Background: The histogenesis of human colorectal hyperplastic polyps and colorectal adenomas is poorly understood even now. Method: Human colorectal adenomas, hyperplastic polyps, and normal colorectal mucosae (patients with familial adenomatous polyposis and hereditary non-polyposis colorectal carcinoma were excluded) were obtained during colonoscopy and microdissected into individual crypts. Morphology, cell proliferation characteristics, and fission indices of crypts isolated from these lesions were then studied. Results: Crypts isolated from colorectal adenomas and colorectal hyperplastic polyps were significantly larger (p<0.001) than crypts from normal colorectal mucosae. Crypt fission was an uncommon event in normal colonic mucosae but common in crypts isolated from adenomas and hyperplastic polyps (p<0.001). Analysis of the distribution of mitoses suggested an upward expansion of the proliferation compartment in adenomas to the surface of the crypt with no reversal of proliferating cell distribution, as has previously been described. Conclusions: Sporadic human colorectal adenomas and hyperplastic polyps grow by the process of crypt fission. Expansion of the proliferative compartment was demonstrated in crypts from adenomas, consistent with deregulation of cell cycle control.

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Diabetic nephropathy is characterized by the rapid onset of hypertrophy and ECM expansion. Previously, we showed that calcineurin phosphatase is required for hypertrophy and ECM synthesis in cultured mesangial cells. Therefore, we examined the effect of calcineurin inhibition on renal hypertrophy and ECM accumulation in streptozotocin-induced diabetic rats. After 2 wk of diabetes, calcineurin protein was increased in whole cortex and glomeruli in conjunction with increased phosphatase activity. Daily administration of cyclosporin A blocked accumulation of both calcineurin protein and calcineurin activity. Also associated with calcineurin upregulation was nuclear localization of the calcineurin substrate NFATc1. Inhibition of calcineurin reduced whole kidney hypertrophy and abolished glomerular hypertrophy in diabetic rats. Furthermore, calcineurin inhibition substantially reduced ECM accumulation in diabetic glomeruli but not in cortical tissue, suggesting a differential effect of calcineurin inhibition in glomerular vs. extraglomerular tissue. Corresponding increases in fibronectin mRNA and transforming growth factor-beta mRNA were observed in tubulointerstitium but not in glomeruli. In summary, calcineurin plays an important role in glomerular hypertrophy and ECM accumulation in diabetic nephropathy.

Since p63 is thought to be a marker of stem cells and may act as an oncogene, our data support the idea that BRCA1 acts as stem cell regulator.

Diversity of cellular metabolism can be harnessed to produce a large space of molecules. However, development of optimal strains with high product titers, rates, and yields required for industrial production is laborious and expensive. To accelerate the strain engineering process, we have recently introduced a modular cell design concept that enables rapid generation of optimal production strains by systematically assembling a modular cell with an exchangeable production module(s) to produce target molecules efficiently. In this study, we formulated the modular cell design concept as a general multiobjective optimization problem with flexible design objectives derived from mass balance. We developed algorithms and an associated software package, named ModCell2, to implement the design. We demonstrated that ModCell2 can systematically identify genetic modifications to design modular cells that can couple with a variety of production modules and exhibit a minimal tradeoff among modularity, performance, and robustness. Analysis of the modular cell designs revealed both intuitive and complex metabolic architectures enabling modular production of these molecules. We envision ModCell2 provides a powerful tool to guide modular cell engineering and sheds light on modular design principles of biological systems.

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Estudos recentes apontam a importância de investigações mais abrangentes sobre o universo da formação médica, ressaltando que esta é constituída por um complexo quadro de atitudes. O curso é extenuante e, mesmo assim, os estudantes se envolvem com uma infinidade de atividades extras durante a sua formação, construindo um vasto currículo paralelo. Por meio da "triangulação metodológica", investigaram-se as concepções de estudantes de Medicina sobre as vivências e papéis das atividades extracurriculares. O estudo buscou o diálogo entre três diferentes estratégias: aplicação de questionário aos estudantes do primeiro ao sexto ano de Medicina (n = 423), entrevistas individuais (n = 24) e entrevistas em dois grupos focais (n = 14). Os dados revelaram que os estudantes de Medicina identificam seu envolvimento com atividades extracurriculares como uma tentativa de preencher lacunas curriculares, integrar-se com colegas, suplementar o curso, obter bem-estar, atender a indagações profissionais, enfim, múltiplas motivações. A dimensão individual e coletiva da metodologia permitiu que toda a heterogeneidade relativa ao cotidiano da formação médica acabasse por emergir.