Implementing Safety Instrumented Burner Management Systems: Challenges and Opportunities

PresentationImplementing a Safety Instrumented Burner Management (SI-BMS) can be challenging, costly, and time consuming. Simply identifying design shortfalls/gaps can be costly, and this does not include costs associated with the capital project to target the gap closure effort itself. Additionally, when one multiplies the costs by the total number of heaters at different sites, these total costs can escalate quickly. However, a “template” approach to implementing SI-BMS in a brownfield environment can offer a very cost effective solution for end users. Creating standard “templates” for all deliverables associated with a SI-BMS will allow each subsequent SI-BMS to be implemented at a fraction of the cost of the first. This is because a template approach minimizes rework associated with creating a new SI-BMS package. The ultimate goal is to standardize implementation of SI-BMS in order to reduce engineering effort, create standard products, and ultimately reduce cost of ownership

Sensing centromere tension: Aurora B and the regulation of kinetochore function

Maintaining genome integrity during cell division requires regulated interactions between chromosomes and spindle microtubules. To ensure that daughter cells inherit the correct chromosomes, the sister kinetochores must attach to opposite spindle poles. Tension across the centromere stabilizes correct attachments, whereas phosphorylation of kinetochore substrates by the conserved Ipl1/Aurora B kinase selectively eliminates incorrect attachments. Here, we review our current understanding of how mechanical forces acting on the kinetochore are linked to biochemical changes to control chromosome segregation. We discuss models for tension sensing and regulation of kinetochore function downstream of Aurora B, and mechanisms that specify Aurora B localization to the inner centromere and determine its interactions with substrates at distinct locations.National Institutes of Health (U.S.) (Grant GM088313)Kinship Foundation. Searle Scholars Progra

In vivo and in silico characterization of apocynin in reducing organ oxidative stress: a pharmacokinetic and pharmacodynamic study

Apocynin has been widely used in vivo as a Nox2-contaninig NADPH oxidase inhibitor. However, its time-dependent tissue distribution and inhibition on organ reactive oxygen species (ROS) production remained unclear. In this study, we examined apocynin pharmacokinetics and pharmacodynamics (PKPD) after iv injection (bolus, 5 mg/kg) of mice (CD1, 12-week). Apocynin was detected using a HPLC coupled to a linear ion-trap tandem mass spectrometer. Apocynin peak concentrations were detected in plasma at 1 min (5494±400 ng/mL) (t1/2=0.05 h, clearance=7.76 L/h/kg), in urine at 15 min (14942±5977 ng/mL), in liver at 5 min (2853±35 ng/g), in heart at 5 min (3161±309 ng/g) and in brain at 1 min (4603±208 ng/g) after iv injection. These were accompanied with reduction of ROS production in the liver, heart and brain homogenates. Diapocynin was not detected in these samples. Therapeutic effect of apocynin was examined using a mouse model (C57BL/6J) of high-fat diet (HFD, 16 weeks)-induced obesity and accelerated aging. Apocynin (5 mM) was supplied in drinking water during the HFD period and was detected at the end of treatment in the brain (5369±1612 ng/g), liver (4818±1340 ng/g) and heart (1795±1487 ng/g) along with significant reductions of ROS production in these organs. In conclusion, apocynin PKPD is characterized by a short half-life, rapid clearance, good distribution and inhibition of ROS production in major organs. Diapocynin is not a metabolite of apocynin in vivo. Apocynin crosses easily the blood-brain barrier and reduces brain oxidative stress associated with metabolic disorders and aging

Optogenetic control of organelle transport using a photocaged chemical inducer of dimerization

SummaryCell polarity, growth and signaling require organelle transport by cytoskeletal motor proteins that are precisely regulated in time and space. Probing these complex, dynamic processes requires experimental techniques with comparable temporal and spatial precision. Inducible dimerization offers the ability to recruit motor proteins to organelles in living cells. Approaches include rapamycin-induced dimerization of motors and cargo-bound binding partners [1] or the recent application of the TULIP light-inducible dimerization system [2,3]. In the latter system, motor recruitment is activated by blue light, and relaxes to an OFF state in the dark within seconds. While rapid relaxation is desirable for some applications, many experiments require sustained motor recruitment. Here, we use a photocaged chemical dimerizer to achieve sustained, spatially-defined motor recruitment to individual organelles with a single pulse of light. We demonstrate the general applicability of the system by recruiting microtubule plus end-directed kinesin-1 and minus end-directed dynein motors to peroxisomes and mitochondria in HeLa cells and primary neurons, leading to alterations in organelle transport on timescales from <10 seconds to >10 minutes after photoactivation

A Calculus for Access Control in Distributed Systems

We study some of the concepts, protocols, and algorithms for access control in distributed systems, from a logical perspective. We account for how a principal may come to believe that another principal is making a request, either on his own or on someone else’s behalf. We also provide a logical language for access control lists and theories for deciding whether requests should be granted

Spindle asymmetry drives non- Mendelian chromosome segregation

International audienceGenetic elements compete for transmission through meiosis, when haploid gametes are created from a diploid parent. Selfish elements can enhance their transmission through a process known as meiotic drive. In female meiosis, selfish elements drive by preferentially attaching to the egg side of the spindle.This implies some asymmetry between the two sides of the spindle, but the molecular mechanisms underlying spindle asymmetry are unknown. Here we found that CDC42 signaling from the cell cortex regulated microtubule tyrosination to induce spindle asymmetry and that non-Mendelian segregation depended on this asymmetry. Cortical CDC42 depends on polarization directed by chromosomes, which are positioned near the cortex to allow the asymmetric cell division.Thus, selfish meiotic drivers exploit the asymmetry inherent in female meiosis to bias their transmission

Aurora B phosphorylates spatially distinct targets to differentially regulate the kinetochore-microtubule interface

Accurate chromosome segregation requires carefully regulated interactions between kinetochores and microtubules, but how plasticity is achieved to correct diverse attachment defects remains unclear. Here we demonstrate that Aurora B kinase phosphorylates three spatially distinct targets within the conserved outer kinetochore KNL1/Mis12 complex/Ndc80 complex (KMN) network, the key player in kinetochore-microtubule attachments. The combinatorial phosphorylation of the KMN network generates graded levels of microtubule-binding activity, with full phosphorylation severely compromising microtubule binding. Altering the phosphorylation state of each protein causes corresponding chromosome segregation defects. Importantly, the spatial distribution of these targets along the kinetochore axis leads to their differential phosphorylation in response to changes in tension and attachment state. In total, rather than generating exclusively binary changes in microtubule binding, our results suggest a mechanism for the tension-dependent fine-tuning of kinetochore-microtubule interactions.Smith Family FoundationMassachusetts Life Sciences CenterKinship Foundation. Searle Scholars ProgramNational Institute of General Medical Sciences (U.S.) (Grant number GM088313

Common Representation of Information Flows for Dynamic Coalitions

We propose a formal foundation for reasoning about access control policies within a Dynamic Coalition, defining an abstraction over existing access control models and providing mechanisms for translation of those models into information-flow domain. The abstracted information-flow domain model, called a Common Representation, can then be used for defining a way to control the evolution of Dynamic Coalitions with respect to information flow

Mps1 regulates kinetochore-microtubule attachment stability via the ska complex to ensure error-free chromosome segregation

The spindle assembly checkpoint kinase Mps1 not only inhibits anaphase but also corrects erroneous attachments that could lead to missegregation and aneuploidy. However, Mps1’s error correction-relevant substrates are unknown. Using a chemically tuned kinetochore-targeting assay, we show that Mps1 destabilizes microtubule attachments (K fibers) epistatically to Aurora B, the other major error-correcting kinase. Through quantitative proteomics, we identify multiple sites of Mps1-regulated phosphorylation at the outer kinetochore. Substrate modification was microtubule sensitive and opposed by PP2A-B56 phosphatases that stabilize chromosome-spindle attachment. Consistently, Mps1 inhibition rescued K-fiber stability after depleting PP2A-B56. We also identify the Ska complex as a key effector of Mps1 at the kinetochore-microtubule interface, as mutations that mimic constitutive phosphorylation destabilized K fibers in vivo and reduced the efficiency of the Ska complex’s conversion from lattice diffusion to end-coupled microtubule binding in vitro. Our results reveal how Mps1 dynamically modifies kinetochores to correct improper attachments and ensure faithful chromosome segregation