Fault-Tolerant Coding for State Machines

Two reliable fault-tolerant coding schemes have been proposed for state machines that are used in field-programmable gate arrays and application-specific integrated circuits to implement sequential logic functions. The schemes apply to strings of bits in state registers, which are typically implemented in practice as assemblies of flip-flop circuits. If a single-event upset (SEU, a radiation-induced change in the bit in one flip-flop) occurs in a state register, the state machine that contains the register could go into an erroneous state or could hang, by which is meant that the machine could remain in undefined states indefinitely. The proposed fault-tolerant coding schemes are intended to prevent the state machine from going into an erroneous or hang state when an SEU occurs. To ensure reliability of the state machine, the coding scheme for bits in the state register must satisfy the following criteria: 1. All possible states are defined. 2. An SEU brings the state machine to a known state. 3. There is no possibility of a hang state. 4. No false state is entered. 5. An SEU exerts no effect on the state machine. Fault-tolerant coding schemes that have been commonly used include binary encoding and "one-hot" encoding. Binary encoding is the simplest state machine encoding and satisfies criteria 1 through 3 if all possible states are defined. Binary encoding is a binary count of the state machine number in sequence; the table represents an eight-state example. In one-hot encoding, N bits are used to represent N states: All except one of the bits in a string are 0, and the position of the 1 in the string represents the state. With proper circuit design, one-hot encoding can satisfy criteria 1 through 4. Unfortunately, the requirement to use N bits to represent N states makes one-hot coding inefficient

1999 Convocation

Prelude: Mr. Drew Massey, 1999 IMSA Graduate Pledge of Allegiance: Ms. Donielle Newell, Student Council President Welcome: Ms. Donielle Newell, Student Council President; Dr. Stephanie Pace Marshall, President; Mr. Eric McLaren, Principal Musical Selection: Mr. Drew Massey Keynote Speaker: Ms. Marcie Edwards Hawkins, 1989 IMSA Graduat

Traumatic brain injury causes selective, CD74-dependent peripheral lymphocyte activation that exacerbates neurodegeneration

INTRODUCTION: Traumatic brain injury (TBI), a significant cause of death and disability, causes, as in any injury, an acute, innate immune response. A key component in the transition between innate and adaptive immunity is the processing and presentation of antigen by professional antigen presenting cells (APCs). Whether an adaptive immune response to brain injury is beneficial or detrimental is not known. Current efforts to understand the contribution of the immune system after TBI have focused on neuroinflammation and brain-infiltrating immune cells. Here, we characterize and target TBI-induced expansion of peripheral immune cells that may act as potential APCs. Because MHC Class II-associated invariant peptide (CLIP) is important for antigen processing and presentation, we engineered a competitive antagonist (CAP) for CLIP, and tested the hypothesis that peptide competition could reverse or prevent neurodegeneration after TBI. RESULTS: We show that after fluid percussion injury (FPI), peripheral splenic lymphocytes, including CD4+ and CD8+ T cells, regulatory T cells (Tregs), and γδ T cells, are increased in number within 24 hours after FPI. These increases were reversed by CAP treatment and this antagonism of CLIP also reduced neuroinflammation and neurodegeneration after TBI. Using a mouse deficient for the precursor of CLIP, CD74, we observed decreased peripheral lymphocyte activation, decreased neurodegeneration, and a significantly smaller lesion size following TBI. CONCLUSION: Taken together, the data support the hypothesis that neurodegeneration following TBI is dependent upon antigen processing and presentation that requires CD74. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-014-0143-5) contains supplementary material, which is available to authorized users

Observations of convective and dynamical instabilities in tropopause folds and their contribution to stratosphere-troposphere exchange

With aircraft-mounted in situ and remote sensing instruments for dynamical, thermal, and chemical measurements we studied two cases of tropopause folding. In both folds we found Kelvin-Helmholtz billows with horizontal wavelength of ∼900 m and thickness of ∼120 m. In one case the instability was effectively mixing the bottomside of the fold, leading to the transfer of stratospheric air into the troposphere. Also, we discovered in both cases small-scale secondary ozone maxima shortly after the aircraft ascended past the topside of the fold that corresponded to regions of convective instability. We interpreted this phenomenon as convectively breaking gravity waves. Therefore we posit that convectively breaking gravity waves acting on tropopause folds must be added to the list of important irreversible mixing mechanisms leading to stratosphere-troposphere exchange.United States. National Aeronautics and Space Administration (Grant NAG2-1105)United States. National Aeronautics and Space Administration (Grant NAGl-1758)United States. National Aeronautics and Space Administration (Grant NAGl-1901

Outcomes of Patients with Nelson's Syndrome after Primary Treatment: A Multicenter Study from 13 UK Pituitary Centers.

CONTEXT: Long-term outcomes of patients with Nelson's syndrome (NS) have been poorly explored, especially in the modern era. OBJECTIVE: To elucidate tumor control rates, effectiveness of various treatments, and markers of prognostic relevance in patients with NS. PATIENTS, DESIGN, AND SETTING: Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1-45) since NS diagnosis. RESULTS: Management of Cushing's disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n = 30; eight patients had 2 and one had 3 pituitary operations), surgery+radiotherapy+adrenalectomy (n = 17; two received >1 courses of irradiation, two had ≥2 pituitary surgeries), radiotherapy+adrenalectomy (n = 2), and adrenalectomy (n = 19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy, and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, and mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (hazard ratio 4.6; 95% confidence interval, 1.6-13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor. CONCLUSIONS: At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis

Large-scale ozone and aerosol distributions, air mass characteristics, and ozone fluxes over the western Pacific Ocean in late winter/early spring

Large‐scale measurements of ozone (O3) and aerosol distributions were made from the NASA DC‐8 aircraft during the Transport and Chemical Evolution over the Pacific (TRACE‐P) field experiment conducted in February–April 2001. Remote measurements were made with an airborne lidar to provide O3 and multiple‐wavelength aerosol backscatter profiles from near the surface to above the tropopause along the flight track. In situ measurements of O3, aerosols, and a wide range of trace gases were made onboard the DC‐8. Five‐day backward trajectories were used in conjunction with the O3 and aerosol distributions on each flight to indicate the possible origin of observed air masses, such as from biomass burning regions, continental pollution, desert regions, and oceanic regions. Average latitudinal O3 and aerosol scattering ratio distributions were derived from all flights west of 150°E, and these distributions showed the average latitude and altitude dependence of different dynamical and chemical processes in determining the atmospheric composition over the western Pacific. TRACE‐P (TP) showed an increase in the average latitudinal distributions of both O3 and aerosols compared to PEM‐West B (PWB), which was conducted in February–March 1994. O3, aerosol, and potential vorticity levels were used to identify nine air mass types and quantify their frequency of occurrence as a function of altitude. This paper discusses the characteristics of the different air mass types encountered during TP and compares them to PWB. These results confirmed that most of the O3 increase in TP was due to photochemistry. The average latitudinal eastward O3 flux in the western Pacific during TP was found to peak near 32°N with a total average O3 flux between 14 and 46°N of 5.2 Tg/day. The eastward total CO flux was calculated to be 2.2 Tg‐C/day with ∼6% estimated from Asia. The Asian flux of CO2 and CH4 was estimated at 4.9 and 0.06 Tg‐C/day

Effects of Elevated Temperature and Carbon Dioxide on the Growth and Survival of Larvae and Juveniles of Three Species of Northwest Atlantic Bivalves

Rising CO2 concentrations and water temperatures this century are likely to have transformative effects on many coastal marine organisms. Here, we compared the responses of two life history stages (larval, juvenile) of three species of calcifying bivalves (Mercenaria mercenaria, Crassostrea virginica, and Argopecten irradians) to temperatures (24 and 28°C) and CO2 concentrations (∼250, 390, and 750 ppm) representative of past, present, and future summer conditions in temperate estuaries. Results demonstrated that increases in temperature and CO2 each significantly depressed survival, development, growth, and lipid synthesis of M. mercenaria and A. irradians larvae and that the effects were additive. Juvenile M. mercenaria and A. irradians were negatively impacted by higher temperatures while C. virginica juveniles were not. C. virginica and A. irradians juveniles were negatively affected by higher CO2 concentrations, while M. mercenaria was not. Larvae were substantially more vulnerable to elevated CO2 than juvenile stages. These findings suggest that current and future increases in temperature and CO2 are likely to have negative consequences for coastal bivalve populations

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Parallel Optimisation of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Chemical Tool

[Image: see text] The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and in vitro pharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure