Identification of CIP-1-associated regulator of cyclin B (CARB), a novel p21-binding protein acting in the G2 phase of the cell cycle

The cyclin-dependent kinase inhibitor p21(cip1) regulates cell cycle progression, DNA replication, and DNA repair by binding to specific cellular proteins through distinct amino- and carboxyl-terminal protein binding motifs. We have identified a novel human gene, CARB (CIP-1-associated regulator of cyclin B), whose product interacts with the p21 carboxyl terminus. Immunocytochemical analysis demonstrates that the CARB protein is perinuclear and predominantly associated with the centrosome and mitotic spindle poles. In addition, CARB is also able to associate with cyclin B1, a key regulator of mitosis. However, cyclin B1-CARB complex formation occurs preferentially in the absence of p21. Unexpectedly, overexpression of CARB is associated with a growth-inhibitory and ultimately lethal phenotype in p21(-/-) cells but not in p21(+/+) cells. These data identify a novel mechanism that may underlie the effects of p21 in the G(2)/M phases of the cell cycle.     

A Randomized,Double-Blind,Placebo-Controlled Trial of Adjunctive Metformin Therapy in Overweight/Obese Youth with Type 1 Diabetes

Context

Insulin resistance has been proposed as one of the causes of poor glycemic control in overweight/obese youth with type 1 diabetes (T1D). However, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear.

Objective

To compare the effect of metformin vs. placebo on hemoglobin A1c (HbA1c), total daily dose (TDD) of insulin, and other parameters in overweight/obese youth with T1D.

Hypothesis

Adjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D.

Design, Setting, and Participants

A 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c >8% (64 mmol/mol), BMI >85%, and T1D > 12 months was conducted at a university outpatient facility. The metformin group consisted of 15 subjects (8 m/ 7f), of age 15.0 ± 2.5 y; while the control group was made up of 13 subjects (5m/ 8f), of age 14.5 ± 3.1y. All participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2)-0-(+2) units to adjust their long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose (FPG) between 90–120 mg/dL (5.0–6.7 mmol/L). Pubertal maturation was determined by Tanner stage.

Results

Over the course of the 9 months of observation, the between-treatment differences in HbA1c of 0.4% (9.85% [8.82 to 10.88] for placebo versus 9.46% [8.47 to 10.46] for metformin) was not significant (p = 0.903). There were non-significant reduction in fasting plasma glucose (189.4 mg/dL [133.2 to 245.6] for placebo versus 170.5 mg/dL [114.3 to 226.7] for metformin), (p = 0.927); total daily dose (TDD) of short-acting insulin per kg body weight/day(p = 0.936); and the TDD of long-acting insulin per kg body weight per day (1.15 units/kg/day [0.89 to 1.41] for placebo versus 0.90 units/kg/day [0.64 to 1.16] for metformin) (p = 0.221). There was no difference in the occurrence of hypoglycemia between the groups.

Conclusions

This 9-month RCT of adjunctive metformin therapy in overweight and obese youth with T1D resulted in a 0.4% lower HbA1c value in the metformin group compared to the placebo group.

Trial Registration

ClinicalTrial.gov NCT01334125     

Anthropogenic influences on macro-level mammal occupancy in the appalachian trail corridor

Anthropogenic effects on wildlife are typically assessed at the local level, but it is often difficult to extrapolate to larger spatial extents. Macro-level occupancy studies are one way to assess impacts of multiple disturbance factors that might vary over different geographic extents. Here we assess anthropogenic effects on occupancy and distribution for several mammal species within the Appalachian Trail (AT), a forest corridor that extends across a broad section of the eastern United States. Utilizing camera traps and a large volunteer network of citizen scientists, we were able to sample 447 sites along a 1024 km section of the AT to assess the effects of available habitat, hunting, recreation, and roads on eight mammal species. Occupancy modeling revealed the importance of available forest to all species except opossums (Didelphis virginiana) and coyotes (Canis latrans). Hunting on adjoining lands was the second strongest predictor of occupancy for three mammal species, negatively influencing black bears (Ursus americanus) and bobcats (Lynx rufus), while positively influencing raccoons (Procyon lotor). Modeling also indicated an avoidance of high trail use areas by bears and proclivity towards high use areas by red fox (Vulpes vulpes). Roads had the lowest predictive power on species occupancy within the corridor and were only significant for deer. The occupancy models stress the importance of compounding direct and indirect anthropogenic influences operating at the regional level. Scientists and managers should consider these human impacts and their potential combined influence on wildlife persistence when assessing optimal habitat or considering management actions.     

Spatial distribution as a measure of conservation needs: an example with Asiatic black bears in south-western China

Aim To create a fine‐scale map of the distribution of Asiatic black bears, identify landscape variables affecting the spatial range of this species and assess population trends using presence–absence data and opinions of local villagers. Location Sichuan Province, south‐western China. Methods We divided the province into 15 × 15 km cells, stratified them by forest cover, elevation and road density and randomly selected 494 cells (21% of province) for surveys. In each cell, we interviewed villagers and ground‐verified their reports of bear presence. We ground‐truthed reports of bear absence by conducting transects for bear sign in the best available habitat. We used logistic regression to identify key variables affecting presence of bears and predict their occurrence in unsampled cells. Results We detected bears in 360 cells (73%). Models correctly predicted bear occurrence in 90.3% of cells where we detected bears and 84.5% of sampled cells where bears were absent. Models predicted 42.7% of Sichuan to be occupied by bears. Bear occurrence was strongly related to forest cover throughout the province. Roads had a negative effect in western region of province. Agricultural lands had a negative effect only when they were distant from forests. Villagers were accurate in their knowledge of bear presence or absence. Interviewed villagers (n = 1816) thought that bears were increasing in 32%, stable in 10%, and decreasing in 58% of cells with bears. Where bear populations were perceived to be declining, villagers identified poaching as the most common cause. Main conclusions Our fine‐scale distribution map can be used for future monitoring and the key landscape factors related to occupancy by bears can be used in management plans for this species. Interviewing local villagers is an efficient and reliable means of assessing distribution, and changes therein, for animals such as bears that often interact with people and leave obvious signs.     

The evolutionary consequences of oxygenic photosynthesis: a body size perspective

The high concentration of molecular oxygen in Earth??s atmosphere is arguably the most conspicuous and geologically important signature of life. Earth??s early atmosphere lacked oxygen; accumulation began after the evolution of oxygenic photosynthesis in cyanobacteria around 3.0?C2.5 billion years ago (Gya). Concentrations of oxygen have since varied, first reaching near-modern values ~600 million years ago (Mya). These fluctuations have been hypothesized to constrain many biological patterns, among them the evolution of body size. Here, we review the state of knowledge relating oxygen availability to body size. Laboratory studies increasingly illuminate the mechanisms by which organisms can adapt physiologically to the variation in oxygen availability, but the extent to which these findings can be extrapolated to evolutionary timescales remains poorly understood. Experiments confirm that animal size is limited by experimental hypoxia, but show that plant vegetative growth is enhanced due to reduced photorespiration at lower O₂:CO₂. Field studies of size distributions across extant higher taxa and individual species in the modern provide qualitative support for a correlation between animal and protist size and oxygen availability, but few allow prediction of maximum or mean size from oxygen concentrations in unstudied regions. There is qualitative support for a link between oxygen availability and body size from the fossil record of protists and animals, but there have been few quantitative analyses confirming or refuting this impression. As oxygen transport limits the thickness or volume-to-surface area ratio??rather than mass or volume??predictions of maximum possible size cannot be constructed simply from metabolic rate and oxygen availability. Thus, it remains difficult to confirm that the largest representatives of fossil or living taxa are limited by oxygen transport rather than other factors. Despite the challenges of integrating findings from experiments on model organisms, comparative observations across living species, and fossil specimens spanning millions to billions of years, numerous tractable avenues of research could greatly improve quantitative constraints on the role of oxygen in the macroevolutionary history of organismal size.     

Evaluating Landscape Options for Corridor Restoration between Giant Panda Reserves

The establishment of corridors can offset the negative effects of habitat fragmentation by connecting isolated habitat patches. However, the practical value of corridor planning is minimal if corridor identification is not based on reliable quantitative information about species-environment relationships. An example of this need for quantitative information is planning for giant panda conservation. Although the species has been the focus of intense conservation efforts for decades, most corridor projects remain hypothetical due to the lack of reliable quantitative researches at an appropriate spatial scale. In this paper, we evaluated a framework for giant panda forest corridor planning. We linked our field survey data with satellite imagery, and conducted species occupancy modelling to examine the habitat use of giant panda within the potential corridor area. We then conducted least-cost and circuit models to identify potential paths of dispersal across the landscape, and compared the predicted cost under current conditions and alternative conservation management options considered during corridor planning. We found that due to giant panda''s association with areas of low elevation and flat terrain, human infrastructures in the same area have resulted in corridor fragmentation. We then identified areas with high potential to function as movement corridors, and our analysis of alternative conservation scenarios showed that both forest/bamboo restoration and automobile tunnel construction would significantly improve the effectiveness of corridor, while residence relocation would not significantly improve corridor effectiveness in comparison with the current condition. The framework has general value in any conservation activities that anticipate improving habitat connectivity in human modified landscapes. Specifically, our study suggested that, in this landscape, automobile tunnels are the best means to remove current barriers to giant panda movements caused by anthropogenic interferences.     

Globally common,locally rare: revisiting disregarded genetic diversity for conservation planning of widespread species

Species endangerment, as determined by the national and international authorities, are crucial in conservation decisions at local and regional scales. While species are the priority unit of conservation, the subspecies of widespread species are often neglected in conservation planning and research, irrespective of their unique genetic identity. Peripheral populations of widespread species are often isolated and endangered while their status on the IUCN Red List is considered as ‘Least Concern’. We advocate for the evaluation of widespread polytypic species, and to recognize the importance of assessing intraspecific populations that are distinct from the distribution of widespread species.