A big data-model integration approach for predicting epizootics and population recovery in a keystone species.

Infectious diseases pose a significant threat to global health and biodiversity. Yet, predicting the spatiotemporal dynamics of wildlife epizootics remains challenging. Disease outbreaks result from complex nonlinear interactions among a large collection of variables that rarely adhere to the assumptions of parametric regression modeling. We adopted a nonparametric machine learning approach to model wildlife epizootics and population recovery, using the disease system of colonial black-tailed prairie dogs (BTPD, Cynomys ludovicianus) and sylvatic plague as an example. We synthesized colony data between 2001 and 2020 from eight USDA Forest Service National Grasslands across the range of BTPDs in central North America. We then modeled extinctions due to plague and colony recovery of BTPDs in relation to complex interactions among climate, topoedaphic variables, colony characteristics, and disease history. Extinctions due to plague occurred more frequently when BTPD colonies were spatially clustered, in closer proximity to colonies decimated by plague during the previous year, following cooler than average temperatures the previous summer, and when wetter winter/springs were preceded by drier summers/falls. Rigorous cross-validations and spatial predictions indicated that our final models predicted plague outbreaks and colony recovery in BTPD with high accuracy (e.g., AUC generally >0.80). Thus, these spatially explicit models can reliably predict the spatial and temporal dynamics of wildlife epizootics and subsequent population recovery in a highly complex host-pathogen system. Our models can be used to support strategic management planning (e.g., plague mitigation) to optimize benefits of this keystone species to associated wildlife communities and ecosystem functioning. This optimization can reduce conflicts among different landowners and resource managers, as well as economic losses to the ranching industry. More broadly, our big data-model integration approach provides a general framework for spatially explicit forecasting of disease-induced population fluctuations for use in natural resource management decision-making.

Process-explicit models reveal pathway to extinction for woolly mammoth using pattern-oriented validation.

Pathways to extinction start long before the death of the last individual. However, causes of early stage population declines and the susceptibility of small residual populations to extirpation are typically studied in isolation. Using validated process-explicit models, we disentangle the ecological mechanisms and threats that were integral in the initial decline and later extinction of the woolly mammoth. We show that reconciling ancient DNA data on woolly mammoth population decline with fossil evidence of location and timing of extinction requires process-explicit models with specific demographic and niche constraints, and a constrained synergy of climatic change and human impacts. Validated models needed humans to hasten climate-driven population declines by many millennia, and to allow woolly mammoths to persist in mainland Arctic refugia until the mid-Holocene. Our results show that the role of humans in the extinction dynamics of woolly mammoth began well before the Holocene, exerting lasting effects on the spatial pattern and timing of its range-wide extinction.

COMPUTED TOMOGRAPHY FOR MEASURING BODY FAT RESERVES IN THE THREATENED MOJAVE DESERT TORTOISE (GOPHERUS AGASSIZII).

Noninvasive methods for measuring fat reserves in both captive and free-ranging animals are important for monitoring individual and population health, but chelonian anatomy and physiology present challenges to accurate measurements. Standard field-based methods for assessing body condition in Mojave desert tortoises (Gopherus agassizii) involve the qualitative body condition score, which relies on the apparent height of the temporalis muscle relative to the sagittal crest (in addition to other characteristics) and quantitative body condition indices that measure relative mass at size. However, it is unclear how these metrics relate to body fat reserves in this species. The aims of this study were to (1) describe the use of noninvasive computed tomography in measuring body fat volume of Mojave desert tortoises, (2) describe the location of fat reserves, (3) investigate relationships between fat reserves and body condition score and body condition index, and (4) explore whether relative temporalis muscle depth, measured via computed tomography, correlates with body condition score. Body condition scores were assessed for eight captive Mojave desert tortoises prior to euthanasia, and computed tomography was performed postmortem to quantify fat volume and measure temporalis muscle depth. At necropsy, the distribution of fat was documented. Fat volume calculated by computed tomography ranged from 2.83 to 145.38 cm3 (0.07-2.5% body volume). Neither qualitative body condition score nor quantitative body condition index was correlated with fat volume. Bladder content did not compromise body condition index. Body condition score was not correlated with relative temporalis muscle depth. Computed tomography is a noninvasive method for successfully identifying fat reserves and estimating total fat volume in Mojave desert tortoises. The lack of a relationship between computed tomography-determined metrics and commonly used body condition metrics indicates that computed tomography fills a critical gap in the health assessment tool kit for captive and free-ranging Mojave desert tortoises.

Adaptive divergence despite low effective population size in a peripherally isolated population of the pygmy rabbit, Brachylagus idahoensis.

Local adaptation can occur when spatially separated populations are subjected to contrasting environmental conditions. Historically, understanding the genetic basis of adaptation has been difficult, but increased availability of genome-wide markers facilitates studies of local adaptation in non-model organisms of conservation concern. The pygmy rabbit (Brachylagus idahoensis) is an imperiled lagomorph that relies on sagebrush for forage and cover. This reliance has led to widespread population declines following reductions in the distribution of sagebrush, leading to geographic separation between populations. In this study, we used >20,000 single nucleotide polymorphisms, genotype-environment association methods, and demographic modeling to examine neutral genetic variation and local adaptation in the pygmy rabbit in Nevada and California. We identified 308 loci as outliers, many of which had functional annotations related to metabolism of plant secondary compounds. Likewise, patterns of spatial variation in outlier loci were correlated with landscape and climatic variables including proximity to streams, sagebrush cover, and precipitation. We found that populations in the Mono Basin of California probably diverged from other Great Basin populations during late Pleistocene climate oscillations, and that this region is adaptively differentiated from other regions in the southern Great Basin despite limited gene flow and low effective population size. Our results demonstrate that peripherally isolated populations can maintain adaptive divergence.

SYNERGIC TRIAL (SYNchronizing Exercises, Remedies in Gait and Cognition) a multi-Centre randomized controlled double blind trial to improve gait and cognition in mild cognitive impairment.

BACKGROUND: Physical exercise, cognitive training, and vitamin D are low cost interventions that have the potential to enhance cognitive function and mobility in older adults, especially in pre-dementia states such as Mild Cognitive Impairment (MCI). Aerobic and progressive resistance exercises have benefits to cognitive performance, though evidence is somewhat inconsistent. We postulate that combined aerobic exercise (AE) and progressive resistance training (RT) (combined exercise) will have a better effect on cognition than a balance and toning control (BAT) intervention in older adults with MCI. We also expect that adding cognitive training and vitamin D supplementation to the combined exercise, as a multimodal intervention, will have synergistic efficacy. METHODS: The SYNERGIC trial (SYNchronizing Exercises, Remedies in GaIt and Cognition) is a multi-site, double-blinded, five-arm, controlled trial that assesses the potential synergic effect of combined AE and RT on cognition and mobility, with and without cognitive training and vitamin D supplementation in older adults with MCI. Two-hundred participants with MCI aged 60 to 85 years old will be randomized to one of five arms, four of which include combined exercise plus combinations of dual-task cognitive training (real vs. sham) and vitamin D supplementation (3 × 10,000 IU/wk. vs. placebo) in a quasi-factorial design, and one arm which receives all control interventions. The primary outcome measure is the ADAS-Cog (13 and plus modalities) measured at baseline and at 6 months of follow-up. Secondary outcomes include neuroimaging, neuro-cognitive performance, gait and mobility performance, and serum biomarkers of inflammation (C reactive protein and interleukin 6), neuroplasticity (brain-derived neurotropic factor), endothelial markers (vascular endothelial growth factor 1), and vitamin D serum levels. DISCUSSION: The SYNERGIC Trial will establish the efficacy and feasibility of a multimodal intervention to improve cognitive performance and mobility outcomes in MCI. These interventions may contribute to new approaches to stabilize and reverse cognitive-mobility decline in older individuals with MCI. TRIAL REGISTRATION: Identifier: NCT02808676. https://www.clinicaltrials.gov/ct2/show/NCT02808676 .

Imidazo[1,2-a]pyridin-6-yl-benzamide analogs as potent RAF inhibitors.

A series of imidazo[1,2-a]pyridin-6-yl-benzamide analogs was designed as inhibitors of B-RAFV600E. Medicinal chemistry techniques were employed to explore the SAR for this series and improve selectivity versus P38 and VEGFR2.

Group-based exercise and cognitive-physical training in older adults with self-reported cognitive complaints: The Multiple-Modality, Mind-Motor (M4) study protocol.

BACKGROUND: Dementia is associated with cognitive and functional deficits, and poses a significant personal, societal, and economic burden. Directing interventions towards older adults with self-reported cognitive complaints may provide the greatest impact on dementia incidence and prevalence. Risk factors for cognitive and functional deficits are multifactorial in nature; many are cardiovascular disease risk factors and are lifestyle-mediated. Evidence suggests that multiple-modality exercise programs can provide cognitive and functional benefits that extend beyond what can be achieved from cognitive, aerobic, or resistance training alone, and preliminary evidence suggests that novel mind-motor interventions (i.e., Square Stepping Exercise; SSE) can benefit cognition and functional fitness. Nevertheless, it remains unclear whether multiple-modality exercise combined with mind-motor interventions can benefit diverse cognitive and functional outcomes in older adults with cognitive complaints. METHODS/DESIGN: The Multiple-Modality, Mind-Motor (M4) study is a randomized controlled trial investigating the cognitive and functional impact of combined physical and cognitive training among community-dwelling adults with self-reported cognitive complaints who are 55 years of age or older. Participants are randomized to a Multiple-Modality and Mind-Motor (M4) intervention group or a Multiple-Modality (M2) comparison group. Participants exercise for 60 minutes/day, 3-days/week for 24 weeks and are assessed at baseline, 24 weeks and 52 weeks. The primary outcome is global cognitive function at 24 weeks, derived from the Cambridge Brain Sciences computerized cognitive battery. Secondary outcomes are: i) global cognitive function at 52 weeks; ii) domain-specific cognitive function at 24 and 52 weeks; iii) mobility (gait characteristics under single and dual-task conditions and balance); and 3) vascular health (blood pressure and carotid arterial measurements). We will analyze data based on an intent-to-treat approach, using mixed models for repeated measurements. DISCUSSION: The design features of the M4 trial and the methods included to address previous limitations within cognitive and exercise research will be discussed. Results from the M4 trial will provide evidence of combined multiple-modality and cognitive training among older adults with self-reported cognitive complaints on cognitive, mobility-related and vascular outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02136368.

Warning times for species extinctions due to climate change.

Climate change is likely to become an increasingly major obstacle to slowing the rate of species extinctions. Several new assessment approaches have been proposed for identifying climate-vulnerable species, based on the assumption that established systems such as the IUCN Red List need revising or replacing because they were not developed to explicitly consider climate change. However, no assessment approach has been tested to determine its ability to provide advanced warning time for conservation action for species that might go extinct due to climate change. To test the performance of the Red List system in this capacity, we used linked niche-demographic models with habitat dynamics driven by a 'business-as-usual' climate change scenario. We generated replicate 100-year trajectories for range-restricted reptiles and amphibians endemic to the United States. For each replicate, we categorized the simulated species according to IUCN Red List criteria at annual, 5-year, and 10-year intervals (the latter representing current practice). For replicates that went extinct, we calculated warning time as the number of years the simulated species was continuously listed in a threatened category prior to extinction. To simulate data limitations, we repeated the analysis using a single criterion at a time (disregarding other listing criteria). Results show that when all criteria can be used, the Red List system would provide several decades of warning time (median = 62 years; >20 years for 99% of replicates), but suggest that conservation actions should begin as soon as a species is listed as Vulnerable, because 50% of replicates went extinct within 20 years of becoming uplisted to Critically Endangered. When only one criterion was used, warning times were substantially shorter, but more frequent assessments increased the warning time by about a decade. Overall, we found that the Red List criteria reliably provide a sensitive and precautionary way to assess extinction risk under climate change.

Inferring the nature of anthropogenic threats from long-term abundance records.

Diagnosing the processes that threaten species persistence is critical for recovery planning and risk forecasting. Dominant threats are typically inferred by experts on the basis of a patchwork of informal methods. Transparent, quantitative diagnostic tools would contribute much-needed consistency, objectivity, and rigor to the process of diagnosing anthropogenic threats. Long-term census records, available for an increasingly large and diverse set of taxa, may exhibit characteristic signatures of specific threatening processes and thereby provide information for threat diagnosis. We developed a flexible Bayesian framework for diagnosing threats on the basis of long-term census records and diverse ancillary sources of information. We tested this framework with simulated data from artificial populations subjected to varying degrees of exploitation and habitat loss and several real-world abundance time series for which threatening processes are relatively well understood: bluefin tuna (Thunnus maccoyii) and Atlantic cod (Gadus morhua) (exploitation) and Red Grouse (Lagopus lagopus scotica) and Eurasian Skylark (Alauda arvensis) (habitat loss). Our method correctly identified the process driving population decline for over 90% of time series simulated under moderate to severe threat scenarios. Successful identification of threats approached 100% for severe exploitation and habitat loss scenarios. Our method identified threats less successfully when threatening processes were weak and when populations were simultaneously affected by multiple threats. Our method selected the presumed true threat model for all real-world case studies, although results were somewhat ambiguous in the case of the Eurasian Skylark. In the latter case, incorporation of an ancillary source of information (records of land-use change) increased the weight assigned to the presumed true model from 70% to 92%, illustrating the value of the proposed framework in bringing diverse sources of information into a common rigorous framework. Ultimately, our framework may greatly assist conservation organizations in documenting threatening processes and planning species recovery.

Evidence of bidirectional flow in the sciatic vasa nervorum.

The purpose of this study was to determine whether bidirectional flow exists in the sciatic vasa nervorum. Images obtained using high-frequency color Doppler ultrasound in duplex imaging mode (Vevo 2100) were studied retroactively. In Fig. 1 (left panel; rat 1), the color Doppler signal and flow-velocity waveforms are indicative of pulsatile flow traveling towards (B) and away (C) from the probe. In the right panel (Fig. 1; rat 2), there appears to be three distinct vessels, reflective of non-pulsatile negative flow (D), and pulsatile positive (E) and negative (F) flows. These data confirm the presence of bidirectional arterial flow in the sciatic vasa nervorum. Investigating bidirectional flow in the intact whole nerve may be helpful in elucidating novel features of nerve blood flow control in healthy and diseased states.

How interactions between animal movement and landscape processes modify local range dynamics and extinction risk.

Forecasts of range dynamics now incorporate many of the mechanisms and interactions that drive species distributions. However, connectivity continues to be simulated using overly simple distance-based dispersal models with little consideration of how the individual behaviour of dispersing organisms interacts with landscape structure (functional connectivity). Here, we link an individual-based model to a niche-population model to test the implications of this omission. We apply this novel approach to a turtle species inhabiting wetlands which are patchily distributed across a tropical savannah, and whose persistence is threatened by two important synergistic drivers of global change: predation by invasive species and overexploitation. We show that projections of local range dynamics in this study system change substantially when functional connectivity is modelled explicitly. Accounting for functional connectivity in model simulations causes the estimate of extinction risk to increase, and predictions of range contraction to slow. We conclude that models of range dynamics that simulate functional connectivity can reduce an important source of bias in predictions of shifts in species distributions and abundances, especially for organisms whose dispersal behaviours are strongly affected by landscape structure.

Effects of large-scale gold mining on habitat use and selection by American pronghorn.

Anthropogenic disturbances, including extraction of natural resources and development of alternative energy, are reducing and fragmenting habitat for wildlife across the globe. Effects of those disturbances have been explored by studying populations that migrate through oil and gas fields or alternative energy facilities. Extraction of minerals, including precious metals and lithium, is increasing rapidly in remote areas, which results in dramatically altered landscapes in areas of resident populations of wildlife. Our goal was to examine how a resident population of American pronghorn (Antilocapra americana) in the Great Basin ecosystem selected resources near a large-scale disturbance year around. We investigated how individuals selected resources around a large, open-pit gold mine. We classified levels of disturbance associated with the mine, and used a random forest model to select ecological covariates associated with habitat selection by pronghorn. We used resource selection functions to examine how disturbances affected habitat selection by pronghorn both annually and seasonally. Pronghorn strongly avoided areas of high disturbance, which included open pits, heap leach fields, rock disposal areas, and a tram. Pronghorn selected areas near roads, although selection was strongest about 2 km away. We observed relatively broad variation among individuals in selection of resources, and how they responded to the mine. The Great Basin is a mineral-rich area that continues to be exploited for natural resources, especially minerals. Sagebrush-dependent species, including pronghorn, that rely on this critical habitat were directly affected by that transformation of the landscape, which is likely to increase with expansion of the mine. As extraction of minerals from remote landscapes around the world continues to fragment habitats for wildlife, increasing our understanding of impacts of those changes on behaviors of wildlife before populations decline, may assist in the mitigation and minimization of negative impacts on mineral-rich landscapes and on wildlife populations.

Reexamining the minimum viable population concept for long-lived species.

For decades conservation biologists have proposed general rules of thumb for minimum viable population size (MVP); typically, they range from hundreds to thousands of individuals. These rules have shifted conservation resources away from small and fragmented populations. We examined whether iteroparous, long-lived species might constitute an exception to general MVP guidelines. On the basis of results from a 10-year capture-recapture study in eastern New York (U.S.A.), we developed a comprehensive demographic model for the globally threatened bog turtle (Glyptemys muhlenbergii), which is designated as endangered by the IUCN in 2011. We assessed population viability across a wide range of initial abundances and carrying capacities. Not accounting for inbreeding, our results suggest that bog turtle colonies with as few as 15 breeding females have >90% probability of persisting for >100 years, provided vital rates and environmental variance remain at currently estimated levels. On the basis of our results, we suggest that MVP thresholds may be 1-2 orders of magnitude too high for many long-lived organisms. Consequently, protection of small and fragmented populations may constitute a viable conservation option for such species, especially in a regional or metapopulation context.

Chapter 3.7.2. Detection of Rabbit hemorrhagic disease virus 2 in the Pygmy Rabbit (Brachylagus idahoensis) in Nevada, USA.

Rabbit hemorrhagic disease virus 2 (RHDV2 or Lagovirus GI.2) began circulating in wild lagomorph populations in the US in March 2020. To date, RHDV2 has been confirmed in several species of cottontail rabbits (Sylvilagus spp.) and hares (Lepus spp.) throughout the US. In February 2022, RHDV2 was detected in a pygmy rabbit (Brachylagus idahoensis). Pygmy rabbits are sagebrush obligates that only occur in the US Intermountain West and are a species of special concern due to the continual degradation and fragmentation of sagebrush-steppe landscapes. The spread of RHDV2 into occupied pygmy rabbit sites may pose a significant threat to their populations because of already declining numbers associated with habitat loss and high mortality rates.

Integrating multiple sign types to improve occupancy estimation for inconspicuous species.

Standard occupancy models enable unbiased estimation of occupancy by accounting for observation errors such as missed detections (false negatives) and, less commonly, incorrect detections (false positives). Occupancy models are fitted to data from repeated site visits in which surveyors record evidence of species presence. Use of indirect sign (e.g., scat, tracks) as evidence of presence can vastly improve survey efficiency for inconspicuous species but can also introduce additional sources of error. We developed a "multi-sign" occupancy approach to model the detection process separately for unique sign types and used this method to improve estimates of occupancy dynamics for an inconspicuous species, the American pika (Ochotona princeps). We investigated how estimates of pika occupancy and environmental drivers differed under four increasingly realistic representations of the observation process: (1) perfect detection (commonly assumed for modeling pika occupancy), (2) standard occupancy model (single observation process without possibility of false detection), (3) multi-sign with no false detections (non-false positive model), and (4) multi-sign with false detections (full model). For the multi-sign occupancy models, we modeled the detection of each sign type (fresh scat, fresh haypiles, pika calls, and pika sightings) separately as a function of climatic and environmental covariates. Estimates of occupancy processes and inferences about environmental drivers were sensitive to different detection models. Simplified representations of the detection processes generally resulted in higher occupancy estimates and higher turnover rates than the full multi-sign model. Environmental drivers also varied in their influence on occupancy models, where (e.g.) forb cover was estimated to more strongly influence occupancy in the full multi-sign model than the simpler models. As has been reported previously in other contexts, unmodeled heterogeneity in the observation process can lead to biases in occupancy processes and uncertainty in the relationships between occupancy and environmental covariates. Overall, our multi-sign approach to dynamic occupancy modeling, which accounts for spatio-temporal variation in reliability among sign types, has strong potential to generate more realistic estimates of occupancy dynamics for inconspicuous species.

Changes in selection of resources with reproductive state in a montane ungulate.

Animals select habitats based on food, water, space, and cover. Each of those components are essential to the ability of an individual to survive and reproduce in a particular habitat. Selection of resources is linked to reproductive fitness and individuals likely vary in how they select resources relative to their reproductive state: during pregnancy, while provisioning young when nutritional needs of the mother are high, but offspring are vulnerable to predation, or if they lose young to mortality. We investigated the effects of reproductive state on selection of resources by maternal female desert bighorn sheep (Ovis canadensis nelsoni) by comparing selection during the last trimester of gestation, following parturition when females were provisioning dependent young, and if the female lost an offspring. We captured, and recaptured each year, 32 female bighorn sheep at Lone Mountain, Nevada, during 2016-2018. Captured females were fit with GPS collars and those that were pregnant received vaginal implant transmitters. We used a Bayesian approach to estimate differences in selection between females provisioning and not provisioning offspring, as well as the length of time it took for females with offspring to return levels of selection similar to that observed prior to parturition. Females that were not provisioning offspring selected areas with higher risk of predation, but greater nutritional resources than those that were provisioning dependent young. When females were provisioning young immediately following parturition, females selected areas that were safe from predators, but had lower nutritional resources. Females displayed varying rates of return to selection strategies associated with access to nutritional resources as young grew and became more agile and less dependent on mothers. We observed clear and substantial shifts in selection of resources associated with reproductive state, and females exhibited tradeoffs in favor of areas that were safer from predators when provisioning dependent young despite loss of nutritional resources to support lactation. As young grew and became less vulnerable to predators, females returned to levels of selection that provided access to nutritional resources to restore somatic reserves lost during lactation.

Testosterone identifies hatchling sex for Mojave desert tortoises (Gopherus agassizii).

The threatened Mojave desert tortoise (Gopherus agassizii) exhibits temperature-dependent sex determination, and individuals appear externally sexually monomorphic until sexual maturity. A non-surgical sex identification method that is suitable for a single in situ encounter with hatchlings is essential for minimizing handling of wild animals. We tested (1) whether plasma testosterone quantified by enzyme-linked immunosorbent assay differentiated males from females in 0-3 month old captive hatchlings, and (2) whether an injection of follicle-stimulating hormone (FSH) differentially elevates testosterone in male hatchlings to aid in identifying sex. We validated sex by ceolioscopic (laparoscopic) surgery. We then fit the testosterone concentrations to lognormal distributions and identified the concentration below which individuals are more likely female, and above which individuals are more likely male. Using a parametric bootstrapping procedure, we estimated a 0.01-0.04% misidentification rate for naïve testosterone samples, and a 1.26-1.39% misidentification rate for challenged (post-FSH injection) testosterone samples. Quantification of plasma testosterone concentration from small volume (0.1 mL) blood samples appears to be a viable, highly accurate method to identify sex of 0-3 month old hatchlings and could be a valuable tool for conservation measures and investigation of trends and variation in sex ratios for in situ wild nests.

Temporal artery Doppler spectrum morphology responses to tilt and LBNP as an early indicator of syncope.

OBJECTIVE: In a study to identify an early hemodynamic predictor of syncope, 12 men (25-40 yr) underwent 30 min of 80 degrees head-up tilt, followed by progressive lower body negative pressure (LBNP) until presyncope. METHODS: Temporal (supplying extracranial tissues: TEMP), middle cerebral (MCA), and superficial femoral (FEM) arterial flow velocity (V) and vascular resistance indices (VR) were evaluated continuously using Doppler ultrasound. Ratios of the Doppler V(MEAN) (V(MCA)/V(FEM) or V(MCA)/ V(TEMP)) were used to assess flow redistribution between these areas. RESULTS: The progression of the testing protocol showed increases in vascular resistance in all territories. At presyncope, both MCA(VR) and FEM(VR) were reduced while there was a large increase in TEMP(VR). Vasoconstriction of the vascular bed supplied by the temporal artery occurred early during central hypovolemia resulting in the appearance of negative velocity deflections, which could be used for the early detection of impending syncope. Analysis of the velocity ratios showed little change until the onset of presyncope where there was an increase in V(MCA)/V(TEMP) which confirmed that vasoconstriction of the vascular bed supplied by the TEMP artery contributed to cardiac output redistribution in favor of the brain, and a reduction in V(MCA)/V(FEM) suggesting a redistribution of cardiac output toward the legs. DISCUSSION: In 67% of the tests, the appearance of the negative component of V(TEMP) was an early sign of increasing TEMP(VR) that occurred before visually detectable changes in VE(FEM) or V(MCA) and within 5 min before presyncope. Such easily identifiable in real time Doppler signs allowed experimenters to anticipate test termination.

A comparison of non-surgical methods for sexing young gopher tortoises (Gopherus polyphemus).

Many turtle species have temperature-dependent sex determination (TSD), raising the prospect that climate change could impact population dynamics by altering sex ratios. Understanding how climate change will affect populations of animals with TSD requires a reliable and minimally invasive method of identifying the sexes of young individuals. This determination is challenging in many turtles, which often lack conspicuous external sexual dimorphism until years after hatching. Here, we explore four alternatives for sexing three age classes of captive-reared young gopher tortoises (Gopherus polyphemus), a terrestrial turtle of conservation concern native to the southeastern United States: (1) naive testosterone levels, (2) testosterone levels following a follicle stimulating hormone (FSH) challenge, (3) linear morphological measurements, and (4) geometric morphometrics. Unlike some other turtle species, male and female neonatal gopher tortoises have overlapping naive testosterone concentration distributions, justifying more complicated methods. We found that sex of neonates (<7 days old) is best predicted by a "random forest" machine learning model with naive testosterone levels and morphological measurements (8% out-of-bag error). Sex of hatchlings (4-8 months old) was predicted with 11% error using a simple threshold on naive testosterone levels, or with 4% error using a simple threshold on post-FSH testosterone levels. Sex of juveniles (approximately 3.5 years old) was perfectly predicted using a simple threshold on naive testosterone levels. Sexing hatchlings at >4 months of age is the easiest and most reliable non-surgical method for sex identification. Given access to a rearing facility and equipment to perform hormone assays, these methods have the potential to supplant laparoscopic surgery as the method of choice for sexing young gopher tortoises.

Identification and structure-activity relationship of 2-morpholino 6-(3-hydroxyphenyl) pyrimidines, a class of potent and selective PI3 kinase inhibitors.

PI3 Kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration, and differentiation. The PI3 kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations, and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe a novel series of PI3K inhibitors sharing a pyrimidine core and showing significant potency against class I PI3 kinases in the biochemical assay and in cells. The discovery, synthesis and SAR of this chemotype are described.