Fast fluorescence dynamics in non-ratiometric calcium indicators

A fluorescence decay of high-affinity non-ratiometric Ca2+ indicator Oregon Green BAPTA-1 (OGB-1) is analyzed with unprecedented temporal resolution in the two-photon excitation regime. A triple exponential decay is shown to best fit the fluorescence dynamics of OGB-1. We provide a new model for accurate measurements of the free Ca2+ concentration and dissociation constants of non-ratiometric calcium indicators.Comment: 3 pages, 2 figures, figures revised, added chi-square goodness of fi

Genome engineering of stem cells for autonomously regulated, closed-loop delivery of biologic drugs

Chronic inflammatory diseases such as arthritis are characterized by dysregulated responses to pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α). Pharmacologic anti-cytokine therapies are often effective at diminishing this inflammatory response but have significant side effects and are used at high, constant doses that do not reflect the dynamic nature of disease activity. Using the CRISPR/Cas9 genome-engineering system, we created stem cells that antagonize IL-1- or TNF-α-mediated inflammation in an autoregulated, feedback-controlled manner. Our results show that genome engineering can be used successfully to rewire endogenous cell circuits to allow for prescribed input/output relationships between inflammatory mediators and their antagonists, providing a foundation for cell-based drug delivery or cell-based vaccines via a rapidly responsive, autoregulated system. The customization of intrinsic cellular signaling pathways in stem cells, as demonstrated here, opens innovative possibilities for safer and more effective therapeutic approaches for a wide variety of diseases

Antiangiogenesis: current clinical data and future perspectives

Neovascularization is a prerequisite for progressive growth of solid tumors and their metastases. This process is tightly regulated by a large number of proangiogenic and antiangiogenic factors such as VEGF, bFGF and matrix-metalloproteinases. The inhibition of angiogenesis is an innovative therapeutic approach and could represent a powerful adjunct to traditional therapy of malignant tumors. Preclinical trials have been very successful but in clinical studies meaningful response rates could only be shown in some cases. This might indicate the existence of different angiogenic phenotypes in humans. It seems that at present only a part of the interactions between the angiogenic cytokines are known. In addition, new receptor/ligand systems which regulate the neovascularization are being described. This article presents an overview of the most important angiogenically active substances, preclinical and clinical data, surrogate markers as well as future perspectives

Spatial and Spectral Characterization of the Gravitational-wave Background with the PTA Optimal Statistic

Pulsar timing arrays (PTAs) have made tremendous progress and are now showing strong evidence for the gravitational-wave background (GWB). Further probing the origin and characteristics of the GWB will require more generalized analysis techniques. Bayesian methods are most often used but can be computationally expensive. On the other hand, frequentist methods, like the PTA Optimal Statistic (OS), are more computationally efficient and can produce results that are complementary to Bayesian methods, allowing for stronger statistical cases to be built from a confluence of different approaches. In this work we expand the capabilities of the OS through a technique we call the Per-Frequency Optimal Statistic (PFOS). The PFOS removes the underlying power-law assumption inherent in previous implementations of the OS, and allows one to estimate the GWB spectrum in a frequency-by-frequency manner. We have also adapted a recent generalization from the OS pipeline into the PFOS, making it capable of accurately characterizing the spectrum in the intermediate and strong GW signal regimes using only a small fraction of the necessary computational resources when compared with fully-correlated Bayesian methods, while also empowering many new types of analyses not possible before. We find that even in the strong GW signal regime, where the GWB dominates over noise in all frequencies, the injected value of the signal lies within the 50th-percentile of the PFOS uncertainty distribution in 41-45% of simulations, remaining 3σ-consistent with unbiased estimation

How couples with dementia experience healthcare, lifestyle, and everyday decision-making

Copyright © International Psychogeriatric Association 2018. Objectives: Recent research has demonstrated the challenges to self-identity associated with dementia, and the importance of maintaining involvement in decision-making while adjusting to changes in role and lifestyle. This study aimed to understand the lived experiences of couples living with dementia, with respect to healthcare, lifestyle, and everyday decision-making.Design: Semi-structured qualitative interviews using Interpretative Phenomenological Analysis as the methodological approach.Setting: Community and residential care settings in Australia.Participants: Twenty eight participants who self-identified as being in a close and continuing relationship (N = 13 people with dementia, N = 15 spouse partners). Nine couples were interviewed together.Results: Participants described a spectrum of decision-making approaches (independent, joint, supported, and substituted), with these approaches often intertwining in everyday life. Couples' approaches to decision-making were influenced by decisional, individual, relational, and external factors. The overarching themes of knowing and being known, maintaining and re-defining couplehood and relational decision-making, are used to interpret these experiences. The spousal relationship provided an important context for decision-making, with couples expressing a history and ongoing preference for joint decision-making, as an integral part of their experience of couplehood. However, the progressive impairments associated with dementia presented challenges to maintaining joint decision-making and mutuality in the relationship.Conclusions: This study illustrates relational perspectives on decision-making in couples with dementia. Post-diagnostic support, education resources, proactive dyadic interventions, and assistance for spouse care partners may facilitate more productive attempts at joint decision-making by couples living with dementia

Making tomorrow's mistakes today: Evolutionary prototyping for risk reduction and shorter development time

In the early days of JPL's solar system exploration, each spacecraft mission required its own dedicated data system with all software applications written in the mainframe's native assembly language. Although these early telemetry processing systems were a triumph of engineering in their day, since that time the computer industry has advanced to the point where it is now advantageous to replace these systems with more modern technology. The Space Flight Operations Center (SFOC) Prototype group was established in 1985 as a workstation and software laboratory. The charter of the lab was to determine if it was possible to construct a multimission telemetry processing system using commercial, off-the-shelf computers that communicated via networks. The staff of the lab mirrored that of a typical skunk works operation -- a small, multi-disciplinary team with a great deal of autonomy that could get complex tasks done quickly. In an effort to determine which approaches would be useful, the prototype group experimented with all types of operating systems, inter-process communication mechanisms, network protocols, packet size parameters. Out of that pioneering work came the confidence that a multi-mission telemetry processing system could be built using high-level languages running in a heterogeneous, networked workstation environment. Experience revealed that the operating systems on all nodes should be similar (i.e., all VMS or all PC-DOS or all UNIX), and that a unique Data Transport Subsystem tool needed to be built to address the incompatibilities of network standards, byte ordering, and socket buffering. The advantages of building a telemetry processing system based on emerging industry standards were numerous: by employing these standards, we would no longer be locked into a single vendor. When new technology came to market which offered ten times the performance at one eighth the cost, it would be possible to attach the new machine to the network, re-compile the application code, and run. In addition, we would no longer be plagued with lack of manufacturer support when we encountered obscure bugs. And maybe, hopefully, the eternal elusive goal of software portability across different vendors' platforms would finally be available. Some highlights of our prototyping efforts are described

Election Security and Economics: It's All About Eve

A system's security must be understood with respect to the capabilities and be- haviors of an adversary Eve. It is often assumed in security analysis that Eve acts as ma- liciously as possible. From an economic perspective, Eve tries to maximize her utility in a game with other participants. The game's rules are determined by the system and its security mechanisms, but Eve can invent new ways of interacting with participants. We show that Eve can be used as an interface to explore the interplay between security and economics in the domain of elections. Through examples, we illustrate how reasoning from both disciplines may be combined to explicate Eve's motives and capabilities and how this analysis could be used for reasoning about the security and performance of elections. We also point to future research directions at the intersection of these disciplines