Time-Lapse Analysis and Mathematical Characterization Elucidate Novel Mechanisms Underlying Muscle Morphogenesis

Skeletal muscle morphogenesis transforms short muscle precursor cells into long, multinucleate myotubes that anchor to tendons via the myotendinous junction (MTJ). In vertebrates, a great deal is known about muscle specification as well as how somitic cells, as a cohort, generate the early myotome. However, the cellular mechanisms that generate long muscle fibers from short cells and the molecular factors that limit elongation are unknown. We show that zebrafish fast muscle fiber morphogenesis consists of three discrete phases: short precursor cells, intercalation/elongation, and boundary capture/myotube formation. In the first phase, cells exhibit randomly directed protrusive activity. The second phase, intercalation/elongation, proceeds via a two-step process: protrusion extension and filling. This repetition of protrusion extension and filling continues until both the anterior and posterior ends of the muscle fiber reach the MTJ. Finally, both ends of the muscle fiber anchor to the MTJ (boundary capture) and undergo further morphogenetic changes as they adopt the stereotypical, cylindrical shape of myotubes. We find that the basement membrane protein laminin is required for efficient elongation, proper fiber orientation, and boundary capture. These early muscle defects in the absence of either lamininβ1 or lamininγ1 contrast with later dystrophic phenotypes in lamininα2 mutant embryos, indicating discrete roles for different laminin chains during early muscle development. Surprisingly, genetic mosaic analysis suggests that boundary capture is a cell-autonomous phenomenon. Taken together, our results define three phases of muscle fiber morphogenesis and show that the critical second phase of elongation proceeds by a repetitive process of protrusion extension and protrusion filling. Furthermore, we show that laminin is a novel and critical molecular cue mediating fiber orientation and limiting muscle cell length

Lbx2 regulates formation of myofibrils

<p>Abstract</p> <p>Background</p> <p>Skeletal muscle differentiation requires assembly of contractile proteins into organized myofibrils. The <it>Drosophila ladybird homeobox </it>gene (<it>lad</it>) functions in founder cells of the segmental border muscle to promote myoblast fusion and muscle shaping. Tetrapods have two homologous genes (<it>Lbx</it>). Lbx1 functions in migration and/or proliferation of hypaxial myoblasts, whereas the function of Lbx2 is poorly understood.</p> <p>Results</p> <p>To elucidate the role of Lbx in vertebrate myogenesis, we examined Lbx function in zebrafish. Zebrafish <it>lbx2 </it>transcripts appear in newly formed paraxial mesoderm and become restricted to adaxial cells, precursors of slow muscle. Slow muscles lose <it>lbx2 </it>expression as they differentiate, while a subset of differentiating fast muscle cells transiently expresses <it>lbx2</it>. Fin and hyoid muscle express <it>lbx2 </it>later. In contrast, <it>lbx1b </it>expression first appears lateral to the somites at late segmentation stages and is later restricted to fin muscle. Morpholino knockdown of Lbx1b and Lbx2 suppresses hypaxial muscle development. Moreover, knockdown of Lbx2 results in malformation of muscle fibers and reduced fusion of fast precursors, although no obvious effects on induction or specification are observed. Expression of myofilament genes, including <it>actin </it>and <it>myosin</it>, requires the engrailed repressor domain of Lbx2.</p> <p>Conclusion</p> <p>Our results elucidate a new function of Lbx2 as a regulator of myofibril formation.</p

Making sense of the evolving nature of depression narratives and their inherent conflicts

Originally a psychiatric diagnosis fashioned by Western psychiatry in the 20th Century, depression evolved to encompass varying lineages of discourse and care. This article elucidates some of the current challenges – as well as emerging discourses – influencing the category of depression. Depression-like experiences are shaped by (at times conflicting) subjectivities, claims to knowledge, material realities, social contexts and access to resources. With no unified understanding of the category of ‘depression’ available, lay people, social and neuro scientists, GPs, psychiatrists, talking therapists and pharmaceutical companies all attempt to shape narratives of depression. The current paper focuses on patient narratives about depression – in the context of these wider debates – to better elucidate the ways in which depression discourses are publically developing along varying lines. In conclusion, the paper suggests that we could better conceptualise the resulting ‘depression(s)’ with concepts such as ‘society of mind’ and notions of subjectivity unbounded by individuals

Leadership after virtue: MacIntyre’s critique of management reconsidered

MacIntyre argues that management embodies emotivism, and thus is inherently amoral and manipulative. His claim that management is necessarily Weberian is, at best, outdated, and the notion that management aims to be neutral and value free is incorrect. However, new forms of management, and in particular the increased emphasis on leadership which emerged after MacIntyre’s critique was published, tend to support his central charge. Indeed, charismatic and transformational forms of leadership seem to embody emotivism to a greater degree than do more Weberian, bureaucratic forms of management, so MacIntyre’s central contention about our emotivistic culture seems to be well-founded. Having criticised the details but defended the essence of MacIntyre’s critique of management, this paper sketches a MacIntyrean approach to management and leadership by highlighting the affinities between MacIntyre’s political philosophy and Greenleaf’s concept of servant leadership

miR-139-5p modulates radiotherapy resistance in breast cancer by repressing multiple gene networks of DNA repair and ROS defense.

Radiotherapy (RT) is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. Here we show that miR-139-5p is a potent modulator of radiotherapy response in breast cancer (BC) via its regulation of genes involved in multiple DNA repair and reactive oxygen species defense pathways. Treatment of breast cancer cells with a miR-139-5p mimic strongly synergized with radiation both in vitro and in vivo, resulting in significantly increased oxidative stress, accumulation of unrepaired DNA damage and induction of apoptosis. Several miR-139-5p target genes were also strongly predictive of outcome, specifically in RT-treated patients across multiple independent breast cancer cohorts. These prognostically relevant miR-139-5p target genes were used as companion biomarkers to identify radioresistant BC xenografts highly amenable to sensitization by co-treatment with a miR-139-5p mimetic

miR-139-5p modulates radiotherapy resistance in breast cancer by repressing multiple gene networks of DNA repair and ROS defense.

Radiotherapy (RT) is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. Here we show that miR-139-5p is a potent modulator of radiotherapy response in breast cancer (BC) via its regulation of genes involved in multiple DNA repair and reactive oxygen species defense pathways. Treatment of breast cancer cells with a miR-139-5p mimic strongly synergized with radiation both in vitro and in vivo, resulting in significantly increased oxidative stress, accumulation of unrepaired DNA damage and induction of apoptosis. Several miR-139-5p target genes were also strongly predictive of outcome, specifically in RT-treated patients across multiple independent breast cancer cohorts. These prognostically relevant miR-139-5p target genes were used as companion biomarkers to identify radioresistant BC xenografts highly amenable to sensitization by co-treatment with a miR-139-5p mimetic