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3D pentaculture model unveils malignant cell-driven macrophage polarization in high-grade serous ovarian cancer
Abstract High-grade serous ovarian cancer (HGSOC) is characterized by a complex, immunosuppressive tumor microenvironment (TME) that contributes to poor clinical outcomes and resistance to therapy. To replicate the human TME in vitro, we develop a 3D pentaculture model incorporating five human cell types: malignant HGSOC cells and primary fibroblasts, mesothelial cells, adipocytes, monocytes. Monocytes differentiate into macrophages without exogenous cytokines in the pentacultures. Bulk RNA sequencing and deconvolution with single-cell RNA data from patient biopsies reveal that macrophage clusters within the pentacultures replicate those found in human HGSOC metastases, and proportions of individual clusters vary according to the malignant cell line. The pentacultures enable detailed analysis of malignant cell–macrophage interactions and highlight the influence of malignant cell genomic, transcriptomic and proteomic heterogeneity on the TME. Furthermore, targeting of “do-not-eat-me” signals with anti-CD47 and anti-CD24 monoclonal antibodies demonstrate differential effects on macrophage activity and cancer cell viability, again depending on the individual malignant cell line. Real-time microscopic monitoring of the pentacultures confirms dynamic modulation of macrophage behavior. We conclude that this pentaculture model offers a platform to study malignant cell control of TME elements and in particular their interactions with myeloid cells.
Lightweight multiscale behavior recognition for caged laying hens using an enhanced YOLOv8 framework
Molecular signatures and causal factors underlying latent cytomegalovirus infection among people living with HIV (PLHIV)
Abstract CMV seropositivity contributes to medical complications in people living with HIV (PLHIV). This study provides a comprehensive evaluation of how CMV seropositivity shapes the immune system of 1,887 PLHIV, by utilizing multi-omics and deep immune phenotyping datasets. The study measured the immune cell profiles from whole blood, and the cytokine production of PBMCs exposed to various ex-vivo stimuli. We observed an increase in pro-inflammatory cytokine production of circulating immune cells and differences in phenotype of innate-like lymphocyte populations associated with CMV seropositivity. This study also measured 5-omics layers, including genomics, DNA methylation, transcriptomics, and plasma protein and metabolites. The DNA methylome and transcriptome demonstrated prominent CMV-induced signatures related to immune functions in PLHIV. Particularly, high FCRL6 expression is a promising biomarker for immune activation, underlined by the demethylation of FCRL6 and up-regulation of gene expression and plasma protein concentrations in CMV-seropositive PLHIV. Host genetics-driven elevation in both gene and protein expression of FCRL6 was also associated with latent CMV infection. A significant CMV-seroprevalence locus was associated with cytokine production capacity and protein abundance. Mendelian randomization analyses demonstrated a causal relationship between elevated FCRL6 expression and CMV seropositivity.
Integrated transcriptomic and metabolomic analyses reveal the regulatory network underlying NtGSTU10-mediated nicotine synthesis and transport in tobacco
Indigenous sovereignty and the limits of the Canadian Precision Health Initiative
Heat shock factor-1 alleviates ER-stress in Caenorhabditis elegans
Abstract Cells can be exposed to many different stimuli that induce a variety of stresses, such as oxidative stress and proteotoxic stress of the cytoplasm, endoplasmic reticulum or mitochondria. These types of stresses trigger conserved molecular pathways (e.g., heat shock response, unfolded protein response, and autophagy) that can restore cellular homeostasis. Dysfunction (deficiency or hyperactivity) of these pathways is associated with aging and pathologies such as neurodegenerative diseases, diabetes and cancer. The basic molecular machinery of these stress response pathways has been elucidated, but how these pathways interact remains a vibrant area of research. Here, we show that the heat shock transcription factor-1 (HSF-1), the master regulator of the heat shock response, is required for efficient activation of the endoplasmic reticulum unfolded protein response (UPR ER ) in the nematode Caenorhabditis elegans . Tolerance against tunicamycin-induced ER stress also requires HSF-1 activity. We found that mRNA levels of several genes involved in the UPR ER are regulated by HSF1 in human cell lines. These results suggest that HSF-1 plays a critical role in the cellular response to ER stress.
Electroreductive Cleavage of C(sp <sup>3</sup> )–N Bonds in Saturated <i>N</i> -Carbonyl Heterocycles
In-situ revitalizing end-of-life MBR membranes via a curtain-type dynamic membrane process
Abstract Membrane bioreactors (MBR), an industrial mainstay with over 15,000 installations worldwide, face severe sustainability challenges from frequent membrane replacement, generating over 500,000 tons of waste annually. Dynamic membranes, a promising alternative, are impeded in large-scale implementation by inherent issues of conventional flat-sheet designs, such as uneven flow distribution and performance instability. Herein, we propose a strategy that directly upcycles end-of-life hollow-fiber MBR membranes as substrates for curtain-type dynamic membranes (CTDMs). The curtain-type substrate layer rapidly forms a biofilm and attains stable effluent quality (turbidity <5 NTU) within 10 minutes. Exposing only 5% of the internal substrate surface for CTDM fabrication restores performance comparable to that of new MBR membranes while meeting discharge standards. Life-cycle assessment reveals a 1,070-fold reduction in carbon emissions (0.0025 vs. 2.67 kg CO 2 m -2 ) and 99.9% lower environmental costs (0.0072 vs. 7.81 USD m -2 ) compared to traditional membrane replacement. Scaling up this approach could mitigate 441 kt of CO 2 in China alone by 2035. This approach concurrently addresses two global crises, accumulating plastic waste from spent membranes and escalating energy costs of water treatment.