaling, inflammatory responses and mitochondria-nuclear communication across different tissues and cell types. However, a detailed understanding of the targets of GPS2/Ubc13 activity is lacking. Here, we have dissected the GPS2-regulated K63 ubiquitome in mouse embryonic fibroblasts and human breast cancer cells, unexpectedly finding an enrichment for proteins involved in RNA binding and translation on the outer mitochondrial membrane. Validation of selected targets of GPS2-mediated regulation, including the RNA-binding protein PABPC1 and translation factors RPS1, RACK1 and eIF3M, revealed a mitochondrial-specific strategy for regulating the translation of nuclear-encoded mitochondrial proteins via non-proteolytic ubiquitination. Removal of GPS2-mediated inhibition, either via genetic deletion or stress-induced nuclear translocation, promotes the import-coupled translation of selected mRNAs leading to the increased expression of an adaptive antioxidant program. In light of GPS2 role in nuclear-mitochondria communication, these findings reveal an exquisite regulatory network for modulating mitochondrial gene expression through spatially coordinated transcription and translation.

PMID:39094987 | DOI:10.1016/j.phrs.2024.107336

Toxicology. 2024 Jul 31:153902. doi: 10.1016/j.tox.2024.153902. Online ahead of print.

ABSTRACT

Glyphosate, the world's most widely used herbicide, has a low toxicity rating despite substantial evidence of adverse health effects. Furthermore, glyphosate-based formulations (GBFs) contain several other chemicals, some of which are known to be harmful. Additionally, chronic, and acute exposure to GBFs among rural workers may lead to health impairments, such as neurodegenerative diseases and cancer. P53 is known as a tumor suppressor protein, acting as a key regulator of the cellular response to stress and DNA damage. Therefore, mutations in the TP53 gene, which encodes p53, are common genetic alterations found in various types of cancer. Therefore, this study aimed to evaluate the cytotoxicity and genotoxicity of GBF in two glioblastoma cell lines: U87MG (TP53-proficient) and U251MG (TP53-mutant). Additionally, the study aimed to identify the main proteins involved in the response to GBF exposure using Systems Biology in a network containing p53 and another network without p53. The MTT assay was used to study the toxicity of GBF in the cell lines, the clonogenic assay was used to investigate cell survival, and the Comet Assay was used for genotoxicity evaluation. For data analysis, bioinformatics tools such as String 12.0 and Stitch 5.0 were applied, serving as a basis for designing binary networks in the Cytoscape 3.10.1 program. From the in vitro test analyses, it was observed a decrease in cell viability at doses starting from 10 ppm. Comet Assay at concentrations of 10 ppm and 30 ppm for the U251MG and U87MG cell lines, respectively observed DNA damage. The network generated with systems biology showed that the presence of p53 is important for the regulation of biological processes involved in genetic stability and neurotoxicity, processes that did not appear in the TP53-mutant network.

PMID:39094917 | DOI:10.1016/j.tox.2024.153902

Int J Biol Macromol. 2024 Jul 31:134370. doi: 10.1016/j.ijbiomac.2024.134370. Online ahead of print.

ABSTRACT

Ulcerative Colitis (UC) is a chronic inflammatory disease of the intestinal tract with unknown definitive etiology. Polysaccharides are among the most important active components of Abelmoschi Corolla, exhibitings various pharmacological activities such as antioxidation and immunomodulation. However, no studies have yet reported the application of Abelmoschi Corolla Polysaccharides (ACP) in treating UC. This study aims to highlight the therapeutic efficacy of ACP in UC and reveal the underlying mechanism. The potential therapeutic effect is initially verified using a dextran sodium sulfate (DSS)-induced colitis model. 16S rRNA sequencing is performed using feces samples and untargeted metabolomics using serum samples to further reveal that ACP reprograms the dysbiosis triggered by UC progression, increases the abundance of Bacteroides spp., Blautia spp., and Parabacteroides spp. at the genus level and enriches the serum concentration of 7-ketodeoxycholic acid (7-KDA). Furthermore, using the FXR-/- mouse model, it is revealed that Farnesoid X Receptor (FXR) is a key target for ACP and the metabolite 7-KDA to block STAT3 phosphorylation by repairing the intestinal barrier to attenuate UC. Taken together, this work highlights the therapeutic potential of ACP against UC, mainly exerting its effects via modulating gut microbiota and regulating the FXR/STAT3 signaling pathway.

PMID:39094864 | DOI:10.1016/j.ijbiomac.2024.134370

Plant Physiol Biochem. 2024 Jul 31;215:108988. doi: 10.1016/j.plaphy.2024.108988. Online ahead of print.

ABSTRACT

Phytochrome-interacting factors (PIFs) are pivotal transcriptional regulators controlling photomorphogenesis, environmental responses, and development in plants. However, their specific roles in coordinating adaptation towards abiotic stress and metabolism remain underexplored in tea plants. Here, we identified seven PIF members from four distinct clades (PIF1, PIF3, PIF7, and PIF8). Promoter analysis implicated CsPIFs in integrating light, stress, hormone, and circadian signals. Most CsPIFs exhibited rapid increase in expression under shading, especially CsPIF7b/8a, which displayed significant changes in long-term shading condition. Under drought/salt stress, CsPIF3b emerged as a potential positive regulator. CsPIF3a was induced by low temperature and co-expressed with CsCBF1/3 and CsDREB2A cold response factors. Dual-luciferase assays confirmed that act as negative regulator of the CBF pathway. Expression profiling across 11 tea cultivars associated specific CsPIFs with chlorophyll biosynthesis and accumulation of anthocyanins, flavonols, and other metabolites. In summary, this study highlights the significance of CsPIFs as central coordinators in managing intricate transcriptional reactions to simultaneous abiotic stresses and metabolic adjustments in tea plants. This insight informs future strategies for enhancing this economically crucial crop through crop improvement initiatives.

PMID:39094480 | DOI:10.1016/j.plaphy.2024.108988

Mol Aspects Med. 2024 Aug 1;99:101302. doi: 10.1016/j.mam.2024.101302. Online ahead of print.

ABSTRACT

Modern methods of molecular diagnostics and therapy have revolutionized the field of medicine in recent years by providing more precise and effective tools for detecting and treating diseases. This progress includes a growing exploration of the body's secreted vesicles, known as extracellular vesicles (EVs), for both diagnostic and therapeutic purposes. EVs are a heterogeneous population of lipid bilayer vesicles secreted by almost every cell type studied so far. They are detected in body fluids and conditioned culture media from living cells. EVs play a crucial role in communication between cells and organs, both locally and over long distances. They are recognized for their ability to transport endogenous RNA and proteins between cells, including messenger RNA (mRNA), microRNA (miRNA), misfolded neurodegenerative proteins, and several other biomolecules. This review explores the dual utilization of EVs, serving not only for diagnostic purposes but also as a platform for delivering therapeutic molecules to cells and tissues. Through an exploration of their composition, biogenesis, and selective cargo packaging, we elucidate the intricate mechanisms behind RNA transport between cells via EVs, highlighting their potential use for both diagnostic and therapeutic applications. Finally, it addresses challenges and outlines prospective directions for the clinical utilization of EVs.

PMID:39094449 | DOI:10.1016/j.mam.2024.101302

Proc Natl Acad Sci U S A. 2024 Aug 6;121(32):e2303439121. doi: 10.1073/pnas.2303439121. Epub 2024 Aug 2.

ABSTRACT

Plants release a wealth of metabolites into the rhizosphere that can shape the composition and activity of microbial communities in response to environmental stress. The connection between rhizodeposition and rhizosphere microbiome succession has been suggested, particularly under environmental stress conditions, yet definitive evidence is scarce. In this study, we investigated the relationship between rhizosphere chemistry, microbiome dynamics, and abiotic stress in the bioenergy crop switchgrass grown in a marginal soil under nutrient-limited, moisture-limited, and nitrogen (N)-replete, phosphorus (P)-replete, and NP-replete conditions. We combined 16S rRNA amplicon sequencing and LC-MS/MS-based metabolomics to link rhizosphere microbial communities and metabolites. We identified significant changes in rhizosphere metabolite profiles in response to abiotic stress and linked them to changes in microbial communities using network analysis. N-limitation amplified the abundance of aromatic acids, pentoses, and their derivatives in the rhizosphere, and their enhanced availability was linked to the abundance of bacterial lineages from Acidobacteria, Verrucomicrobia, Planctomycetes, and Alphaproteobacteria. Conversely, N-amended conditions increased the availability of N-rich rhizosphere compounds, which coincided with proliferation of Actinobacteria. Treatments with contrasting N availability differed greatly in the abundance of potential keystone metabolites; serotonin and ectoine were particularly abundant in N-replete soils, while chlorogenic, cinnamic, and glucuronic acids were enriched in N-limited soils. Serotonin, the keystone metabolite we identified with the largest number of links to microbial taxa, significantly affected root architecture and growth of rhizosphere microorganisms, highlighting its potential to shape microbial community and mediate rhizosphere plant-microbe interactions.

PMID:39093948 | DOI:10.1073/pnas.2303439121

Genet Mol Biol. 2024 Jul 29;47(2):e20230320. doi: 10.1590/1678-4685-GMB-2023-0320. eCollection 2024.

ABSTRACT

Free-living amoebas are natural predators of fungi, including human pathogens of the Cryptococcus genus. To survive and proliferate inside phagocytes, cryptococcal cells must acquire several nutrients. Zinc is fundamental for all life forms and develops a crucial role in the virulence of fungal pathogens, phagocytes reduce the availability of this metal to reduce the development of infection. The Acanthamoeba castellanii ACA1_271600 gene codes a metal transporter that is possibly associated with such antifungal strategy. Here, we evaluated the impact of A. castellanii metal homeostasis on C. gattii survival. Gene silencing of ACA1_271600 was performed and the interaction outcome of amoeba cells with both WT and zinc homeostasis-impaired mutant cryptococcal cells was evaluated. Decreased levels of ACA1_271600 in silenced amoeba cells led to higher proliferation of such cryptococcal strains. This effect was more pronounced in the zip1 mutant of C. gattii, suggesting that ACA1_271600 gene product modulates metal availability in Cryptococcus-infected amoebae. In addition, a systems biology analysis allowed us to infer that ACA1_271600 may also be involved in other biological processes that could compromise amoebae activity over cryptococcal cells. These results support the hypothesis that A. castellanii can apply nutritional immunity to hamper cryptococcal survival.

PMID:39093931 | DOI:10.1590/1678-4685-GMB-2023-0320

Medicine (Baltimore). 2024 Aug 2;103(31):e39057. doi: 10.1097/MD.0000000000039057.

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, poses a huge threat to human health. Pancreatic cancer (PC) is a malignant tumor with high mortality. Research suggests that infection with SARS-CoV-2 may increase disease severity and risk of death in patients with pancreatic cancer, while pancreatic cancer may also increase the likelihood of contracting SARS-CoV-2, but the link is unclear.

METHODS: This study investigated the transcriptional profiles of COVID-19 and PC patients, along with their respective healthy controls, using bioinformatics and systems biology approaches to uncover the molecular mechanisms linking the 2 diseases. Specifically, gene expression data for COVID-19 and PC patients were obtained from the Gene Expression Omnibus datasets, and common differentially expressed genes (DEGs) were identified. Gene ontology and pathway enrichment analyses were performed on the common DEGs to elucidate the regulatory relationships between the diseases. Additionally, hub genes were identified by constructing a protein-protein interaction network from the shared DEGs. Using these hub genes, we conducted regulatory network analyses of microRNA/transcription factors-genes relationships, and predicted potential drugs for treating COVID-19 and PC.

RESULTS: A total of 1722 and 2979 DEGs were identified from the transcriptome data of PC (GSE119794) and COVID-19 (GSE196822), respectively. Among these, 236 common DEGs were found between COVID-19 and PC based on protein-protein interaction analysis. Functional enrichment analysis indicated that these shared DEGs were involved in pathways related to viral genome replication and tumorigenesis. Additionally, 10 hub genes, including extra spindle pole bodies like 1, holliday junction recognition protein, marker of proliferation Ki-67, kinesin family member 4A, cyclin-dependent kinase 1, topoisomerase II alpha, cyclin B2, ubiquitin-conjugating enzyme E2 C, aurora kinase B, and targeting protein for Xklp2, were identified. Regulatory network analysis revealed 42 transcription factors and 23 microRNAs as transcriptional regulatory signals. Importantly, lucanthone, etoposide, troglitazone, resveratrol, calcitriol, ciclopirox, dasatinib, enterolactone, methotrexate, and irinotecan emerged as potential therapeutic agents against both COVID-19 and PC.

CONCLUSION: This study unveils potential shared pathogenic mechanisms between PC and COVID-19, offering novel insights for future research and therapeutic strategies for the treatment of PC and SARS-CoV-2 infection.

PMID:39093763 | DOI:10.1097/MD.0000000000039057

Epigenomics. 2024 Aug 2:1-14. doi: 10.1080/17501911.2024.2379242. Online ahead of print.

ABSTRACT

DNA methylation (DNAm)-based deconvolution estimates contain relative data, forming a composition, that standard methods (testing directly on cell proportions) are ill-suited to handle. In this study we examined the performance of an alternative method, analysis of compositions of microbiomes (ANCOM), for the analysis of DNAm-based deconvolution estimates. We performed two different simulation studies comparing ANCOM to a standard approach (two sample t-test performed directly on cell proportions) and analyzed a real-world data from the Women's Health Initiative to evaluate the applicability of ANCOM to DNAm-based deconvolution estimates. Our findings indicate that ANCOM can effectively account for the compositional nature of DNAm-based deconvolution estimates. ANCOM adequately controls the false discovery rate while maintaining statistical power comparable to that of standard methods.

PMID:39093129 | DOI:10.1080/17501911.2024.2379242