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Viral membrane fusion
Infection by viruses having lipid-bilayer envelopes proceeds through fusion of the viral membrane with a membrane of the target cell. Viral 'fusion proteins' facilitate this process. They vary greatly in structure, but all seem to have a common mechanism of action, in which a ligand-triggered, large-scale conformational change in the fusion protein is coupled to apposition and merger of the two bilayers. We describe three examples—the influenza virus hemagglutinin, the flavivirus E protein and the vesicular stomatitis virus G protein—in some detail, to illustrate the ways in which different structures have evolved to implement this common mechanism. Fusion inhibitors can be effective antiviral agents.
Journal Article
The jazz age : American style in the 1920s
An exhilarating look at Art Deco design in 1920s America, using jazz as its unifying metaphor. Capturing the dynamic pulse of the era's jazz music, this lavishly illustrated publication explores American taste and style during the golden age of the 1920s. Following the destructive years of the First World War, this flourishing decade marked a rebirth of aesthetic innovation that was cultivated to a great extent by American talent and patronage. Due to an influx of European emigres to the United States, as well as American enthusiasm for traveling to Europe's cultural capitals, a reciprocal wave of experimental attitudes began traveling back and forth across the Atlantic, forming a creative vocabulary that mirrored the ecstatic spirit of the times. \"\" showcases developments in design, art, architecture, and technology during the '20s and early '30s, and places new emphasis on the United States as a vital part of the emerging marketplace for Art Deco luxury goods. Featuring hundreds of full-color illustrations and essays by two leading historians of decorative arts, this comprehensive catalogue shows how America and the rest of the world worked to establish a new visual representation of modernity.
Book
Challenges and opportunities in NASH drug development
Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), represent a growing worldwide epidemic and a high unmet medical need, as no licensed drugs have been approved thus far. Currently, histopathological assessment of liver biopsies is mandatory as a primary endpoint for conditional drug approval. This requirement represents one of the main challenges in the field, as there is substantial variability in this invasive histopathological assessment, which leads to dramatically high screen-failure rates in clinical trials. Over the past decades, several non-invasive tests have been developed to correlate with liver histology and, eventually, outcomes to assess disease severity and longitudinal changes non-invasively. However, further data are needed to ensure their endorsement by regulatory authorities as alternatives to histological endpoints in phase 3 trials. This Review describes the challenges of drug development in NAFLD–NASH trials and potential mitigating strategies to move the field forward.
This Review surveys the NASH clinical trial landscape and the main challenges to drug approval, and discusses new approaches to overcoming these, including innovative trial designs, non-invasive tests and biomarkers.
Journal Article
Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial
Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. MAESTRO-NAFLD-1 was a 52-week randomized, double-blind, placebo-controlled phase 3 trial evaluating the safety of resmetirom in adults with nonalcoholic fatty liver disease and presumed NASH. Patients were randomized to three double-blind arms (100 mg resmetirom (
n
= 325), 80 mg resmetirom (
n
= 327) or placebo (
n
= 320)) or open-label 100 mg resmetirom (
n
= 171). The primary end point was incidence of treatment-emergent adverse events (TEAEs) over 52 weeks and key secondary end points were LDL-C, apoB, triglycerides (over 24 weeks), hepatic fat (over 16 and 52 weeks) and liver stiffness (over 52 weeks). Resmetirom was safe and well tolerated. TEAEs occurred in 86.5% (open-label 100 mg resmetirom), 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom) and 81.8% (placebo) of patients. TEAEs in excess of placebo included diarrhea and nausea at the initiation of treatment. Key secondary end points included least square means difference from placebo at 80 mg, 100 mg resmetirom: LDL-C (−11.1%, −12.6%), apoB (−15.6%, −18.0%), triglycerides (−15.4%, −20.4%), 16-week hepatic fat (−34.9%, −38.6%), (
P
< 0.0001) and liver stiffness (−1.02, −1.70) and 52-week hepatic fat (−28.8, −33.9). These findings demonstrate resmetirom was safe and well tolerated in adults with presumed NASH, supporting a role for further clinical development. (ClinicalTrials.gov identifier
NCT04197479
).
In the phase 3 MAESTRO-NAFLD-1 trial, the liver-targeted thyroid hormone receptor-β selective agonist resmetirom was well tolerated and improved liver biomarkers in adults with nonalcoholic fatty liver disease.
Journal Article
A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis
Patients with nonalcoholic steatohepatitis were randomly assigned to receive subcutaneous semaglutide or placebo. The incidence of NASH resolution was significantly higher with semaglutide than with placebo, but the between-group difference in the incidence of an improvement in fibrosis stage was not significant.
Journal Article
A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis
Resmetirom is a selective agonist of THR-β. In adults with nonalcoholic steatohepatitis and fibrosis, daily resmetirom (80 mg or 100 mg) was superior to placebo with respect to NASH resolution and fibrosis improvement.
Journal Article
Structure of the DASH/Dam1 complex shows its role at the yeast kinetochore-microtubule interface
When a cell prepares to divide, it copies its DNA into pairs of each chromosome, called chromatids. Microtubules attach to the chromosome pairs through protein complexes called kinetochores. During cell division, microtubule depolymerization pulls the chromatids apart. Jenni and Harrison describe the structure of an essential component of the yeast kinetochore, the DASH/Dam1c complex, that forms a ring around a microtubule. The structure shows how the DASH/Dam1c ring interacts with the microtubule and kinetochore components so that the kinetochore can track to the end of the microtubule through cycles of growth and shrinkage. Science , this issue p. 552 A cryo-EM–derived structure of the DASH/Dam1 complex suggests how microtubule depolymerization drives chromosome separation. Kinetochores connect mitotic-spindle microtubules with chromosomes, allowing microtubule depolymerization to pull chromosomes apart during anaphase while resisting detachment as the microtubule shortens. The heterodecameric DASH/Dam1 complex (DASH/Dam1c), an essential component of yeast kinetochores, assembles into a microtubule-encircling ring. The ring associates with rodlike Ndc80 complexes to organize the kinetochore-microtubule interface. We report the cryo–electron microscopy structure (at ~4.5-angstrom resolution) of a DASH/Dam1c ring and a molecular model of its ordered components, validated by evolutionary direct-coupling analysis. Integrating this structure with that of the Ndc80 complex and with published interaction data yields a molecular picture of kinetochore-microtubule attachment, including how flexible, C-terminal extensions of DASH/Dam1c subunits project and contact widely separated sites on the Ndc80 complex rod and how phosphorylation at previously identified sites might regulate kinetochore assembly.
Journal Article
Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial
Preclinical and clinical data suggest that fibroblast growth factor 21 (FGF21) is anti-fibrotic, improves metabolic status and has potential to treat non-alcoholic steatohepatitis (NASH). We assessed the safety and efficacy of efruxifermin, a long-acting Fc-FGF21 fusion protein, for the treatment of NASH. BALANCED was a randomized, placebo-controlled study in patients with NASH conducted at 27 centers in the United States (ClinicalTrials.gov
NCT03976401
). Eighty patients, stratified by hepatic fat fraction (HFF) and fibrosis stage, were randomized using a centrally administered minimization algorithm 1:1:1:1 to receive placebo (
n
= 21) or efruxifermin 28 mg (
n
= 19), efruxifermin 50 mg (
n
= 20) or efruxifermin 70 mg (
n
= 20) via weekly subcutaneous injection for 16 weeks. The primary endpoint—absolute change from baseline in HFF measured as magnetic resonance imaging–proton density fat fraction at week 12—was met. For the full analysis set, the least squares mean absolute changes (one-sided 97.5% confidence interval) from baseline in HFF were −12.3% (−infinity (−inf), −10.3), −13.4% (−inf, −11.4) and −14.1% (−inf, −12.1) in the 28-, 50- and 70-mg groups, respectively, versus 0.3% (−inf, 1.6) in the placebo group, with statistically significant differences between efruxifermin groups and placebo (
P
< 0.0001 each). Overall, 70 of 79 patients who received the study drug (89%) experienced at least one treatment-emergent adverse event (TEAE), with the majority grade 1–2 (64 (81%)), five (6%) grade 3 and one grade 4. The most commonly reported drug-related TEAEs were grade 1–2 gastrointestinal (36 (46%)). Treatment with efruxifermin significantly reduced HFF in patients with F1–F3 stage NASH, with an acceptable safety profile.
Results from BALANCED, a phase 2a, multicenter, randomized controlled trial testing efruxifermin (a long-acting Fc-FGF21 fusion protein) over 16 weeks, demonstrated significant reductions in the hepatic fat fraction in patients with F1–F3 stage non-alcoholic steatohepatitis.
Journal Article
The structure of the Ctf19c/CCAN from budding yeast
Eukaryotic kinetochores connect spindlemicrotubules to chromosomal centromeres. A group of proteins called the Ctf19 complex (Ctf19c) in yeast and the constitutive centromere associated network (CCAN) in other organisms creates the foundation of a kinetochore. The Ctf19c/CCAN influences the timing of kinetochore assembly, sets its location by associating with a specialized nucleosome containing the histone H3 variant Cse4/CENP-A, and determines the organization of the microtubule attachment apparatus. We present here the structure of a reconstituted 13-subunit Ctf19c determined by cryo-electron microscopy at ~4 Å resolution. The structure accounts for known and inferred contacts with the Cse4 nucleosome and for an observed assembly hierarchy. We describe its implications for establishment of kinetochores and for their regulation by kinases throughout the cell cycle.
Journal Article