Unstable argininosuccinate lyase in variant forms of the urea cycle disorder argininosuccinic aciduria.

Loss of function of the urea cycle enzyme argininosuccinate lyase (ASL) is caused by mutations in the ASL gene leading to ASL deficiency (ASLD). ASLD has a broad clinical spectrum ranging from life-threatening severe neonatal to asymptomatic forms. Different levels of residual ASL activity probably contribute to the phenotypic variability but reliable expression systems allowing clinically useful conclusions are not yet available. In order to define the molecular characteristics underlying the phenotypic variability, we investigated all ASL mutations that were hitherto identified in patients with late onset or mild clinical and biochemical courses by ASL expression in human embryonic kidney 293 T cells. We found residual activities >3 % of ASL wild type (WT) in nine of 11 ASL mutations. Six ASL mutations (p.Arg95Cys, p.Ile100Thr, p.Val178Met, p.Glu189Gly, p.Val335Leu, and p.Arg379Cys) with residual activities ≥16 % of ASL WT showed no significant or less than twofold reduced Km values, but displayed thermal instability. Computational structural analysis supported the biochemical findings by revealing multiple effects including protein instability, disruption of ionic interactions and hydrogen bonds between residues in the monomeric form of the protein, and disruption of contacts between adjacent monomeric units in the ASL tetramer. These findings suggest that the clinical and biochemical course in variant forms of ASLD is associated with relevant residual levels of ASL activity as well as instability of mutant ASL proteins. Since about 30 % of known ASLD genotypes are affected by mutations studied here, ASLD should be considered as a candidate for chaperone treatment to improve mutant protein stability.

Performance of gene-expression profiling test score variability to predict future clinical events in heart transplant recipients.

BACKGROUND A single non-invasive gene expression profiling (GEP) test (AlloMap®) is often used to discriminate if a heart transplant recipient is at a low risk of acute cellular rejection at time of testing. In a randomized trial, use of the test (a GEP score from 0-40) has been shown to be non-inferior to a routine endomyocardial biopsy for surveillance after heart transplantation in selected low-risk patients with respect to clinical outcomes. Recently, it was suggested that the within-patient variability of consecutive GEP scores may be used to independently predict future clinical events; however, future studies were recommended. Here we performed an analysis of an independent patient population to determine the prognostic utility of within-patient variability of GEP scores in predicting future clinical events. METHODS We defined the GEP score variability as the standard deviation of four GEP scores collected ≥315 days post-transplantation. Of the 737 patients from the Cardiac Allograft Rejection Gene Expression Observational (CARGO) II trial, 36 were assigned to the composite event group (death, re-transplantation or graft failure ≥315 days post-transplantation and within 3 years of the final GEP test) and 55 were assigned to the control group (non-event patients). In this case-controlled study, the performance of GEP score variability to predict future events was evaluated by the area under the receiver operator characteristics curve (AUC ROC). The negative predictive values (NPV) and positive predictive values (PPV) including 95 % confidence intervals (CI) of GEP score variability were calculated. RESULTS The estimated prevalence of events was 17 %. Events occurred at a median of 391 (inter-quartile range 376) days after the final GEP test. The GEP variability AUC ROC for the prediction of a composite event was 0.72 (95 % CI 0.6-0.8). The NPV for GEP score variability of 0.6 was 97 % (95 % CI 91.4-100.0); the PPV for GEP score variability of 1.5 was 35.4 % (95 % CI 13.5-75.8). CONCLUSION In heart transplant recipients, a GEP score variability may be used to predict the probability that a composite event will occur within 3 years after the last GEP score. TRIAL REGISTRATION Clinicaltrials.gov identifier NCT00761787.

Satellite-Measured Chlorophyll and Temperature Variability Off Northern Chile During the 1996-1998 La Niña and El Niño

Time series of satellite measurements are used to describe patterns of surface temperature and chlorophyll associated with the 1996 cold La Nina phase and the 1997-1998 warm El Nino phase of the El Nino - Southern Oscillation cycle in the upwelling region off northern Chile. Surface temperature data are available through the entire study period. Sea-viewing Wide Field-of-view Sensor (SeaWiFS) data first became available in September 1997 during a relaxation in El Nino conditions identified by in situ hydrographic data. Over the time period of coincident satellite data, chlorophyll patterns closely track surface temperature patterns. Increases both in nearshore chlorophyll concentration and in cross-shelf extension of elevated concentrations are associated with decreased coastal temperatures during both the relaxation in El Nino conditions in September-November 1997 and the recovery from EI Nino conditions after March 1998. Between these two periods during austral summer (December 1997 to March 1998) and maximum El Nino temperature anomalies, temperature patterns normally associated with upwelling were absent and chlorophyll concentrations were minimal. Cross-shelf chlorophyll distributions appear to be modulated by surface temperature frontal zones and are positively correlated with a satellite-derived upwelling index. Frontal zone patterns and the upwelling index in 1996 imply an austral summer nearshore chlorophyll maximum, consistent with SeaWiFS data from I 1998-1999, after the El Nino. SeaWiFS retrievals in the data set used here are higher than in situ measurements by a factor of 2-4; however, consistency in the offset suggests relative patterns are valid.

Tracking the Trends in Inventory Management in the Automobile Manufacturing Industry Throughout the Business Cycle

This paper investigates the trends in inventory management in the automobile manufacturing industry during recessionary vs. non-recessionary periods. It is an empirical approach to testing the validity of the hypothesis that firms which carry leaner inventories perform better throughout the business cycle and are less affected by variability in the economy than less lean firms. The research also hopes to shed some light on how firm's financial statements can be manipulated through discretionary adjustments made by management pertaining to the valuation of inventories.

Tracking of plasma lipids and lipoproteins, within-person and year-to-year variability in plasma cholesterol levels among participants from age 8 to 18 in Project HeartBeat!

Coronary heart disease remains the leading cause of death in the United States and increased blood cholesterol level has been found to be a major risk factor with roots in childhood. Tracking of cholesterol, i.e., the tendency to maintain a particular cholesterol level relative to the rest of the population, and variability in blood lipid levels with increase in age have implications for cholesterol screening and assessment of lipid levels in children for possible prevention of further rise to prevent adulthood heart disease. In this study the pattern of change in plasma lipids, over time, and their tracking were investigated. Also, within-person variance and retest reliability defined as the square root of within-person variance for plasma total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides and their relation to age, sex and body mass index among participants from age 8 to 18 years were investigated. ^ In Project HeartBeat!, 678 healthy children aged 8, 11 and 14 years at baseline were enrolled and examined at 4-monthly intervals for up to 4 years. We examined the relationship between repeated observations by Pearson's correlations. Age- and sex-specific quintiles were calculated and the probability of participants to remain in the uppermost quintile of their respective distribution was evaluated with life table methods. Plasma total cholesterol, HDL-C and LDL-C at baseline were strongly and significantly correlated with measurements at subsequent visits across the sex and age groups. Plasma triglyceride at baseline was also significantly correlated with subsequent measurements but less strongly than was the case for other plasma lipids. The probability to remain in the upper quintile was also high (60 to 70%) for plasma total cholesterol, HDL-C and LDL-C. ^ We used a mixed longitudinal, or synthetic cohort design with continuous observations from age 8 to 18 years to estimate within person variance of plasma total cholesterol, HDL-C, LDL-C and triglycerides. A total of 5809 measurements were available for both cholesterol and triglycerides. A multilevel linear model was used. Within-person variance among repeated measures over up to four years of follow-up was estimated for total cholesterol, HDL-C, LDL-C and triglycerides separately. The relationship of within-person and inter-individual variance with age, sex, and body mass index was evaluated. Likelihood ratio tests were conducted by calculating the deviation of −2log (likelihood) within the basic model and alternative models. The square root of within-person variance provided the retest reliability (within person standard deviation) for plasma total cholesterol, HDL-C, LDL-C and triglycerides. We found 13.6 percent retest reliability for plasma cholesterol, 6.1 percent for HDL-cholesterol, 11.9 percent for LDL-cholesterol and 32.4 percent for triglycerides. Retest reliability of plasma lipids was significantly related with age and body mass index. It increased with increase in body mass index and age. These findings have implications for screening guidelines, as participants in the uppermost quintile tended to maintain their status in each of the age groups during a four-year follow-up. The magnitude of within-person variability of plasma lipids influences the ability to classify children into risk categories recommended by the National Cholesterol Education Program. ^

Plant-wax, alkenone and major element analyses of ODP Site 659 for the Last Glacial cycle and associated coretop data

We present a hydrologic reconstruction of the Sahara-Sahel transition, covering the complete last glacial cycle (130 ka), based on a combination of plant-wax-specific hydrogen (dD) and carbon isotopes (d13C). The dD and d13C signatures of long-chain n-alkanes from ODP Site 659 off NW Africa reveal a significant anti-correlation. Complementary to published pollen data, we infer that this plant-wax signal reflects sensitive responses of the vegetation cover to precipitation changes in the Sahel region, as well as varying contributions from biomes north of the Sahara (C3 domain) by North-East Trade Winds (NETW). During arid phases, especially the northern parts of the Sahel likely experienced crucial water stress, which resulted in a pronounced contraction of the vegetation cover, thus reducing the amount of C4 plant waxes from the region. The increase in NETW strength during dry periods further promoted a more pronounced C3-plant-wax signal derived from the North African C3 plant domain. During humid periods, the C4-dominated Sahelian environments spread northward into the Saharan realm, in association with lower NETW inputs of C3 plant waxes. Arid-humid cycles deduced from plant-wax dD are in accordance with concomitant changes in weathering intensity reflected in varying major element distributions. Environmental shifts are generally linked to periods with large fluctuations in Northern Hemisphere summer insolation. During Marine Isotope Stages 2 and 3, when insolation variability was low, coupling of the hydrologic regime to alkenone-based estimates of NE Atlantic sea-surface temperatures becomes apparent.

Gametogenic cycle of Mesodesma donacium

Large-scale environmental patterns in the Humboldt Current System (HCS) show major changes during strong El Niño episodes, leading to the mass mortality of dominant species in coastal ecosystems. Here we explore how these changes affect the life-history traits of the surf clam Mesodesma donacium. Growth and mortality rates under normal temperature and salinity were compared to those under anomalous (El Niño) higher temperature and reduced salinity. Moreover, the reproductive spatial-temporal patterns along the distribution range were studied, and their relationship to large-scale environmental variability was assessed. M. donacium is highly sensitive to temperature changes, supporting the hypothesis of temperature as the key factor leading to mass mortality events of this clam in northern populations. In contrast, this species, particularly juveniles, was remarkably tolerant to low salinity, which may be related to submarine groundwater discharge in Hornitos, northern Chile. The enhanced osmotic tolerance by juveniles may represent an adaptation of early life stages allowing settlement in vacant areas at outlets of estuarine areas. The strong seasonality in freshwater input and in upwelling strength seems to be linked to the spatial and temporal patterns in the reproductive cycle. Owing to its origin and thermal sensitivity, the expansion and dominance of M. donacium from the Pliocene/Pleistocene transition until the present seem closely linked to the establishment and development of the cold HCS. Therefore, the recurrence of warming events (particularly El Niño since at least the Holocene) has submitted this cold-water species to a continuous local extinction-recolonization process.