We show that strongly monotone systems of ordinary differential equations which have a certain translation-invariance property are so that all solutions converge to a unique equilibrium. The result may be seen as a dual of a well-known theorem of Mierczynski for systems that satisfy a conservation law. An application to a reaction of interest in biochemistry is provided as an illustration.

We consider in this paper the behavior of the least squares problem that arises when one attempts to train a feedforward net with no hidden neurons. It is assumed that the net has monotonic non-linear output units. Under the assumption that a training set is sepamble, that is that there is a set of achievable outputs for which the error is zero, we show that there are no non-global minima. More precisely, we assume that the error is of a threshold LMS type, in that the error function is zero for values 'beyond" the target value.Our proof gives in addition the following stronger result: the continuous gradient adjustment procedure is such that from any initial weight wnfigumtion a sepiirating set of weights is obtained in finite time. Thus we have a pre-cise analogue of the perceptron l+ng theorem. We contrast our results with the more classical pattern recognition problem of threshold LMS with linear output units.

223 words Introduction 533 words = 3995 words Methods 375 words Results 2382 words References 49 references Key Points • Patient-derived KIT D816V iPSCs and CRISPR-engineered KIT D816V ESCs model SM disease heterogeneity and serve as drug screening platform • Nintedanib selectively targets KIT D816V iPSC-and ESC-derived cells and primary samples of SM patients Primary Scientific Category: Myeloid neoplasia Abstract The KIT D816V mutation is found in more than 80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs. KIT D816V therefore represents a prime therapeutic target for SM. Here we generated a panel of patient-specific KIT D816V induced pluripotent stem cells (iPSCs) from patients with aggressive SM (ASM) and mast cell leukemia (MCL) to develop a patient-specific SM disease model for mechanistic and drug discovery studies. KIT D816V iPSCs differentiated into neoplastic hematopoietic progenitor cells and MCs with patient-specific phenotypic features, thereby reflecting the heterogeneity of the disease. CRISPR/Cas9n-engineered KIT D816V human embryonic stem cells (ESCs), when differentiated into hematopoietic cells, recapitulated the phenotype observed for KIT D816V iPSC hematopoiesis. KIT D816V causes constitutive activation of the KIT tyrosine kinase receptor and we exploited our iPSCs and ESCs to investigate new tyrosine kinase inhibitors targeting KIT D816V. Our study identified nintedanib as a novel KIT D816V inhibitor. Nintedanib selectively reduced the viability of iPSC-derived KIT D816V hematopoietic progenitor cells and MCs in the nanomolar range. Nintedanib was also active on primary samples of KIT D816V SM patients. Molecular docking studies show that nintedanib binds to the ATP binding pocket of inactive KIT D816V. Our results suggest nintedanib as a new drug candidate for KIT D816V targeted therapy of advanced SM.

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