Climate Spaces and Cliffs: A Novel Bovine Thermodynamic and Mass Balances Model.

The effects of climate change on animals are typically viewed in terms of survivability and wellbeing. In this study, we broaden that purview to include climate impacts on reproductive capability. There are not only climate spaces for daily function, but climate cliffs that represent reproductive failures in the face of climate warming. This alternative focus suggests that climate warming challenges may be more immediate and profound than initially imagined. This research describes a state-of-the-art mechanistic model, Dairy Niche Mapper (DNM), and independent validation tests. Where test data are absent, the calculated results are consistent with expected responses. Simulations of metabolic chamber conditions reveal the local steady-state impacts of climate and animal variables on milk production capacity, metabolic rate, food consumption and water needs. Simulations of a temperature humidity index (THI) show strengths and limitations of that approach. Broader time- and spatial-scale calculations applied in the western and eastern halves of the northern hemisphere identify current and future monthly latitudinal climate change impacts on milk production potential, feed and water needs in dairy cows of different sizes. Dairy Niche Mapper (DNM) was developed from a broadly tested mechanistic microclimate-animal model, Niche Mapper (NM). DNM provides an improved quantitative understanding of the complex nonlinear interactions of climate variation and dairy bovine properties' effects on current and future milk production, feed and water needs for grazing and confinement dairy operations. DNM outputs include feasible activity times, milk production and water and feed needs of different-sized Holstein cows on high-grain (confinement feeding) versus high-forage (grazing feeding) diets at three arbitrary north latitudes, 12°, 30° and 60°, for North and Central America and for Asia. These three latitudes encompass current northern hemisphere bovine production environments and possible future production locations. The greatest impacts of climate change will be in the low elevations in tropical and subtropical regions. Global regions above 30° and below 60° latitude with reliable rainfall will be least affected by current projected levels of climate change. This work provides the basis for computational animal design for guiding agricultural development via breeding programs, genetic engineering, management options including siting or the manipulation of other relevant environmental and animal variables.

Incorporating species-specific morphology improves model predictions of thermal and hydric stress in the sand fiddler crab, Leptuca pugilator.

Understanding where and why organisms are experiencing thermal and hydric stress is critical for predicting species' responses to climate change. Biophysical models that explicitly link organismal functional traits like morphology, physiology, and behavior to environmental conditions can provide valuable insight into determinants of thermal and hydric stress. Here we use a combination of direct measurements, 3D modeling, and computational fluid dynamics to develop a detailed biophysical model of the sand fiddler crab, Leptuca pugilator. We compare the detailed model's performance to a model using a simpler ellipsoidal approximation of a crab. The detailed model predicted crab body temperatures within 1 °C of observed in both laboratory and field settings; the ellipsoidal approximation model predicted body temperatures within 2 °C of observed body temperatures. Model predictions are meaningfully improved through efforts to incorporate species-specific morphological properties rather than relying on simple geometric approximations. Experimental evaporative water loss (EWL) measurements indicate that L. pugilator can modify its permeability to EWL as a function of vapor density gradients, providing novel insight into physiological thermoregulation in the species. Body temperature and EWL predictions made over the course of a year at a single site demonstrate how such biophysical models can be used to explore mechanistic drivers and spatiotemporal patterns of thermal and hydric stress, providing insight into current and future distributions in the face of climate change.

Behavioural responses of a large, heat-sensitive mammal to climatic variation at multiple spatial scales.

Climate warming creates energetic challenges for endothermic species by increasing metabolic and hydric costs of thermoregulation. Although endotherms can invoke an array of behavioural and physiological strategies for maintaining homeostasis, the relative effectiveness of those strategies in a climate that is becoming both warmer and drier is not well understood. In accordance with the heat dissipation limit theory which suggests that allocation of energy to growth and reproduction by endotherms is constrained by the ability to dissipate heat, we expected that patterns of habitat use by large, heat-sensitive mammals across multiple scales are critical for behavioural thermoregulation during periods of potential heat stress and that they must invest a large portion of time to maintain heat balance. To test our predictions, we evaluated mechanisms underpinning the effectiveness of bed sites for ameliorating daytime heat loads and potential heat stress across the landscape while accounting for other factors known to affect behaviour. We integrated detailed data on microclimate and animal attributes of moose Alces alces, into a biophysical model to quantify costs of thermoregulation at fine and coarse spatial scales. During summer, moose spent an average of 67.8% of daylight hours bedded, and selected bed sites and home ranges that reduced risk of experiencing heat stress. For most of the day, shade could effectively mitigate the risk of experiencing heat stress up to 10°C, but at warmer temperatures (up to 20°C) wet soil was necessary to maintain homeostasis via conductive heat loss. Consistent selection across spatial scales for locations that reduced heat load underscores the importance of the thermal environment as a driver of behaviour in this heat-sensitive mammal. Moose in North America have long been characterized as riparian-obligate species because of their dependence on woody plant species for food. Nevertheless, the importance of dissipating endogenous heat loads conductively through wet soil suggests riparian habitats also are critical thermal refuges for moose. Such refuges may be especially important in the face of a warming climate in which both high environmental temperatures and drier conditions will likely exacerbate limits to heat dissipation, especially for large, heat-sensitive animals.

Physiological costs of undocumented human migration across the southern United States border.

Political, economic, and climatic upheaval can result in mass human migration across extreme terrain in search of more humane living conditions, exposing migrants to environments that challenge human tolerance. An empirical understanding of the biological stresses associated with these migrations will play a key role in the development of social, political, and medical strategies for alleviating adverse effects and risk of death. We model physiological stress associated with undocumented migration across a commonly traversed section of the southern border of the United States and find that locations of migrant death are disproportionately clustered within regions of greatest predicted physiological stress (evaporative water loss). Minimum values of estimated evaporative water loss were sufficient to cause severe dehydration and associated proximate causes of mortality. Integration of future climate predictions into models increased predicted physiological costs of migration by up to 34.1% over the next 30 years.

North Atlantic winter cyclones starve seabirds.

Each winter, the North Atlantic Ocean is the stage for numerous cyclones, the most severe ones leading to seabird mass-mortality events called "winter wrecks."1-3 During these, thousands of emaciated seabird carcasses are washed ashore along European and North American coasts. Winter cyclones can therefore shape seabird population dynamics4,5 by affecting survival rates as well as the body condition of surviving individuals and thus their future reproduction. However, most often the geographic origins of impacted seabirds and the causes of their deaths remain unclear.6 We performed the first ocean-basin scale assessment of cyclone exposure in a seabird community by coupling winter tracking data for ∼1,500 individuals of five key North Atlantic seabird species (Alle alle, Fratercula arctica, Uria aalge, Uria lomvia, and Rissa tridactyla) and cyclone locations. We then explored the energetic consequences of different cyclonic conditions using a mechanistic bioenergetics model7 and tested the hypothesis that cyclones dramatically increase seabird energy requirements. We demonstrated that cyclones of high intensity impacted birds from all studied species and breeding colonies during winter but especially those aggregating in the Labrador Sea, the Davis Strait, the surroundings of Iceland, and the Barents Sea. Our broad-scale analyses suggested that cyclonic conditions do not increase seabird energy requirements, implying that they die because of the unavailability of their prey and/or their inability to feed during cyclones. Our study provides essential information on seabird cyclone exposure in a context of marked cyclone regime changes due to global warming.8.

Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor.

The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.

Meeting Paris agreement objectives will temper seabird winter distribution shifts in the North Atlantic Ocean.

We explored the implications of reaching the Paris Agreement Objective of limiting global warming to <2°C for the future winter distribution of the North Atlantic seabird community. We predicted and quantified current and future winter habitats of five North Atlantic Ocean seabird species (Alle alle, Fratercula arctica, Uria aalge, Uria lomvia and Rissa tridactyla) using tracking data for ~1500 individuals through resource selection functions based on mechanistic modeling of seabird energy requirements, and a dynamic bioclimate envelope model of seabird prey. Future winter distributions were predicted to shift with climate change, especially when global warming exceed 2°C under a "no mitigation" scenario, modifying seabird wintering hotspots in the North Atlantic Ocean. Our findings suggest that meeting Paris agreement objectives will limit changes in seabird selected habitat location and size in the North Atlantic Ocean during the 21st century. We thereby provide key information for the design of adaptive marine-protected areas in a changing ocean.

Field data confirm the ability of a biophysical model to predict wild primate body temperature.

In the face of climate change there is an urgent need to understand how animal performance is affected by environmental conditions. Biophysical models that use principles of heat and mass transfer can be used to explore how an animal's morphology, physiology, and behavior interact with its environment in terms of energy, mass and water balances to affect fitness and performance. We used Niche Mapper™ (NM) to build a vervet monkey (Chlorocebus pygerythrus) biophysical model and tested the model's ability to predict core body temperature (Tb) variation and thermal stress against Tb and behavioral data collected from wild vervets in South Africa. The mean observed Tb in both males and females was within 0.5 °C of NM's predicted Tbs for 91% of hours over the five-year study period. This is the first time that NM's Tb predictions have been validated against field data from a wild endotherm. Overall, these results provide confidence that NM can accurately predict thermal stress and can be used to provide insight into the thermoregulatory consequences of morphological (e.g., body size, shape, fur depth), physiological (e.g. Tb plasticity) and behavioral (e.g., huddling, resting, shade seeking) adaptations. Such an approach allows users to test hypotheses about how animals adapt to thermoregulatory challenges and make informed predictions about potential responses to environmental change such as climate change or habitat conversion. Importantly, NM's animal submodel is a general model that can be adapted to other species, requiring only basic information on an animal's morphology, physiology and behavior.

Infrared thermography cannot be used to approximate core body temperature in wild primates.

Understanding the physiological processes that underpin primate performance is key if we are to assess how a primate might respond when navigating new and changing environments. Given the connection between a mammal's ability to thermoregulate and the changing demands of its thermal environment, increasing attention is being devoted to the study of thermoregulatory processes as a means to assess primate performance. Infrared thermography can be used to record the body surface temperatures of free-ranging animals. However, some uncertainty remains as to how these measurements can be used to approximate core body temperature. Here, we use data collected from wild vervet monkeys (Chlorocebus pygerythrus) to examine the relationship between infrared body surface temperature, core body (intra-abdominal) temperature, and local climate, to determine to what extent surface temperatures reflect core body temperature. While we report a positive association between surface and core body temperature-a finding that has previously been used to justify the use of surface temperature measurements as a proxy for core temperature regulation-when we controlled for the effect of the local climate in our analyses, this relationship was no longer observed. That is, body surface temperatures were solely predicted by local climate, and not core body temperatures, suggesting that surface temperatures tell us more about the environment a primate is in, and less about the thermal status of its body core in that environment. Despite the advantages of a noninvasive means to detect and record animal temperatures, infrared thermography alone cannot be used to approximate core body temperature in wild primates.

High accuracy gene expression profiling of sorted cell subpopulations from breast cancer PDX model tissue.

Intratumor Heterogeneity (ITH) is a functionally important property of tumor tissue and may be involved in drug resistance mechanisms. Although descriptions of ITH can be traced back to very early reports about cancer tissue, mechanistic investigations are still limited by the precision of analysis methods and access to relevant tissue sources. PDX models have provided a reproducible source of tissue with at least a partial representation of naturally occurring ITH. We investigated the properties of phenotypically distinct cell populations by Fluorescence activated cell sorting (FACS) tissue derived cells from multiple tumors from a triple negative breast cancer patient derived xenograft (PDX) model. We subsequently subjected each population to in depth gene expression analysis. Our findings suggest that process related gene expression changes (caused by tissue dissociation and FACS sorting) are restricted to Immediate Early Genes (IEGs). This allowed us to discover highly reproducible gene expression profiles of distinct cellular compartments identifiable by cell surface markers in this particular tumor model. Within the context of data from a previously published model our work suggests that gene expression profiles associated with hypoxia, stemness and drug resistance may reside in tumor subpopulations predictably growing in PDX models. This approach provides a novel opportunity for prospective mechanistic studies of ITH.

Future winters present a complex energetic landscape of decreased costs and reduced risk for a freeze-tolerant amphibian, the Wood Frog (Lithobates sylvaticus).

Winter climate warming is rapidly leading to changes in snow depth and soil temperatures across mid- and high-latitude ecosystems, with important implications for survival and distribution of species that overwinter beneath the snow. Amphibians are a particularly vulnerable group to winter climate change because of the tight coupling between their body temperature and metabolic rate. Here, we used a mechanistic microclimate model coupled to an animal biophysics model to predict the spatially explicit effects of future climate change on the wintering energetics of a freeze-tolerant amphibian, the Wood Frog (Lithobates sylvaticus), across its distributional range in the eastern United States. Our below-the-snow microclimate simulations were driven by dynamically downscaled climate projections from a regional climate model coupled to a one-dimensional model of the Laurentian Great Lakes. We found that warming soil temperatures and decreasing winter length have opposing effects on Wood Frog winter energy requirements, leading to geographically heterogeneous implications for Wood Frogs. While energy expenditures and peak body ice content were predicted to decline in Wood Frogs across most of our study region, we identified an area of heightened energetic risk in the northwestern part of the Great Lakes region where energy requirements were predicted to increase. Because Wood Frogs rely on body stores acquired in fall to fuel winter survival and spring breeding, increased winter energy requirements have the potential to impact local survival and reproduction. Given the geographically variable and intertwined drivers of future under-snow conditions (e.g., declining snow depths, rising air temperatures, shortening winters), spatially explicit assessments of species energetics and risk will be important to understanding the vulnerability of subnivium-adapted species.

Landscape scale thermoregulatory costs from sublethal exposure to Deep Water Horizon oil in the double-crested cormorant.

Toxic effects of heavy oiling to wildlife are well known from oil spills, although sublethal oil exposure effects are poorly understood. We used Niche Mapper™, to compute spatially and temporally specific energetic and behavioral impacts of repeated sublethal oil exposure to double-crested cormorants (Phalacrocorax auritus). During winter (October-March) cormorants exposed to 13 g, 39 g, and 65-78 g of oil, had on average a 31%, 59%, and 76% predicted increase in total resting energetic requirements (RMR) compared to unoiled birds, respectively. Increased RMR resulted in a mean (±SD) predicted increase in time spent foraging of 36 (±13) min·d-1. During the breeding season (April-September), cormorants had on average a 29%, 57% and 73% increase in total RMR and the mean predicted increase in time spent foraging was 131 (±49) min·d-1. Thermoregulatory effects of sublethal oil exposure may cause greater impacts to bird populations than is currently understood.

Modeling Dragons: Using linked mechanistic physiological and microclimate models to explore environmental, physiological, and morphological constraints on the early evolution of dinosaurs.

We employed the widely-tested biophysiological modeling software, Niche Mapper™ to investigate the metabolic function of the Late Triassic dinosaurs Plateosaurus and Coelophysis during global greenhouse conditions. We tested a variety of assumptions about resting metabolic rate, each evaluated within six microclimate models that bound paleoenvironmental conditions at 12° N paleolatitude, as determined by sedimentological and isotopic proxies for climate within the Chinle Formation of the southwestern United States. Sensitivity testing of metabolic variables and simulated "metabolic chamber" analyses support elevated "ratite-like" metabolic rates and intermediate "monotreme-like" core temperature ranges in these species of early saurischian dinosaur. Our results suggest small theropods may have needed partial to full epidermal insulation in temperate environments, while fully grown prosauropods would have likely been heat stressed in open, hot environments and should have been restricted to cooler microclimates such as dense forests or higher latitudes and elevations. This is in agreement with the Late Triassic fossil record and may have contributed to the latitudinal gap in the Triassic prosauropod record.

Evaporative water loss simulation improves models' prediction of habitat suitability for a high-elevation forest skink.

Accurate evaluation of habitat availability for wildlife is relevant for ecological applications. Researchers have frequently used models to simulate habitats thermally suitable for reptiles, but these results have limited application for species highly selective for habitat humidity. Here, we use the biophysical Niche Mapper™ model to investigate impacts of vegetation cover on the habitat quality of a high-elevation forest skink, Sphenomorphus taiwanensis, and to predict changes in habitat suitability in a future warmer climate (3 °C increase in air temperature). We assess habitat suitability with different densities of canopy cover in our study areas using two ecologically relevant estimates for lizards: maximum activity time and evaporative water loss (EWL) during the activity season. We measured preferred body temperature and EWL of this species for model parameterization, and behavioral response to EWL to supplement habitat quality assessment. The results indicated that this species is sensitive to EWL and reduces its activity when dehydrated. The model predicted that denser canopy levels increase microclimate cooling and humidity, and that most canopy levels are thermally suitable for this species, as the lizard can thermoregulate to manage adverse temperatures. Nevertheless, increasing canopy density could significantly decrease EWL during activity. In the warmer climate scenario, simulated maximum activity time and EWL changed little because of thermoregulation behavior. Our results suggest that habitat preference of this species is a consequence of water and energy requirements, and we note that combining EWL and maximum activity time data can enhance model accuracy of lizards' habitat quality in a warmer climate.

Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints.

Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aß in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.

Climate change could overturn bird migration: Transarctic flights and high-latitude residency in a sea ice free Arctic.

Climate models predict that by 2050 the Arctic Ocean will be sea ice free each summer. Removing this barrier between the Atlantic and the Pacific will modify a wide range of ecological processes, including bird migration. Using published information, we identified 29 arctic-breeding seabird species, which currently migrate in the North Atlantic and could shift to a transarctic migration towards the North Pacific. We also identified 24 arctic-breeding seabird species which may shift from a migratory strategy to high-arctic year-round residency. To illustrate the biogeographical consequences of such drastic migratory shifts, we performed an in-depth study of little auks (Alle alle), the most numerous artic seabird. Coupling species distribution models and climatic models, we assessed the adequacy of future wintering and breeding areas for transarctic migrants and high-arctic year-round residents. Further, we used a mechanistic bioenergetics model (Niche Mapper), to compare the energetic costs of current little auk migration in the North Atlantic with potential transarctic and high-arctic residency strategies. Surprisingly, our results indicate that transarctic little auk migration, from the North Atlantic towards the North Pacific, may only be half as costly, energetically, than high-arctic residency or migration to the North Atlantic. Our study illustrates how global warming may radically modify the biogeography of migratory species, and provides a general methodological framework linking migratory energetics and spatial ecology.

Correction: Flow based single cell analysis of the immune landscape distinguishes Barrett's esophagus from adjacent normal tissue.

[This corrects the article DOI: 10.18632/oncotarget.26911.].

Evaporative cooling provides a major metabolic energy sink.

OBJECTIVE: Elimination of food calories as heat could help redress the excess accumulation of metabolic energy exhibited as obesity. Prior studies have focused on the induction of thermogenesis in beige and brown adipose tissues as the application of this principle, particularly because the ß-adrenergic environment associated with thermogenic activation has been shown to have positive health implications. The counterpoint to this strategy is the regulation of heat loss; we propose that mammals with inefficient heat conservation will require more thermogenesis to maintain body temperature. METHODS: Surface temperature thermography and rates of trans-epidermal water loss were integrated to profile the total heat transfer of genetically-engineered and genetically variable mice. RESULTS: These data were incorporated with energy expenditure data to generate a biophysical profile to test the significance of increased rates of evaporative cooling. CONCLUSIONS: We show that mouse skins vary considerably in their heat retention properties, whether because of naturally occurring variation (SKH-1 mice), or genetic modification of the heat-retaining lipid lamellae (SCD1, DGAT1 or Agouti Ay obese mice). In particular, we turn attention to widely different rates of evaporative cooling as the result of trans-epidermal water loss; higher rates of heat loss by evaporative cooling leads to increased demand for thermogenesis. We speculate that this physiology could be harnessed to create an energy sink to assist with strategies aimed at treating metabolic diseases.

Flow based single cell analysis of the immune landscape distinguishes Barrett's esophagus from adjacent normal tissue.

Barrett's esophagus (BE) is metaplasia of the squamous epithelium to a specialized columnar epithelium. BE progresses through low- and high-grade dysplasia before developing into esophageal adenocarcinoma. The BE microenvironment is not well defined. We compare 12 human clinical BE and adjacent normal squamous epithelium biopsies using single cell immunophenotyping by flow cytometry. A cassette of 19 epithelial and immune cell markers was used to detect differences between cellular compartments in normal and BE tissues. We found that the BE microenvironment has an immunological landscape distinct from adjacent normal epithelium. BE has an increased percentage of epithelial cells with a concomitant decrease in the percentage of immune cells, accompanied by a shift in the immune landscape from a predominantly T cell rich microenvironment in normal tissue to a B cell rich landscape in BE tissue. Hierarchical clustering separates BE and normal samples into two discrete groups based upon our 19-marker panel, but also reveals unexpected, shared phenotypes for three patients. Our results suggest that flow based single cell analysis may have the potential for revealing clinically relevant differences between BE and normal adjacent tissue, and that surface immunophenotypes could identify specific subpopulations from dysplastic tissue for further investigation.

Shifts in metabolic fuel use coincide with maximal rates of ventilation and body surface rewarming in an arousing hibernator.

It is well established that hibernating mammals rely predominantly on lipid stores to fuel metabolism throughout the hibernation season. However, it is unclear if other endogenous fuels contribute to the rapid, ~400-fold increase in metabolic rate during the early phase of arousal from torpor. To investigate this issue, we used cavity ring-down spectroscopy, a technique that provides a real-time indication of fuel use by measuring the ratio of 13C to 12C in the exhaled CO2 of arousing 13-lined ground squirrels (Ictidomys tridecemlineatus). We used infrared thermography to simultaneously measure ventilation and surface temperature change in various body regions, and we interpreted these data in light of changing plasma metabolite abundances at multiple stages of arousal from torpor. We found that hibernating squirrels use a combination of lipids and, likely, carbohydrates to fuel the initial ~60 min of arousal before switching to predominantly lipid oxidation. This fuel switch coincided with times of maximal rates of ventilation and rewarming of different body surface regions, including brown adipose tissue. Infrared thermography revealed zonal rewarming, whereby the brown adipose tissue region was the first to warm, followed by the thoracic and head regions and, finally, the posterior half of the body. Consistent with the results from cavity ring-down spectroscopy, plasma metabolite dynamics during early arousal suggested a large reliance on fatty acids, with a contribution from carbohydrates and glycerol. Because of their high oxidative flux rates and efficient O2 use, carbohydrates might be an advantageous metabolic fuel during the early phase of arousal, when metabolic demands are high but ventilation rates and, thus, O2 supply are relatively low.