A Randomized Community-based Intervention Trial Comparing Faith Community Nurse Referrals to Telephone-Assisted Physician Appointments for Health Fair Participants with Elevated Blood Pressure

To measure the effect of faith community nurse referrals versus telephone-assisted physician appointments on blood pressure control among persons with elevated blood pressure at health fairs. Randomized community-based intervention trial conducted from October 2006 to October 2007 of 100 adults who had an average blood pressure reading equal to or above a systolic of 140 mm Hg or a diastolic of 90 mm Hg obtained at a faith community nurse-led church health event. Participants were randomized to either referral to a faith community nurse or to a telephone-assisted physician appointment. The average enrollment systolic blood pressure (SBP) was 149 ± 14 mm Hg, diastolic blood pressure (DBP) was 87 ± 11 mm Hg, 57% were uninsured and 25% were undiagnosed at the time of enrollment. The follow-up rate was 85% at 4 months. Patients in the faith community nurse referral arm had a 7 ± 15 mm Hg drop in SBP versus a 14 ± 15 mm Hg drop in the telephone-assisted physician appointment arm (p = 0.04). Twenty-seven percent of the patients in the faith community nurse referral arm had medication intensification compared to 32% in the telephone-assisted physician appointment arm (p = 0.98). Church health fairs conducted in low-income, multiethnic communities can identify many people with elevated blood pressure. Facilitating physician appointments for people with elevated blood pressure identified at health fairs confers a greater decrease in SBP than referral to a faith community nurse at four months

Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria

Even in the setting of optimal resuscitation in high-income countries severe sepsis and septic shock have a mortality of 20–40%, with antibiotic resistance dramatically increasing this mortality risk. To develop a reference dataset enabling the identification of common bacterial targets for therapeutic intervention, we applied a standardized genomic, transcriptomic, proteomic and metabolomic technological framework to multiple clinical isolates of four sepsis-causing pathogens: Escherichia coli, Klebsiella pneumoniae species complex, Staphylococcus aureus and Streptococcus pyogenes. Exposure to human serum generated a sepsis molecular signature containing global increases in fatty acid and lipid biosynthesis and metabolism, consistent with cell envelope remodelling and nutrient adaptation for osmoprotection. In addition, acquisition of cholesterol was identified across the bacterial species. This detailed reference dataset has been established as an open resource to support discovery and translational research

WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of LRP6 and establish a negative feedback loop

β-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through a WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates WNT signaling through internalization and degradation of the receptor complex. Here, using a gain-of-function screen of the human kinome, we report that the AP2 associated kinase 1 (AAK1), a known CME enhancer, inhibits WNT signaling. Reciprocally, AAK1 genetic silencing or its pharmacological inhibition using a potent and selective inhibitor activates WNT signaling. Mechanistically, we show that AAK1 promotes clearance of LRP6 from the plasma membrane to suppress the WNT pathway. Time-course experiments support a transcription-uncoupled, WNT-driven negative feedback loop; prolonged WNT treatment drives AAK1-dependent phosphorylation of AP2M1, clathrin-coated pit maturation, and endocytosis of LRP6. We propose that, following WNT receptor activation, increased AAK1 function and CME limits WNT signaling longevity

WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of LRP6 and establish a negative feedback loop

β-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through a WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates WNT signaling through internalization and degradation of the receptor complex. Here, using a gain-of-function screen of the human kinome, we report that the AP2 associated kinase 1 (AAK1), a known CME enhancer, inhibits WNT signaling. Reciprocally, AAK1 genetic silencing or its pharmacological inhibition using a potent and selective inhibitor activates WNT signaling. Mechanistically, we show that AAK1 promotes clearance of LRP6 from the plasma membrane to suppress the WNT pathway. Time-course experiments support a transcription-uncoupled, WNT-driven negative feedback loop; prolonged WNT treatment drives AAK1-dependent phosphorylation of AP2M1, clathrin-coated pit maturation, and endocytosis of LRP6. We propose that, following WNT receptor activation, increased AAK1 function and CME limits WNT signaling longevity