a mechanism design approach

We study road congestion as a mechanism design problem. In our basic model we analyze the allocation of a set of drivers among two roads, one of which may be congested. An additional driver on the congestible road imposes an externality on the other drivers by increasing their travel time. Each driver is privately informed about her value of time and asked to report that value to the mechanism designer, who assigns drivers to roads. With a finite number of drivers, there is aggregate uncertainty and the efficient allocation is ex ante unknown. Setting a single Pigouvian price is then not optimal. However, the efficient allocation is implementable by a Vickrey-Clarke-Groves price schedule that lets each driver pay the externality she imposes on other drivers. This allows drivers to pay to have other drivers use the slow road instead of the congestible road. As the number of drivers becomes large, there is a single optimal Pigouvian price that leads to an efficient allocation. However, finding this price requires the mechanism designer to either know the precise distribution of the value of time or the use of our mechanism. We analyze some extensions and apply our model to various congestion problems arising in other contexts

Our Administrative System of Criminal Justice

To commemorate our founding in 1914, the Board of Editors has selected six influential pieces published by the Law Review over the past 100 years and will republish one piece in each issue. The fourth piece selected by the Board is Our Administrative System of Criminal Justice, an article written by Gerard E. Lynch that is among the most cited works in the Law Review’s history. This article illustrates how the practice of plea bargaining blurs the boundaries between adversarial and inquisitorial criminal justice systems. Judge Lynch now sits on the Second Circuit having eventually succeeded the late Judge Joseph M. McLaughlin, who also is honored in the pages of this book for the permanent mark he left on Fordham Law School and the Law Review. We think it is fitting that the Law Review feature two of the many contributions that judges of the Second Circuit have made to legal education and scholarship in this issue

Biological mechanisms of aging predict age-related disease co-occurrence in patients

Genetic, environmental, and pharmacological interventions into the aging process can confer resistance to multiple age-related diseases in laboratory animals, including rhesus monkeys. These findings imply that individual mechanisms of aging might contribute to the co-occurrence of age-related diseases in humans and could be targeted to prevent these conditions simultaneously. To address this question, we text mined 917,645 literature abstracts followed by manual curation and found strong, non-random associations between age-related diseases and aging mechanisms in humans, confirmed by gene set enrichment analysis of GWAS data. Integration of these associations with clinical data from 3.01 million patients showed that age-related diseases associated with each of five aging mechanisms were more likely than chance to be present together in patients. Genetic evidence revealed that innate and adaptive immunity, the intrinsic apoptotic signaling pathway and activity of the ERK1/2 pathway were associated with multiple aging mechanisms and diverse age-related diseases. Mechanisms of aging hence contribute both together and individually to age-related disease co-occurrence in humans and could potentially be targeted accordingly to prevent multimorbidity

Fast and Compact Distributed Verification and Self-Stabilization of a DFS Tree

We present algorithms for distributed verification and silent-stabilization of a DFS(Depth First Search) spanning tree of a connected network. Computing and maintaining such a DFS tree is an important task, e.g., for constructing efficient routing schemes. Our algorithm improves upon previous work in various ways. Comparable previous work has space and time complexities of $O(n\log \Delta)$ bits per node and $O(nD)$ respectively, where $\Delta$ is the highest degree of a node, $n$ is the number of nodes and $D$ is the diameter of the network. In contrast, our algorithm has a space complexity of $O(\log n)$ bits per node, which is optimal for silent-stabilizing spanning trees and runs in $O(n)$ time. In addition, our solution is modular since it utilizes the distributed verification algorithm as an independent subtask of the overall solution. It is possible to use the verification algorithm as a stand alone task or as a subtask in another algorithm. To demonstrate the simplicity of constructing efficient DFS algorithms using the modular approach, We also present a (non-sielnt) self-stabilizing DFS token circulation algorithm for general networks based on our silent-stabilizing DFS tree. The complexities of this token circulation algorithm are comparable to the known ones

Advances in automatic identifcation of flying insects using optical sensors and machine learning

Worldwide, farmers use insecticides to prevent crop damage caused by insect pests, while they also rely on insect pollinators to enhance crop yield and other insect as natural enemies of pests. In order to target pesticides to pests only, farmers must know exactly where and when pests and beneficial insects are present in the field. A promising solution to this problem could be optical sensors combined with machine learning. We obtained around 10,000 records of flying insects found in oilseed rape (Brassica napus) crops, using an optical remote sensor and evaluated three different classification methods for the obtained signals, reaching over 80% accuracy. We demonstrate that it is possible to classify insects in fight, making it possible to optimize the application of insecticides in space and time. This will enable a technological leap in precision agriculture, where focus on prudent and environmentally-sensitive use of pesticides is a top priority

Self-stabilizing algorithms for Connected Vertex Cover and Clique decomposition problems

In many wireless networks, there is no fixed physical backbone nor centralized network management. The nodes of such a network have to self-organize in order to maintain a virtual backbone used to route messages. Moreover, any node of the network can be a priori at the origin of a malicious attack. Thus, in one hand the backbone must be fault-tolerant and in other hand it can be useful to monitor all network communications to identify an attack as soon as possible. We are interested in the minimum \emph{Connected Vertex Cover} problem, a generalization of the classical minimum Vertex Cover problem, which allows to obtain a connected backbone. Recently, Delbot et al.~\cite{DelbotLP13} proposed a new centralized algorithm with a constant approximation ratio of $2$ for this problem. In this paper, we propose a distributed and self-stabilizing version of their algorithm with the same approximation guarantee. To the best knowledge of the authors, it is the first distributed and fault-tolerant algorithm for this problem. The approach followed to solve the considered problem is based on the construction of a connected minimal clique partition. Therefore, we also design the first distributed self-stabilizing algorithm for this problem, which is of independent interest

Molecular and functional characterization of BDNF-overexpressing human retinal pigment epithelial cells established by sleeping beauty transposon-mediated gene transfer

More and more patients suffer from multifactorial neurodegenerative diseases, such as age-related macular degeneration (AMD). However, their pathological mechanisms are still poorly understood, which complicates the development of effective therapies. To improve treatment of multifactorial diseases, cell-based gene therapy can be used to increase the expression of therapeutic factors. To date, there is no approved therapy for dry AMD, including late-stage geographic atrophy. We present a treatment option for dry AMD that transfers the brain-derived neurotrophic factor (BDNF) gene into retinal pigment epithelial (RPE) cells by electroporation using the plasmid-based Sleeping Beauty (SB) transposon system. ARPE-19 cells and primary human RPE cells were co-transfected with two plasmids encoding the (SB100X) transposase and the transposon carrying a BDNF transcription cassette. We demonstrated efficient expression and secretion of BDNF in both RPE cell types, which were further increased in ARPE-19 cell cultures exposed to hydrogen peroxide. BDNF-transfected cells exhibited lower apoptosis rates and stimulated neurite outgrowth in human SH-SY5Y cells. This study is an important step in the development of a cell-based BDNF gene therapy that could be applied as an advanced therapy medicinal product to treat dry AMD or other degenerative retinal diseases

GMP-grade manufacturing and quality control of a non-virally engineered advanced therapy medicinal product for personalized treatment of age-related macular degeneration

The introduction of new therapeutics requires validation of Good Manufacturing Practice (GMP)-grade manufacturing including suitable quality controls. This is challenging for Advanced Therapy Medicinal Products (ATMP) with personalized batches. We have developed a person-alized, cell-based gene therapy to treat age-related macular degeneration and established a vali-dation strategy of the GMP-grade manufacture for the ATMP; manufacturing and quality control were challenging due to a low cell number, batch-to-batch variability and short production duration. Instead of patient iris pigment epithelial cells, human donor tissue was used to produce the transfected cell product ("tIPE"). We implemented an extended validation of 104 tIPE productions. Procedure, operators and devices have been validated and qualified by determining cell number, viability, extracellular DNA, sterility, duration, temperature and volume. Transfected autologous cells were transplanted to rabbits verifying feasibility of the treatment. A container has been engineered to ensure a safe transport from the production to the surgery site. Criteria for successful validation and qualification were based on tIPE's Critical Quality Attributes and Process Parameters, its manufacture and release criteria. The validated process and qualified operators are essential to bring the ATMP into clinic and offer a general strategy for the transfer to other manufacture centers and personalized ATMPs

Development of an enzyme-linked immunosorbent assay for the detection of human calretinin in plasma and serum of mesothelioma patients

<p>Abstract</p> <p>Background</p> <p>Calretinin is one of the well-established immunohistochemical markers in the diagnostics of malignant mesothelioma (MM). Its utility as a diagnostic tool in human blood, however, is scarcely investigated. The aim of this study was to develop an enzyme-linked immunosorbent assay (ELISA) for human calretinin in blood and to assess its usefulness as a potential minimally invasive diagnostic marker for MM.</p> <p>Methods</p> <p>Initially, attempts were made to establish an assay using commercially available antibodies and to optimize it by including a biotin-streptavidin complex into the assay protocol. Subsequently, a novel ELISA based on polyclonal antibodies raised in rabbit immunized with human recombinant calretinin was developed. The assay performance in human serum and plasma (EDTA/heparin) and the influence of calcium concentrations on antibody recognition were studied. Stability of spiked-in calretinin in EDTA plasma under different storage conditions was also examined. In preliminary studies serum and plasma samples from 97 healthy volunteers, 35 asbestos-exposed workers, and 42 MM patients were analyzed.</p> <p>Results</p> <p>The mean detection range of the new ELISA was 0.12 to 8.97 ng/ml calretinin. The assay demonstrated markedly lower background and significantly higher sensitivity compared to the initially contrived assay that used commercial antibodies. Recovery rate experiments confirmed dependence of calretinin antibody recognition on calcium concentration. Calcium adjustment is necessary for calretinin measurement in EDTA plasma. Spiked-in calretinin revealed high stability in EDTA plasma when stored at room temperature, 4°C, or after repeated freeze/thaw cycles. Median calretinin values in healthy volunteers, asbestos workers, and MM patients were 0.20, 0.33, and 0.84 ng/ml, respectively (p < 0.0001 for healthy vs. MM, p = 0.0036 for healthy vs. asbestos-exposed, p < 0.0001 for asbestos-exposed vs. MM). Median values in patients with epithelioid and biphasic MM were similar. No influence of age, gender, smoking status, or type of medium (plasma/serum) on calretinin values was found.</p> <p>Conclusions</p> <p>The novel assay is highly sensitive and applicable to human serum and plasma. Calretinin appears to be a promising marker for the blood-based detection of MM and might complement other markers. However, further studies are required to prove its usefulness in the diagnosis of MM patients.</p