A Flexible and Qualitatively Stable Model for Cell Cycle Dynamics Including DNA Damage Effects

This paper includes a conceptual framework for cell cycle modeling into which the experimenter can map observed data and evaluate mechanisms of cell cycle control. The basic model exhibits qualitative stability, meaning that regardless of magnitudes of system parameters its instances are guaranteed to be stable in the sense that all feasible trajectories converge to a certain trajectory. Qualitative stability can also be described by the signs of real parts of eigenvalues of the system matrix. On the biological side, the resulting model can be tuned to approximate experimental data pertaining to human fibroblast cell lines treated with ionizing radiation, with or without disabled DNA damage checkpoints. Together these properties validate a fundamental, first order systems view of cell dynamics. Classification Codes: 15A6

The stellar association around Gamma Velorum and its relationship with Vela OB2

We present the results of a photometric BVI survey of 0.9 square degrees around the Wolf-Rayet binary gamma^2 Vel and its early-type companion gamma^1 Vel. Several hundred PMS stars are identified and the youth of a subset of these is confirmed by the presence of lithium, H-alpha emission and X-ray activity. We show that the PMS stars are kinematically coherent and spatially concentrated around gamma Vel. The PMS stars have similar proper motions to gamma Vel, to main-sequence stars around gammaVel and to early-type stars of the wider Vela OB2 association of which gamma^2 Vel is the brightest member. The ratio of main-sequence stars to low-mass (0.1-0.6 Msun) PMS stars is consistent with a Kroupa mass function. Main-sequence fitting to stars around gamma Vel gives a distance modulus of 7.76+/-0.07 mag, consistent with a similarly-determined distance for Vela OB2 and with interferometric distances to gamma^2 Vel. High-mass stellar models indicate an age of 3-4 Myr for gamma^2 Vel, but the low-mass PMS stars have ages of ~10 Myr according to low-mass evolutionary models and 5-10 Myr by empirically placing them in an age sequence with other clusters based on colour-magnitude diagrams and lithium depletion. We conclude that the low-mass PMS stars form a genuine association with gamma Vel and that this is a subcluster within the larger Vela OB2 association. We speculate that gamma^2 Vel formed after the low-mass stars, expelling gas, terminating star formation and unbinding the association. The velocity dispersion of the PMS stars is too low for this star forming event to have produced all the stars in Vela OB2. Instead, star formation must have started at several sites within a molecular cloud, either sequentially or, simultaneously after some triggering event [abridged].Comment: Accepted for publication in MNRA

Additional layers of gene regulatory complexity from recently discovered microRNA mechanisms

In recent years microRNAs have become recognized as pervasive, versatile agents of gene regulation. Some widely embraced rules involving Watson-Crick hybridization of microRNAs with mRNAs have generated great interest as scientists envision potential RNA cargoes for gene therapy and other experimental systems. However, while researchers ardently seek simplifying principles, nature seems very uncooperative. This article reviews some small RNA mechanisms that potentially regulate genes and which are not covered by previous microRNAs characterizations. In addition, we report here results of fluorescence microscopy experiments to directly demonstrate nuclear importation of small RNAs equal in length to typical mature microRNAs, implying that gene regulation at the locus of transcription might be possible

microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder

BACKGROUND: microRNAs (miRNAs) are small, noncoding RNA molecules that are now thought to regulate the expression of many mRNAs. They have been implicated in the etiology of a variety of complex diseases, including Tourette's syndrome, Fragile × syndrome, and several types of cancer. RESULTS: We hypothesized that schizophrenia might be associated with altered miRNA profiles. To investigate this possibility we compared the expression of 264 human miRNAs from postmortem prefrontal cortex tissue of individuals with schizophrenia (n = 13) or schizoaffective disorder (n = 2) to tissue of 21 psychiatrically unaffected individuals using a custom miRNA microarray. Allowing a 5% false discovery rate, we found that 16 miRNAs were differentially expressed in prefrontal cortex of patient subjects, with 15 expressed at lower levels (fold change 0.63 to 0.89) and 1 at a higher level (fold change 1.77) than in the psychiatrically unaffected comparison subjects. The expression levels of 12 selected miRNAs were also determined by quantitative RT-PCR in our lab. For the eight miRNAs distinguished by being expressed at lower microarray levels in schizophrenia samples versus comparison samples, seven were also expressed at lower levels with quantitative RT-PCR. CONCLUSION: This study is the first to find altered miRNA profiles in postmortem prefrontal cortex from schizophrenia patients

Expressions 2010

https://openspace.dmacc.edu/expressions/1026/thumbnail.jp

Severity of thought disorder predicts psychosis in persons at clinical high-risk

BACKGROUND: Improving predictive accuracy is of paramount importance for early detection and prevention of psychosis. We sought a symptom severity classifier that would improve psychosis risk prediction. METHODS: Subjects were from two cohorts of the North American Prodrome Longitudinal Study. All subjects met Criteria of Psychosis-Risk States. In Cohort-1 (n=296) we developed a classifier that included those items of the Scale of Psychosis-Risk Symptoms that best distinguished subjects who converted to psychosis from nonconverters, with performance initially validated by randomization tests in Cohort-1. Cohort-2 (n=592) served as an independent test set. RESULTS: We derived 2-Item and 4-Item subscales. Both included unusual thought content and suspiciousness; the latter added reduced ideational richness and difficulties with focus/concentration. The Concordance Index (C-Index), a measure of discrimination, was similar for each subscale across cohorts (4-Item subscale Cohort-2: 0.71, 95% CI=[0.64, 0.77], Cohort-1: 0.74, 95% CI=[0.69, 0.80]; 2-Item subscale Cohort-2: 0.68, 95% CI=[0.3, 0.76], Cohort-1: 0.72, 95% CI=[0.66-0.79]). The 4-Item performed better than the 2-Item subscale in 742/1000 random selections of 80% subsets of Cohort-2 subjects (p-value=1.3E-55). Subscale calibration between cohorts was proportional (higher scores/lower survival), but absolute conversion risk predicted from Cohort-1 was higher than that observed in Cohort-2, reflecting the cohorts\u27 differences in 2-year conversion rates (Cohort-2: 0.16, 95% CI=[0.13, 0.19]; Cohort-1: 0.30, 95% CI=[0.24, 0.36]). CONCLUSION: Severity of unusual thought content, suspiciousness, reduced ideational richness, and difficulty with focus/concentration informed psychosis risk prediction. Scales based on these symptoms may have utility in research and, assuming further validation, eventual clinical applications

An Individualized Risk Calculator for Research in Prodromal Psychosis

About 20–35% of individuals aged 12–30 years who meet criteria for a prodromal risk syndrome convert to psychosis within two years. However, this estimate ignores the fact that clinical high-risk (CHR) cases vary considerably in risk. Here we sought to create a risk calculator that can ascertain the probability of conversion to psychosis in individual patients based on profiles of risk indicators. The high risk category predicted by this calculator can inform research criteria going forward

Consequences of high temperatures and premature mortality on the transcriptome and blood physiology of wild adult sockeye salmon (Oncorhynchus nerka)

Elevated river water temperature in the Fraser River, British Columbia, Canada, hasbeen associated with enhanced mortality of adult sockeye salmon (Oncorhynchusnerka) during their upriver migration to spawning grounds.We undertook a studyto assess the effects of elevated water temperatures on the gill transcriptome andblood plasma variables in wild-caught sockeye salmon. Naturally migrating sockeyesalmon returning to the Fraser River were collected and held at ecologicallyrelevant temperatures of 14◦C and 19◦C for seven days, a period representing asignificant portion of their upstream migration. After seven days, sockeye salmonheld at 19◦C stimulated heat shock response genes as well as many genes associated with an immune response when compared with fish held at 14◦C. Additionally, fish at 19◦C had elevated plasma chloride and lactate, suggestive of a disturbance in osmoregulatory homeostasis and a stress response detectable in the blood plasma. Fish that died prematurely over the course of the holding study were compared with time-matched surviving fish; the former fish were characterized by an upregulation of several transcription factors associated with apoptosis and downregulation of genes involved in immune function and antioxidant activity. Ornithine decarboxylase(ODC1) was the most significantly upregulated gene in dying salmon, which suggests an association with cellular apoptosis. We hypothesize that the observed decrease in plasma ions and increases in plasma cortisol that occur in dying fish may be linked to the increase in ODC1. By highlighting these underlyingphysiological mechanisms, this study enhances our understanding of the processesinvolved in premature mortality and temperature stress in Pacific salmon duringmigration to spawning grounds.<br /

Physiological Benefits of Being Small in a Changing World: Responses of Coho Salmon (Oncorhynchus kisutch) to an Acute Thermal Challenge and a Simulated Capture Event

Evidence is building to suggest that both chronic and acute warm temperature exposure, as well as other anthropogenic perturbations, may select for small adult fish within a species. To shed light on this phenomenon, we investigated physiological and anatomical attributes associated with size-specific responses to an acute thermal challenge and a fisheries capture simulation (exercise+air exposure) in maturing male coho salmon (Oncorhynchus kisutch). Full-size females were included for a sex-specific comparison. A size-specific response in haematology to an acute thermal challenge (from 7 to 20°C at 3°C h−1) was apparent only for plasma potassium, whereby full-size males exhibited a significant increase in comparison with smaller males (‘jacks’). Full-size females exhibited an elevated blood stress response in comparison with full-size males. Metabolic recovery following exhaustive exercise at 7°C was size-specific, with jacks regaining resting levels of metabolism at 9.3±0.5 h post-exercise in comparison with 12.3±0.4 h for full-size fish of both sexes. Excess post-exercise oxygen consumption scaled with body mass in male fish with an exponent of b = 1.20±0.08. Jacks appeared to regain osmoregulatory homeostasis faster than full-size males, and they had higher ventilation rates at 1 h post-exercise. Peak metabolic rate during post-exercise recovery scaled with body mass with an exponent of b∼1, suggesting that the slower metabolic recovery in large fish was not due to limitations in diffusive or convective oxygen transport, but that large fish simply accumulated a greater ‘oxygen debt’ that took longer to pay back at the size-independent peak metabolic rate of ∼6 mg min−1 kg−1. Post-exercise recovery of plasma testosterone was faster in jacks compared with full-size males, suggesting less impairment of the maturation trajectory of smaller fish. Supporting previous studies, these findings suggest that environmental change and non-lethal fisheries interactions have the potential to select for small individuals within fish populations over time

Sex and proximity to reproductive maturity influence the survival, final maturation, and blood physiology of Pacific salmon when exposed to high temperature during a simulated migration

Some Pacific salmon populations have been experiencing increasingly warmer river temperatures during their once-in-a-lifetime spawning migration, which has been associated with en route and prespawn mortality. The mechanisms underlying such temperature-mediated mortality are poorly understood. Wild adult pink (Oncorhynchus gorbuscha) and sockeye (Oncorhynchus nerka) salmon were used in this study. The objectives were to investigate the effects of elevated water temperature on mortality, final maturation, and blood properties under controlled conditions that simulated a &quot;cool&quot; (13&deg;C) and &quot;warm&quot; (19&deg;C) freshwater spawning migration. After 10 d at 13&deg;C, observed mortality was 50%-80% in all groups, which suggested that there was likely some mortality associated with handling and confinement. Observed mortality after 10 d at 19&deg;C was higher, reaching &ge;98% in male pink salmon and female pink and sockeye salmon. Thus, male sockeye salmon were the most thermally tolerant (54% observed mortality). Model selection supported the temperature- and sex-specific mortality patterns. The pink salmon were closer to reproductive maturation and farther along the senescence trajectory than sockeye salmon, which likely influenced their survival and physiological responses throughout the experiment. Females of both species held at 19&deg;C had reduced plasma sex steroids compared with those held at 13&deg;C, and female pink salmon were less likely to become fully mature at 19&deg; than at 13&deg;C. Male and female sockeye salmon held at 19&deg;C had higher plasma chloride and osmolality than those held at 13&deg;C, indicative of a thermally related stress response. These findings suggest that sex differences and proximity to reproductive maturity must be considered when predicting thermal tolerance and the magnitude of en route and prespawn mortality for Pacific salmon