Genetic Variation Shapes Protein Networks Mainly through Non-transcriptional Mechanisms

Variation in the levels of co-regulated proteins that function within networks in an outbred yeast population is not driven by variation in the corresponding transcripts

Klf4 and Klf5 differentially inhibit mesoderm and endoderm differentiation in embryonic stem cells

Kruppel-like factors (Klf) 4 and 5 are two closely related members of the Klf family, known to play key roles in cell cycle regulation, somatic cell reprogramming and pluripotency. Here we focus on the functional divergence between Klf4 and Klf5 in the inhibition of mouse embryonic stem (ES) cell differentiation. Using microarrays and chromatin immunoprecipitation coupled to ultra-high-throughput DNA sequencing, we show that Klf4 negatively regulates the expression of endodermal markers in the undifferentiated ES cells, including transcription factors involved in the commitment of pluripotent stem cells to endoderm differentiation. Knockdown of Klf4 enhances differentiation towards visceral and definitive endoderm. In contrast, Klf5 negatively regulates the expression of mesodermal markers, some of which control commitment to the mesoderm lineage, and knockdown of Klf5 specifically enhances differentiation towards mesoderm. We conclude that Klf4 and Klf5 differentially inhibit mesoderm and endoderm differentiation in murine ES cells

Adjunctive Glucocorticoid Therapy for Pneumocystis jirovecii Pneumonia in Solid Organ Transplant Recipients: A Multicenter Cohort, 2015-2020.

Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, examined whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day in-hospital death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP [median (IQR) age: 60 (51.5-67.0) years, 58 female (33.5%)], the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission [aOR (CI95%): 0.49 (0.21-1.12)], death [aOR (CI95%): 0.80 (0.30-2.17)], or the composite outcome [aOR (CI95%): 10.97 (0.71-1.31)] in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1-unit SOFAResp (the respiratory portion of the Sequential Organ Failure Assessment score) improvement by day 5 [12/37 (32.4%) vs 39/111 (35.1%), p=0.76)]. We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a re-evaluation of routine AGT administration in post-transplant PJP treatment and highlight the need for interventional studies

Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks

A principal task in dissecting the genetics of complex traits is to identify causal genes for disease phenotypes. We previously developed a method to infer causal relationships among genes through the integration of DNA variation, gene transcription and phenotypic information. Here we have validated our method through the characterization of transgenic and knockout mouse models of genes predicted to be causal for abdominal obesity. Perturbation of eight out of the nine genes, with Gas7, Me1 and Gpx3 being newly confirmed, resulted in significant changes in obesity-related traits. Liver expression signatures revealed alterations in common metabolic pathways and networks contributing to abdominal obesity and overlapped with a macrophage-enriched metabolic network module that is highly associated with metabolic traits in mice and humans. Integration of gene expression in the design and analysis of traditional F(2) intercross studies allows high-confidence prediction of causal genes and identification of pathways and networks involved