iPSCs, and iPSC-EVs were injected intramyocardially at 48 hours after a reperfused myocardial infarction in mice. Compared with vehicle-injected mice, both iPSC-and iPSC-EV-treated mice exhibited improved left ventricular function at 35 d after myocardial infarction, albeit iPSC-EVs rendered greater improvement. iPSC-EV injection also resulted in reduction in left ventricular mass and superior perfusion in the infarct zone.Both iPSCs and iPSC-EVs preserved viable myocardium in the infarct zone, whereas reduction in apoptosis was significant with iPSC-EVs. iPSC injection resulted in teratoma formation, whereas iPSC-EV injection was safe. Conclusions: iPSC-derived
Petri nets, also known as vector addition systems, are a long established model of concurrency with extensive applications in modeling and analysis of hardware, software, and database systems, as well as chemical, biological, and business processes. The central algorithmic problem for Petri nets is reachability: whether from the given initial configuration there exists a sequence of valid execution steps that reaches the given final configuration. The complexity of the problem has remained unsettled since the 1960s, and it is one of the most prominent open questions in the theory of verification. Decidability was proved by Mayr in his seminal STOC 1981 work, and, currently, the best published upper bound is non-primitive recursive Ackermannian of Leroux and Schmitz from Symposium on Logic in Computer Science 2019. We establish a non-elementary lower bound, i.e., that the reachability problem needs a tower of exponentials of time and space. Until this work, the best lower bound has been exponential space, due to Lipton in 1976. The new lower bound is a major breakthrough for several reasons. Firstly, it shows that the reachability problem is much harder than the coverability (i.e., state reachability) problem, which is also ubiquitous but has been known to be complete for exponential space since the late 1970s. Secondly, it implies that a plethora of problems from formal languages, logic, concurrent systems, process calculi, and other areas, which are known to admit reductions from the Petri nets reachability problem, are also not elementary. Thirdly, it makes obsolete the current best lower bounds for the reachability problems for two key extensions of Petri nets: with branching and with a pushdown stack. We develop a construction that uses arbitrarily large pairs of values with ratio R to provide zero testable counters that are bounded by R . At the heart of our proof is then a novel gadget, the so-called factorial amplifier that, assuming availability of counters that are zero testable and bounded by k , guarantees to produce arbitrarily large pairs of values whose ratio is exactly the factorial of k . Repeatedly composing the factorial amplifier with itself by means of the former construction enables us to compute, in linear time, Petri nets that simulate Minsky machines whose counters are bounded by a tower of exponentials, which yields the non-elementary lower bound. By refining this scheme further, we, in fact, already establish hardness for h -exponential space for Petri nets with h + 13 counters.
Petri nets, also known as vector addition systems, are a long established model of concurrency with extensive applications in modelling and analysis of hardware, software and database systems, as well as chemical, biological and business processes. The central algorithmic problem for Petri nets is reachability: whether from the given initial configuration there exists a sequence of valid execution steps that reaches the given final configuration. The complexity of the problem has remained unsettled since the 1960s, and it is one of the most prominent open questions in the theory of verification. Decidability was proved by Mayr in his seminal STOC 1981 work, and the currently best published upper bound is non-primitive recursive Ackermannian of Leroux and Schmitz from LICS 2019. We establish a non-elementary lower bound, i.e. that the reachability problem needs a tower of exponentials of time and space. Until this work, the best lower bound has been exponential space, due to Lipton in 1976. The new lower bound is a major breakthrough for several reasons. Firstly, it shows that the reachability problem is much harder than the coverability (i.e., state reachability) problem, which is also ubiquitous but has been known to be complete for exponential space since the late 1970s. Secondly, it implies that a plethora of problems from formal languages, logic, concurrent systems, process calculi and other areas, that are known to admit reductions from the Petri nets reachability problem, are also not elementary. Thirdly, it makes obsolete the currently best lower bounds for the reachability problems for two key extensions of Petri nets: with branching and with a pushdown stack.At the heart of our proof is a novel gadget so called the factorial amplifier that, assuming availability of counters that are zero testable and bounded by k, guarantees to produce arbitrarily large pairs of values whose ratio is exactly the factorial of k. We also develop a novel construction that uses arbitrarily large pairs of values with ratio R to provide zero testable counters that are bounded by R. Repeatedly composing the factorial amplifier with itself by means of the construction then enables us to compute in linear time Petri nets that simulate Minsky machines whose counters are bounded by a tower of exponentials, which yields the non-elementary lower bound. By refining this scheme further, we in fact establish hardness for h-exponential space already for Petri nets with h + 13 counters. *
Abstract.A notion of alternating timed automata is proposed. It is shown that such automata with only one clock have decidable emptiness problem. This gives a new class of timed languages which is closed under boolean operations and which has an effective presentation. We prove that the complexity of the emptiness problem for alternating timed automata with one clock is non-primitive recursive. The proof gives also the same lower bound for the universality problem for nondeterministic timed automata with one clock thereby answering a question asked in a recent paper by Ouaknine and Worrell.
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