Atopic dermatitis (AD) is a common inflammatory skin disorder that manifests as eczematous lesions, often associated with allergic rhinitis and asthma. Historically, moderate-to-severe disease has been managed with systemic immunosuppression, such as oral corticosteroids, which result in relapse and limiting side effects. Due to recent advancements in the identification of interleukin (IL)-4 and IL-13 as key mediators in AD, new biological agents have been developed for treatment. Dupilumab is a recently approved monoclonal antibody that targets the alpha subunit of the IL-4 receptor and, thus, downregulates activity of IL-4 and IL-13. This review discusses the profile of dupilumab and its potential for efficacy and safety in treating moderate-to-severe AD by reviewing data from Phase I–III clinical trials. Results suggest that dupilumab shows great therapeutic promise for AD. Further studies investigating extended use of dupilumab and dupilumab in comparison to other agents are needed to establish long-term efficacy and safety.
The Paramyxoviridae comprise a large family of enveloped, negative-sense, single-stranded RNA viruses with significant economic and public health implications. For nearly all paramyxoviruses, infection is initiated by fusion of the viral and host cell plasma membranes in a pH-independent fashion. Fusion is orchestrated by the receptor binding protein hemagglutinin-neuraminidase (HN; also called H or G depending on the virus type) protein and a fusion (F) protein, the latter undergoing a major refolding process to merge the two membranes. Mechanistic details regarding the coupling of receptor binding to F activation are not fully understood. Here, we have identified the flexible loop region connecting the bulky enzymatically active head and the four-helix bundle stalk to be essential for fusion promotion. Proline substitution in this region of HN of parainfluenza virus 5 (PIV5) and Newcastle disease virus HN abolishes cell-cell fusion, whereas HN retains receptor binding and neuraminidase activity. By using reverse genetics, we engineered recombinant PIV5-EGFP viruses with mutations in the head-stalk linker region of HN. Mutations in this region abolished virus recovery and infectivity. In sum, our data suggest that the loop region acts as a "hinge" around which the bulky head of HN swings to-and-fro to facilitate timely HN-mediate F-triggering, a notion consistent with the stalk-mediated activation model of paramyxovirus fusion.
IMPORTANCE
Paramyxovirus fusion with the host cell plasma membrane is essential for virus infection. Membrane fusion is orchestrated via interaction of the receptor binding protein (HN, H, or G) with the viral fusion glycoprotein (F). Two distinct models have been suggested to describe the mechanism of fusion: these include "the clamp" and the "provocateur" model of activation. By using biochemical and reverse genetics tools, we have obtained strong evidence in favor of the HN stalk-mediated activation of paramyxovirus fusion. Specifically, our data strongly support the notion that the short linker between the head and stalk plays a role in "conformational switching" of the head group to facilitate F-HN interaction and triggering.
The Paramyxoviridae comprise a large family of enveloped, negative sense, single-stranded RNA viruses that are responsible for many important human and other animal diseases. Among these viruses are mumps virus, measles virus, respiratory syncytial virus, canine distemper virus, Newcastle disease virus (NDV), and parainfluenza viruses 1 to 5 (PIV1-5), as well as the Hendra and Nipah viruses (1-13). Paramyxoviruses cause significant threat to public health and safety and an economic loss to agribusiness. For entry into cells, all paramyxoviruses require fusion of their membrane with their target host cell plasma membrane (4, 14-21). A detailed understanding of the fusion mechanism is key to the development of therapeutic and vaccine strategies to prevent outbreaks.Unlike enveloped viruses that require a single glycoprotein for fusion, such as influenza v...
UNSTRUCTURED
This study underscores the persistent underrepresentation of women in academic dermatology leadership positions by examining the gender composition of editorial boards across top dermatology journals, emphasizing the urgent need for proactive strategies to promote diversity, equity, and inclusion.
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