The formal verification of a pipelined double-precision IEEE floating-point multiplier

Floating-point circuits are notoriously difficult to design and verify. For verification, simulation barely offers adequate coverage, conventional model-checking techniques are infeasible, and theorem-proving based verification is not sufficiently mature. In this paper we present the formal verification of a radix-eight, pipelined, IEEE double-precision floating-point multiplier. The verification was carried out using a mixture of model-checking and theorem-proving techniques in the Voss hardware verification system. By combining model-checking and theorem-proving we were able to build on the strengths of both areas and achieve significant results with a reasonable amount of effort.

Gene deletion in a patient with chronic granulomatous disease and McLeod syndrome: fine mapping of the Xk gene locus

In a patient suffering from X-linked chronic granulomatous disease (X- CGD)--a disorder of phagocytesuperoxide generation--and McLeod syndrome, characterized by the absence of the red cell Kell antigen, we identified a deletion of the entire X-CGD gene by means of DNA hybridization with a cDNA probe. Our findings suggest that the X-CGD and McLeod loci are physically close in the p21 region of the X chromosome proximal to the Duchenne muscular dystrophy locus

Chronic granulomatous disease: the European experience.

CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a "respiratory burst", essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. However, a clear picture of the clinical course of CGD is hampered by its low prevalence (approximately 1:250,000). Therefore, extensive clinical data from 429 European patients were collected and analyzed. Of these patients 351 were males and 78 were females. X-linked (XL) CGD (gp91(phox) deficient) accounted for 67% of the cases, autosomal recessive (AR) inheritance for 33%. AR-CGD was diagnosed later in life, and the mean survival time was significantly better in AR patients (49.6 years) than in XL CGD (37.8 years), suggesting a milder disease course in AR patients. The disease manifested itself most frequently in the lungs (66% of patients), skin (53%), lymph nodes (50%), gastrointestinal tract (48%) and liver (32%). The most frequently cultured micro-organisms per episode were Staphylococcus aureus (30%), Aspergillus spp. (26%), and Salmonella spp. (16%). Surprisingly, Pseudomonas spp. (2%) and Burkholderia cepacia (<1%) were found only sporadically. Lesions induced by inoculation with BCG occurred in 8% of the patients. Only 71% of the patients received antibiotic maintenance therapy, and 53% antifungal prophylaxis. 33% were treated with gamma-interferon. 24 patients (6%) had received a stem cell transplantation. The most prominent reason of death was pneumonia and pulmonary abscess (18/84 cases), septicemia (16/84) and brain abscess (4/84). These data provide further insight in the clinical course of CGD in Europe and hopefully can help to increase awareness and optimize the treatment of these patients

Partition Functions in Statistical Mechanics, Symmetric Functions, and Group Representations

Partition functions for non-interacting particles are known to be symmetric functions. It is shown that powerful group-theoretical techniques can be used not only to derive these relationships, but also to significantly simplify calculation of the partition functions for particles that carry internal quantum numbers. The partition function is shown to be a sum of one or more group characters. The utility of character expansions in calculating the partition functions is explored. Several examples are given to illustrate these techniques.Comment: 16 pages of RevTe

A variational approach to the stochastic aspects of cellular signal transduction

Cellular signaling networks have evolved to cope with intrinsic fluctuations, coming from the small numbers of constituents, and the environmental noise. Stochastic chemical kinetics equations govern the way biochemical networks process noisy signals. The essential difficulty associated with the master equation approach to solving the stochastic chemical kinetics problem is the enormous number of ordinary differential equations involved. In this work, we show how to achieve tremendous reduction in the dimensionality of specific reaction cascade dynamics by solving variationally an equivalent quantum field theoretic formulation of stochastic chemical kinetics. The present formulation avoids cumbersome commutator computations in the derivation of evolution equations, making more transparent the physical significance of the variational method. We propose novel time-dependent basis functions which work well over a wide range of rate parameters. We apply the new basis functions to describe stochastic signaling in several enzymatic cascades and compare the results so obtained with those from alternative solution techniques. The variational ansatz gives probability distributions that agree well with the exact ones, even when fluctuations are large and discreteness and nonlinearity are important. A numerical implementation of our technique is many orders of magnitude more efficient computationally compared with the traditional Monte Carlo simulation algorithms or the Langevin simulations.Comment: 15 pages, 11 figure

Variation in developmental rates is not linked to environmental unpredictability in annual killifishes

Comparative evidence suggests that adaptive plasticity may evolve as a response to predictable environmental variation. However, less attention has been placed on unpredictable environmental variation, which is considered to affect evolutionary trajectories by increasing phenotypic variation (or bet hedging). Here, we examine the occurrence of bet hedging in egg developmental rates in seven species of annual killifish that originate from a gradient of variation in precipitation rates, under three treatment incubation temperatures (21, 23, and 25 degrees C). In the wild, these species survive regular and seasonal habitat desiccation, as dormant eggs buried in the soil. At the onset of the rainy season, embryos must be sufficiently developed in order to hatch and complete their life cycle. We found substantial differences among species in both the mean and variation of egg development rates, as well as species-specific plastic responses to incubation temperature. Yet, there was no clear relationship between variation in egg development time and variation in precipitation rate (environmental predictability). The exact cause of these differences therefore remains enigmatic, possibly depending on differences in other natural environmental conditions in addition to precipitation predictability. Hence, if species-specific variances are adaptive, the relationship between development and variation in precipitation is complex and does not diverge in accordance with simple linear relationships

The Value of Information for Populations in Varying Environments

The notion of information pervades informal descriptions of biological systems, but formal treatments face the problem of defining a quantitative measure of information rooted in a concept of fitness, which is itself an elusive notion. Here, we present a model of population dynamics where this problem is amenable to a mathematical analysis. In the limit where any information about future environmental variations is common to the members of the population, our model is equivalent to known models of financial investment. In this case, the population can be interpreted as a portfolio of financial assets and previous analyses have shown that a key quantity of Shannon's communication theory, the mutual information, sets a fundamental limit on the value of information. We show that this bound can be violated when accounting for features that are irrelevant in finance but inherent to biological systems, such as the stochasticity present at the individual level. This leads us to generalize the measures of uncertainty and information usually encountered in information theory

Characterisation of the structural heterogeneity of the soil layer by using in situ 2D and 3D electrical resistivity measurements

Introduction Soil structure i. e. the arrangement of soil particles in space (Guérif, 1987) is one important factor of physic quality of soils. In the agricultural context, this structure is modified at several space and time scales by different constraints or processes: tillage, compaction by traffic, natural effects. We need methods to characterize its in situ state. They already exist but they are destructive and time consuming. Recent works (Besson et al., 2004) have shown that a compacte..

Neuronally derived extracellular vesicle α-synuclein as a serum biomarker for individuals at risk of developing Parkinson disease

IMPORTANCE: Nonmotor symptoms of Parkinson disease (PD) often predate the movement disorder by decades. Currently, there is no blood biomarker to define this prodromal phase. OBJECTIVE: To investigate whether α-synuclein in neuronally derived serum-extracellular vesicles identifies individuals at risk of developing PD and related dementia. DESIGN, SETTING, and PARTICIPANTS: This retrospective, cross-sectional multicenter study of serum samples included the Oxford Discovery, Marburg, Cologne, and Parkinson’s Progression Markers Initiative cohorts. Participants were recruited from July 2013 through August 2023 and samples were analyzed from April 2022 through September 2023. The derivation group (n = 170) included participants with isolated rapid eye movement sleep behavior disorder (iRBD) and controls. Two validation groups were used: the first (n = 122) included participants with iRBD and controls and the second (n = 263) included nonmanifest GBA1N409S gene carriers, participants with iRBD or hyposmia, and available dopamine transporter single-photon emission computed tomography, healthy controls, and patients with sporadic PD. Overall the study included 199 participants with iRBD, 20 hyposmic participants with available dopamine transporter single-photon emission computed tomography, 146 nonmanifest GBA1N409S gene carriers, 21 GBA1N409S gene carrier patients with PD, 50 patients with sporadic PD, and 140 healthy controls. In the derivation group and validation group 1, participants with polysomnographically confirmed iRBD were included. In the validation group 2, at-risk participants with available Movement Disorder Society prodromal markers and serum samples were included. Among 580 potential participants, 4 were excluded due to alternative diagnoses. EXPOSURES: Clinical assessments, imaging, and serum collection. MAIN OUTCOME AND MEASURES: L1CAM-positive extracellular vesicles (L1EV) were immunocaptured from serum. α-Synuclein and syntenin-1 were measured by electrochemiluminescence. Area under the receiver operating characteristic (ROC) curve (AUC) with 95% CIs evaluated biomarker performance. Probable prodromal PD was determined using the updated Movement Disorder Society research criteria. Multiple linear regression models assessed the association between L1EV α-synuclein and prodromal markers. RESULTS: Among 576 participants included, the mean (SD) age was 64.30 (8.27) years, 394 were male (68.4%), and 182 were female (31.6%). A derived threshold of serum L1EV α-synuclein distinguished participants with iRBD from controls (AUC = 0.91; 95% CI, 0.86-0.96) and those with more than 80% probability of having prodromal PD from participants with less than 5% probability (AUC = 0.80; 95% CI, 0.71-0.89). Subgroup analyses revealed that specific combinations of prodromal markers were associated with increased L1EV α-synuclein levels. Across all cohorts, L1EV α-synuclein differentiated participants with more than 80% probability of having prodromal PD from current and historic healthy control populations (AUC = 0.90; 95% CI, 0.87-0.93), irrespective of initial diagnosis. L1EV α-synuclein was increased in at-risk participants with a positive cerebrospinal fluid seed amplification assay and was above the identified threshold in 80% of cases (n = 40) that phenoconverted to PD or related dementia. CONCLUSIONS AND RELEVANCE: L1EV α-synuclein in combination with prodromal markers should be considered in the stratification of those at high risk of developing PD and related Lewy body diseases