SummaryCells in the mucosal barrier are equipped to sense and respond to microbes in the lumen and translate this molecular information into signals that can reach local or distant sites. The interaction of P-®mbriated Escherichia coli with human uroepithelial cells is a model to study the molecular mechanism of epithelial cell activation by mucosal pathogens. Here, we examine the role of lipopolysaccharide (LPS) as a co-stimulatory molecule in epithelial cell activation by P-®mbriated E. coli. P-®mbriated clinical isolates or recombinant strains were shown to trigger a ®mbriae-dependent epithelial cell cytokine response. Mutational inactivation of the msbB sequences that control lipid A myristoylation drastically impaired monocyte stimulation but not epithelial responses to P-®mbriated bacteria. Polymyxin B or bactericidal/permeability increasing factor (BPI) neutralized the effects of lipid A in the monocyte assay, but did not reduce epithelial responses. Finally, isolated LPS of the smooth, rough and deep rough chemotypes were poor epithelial cell activators. The cells were shown to lack surface CD14 or CD14 mRNA as well as the CD14 co-receptor function and were also very poor LPS responders in the presence of human serum. These results demonstrate that epithelial cell responses to P-®mbriated E. coli are CD14 and LPS independent, and suggest that attaching pathogens can overcome the LPS unresponsiveness of epithelial cells by ®mbriae-dependent activation mechanisms.

Hypoxia-inducible factors enhance glioma stemness, and glioma stem cells have an amplified hypoxic response despite residing within a perivascular niche. Still, little is known about differential HIF regulation in stem versus bulk glioma cells. We show that the intracellular domain of stem cell marker CD44 (CD44ICD) is released at hypoxia, binds HIF-2α (but not HIF-1α), enhances HIF target gene activation, and is required for hypoxia-induced stemness in glioma. In a glioma mouse model, CD44 was restricted to hypoxic and perivascular tumor regions, and in human glioma, a hypoxia signature correlated with CD44. The CD44ICD was sufficient to induce hypoxic signaling at perivascular oxygen tensions, and blocking CD44 cleavage decreased HIF-2α stabilization in CD44-expressing cells. Our data indicate that the stem cell marker CD44 modulates the hypoxic response of glioma cells and that the pseudo-hypoxic phenotype of stem-like glioma cells is achieved by stabilization of HIF-2α through interaction with CD44, independently of oxygen.

Hematopoietic stem and progenitor cells (HSPCs) in the fetus and adult possess distinct molecular landscapes that regulate cell fate and change their susceptibility to initiation and progression of hematopoietic malignancies. Here, we applied in-depth quantitative proteomics to comprehensively describe and compare the proteome of fetal and adult HSPCs. Our data uncover a striking difference in complexity of the cellular proteomes, with more diverse adult-specific HSPC proteomic signatures. The differential protein content in fetal and adult HSPCs indicate distinct metabolic profiles and protein complex stoichiometries. Additionally, adult characteristics include an arsenal of proteins linked to viral and bacterial defense, as well as protection against ROS-induced protein oxidation. Further analyses show that interferon α, as well as Neutrophil elastase, has distinct functional effects in fetal and adult HSPCs. This study provides a rich resource aimed toward an enhanced mechanistic understanding of normal and malignant hematopoiesis during fetal and adult life.

When planning interventions to limit the spread of Covid-, the current state of knowledge about the disease and specific characteristics of the population need to be considered. Simulations can facilitate policy making as they take prevailing circumstances into account. Moreover, they allow for the investigation of the potential e ects of di erent interventions using an artificial population. Agent-based Social Simulation (ABSS) is argued to be particularly useful as it can capture the behavior of and interactions between individuals. We performed a systematic literature review and identified articles that describe ABSS of Covid-transmission processes. Our review showed that ABSS is widely used for investigating the spread of Covid-. Existing models are very heterogeneous with respect to their purpose, the number of simulated individuals, and the modeled geographical region, as well as how they model transmission dynamics, disease states, human behavior, and interventions. To this end, a discrepancy can be identified between the needs of policy makers and what is implemented by the simulation models. This also includes how thoroughly the models consider and represent the real world, e.g. in terms of factors that a ect the transmission probability or how humans make decisions. Shortcomings were also identified in the transparency of the presented models, e.g. in terms of documentation or availability, as well as in their validation, which might limit their suitability for supporting decision-making processes. We discuss how these issues can be mitigated to further establish ABSS as a powerful tool for crisis management.