Functional annotation of genetic loci associated with sepsis prioritizes immune and endothelial cell pathways

Due to limited sepsis patient cohort size and extreme heterogeneity, only one significant locus and suggestive associations at several independent loci were implicated by three genome-wide association studies. However, genes from such suggestive loci may also provide crucial information to unravel genetic mechanisms that determine sepsis heterogeneity. Therefore, in this study, we made use of integrative approaches to prioritize genes and pathways affected by sepsis associated genetic variants. By integrating expression quantitative trait loci (eQTL) results from the largest whole-blood eQTL database, cytokine QTLs from pathogen-stimulated peripheral blood mononuclear cells (PBMCs), publicly available blood transcriptome data from pneumoniae-derived sepsis patients, and transcriptome data from pathogen-stimulated PBMCs, we identified 55 potential genes affected by 39 independent loci. By performing pathway enrichment analysis at these loci we found enrichment of genes for adherences-junction pathway. Finally, we investigated the functional role of the only one GWAS significant SNP rs4957796 on sepsis survival in altering transcription factor binding affinity in monocytes and endothelial cells. We also found that transient deficiency of FER and MAN2A1 affect endothelial response to stimulation, indicating that both FER and MAN2A1 could be the causal genes at this locus. Taken together, our study suggests that in addition to immune pathways, genetic variants may also affect non-immune related pathways

Occurrence of antibiotic residues and antibiotic-resistant bacteria in effluents of pharmaceutical manufacturers and other sources around Hanoi, Vietnam

Pharmaceutical manufacturers in Vietnam are producing a wide variety of antibiotics for human and veterinary use. Consequently, the water discharged from those facilities can contain residues of antibiotics, which could have adverse impact on the environment. However, studies on the occurrence of antibiotics in the wastewater from pharmaceutical manufacturers in Vietnam are almost non-existent. In this study, water samples were collected at around the outlets of four pharmaceutical manufacturing plants as well as from a hospital and an aquaculture farm around Hanoi in 2016 and 2017. Fifteen antibiotics from four major classes (β-lactam, quinolones, macrolides, sulfonamides) were monitored, using a validated LC-MS/MS method, based on their number of registrations at the Ministry of Health. Ten antibiotics, ampicillin, cefuroxime, cefotaxime, clarithromycin, azithromycin, sulfamethoxazole, trimethoprim, ofloxacin, norfloxacin, and ciprofloxacin were detected in the samples at different concentrations. Notably, sulfonamides and quinolones were occasionally detected at very high concentration, such as sulfamethoxazole (252 μg/L), trimethoprim (107 μg/L), ofloxacin (85 μg/L), and ciprofloxacin (41 μg/L). In this study, concentrations of antibiotic residues in effluent of pharmaceutical plants were higher than those from other sources. The antibiotic-resistance tests indicated the widespread resistance to common antibiotics like quinolone and sulfonamides in the collected samples. This finding suggests that wastewater from pharmaceutical manufacturers could be an important source of antibiotics and antibiotic-resistant bacteria in the aquatic environment of Vietnam

Inflammatory Protein Profiles in Plasma of Candidaemia Patients and the Contribution of Host Genetics to Their Variability

Circulatory inflammatory proteins play a significant role in anti- Candida host immune defence. However, little is known about the genetic variation that contributes to the variability of inflammatory responses in response to C. albicans . To systematically characterize inflammatory responses in Candida infection, we profiled 91 circulatory inflammatory proteins in peripheral blood mononuclear cells (PBMCs) stimulated with C. albicans yeast isolated from 378 individuals of European origin from the 500 Functional Genomics (500FG) cohort of the Human Functional Genomics Project (HFGP) and Lifelines Deep cohort. To identify the genetic factors that determine variation in inflammatory protein responses, we correlated genome-wide single nucleotide polymorphism (SNP) genotypes with protein abundance (protein quantitative trait loci, pQTLs) produced by the Candida -stimulated PBMCs. Furthermore, we investigated whether differences in survival of candidaemia patients can be explained by modulating levels of inflammatory proteins. We identified five genome-wide significant pQTLs that modulate IL-8, MCP-2, MMP-1, and CCL3 in response to C. albicans . In addition, our genetic analysis suggested that GADD45G from rs10114707 locus that reached genome-wide significance could be a potential core gene that regulates a cytokine network upon Candida infection. Last but not least, we observed that a trans-pQTL marked from SNP rs7651677 at chromosome 3 that influences urokinase plasminogen activator (uPA) is strongly associated with patient survival ( P survival = 3.52 x 10 -5 , OR 3). Overall, our genetic analysis showed that genetic variation determines the abundance of circulatory proteins in response to Candida infection

Standardizing designed and emergent quantitative features in microphysiological systems

Microphysiological systems (MPSs) are cellular models that replicate aspects of organ and tissue functions in vitro. In contrast with conventional cell cultures, MPSs often provide physiological mechanical cues to cells, include fluid flow and can be interlinked (hence, they are often referred to as microfluidic tissue chips or organs-on-chips). Here, by means of examples of MPSs of the vascular system, intestine, brain and heart, we advocate for the development of standards that allow for comparisons of quantitative physiological features in MPSs and humans. Such standards should ensure that the in vivo relevance and predictive value of MPSs can be properly assessed as fit-for-purpose in specific applications, such as the assessment of drug toxicity, the identification of therapeutics or the understanding of human physiology or disease. Specifically, we distinguish designed features, which can be controlled via the design of the MPS, from emergent features, which describe cellular function, and propose methods for improving MPSs with readouts and sensors for the quantitative monitoring of complex physiology towards enabling wider end-user adoption and regulatory acceptance

Standardizing designed and emergent quantitative features in microphysiological systems

Microphysiological systems (MPSs) are cellular models that replicate aspects of organ and tissue functions in vitro. In contrast with conventional cell cultures, MPSs often provide physiological mechanical cues to cells, include fluid flow and can be interlinked (hence, they are often referred to as microfluidic tissue chips or organs-on-chips). Here, by means of examples of MPSs of the vascular system, intestine, brain and heart, we advocate for the development of standards that allow for comparisons of quantitative physiological features in MPSs and humans. Such standards should ensure that the in vivo relevance and predictive value of MPSs can be properly assessed as fit-for-purpose in specific applications, such as the assessment of drug toxicity, the identification of therapeutics or the understanding of human physiology or disease. Specifically, we distinguish designed features, which can be controlled via the design of the MPS, from emergent features, which describe cellular function, and propose methods for improving MPSs with readouts and sensors for the quantitative monitoring of complex physiology towards enabling wider end-user adoption and regulatory acceptance.</p