Increased overwinter mortalities of white-tailed deer (Odocoileus virginianus) fawns during a drought year

Mortality rates of white-tailed deer (Odocoileus virginianus (Zimmerman, 1780)) fawns have been quantified throughout North America. Few studies, however, have assessed cause-specific mortality of fawns after the first 3 months of life or during a severe weather event. During 2010-2014, we captured and radiotracked 93 fawns in southern and central Illinois and recorded 18 mortality events. In order of importance, survival rates were affected by days since capture, year of drought, age at capture, week post-capture (1/0 indicator), and region. Estimated overwinter (fall through spring) survival rate (± SE) of fawns in both regions during 2010-14 was 0.83 ± 0.04. However, estimated overwinter survival rates were depressed during 2012-13, following the severe drought of 2012 (0.63 ± 0.11 or 0.66 ± 0.11 depending on model). Main causes of mortality were capture-related and predation, though some dead deer also showed signs of hemorrhagic disease. We suspect that the extreme drought of 2012 created favorable conditions for fall-spring mortality of fawns, due to elevated disease transmission and lower forage quality and quantity for deer. In addition, drought may have contributed to predation by reducing abundance of alternative prey. Our results suggest that severe weather conditions during summer can substantially impact overwinter fawn survival

Evolution of the patellar sesamoid bone in mammals

The patella is a sesamoid bone located in the major extensor tendon of the knee joint, in the hindlimb of many tetrapods. Although numerous aspects of knee morphology are ancient and conserved among most tetrapods, the evolutionary occurrence of an ossified patella is highly variable. Among extant (crown clade) groups it is found in most birds, most lizards, the monotreme mammals and almost all placental mammals, but it is absent in most marsupial mammals as well as many reptiles. Here, we integrate data from the literature and first-hand studies of fossil and recent skeletal remains to reconstruct the evolution of the mammalian patella. We infer that bony patellae most likely evolved between four and six times in crown group Mammalia: in monotremes, in the extinct multituberculates, in one or more stem-mammal genera outside of therian or eutherian mammals and up to three times in therian mammals. Furthermore, an ossified patella was lost several times in mammals, not including those with absent hindlimbs: once or more in marsupials (with some re-acquisition) and at least once in bats. Our inferences about patellar evolution in mammals are reciprocally informed by the existence of several human genetic conditions in which the patella is either absent or severely reduced. Clearly, development of the patella is under close genomic control, although its responsiveness to its mechanical environment is also important (and perhaps variable among taxa). Where a bony patella is present it plays an important role in hindlimb function, especially in resisting gravity by providing an enhanced lever system for the knee joint. Yet the evolutionary origins, persistence and modifications of a patella in diverse groups with widely varying habits and habitats—from digging to running to aquatic, small or large body sizes, bipeds or quadrupeds—remain complex and perplexing, impeding a conclusive synthesis of form, function, development and genetics across mammalian evolution. This meta-analysis takes an initial step toward such a synthesis by collating available data and elucidating areas of promising future inquiry

Comparative genomics reveals insights into avian genome evolution and adaptation

Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

DISPERSAL BEHAVIOR OF WHITE-TAILED DEER IN AN AGRICULTURAL LANDSCAPE

White-tailed deer (Odocoileus virginianus) dispersal and excursion movements impact gene flow, population dynamics, and disease spread. Knowledge of movement characteristics and habitat selection during dispersal could provide the ability to predict how deer may relocate themselves within the landscape while providing managers valuable information regarding corridors for gene flow and disease spread. My objectives were to 1) test the hypothesis that extra-home-range movements occur as a strategy to broaden mating opportunities or as a means of searching for higher quality resources in this fragmented landscape, 2) compare occurrence rates and path movement metrics for dispersal and excursion movements to determine if underlying differences in behavior exist that would allude to mechanisms for accepting the risk of leaving a home range, 3) create and test the performance of expert opinion and step selection function resistance models at predicting deer dispersal movements, and 4) fit single and multiple random walk models to dispersal path data to determine movement states occurring within this behavior. During 2011-2014, I placed GPS collars programmed to take hourly locations on 49 fawn and yearling white-tailed deer in agricultural east-central Illinois to record dispersal and excursion movement paths. Linear mixed effects models were used to test for differences in path characteristics between sexes and ages (e.g., distance, straightness, duration, and speed). I used known-fate models, with demographic, temporal, and home range variables as covariates, to obtain dispersal and excursion occurrence rate estimates. Ten dispersal and 54 excursion movement paths were recorded during the study. Dispersal paths were longer and straighter (P \u3c 0.001), and trended toward being longer in duration (P = 0.080) and faster in speed (P = 0.085), than excursion paths. Dispersal rates differed by sex (annual estimate ± SE with ages pooled: males 0.81 ± 0.12, females 0.16 ± 0.15) and were greatest during the breeding season (14-day estimates for males: winter 0.00 ± 0.01, fawning 0.02 ± 0.1, prebreeding 0.01 ± 0.01, and breeding 0.31 ± 0.15, and females: winter 0.00 ± 0.01, fawning 0.01 ± 0.1, prebreeding 0.01 ± 0.01, and breeding 0.04 ± 0.03). In contrast, I found no evidence that excursion rates were influenced by demographic, temporal, or home range variables (annual: 0.78 ± 0.06). I compared 2 methods of resistance modeling for predicting deer dispersal paths. I created an expert opinion survey and calculated a dispersal step selection function (SSF) to rank habitat variables and create 2 types of resistance maps to dispersal movements. I created least-cost paths with the starting and ending points coinciding with recorded dispersal paths within these 2 resistance maps. I compared the created paths to actual paths and a null straight line path using a path deviation index (PDI), path straightness, and path cost/m as variables of interest. Experts ranked land cover variables differently by season, applying a lower resistance value to agriculture cover during the summer/fall period, so 2 versions of the expert opinion resistance maps were created. For the SSF, I found that both forest cover and streams had significant nonlinear effects on deer dispersal movements. Assuming that all other factors remained constant, deer were more likely (≥ 0.50 probability) to move toward forested habitat when located \u3c 335 m and when \u3e 2795 m away. Deer dispersal movement behavior relating to streams followed a similar trend but with deer always having \u3e 0.56 probability to move toward a stream than away. For least-cost path comparison, I conducted 3 ANOVAs (α = 0.05 throughout) to test for mean differences in calculated path metrics for all paths with path type as a within-subjects effect. I found no difference between the expert opinion survey model, the SSF model, and the null straight line model at predicting dispersal paths. PDI values were similar among all models (F1,9 = 0.004, P = 0.99). The SSF paths (0.91 ± 0.02) were significantly straighter then both the expert opinion (0.57 ± 0.03) and actual deer paths (0.44 ± 0.06; F1, 9 = 32.65, P \u3c 0.001), but the expert opinion path did not differ from the actual path (P = 0.08). Path costs differed within the expert opinion survey resistance map (F1, 9 = 14.21, P \u3c 0.001) with the expert opinion least cost paths (23.64 ± 3.14) having lower resistance/m than both the actual (46.15 ± 3.85) and straight line paths (48.74 ± 3.94; P \u3c 0.001 for both). However, the actual and straight line paths did not differ (P = 0.872). There were no difference in path costs between the actual, SSF least-cost path, and straight line paths within the SSF resistance map (F1, 9 = 0.454, P = 0.64). I constructed and attempted to fit single and multiple random models to collected dispersal locations using WinBUGS v. 1.4.3. I was able to fit a single random walk model to deer dispersal paths but the more complex random walk models did not converge. I used the average parameter values derived from the single model to simulate deer dispersal paths and compared them to observed Net Squared Displacement. My simulated paths underpredicted deer displacement for 0.90 of individuals. Deer in east-central Illinois are very mobile and commonly make excursion movements throughout the year. The fact that I recorded differing dispersal rates within the same study area over a temporally short period from a previous study highlight the need for managers to obtain recent estimates of population parameters when making management decisions. The frequency of excursion movements should not be overlooked by managers as it is a behavior that can influence gene flow and potentially spread disease across the landscape at a localized scale. The preference for forest and stream habitats during dispersal can allow managers to focus surveillance or culling efforts around these types of habitats. The application of the least-cost path modeling technique appears to be ineffective at predicting deer dispersal paths, which emphasizes the importance of validating these types of models with actual data. The results from the random walk analysis highlight the need to collect as many locations as possible during temporally-short movements to understand the mechanisms acting upon them

Pleiotrophin Gene Therapy for Peripheral Ischemia: Evaluation of Full-Length and Truncated Gene Variants

Pleiotrophin (PTN) is a growth factor with both pro-angiogenic and limited pro-tumorigenic activity. We evaluated the potential for PTN to be used for safe angiogenic gene therapy using the full length gene and a truncated gene variant lacking the domain

Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia

*This article is free to read on the publisher's website* We show that imatinib, nilotinib, and dasatinib possess weak off-target activity against RAF and, therefore, drive paradoxical activation of BRAF and CRAF in a RAS-dependent manner. Critically, because RAS is activated by BCR-ABL, in drug-resistant chronic myeloid leukemia (CML) cells, RAS activity persists in the presence of these drugs, driving paradoxical activation of BRAF, CRAF, MEK, and ERK, and leading to an unexpected dependency on the pathway. Consequently, nilotinib synergizes with MEK inhibitors to kill drug-resistant CML cells and block tumor growth in mice. Thus, we show that imatinib, nilotinib, and dasatinib drive paradoxical RAF/MEK/ERK pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug-resistant CML cells in vitro and in vivo