The roll back chip: hardware support for distributed simulation using time warp

Journal ArticleDistributed simulation offers an attractive means of meeting the high computational demands of discrete event simulation programs. The Time Warp mechanism has been proposed to ensure correct sequencing of events in distributed simulation programs without blocking processes unnecessarily. However, the overhead of state saving and rollback in Time Warp is one obstacle that may severely degrade performance. A special purpose hardware component, the rollback chip (RBC), is proposed to manage the state of a processor and provide an efficient rollback mechanism within a node of a parallel computer. The chip may be viewed as a special purpose memory management unit that lies on the data path between processor and memory. The algorithm implemented by the rollback chip is described, as well as extensions to the basic design. Implementation of the chip is briefly discussed. In addition to distributed simulation, the rollback chip may be used in other applications using the Time Warp mechanism, notably distributed database concurrency control

Design and evaluation of the rollback chip: special purpose hardware for time warp

technical reportThe Time Warp mechanism offers an elegant approach to attacking difficult clock synchronization problems that arise in applications such as parallel discrete event simulation. However, because Time Warp relies on a lookahead and rollback mechanism to achieve widespread exploitation of parallelism, the state of each process must periodically be saved. Existing approaches to implementing state saving and rollback are not appropriate for large Time Warp programs. We propose a component called the rollback chip (RBC) to efficiently implement these functions. Such a component could be used in a programmable, special purpose parallel discrete event simulation engine based on Time Warp. The algorithms implemented by the rollback chip are described, as well as mechanisms that allow efficient implementation. Results of simulation studies are presented that show that the rollback chip can virtually eliminate the state saving and rollback overheads that plague current software implementations of Time Warp. Index terms ? state saving, rollback, Time Warp, parallel discrete event simulation, VLSI component, special purpose computers

An Implicit Interface Boundary Integral Method for Poisson’s Equation on Arbitrary Domains

We propose a simple formulation for constructing boundary integral methods to solve Poisson’s equation on domains with smooth boundaries defined through their signed distance function. Our formulation is based on averaging a family of parameterizations of an integral equation defined on the boundary of the domain, where the integrations are carried out in the level set framework using an appropriate Jacobian. By the coarea formula, the algorithm operates in the Euclidean space and does not require any explicit parameterization of the boundaries. We present numerical results in two and three dimensions

MRI of Suspected Appendicitis During Pregnancy: Interradiologist Agreement, Indeterminate Interpretation and the Meaning of Non-Visualization of the Appendix

Objective: To determine the degree of interradiologist agreement between the MRI features of appendicitis during pregnancy, the outcomes associated with an indeterminate interpretation and the negative predictive value of non-visualization of the appendix. Methods: Our study was approved by the institutional review board at the Washington University in St. Louis, Missouri (WUStL) and was HIPAA (Health Insurance Portability and Accountability Act of 1996)-compliant. The informed consent requirement was waived. Cases of suspected appendicitis during pregnancy evaluated using MRI were retrospectively identified using search queries. Scans were re-reviewed by two radiologists (7 and 9 years experience, respectively) to evaluate the interradiologist agreement of different MRI features of appendicitis during pregnancy (visualization of the appendix, appendiceal diameter, appendiceal wall thickening, periappendiceal fat stranding, fluid-filled appendix and periappendiceal fluid). The radiologists were blinded to patient outcome, patient intervention, laboratory data, demographic data and the original MRI reports. Clinical outcomes were documented by surgical pathology or clinical observation. Interradiologist agreement was analysed using Cohen’s κ, while patient demographic and clinical data was analysed using Student\u27s t-testing. Results: 233 females with suspected appendicitis during pregnancy were evaluated using MRI over a 13-year period (mean age, 28.4 years; range, 17–38 years). There were 14 (6%) positive examinations for appendicitis during pregnancy, including 1 patient whose MRI was interpreted as negative, proven by surgical pathology. The presence of periappendiceal soft-tissue stranding and the final overall impression had the most interradiologist agreement (к = 0.81–1). There were no pregnant patients found to have acute appendicitis who had an indeterminate MR interpretation or when the appendix could not be visualized. Conclusion: The final impression by the two retrospectively reviewing radiologists of MR examinations performed for suspected appendicitis during pregnancy had near-perfect agreement. In patients where the appendix could not be visualized or in patients that were interpreted as indeterminate, no patients had acute appendicitis. Advances in Knowledge: MR impression for suspected appendicitis in the pregnant patient has high interradiologist agreement, and a non-visualized appendix or lack of inflammatory findings at the time of MR, reliably excludes surgical appendicitis

Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy.

BackgroundThe trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown.MethodWe investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation.ResultsIncreased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo.ConclusionsWe report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy

A Comprehensive Optogenetic Pharmacology Toolkit for In Vivo Control of GABAA Receptors and Synaptic Inhibition

SummaryExogenously expressed opsins are valuable tools for optogenetic control of neurons in circuits. A deeper understanding of neural function can be gained by bringing control to endogenous neurotransmitter receptors that mediate synaptic transmission. Here we introduce a comprehensive optogenetic toolkit for controlling GABAA receptor-mediated inhibition in the brain. We developed a series of photoswitch ligands and the complementary genetically modified GABAA receptor subunits. By conjugating the two components, we generated light-sensitive versions of the entire GABAA receptor family. We validated these light-sensitive receptors for applications across a broad range of spatial scales, from subcellular receptor mapping to in vivo photo-control of visual responses in the cerebral cortex. Finally, we generated a knockin mouse in which the “photoswitch-ready” version of a GABAA receptor subunit genomically replaces its wild-type counterpart, ensuring normal receptor expression. This optogenetic pharmacology toolkit allows scalable interrogation of endogenous GABAA receptor function with high spatial, temporal, and biochemical precision