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Background: The degree of human hepatocyte replacement in chimeric mice with humanized liver has previously been shown to correlate with human plasma albumin measurements. However, there are no reports that directly compare the remaining endogenous mouse albumin with the newly expressed human albumin following engraftment. To better understand the disposition of serum albumin in PXB-mice, we developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to simultaneously quantitate both human and mouse albumin from plasma. Results: A robust correlation was observed between the serum human albumin levels measured by LC-MS/MS and the estimated replacement index of PXB-mice. Conclusion: All data were shown to be specific and suitable to accurately quantify both human and mouse albumin from plasma of chimeric mice with humanized livers.

Snakebite envenomation continues to contribute to high fatality and morbidity rates across Asia. Yet snake bite is one of many outcomes due to human-snake conflicts, which themselves are only one type of human-snake relationship among the diversity of such interactions. We propose that human-snake relationships need to be explored from a perspective integrative of history, ecology, and culture in order to adequately and holistically address snake bite. In order to contextualize this concept within a language already understood in conservation research, we characterize and develop four interconnected themes defining human-snake relationships as a social ecological system. By breaking down the multifaceted nature of human-snake relationships under a social ecological systems framework, we explore its applicability in contributing to a unified strategy, drawing from both social and natural sciences for ending the snakebite crisis.

Background: Discussing goals of care with heart failure patients is recommended but is not done systematically, due to factors such as time and personal beliefs. A recent survey showed that one-fifth of clinicians believe that implantable cardioverter defibrillator deactivation (ICDD) is unethical or constitutes physician-assisted suicide. We investigated whether individuals' characteristics are associated with these beliefs., Methods: The Decision-Making About Goals of Care for Hospitalize d Pati e nts With H eart F ailure (DECIDE-HF) survey was given to healthcare providers at 9 hospitals to assess their perceived barriers to goals-of-care discussions. The association between respondent characteristics and their beliefs was examined using 2 adjusted logistic regression models., Results: We included 760 clinicians (459 nurses, 94 fellows, and 207 cardiologists). The responses varied among professions, with the belief that ICDD is unethical considered to be important barrier by nurses (24%), fellows (10%), and staff (7%); P < 0.001). After adjusting for site, spirituality being more important in life (odds ratio [OR]: 2.21; 95% confidence interval [CI]:1.37-3.56; P  = 0.001, compared to less important), region of training (Asia [OR: 5.88; 95% CI: 2.12-16.31; P  = 0.001] and Middle East [OR: 5.55; 95% CI:1.57-19.63; P  = 0.008] compared to Canada), and years in practice (OR: 1.32; 95% CI: 1.07-1.63; P  = 0.01 per decade) influenced beliefs about ICDD being unethical, with similar results for the belief that ICDD represents physician-assisted suicide., Conclusions: Sociocultural factors, region of training, and profession influence clinicians' beliefs about ICDD being unethical and representing physician-assisted suicide. These factors and beliefs must be acknowledged when facing the delicate issue of end-of-life discussion., (© 2021 The Authors.)

Background: Surrogate monoclonal antibodies (mAbs) used in preclinical in vivo studies can be challenging to quantify due to lack of suitable immunoaffinity reagents or unavailability of the mAb protein sequence. Generic immunoaffinity reagents were evaluated to develop sensitive LC-MS/MS assays. Peptides of unknown sequence can be used for selective LC-MS quantification. Results: anti-mouse IgG1 was found to be an effective immunoaffinity reagent, enabling quantification of mouse IgG1 mAbs in mouse serum. Selective peptides of unknown sequence were applied for multiplex LC-MS quantification of two rat mAbs co-dosed in mouse. Conclusion: Generic anti-mouse IgG subtype-specific antibodies can be used to improve assay sensitivity and peptides of unknown sequence can be used to quantify surrogate mAbs when the mAb protein sequence in unavailable.

Objectives: The Pediatric Logistic Organ Dysfunction-2 is a validated score that quantifies organ dysfunction severity and requires complex data collection that is time-consuming and subject to errors. We hypothesized that a computer algorithm that automatically collects and calculates the Pediatric Logistic Organ Dysfunction-2 (aPELOD-2) score would be valid, fast and at least as accurate as a manual approach (mPELOD-2)., Design: Retrospective cohort study., Setting: Single center tertiary medical and surgical pediatric critical care unit (Sainte-Justine Hospital, Montreal, Canada)., Patients: Critically ill children participating in four clinical studies between January 2013 and August 2018, a period during which mPELOD-2 data were manually collected., Interventions: None., Measurements and Main Results: The aPELOD-2 was calculated for all consecutive admissions between 2013 and 2018 (n = 5,279) and had a good survival discrimination with an area under the receiver operating characteristic curve of 0.84 (95% CI, 0.81-0.88). We also collected data from four single-center studies in which mPELOD-2 was calculated (n = 796, 57% medical, 43% surgical) and compared these measurements to those of the aPELOD-2. For those patients, median age was 15 months (interquartile range, 3-73 mo), median ICU stay was 5 days (interquartile range, 3-9 d), mortality was 3.9% (n = 28). The intraclass correlation coefficient between mPELOD-2 and aPELOD-2 was 0.75 (95% CI, 0.73-0.77). The Bland-Altman showed a bias of 1.9 (95% CI, 1.7-2) and limits of agreement of -3.1 (95% CI, -3.4 to -2.8) to 6.8 (95% CI, 6.5-7.2). The highest agreement (Cohen's Kappa) of the Pediatric Logistic Organ Dysfunction-2 components was noted for lactate level (0.88), invasive ventilation (0.86), and creatinine level (0.82) and the lowest for the Glasgow Coma Scale (0.52). The proportion of patients with multiple organ dysfunction syndrome was higher for aPELOD-2 (78%) than mPELOD-2 (72%; p = 0.002). The aPELOD-2 had a better survival discrimination (area under the receiver operating characteristic curve, 0.81; 95% CI, 0.72-0.90) over mPELOD-2 (area under the receiver operating characteristic curve, 0.70; 95% CI, 0.59-0.82; p = 0.01)., Conclusions: We successfully created a freely available automatic algorithm to calculate the Pediatric Logistic Organ Dysfunction-2 score that is less labor intensive and has better survival discrimination than the manual calculation. Use of an automated system could greatly facilitate integration of the Pediatric Logistic Organ Dysfunction-2 score at the bedside and within clinical decision support systems.

Anogenital distance (AGD) is positively correlated to fetal androgen exposure and developmental masculinization in mammals. Independent of overall body size, AGD shows a strong positive correlation with male fertility and in rodents, AGD is a good indicator of male competitive ability and is associated with female choice. We hypothesized that AGD will also predict male competitive ability in non-human primates. To test this, we measured AGD noninvasively with a parallel laser in a wild population of Angolan colobus monkeys (Colobus angolensis ruwenzorii) in Uganda and correlated to it to their social structure. C. angolensis ruwenzorii form a multilevel society with both one-male/multifemale units (OMUs) and multimale/multifemale units (MMUs). We compared AGD in males from five OMUs and six MMUs and related it to their fecal androgen metabolite concentrations, dominance rank and body size, and to the number of females in their unit. Males in OMUs had greater access to females, so were predicted to have longer AGDs, but this was not found. AGD also did not correlate overall with mean fecal androgen metabolites in MMUs. However, AGD was correlated with dominance rank in MMUs, demonstrating that higher-ranking males in these multimale units had longer AGDs. Body size did not show the same relationship with dominance rank, suggesting that male rank was not just a reflection of absolute male size. Our findings indicate that AGD predicts male competitive ability in this species and that it may be a useful correlate throughout the non-human primates. These results also support the idea that prenatal androgen exposure increases the likelihood of the expression of behaviors that maintain high dominance rank., (© 2020 Wiley Periodicals, Inc.)

Preferred temperature (Tpref) has been measured in over 100 species of aquatic and 300 species of terrestrial ectotherms as a metric for assessing behavioural thermoregulation in variable environments and, as such, has been linked to ecological processes ranging from individual behaviour to population and community dynamics. Due to the asymmetric shape of performance curves, Tpref is typically lower than the optimal temperature (Topt, where physiological performance is at its peak), and the degree of this mismatch increases with variability in Tb. Intertidal ectotherms experience huge variability in Tb on a daily basis and therefore provide a good system to test whether the relationship between Tpref and variation in Tb holds in more extreme environments. A review of the literature, however, only revealed comparisons between Tpref and Topt for five intertidal species and measurements of Tpref for 23 species. An analysis of this limited literature for intertidal ectotherms showed a positive relationship between acclimation temperature and Tpref. There was, however, great variation in the methodologies employed to make these assessments. Factors contributing to behavioural thermoregulation in intertidal ectotherms including small body size; low mobility; interactions among individuals; endogenous clocks; metabolic effects; thermal sensitivity; sampling of the thermal environment and recent acclimation history were considered to varying degrees when measuring Tpref, confounding comparisons between species. The methodologies used to measure Tpref in intertidal ectotherms were reviewed in light of each of these factors, and methodologies proposed to standardize approaches. Given the theoretical predictions about the relationships between Tpref and variability in Tb, the spatial and temporal thermal variability experienced by intertidal ectotherms provides numerous opportunities to test these expectations if assessed in a standardized manner, and can potentially provide insights into the value of behavioural thermoregulation in the more thermally variable environments predicted to occur in the near future., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Soft sediment shores in the tropics are highly dynamic environments, where behavioural patterns of organisms are constrained by tidal conditions, and environmental temperatures during an organisms' activity periods can exceed their thermal tolerance levels. In such extreme habitats, behavioural responses to environmental changes are key to survival, driving differential performance. We investigated sponging behaviour (water uptake from sediments) of the deposit-feeding crab, Scopimera intermedia, on tropical sandy shores to determine its thermoregulatory function. The thermal physiology of the crabs and their habitat conditions were quantified by measuring thermal performance curves and recording environmental temperatures during the crabs' activity periods. Environmental temperatures were combined with experimental data to investigate the role of sponging on the thermal performances of the crabs by simulating field body temperatures. Sponging rate was strongly and positively correlated with feeding rate, as sponging replenishes water for flotation feeding. Sponging, however, also reduced body temperatures on average by 1.3 °C. Simulated populations of crabs which were unable to sponge had more variable body temperatures, which exceeded the critical thermal maximum of the crabs (~ 39 °C) nearly 2000 times more often than crabs able to sponge. Sponging is, therefore, a multifunctional behavioural trait important for both feeding and thermoregulation. The evolution of such multifunctional traits is likely to be a widespread, but overlooked phenomenon in intertidal species, as maintaining a functional body temperature is energetically costly in habitats where environmental conditions fluctuate strongly such as on tropical shores.

Susceptibility of species to climate change varies depending on many biological and environmental traits, such as reproductive mode and climatic exposure. For example, wider thermal tolerance breadths are associated with more climatically variable habitats and viviparity could be associated with greater vulnerability relative to oviparity. However, few examples exist detailing how such physiological and environmental traits together might shape species thermal performance. In this study we compared the thermal tolerance and performance of two sympatric skink congeners in Hong Kong that differ in habitat use and reproductive mode. The viviparous Sphenomorphus indicus lives on the forest floor while the oviparous Sphenomorphus incognitus occupies stream edges. We quantified the thermal environments in each of these habitats to compare climatic exposure and then calculated thermal safety margins, potential daily activity times within each species' thermal optimal range, and possible climate change vulnerability. Although we did not detect any differences in thermal tolerance range or thermal environments across habitats, we found cooler performance in S. indicus relative to S. incognitus. Moreover, while optimal activity time increases for both skinks under a warming scenario, we project that the thermal safety margin of S. indicus would narrow to nearly zero, thus losing its buffering capacity to potential extreme climate events in the future. This research is thus consistent with recent studies emphasizing the vulnerability of viviparous reptiles to a warming climate. The results together furthermore highlight the complexity in how environmental and physiological traits at multiple spatial scales structure climate change vulnerability of ectothermic species., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Multiple control methods have been used in North America to manage the spread of rabies caused by the raccoon (Procyon lotor) rabies virus variant (RRVV). Recently, oral vaccination with ONRAB(®) vaccine baits, which contain an adenovirus rabies glycoprotein recombinant, has been made available as an additional tool for rabies control. Our objectives were to estimate rabies antibody prevalence in wild-caught raccoons and striped skunks (Mephitis mephitis), and identify factors influencing the probability of being antibody positive at the individual level in these species, following oral rabies vaccination (ORV) campaigns in which ONRAB was distributed aerially in 2007-2009 in southern Québec, Canada. Following the aerial distribution of 43-155 ONRAB baits/km(2), the annual percentages of antibody-positive raccoons and skunks varied between 35% and 56% and 11% and 17%, respectively. In raccoons, the probability of being antibody positive was positively associated with age and density of ONRAB distributed, and influenced by the number of previous ORV campaigns conducted. Conversely, this probability was negatively associated with estimated abundance of raccoons in the trapping cell and proportion of residential areas near the raccoon capture location. None of the variables examined explained variation in the probability of being antibody positive in skunks. Our results indicate that the ONRAB density applied during ORV campaigns should be adjusted to account for variations in raccoon population density and presence of residential areas to increase the likelihood of creating an effective immunological barrier against RRVV. The high percentage of juvenile raccoons (annual mean =45 ± 3 [SE]%) and skunks (66 ± 2%) captured during post-ORV monitoring suggests that ORV campaigns should be conducted at least annually to account for the recruitment of naïve individuals into the populations. In Québec, the increasing use of ONRAB coincided with the elimination of rabies caused by RRVV. Nonetheless, our results indicate that improvements to this vaccine bait and/or the distribution techniques are required to increase its efficacy, especially in striped skunks.

Despite the need for new antibiotics to treat drug-resistant bacteria, current clinical combinations are largely restricted to β-lactam antibiotics paired with β-lactamase inhibitors. We have adapted a Staphylococcus aureus antisense knockdown strategy to genetically identify the cell division Z ring components-FtsA, FtsZ, and FtsW-as β-lactam susceptibility determinants of methicillin-resistant S. aureus (MRSA). We demonstrate that the FtsZ-specific inhibitor PC190723 acts synergistically with β-lactam antibiotics in vitro and in vivo and that this combination is efficacious in a murine model of MRSA infection. Fluorescence microscopy localization studies reveal that synergy between these agents is likely to be elicited by the concomitant delocalization of their cognate drug targets (FtsZ and PBP2) in MRSA treated with PC190723. A 2.0 Å crystal structure of S. aureus FtsZ in complex with PC190723 identifies the compound binding site, which corresponds to the predominant location of mutations conferring resistance to PC190723 (PC190723(R)). Although structural studies suggested that these drug resistance mutations may be difficult to combat through chemical modification of PC190723, combining PC190723 with the β-lactam antibiotic imipenem markedly reduced the spontaneous frequency of PC190723(R) mutants. Multiple MRSA PC190723(R) FtsZ mutants also displayed attenuated virulence and restored susceptibility to β-lactam antibiotics in vitro and in a mouse model of imipenem efficacy. Collectively, these data support a target-based approach to rationally develop synergistic combination agents that mitigate drug resistance and effectively treat MRSA infections.

According to the 'pace-of-life' syndrome hypothesis, differences in resting metabolic rate (RMR) should be genetically associated with exploratory behaviour. A large number of studies reported significant heritability for both RMR and exploratory behaviour, but the genetic correlation between the two has yet to be documented. We used a quantitative genetic approach to decompose the phenotypic (co)variance of several metabolic and behavioural measures into components of additive genetic, common environment and permanent environment variance in captive deer mice. We found significant additive genetic variance for two mass-independent metabolic measures (RMR and the average metabolic rate throughout the respirometry run) and two behavioural measures (time spent in centre and distance moved in a novel environment). We also detected positive additive genetic correlation between mass-independent RMR and distance moved (r(A) = 0.78 ± 0.23). Our results suggest that RMR and exploratory behaviour are functionally integrated traits in deer mice, providing empirical support for one of the connections within the pace-of-life syndrome hypothesis., (© 2011 The Authors. Journal of Evolutionary Biology © 2011 European Society For Evolutionary Biology.)

A positive correlation between stearoyl-CoA desaturase (SCD)1 expression and metabolic diseases has been reported in rodents and humans. These findings indicate that SCD1 is a promising therapeutic target for the chronic treatment of diabetes and dyslipidemia. The SCD1 enzyme is expressed at high levels in several human tissues and is required for the biosynthesis of monounsaturated fatty acids, which are involved in many biological processes. Liver-targeted SCD inhibitors were designed to pharmacologically manipulate SCD1 activity in the liver to avoid adverse events due to systemic inhibition. This article describes the development of a plasma-based SCD assay to assess the level of SCD inhibition, which is defined in this article as target engagement. Essentially, animals are dosed with an exogenous deuterated tracer (d7-stearic acid) as substrate, and the converted d7-oleic acid product is measured to monitor SCD1 inhibition. This study reveals that this plasma-based assay correlates with liver SCD1 inhibition and can thus have clinical utility.

The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.

Aims: To reduce carbonated ferric green rust (GR*) using an iron respiring bacterium and obtain its reduced homologue, the mixed Fe(II)-Fe(III) carbonated green rust (GR)., Methods and Results: The GR* was chemically synthesized by oxidation of the GR and was incubated with Shewanella putrefaciens cells at a defined [Fe(III)]/[cell] ratio. Sodium methanoate served as the sole electron donor. The GR* was quickly transformed in GR (iron reducing rate = 8.7 mmol l(-1) h(-1))., Conclusions: Ferric green rust is available for S. putrefaciens respiration as an electron acceptor. The reversibility of the GR redox state can be driven by bacterial activity., Significance and Impact of the Study: This work suggests that GRs would act as an electronic balance in presence of bacteria. It provides also new perspectives for using iron reducing bacterial activity to regenerate the reactive form of GR during soil or water decontamination processes.

The acute and chronic toxicity of the nitrate ion (NO3-) to the embryos, alevins, and swim-up fry of lake trout (Salvelinus namaycush) and lake whitefish (Coregonus clupeaformis) were tested in laboratory aquaria. The acute (96-h) median lethal concentration (LC50) for swim-up fry was 1,121 mg NO3-N/L for lake trout and 1,903 mg NO3-N/L for lake whitefish. The chronic (approximately 130-150-d) LC50s for embryos to swim-up fry were 190 and 64 mg NO3-N/L, respectively. Sublethal effects on developmental timing and fry body size were observed at concentrations of 6.25 and 25 mg NO3-N/L, respectively, in the chronic tests. These results confirm that the Canadian nitrate water-quality guideline of 2.9 mg NO3-N/L, which was derived from chronic tests on a temperate-zone amphibian, is applicable to the early life stages of two species of Arctic fish. However, it does not support use of the guideline for acute exposures during early life stages of salmonid fish or for acute or chronic exposures to adult fish, which are relatively insensitive to nitrate.

In several species, the ability to locate a disappearing object is an adaptive component of predatory and social behaviour. In domestic dogs, spatial memory for hidden objects is primarily based on an egocentric frame of reference. We investigated the geometric components of egocentric spatial information used by domestic dogs to locate an object they saw move and disappear. In experiment 1, the distance and the direction between the position of the animal and the hiding location were put in conflict. Results showed that the dogs primarily used the directional information between their own spatial coordinates and the target position. In experiment 2, the accuracy of the dogs in finding a hidden object by using directional information was estimated by manipulating the angular deviation between adjacent hiding locations and the position of the animal. Four angular deviations were tested: 5, 7.5, 10 and 15 degrees . Results showed that the performance of the dogs decreased as a function of the angular deviations but it clearly remained well above chance, revealing that the representation of the dogs for direction is precise. In the discussion, we examine how and why domestic dogs determine the direction in which they saw an object disappear.

Two experiments explored the duration of dogs' working memory in an object permanence task: a delay was introduced between the disappearance of a moving object behind a box and the beginning of the search by the animal. In experiment 1, the dogs were tested with retention intervals of 0, 10, 30, and 60 s. Results revealed that the dogs' accuracy declined as a function of the length of the retention interval but remained above chance for each retention interval. In experiment 2, with new subjects, longer retention intervals (0, 30, 60, 120, and 240 s) were presented to the dogs. Results replicated findings from experiment 1 and revealed that the dogs' accuracy remained higher than chance level with delays up to 240 s. In both experiments, the analysis of errors also showed that the dogs searched as a function of the proximity of the target box and were not subject to intertrial proactive interference. In the discussion, we explore different alternatives to explain why dogs' search behaviour for hidden objects decreased as a function of the retention intervals.

Background: Mechanisms triggering prostatic NE differentiation are poorly understood. Since dog and man naturally develop prostatic proliferative diseases with age, our objectives were to confirm the presence of NE cells in the dog prostate and test their hormonal regulation in both species., Methods: Serotonin staining was examined by immunohistochemistry in 37 dog prostates: 17 from intact and 20 from castrated animals. In intact dogs, 9 prostates were normal and 8 hyperplastic. In the castrated group, 6 dogs were left untreated while androgens and estrogens were administered to 7 dogs, each. Human prostates were from 48 prostate cancer patients; half of them were submitted to androgen ablation prior to prostatectomy. The density of serotonin-positive NE cells was expressed relatively to the number of acini., Results: Serotonin-positive NE cells were morphologically similar in dog and human prostates and identified in all groups, independent of the hormonal status. NE cell densities were within the same range in normal and hyperplastic dog prostates but significantly higher after castration. Androgens and estrogens after castration restored NE cell density to normal values and induced luminal differentiation and basal metaplasia, respectively. In human, the density of serotonin-positive NE cells was also significantly higher in benign glands after androgen ablation., Conclusions: The dog is a suitable animal model and mimics the human, since androgen ablation favored prostatic NE differentiation in both species. The down-regulation elicited by steroids suggests that the process may be reversible and hormonally-repressed., (Copyright 2002 Wiley-Liss, Inc.)

The plasma membrane (PM) is an organized biological system that serves as a structural barrier and communication interface with the extracellular environment. Many basic questions regarding the PM as a system remain unanswered. In particular, we do not understand the scope of similarity and differences in protein expression at the PM. This study takes an initial step toward addressing these questions by comparing the PM proteomes of fibroblasts and mammary carcinoma cells. Three sets of proteins were revealed by the study. The first set comprises between 9 and 23% of all proteins at the PM and appears to be common to both fibroblasts and mammary carcinoma. A second group of proteins, comprising approximately 40% of the proteins at the PM, is tightly linked to cell lineage. The third set of proteins is unique to each cell line and is independent of cell lineage. It is reasonable to hypothesize then, that this third group of proteins is responsible for unique aspects of cell behavior. In an effort to find proteins linked to the metastatic phenotype, we identified several proteins that are uniquely expressed at the PM of the metastatic MDA-MB-435 cells. These proteins have functions ranging from cell adhesion to the regulation of translation and the control of oxidant stress.

Previous research on food choice of pigeons foraging alone and in competition showed an indirect response to the competitor, mediated by the resource depletion associated with the competitor. This experiment showed, in addition, that pigeons can adjust their food choice in direct response to the competitor itself. Pigeons foraged for large, preferred grains of maize and smaller, unpreferred grains of wheat presented in bowls covered with sawdust. In a within-subject design, pigeons were tested alone or in competition with another pigeon. In competition, a higher choice proportion of the wheat grains was observed on the first two choices out of 48 items, and this effect increased with time in the experiment. This result underscores the role of learning in group foraging behaviour. It also suggests a possible ecological implication: that individuals that learn faster may enjoy a competitive advantage in terms of reduced delay in responding to the presence of a conspecific.