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

Ultra Compact and Low-power TDC and TAC Architectures for Highly-Parallel Implementation in Time-Resolved Image Sensors

We report on the design and characterization of three different architectures, namely two Time-to- Digital Converters (TDCs) and a Time-to-Amplitude Converter (TAC) with embedded analog-to-digital conversion, implemented in a 130-nm CMOS imaging technology. The proposed circuit solutions are conceived for implementation at pixel-level, in image sensors exploiting Single-Photon Avalanche Diodes as photodetectors. The fabricated 32x32 TDCs/TACs arrays have a pitch of 50μm in both directions while the average power consumption is between 28mW and 300mW depending on the architectural choice. The TAC achieves a time resolution of 160ps on a 20-ns time range with a differential and integral non-linearity (DNL, INL) of 0.7LSB and 1.9LSB, respectively. The two TDCs have a 10-bit resolution with a minimum time resolution between 50ps and 119ps and a worst-case accuracy of ±0.5 LSB DNL and 2.4 LSB INL. An overview of the performance is given together with the analysis of the pros and cons for each architecture

In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a devastating disease affecting about 1 out of 5000 male births and caused by mutations in the dystrophin gene. Genome editing has the potential to restore expression of a modified dystrophin gene from the native locus to modulate disease progression. In this study, adeno-associated virus was used to deliver the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to the mdx mousemodel of DMD to remove the mutated exon 23 from the dystrophin gene. This includes local and systemic delivery to adult mice and systemic delivery to neonatal mice. Exon 23 deletion by CRISPR-Cas9 resulted in expression of the modified dystrophin gene, partial recovery of functional dystrophin protein in skeletal myofibers and cardiac muscle, improvement of muscle biochemistry, and significant enhancement of muscle force.This work establishes CRISPR-Cas9-based genome editing as a potential therapy to treat DMD.Muscular Dystrophy Association (Award MDA277360)National Institutes of Health (U.S.) (Grant 5DP1-MH100706)National Institutes of Health (U.S.) (Grant R01DK097768

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

A 32x32 50ps Resolution 10 bit Time to Digital Converter Array in 130nm CMOS for Time Correlated Imaging

We report the design and characterisation of a 32x32 time to digital (TDC) converter plus single photon avalanche diode (SPAD) pixel array implemented in a 130nm imaging process. Based on a gated ring oscillator approach, the 10 bit, 50mm pitch TDC array exhibits a minimum time resolution of 50ps, with accuracy of ±0.5 LSB DNL and 4 LSB INL. Process, voltage and temperature compensation (PVT) is achieved by locking the array to a stable external clock. The resulting time correlated pixel array is a viable candidate for single photon counting (TCSPC) applications such as fluorescent lifetime imaging microscopy (FLIM), nuclear or 3D imaging and permits scaling to larger array formats

Unraveling Short- and Farsightedness in Politics

The absence of the deselection threat in incumbents’ last term in office can be negative or positive for society. Some politicians may reduce their efforts, while others may pursue beneficial long-term policies that may be unpopular in the short term. We propose a novel pension system that solves the effort problem while preserving willingness to implement long-term policies. The idea is to give politicians the option to choose between a flexible pension scheme and a fixed pension scheme. In a flexible pension scheme, the pension increases with short term performance as measured by the vote share of the officeholder’s party in the next election. This system increases social welfare by letting officeholders self-select into those activities that most benefit society. We analyze the properties and consequences of such a system and assess its robustness. Finally, we extend the pension system with choice to non-last-term situations and derive a general welfare result

PARP1 is required for adhesion molecule expression in atherogenesis

Aims Atherosclerosis is the leading cause of death in Western societies and a chronic inflammatory disease. However, the key mediators linking recruitment of inflammatory cells to atherogenesis remain poorly defined. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme, which plays a role in acute inflammatory diseases. Methods and results In order to test the role of PARP in atherogenesis, we applied chronic pharmacological PARP inhibition or genetic PARP1 deletion in atherosclerosis-prone apolipoprotein E-deficient mice and measured plaque formation, adhesion molecules, and features of plaque vulnerability. After 12 weeks of high-cholesterol diet, plaque formation in male apolipoprotein E-deficient mice was decreased by chronic inhibition of enzymatic PARP activity or genetic deletion of PARP1 by 46 or 51%, respectively (P < 0.05, n ≥ 9). PARP inhibition or PARP1 deletion reduced PARP activity and diminished expression of inducible nitric oxide synthase, vascular cell adhesion molecule-1, and P- and E-selectin. Furthermore, chronic PARP inhibition reduced plaque macrophage (CD68) and T-cell infiltration (CD3), increased fibrous cap thickness, and decreased necrotic core size and cell death (P < 0.05, n ≥ 6). Conclusion Our data provide pharmacological and genetic evidence that endogenous PARP1 is required for atherogenesis in vivo by increasing adhesion molecules with endothelial activation, enhancing inflammation, and inducing features of plaque vulnerability. Thus, inhibition of PARP1 may represent a promising therapeutic target in atherosclerosi

Deposit Insurance in General Equilibrium

We study the consequences and optimal design of bank deposit insurance in a general equilibrium model. The model involves two production sectors. One sector is financed by issuing bonds to risk-averse households. Firms in the other sector are monitored and financed by banks. Households fund banks through deposits and equity. Deposits are explicitly insured by a de- posit insurance fund. Any remaining shortfall is implicitly guaranteed by the government. The deposit insurance fund charges banks a premium per unit of deposits whereas the government finances any necessary bail-outs by lump-sum taxation of households. When the deposit insurance premium is actuarially fair or higher than actuarially fair, two types of equilibria emerge: One type of equilibria supports the socially optimal (Arrow-Debreu) allo- cation, and the other type does not. In the latter case, bank lending is too large relative to equity and the probability that the banking system collapses is positive. Next, we show that a judicious combination of deposit insurance and reinsurance eliminates all non-optimal equilibrium allocations

In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a devastating disease affecting about 1 out of 5000 male births and caused by mutations in the dystrophin gene. Genome editing has the potential to restore expression of a modified dystrophin gene from the native locus to modulate disease progression. In this study, adeno-associated virus was used to deliver the CRISPR/Cas9 system to the mdx mouse model of DMD to remove the mutated exon 23 from the dystrophin gene. This includes local and systemic delivery to adult mice and systemic delivery to neonatal mice. Exon 23 deletion by CRISPR/Cas9 resulted in expression of the modified dystrophin gene, partial recovery of functional dystrophin protein in skeletal myofibers and cardiac muscle, improvement of muscle biochemistry, and significant enhancement of muscle force. This work establishes CRISPR/Cas9-based genome editing as a potential therapy to treat DMD