Gene expression during normal and FSHD myogenesis

<p>Abstract</p> <p>Background</p> <p>Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contraction of an array of tandem 3.3-kb repeats (D4Z4) at 4q35. Within each repeat unit is a gene, <it>DUX4</it>, that can encode a protein containing two homeodomains. A <it>DUX4 </it>transcript derived from the last repeat unit in a contracted array is associated with pathogenesis but it is unclear how.</p> <p>Methods</p> <p>Using exon-based microarrays, the expression profiles of myogenic precursor cells were determined. Both undifferentiated myoblasts and myoblasts differentiated to myotubes derived from FSHD patients and controls were studied after immunocytochemical verification of the quality of the cultures. To further our understanding of FSHD and normal myogenesis, the expression profiles obtained were compared to those of 19 non-muscle cell types analyzed by identical methods.</p> <p>Results</p> <p>Many of the ~17,000 examined genes were differentially expressed (> 2-fold, <it>p </it>< 0.01) in control myoblasts or myotubes vs. non-muscle cells (2185 and 3006, respectively) or in FSHD vs. control myoblasts or myotubes (295 and 797, respectively). Surprisingly, despite the morphologically normal differentiation of FSHD myoblasts to myotubes, most of the disease-related dysregulation was seen as dampening of normal myogenesis-specific expression changes, including in genes for muscle structure, mitochondrial function, stress responses, and signal transduction. Other classes of genes, including those encoding extracellular matrix or pro-inflammatory proteins, were upregulated in FSHD myogenic cells independent of an inverse myogenesis association. Importantly, the disease-linked <it>DUX4 </it>RNA isoform was detected by RT-PCR in FSHD myoblast and myotube preparations only at extremely low levels. Unique insights into myogenesis-specific gene expression were also obtained. For example, all four Argonaute genes involved in RNA-silencing were significantly upregulated during normal (but not FSHD) myogenesis relative to non-muscle cell types.</p> <p>Conclusions</p> <p><it>DUX4</it>'s pathogenic effect in FSHD may occur transiently at or before the stage of myoblast formation to establish a cascade of gene dysregulation. This contrasts with the current emphasis on toxic effects of experimentally upregulated <it>DUX4 </it>expression at the myoblast or myotube stages. Our model could explain why <it>DUX4</it>'s inappropriate expression was barely detectable in myoblasts and myotubes but nonetheless linked to FSHD.</p

Household-level effects of providing forecast-based cash in anticipation of extreme weather events:Quasi-experimental evidence from humanitarian interventions in the 2017 floods in Bangladesh

In 2017, Bangladesh experienced the worst floods in recent decades. Based on a forecast and pre-defined trigger level, a Red Cross Red Crescent project distributed an unconditional cash grant of BDT 5000 (USD 60 equivalent) to 1039 poor households in highly vulnerable, flood-prone communities in the Brahmaputra river basin before an early flood peak. Systems that can deliver forecast-based cash grants are a potential adaptation strategy to deal with changes in extreme events linked to climate change. This paper presents the results of a mixed-methods, quasi-experimental study, based on a post-disaster household survey. The research assesses the effectiveness of the forecast-based cash distribution in helping beneficiaries to take preparatory early actions and reduce the negative impacts of the flood on their health, well-being, assets and livelihoods. The assessment shows that the cash grants contributed to improving households' access to food, a reduction in high-interest debt accrual of vulnerable households, and reduced psychosocial stress during and after the flood period, compared to a control group of similarly vulnerable and flood-affected communities that did not receive the forecast-based cash assistance. The intervention may also have prevented households from being forced to make destitution sales of valuable assets, as indicated by qualitative data collected in July, but we do not see these benefits sustained after a second flood peak in August 2017. There is a need for further research to assess the longer-term effects of forecast-based cash on the socio-economic development and well-being of the most vulnerable