Proximity-dependent mapping of the HCMV US28 interactome identifies RhoGEF signaling as a requirement for efficient viral reactivation.

Human cytomegalovirus (HCMV) encodes multiple putative G protein-coupled receptors (GPCRs). US28 functions as a viral chemokine receptor and is expressed during both latent and lytic phases of virus infection. US28 actively promotes cellular migration, transformation, and plays a major role in mediating viral latency and reactivation; however, knowledge about the interaction partners involved in these processes is still incomplete. Herein, we utilized a proximity-dependent biotinylating enzyme (TurboID) to characterize the US28 interactome when expressed in isolation, and during both latent (CD34+ hematopoietic progenitor cells) and lytic (fibroblasts) HCMV infection. Our analyses indicate that the US28 signalosome converges with RhoA and EGFR signal transduction pathways, sharing multiple mediators that are major actors in processes such as cellular proliferation and differentiation. Integral members of the US28 signaling complex were validated in functional assays by immunoblot and small-molecule inhibitors. Importantly, we identified RhoGEFs as key US28 signaling intermediaries. In vitro latency and reactivation assays utilizing primary CD34+ hematopoietic progenitor cells (HPCs) treated with the small-molecule inhibitors Rhosin or Y16 indicated that US28 -RhoGEF interactions are required for efficient viral reactivation. These findings were recapitulated in vivo using a humanized mouse model where inhibition of RhoGEFs resulted in a failure of the virus to reactivate. Together, our data identifies multiple new proteins in the US28 interactome that play major roles in viral latency and reactivation, highlights the utility of proximity-sensor labeling to characterize protein interactomes, and provides insight into targets for the development of novel anti-HCMV therapeutics

Mayaro virus pathogenesis and immunity in rhesus macaques.

Mayaro virus (MAYV) is a mosquito-transmitted alphavirus that causes debilitating and persistent arthritogenic disease. While MAYV was previously reported to infect non-human primates (NHP), characterization of MAYV pathogenesis is currently lacking. Therefore, in this study we characterized MAYV infection and immunity in rhesus macaques. To inform the selection of a viral strain for NHP experiments, we evaluated five MAYV strains in C57BL/6 mice and showed that MAYV strain BeAr505411 induced robust tissue dissemination and disease. Three male rhesus macaques were subcutaneously challenged with 105 plaque-forming units of this strain into the arms. Peak plasma viremia occurred at 2 days post-infection (dpi). NHPs were taken to necropsy at 10 dpi to assess viral dissemination, which included the muscles and joints, lymphoid tissues, major organs, male reproductive tissues, as well as peripheral and central nervous system tissues. Histological examination demonstrated that MAYV infection was associated with appendicular joint and muscle inflammation as well as presence of perivascular inflammation in a wide variety of tissues. One animal developed a maculopapular rash and two NHP had viral RNA detected in upper torso skin samples, which was associated with the presence of perivascular and perifollicular lymphocytic aggregation. Analysis of longitudinal peripheral blood samples indicated a robust innate and adaptive immune activation, including the presence of anti-MAYV neutralizing antibodies with activity against related Una virus and chikungunya virus. Inflammatory cytokines and monocyte activation also peaked coincident with viremia, which was well supported by our transcriptomic analysis highlighting enrichment of interferon signaling and other antiviral processes at 2 days post MAYV infection. The rhesus macaque model of MAYV infection recapitulates many of the aspects of human infection and is poised to facilitate the evaluation of novel therapies and vaccines targeting this re-emerging virus

Pamphlets - homoeopathic.

-- Work of the National Association of Homoeopathic Members of Examining and Licensing Boards / H.M. Paine -- Pabula Neonatorum, a guide to the feeding of infants / G.B. Peck -- Treatment of scarlatina and measles / G.B. Peck -- Flotsam and jetsam / O.S. Runnels -- Constitution and by-laws, code of ethics, officers and members / Southern Homoeopathic Medical Association -- Science and homoeopathy / F.P. WebsterLetter to the members of the American Institute from A.B. Norton / American Institute of Homeopathy -- Important notice to the members of the American Institute of Homoeopathy in relation to the repertory of the Cyclopaedia of Drug Pathogenesy / R. Hughes -- Constitution and by-laws / American Institute of Homeopathy -- Code of medical ethics, constitution, by-laws, and list of members of the American Institute of Homoeopathy / American Institute of Homeopathy -- Homoeopathy in the public service / B.F.Bailey -- Proof of the law of similia from the electro-chemico-physiological standpoint / E.H.S. Bailey -- Two cases of brain tumor : a contribution to cerebral surgery / C. Bartlett -- Concerning Hensel's Tonicum... / Boericke & Tafel -- Homoeopathy : some observations in regard to its progress for forty years / G.W. Bowen -- Tubercular cystitis / B.G. Carleton -- Proving of the Apis Mellifica / Central New-York Homoeopathic Society -- On supra-pubic cystotomy and catheterization as a guide in perineal section for obliterative urethritis / H. Crutcher -- Test at the bed-side / P. Dudley -- Dietetic, climatic and hygienic treatment of tuberculosis / F.A. Faust -- Concordance repertory, of the well proven and most reliable symptoms of the homoeopathic Materia Medica / W.D. Gentry -- Sanitation on the farm / W.B. Hinsdale -- June number of the New England Medical Gazette...contains a paper... / Editor of Homoeopathic Recorder -- Samuel Hahnemann : a lecture / H.P. Holmes -- Urine of uro-genital tuberculosis / G.F. Laidlaw -- Plea for homeopathic solidarity and independent work / S. Leavitt -- Ups and downs of a doctor's life, being the closing lecture of the course delivered in the Hahnemann Medical College for the session of 1863-64 / R. Ludlam -- Study of Materia Medica / C. Mohr -- Twentieth century homoeopathy / J.H. Moore -- Spinal Affections / E.A. Murphy, M.D. -- Yellow fever, its treatment and prevention / E.A. Murphy, M.D.Mode of access: Internet