Process Algebraic Approach to the Schedulability Analysis and Workload Abstraction of Hierarchical Real-Time Systems

Real-time embedded systems have increased in complexity. As microprocessors become more powerful, the software complexity of real-time embedded systems has increased steadily. The requirements for increased functionality and adaptability make the development of real-time embedded software complex and error-prone. Component-based design has been widely accepted as a compositional approach to facilitate the design of complex systems. It provides a means for decomposing a complex system into simpler subsystems and composing the subsystems in a hierarchical manner. A system composed of real-time subsystems with hierarchy is called a hierarchical real-time system This paper describes a process algebraic approach to schedulability analysis of hierarchical real-time systems. To facilitate modeling and analyzing hierarchical real-time systems, we conservatively extend an existing process algebraic theory based on ACSR-VP (Algebra of Communicating Shared Resources with Value-Passing) for the schedulability of real-time systems. We explain a method to model a resource model in ACSR-VP which may be partitioned for a subsystem. We also introduce schedulability relation to define the schedulability of hierarchical real-time systems and show that satisfaction checking of the relation is reducible to deadlock checking in ACSR-VP and can be done automatically by the tool support of ERSA (Verification, Execution and Rewrite System for ACSR). With the schedulability relation, we present algorithms for abstracting real-time system workloads

Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations : a pooled analysis from four clinical trials

TP53 aberrations [del(17p) or TP53 mutation] predict poor survival with chemoimmunotherapy in patients with chronic lymphocytic leukaemia (CLL). We evaluated long-term efficacy and safety of first-line ibrutinib-based therapy in patients with CLL bearing TP53 aberrations in a pooled analysis across four studies: PCYC-1122e, RESONATE-2 (PCYC-1115/16), iLLUMINATE (PCYC-1130) and ECOG-ACRIN E1912. The pooled analysis included 89 patients with TP53 aberrations receiving first-line treatment with single-agent ibrutinib (n = 45) or ibrutinib in combination with an anti-CD20 antibody (n = 44). All 89 patients had del(17p) (53% of 89 patients) and/or TP53 mutation (91% of 58 patients with TP53 sequencing results available). With a median follow-up of 49·8 months (range, 0·1-95·9), median progression-free survival was not reached. Progression-free survival rate and overall survival rate estimates at four years were 79% and 88%, respectively. Overall response rate was 93%, including complete response in 39% of patients. No new safety signals were identified in this analysis. Forty-six percent of patients remained on ibrutinib treatment at last follow-up. With median follow-up of four years (up to eight years), results from this large, pooled, multi-study data set suggest promising long-term outcomes of first-line ibrutinib-based therapy in patients with TP53 aberrations. Registered at ClinicalTrials.gov (NCT01500733, NCT01722487, NCT02264574 and NCT02048813)

A giant stem-group chaetognath

Chaetognaths, with their characteristic grasping spines, are the oldest known pelagic predators, found in the lowest Cambrian (Terreneuvian). Here, we describe a large stem chaetognath, Timorebestia koprii gen. et sp. nov., from the lower Cambrian Sirius Passet Lagerstätte, which exhibits lateral and caudal fins, a distinct head region with long antennae and a jaw apparatus similar to Amiskwia sagittiformis. Amiskwia has previously been interpreted as a total-group chaetognathiferan, as either a stem-chaetognath or gnathostomulid. We show that T. koprii shares a ventral ganglion with chaetognaths to the exclusion of other animal groups, firmly placing these fossils on the chaetognath stem. The large size (up to 30 cm) and gut contents in T. koprii suggest that early chaetognaths occupied a higher trophic position in pelagic food chains than today

A giant stem-group chaetognath.

Chaetognaths, with their characteristic grasping spines, are the oldest known pelagic predators, found in the lowest Cambrian (Terreneuvian). Here, we describe a large stem chaetognath, gen. et sp. nov., from the lower Cambrian Sirius Passet Lagerstätte, which exhibits lateral and caudal fins, a distinct head region with long antennae and a jaw apparatus similar to . has previously been interpreted as a total-group chaetognathiferan, as either a stem-chaetognath or gnathostomulid. We show that shares a ventral ganglion with chaetognaths to the exclusion of other animal groups, firmly placing these fossils on the chaetognath stem. The large size (up to 30 cm) and gut contents in suggest that early chaetognaths occupied a higher trophic position in pelagic food chains than today

Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors

Dilemmas in Treating Smoldering Multiple Myeloma

Novel therapies hold promise for high-risk smoldering multiple myeloma (SMM). Recent studies suggest that modern combination approaches can be options for high-risk SMM to obtain deep molecular responses with favorable toxicity profiles. Although pioneering treatment trials based on small numbers of patients suggest progression-free and overall survival benefits, application of the data to real-life practice remains to be validated. Therapeutic modulation of disease tempo, disease burden, clonal evolution, and tumor microenvironment in SMM remains to be understood and calls for reliable biomarkers reflective of disease biology. Here, we review studies that open a new management platform for SMM, address ongoing dilemmas in practice and under investigation, and highlight emerging scientific questions in the era of SMM treatment

Asymmetric polystyrene-polylactide bottlebrush random copolymers: Synthesis, self-assembly and nanoporous structures

Control of polymer architecture can be a powerful strategy to refine the structure and properties without changing the chemical structure of the monomers. Here, we exploit a highly branched bottlebrush architecture to access tailored self-assembled morphologies and nanoporous structures. To this end, a series of well-defined bottlebrush random copolymers are synthesized by macromonomer approach, where polystyrene (PS) and poly(D,L-lactide) (PLA) side chains of non-equal molecular weights are grafted to the polynorbornene backbone. These bottlebrush copolymers exhibit microphase-separated structures including lamellar, hexagonal cylinders and disordered structures with the domain sizes of 13???20 nm depending on the relative volume fraction (f) of PS and PLA side chain. Due to highly asymmetric nature, these bottlebrush copolymers exhibit cylinders at f PS = 41???50% and lamellar at f PS = 67???70%, unlike the case of linear diblock copolymers. The selective degradation of PLA from these bottlebrushes allows for nanoporous structures to be created of which size, distribution and connectivity of pores are dictated by the composition of bottlebrush precursors. The ability to exploit the bottlebrush architecture to manipulate self-assembled morphologies and nanoporous structures may be a useful way to design materials for adsorptions, separations, catalysis and gas storages

B-cell Receptor Pathway Mutations Are Infrequent in Patients with Chronic Lymphocytic Leukemia on Continuous Ibrutinib Therapy

Purpose: Acquired mutations in Bruton's tyrosine kinase (BTK) or phospholipase C-γ2 (PLCG2) genes are associated with clinical progressive disease (PD) in patients with chronic lymphocytic leukemia (CLL) treated with BTK inhibitors. Data on mutation rates in patients without PD on ibrutinib treatment are limited. Experimental design: We evaluated frequency and time to detection of BTK and PLCG2 mutations in peripheral blood samples from 388 patients with previously untreated (n = 238) or relapsed/refractory (n = 150) CLL across five clinical trials. Results: With median follow-up of 35 months (range, 0-72) without PD at last sampling, mutations in BTK (3%), PLCG2 (2%), or both genes (1%) were rare in previously untreated patients. With median follow-up of 35 months (range, 1-70) without PD at last sample, mutations in BTK (30%), PLCG2 (7%), or both genes (5%) were more common in patients with relapsed/refractory CLL. Median time to first detection of BTK C481S mutation was not reached in previously untreated patients and was >5 years in patients with relapsed/refractory CLL. Among patients evaluable at PD, previously untreated patients (n = 12) had lower rates than those with relapsed/refractory disease (n = 45) of BTK (25% vs. 49%) and PLCG2 mutations (8% vs. 13%). Time from first detection of BTK C481S mutation to PD was 11.3 months in 1 previously untreated patient and median 8.5 months (range, 0-35.7) among 23 patients with relapsed/refractory CLL. Conclusions: This systematic investigation describes development of mutations over time in patients without PD and informs the potential clinical opportunity to optimize ongoing benefits for such patients

IrO2-ZnO Hybrid Nanoparticles as Highly Efficient Trifunctional Electrocatalysts

Development of high-performance catalysts is very crucial for the commercialization of sustainable energy conversion technologies. Searching for stable, highly active, and low-cost multifunctional catalysts has become a critical issue. In this study, we report the synthesis of IrO2-ZnO hybrid nanoparticles and their highly efficient electrocatalytic activities toward oxygen/hydrogen evolution reaction (OER/HER) as well as oxygen reduction reaction (ORR). For comparison, we synthesized RuO2-ZnO, showing a smaller catalytic activity than IrO2-ZnO, which provides robust evidence for the unique synergic effect of these hybrid structures. IrO2-ZnO and RuO2-ZnO exhibit excellent OER catalytic performance with Tafel slopes of 57 and 59 mV decade-1, respectively. For HER, IrO2-ZnO shows a higher catalytic activity than RuO2-ZnO. The numbers of electrons involved in the ORR were 3.7 and 2.8, respectively, for IrO2-ZnO and RuO2-ZnO. The remarkable catalytic performance of IrO2-ZnO would be ascribed to the abundant oxygen vacancies and the metallic states of Ir, which ensure excellent catalytic activity and stability. (Graph Presented)