Immunosuppression during Acute Infection with Foot-and-Mouth Disease Virus in Swine Is Mediated by IL-10

Foot-and-mouth disease virus (FMDV) is one of the most contagious animal viruses, causing a devastating disease in cloven-hoofed animals with enormous economic consequences. Identification of the different parameters involved in the immune response elicited against FMDV remains unclear, and it is fundamental the understanding of such parameters before effective control measures can be put in place. In the present study, we show that interleukin-10 (IL-10) production by dendritic cells (DCs) is drastically increased during acute infection with FMDV in swine. In vitro blockade of IL-10 with a neutralizing antibody against porcine IL-10 restores T cell activation by DCs. Additionally, we describe that FMDV infects DC precursors and interferes with DC maturation and antigen presentation capacity. Thus, we propose a new mechanism of virus immunity in which a non-persistent virus, FMDV, induces immunosuppression by an increment in the production of IL-10, which in turn, reduces T cell function. This reduction of T cell activity may result in a more potent induction of neutralizing antibody responses, clearing the viral infection

Kinetically E-selective macrocyclic ring-closing metathesis

Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin). To this end, the catalytic process known as ring-closing metathesis (RCM) has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production. Stereoselectivity is often critical in such cases: The potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation). Kinetically controlled Z-selective RCM reactions have been reported, but the only available metathesis approach for accessing macrocyclic E-olefins entails selective removal of the Z-component of a stereoisomeric mixture by ethenolysis, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization- A particularly serious problem when the E-alkene is energetically less favoured. Here, we show that dienes containing an E-alkenyl-B(pinacolato) group, widely used in catalytic cross-coupling, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E-macrocyclic alkenes. The reaction is promoted by a molybdenum monoaryloxide pyrrolide complex and affords products at a yield of up to 73 per cent and an E/Z ratio greater than 98/2. We highlight the utility of the approach by preparing recifeiolide (a 12-membered-ring antibiotic) and pacritinib (an 18-membered-ring enzyme inhibitor), the Z-isomer of which is less potent than the E-isomer. Notably, the 18-membered-ring moiety of pacritinib- A potent anti-cancer agent that is in advanced clinical trials for treating lymphoma and myelofibrosis-was prepared by RCM carried out at a substrate concentration 20 times greater than when a ruthenium carbene was used.National Institutes of Health (U.S.) (Grant GM-59426)National Science Foundation (U.S.) (Grant CHE-1362763

Clinical advantages and disadvantages of anabolic bone therapies targeting the WNT pathway

Diabetes mellitus: pathophysiological changes and therap

Genetics of Skeletal Disorders

Bone and mineral diseases encompass a variety of conditions that involve altered skeletal homeostasis and are frequently associated with changes in circulating calcium, phosphate, or vitamin D metabolites. These disorders often have a genetic etiology and comprise monogenic disorders caused by a single-gene mutation, which may be germline or somatic, or an oligogenic or polygenic condition involving multiple genetic variants. Single-gene mutations causing Mendelian diseases are usually highly penetrant, whereas the gene variants contributing to oligogenic or polygenic disorders are each associated with smaller effects with additional contributions from environmental factors. The detection of monogenic disorders is clinically important and facilitates timely assessment and management of the patient and their affected relatives. The diagnosis of monogenic metabolic bone disorders requires detailed clinical assessment of the wide variety of symptoms and signs associated with these diseases. Thus, clinicians should undertake a systematic approach commencing with careful history taking and physical examination, followed by appropriate laboratory and skeletal imaging investigations. Finally, clinicians should be familiar with the range of molecular genetic tests available to ensure their appropriate use and interpretation. These considerations are reviewed in this chapter