Myotome adaptability confers developmental robustness to somitic myogenesis in response to fibre number alteration

Balancing the number of stem cells and their progeny is crucial for tissue development and repair. Here we examine how cell numbers and overall muscle size are tightly regulated during zebrafish somitic muscle development. Muscle stem/precursor cell (MPCs) expressing Pax7 are initially located in the dermomyotome (DM) external cell layer, adopt a highly stereotypical distribution and thereafter a proportion of MPCs migrate into the myotome. Regional variations in the proliferation and terminal differentiation of MPCs contribute to growth of the myotome. To probe the robustness of muscle size control and spatiotemporal regulation of MPCs, we compared the behaviour of wild type (wt) MPCs with those in mutant zebrafish that lack the muscle regulatory factor Myod. Myod(fh261) mutants form one third fewer multinucleate fast muscle fibres than wt and show a significant expansion of the Pax(7+) MPC population in the DM. Subsequently, myod(fh261) mutant fibres generate more cytoplasm per nucleus, leading to recovery of muscle bulk. In addition, relative to wt siblings, there is an increased number of MPCs in myod(fh261) mutants and these migrate prematurely into the myotome, differentiate and contribute to the hypertrophy of existing fibres. Thus, homeostatic reduction of the excess MPCs returns their number to normal levels, but fibre numbers remain low. The GSK3 antagonist BIO prevents MPC migration into the deep myotome, suggesting that canonical Wnt pathway activation maintains the DM in zebrafish, as in amniotes. BIO does not, however, block recovery of the myod(fh261) mutant myotome, indicating that homeostasis acts on fibre intrinsic growth to maintain muscle bulk. The findings suggest the existence of a critical window for early fast fibre formation followed by a period in which homeostatic mechanisms regulate myotome growth by controlling fibre size. The feedback controls we reveal in muscle help explain the extremely precise grading of myotome size along the body axis irrespective of fish size, nutrition and genetic variation and may form a paradigm for wider matching of organ size

Research on the Mathematical Model for Optimal Allocation of Human Resources in the Operation and Maintenance Units of a Heavy Haul Railway

According to the existing personnel structure, quantity, development strategy, and market demand of the Shuohuang Railway Company’s operation and maintenance project, the demand quantity of various employees of the company for the past three years is predicted, and a human resource optimization model based on existing human resources and future plans is established. Then, the optimal solutions of the two mathematical models were calculated and analyzed using LINGO software. Finally, combined with the actual situation, the optimal allocation of human resources for the operation and maintenance project of KY company was obtained. The following conclusions are obtained. (1) For the optimal allocation model of existing human resources, the maximum net profit of the optimal staffing model is CNY 3258000. (2) The human resources allocation cost of the minimum dismissal model is CNY 81000. (3) The human resources allocation cost of the lowest cost model is CNY 15500. The research results can effectively guide the human resource management of the operation and maintenance project of the Shuohuang Railway Company, and have important theoretical and practical significance for further analysis of human resources model and its optimal allocation method

Ypp1/YGR198w plays an essential role in phosphoinositide signalling at the plasma membrane

International audiencePhosphoinositide signalling through the eukaryotic plasma membrane makes essential contributions to many processes, including re-modelling of the actin cytoskeleton, vesicle trafficking and signalling from the cell surface. A proteome-wide screen performed in Saccharomyces cerevisiae revealed that Ypp1 physically interacts with the plasma-membrane associated phosphatidylinositol 4-kinase Stt4. Here we demonstrate that phenotypes of ypp1 and stt4 conditional mutants are identical, namely osmoremedial temperature sensitivity, hypersensitivity to cell wall destabilizers and defective organization of actin. We go on to show that overexpression of STT4 suppresses the temperature sensitive growth defect of ypp1 mutants. In contrast, overexpression of genes encoding the other two phosphatidylinositol 4-kinases in yeast, Pik1 and Lsb6, do not suppress this phenotype. This implies a role for Ypp1 in Stt4-dependant events at the plasma membrane, as opposed to a general role in overall metabolism of phosphatidylinositol 4-phosphate. Use of a pleckstrin homology domain sensor reveals there are substantially less plasma membrane associated 4-phosphorylated phosphoinositides in ypp1 mutants, in comparison to wild-type cells. Furthermore, in vivo labelling with [3H]inositol indicates a dramatic reduction in the level of phosphatidylinositol 4-phosphate in ypp1 mutants. This is the principal cause of lethality at non-permissive conditions in ypp1 mutants, as limiting the activity of the Sac1 phosphatidylinositol 4-phosphate phosphatase leads to restoration of viability. Additionally, the endocytic defect associated with elevated levels of phosphatidylinositol 4-phosphate in sac1Δ cells is restored in combination with a ypp1 mutant, consistent with the opposing effects these two mutations have on levels of this phosphoinositide

Research on the Mathematical Model for Optimal Allocation of Human Resources in the Operation and Maintenance Units of a Heavy Haul Railway

According to the existing personnel structure, quantity, development strategy, and market demand of the Shuohuang Railway Company’s operation and maintenance project, the demand quantity of various employees of the company for the past three years is predicted, and a human resource optimization model based on existing human resources and future plans is established. Then, the optimal solutions of the two mathematical models were calculated and analyzed using LINGO software. Finally, combined with the actual situation, the optimal allocation of human resources for the operation and maintenance project of KY company was obtained. The following conclusions are obtained. (1) For the optimal allocation model of existing human resources, the maximum net profit of the optimal staffing model is CNY 3258000. (2) The human resources allocation cost of the minimum dismissal model is CNY 81000. (3) The human resources allocation cost of the lowest cost model is CNY 15500. The research results can effectively guide the human resource management of the operation and maintenance project of the Shuohuang Railway Company, and have important theoretical and practical significance for further analysis of human resources model and its optimal allocation method

Structural and functional coupling of Hsp90- and Sgt1-centred multi-protein complexes

Sgt1 is an adaptor protein implicated in a variety of processes, including formation of the kinetochore complex in yeast, and regulation of innate immunity systems in plants and animals. Sgt1 has been found to associate with SCF E3 ubiquitin ligases, the CBF3 kinetochore complex, plant R proteins and related animal Nod-like receptors, and with the Hsp90 molecular chaperone. We have determined the crystal structure of the core Hsp90-Sgt1 complex, revealing a distinct site of interaction on the Hsp90 N-terminal domain. Using the structure, we developed mutations in Sgt1 interfacial residues, which specifically abrogate interaction with Hsp90, and disrupt Sgt1-dependent functions in vivo, in plants and yeast. We show that Sgt1 bridges the Hsp90 molecular chaperone system to the substrate-specific arm of SCF ubiquitin ligase complexes, suggesting a role in SCF assembly and regulation, and providing multiple complementary routes for ubiquitination of Hsp90 client proteins

Cdkn1c drives muscle differentiation through a positive feedback loop with Myod

Differentiation often requires conversion of analogue signals to a stable binary output through positive feedback. Hedgehog (Hh) signalling promotes myogenesis in the vertebrate somite, in part by raising the activity of muscle regulatory factors (MRFs) of the Myod family above a threshold. Hh is known to enhance MRF expression. Here we show that Hh is also essential at a second step that increases Myod protein activity, permitting it to promote Myogenin expression. Hh acts by inducing expression of cdkn1c (p57Kip2) in slow muscle precursor cells, but neither Hh nor Cdkn1c is required for their cell cycle exit. Cdkn1c co-operates with Myod to drive differentiation of several early zebrafish muscle fibre types. Myod in turn up-regulates cdkn1c, thereby providing a positive feedback loop that switches myogenic cells to terminal differentiation