Architectural synthesis of timed asynchronous systems

Journal ArticleThis paper describes a new method for architectural synthesis of timed asynchronous systems. Due to the variable delays associated with asynchronous resources, implicit schedules are created by the addition of supplementary constraints between resources. Since the number of schedules grows exponentially with respect to the size of the given data flow graph, pruning techniques are introduced which dramatically improve run-time without significantly affecting the quality of the results. Using a combination of data and resource constraints, as well as an analysis of bounded delay information, our method determines the minimum number of resources and registers needed to implement a given schedule. Results are demonstrated using some high-level synthesis benchmark circuits and an industrial example

Efficacious Intermittent Dosing of a Novel JAK2 Inhibitor in Mouse Models of Polycythemia Vera

A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients

Architectural Synthesis of Timed Asynchronous Systems

This paper describes a new method for architectural synthesis of timed asynchronous systems. Due to the variable delays associated with asynchronous resources, implicit schedules are created by the addition of supplementary constraints between resources. Since the number of schedules grows exponentially with respect to the size of the given data ow graph, pruning techniques are introduced which dramatically improve runtime without signicantly aecting the quality of the results. Using a combination of data and resource constraints, as well as an analysis of bounded delay information, our method determines the minimum number of resources and registers needed to implement a given schedule. Results are demonstrated using some high-level synthesis benchmark circuits and an industrial example. 1. Introduction Architectural-level synthesis is the process of taking an abstract behavioral model of a desired circuit and rening it to an optimal macroscopic structure. Issues such as latency, ..

Low oxygen: A (tough) way of life for Okavango fishes.

Botswana's Okavango Delta is a World Heritage Site and biodiverse wilderness. In 2016-2018, following arrival of the annual flood of rainwater from Angola's highlands, and using continuous oxygen logging, we documented profound aquatic hypoxia that persisted for 3.5 to 5 months in the river channel. Within these periods, dissolved oxygen rarely exceeded 3 mg/L and dropped below 0.5 mg/L for up to two weeks at a time. Although these dissolved oxygen levels are low enough to qualify parts of the Delta as a dead zone, the region is a biodiversity hotspot, raising the question of how fish survive. In association with the hypoxia, histological samples, collected from native Oreochromis andersonii (threespot tilapia), Coptodon rendalli (redbreast tilapia), and Oreochromis macrochir (greenhead tilapia), exhibited widespread hepatic and splenic inflammation with marked granulocyte infiltration, melanomacrophage aggregates, and ceroid and hemosiderin accumulations. It is likely that direct tissue hypoxia and polycythemia-related iron deposition caused this pathology. We propose that Okavango cichlids respond to extended natural hypoxia by increasing erythrocyte production, but with significant health costs. Our findings highlight seasonal hypoxia as an important recurring stressor, which may limit fishery resilience in the Okavango as concurrent human impacts rise. Moreover, they illustrate how fish might respond to hypoxia elsewhere in the world, where dead zones are becoming more common

Effect of 2 Cycles of Intermittent Dosing (3 days on, 4 days off) of MRLB-11055 on V617F-Luc2 Mice (N = 10).

<p>Effect on A & B. Bioluminescence in spleen C. Hematocrit D. Multiple endpoints at end of study (Day 14).</p

Effect of MRLB-11055 in a Darbepoetin-Induced PV Efficacy Model.

<p>The ability of MRLB-11055 to prevent darbepoetin-induced increases in hematocrit (Hct) and spleen mass (SPL) over 7 days is shown, as is the impact of MRLB-11055 on white blood cells (WBC) and its concentration in blood (PK). Dashed line indicates <i>in vivo</i> IC50 value.</p

Effect of MRLB-11055 on major lymphoid populations in spleen of WT B6 mice.

<p>MRLB-11055 was given for either 3 or 6 days (on), followed up by either a 0 or 4 day holiday (off), for up to 4 cycles. Effects on NK, B and T cells were measured by flow cytometry.</p

Exposure and target engagement of MRLB-11055 in the peripheral blood of C57BL/6 mice stimulated with darbepoetin.

<p>A. Effect of MRLB-11055 on phosphoSTAT5 levels at various times post-dose. B. Calculation of IC50 value for inhibition of phosphoSTAT5. C. PK of 3 doses of MRLB-11055 in mouse blood, with calculated IC50 superimposed (dashed line).</p