Flaviviruses are emerging and re-emerging arthropod-borne pathogens responsible for significant mortality and morbidity worldwide. The genus comprises more than seventy small, positive-sense, single-stranded RNA viruses, which are responsible for a spectrum of human and animal diseases ranging in symptoms from mild, influenza-like infection to fatal encephalitis and haemorrhagic fever. Despite genomic and structural similarities across the genus, infections by different flaviviruses result in disparate clinical presentations. This review focusses on two haemorrhagic flaviviruses, dengue virus and yellow fever virus, and two neurotropic flaviviruses, Japanese encephalitis virus and Zika virus. We review current knowledge on host-pathogen interactions, virus entry strategies and tropism.
Facioscapulohumeral muscular dystrophy is a dominantly inherited myopathy associated with chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4. DUX4 is encoded within each unit of the D4Z4 array where it is normally transcriptionally silenced and packaged as constitutive heterochromatin. Truncation of the array to less than 11 D4Z4 units (FSHD1) or mutations in SMCHD1 (FSHD2) results in chromatin relaxation and a small percentage of cultured myoblasts from these individuals exhibit infrequent bursts of DUX4 expression. There are no cellular or animal models to determine the trigger of the DUX4 producing transcriptional bursts and there has been a failure to date to detect the protein in significant numbers of cells from FSHD-affected individuals. Here, we demonstrate for the first time that myotubes generated from FSHD patients express sufficient amounts of DUX4 to undergo DUX4-dependent apoptosis. We show that activation of the Wnt/β-catenin signaling pathway suppresses DUX4 transcription in FSHD1 and FSHD2 myotubes and can rescue DUX4-mediated myotube apoptosis. In addition, reduction of mRNA transcripts from Wnt pathway genes β-catenin, Wnt3A and Wnt9B results in DUX4 activation. We propose that Wnt/β-catenin signaling is important for transcriptional repression of DUX4 and identify a novel group of therapeutic targets for the treatment of FSHD.
Background Neurodegeneration plays an important role in permanent disability in multiple sclerosis (MS). Objective To determine whether progressive neurodegeneration occurs in MS eyes without clinically-evident inflammation. Methods Retinal nerve fiver layer thickness (RNFLT) and ganglion cell-inner plexiform layer thickness (GCIPT) were measured using Cirrus optical coherence tomography (OCT) in 133 relapsing-remitting MS (RRMS) patients (149 no-ON, 97 ON eyes, last optic neuritis (ON) ≥6 months). 93 patients were scanned at two visits. Percents of abnormal GCIPT vs RNFLT (<5% of machine norms) in cross-sectional data were compared. Relations between RNFLT/GCIPT and MS duration (cross-sectional) and follow-up time (longitudinal) were assessed. Results GCIPT was abnormal in more eyes than RNFLT (27% vs 16% p=0.004 in no-ON, 82% vs 72% p=0.007 in ON). RNFLT and GCIPT decreased with MS duration by −0.49 µm/yr (p=0.0001) and −0.36 (p=0.005) for no-ON; −0.52 (p=0.003) and −0.41 (p=0.007) for ON. RNFLT and GCIPT decreased with follow-up time by −1.49 µm/yr (p<0.0001) and −0.53 (p=0.004) for no-ON, −1.27 (p=0.002) and −0.49 (p=0.04) for ON. Conclusions In RRMS eyes without clinically-evident inflammation, progressive loss of RNFLT and GCIPT occurred, supporting the need for neuroprotection in addition to suppression of auto-immune responses and inflammation.
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