Roee Gutman

TEMPORAL PARTITIONING: AN EXPERIMENT WITH TWO SPECIES OF SPINY MICE

We studied temporal partitioning between two spiny mouse species that coexist in hot rocky deserts in the Middle East: nocturnal common spiny mice (Acomys cahirinus) and diurnally active golden spiny mice (A. russatus). Although A. russatus is diurnally active, it retains the physical activity and body temperature rhythms of nocturnal mammals. We studied the two species in four 1000-m 2 enclosures at Ein Gedi, Israel: two experimental enclosures with A. russatus kept alone, and two controls with individuals of both species kept together. We monitored activity with Sherman traps and by studying foraging microhabitat use and efficiency using giving-up densities (GUDs) in food trays. The trays contained broken sunflower seeds mixed in local soil and placed in three micro- habitats: under boulders, between boulders, and in the open. Trapping revealed that, in the absence of A. cahirinus, the usually diurnal A. russatus was active both day and night. However, during the day A. russatus still foraged in significantly more patches and to significantly lower GUDs than during the night. Both species, but in particular A. russatus, preferred to forage in the boulder habitat. Spiny mice foraged in the same number of trays in the under- and between-boulder microhabitats, but to lower GUDs in the under-boulder microhabitat, both during the day (A. russatus) and during the night (both species). The nocturnal A. cahirinus exploited more patches with greater efficiency than did A. russatus either during the day or during the night. This result suggests that foraging trade-offs that give each species a competitive advantage along some portion of the resource axis cannot be a mechanism of nocturnal coexistence between the two species. Perhaps this is why A. russatus resorts to diurnal activity in this hot rocky desert and why the otherwise rare mechanism of temporal partitioning occurs for these species.

Effects of Chronic Weight Perturbation on Energy Homeostasis and Brain Structure in Mice

Maintenance of reduced body weight in lean and obese human subjects results in the persistent decrease in energy expenditure below what can be accounted for by changes in body mass and composition. Genetic and developmental factors may determine a central nervous system (CNS)-mediated minimum threshold of somatic energy stores below which behavioral and metabolic compensations for weight loss are invoked. A critical question is whether this threshold can be altered by environmental influences and by what mechanisms such alterations might be achieved. We examined the bioenergetic, behavioral, and CNS structural responses to weight reduction of diet-induced obese (DIO) and never-obese (CON) C57BL/6J male mice. We found that weight-reduced (WR) DIO-WR and CON-WR animals showed reductions in energy expenditure, adjusted for body mass and composition, comparable (-10-15%) to those seen in human subjects. The proportion of excitatory synapses on arcuate nucleus proopiomelanocortin neurons was decreased by ∼50% in both DIO-WR and CON-WR mice. These data suggest that prolonged maintenance of an elevated body weight (fat) alters energy homeostatic systems to defend a higher level of body fat. The synaptic changes could provide a neural substrate for the disproportionate decline in energy expenditure in weight-reduced individuals. This response to chronic weight elevation may also occur in humans. The mouse model described here could help to identify the molecular/cellular mechanisms underlying both the defense mechanisms against sustained weight loss and the upward resetting of those mechanisms following sustained weight gain.

QuasiMotiFinder: protein annotation by searching for evolutionarily conserved motif-like patterns

Sequence signature databases such as PROSITE, which include amino acid segments that are indicative of a proteins function, are useful for protein annotation. Lamentably, the annotation is not always accurate. A signature may be falsely detected in a protein that does not carry out the associated function (false positive prediction, FP) or may be overlooked in a protein that does carry out the function (false negative prediction, FN). A new approach has emerged in which a signature is replaced with a sequence profile, calculated based on multiple sequence alignment (MSA) of homologous proteins that share the same function. This approach, which is superior to the simple pattern search, essentially searches with the sequence of the query protein against an MSA library. We suggest here an alternative approach, implemented in the QuasiMotiFinder web server (), which is based on a search with an MSA of homologous query proteins against the original PROSITE signatures. The explicit use of the average evolutionary conservation of the signature in the query proteins significantly reduces the rate of FP prediction compared with the simple pattern search. QuasiMotiFinder also has a reduced rate of FN prediction compared with simple pattern searches, since the traditional search for precise signatures has been replaced by a permissive search for signature-like patterns that are physicochemically similar to known signatures. Overall, QuasiMotiFinder and the profile search are comparable to each other in terms of performance. They are also complementary to each other in that signatures that are falsely detected in (or overlooked by) one may be correctly detected by the other.

Estimating energy expenditure in mice using an energy balance technique

Objective:To compare, in mice, the accuracy of estimates of energy expenditure (EE) using an energy balance technique (TEEbal: food energy intake and body composition change) vs indirect calorimetry (TEEIC).Subjects:In 32 male C57BL/6J mice, EE was estimated using an energy balance (caloric intake minus change in body energy stores) method over a 37-day period. EE was also measured in the same animals by indirect calorimetry. These measures were compared.Results:The two methods were highly correlated (r2=0.87: TEEbal=1.07*TEEIC–0.22, P<0.0001). By Bland–Altman analysis, TEEbal estimates were slightly higher (4.6±1.5%; P<0.05) than TEEIC estimates (Bias=0.55 kcal per 24 h).Conclusion:TEEbal can be performed in ‘home cages’ and provides an accurate integrated long-term measurement of EE while minimizing potentially confounding stress that may accompany the use of indirect calorimetry systems. The technique can also be used to assess long-term energy intake.

Breast cancer in octogenarians

The number of older cancer patients has increased in recent years. Guidelines for their care are often lacking. Data on the natural course of breast cancer and outcome of therapy in this population are needed.

A Bayesian Procedure for File Linking to Analyze End-of-Life Medical Costs

End-of-life medical expenses are a significant proportion of all health care expenditures. These costs were studied using costs of services from Medicare claims and cause of death (CoD) from death certificates. In the absence of a unique identifier linking the two datasets, common variables identified unique matches for only 33% of deaths. The remaining cases formed cells with multiple cases (32% in cells with an equal number of cases from each file and 35% in cells with an unequal number). We sampled from the joint posterior distribution of model parameters and the permutations that link cases from the two files within each cell. The linking models included the regression of location of death on CoD and other parameters, and the regression of cost measures with a monotone missing data pattern on CoD and other demographic characteristics. Permutations were sampled by enumerating the exact distribution for small cells and by the Metropolis algorithm for large cells. Sparse matrix data structures enabled efficient calculations despite the large dataset (≈1.7 million cases). The procedure generates m datasets in which the matches between the two files are imputed. The m datasets can be analyzed independently and results can be combined using Rubin’s multiple imputation rules. Our approach can be applied in other file-linking applications. Supplementary materials for this article are available online.

The effect of the lunar cycle on fecal cortisol metabolite levels and foraging ecology of nocturnally and diurnally active spiny mice.

We studied stress hormones and foraging of nocturnal Acomys cahirinus and diurnal A. russatus in field populations as well as in two field enclosures populated by both species and two field enclosures with individuals of A. russatus alone. When alone, A. russatus individuals become also nocturnally active. We asked whether nocturnally active A. russatus will respond to moon phase and whether this response will be obtained also in diurnally active individuals. We studied giving-up densities (GUDs) in artificial foraging patches and fecal cortisol metabolite levels. Both species exhibited elevated fecal cortisol metabolite levels and foraged to higher GUDs in full moon nights; thus A. russatus retains physiological response and behavioral patterns that correlate with full moon conditions, as can be expected in nocturnal rodents, in spite of its diurnal activity. The endocrinological and behavioral response of this diurnal species to moon phase reflects its evolutionary heritage.

Robust estimation of causal effects of binary treatments in unconfounded studies with dichotomous outcomes

The estimation of causal effects has been the subject of extensive research. In unconfounded studies with a dichotomous outcome, Y, Cangul, Chretien, Gutman and Rubin (2009) demonstrated that logistic regression for a scalar continuous covariate X is generally statistically invalid for testing null treatment effects when the distributions of X in the treated and control populations differ and the logistic model for Y given X is misspecified. In addition, they showed that an approximately valid statistical test can be generally obtained by discretizing X followed by regression adjustment within each interval defined by the discretized X. This paper extends the work of Cangul et al. 2009 in three major directions. First, we consider additional estimation procedures, including a new one that is based on two independent splines and multiple imputation; second, we consider additional distributional factors; and third, we examine the performance of the procedures when the treatment effect is non-null. Of all the methods considered and in most of the experimental conditions that were examined, our proposed new methodology appears to work best in terms of point and interval estimation.

Dissecting the fission yeast regulatory network reveals phase-specific control elements of its cell cycle

BackgroundFission yeast Schizosaccharomyces pombe and budding yeast Saccharomyces cerevisiae are among the original model organisms in the study of the cell-division cycle. Unlike budding yeast, no large-scale regulatory network has been constructed for fission yeast. It has only been partially characterized. As a result, important regulatory cascades in budding yeast have no known or complete counterpart in fission yeast.ResultsBy integrating genome-wide data from multiple time course cell cycle microarray experiments we reconstructed a gene regulatory network. Based on the network, we discovered in addition to previously known regulatory hubs in M phase, a new putative regulatory hub in the form of the HMG box transcription factor SPBC19G7.04. Further, we inferred periodic activities of several less known transcription factors over the course of the cell cycle, identified over 500 putative regulatory targets and detected many new phase-specific and conserved cis-regulatory motifs. In particular, we show that SPBC19G7.04 has highly significant periodic activity that peaks in early M phase, which is coordinated with the late G2 activity of the forkhead transcription factor fkh2. Finally, using an enhanced Bayesian algorithm to co-cluster the expression data, we obtained 31 clusters of co-regulated genes 1) which constitute regulatory modules from different phases of the cell cycle, 2) whose phase order is coherent across the 10 time course experiments, and 3) which lead to identification of phase-specific control elements at both the transcriptional and post-transcriptional levels in S. pombe. In particular, the ribosome biogenesis clusters expressed in G2 phase reveal new, highly conserved RNA motifs.ConclusionUsing a systems-level analysis of the phase-specific nature of the S. pombe cell cycle gene regulation, we have provided new testable evidence for post-transcriptional regulation in the G2 phase of the fission yeast cell cycle. Based on this comprehensive gene regulatory network, we demonstrated how one can generate and investigate plausible hypotheses on fission yeast cell cycle regulation which can potentially be explored experimentally.

Effect of food availability and leptin on the physiology and hypothalamic gene expression of the golden spiny mouse: a desert rodent that does not hoard food

Food availability and quality in desert habitats are spatially and temporally unpredictable, and animals face periods of food shortage. The golden spiny mouse (Acomys russatus) is an omnivorous desert rodent that does not hoard food, requiring it to withstand such periods by physiological means alone. In response to food restriction, plasma leptin concentrations, core body temperature, and energy expenditure of the spiny mouse decrease significantly after 24 h, and most spiny mice are able to maintain their body mass to approximately 85% of ad libitum for a prolonged period of time. Both 1-day food deprivation and long-term food restriction had a significant effect on body mass and plasma leptin concentrations, which decreased significantly with a high correlation, as well as on the orexigenic agouti-related protein, which increased significantly as a result of the 24-h food deprivation; and on neuropeptide Y (NPY), in which the increase was more pronounced under long-term food restriction. Food restriction and food deprivation had no effect, however, on the anorexigenic pro-opiomelanocortin and cocaine and amphetamine-related transcript. Leptin administration to food-restricted spiny mice did not affect food intake or the rate of decrease in body mass, indicating that it cannot overcome the drive to eat when food is scarce. However, it did result in a significant decrease in NPY levels, and the spiny mice spent less time at low body temperatures compared with PBS-treated golden spiny mice. These results show that in food-restricted golden spiny mice, leptin affects thermogenesis, but not food consumption, and suggest that the thermoregulatory effects of leptin are mediated by NPY.