Azacyclic FTY720 Analogues That Limit Nutrient Transporter Expression but Lack S1P Receptor Activity and Negative Chronotropic Effects Offer a Novel and Effective Strategy to Kill Cancer Cells in Vivo

FTY720 sequesters lymphocytes in secondary lymphoid organs through effects on sphingosine-1-phosphate (S1P) receptors. However, at higher doses than are required for immunosuppression, FTY720 also functions as an anticancer agent in multiple animal models. Our published work indicates that the anticancer effects of FTY720 do not depend on actions at S1P receptors but instead stem from FTY720s ability to restrict access to extracellular nutrients by down-regulating nutrient transporter proteins. This result was significant because S1P receptor activation is responsible for FTY720s dose-limiting toxicity, bradycardia, that prevents its use in cancer patients. Here, we describe diastereomeric and enantiomeric 3- and 4-C-aryl 2-hydroxymethyl pyrrolidines that are more active than the previously known analogues. Of importance is that these compounds fail to activate S1P1 or S1P3 receptors in vivo but retain inhibitory effects on nutrient transporter proteins and anticancer activity in solid tumor xenograft models. Our studies reaffirm that the anticancer activity of FTY720 does not depend upon S1P receptor activation and uphold the promise of using S1P receptor-inactive azacyclic FTY720 analogues in human cancer patients.

Herbivores limit the population size of big-leaf mahogany trees in an Amazonian forest

The Janzen–Connell hypothesis proposes that specialized herbivores maintain high numbers of tree species in tropical forests by restricting adult recruitment so that host populations remain at low densities. We tested this prediction for the large timber tree species, Swietenia macrophylla, whose seeds and seedlings are preyed upon by small mammals and a host-specific moth caterpillar Steniscadia poliophaea, respectively. At a primary forest site, experimental seed additions to gaps – canopy-disturbed areas that enhance seedling growth into saplings – over three years revealed lower survival and seedling recruitment closer to conspecific trees and in higher basal area neighborhoods, as well as reduced subsequent seedling survival and height growth. When we included these Janzen–Connell effects in a spatially explicit individual-based population model, the caterpillar's impact was critical to limiting Swietenia's adult tree density, with a > 10-fold reduction estimated at 300 years. Our research demonstrates the crucial but oft-ignored linkage between Janzen–Connell effects on offspring and population-level consequences for a long-lived, potentially dominant tree species.

Influence and Impact of Cognitive Trajectories on Outcome in Patients Undergoing Radical Cystectomy: an Observational Study

OBJECTIVES To evaluate cognitive trajectories after radical cystectomy and their impact on surgical outcomes, including urinary continence. METHODS Ninety patients received cognitive testing using the Mini Mental State Exam (MMSE) before open radical cystectomy as well as 3 days and 2 weeks after surgery. Based on MMSE changes ≥3 points between the three time points, five cognitive trajectories emerged (stable cognition, persistent or transient deterioration or persistent or transient improvement). Surgical outcomes were assessed 90 days, 6 months and 1 year postoperatively. RESULTS Mean age was 67.9 ± 9.3 years (range 40 - 88 years). Sixty-six patients (73.3%) had stable cognition, nine patients (10.0%) persistent and seven patients (7.8%) transient deterioration, five patients (5.6%) persistent and three patients (3.3%) transient improvement. An impaired preoperative cognition was the only significant risk factor of short-term cognitive deterioration (OR adjusted for age and sex 9.4, 95%CI 1.6-56.5, p=0.014). Cognition showed no associations with 1-year mortality, 90-day complication rate, cancer progression or duration of in-hospital stay. Patients with transient or persistent cognitive deterioration had an increased risk for nighttime incontinence (OR adjusted for age and sex 5.1, 95%CI 1.1-22.4, p=0.032). CONCLUSIONS In this study, the majority of patients showed stable cognition after major abdominopelvic surgery. Cognitive deterioration occurred in a small subgroup of patients, and an impaired preoperative cognition was the only significant risk factor. Postoperative cognitive deterioration was associated with nighttime incontinence.

Implications of Longterm Diameter-Limit Harvesting: Effects on Radial Growth of Red Spruce (Picea rubens) and Genetic Diversity of White Pine (Pinus strobus)

For over 3 centuries, diameter-limit harvesting has been a predominant logging method in the northeastern United States. Silvicultural theory asserts that such intensively selective harvesting can lead to genetic degradation. A decrease in softwood productivity has recently been reported in Maine - has a long history of dysgenic selection degraded the genetic resources of Maine softwoods, contributing to a decrease in growth and productivity? This study examines two aspects of potential implications of diameter-limit harvesting: effects on residual phenotypes of red spruce and impacts on genetic diversity of white pine. Radial growth of residual red spruce trees in stands experiencing 50 years of fixed diameter-limit harvesting was measured using annual increment rings and compared with residual red spruce trees in positive selection stands. Trees remaiaing after several rounds of diameter-limit harvesting exhibited sigdicantl y smaller radial sizes throughout their lives, and displayed significantly slower growth rates for the first 80 years of measured growth. These results strongly suggest that the largest and fastest-growing genotypes and their respective gene complexes determining good radial growth have been removed from the diameter-limit stand. Dysgenic selection can be observed in fixed diarneter-limit stands, resulting in a diminished genetic resource and decreased residual stand value. To examine more direct genetic implications of long-term diameter-limit harvesting, microsatellite DNA markers were implemented to study genetic diversity of eastern white pine in Maine. Three age groups of trees were studied: mature trees older than 200 years, juvenile trees 5-30 years old, and embryos. Trees were genotyped at 10 microsatellite loci. Overall genetic diversity levels of eastern white pine in Maine were extremely high, with an average observed heterozygosity of 0.762. Genetic differentiation was minimal among and between all three age groups, although an excess of heterozygotes was shown in the mature and juvenile groups that was not reflected in the embryo group, which actually had a slight heterozygote deficiency. Allele frequencies did not differ significantly between age groups, but did reveal more rare and low frequency alleles in the embryo groups than in the mature group. Overall, low frequency alleles comprise the largest portion of alleles in the sample population, with no common alleles evident overall. These results suggest that significant genetic degradation has either not occurred for white pine, or that the results of dysgenic selection have not yet emerged. It is clear, however, that selective harvesting could result in a loss of low frequency alleles, which are a primary reserve of evolutionary potential in a species. Implications of these studies affect industrial forestry, regional economics, and ecological concerns for the northeast. Long-term diameter-limit harvesting can lead to a degradation of residual phenotypes, and an overall decrease in stand quality. Potentially, a loss of low frequency, locally adapted alleles could result in a decrease of allelic richness and degradation of the regidnal genetic resource. Decreased genetic variation can lead to seriously limited evolutionary potential of species and ecosystems, particularly in rapidly changing environments. Based on these findings, I recommend a reassessment of any harvesting prescription that includes fixed diameter-limit removals, particularly for species that have low natural genetic diversity levels or a limited natural range, such as red spruce. Maintenance of a healthy genetic reserve can avoid effects of dysgenic harvesting.

Body mass index trajectories and predictors among 3rd to 12th graders using growth curve mixture modeling the Child and Adolescent Trial for Cardiovascular Health (CATCH) study

This dissertation examined body mass index (BMI) growth trajectories and the effects of gender, ethnicity, dietary intake, and physical activity (PA) on BMI growth trajectories among 3rd to 12th graders (9-18 years of age). Growth curve model analysis was performed using data from The Child and Adolescent Trial for Cardiovascular Health (CATCH) study. The study population included 2909 students who were followed up from grades 3-12. The main outcome was BMI at grades 3, 4, 5, 8, and 12. ^ The results revealed that BMI growth differed across two distinct developmental periods of childhood and adolescence. Rate of BMI growth was faster in middle childhood (9-11 years old or 3rd - 5th grades) than in adolescence (11-18 years old or 5th - 12th grades). Students with higher BMI at 3rd grade (baseline) had faster rates of BMI growth. Three groups of students with distinct BMI growth trajectories were identified: high, average, and low. ^ Black and Hispanic children were more likely to be in the groups with higher baseline BMI and faster rates of BMI growth over time. The effects of gender or ethnicity on BMI growth differed across the three groups. The effects of ethnicity on BMI growth were weakened as the children aged. The effects of gender on BMI growth were attenuated in the groups with a large proportion of black and Hispanic children, i.e., “high” or “average” BMI trajectory group. After controlling for gender, ethnicity, and age at baseline, in the “high BMI trajectory”, rate of yearly BMI growth in middle childhood increased 0.102 for every 500 Kcals increase (p=0.049). No significant effects of percentage of energy from total fat and saturated fat on BMI growth were found. Baseline BMI increased 0.041 for every 30 minutes increased in moderate-to-vigorous PA (MVPA) in the “low BMI trajectory”, while Baseline BMI decreased 0.345 for every 30 minutes increased in vigorous PA (VPA) in the “high BMI trajectory”. ^ Childhood overweight and obesity interventions should start at the earliest possible ages, prior to 3rd grade and continue through grade school. Interventions should focus on all children, but specifically black and Hispanic children, who are more likely to be highest at-risk. Promoting VPA earlier in childhood is important for preventing overweight and obesity among children and adolescents. Interventions should target total energy intake, rather than only percentage of energy from total fat or saturated fat. ^

Rules to limit snacking in front of the TV and childhood BMI status: Findings from the "Fun Families Study"

Childhood obesity is increasing at epidemic rates, and thus there is a need to target appropriate childhood behaviors that contribute to obesity. Many factors contribute to childhood weight status. The aim of this study was to look at relationships between parental rules to limit snacking while watching television and childhood weight status. The study looked at the presence of the behavior of snacking while watching television yesterday, congruence between child- and parent-reported perception of the presence of rules to limit snacking while watching television, and parent-reported frequency of children following rules to limit snacking while watching television. The outcomes were examined in a multi-ethnic population of children ages 6 to 9 years in Southeast Texas.^ This study was a cross-sectional secondary data analysis of the pilot program, Fun Families. This study examined baseline data from 202 parent-child dyads, which included both the control ( N= 101) and intervention groups (N= 101). Data were gathered using validated questions that were administered to 6-9 year old children and their primary caregiver (referred to as parent in the rest of the discussion) in Southeast Texas, between 2006 and 2008. The main study outcome was childhood weight status based on CDC BMI-for-age categories. The independent variables are (1) the presence of parental rules to limit snacking while watching television, (2) the congruence between child and parent about the presence of rules to limit snacking while watching television, and (3) the parent-reported frequency of the child following the rules to limit snacking while watching television. Chi-Square analyses were used to determine if weight status was different for (1) children who reported rules to limit snacking yesterday, (2) children who reported snacking, (3) children whose parents reported rules were present, and (4) those who had rule congruence with the parents not. Chi-Square analyses also examined if there was a difference in the presence of snacking behavior for children who reported rules, for children whose parents reported rules, and for those children who had congruence about rules. Linear regressions were used to determine if any of the studied variables predicted increased weight status or reported snacking while watching television yesterday.^ This study found that child-reported snacking yesterday was significantly different for children who reported rules (4.12, p= 0.04). Child-reported rules was significantly associated with (p= -0.14, α= 0.04) and predicted child-reported snacking yesterday (R 2 0.021, p= 0.04, t= -2.04, 95% CI -0.31, -0.01). There was statistical significant incongruence between child and parent perception about the presence of rules to limit snacking yesterday (15.06, p= 0.00). For this population, parent education level was significantly associated with child-reported rules (r= -0.16, p= 0.02), child-reported snacking yesterday (r= -0.15, p= 0.04), and parent-reported frequency of child following rules to limit snacking (r= 0.29, p= -0.01). Parent-reported speaking another language besides English at home was significantly associated with parent-reported rules (r= 0.17, p= 0.02).^ Although the studied variables did not show any significant associations or predictors for childhood weight status, the significant discord between parent and child perception about the presence of rules provides valuable information to future interventions that aim to reduce childhood weight status. Including the creation and enforcement of parental rules in interventions to reduce childhood weight status will be beneficial for future studies.^

Robust effect sizes and their confidence intervals for group difference between trajectories in hierarchical linear growth model

Hierarchical linear growth model (HLGM), as a flexible and powerful analytic method, has played an increased important role in psychology, public health and medical sciences in recent decades. Mostly, researchers who conduct HLGM are interested in the treatment effect on individual trajectories, which can be indicated by the cross-level interaction effects. However, the statistical hypothesis test for the effect of cross-level interaction in HLGM only show us whether there is a significant group difference in the average rate of change, rate of acceleration or higher polynomial effect; it fails to convey information about the magnitude of the difference between the group trajectories at specific time point. Thus, reporting and interpreting effect sizes have been increased emphases in HLGM in recent years, due to the limitations and increased criticisms for statistical hypothesis testing. However, most researchers fail to report these model-implied effect sizes for group trajectories comparison and their corresponding confidence intervals in HLGM analysis, since lack of appropriate and standard functions to estimate effect sizes associated with the model-implied difference between grouping trajectories in HLGM, and also lack of computing packages in the popular statistical software to automatically calculate them. ^ The present project is the first to establish the appropriate computing functions to assess the standard difference between grouping trajectories in HLGM. We proposed the two functions to estimate effect sizes on model-based grouping trajectories difference at specific time, we also suggested the robust effect sizes to reduce the bias of estimated effect sizes. Then, we applied the proposed functions to estimate the population effect sizes (d ) and robust effect sizes (du) on the cross-level interaction in HLGM by using the three simulated datasets, and also we compared the three methods of constructing confidence intervals around d and du recommended the best one for application. At the end, we constructed 95% confidence intervals with the suitable method for the effect sizes what we obtained with the three simulated datasets. ^ The effect sizes between grouping trajectories for the three simulated longitudinal datasets indicated that even though the statistical hypothesis test shows no significant difference between grouping trajectories, effect sizes between these grouping trajectories can still be large at some time points. Therefore, effect sizes between grouping trajectories in HLGM analysis provide us additional and meaningful information to assess group effect on individual trajectories. In addition, we also compared the three methods to construct 95% confident intervals around corresponding effect sizes in this project, which handled with the uncertainty of effect sizes to population parameter. We suggested the noncentral t-distribution based method when the assumptions held, and the bootstrap bias-corrected and accelerated method when the assumptions are not met.^

Sea ice limit in the Southern Ocean 1950/51

Die zwei Südwinter und einen Südsommer umspannende Expedition erbrachte so umfangreiche Ergebnisse, daß mit deren Veröffentlichung erst in Jahren gerechnet werden kann. Aus der Fülle der Beobachtungen und Messungen seien herausgegriffen: der wechselnde Verlauf der Packeisgrenze der Antarktis.

Impact of thermal stress on evolutionary trajectories of pathogen resistance in three-spined stickleback (Gasterosteus aculeatus), supplementary material

Background: Pathogens are a major regulatory force for host populations, especially under stressful conditions. Elevated temperatures may enhance the development of pathogens, increase the number of transmission stages, and can negatively influence host susceptibility depending on host thermal tolerance. As a net result, this can lead to a higher prevalence of epidemics during summer months. These conditions also apply to marine ecosystems, where possible ecological impacts and the population-specific potential for evolutionary responses to changing environments and increasing disease prevalence are, however, less known. Therefore, we investigated the influence of thermal stress on the evolutionary trajectories of disease resistance in three marine populations of three-spined sticklebacks Gasterosteus aculeatus by combining the effects of elevated temperature and infection with a bacterial strain of Vibrio sp. using a common garden experiment. Results: We found that thermal stress had an impact on fish weight and especially on survival after infection after only short periods of thermal acclimation. Environmental stress reduced genetic differentiation (QST) between populations by releasing cryptic within-population variation. While life history traits displayed positive genetic correlations across environments with relatively weak genotype by environment interactions (GxE), environmental stress led to negative genetic correlations across environments in pathogen resistance. This reversal of genetic effects governing resistance is probably attributable to changing environment-dependent virulence mechanisms of the pathogen interacting differently with host genotypes, i.e. GPathogenxGHostxE or (GPathogenxE)x(GHostxE) interactions, rather than to pure host genetic effects, i.e. GHostxE interactions. Conclusion: To cope with climatic changes and the associated increase in pathogen virulence, host species require wide thermal tolerances and pathogen-resistant genotypes. The higher resistance we found for some families at elevated temperatures showed that there is evolutionary potential for resistance to Vibrio sp. in both thermal environments. The negative genetic correlation of pathogen resistance between thermal environments, on the other hand, indicates that adaptation to current conditions can be a weak predictor for performance in changing environments. The observed feedback on selective gradients exerted on life history traits may exacerbate this effect, as it can also modify the response to selection for other vital components of fitness.

Shoreline change on nine reef islands over a seven-decade period

Atoll islands are subject to a variety of processes that influence their geomorphological development. Analysis of historical shoreline changes using remotely sensed images has become an efficient approach to both quantify past changes and estimate future island response. However, the detection of long-term changes in beach width is challenging mainly for two reasons: first, data availability is limited for many remote Pacific islands. Second, beach environments are highly dynamic and strongly influenced by seasonal or episodic shoreline oscillations. Consequently, remote-sensing studies on beach morphodynamics of atoll islands deal with dynamic features covered by a low sampling frequency. Here we present a study of beach dynamics for nine islands on Takú Atoll, Papua New Guinea, over a seven-decade period. A considerable chronological gap between aerial photographs and satellite images was addressed by applying a new method that reweighted positions of the beach limit by identifying "outlier" shoreline positions. On top of natural beach variability observed along the reweighted beach sections, we found that one third of the analyzed islands show a statistically significant decrease in reweighted beach width since 1943. The total loss of beach area for all islands corresponds to 44% of the initial beach area. Variable shoreline trajectories suggest that changes in beach width on Takú Atoll are dependent on local control (that is, human activity and longshore sediment transport). Our results show that remote imagery with a low sampling frequency may be sufficient to characterize prominent morphological changes in planform beach configuration of reef islands.

Reconstructed ice-sheet limit in the Kara and Barents Sea area at about 50,000 years ago (Markhida Line)

Glacial landforms in northern Russia, from the Timan Ridge in the west to the east of the Urals, have been mapped by aerial photographs and satellite images supported by field observations. An east-west trending belt of fresh hummock-and-lake glaciokarst landscapes has been traced to the north of 67°N. The southern boundary of these landscapes is called the Markhida Line, which is interpreted as a nearly synchronous limit of the last ice sheet that affected this region. The hummocky landscapes are subdivided into three types according to the stage of postglacial modification: Markhida, Harbei and Halmer. The Halmer landscape on the Uralian piedmont in the east is the freshest, whereas the westernmost Markhida landscape is more eroded. The west- east gradient in morphology is considered to be a result of the time-transgressive melting of stagnant glacier ice and of the underlying permafrost. The pattern of ice-pushed ridges and other directional features reflects a dominant ice flow direction from the Kara Sea shelf. Traces of ice movement from the central Barents Sea are only discernible in the Pechora River left bank area west of 50°E. In the Polar Urals the horseshoe-shaped end moraines at altitudes of up to 560 m a.s.l. reflect ice movement up-valley from the Kara Ice Sheet, indicating the absence of a contemporaneous ice dome in the mountains. The Markhida moraines, superimposed onto the Eemian strata, represent the maximum ice sheet extent in the western part of the Pechora Basin during the Weichselian. The Markhida Line truncates the huge arcs of the Laya-Adzva and Rogovaya ice-pushed ridges protruding to the south. The latter moraines therefore reflect an older ice advance, probably also of Weichselian age. Still farther south, fluvially dissected morainic plateaus without lakes are of pre-Eemian age, because they plunge northwards under marine Eemian sediments. Shorelines of the large ice-dammed Lake Komi, identified between 90 and 110 m a.s.l. in the areas south of the Markhida Line, are radiocarbon dated to be older than 45 ka. The shorelines, incised into the Laya-Adzva moraines, morphologically interfinger with the Markhida moraines, indicating that the last ice advance onto the Russian mainland reached the Markhida Line during the Middle or Early Weichselian, before 45 ka ago.