mTOR signalling, embryogenesis and the control of lung development

The existence of a nutrient sensitive “autocatakinetic” regulator of embryonic tissue growth has been hypothesised since the early 20th century, beginning with pioneering work on the determinants of foetal size by the Australian physiologist, Thorburn Brailsford-Robertson. We now know that the mammalian target of rapamycin complexes (mTORC1 and 2) perform this essential function in all eukaryotic tissues by balancing nutrient and energy supply during the first stages of embryonic cleavage, the formation of embryonic stem cell layers and niches, the highly specified programmes of tissue growth during organogenesis and, at birth, paving the way for the first few breaths of life. This review provides a synopsis of the role of the mTOR complexes in each of these events, culminating in an analysis of lung branching morphogenesis as a way of demonstrating the central role mTOR in defining organ structural complexity. We conclude that the mTOR complexes satisfy the key requirements of a nutrient sensitive growth controller and can therefore be considered as Brailsford-Robertson's autocatakinetic centre that drives tissue growth programmes during foetal development

An Empirical Test for Branch-Specific Positive Selection

The use of phylogenetic analysis to predict positive selection specific to human genes is complicated by the very close evolutionary relationship with our nearest extant primate relatives, chimpanzees. To assess the power and limitations inherent in use of maximum-likelihood (ML) analysis of codon substitution patterns in such recently diverged species, a series of simulations was performed to assess the impact of several parameters of the evolutionary model on prediction of human-specific positive selection, including branch length and dN/dS ratio. Parameters were varied across a range of values observed in alignments of 175 transcription factor (TF) genes that were sequenced in 12 primate species. The ML method largely lacks the power to detect positive selection that has occurred since the most recent common ancestor between humans and chimpanzees. An alternative null model was developed on the basis of gene-specific evaluation of the empirical distribution of ML results, using simulated neutrally evolving sequences. This empirical test provides greater sensitivity to detect lineage-specific positive selection in the context of recent evolutionary divergence

Results of the Intergroup Rhabdomyosarcoma Study Group D9602 Protocol, Using Vincristine and Dactinomycin With or Without Cyclophosphamide and Radiation Therapy, for Newly Diagnosed Patients With Low-Risk Embryonal Rhabdomyosarcoma: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group

PURPOSE: Patients with localized, grossly resected, or gross residual (orbital only) embryonal rhabdomyosarcoma (ERMS) had 5-year failure-free survival (FFS) rates of 83% and overall survival rates of 95% on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III/IV. IRSG D9602 protocol (1997 to 2004) objectives were to decrease toxicity in similar patients by reducing radiotherapy (RT) doses and eliminating cyclophosphamide for the lowest-risk patients. PATIENTS AND METHODS: Subgroup A patients (lowest risk, with ERMS, stage 1 group I/IIA, stage 1 group III orbit, stage 2 group I) received vincristine plus dactinomycin (VA). Subgroup B patients (ERMS, stage 1 group IIB/C, stage I group III nonorbit, stage 2 group II, stage 3 group I/II) received VA plus cyclophosphamide. Patients in group II/III received RT. Compared with IRS-IV, doses were reduced from 41.4 to 36 Gy for stage 1 group IIA patients and from 50 or 59 to 45 Gy for group III orbit patients. RESULTS: Estimated 5-year FFS rates were 89% (95% CI, 84% to 92%) for subgroup A patients (n = 264) and 85% (95% CI, 74%, 91%) for subgroup B patients (n = 78); median follow-up: 5.1 years. Estimated 5-year FFS rates were 81% (95% CI, 68% to 90%) for patients with stage 1 group IIA tumors (n = 62) and 86% (95% CI, 76% to 92%) for patients with group III orbit tumors (n = 77). CONCLUSION: Five-year FFS and OS rates were similar to those observed in comparable IRS-III patients, including patients receiving reduced RT doses, but were lower than in comparable IRS-IV patients receiving VA plus cyclophosphamide. Five-year FFS rates were similar among subgroups A and B patients

sj-pdf-1-inv-10.1177_15569845241232685 – Supplemental material for Proof of Concept: Development of a Mitral Annuloplasty Ring With Crosshatch Net

Supplemental material, sj-pdf-1-inv-10.1177_15569845241232685 for Proof of Concept: Development of a Mitral Annuloplasty Ring With Crosshatch Net by Benjamin D. Seadler, David L. Joyce, James Zelten, Kevin Sweeney, Taylor Wisgerhof, Zoey Slettehaugh, Y. William Yuan, Brandon Tefft and Paul J. Pearson in Innovations</p

Sociable (social) science – crafting new relationships between research and government

The civil service represents a significant community of analysts and researchers, but their work can at times seem independent from that taking place within academia. Ben Hepworth describes how the UK’s Ministry of Justice has worked to reframe its relationship with external academics and how a more collaborative and co-productive approach has enabled the department to approach emerging challenges in innovative ways