Type I Interferons Link Viral Infection to Enhanced Epithelial Turnover and Repair

The host immune system functions constantly to maintain chronic commensal and pathogenic organisms in check. The consequences of these immune responses on host physiology are as yet unexplored, and may have long-term implications in health and disease. We show that chronic viral infection increases epithelial turnover in multiple tissues, and the antiviral cytokines type I interferons (IFNs) mediate this response. Using a murine model with persistently elevated type I IFNs in the absence of exogenous viral infection, the Irgm1−/− mouse, we demonstrate that type I IFNs act through nonepithelial cells, including macrophages, to promote increased epithelial turnover and wound repair. Downstream of type I IFN signaling, the highly related IFN-stimulated genes Apolipoprotein L9a and b activate epithelial proliferation through ERK activation. Our findings demonstrate that the host immune response to chronic viral infection has systemic effects on epithelial turnover through a myeloid-epithelial circuit

Patient Choice in the Post-Semashko Health Care System

The opportunity for patient choice in the health care system in CIS countries was created by the partial destruction of the referral system and the development of paid medical services. The data of two population surveys conducted in Russia in 2009 and 2011 show that patient choice of medical facility and physician is taking place in the post-Semashko health care system, and it is not restricted to the area of paid medical services. However for the majority of population the choice of medical facility and physician is not a necessity. Part of reason for patient choice is caused by the failure of the patient referral system to ensure the necessary treatment. For some Russian citizens, the choice of health care provider is a means to obtain better quality care, and in this respect the enhancement of patient choice is leading to the improved efficiency of the emerging health care system.Была создана возможность для выбора пациента в системе здравоохранения в странах СНГ путем частичного разрушения системы направлений и развития платных медицинских услуг. Данные двух исследований, проведенных в области народонаселения в России в 2009 и 2011 показывают, что выбор медицинского учреждения и врача пациентом происходит в после-семашковской системе здравоохранения, и не ограничивается областью платных медицинских услуг. Однако для большинства населения выбор медицинского учреждения и врача не является необходимостью. Часть причины для выбора пациента вызвано неспособностью пациента реферальной системы в обеспечить необходимое лечение. Для некоторых российских граждан, выбор медицинских услуг является средством для получения лучшего качества медицинской помощи, и в этом отношении поощрение выбора пациента ведет к повышению эффективности создаваемой системы здравоохранения

Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo

Lipidated Rho and Rab GTP-binding proteins are transported between membranes in complex with solubilizing factors called 'guanine nucleotide dissociation inhibitors' (GDIs). Unloading from GDIs using GDI displacement factors (GDFs) has been proposed but remains mechanistically elusive. PDEδ is a putative solubilizing factor for several prenylated Ras-subfamily proteins. Here we report the structure of fully modified farnesylated Rheb-GDP in complex with PDEδ. The structure explains the nucleotide-independent binding of Rheb to PDEδ and the relaxed specificity of PDEδ. We demonstrate that the G proteins Arl2 and Arl3 act in a GTP-dependent manner as allosteric release factors for farnesylated cargo. We thus describe a new transport system for farnesylated G proteins involving a GDI-like molecule and an unequivocal GDF. Considering the importance of PDEδ for proper Ras and Rheb signaling, this study is instrumental in developing a new target for anticancer therapy

Identification of context-dependent expression quantitative trait loci in whole blood

Genetic risk factors often localize to noncoding regions of the genome with unknown effects on disease etiology. Expression quantitative trait loci (eQTLs) help to explain the regulatory mechanisms underlying these genetic associations. Knowledge of the context that determines the nature and strength of eQTLs may help identify cell types relevant to pathophysiology and the regulatory networks underlying disease. Here we generated peripheral blood RNA-seq data from 2,116 unrelated individuals and systematically identified context-dependent eQTLs using a hypothesis-free strategy that does not require previous knowledge of the identity of the modifiers. Of the 23,060 significant cis-regulated genes (false discovery rate (FDR) ≤ 0.05), 2,743 (12%) showed context-dependent eQTL effects. The majority of these effects were influenced by cell type composition. A set of 145 cis-eQTLs depended on type I interferon signaling. Others were modulated by specific transcription factors binding to the eQTL SNPs