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Simple Summary: This study aimed to evaluate heavy metal deposits in the feathers, livers, and kidneys of 37 wild bird species in Thailand. Interspecies differences in metal residues were noticed in the livers and kidneys but not in the feathers. The species-specific circumstances of the granivorous birds, especially the feeding behavior, and/or the ingestion of metal-contaminated seeds may result in a higher accumulation of Cd in their livers and kidneys compared to those in water birds. The Pb concentration in the livers (>15 ppm) and feathers (>4 ppm) exceeded the thresholds, causing potential lead poisoning and affecting the reproductive success in all the groups of birds. The Cd level in the kidneys was above 2–8 ppm, indicating increased environmental exposure to Cd in these wild birds. The correlations showed the suitability of the liver or kidney as an alternative sample for each other in studying the accumulation of Cd, Pb, Ni, Zn, and Fe, while Pb in the liver could be estimated using feathers. Birds are useful as bioindicators of metal pollution, but the variety of species and tissue distribution may influence the study of heavy metal burdens in birds. The objective of this study was to determine the levels of heavy metals in wild birds' carcasses to acquire information on species differences and the tissue distribution of metals in wild birds in Thailand. Species differences in metal buildup were observed in the livers and kidneys, but not in the feathers. A significantly higher accumulation of Cd was found in the livers and kidneys of the granivorous birds compared to those in the water birds. In all the groups of birds, the Pb level in the livers (>15 ppm) and feathers (>4 ppm) exceeded the threshold limits, causing potential lead poisoning and disturbing the reproductive success. The Cd accumulation in the kidneys was above 2–8 ppm, indicating increased environmental exposure to Cd in these birds. The Cd, Pb, Ni, Zn, and Fe concentrations in the livers could be estimated using the kidneys, while the Pb level in the liver may be predicted using feathers. Furthermore, water birds' feathers may be potentially appropriate bioindicators for long-term exposure. Research on the origin of metal contamination is needed to reduce the threat of heavy metals to the health of both birds and other wildlife species. [ABSTRACT FROM AUTHOR]

Regenerating the injured spinal cord is a substantial challenge with many obstacles that need to be overcome to achieve robust functional benefits. This abundance of hurdles can partly explain the limited success when applying regenerative intervention treatments in animal models and/or people. In this article, we elaborate on a few of these obstacles, starting with the applicability of animal models and how they compare to the clinical setting. We then discuss the requirement for combinatorial interventions and the associated problems in experimental design, including the addition of rehabilitative training. The article expands on differences in lesion sizes and locations between humans and common animal models, and how this difference can determine the success or failure of an intervention. An additional and frequently overlooked problem in the translation of interventions that applies beyond the field of neuroregeneration is the reporting bias and the lack of transparency in reporting findings. New data mandates are tackling this problem and will eventually result in a more balanced view of the field. Finally, we will discuss strategies to negotiate the challenging course of successful translation to facilitate successful translation of regeneration promoting interventions. [ABSTRACT FROM AUTHOR]

Alcohol intake leading to blood ethanol concentrations (BEC) ≥ legal intoxication modifies brain blood flow with increases in some regions and decreases in others. Brain regions receive blood from the Willis' circle branches: anterior, middle (MCA) and posterior cerebral (PCA), and basilar (BA) arteries. Rats and mice have been used to identify the targets mediating ethanol-induced effects on cerebral arteries, with conclusions being freely interchanged, albeit data were obtained in different species/arterial branches. We tested whether ethanol action on cerebral arteries differed between male rat and mouse and/or across different brain regions and identified the targets of alcohol action. In both species and all Willis' circle branches, ethanol evoked reversible and concentrationdependent constriction (EC50s ≈ 37-86 mM; below lethal BEC in alcohol-naïve humans). Although showing similar constriction to depolarization, both species displayed differential responses to ethanol: in mice, MCA constriction was highly sensitive to the presence/absence of the endothelium, whereas in rat PCA was significantly more sensitive to ethanol than its mouse counterpart. In the rat, but not the mouse, BA was more ethanol sensitive than other branches. Both interspecies and regional variability were ameliorated by endothelium. Selective large conductance (BK) channel block in de-endothelialized vessels demonstrated that these channels were the effectors of alcohol-induced cerebral artery constriction across regions and species. Variabilities in alcohol actions did not fully matched KCNMB1 expression across vessels. However, immunofluorescence data from KCNMB1-/- mouse arteries electroporated with KCNMB1-coding cDNA demonstrate that KCNMB1 proteins, which regulate smooth muscle (SM) BK channel function and vasodilation, regulate interspecies and regional variability of brain artery responses to alcohol. [ABSTRACT FROM AUTHOR]

Birds are useful as bioindicators of metal pollution, but the variety of species and tissue distribution may influence the study of heavy metal burdens in birds. The objective of this study was to determine the levels of heavy metals in wild birds’ carcasses to acquire information on species differences and the tissue distribution of metals in wild birds in Thailand. Species differences in metal buildup were observed in the livers and kidneys, but not in the feathers. A significantly higher accumulation of Cd was found in the livers and kidneys of the granivorous birds compared to those in the water birds. In all the groups of birds, the Pb level in the livers (>15 ppm) and feathers (>4 ppm) exceeded the threshold limits, causing potential lead poisoning and disturbing the reproductive success. The Cd accumulation in the kidneys was above 2–8 ppm, indicating increased environmental exposure to Cd in these birds. The Cd, Pb, Ni, Zn, and Fe concentrations in the livers could be estimated using the kidneys, while the Pb level in the liver may be predicted using feathers. Furthermore, water birds’ feathers may be potentially appropriate bioindicators for long-term exposure. Research on the origin of metal contamination is needed to reduce the threat of heavy metals to the health of both birds and other wildlife species.

Brain organoids have the potential to improve clinical translation, with the added benefit of reducing any extraneous use of experimental animals. As brain organoids are three‐dimensional in vitro constructs that emulate the human brain, they bridge in vitro and in vivo studies more appropriately than monocultures. Although many factors contribute to the failure of extrapolating monoculture‐based information to animal‐based experiments and clinical trials, for the purpose of this review, we will focus on glia (non‐neuronal brain cells), whose functions and transcriptome are particularly abnormal in monocultures. As discussed herein, glia require signals from—and contact with—other cell types to exist in their homeostatic state, which likely contributes to some of the differences between data derived from monocultures and data derived from brain organoids and even two‐dimensional co‐cultures. Furthermore, we highlight transcriptomic differences between humans and mice in regard to aging and Alzheimer's disease, emphasizing need for a model using the human genome—again, a benefit of brain organoids—to complement data derived from animals. We also identify an urgency for guidelines to improve the reporting and transparency of research using organoids. The lack of reporting standards creates challenges for the comparison and discussion of data from different articles. Importantly, brain organoids mark the first human model enabling the study of brain cytoarchitecture and development. [ABSTRACT FROM AUTHOR]

300 million people live with at least one of 6,000 rare diseases worldwide. However, rare disease research is not always reviewed with scrutiny, making it susceptible to what the author refers to as nontransparent science. Nontransparent science can obscure animal model flaws, misguide medicine regulators and drug developers, delay or frustrate orphan drug development, or waste limited resources for rare disease research. Flawed animal models not only lack pharmacologic relevance, but also give rise to issue of clinical translatability. Sadly, these consequences and risks are grossly overlooked. Nontransparency in science can take many forms, such as premature publication of animal models without clinically significant data, not providing corrections when flaws to the model are discovered, lack of warning of critical study limitations, missing critical control data, questionable data quality, surprising results without a sound explanation, failure to rule out potential factors which may affect study conclusions, lack of sufficient detail for others to replicate the study, dubious authorship and study accountability. Science has no boarders, neither does nontransparent science. Nontransparent science can happen irrespective of the researcher's senority, institutional affiliation or country. As a patient-turned researcher suffering from Bietti crystalline dystrophy (BCD), I use BCD as an example to analyze various forms of nontransparent science in rare disease research. This article analyzes three papers published by different research groups on Cyp4v3−/−, high-fat diet (HFD)-Cyp4v3−/−, and Exon1-Cyp4v3−/− mouse models of BCD. As the discussion probes various forms of nontransparent science, the flaws of these knockout mouse models are uncovered. These mouse models do not mimic BCD in humans nor do they address the lack of Cyp4v3 (murine ortholog of human CYP4V2) expression in wild type (WT) mouse retina which is markedly different from CYP4V2 expression in human retina. Further, this article discusses the impact of nontransparent science on drug development which can lead to significant delays ultimately affecting the patients. Lessons from BCD research can be helpful to all those suffering from rare diseases. As a patient, I call for transparent science in rare disease research. [ABSTRACT FROM AUTHOR]

The hippocampus is one of the few privileged regions (neural stem cell niche) of the brain, where neural stem cells differentiate into new neurons throughout adulthood. However, dysregulation of hippocampal neurogenesis with aging, injury, depression and neurodegenerative disease leads to debilitating cognitive impacts. These debilitating symptoms deteriorate the quality of life in the afflicted individuals. Impaired hippocampal neurogenesis is especially difficult to rescue with increasing age and neurodegeneration. However, the potential to boost endogenous Wnt signaling by influencing pathway modulators such as receptors, agonists, and antagonists through drug and cell therapy-based interventions offers hope. Restoration and augmentation of hampered Wnt signaling to facilitate increased hippocampal neurogenesis would serve as an endogenous repair mechanism and contribute to hippocampal structural and functional plasticity. This review focuses on the possible interaction between neurogenesis and Wnt signaling under the control of antidepressants and mesenchymal stem cells (MSCs) to overcome debilitating symptoms caused by age, diseases, or environmental factors such as stress. It will also address some current limitations hindering the direct extrapolation of research from animal models to human application, and the technical challenges associated with the MSCs and their cellular products as potential therapeutic solutions. [ABSTRACT FROM AUTHOR]

Deoxynivalenol (DON) and its modified forms, including DON-3-glucoside (DON-3G), pose a major agricultural and food safety issue in the world. Their metabolites are relatively well-characterized; however, their metabolizing enzymes have not been fully explored. UDP-glucuronosyltransferases, 3-O-acetyltransferase, and glutathione S-transferase are involved in the formation of DON-glucuronides, 3-acetyl-DON, and DON-glutathione, respectively. There are interindividual differences in the metabolism of these toxins, including variation with respect to sex. Furthermore, interspecies differences in DON metabolism have been revealed, including differences in the major metabolites of DON, the role of de-acetylation, and the hydrolysis of DON-3G. In this review, we summarized the major enzymes involved in metabolizing DON to its modified forms, focusing on the differences in metabolism of DON and its modified forms between individuals and species. This work provides important insight into the toxicity of DON and its derivatives in humans and animals, and provides scientific basis for the development of safer and more efficient biological detoxification methods. [ABSTRACT FROM AUTHOR]

Background/Introduction: Plasma protein binding (PPB) continues to be a key aspect of antibiotic development and clinical use. PPB is essential to understand several properties of drug candidates, including antimicrobial activity, drug-drug interaction, drug clearance, volume of distribution, and therapeutic index. Focus areas of the review: In this review, we discuss the basics of PPB, including the main drug binding proteins i.e., Albumin and α-1-acid glycoprotein (AAG). Furthermore, we present the effects of PPB on the antimicrobial activity of antibiotics and the current role of PPB in in vitro pharmacodynamic (PD) models of antibiotics. Moreover, the effect of PPB on the PK/PD of antibiotics has been discussed in this review. A key aspect of this paper is a concise evaluation of PPB between animal species (dog, rat, mouse, rabbit and monkey) and humans. Our statistical analysis of the data available in the literature suggests a significant difference between antibiotic binding in humans and that of dogs or mice, with the majority of measurements from the pre-clinical species falling within five-fold of the human plasma value. Conversely, no significant difference in binding was found between humans and rats, rabbits, or monkeys. This information may be helpful for drug researchers to select the most relevant animal species in which the metabolism of a compound can be studied for extrapolating the results to humans. Furthermore, state-of-the-art methods for determining PPB such as equilibrium dialysis, ultracentrifugation, microdialysis, gel filtration, chromatographic methods and fluorescence spectroscopy are highlighted with their advantages and disadvantages. [ABSTRACT FROM AUTHOR]

Paragonimus proliferus (P. proliferus), one of 46 Paragonimus species registered in the National Center for Biotechnology Information database, may be much more widely distributed in Southeast Asia than previously thought, as its reported natural foci have increased in the past decades. However, very little is known about its molecular biology, especially at the transcriptome level. For the first time, the transcriptome of this species was sequenced and compared with four other common Paragonimus species, namely Paragonimus skrjabini, Paragonimus kellicotti, Paragonimus miyazakii, and Paragonimus westermani, to predict homologous genes and differentially expressed homologous genes to explore interspecies differences of Paragonimus proliferus.

Zearalenone (ZEN) is a mycotoxin known for its estrogenic activities. The metabolism of ZEN plays a role in the interspecies differences in sensitivity to ZEN, and is known to occur in the liver and via the intestinal microbiota, although the relative contribution of these two pathways remains to be characterized. In the present study a fecal in vitro model was optimized and used to quantify the interspecies differences in kinetics of the intestinal microbial metabolism of ZEN in rat, pig and human. Vmax, Km, and catalytic efficiencies (kcat) were determined, and results obtained reveal that the kcat values for formation of α-ZEL and β-ZEL amounted to 0.73 and 0.12 mL/h/kg bw for human microbiota, 2.6 and 1.3 mL/h/kg bw for rat microbiota and 9.4 and 6.3 mL/h/kg bw for pig microbiota showing that overall ZEN metabolism increased in the order human

Introduction. The purposes of this study were to determine the presence of daily variations in hematological parameters of the black rat snake (Pantherophis obsoletus) and to compare them with the reference interval values of its subspecies, yellow rat snake (Pantherophis obsoleta quadrivittata). Materials and Methods. Blood from four black rat snakes was collected in the morning and in the evening, and after each collection, blood smears, packed cell volume (PCV), red blood cell count (RBC) and hemoglobin concentration (HGB) were determined, while erythrocyte indices of mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) were calculated and differential leukocyte counts were evaluated. Results and Conclusions. There were no statistically significant differences in any of the blood parameters in the morning and in the evening. Most of the complete blood count values in the black rat snakes were lower, but still within the reference range of those found in the literature for the yellow rat snake. The results of hematological parameters of the black rat snake could be beneficial for further research of physiological and pathological variations in complete blood count of these snakes, for diagnosing health conditions and for detecting various diseases.

The A3 adenosine receptor (AR) is emerging as an attractive drug target. Antagonists are proposed for the potential treatment of glaucoma and asthma. However, currently available A3AR antagonists are potent in human and some large animals, but weak or inactive in mouse and rat. In this study, we re-synthesized a previously reported A3AR antagonist, DPTN, and evaluated its affinity and selectivity at human, mouse, and rat ARs. We showed that DPTN, indeed, is a potent A3AR antagonist for all three species tested, albeit a little less selective for mouse and rat A3AR in comparison to the human A3AR. DPTN's Ki values at respective A1, A2A, A2B, and A3 receptors were (nM) 162, 121, 230, and 1.65 (human); 411, 830, 189, and 9.61 (mouse); and 333, 1147, 163, and 8.53 (rat). Its antagonist activity at both human and mouse A3ARs was confirmed in a cyclic AMP functional assay. Considering controversial use of currently commercially available A3AR antagonists in rats and mice, we also re-examined other commonly used and selective A3AR antagonists under the same experimental conditions. The Ki values of MRS1523 were shown to be 43.9, 349, and 216 nM at human, mouse, and rat A3ARs, respectively. MRS1191 and MRS1334 showed incomplete inhibition of [125I]I-AB-MECA binding to mouse and rat A3ARs, while potent human A3AR antagonists, MRS1220, MRE3008F20, PSB10, PSB-11, and VUF5574 were largely inactive. Thus, we demonstrated that DPTN and MRS1523 are among the only validated A3AR antagonists that can be possibly used (at an appropriate concentration) in mouse or rat to confirm an A3AR-related mechanism or function. [ABSTRACT FROM AUTHOR]

BACKGROUND: The effects of temperature on micro-rheological variables have not been completely revealed yet. OBJECTIVE: To investigate micro-rheological effects of heat treatment in human, rat, dog, and porcine blood samples. METHODS: Red blood cell (RBC) - buffer suspensions were prepared and immersed in a 37, 40, and 43°C heat-controlled water bath for 10 minutes. Deformability, as well as mechanical stability of RBCs were measured in ektacytometer. These tests were also examined in whole blood samples at various temperatures, gradually between 37 and 45°C in the ektacytometer. RESULTS: RBC deformability significantly worsened in the samples treated at 40 and 43°C, more expressed in human, porcine, rat, and in smaller degree in canine samples. The way of heating (incubation vs. ektacytometer temperation) and the composition of the sample (RBC-PBS suspension or whole blood) resulted in the different magnitude of RBC deformability deterioration. Heating affected RBC membrane (mechanical) stability, showing controversial alterations. CONCLUSION: Significant changes occur in RBC deformability by increasing temperature, showing inter-species differences. The magnitude of alterations is depending on the way of heating and the composition of the sample. The results may contribute to better understanding the micro-rheological deterioration in hyperthermia or fever. [ABSTRACT FROM AUTHOR]

Background/Introduction: Plasma protein binding (PPB) continues to be a key aspect of antibiotic development and clinical use. PPB is essential to understand several properties of drug candidates, including antimicrobial activity, drug-drug interaction, drug clearance, volume of distribution, and therapeutic index. Focus areas of the review: In this review, we discuss the basics of PPB, including the main drug binding proteins i.e., Albumin and α-1-acid glycoprotein (AAG). Furthermore, we present the effects of PPB on the antimicrobial activity of antibiotics and the current role of PPB in in vitro pharmacodynamic (PD) models of antibiotics. Moreover, the effect of PPB on the PK/PD of antibiotics has been discussed in this review. A key aspect of this paper is a concise evaluation of PPB between animal species (dog, rat, mouse, rabbit and monkey) and humans. Our statistical analysis of the data available in the literature suggests a significant difference between antibiotic binding in humans and that of dogs or mice, with the majority of measurements from the pre-clinical species falling within five-fold of the human plasma value. Conversely, no significant difference in binding was found between humans and rats, rabbits, or monkeys. This information may be helpful for drug researchers to select the most relevant animal species in which the metabolism of a compound can be studied for extrapolating the results to humans. Furthermore, state-of-the-art methods for determining PPB such as equilibrium dialysis, ultracentrifugation, microdialysis, gel filtration, chromatographic methods and fluorescence spectroscopy are highlighted with their advantages and disadvantages.

We have created entirely biological tissue-engineered vascular grafts (TEVGs) using sheets of cell-assembled extracellular matrix (CAM) produced by human fibroblasts in vitro. A large animal TEVG would allow long-term pre-clinical studies in a clinically relevant setting (graft size and allogeneic setting). Therefore, canine, porcine, ovine, and human skin fibroblasts were compared for their ability to form CAM sheets. Serum sourcing greatly influenced CAM production in a species-dependent manner. Ovine cells produced the most homogenous and strongest animal CAM sheets but remained ≈3-fold weaker than human sheets despite variations of serum, ascorbate, insulin, or growth factor supplementations. Key differences in cell growth dynamics, tissue development, and tissue architecture and composition were observed between human and ovine. This study demonstrates critical species-to-species differences in fibroblast behavior and how they pose a challenge when attempting to substitute animal cells for human cells during the development of tissue-engineered constructs that require long-term cultures. [ABSTRACT FROM AUTHOR]

For antimicrobial agents in particular, plasma protein binding (PPB) plays a pivotal role in deciphering key properties of drug candidates. Animal models are generally used in the preclinical development of new drugs to predict their effects in humans using translational pharmacokinetics/pharmacodynamics (PK/PD). Thus, we compared the protein binding (PB) of cefazolin as well as bacterial growth under various conditions in vitro . The PB extent of cefazolin was studied in human, bovine, and rat plasmas at different antibiotic concentrations in buffer and media containing 20-70% plasma or pure plasma using ultrafiltration (UF) and equilibrium dialysis (ED). Moreover, bacterial growth and time-kill assays were performed in Mueller Hinton Broth (MHB) containing various plasma percentages. The pattern for cefazolin binding to plasma proteins was found to be similar for both UF and ED. There was a significant decrease in cefazolin binding to bovine plasma compared to human plasma, whereas the pattern in rat plasma was more consistent with that in human plasma. Our growth curve analysis revealed considerable growth inhibition of Escherichia coli at 70% bovine or rat plasma compared with 70% human plasma or pure MHB. As expected, our experiments with cefazolin at low concentrations showed that E. coli grew slightly better in 20% human and rat plasma compared to MHB, most probably due to cefazolin binding to proteins in the plasma. Based on the example of cefazolin, our study highlights the interspecies differences of PB with potential impact on PK/PD. These findings should be considered before preclinical PK/PD data can be extrapolated to human patients., Competing Interests: The authors declare no conflict of interest.

Transient receptor potential vanilloid 1-4 (TRPV1-4) expression and functionality were investigated in brain microvessel endothelial cells (BMEC) forming the blood–brain barrier (BBB) from rat and human origins. In rat, Trpv1-4 were detected by qRT-PCR in the brain cortex, brain microvessels, and in primary cultures of brain microvessel endothelial cells [rat brain microvessel endothelial cells (rPBMEC)]. A similar Trpv1-4 expression profile in isolated brain microvessels and rPBMEC was found with the following order: Trpv4 > Trpv2 > Trpv3 > Trpv1. In human, TRPV1-4 were detected in the BBB cell line human cerebral microvessel endothelial cells D3 cells (hCMEC/D3) and in primary cultures of BMEC isolated from human adult and children brain resections [human brain microvascular endothelial cells (hPBMEC)], showing a similar TRPV1-4 expression profile in both hCMEC/D3 cells and hPBMECs as follow: TRPV2 > > TRPV4 > TRPV1 > TRPV3. Western blotting and immunofluorescence experiments confirmed that TRPV2 and TRPV4 are the most expressed TRPV isoforms in hCMEC/D3 cells with a clear staining at the plasma membrane. A fluorescent dye Fluo-4 AM ester was applied to record intracellular Ca2+ levels. TRPV4 functional activity was demonstrated in mediating Ca2+ influx under stimulation with the specific agonist GSK1016790A (ranging from 3 to 1000 nM, EC50 of 16.2 ± 4.5 nM), which was inhibited by the specific TRPV4 antagonist, RN1734 (30 μM). In contrast, TRPV1 was slightly activated in hCMEC/D3 cells as shown by the weak Ca2+ influx induced by capsaicin at a high concentration (3 μM), a highly potent and specific TRPV1 agonist. Heat-induced Ca2+ influx was not altered by co-treatment with a selective potent TRPV1 antagonist capsazepine (20 μM), in agreement with the low expression of TRPV1 as assessed by qRT-PCR. Our present study reveals an interspecies difference between Rat and Human. Functional contributions of TRPV1-4 subtype expression were not identical in rat and human tissues reflective of BBB integrity. TRPV2 was predominant in the human whereas TRPV4 had a larger role in the rat. This interspecies difference from a gene expression point of view should be taken into consideration when modulators of TRPV2 or TRPV4 are investigated in rat models of brain disorders.

Resume. The paper presents literature data about the interspecific differences of the pharmacokinetics of peptide drugs and the results of our own studies on the inter-specific features of the pharmacokinetics of the 3 modified analogues of endogenous neuropeptides (noopept, dilept and GB-115) in animals of 2 species (rat, rabbit) and human wich purpose of choosing the optimal extrapolation model for predicting the pharmacokinetics of new peptide drugs in humans by pharmacokinetic parameters. Interspecific differences in the pharmacokinetics of the absorption, metabolism and elimination of dipeptide preparations are established. For the dilept - methyl ester of N-caproyl-L-prolyl-L-tyrosine - dipeptide analogue of the natural neuroleptin neurotensine, using the allometric Dedric method, it was established that the pharmacokinetics in humans can be predicted from a close fit of the pharmacokinetic parameters obtained in animals. For anxiolytic GB-115, the linearity of pharmacokinetic parameters in volunteers is shown in the use of doses in the range 1-15 mg. It is shown that the half-life of the studied peptide compounds in experimental animals is a prognostically significant parameter for extrapolating their pharmacokinetics on humans. In view of the proximity of enzymatic systems in rats and humans, it is advisable to use this species of animals at the stage of studying the pharmacokinetics of the substance of new peptide compounds to obtain general information about their pharmacokinetics and the main metabolic pathways. At the stage of studying the dosage drugs forms of these compounds preference should be given to rabbits as an experimental model, due to the possibility of obtaining the entire pharmacokinetic profile in one animal and calculating individual pharmacokinetic parameters of new peptide drugs.

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Abstract Background α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor is a primary mediator of fast glutamatergic excitatory signaling in the brain and has been implicated in diverse neuropsychiatric diseases. We recently developed a novel positron emission tomography (PET) ligand, 2-(1-(3-([11C]methylamino)phenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([11C]HMS011). This compound is a radiolabelled derivative of perampanel, an antiepileptic drug acting on AMPA receptors, and was demonstrated to have promising in vivo properties in the rat and monkey brains. In the current study, we performed a human PET study using [11C]HMS011 to evaluate its safety and kinetics. Four healthy male subjects underwent a 120-min PET scan after injection of [11C]HMS011. Arterial blood sampling and metabolite analysis were performed to obtain parent input functions for three of the subjects using high-performance liquid chromatography. Regional distribution volumes (V Ts) were calculated based on kinetic models with and without considering radiometabolite in the brain. The binding was also quantified using a reference tissue model with white matter as reference. Results Brain uptake of [11C]HMS011 was observed quickly after the injection, followed by a rapid clearance. Three hydrophilic and one lipophilic radiometabolites appeared in the plasma, with notable individual variability. The kinetics in the brain with apparent radioactivity retention suggested that the lipophilic radiometabolite could enter the brain. A dual-input graphical model, an analytical model designed in consideration of a radiometabolite entering the brain, well described the kinetics of [11C]HMS011. A reference tissue model showed small radioligand binding potential (BP*ND) values in the cortical regions (BP*ND = 0–0.15). These data suggested specific binding component of [11C]HMS011 in the brain. Conclusions Kinetic analyses support some specific binding of [11C]HMS011 in the human cortex. However, this ligand may not be suitable for practical AMPA receptor PET imaging due to the small dynamic range and metabolite in the brain.

Results of pharmacokinetic study of a new dipeptide anxiolytic GB-115 in rats, rabbits and volunteers were presented. After oral drug administration significant differences were found. For example, a dose-independent parameter - the elimination rate constant was decreased: rat < human < rabbit. By contrast the half-life of GB-115 was increased: rat

In the present study we analyze the synthesis as well as biotransformation pathways and metabolic stability of 4-fluoro- N -(1-{2-[2-(methylsulfanyl)phenoxy]ethyl}pyrrolidin-3-yl) benzene sulfonamide – thioether compound 5, with the affinity for several subtypes of the serotonin and dopamine receptor. Studies were conducted in vitro on liver microsomes from three species – mouse, rat, and human. The biotransformation was analyzed using liquid chromatography coupled with mass spectrometry. Two major metabolites (M1 and M2) – products of S-oxidation of the parent molecule – were generated both by in silico and in vitro methods. Use of three species allowed us to determine the interspecies differences in metabolic stability of tested compound. Two parameters, t0.5 and Clint , were calculated. Compound 5 was the most stable in human liver microsomes. Results are useful for understanding the interspecies differences in metabolism of the serotonin and dopamine receptor ligand associated with sulfur atom. [ABSTRACT FROM AUTHOR]

Significant interspecies differences were established in activities of aminotransferases, alanine aminotransferase (ALT, EC 2.6.1.2) and aspartate aminotransferase (AST, EC 2.6.1.1), and alkaline phosphatase (ALP, EC 3.1.3.1) in the gonads of seven Black Sea fish species during spawning and non-spawning seasons. In most species, ALT and AST activities were higher in the non-spawning phase compared to the spawning one, while ALP activity demonstrated an opposite trend. The peak enzymatic activities were found in the gonads of the whiting, probably due to its spawning in the winter season. No significant differences were revealed between the test parameters in animals of different ecological groups. ALT, AST and ALP activities in fish gonads can be used as convenient and efficient markers to explore both the peculiarities of the gonadogenesis at different stages of the reproductive cycle and the ability of different fish species to adapt to unfavorable environments, including those caused by anthropogenic pollution. [ABSTRACT FROM AUTHOR]

Sodium (S)− 2-(dithiocarboxylato((2 S,3 R,4 R,5 R)− 2,3,4,5,6-pentahydroxyhexyl)amino)− 4(methylthio)butanoate (GMDTC) is a compound that removes cadmium from kidney cells. This study aims to investigate the metabolic stability and metabolite identification of GMDTC in various liver microsomes, including those from human, monkey, dog, rat and mouse. The results show that the T 1/2 values of GMDTC in human, monkey, dog, rat and mouse liver microsomes were 16.54, 18.14, 16.58, 15.16 and 16.00 min, respectively. While the hepatic extraction ratios (ER h) of GMDTC measured after 60 min incubation in these liver microsomes were 0.82, 0.70, 0.80, 0.75 and 0.79, respectively, indicating that GMDTC exhibits rapid hepatic metabolism and high hepatic clearance with no significant interspecies differences. Subsequent metabolite identification by high-resolution mass spectrometry revealed the presence of three metabolites, designated M1∼M3. The major metabolite products of GMDTC were found to be M1 and M2. The relative abundances of the hydrolysis products (M1 and M2) in human, monkey, dog, rat and mouse liver microsomes were found to be 97.18%, 97.99%, 95.94%, 96.31% and 93.43%, respectively, indicating that hydrolysis is the primary metabolic pathway of GMDTC in liver microsomes in vitro, and with no significant interspecies differences. • The metabolic stability and metabolite identification of GMDTC in various liver microsomes have been investigated. • GMDTC exhibits rapid hepatic metabolism and high hepatic clearance with no significant interspecies differences. • The hydrolysis is the primary metabolic pathway of GMDTC in liver microsomes with no significant interspecies differences. [ABSTRACT FROM AUTHOR]

In this paper, I propose a new evenness-based method for calculating plot-to-plot (dis)similarity coefficients. The method is very flexible, as (dis)similarity can be calculated for any kind of species abundance data (also including functional or phylogenetic differences between species), and can be easily generalized to multiple sites. To show how the proposed method works in practice, the behavior of two similarity coefficients based on Pielou's and Williams’ evenness is examined with simulated data representing an ideal ecological gradient. Being derived from classical evenness indices, which have been used in ecology for decades, this new family of measures has a great potential for future research in community ecology and multivariate analysis. [ABSTRACT FROM AUTHOR]

This study investigated the metabolic transformation of carbofuran in seven species of mammals using LC-MS/MS and liver microsomes. The results revealed species-specific differences in metabolite formation, indicating the potential role of metabolic pathways in toxicity and risk assessment. The majority of carbofuran was metabolized through the 3-hydroxycarbofuran pathway, with the highest levels observed in dogLM and the lowest in humanLM. Further analysis was conducted to investigate the human cytochrome P450-mediated metabolism of carbofuran, with CYP3A4 being found to be the most efficient enzyme with the highest contribution to the 3-hydroxycarbofuran pathway. Inhibition of CYP3A4 with ketoconazole resulted in a substantial decrease in carbofuran metabolism. In addition, carbofuran exhibited inhibitory effects on human CYP3A4 and CYP2B6, demonstrating the potential for carbofuran to interact with these enzymes. The findings highlight the importance of in vitro screening for metabolic processes and provide insights into the biotransformation of carbofuran. • LC-MS/MS used to compare carbofuran metabolism in 7 mammalian species. • Metabolite formation and metabolic pathways differed by species. • CYP3A4 most efficient human CYP enzyme in carbofuran metabolism. • Carbofuran inhibits human hepatic P450 enzymes (CYP3A4 and CYP2B6). • In vitro screening crucial for metabolic process-based risk assessment. [ABSTRACT FROM AUTHOR]

Background: α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor is a primary mediator of fast glutamatergic excitatory signaling in the brain and has been implicated in diverse neuropsychiatric diseases. We recently developed a novel positron emission tomography (PET) ligand, 2-(1-(3-([C]methylamino)phenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([C]HMS011). This compound is a radiolabelled derivative of perampanel, an antiepileptic drug acting on AMPA receptors, and was demonstrated to have promising in vivo properties in the rat and monkey brains. In the current study, we performed a human PET study using [C]HMS011 to evaluate its safety and kinetics. Four healthy male subjects underwent a 120-min PET scan after injection of [C]HMS011. Arterial blood sampling and metabolite analysis were performed to obtain parent input functions for three of the subjects using high-performance liquid chromatography. Regional distribution volumes ( V s) were calculated based on kinetic models with and without considering radiometabolite in the brain. The binding was also quantified using a reference tissue model with white matter as reference. Results: Brain uptake of [C]HMS011 was observed quickly after the injection, followed by a rapid clearance. Three hydrophilic and one lipophilic radiometabolites appeared in the plasma, with notable individual variability. The kinetics in the brain with apparent radioactivity retention suggested that the lipophilic radiometabolite could enter the brain. A dual-input graphical model, an analytical model designed in consideration of a radiometabolite entering the brain, well described the kinetics of [C]HMS011. A reference tissue model showed small radioligand binding potential ( BP*) values in the cortical regions ( BP* = 0-0.15). These data suggested specific binding component of [C]HMS011 in the brain. Conclusions: Kinetic analyses support some specific binding of [C]HMS011 in the human cortex. However, this ligand may not be suitable for practical AMPA receptor PET imaging due to the small dynamic range and metabolite in the brain. [ABSTRACT FROM AUTHOR]

Using the example of three morphologically similar species of the Far Eastern redfins of the genus Tribolodon, it has been shown that an analysis of scale structure allows species identification of not only adults, when they are not in their characteristic spawning dress, but also immature individuals. The most distinct interspecies differences of redfins have been found in the case of the combined use of three basic parameters of scales: lesser diameter, greater diameter, and number of radii. The differences between redfins in the shape and structure of their scales can be explained by the features of ecology of these species, e.g. the velocity of water flow in the breeding grounds and during overwintering in rivers. [ABSTRACT FROM AUTHOR]

Aim In spite of screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of proarrhythmic activity using a comprehensive in vitro proarrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. In the present study, we evaluated the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans. Methods Using estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of nine compounds with varying QT-prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymized NCEs) were analysed. Mean slope estimates varied between −0.98 ms μM-1 and 6.1 ms μM-1 in dogs and −10 ms μM-1 and 90 ms μM-1 in humans, indicating a wide range of effects on the QT interval. Linear regression techniques were then applied to characterize the correlation between the parameter estimates across species. Results For compounds without a mixed ion channel block, a correlation was observed between the drug-specific parameter in dogs and humans (y = −1.709 + 11.6x; R2 = 0.989) . These results show that per unit concentration, the drug effect on the QT interval in humans is 11.6-fold larger than in dogs. Conclusions Together with information about the expected therapeutic exposure, the evidence of a correlation between the compound-specific parameter in dogs and in humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalizability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans. [ABSTRACT FROM AUTHOR]

The trophic transfer of two essential metals (Co and Zn) was investigated in two tropical euryhaline fish species ( Monodactylus argenteus and Scatophagus argus ), at both the adult and juvenile stages, using the pulse-chase feeding method and radiotracers ( 57 Co and 65 Zn). The food selected was brine shrimp ( Artemia salina ) previously exposed to dissolved radiotracers. Depuration kinetics of both elements were followed for 45 d. During this period, 57 Co and 65 Zn distribution was also determined at different time intervals among 15 different body compartments. Results showed that, in juveniles, the ingested Co was poorly assimilated by both species (AE < 6%), whereas S. argus assimilated 65 Zn more efficiently than M. argenteus (AE = 24% vs. 15%). In terms of body distribution of these essential elements, the trends were similar between adults and juveniles of both species: Co was concentrated and mainly distributed in the liver in S. argus , highlighting the role of this organ in the storage of Co. Conversely, in both species, ingested Zn was more diffusely distributed throughout the body. The differences observed between species could be related to a difference in the digestive enzymatic system in each studied species, which in turn is related to their slightly different feeding habits in the natural environment. [ABSTRACT FROM AUTHOR]

We describe pronounced differences in gestation length and the onset of feto-placental progestagen production in three rhinoceros species. Daylight length at birth significantly influenced gestation length. A concentration of 1000 ng/g faeces was set as the threshold for the onset of feto-placental progestagen production. (Dots in graphs refers to individual gestations) [Display omitted] • Pronounced individual differences in the onset of feto-placental progestagen production. • Pronounced individual differences in gestation length. • Mean gestation length in the black, white and GOH rhinoceros is 460, 504 and 480 days. • Daylight length at birth significantly affected gestation length. • Gestation is about one week shorter when the birth occurs in summer as opposed to winter. This comparative analysis evaluated endocrine profiles and gestation length data of captive pregnant black rhinoceros (Diceros bicornis) , white rhinoceros (Ceratotherium simum), and greater one-horned (GOH) rhinoceros (Rhinoceros unicornis). Hormone profiles were collected over three decades as part of pregnancy diagnoses. After the third month of gestation, the luteo-placental shift in progesterone production in pregnant rhinoceroses causes a significant increase in the concentration of faecal progesterone metabolites. We defined a laboratory-specific value of 1000 ng/g faeces as a threshold for incipient feto-placental progesterone production. Using this value allowed a comparison between species and revealed significant individual differences within a species. The mean ± SEM gestation days for reaching the 1000 ng/g faeces threshold were 89.5 ± 2.9 (range 56–138 days; n = 39) in black, 96.0 ± 2.6 (58–138; n = 39) in white, and 117.8 ± 5.3 (74–173; n = 19) in GOH rhinoceroses. For the calculations of gestation length, we complemented our results from three decades of reproductive monitoring with data from the literature, resulting in about 70 values for each species. Gestation length in the black, the white and the GOH rhinoceros was 460.6 ± 1.5 (range: 436 – 486), 503.8 ± 1.3 (range: 480 – 525) and 480.5 ± 1.1 (range: 453 – 505) days, respectively. Daylight length significantly affected gestation length, while the sex of offspring had no effect. On average, pregnancies with parturitions in spring and summer were one week shorter than those in autumn and winter. Although rhinoceroses are non-seasonal breeders, most parturitions in captivity occur in autumn and winter. We also analysed preconception endocrine profiles in the white rhinoceros. Conceptions in this species occurred after oestrous cycles of approximately 35 days (n = 18), 70 days (n = 3), 15 days (n = 1), after periods of ovarian inactivity (n = 5), and during a foal heat within one month after stillbirth parturition (n = 1). In conclusion, this study provides a comprehensive overview of gestational parameters in three rhinoceros species. [ABSTRACT FROM AUTHOR]

The quantification of stems (under- and overbark), foliage and fine roots in 14-year-old stands of European beech and Norway spruce grown on the same site were evaluated. Therefore, 60 trees of each species were sampled, dry masses of stems and foliage were established and expressed by allometric equations with stem diameter as an independent variable. The spruce allocated a much larger portion of biomass into the foliage than beech. The equations on a tree level were constructed also for specific leaf area and one-sided projected leaf area. Moreover, the quantity and morphological characteristics of fine roots in both stands were surveyed through soil coring. While standing stocks of fine roots were similar in the stands of both tree species, significant interspecies differences occurred in morphological properties of roots. Growth efficiency, expressing annual stem production on a variety of foliage and fine root parameters was calculated. The largest differences, specifically fivefold in favour of spruce, were found in growth efficiency based on a number of root tips.

Background and Purpose: The selection of the most suitable animal species and subsequent translation of the concentration-effect relationship to humans are critical steps for accurate assessment of the pro-arrhythmic risk of candidate molecules. The objective of this investigation was to assess quantitatively the differences in the QTc prolonging effects of moxifloxacin between cynomolgus monkeys, dogs and humans. The impact of interspecies differences is also illustrated for a new candidate molecule. Experimental Approach: Pharmacokinetic data and ECG recordings from pre-clinical protocols in monkeys and dogs and from a phase I trial in healthy subjects were identified for the purpose of this analysis. A previously established Bayesian model describing the combined effect of heart rate, circadian variation and drug effect on the QT interval was used to describe the pharmacokinetic-pharmacodynamic relationships. The probability of a ≥10 ms increase in QT was derived as measure of the pro-arrhythmic effect. Key Results: For moxifloxacin, the concentrations associated with a 50% probability of QT prolongation ≥10 ms (Cp) varied from 20.3 to 6.4 and 2.6 μM in dogs, monkeys and humans, respectively. For NCE05, these values were 0.4 μM vs 2.0 μM for monkeys and humans, respectively. Conclusions and Implications: Our findings reveal significant interspecies differences in the QT-prolonging effect of moxifloxacin. In addition to the dissimilarity in pharmacokinetics across species, it is likely that differences in pharmacodynamics also play an important role. It appears that, regardless of the animal model used, a translation function is needed to predict concentration-effect relationships in humans. [ABSTRACT FROM AUTHOR]

In this study, the contamination levels and seasonal variation of 22 PFASs were investigated in coastal reef-building corals (n = 68) from the northern South China Sea (SCS) during wet and dry seasons. Perfluorohexane sulfonate (PFHxS) was the predominant PFASs in all coral samples, representing 43% of the total PFAS. Long-chain PFASs, as well as PFAS alternatives, were frequently detected above the MQL (>88%) but showed relatively low concentrations compared to short-chain PFASs in most species and seasons. Seasonal variation of PFAS concentrations were observed in branching corals, indicating that the accumulation of PFASs may be associated with coral morphological structures. Interspecies differences in PFAS levels agree well with different bioaccumulation potentials among coral species. Redundancy analysis (RDA) showed that seasonal factor and coral genus could partly influence PFAS concentrations in coral tissues. In summary, our study firstly reported the occurrence of PFASs in coral communities from the SCS and highlights the necessity for future investigations on more toxicity data for coral communities. [Display omitted] • This is the first study about PFAS occurrence in coral reef ecosystem. • PFHxS was the predominant PFAS in all coral species. • Short-chain PFASs presented low detection frequencies but relatively high levels. • Branching species are particularly susceptible to PFAS exposure. • Seasonal factor and coral genus have certain effects on the accumulation of PFASs. [ABSTRACT FROM AUTHOR]

Rats are extensively used as a preclinical model for assessing drug pharmacokinetics (PK) and tissue distribution; however, successful translation of the rat data requires information on the differences in drug metabolism and transport mechanisms between rats and humans. To partly fill this knowledge gap, we quantified clinically relevant drug-metabolizing enzymes and transporters (DMETs) in the liver and different intestinal segments of Sprague-Dawley rats. The levels of DMET proteins in rats were quantified using the global proteomics-based total protein approach (TPA) and targeted proteomics. The abundance of the major DMET proteins was largely comparable using quantitative global and targeted proteomics. However, global proteomics-based TPA was able to detect and quantify a comprehensive list of 66 DMET proteins in the liver and 37 DMET proteins in the intestinal segments of SD rats without the need for peptide standards. Cytochrome P450 (Cyp) and UDP-glycosyltransferase (Ugt) enzymes were mainly detected in the liver with the abundance ranging from 8 to 6502 and 74 to 2558 pmol/g tissue. P-gp abundance was higher in the intestine (124.1 pmol/g) as compared to that in the liver (26.6 pmol/g) using the targeted analysis. Breast cancer resistance protein (Bcrp) was most abundant in the intestinal segments, whereas organic anion transporting polypeptides (Oatp) 1a1, 1a4, 1b2, and 2a1 and multidrug resistance proteins (Mrp) 2 and 6 were predominantly detected in the liver. To demonstrate the utility of these data, we modeled digoxin PK by integrating protein abundance of P-gp and Cyp3a2 into a physiologically based PK (PBPK) model constructed using PK-Sim software. The model was able to reliably predict the systemic as well as tissue concentrations of digoxin in rats. These findings suggest that proteomics-informed PBPK models in preclinical species can allow mechanistic PK predictions in animal models including tissue drug concentrations.

Among the haemorheological parameters, red blood cell (RBC) aggregation shows the largest interspecies diversity, and often controversial data can be found in the literature, besides the methodology-dependent issues. In this present investigation, we compared four experimental/laboratory animal species' RBC aggregation by two different photometric methods for better revealing the differences. Blood samples (K3-EDTA, 1.5 mg/ml) were taken from female animals: 16 inbred mice ( Mus musculus, cardiac puncture), 15 outbred rats ( Rattus norvegicus, caudal caval vein puncture), 15 beagle dogs ( Canis canis, cephalic vein) and 23 juvenile pigs ( Sus scrofa domesticus, medial saphenous vein). Haematological parameters (microcell counter) and RBC aggregation (light transmission and syllectometry-laser backscatter methods) were determined within 2 h after sampling. Describing the first 5-10 s of the aggregation process, additional parameters were calculated out of the syllectometric raw data. Standardized difference was calculated to determine the sensitivity of the two devices. Parameters describing the extent and magnitude of red blood cell aggregation showed the lowest values in the rat and the highest in the pig and canine blood. In turn, parameters describing the kinetics of aggregation showed the lowest values in the mouse and the highest in the rat. The standardized difference values for the laser backscattering method were 2-4 times larger vs. the light transmission one. The magnitude of the differences was not consequent in the aggregation parameters. These comparative results show that the laser backscattering method can detect the RBC aggregation differences between the investigated species more sensitively than the light transmission method. [ABSTRACT FROM AUTHOR]

17β-Estradiol (E2), the most potent human estrogen, is known to be involved in the etiology of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step of E2 biosynthesis and is thus a promising target for the treatment of EDD. The previously described bicyclic substituted hydroxyphenylmethanones (BSHs) display high inhibitory potency towards human 17β-HSD1, but marginal activity towards rodent 17β-HSD1, precluding a proof of principle study in an animal endometriosis model. The aim of this work was to perform structural optimizations in the BSHs class to enhance inhibitory activity against rodent (mouse and rat) 17β-HSD1 while maintaining activity against the human enzyme. The introduction of fluorine atoms on the benzoyl moiety resulted in compounds with the desired properties. Molecular docking and homology modeling were applied to elucidate the binding mode and interspecies differences in activity. Compound 33 is the most potent inhibitor of both human and rat 17β-HSD1 up to date (IC 50 = 2 nM and 97 nM, respectively). [ABSTRACT FROM AUTHOR]

Homing behaviors are seen across the animal kingdom, with the magnitude and scale of these movements varying to a great degree. Invertebrates, such as crayfish, prove to be excellent models for comparative research, with relatively simple nervous systems that have been extensively studied combined with a rich behavioral repertoire that has been well documented. Here we explore whether two crayfish species (a primary burrower and a tertiary burrower) can home to artificial burrows and if so, whether their homing abilities differ. The two species of crayfish, Orconectes rusticus and Fallicambarus fodiens, were examined for their ability to home to artificial burrows in a laboratory setting. Animals were placed in a homing arena, motivated to search by the presence of food, and subsequently return to the burrows. The movements of each individual crayfish were digitized and analyzed for changes in walking speed, velocity and heading angle relative to burrows, total distance travelled and path turning angles. Crayfish of both species successfully returned home, although F. fodiens had a higher homing success rate than O. rusticus. Detailed kinematic analysis showed that walking speeds almost doubled during homing to burrows and heading angles were significantly closer to zero than on the outward journeys for both species. Path turning angles were significantly lower for O. rusticus than for F. fodiens. These findings indicate that these species of crayfish can successfully home without the visual landmark of burrow chimneys and that the primary burrower ( F. fodiens) appears to be more successful with straighter return paths. The differences in these two species to home and the underlying mechanisms of homing may be due to the differences in burrow use with primary burrowers showing more efficient homing than tertiary burrowers. [ABSTRACT FROM AUTHOR]

Soft tissue filler products have become very popular in recent years, with ever-increasing medical and aesthetic indications. While generally considered safe, the number of reported complications with tissue fillers is growing. Nevertheless, there is no specific animal model that is considered as the gold standard for assessing safety or efficacy of tissue fillers, and there are very little data on interspecies differences in reaction to these products. Here, we report on interspecies differences in reaction to a subcutaneous injectable co-polyester, composed of castor oil and citric acid. Comparison of the histopathological local tissue changes following 1-month postimplantation, indicated that in rats the reaction consisted of cavities, surrounded by relatively thin fibrotic enveloping capsule. In contrast, an unexpected severe inflammatory granulomatous reaction was noticed in Sinclair minipigs. To our knowledge, this is the first report on significant interspecies differences in sensitivity to tissue fillers. It emphasizes the importance of using the appropriate animal model for performing preclinical biocompatibility assays for biodegradable polymers, tissue fillers, and implanted medical devices in general. It also makes the Sinclair minipig subject for scrutiny as an animal model in future biocompatibility studies. [ABSTRACT FROM AUTHOR]

Purpose: Beagle dogs are used to study oral pharmacokinetics and guide development of drug formulations for human use. Since mechanistic insight into species differences is needed to translate findings in this species to human, abundances of cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) drug metabolizing enzymes have been quantified in dog liver and intestine. Methods: Abundances of enzymes were measured in Beagle dog intestine and liver using selected reaction monitoring mass spectrometry. Results: Seven and two CYPs were present in the liver and intestine, respectively. CYP3A12 was the most abundant CYP in both tissues. Seven UGT enzymes were quantified in the liver and seven in the intestine although UGT1A11 and UGT1A9 were present only in the intestine and UGT1A7 and UGT2B31 were found only in the liver. UGT1A11 and UGT1A2 were the most abundant UGTs in the intestine and UGT2B31 was the most abundant UGT in the liver. Summed abundance of UGT enzymes was similar to the sum of CYP enzymes in the liver whereas intestinal UGTs were up to four times more abundant than CYPs. The estimated coefficients of variation of abundance estimates in the livers of 14 donors were separated into biological and technical components which ranged from 14 to 49% and 20 to 39%, respectively. Conclusions: Abundances of canine CYP enzymes in liver and intestine have been confirmed in a larger number of dogs and UGT abundances have been quantified for the first time. The biological variability in hepatic CYPs and UGTs has also been estimated. [ABSTRACT FROM AUTHOR]

In this study, eight Tridacnidae specimens of three different species ( Tridacna gigas , Tridacna derasa and Hippopus hippopus ) were collected from Xisha Islands of South China Sea. The Sr/Ca ratio, which has been widely used as sea surface temperature (SST) proxy in coral samples, was determined on these specimens using ICP-OES to examine their potential for paleoclimate reconstruction. While within-species differences were found to be insignificant, the mean Sr/Ca ratios of the three species (2.24 ± 0.1, 1.77 ± 0.1 and 1.91 ± 0.14 mmol/mol for modern T. gigas , T. derasa and H. hippopus specimens, respectively) are statistically different. Species identification, therefore, is necessary before using Tridacnidae Sr/Ca ratios as paleoclimate recorders. While the relationship between local SST and Sr/Ca ratios of H. hippopus was unclear, the Sr/Ca profiles of modern T. gigas and T. derasa specimens are significantly correlated to local SST, implying that they can be used as SST proxies. The range of Sr/Ca ratios measured in this study is comparable to the Tridacnidae Sr/Ca measurements obtained in previous studies from other areas, but there are also substantial differences in detail, indicating that calibration for regional differences is also needed before paleoclimate reconstruction is attempted. In addition, although the mean Sr/Ca values of T. gigas , T. derasa and coral samples in Xisha Islands were significantly different, their Sr/Ca-SST calibration slopes were comparable, pointing to a similar thermodynamic fractionation and highlighting the potential of the combination of Tridacnidae and coral samples for paleo-SST seasonality reconstruction. [ABSTRACT FROM AUTHOR]

Aflatoxins are potent hepatocarcinogen in animal models and suspected carcinogen in humans. The most important aflatoxin in terms of toxic potency and occurrence is aflatoxin B1 (AFB1). In this review, we mainly summarized the key metabolizing enzymes of AFB1 in animals and humans. Moreover, the interindividual and the interspecies differences in AFB1 metabolism are highly concerned. In human liver, CYP3A4 plays an important role in biotransforming AFB1 to the toxic product AFB1-8,9-epoxide. In human lung, CYP2A13 has a significant activity in metabolizing AFB1 to AFB1-8,9-epoxide and AFM1-8,9-epoxide. The epoxide of AFB1-8,9-epoxide could conjugate with glutathione to reduce the toxicity by glutathione-S-transferase (GST). In poultry species, CYP2A6, CYP3A37, CYP1A5, and CYP1A1 are responsible for bioactivation of AFB1. There are interindividual variations in the rate of activation of aflatoxins in various species, and there are also differences between children and adults. The age and living regions are important factors affecting resistance of species to AFB1. The rate of AFB1-8,9-epoxide formation and its conjugation with glutathione are key parameters in interspecies and interindividual differences in sensitivity to the toxic effect of AFB1. This review provides an important information for key metabolizing enzymes and the global metabolism of aflatoxins in different species. [ABSTRACT FROM AUTHOR]