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In this paper we present a procedure for the isolation of the native bovine α chain. The method is based on affinity chromatography. The results show that the ligand-binding properties of the bovine α chain are almost identical to those of the human α chain. The hybrid α2B β2H prepared by mixing bovine α chains a human β chains shows ligand binding properties similar to those of human hemoglobin and different from those of bovine hemoglobin. [ABSTRACT FROM AUTHOR]

The sequences of the 119 amino acids of bovine and porcine luteinizing hormone β-subunits were determined, 17 amino acid replacements being observed between these species. Variability in the primary structure was observed for porcine β-subunit, in that position 10 is occupied by both arginyl and glutamyl residues. No free amino terminal residue was detected for both porcine and bovine β-polypeptide chains and both exhibited carboxy-terminal heterogeneity. The homology of the β-subunits of luteinizing hormone from various species and the β-subunit of the bovine thyroid-stimulating hormone is discussed as the subunit of both hormones can combine with a similar α-subunit. [ABSTRACT FROM AUTHOR]

The αA2 chain of bovine α-crystallin was fragmented by means of cyanogen bromide treatment and by tryptic, chymotryptic and thermolytic digestions. Twenty tryptic peptides were obtained from the S-aminoethylated αA2 chain, accounting together for the complete sequence. The direct Edman degradation and the dansyl-Edman technique were used to determine the sequences of the tryptic peptides. The order of the tryptic peptides was deduced from overlapping peptides obtained by cyanogen bromide treatment, tryptic digestion of the maleylated chain and chymotryptic and thermolytic digestion of the S-aminoethylated chain. The sequence of the αA2 chain comprises 173 residues and corresponds to a molecular weight of 19832. [ABSTRACT FROM AUTHOR]

Rat liver microsomes were separated into three subfractions by means of ultracentrifugation through sucrose media of different densities and in the presence of different cations. Detergent extracts of these preparations were analysed by double diffusion in agar gel and immunoelectrophoresis with rabbit antisera against each of the subfractions. One subfraction was derived from the ‘rough’ and another from the ‘smooth’ part of the endoplasmic reticulum of the liver parenchymal cells. Their extracts contained at least thirteen soluble antigens in common. However, fraction-specific antigens were also present. Thus, the extracts of the rough (R) membranes contained at least one typical antigen, not found in any of the other fractions. An antiserum against this component also precipitated a non-migrating antigen present only in the extracts of smooth (Sa) membranes. These two antigens may represent different molecular forms of a substance involved in binding of the ribosomes or in the assembly of membrane subunits. At least eleven of the antigens common for the two fractions exhibited enzymatic activities when assayed after precipitation with antibody in the immunoelectro- phoretic plates. Six immunologically and electrophoretically distinct antigens had esterase activity with α-naphthyl propionate as substrate. Two of these esterases also split indoxyl acetate. Three other antigens with acid phosphatase activity split both α-naphthyl acid phosphate and β-glycerophosphate. Three antigens had nucleoside diphosphatase activity when tested with uridine- or inosine-diphosphate. Preliminary experiments also suggested that two additional antigens possessed NADH-diaphorase activity and thus could belong to the microsomal electron trans- port systems. The third subfraction consisted of electron-microscopically smooth membranes (Sb), enzymatically different from those of the endoplasmic reticulum. The antigens typical for the latter were either absent or present only in minor and variable concentrations. Its extracts contained at least two typical antigens. One of these was identified as contaminating ferritin. The nature and origin of the other antigen has not yet been established. All antigens described in this paper were immunologically different from the common rat serum proteins. [ABSTRACT FROM AUTHOR]

Two factors essential for the lysis of EAC'142 cells are described and designated as Β and d. These factors are distinct from the C'3-subunits a, b and c described earlier; they can be separated by chemical procedures. A simple assay method for both factors is given. Four highly reactive intermediates, EAC'142,a; EAC'142,a,b; EAC'142,a,b,Β and EAC'142,a,b,Β,c can be prepared and characterized by their lytic reactivity pattern against different systems of incomplete C'3. Evidence is presented that the subunits of the C'3-system interact with EAC'142 in a sequential order corresponding to the formula a-b-Β-c-d. [ABSTRACT FROM AUTHOR]

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Introduction: 3D printing is experiencing significant growth in the teaching and learning process. This study aims to present a 3D printed skull model for preclinical intraoral radiographic practice. Materials and Methods: Two 3D printed mannequins were created. One mannequin used an STL file of a skull that was edited using two 3D modelling software (Meshmixer and Netfabb). The second mannequin was designed directly from a patient's segmented CBCT data and then converted into an STL file. Both mannequins were printed using fused deposition modelling (FDM) technology and polylactic acid (PLA) filament; teeth for the second mannequin were also printed using digital light processing (DLP). The printed skull bones were attached, the mandible was articulated to the articular fossa of the temporal bone, and the teeth were inserted into the alveoli. Intraoral radiographs of both mannequins were taken using a digital sensor (RVG 5100, Carestream). Results: Both 3D printed mannequins showed satisfactory radiographic appearance, allowing geometric representation of each intraoral radiographic projection, regardless of STL file origin. Anatomical structures, such as the periodontal ligament space, zygomatic process of the maxilla and intermaxillary suture, were represented. The material cost of the first and second printed prototype was $34.00 and $39.00, respectively. Conclusions: The use of 3D printed models is presented as an alternative to artificial commercial phantoms for the preclinical training of intraoral radiographic techniques through the combined benefits of superior radiographic projection quality, the possibility of model manipulation and an affordable price. [ABSTRACT FROM AUTHOR]

Background and Purpose: Opioids and benzodiazepines are frequently combined in medical as well as in non‐medical contexts. At high doses, such combinations often result in serious health complications attributed to pharmacodynamics interactions. Here, we investigate the contribution of the metabolic interactions between oxycodone, diazepam and diclazepam (a designer benzodiazepine) in abuse/overdose conditions through ex vivo, in vivo and in silico approaches. Experimental Approach A preparation of pooled human liver microsomes was used to study oxycodone metabolism in the presence or absence of diazepam or diclazepam. In mice, diazepam or diclazepam was concomitantly administered with oxycodone to mimic acute intoxication. Diclazepam was introduced on Day 10 in mice continuously infused with oxycodone for 15 days to mimic chronic intoxication. In silico modelling was used to study the molecular interactions of the three drugs with CYP3A4 and 2D6. Key Results: In mice, in acute conditions, both diazepam and diclazepam inhibited the metabolism of oxycodone. In chronic conditions and at pharmacologically equivalent doses, diclazepam drastically enhanced the production of oxymorphone. In silico, the affinity of benzodiazepines was higher than oxycodone for CYP3A4, inhibiting oxycodone metabolism through CYP3A4. Oxycodone metabolism is likely to be diverted towards CYP2D6. Conclusion and Implications: Acute doses of diazepam or diclazepam result in the accumulation of oxycodone, whereas chronic administration induces the accumulation of oxymorphone, the toxic metabolite. This suggests that overdoses of opioids in the presence of benzodiazepines are partly due to metabolic interactions, which in turn explain the patterns of toxicity dependent on usage. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc [ABSTRACT FROM AUTHOR]

The field of immunotargcting, and the challenges met when this technique is applied in experimental animals or in patients, are reviewed. Even with highly specific monoclonal antibodies, non-specific uptake in normal tissues and high background level of unbound radioactivity in blood and extravascular body fluids remain significant problems. Further experimental work in animal model systems is needed to bring this technique from the state of being an experimental method, with limited clinical application, to a routine diagnostic or therapeutic method. Different animal models are available, and their potential for elucidation of the various methodological problems in radio-immunotargeting are discussed in the present paper. In our laboratory, two intraperitoneal models were devised, having relevance for gynecologic and other forms of intraperitoneal malignancies. These models were elaborated with special emphasis on the possibility for exact measurement of important parameters in immunotargcting reactions. In the first model, hybridoma cells are inoculated intraperitoneally to mimic intraperitoneal carcino-matosis, and the monoclonal antibody produced by the hybridoma is used as serum tumor marker. In the second model the tumor cells are contained within intraperitoneally implanted micropore chambers, resembling a localized tumor. An artificial tumor like this allows control with the antigen load in the target, and measurement of the concentration of the injected antibody in the fluid within the target. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the potential usefulness of an animal model to predict the appropriate dose of newly developed drugs for treating relapsing remitting multiple sclerosis (RRMS). Conversion of the lowest effective dose (LEffD) for mice and rats in the experimental autoimmune encephalomyelitis (EAE) model was used to predict the human effective dose utilizing the body surface area correction factor found in the 2005 US Food and Drug Administration (FDA) Guidance for Industry in selecting safe starting doses for clinical trials. Predictions were also tested by comparison with doses estimated by scaling up the LEffD in the model by the human to animal clearance ratio. Although initial proof‐of‐concept studies of oral fingolimod tested the efficacy and safety of 1.25 and 5 mg in treating RRMS, the EAE animal model predicted the approved dose of this drug, 0.5 mg daily. This approach would have also provided useful predictions of the approved human oral doses for cladribine, dimethyl fumarate, ozanimod, ponesimod, siponimod, and teriflunomide, drugs developed with more than one supposed mechanism of action. The procedure was not useful for i.v. dosed drugs, including monoclonal antibodies. We maintain that drug development scientists should always examine a simple allometric method to predict the therapeutic effective dose in humans. Then, following clinical studies, we believe that the animal model might be expected to yield useful predictions of other drugs developed to treat the same condition. The methodology may not always be predictive, but the approach is so simple it should be investigated. [ABSTRACT FROM AUTHOR]

The brain‐targeted delivery of therapeutic oligonucleotides has been investigated as a new treatment modality for various brain diseases, such as brain tumors. However, delivery efficiency into the brain has been limited due to the blood–brain barrier. In this research, brain‐targeted exosome‐mimetic cell membrane nanovesicles (CMNVs) were designed to enhance the delivery of therapeutic oligonucleotides into the brain. First, CMNVs were produced by extrusion with isolated C6 cell membrane fragments. Then, CMNVs were decorated with cholesterol‐linked T7 peptides as a targeting ligand by hydrophobic interaction, producing T7‐CMNV. T7‐CMNV was in aqueous solution maintained its nanoparticle size for over 21 days. The targeting and delivery effects of T7‐CMNVs were evaluated in an orthotopic glioblastoma animal model. 2′‐O‐metyl and cholesterol‐TEG modified anti‐microRNA‐21 oligonucleotides (AMO21c) were loaded into T7‐CMNVs, and biodistribution experiments indicated that T7‐CMNVs delivered AMO21c more efficiently into the brain than CMNVs, scrambled T7‐CMNVs, lipofectamine, and naked AMO21c after systemic administration. In addition, AMO21c down‐regulated miRNA‐21 (miR‐21) levels in glioblastoma tissue most efficiently in the T7‐CMNVs group. This enhanced suppression of miR‐21 resulted in the up‐regulation of PDCD4 and PTEN. Eventually, brain tumor size was reduced in the T7‐CMNVs group more efficiently than in the other control groups. With stability, low toxicity, and targeting efficiency, T7‐CMNVs may be useful to the development of oligonucleotide therapy for brain tumors. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IVDD), a widely recognized cause of lower back pain, is the leading cause of disability worldwide. A myriad of preclinical in vivo animal models of IVDD have been described in the literature. There is a need for critical evaluation of these models to better inform researchers and clinicians to optimize study design and ultimately, enhance experimental outcomes. The purpose of this study was to conduct an extensive systematic literature review to report the variability of animal species, IVDD induction method, and experimental timepoints and endpoints used in in vivo IVDD preclinical research. A systematic literature review of peer‐reviewed manuscripts featured on PubMed and EMBASE databases was conducted in accordance with PRISMA guidelines. Studies were included if they reported an in vivo animal model of IVDD and included details of the species used, how disc degeneration was induced, and the experimental endpoints used for analysis. Two‐hundred and fifty‐nine (259) studies were reviewed. The most common species, IVDD induction method and experimental endpoint used was rodents(140/259, 54.05%), surgery (168/259, 64.86%) and histology (217/259, 83.78%), respectively. Experimental timepoint varied greatly between studies, ranging from 1 week (dog and rodent models), to >104 weeks in dog, horse, monkey, rabbit, and sheep models. The two most common timepoints used across all species were 4 weeks (49 manuscripts) and 12 weeks (44 manuscripts). A comprehensive discussion of the species, methods of IVDD induction and experimental endpoints is presented. There was great variability across all categories: animal species, method of IVDD induction, timepoints and experimental endpoints. While no animal model can replicate the human scenario, the most appropriate model should be selected in line with the study objectives to optimize experimental design, outcomes and improve comparisons between studies. [ABSTRACT FROM AUTHOR]

Animal models have been invaluable in the identification of molecular events occurring in and contributing to intervertebral disc (IVD) degeneration and important therapeutic targets have been identified. Some outstanding animal models (murine, ovine, chondrodystrophoid canine) have been identified with their own strengths and weaknesses. The llama/alpaca, horse and kangaroo have emerged as new large species for IVD studies, and only time will tell if they will surpass the utility of existing models. The complexity of IVD degeneration poses difficulties in the selection of the most appropriate molecular target of many potential candidates, to focus on in the formulation of strategies to effect disc repair and regeneration. It may well be that many therapeutic objectives should be targeted simultaneously to effect a favorable outcome in human IVD degeneration. Use of animal models in isolation will not allow resolution of this complex issue and a paradigm shift and adoption of new methodologies is required to provide the next step forward in the determination of an effective repairative strategy for the IVD. AI has improved the accuracy and assessment of spinal imaging supporting clinical diagnostics and research efforts to better understand IVD degeneration and its treatment. Implementation of AI in the evaluation of histology data has improved the usefulness of a popular murine IVD model and could also be used in an ovine histopathological grading scheme that has been used to quantify degenerative IVD changes and stem cell mediated regeneration. These models are also attractive candidates for the evaluation of novel anti‐oxidant compounds that counter inflammatory conditions in degenerate IVDs and promote IVD regeneration. Some of these compounds also have pain‐relieving properties. AI has facilitated development of facial recognition pain assessment in animal IVD models offering the possibility of correlating the potential pain alleviating properties of some of these compounds with IVD regeneration. [ABSTRACT FROM AUTHOR]

Even though Helicobacter pylori infection was the most causative factor of gastric cancer, numerous in vivo studies failed to induce gastric cancer using H. pylori infection only. The utilization of established animal studies in cancer research is crucial as they aim to investigate the coincidental association between suspected oncogenes and pathogenesis as well as generate models for the development and testing of potential treatments. The methods to establish gastric cancer using infected animal models remain limited, diverse in methods, and showed different results. This study investigates the differences in animal models, which highlight different pathological results in gaster by literature research. Electronic databases searched were performed in PubMed, Science Direct, and Cochrane, without a period filter. A total of 135 articles were used in this study after a full‐text assessment was conducted. The most frequent animal models used for gastric cancer were Mice, while Mongolian gerbils and Transgenic mice were the most susceptible model for gastric cancer associated with H. pylori infection. Additionally, transgenic mice showed that the susceptibility to gastric cancer progression was due to genetic and epigenetic factors. These studies showed that in Mongolian gerbil models, H. pylori could function as a single agent to trigger stomach cancer. However, most gastric cancer susceptibilities were not solely relying on H. pylori infection, and numerous factors are involved in cancer progression. Further study using Mongolian gerbils and Transgenic mice is crucial to conduct and establish the best models for gastric cancer associated H. pylori. [ABSTRACT FROM AUTHOR]

Cutaneous squamous cell carcinoma (cSCC) leads to significant morbidity for patients with progression and metastases. However, the molecular underpinnings of these tumors are still poorly understood. Dissecting human cSCC pathogenesis amplifies the exigence for preclinical models that mimic invasion and nodal spread. This review discusses the currently available models, including two‐ and three‐dimensional tissue cultures, syngeneic and transgenic mice, and cell line‐derived and patient‐derived xenografts. We further highlight studies that have utilized the different models, considering how they recapitulate specific hallmarks of cSCC. Finally, we discuss the advantages, limitations and future research directions. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate docosahexaenoic acid (DHA) as a potential antifibrotic agent after glaucoma filtration surgery (GFS) in rats. Methods: A total of 36 10‐week‐old Brown Norway rats underwent GFS. Animals were equally divided into three groups: a control group, a DHA group and a mitomycin C (MMC) group. Intraocular pressure (IOP) was measured using a dynamic rebound tonometer, and a photograph of the surgical site was taken on days 1, 3, 7, 10, 14 and 17. The incorporation of DHA into fibroblasts was evaluated by gas chromatography. The expression of alfa‐smooth muscle actin (α‐SMA) and Smad proteins was assessed by Western blotting. Results: IOP decreased after surgery in animals from the three groups on day 1 after surgery. Over time, IOP remained lower in the DHA and MMC groups than in the control group (median [interquartile range] 8.0 [7.0–8.0] and 8.0 [7.3–8.0] mmHg vs. 9.0 [8.0–9.0] mmHg, respectively; p < 0.001). Bleb area in the DHA and MMC groups remained larger than that of the control group from day 7 to day 14 (3.9 [2.9–5.2] and 3.5 [2.3–4.4] mm2 vs. 2.3 [2.0–2.8] mm2, respectively; p = 0.0021). We did not observe any change in DHA concentrations in the fibroblasts of the DHA group compared with the other groups. Conclusion: The impact of DHA on IOP and bleb area was similar to that of MMC. The mechanisms of action of DHA in rat eye fibroblasts deserve further investigation. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a heterogeneous multi‐systemic disorder unique to humans characterized by motor and non‐motor symptoms. Preclinical experimental models of PD present limitations and inconsistent neurochemical, histological, and behavioral readouts. The 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of PD is the most common in vivo screening platform for novel drug therapies; nonetheless, behavioral endpoints yielded amongst laboratories are often discordant and inconclusive. In this study, we characterized neurochemically, histologically, and behaviorally three different MPTP mouse models of PD to identify translational traits reminiscent of PD symptomatology. MPTP was intraperitoneally (i.p.) administered in three different regimens: (i) acute—four injections of 20 mg/kg of MPTP every 2 h; (ii) sub‐acute—one daily injection of 30 mg/kg of MPTP for 5 consecutive days; and (iii) chronic—one daily injection of 4 mg/kg of MPTP for 28 consecutive days. A series of behavioral tests were conducted to assess motor and non‐motor behavioral changes including anxiety, endurance, gait, motor deficits, cognitive impairment, circadian rhythm and food consumption. Impairments in balance and gait were confirmed in the chronic and acute models, respectively, with the latter showing significant correlation with lesion size. The sub‐acute model, by contrast, presented with generalized hyperactivity. Both, motor and non‐motor changes were identified in the acute and sub‐acute regime where habituation to a novel environment was significantly reduced. Moreover, we report increased water and food intake across all three models. Overall, the acute model displayed the most severe lesion size, while across the three models striatal dopamine content (DA) did not correlate with the behavioral performance. The present study demonstrates that detection of behavioral changes following MPTP exposure is challenging and does not correlate with the dopaminergic lesion extent. [ABSTRACT FROM AUTHOR]

Genomic relationships can be computed with dense genome‐wide genotypes through different methods, either based on identity‐by‐state (IBS) or identity‐by‐descent (IBD). The latter has been shown to increase the accuracy of both estimated relationships and predicted breeding values. However, it is not clear whether an IBD approach would achieve greater heritability (h2) and predictive ability (r̂y,ŷ) than its IBS counterpart for data with low‐depth pedigrees. Here, we compare both approaches in terms of the estimated of h2 and r̂y,ŷ, using data on meat quality and carcass traits recorded in experimental crossbred pigs, with a pedigree constrained to only three generations. Three animal models were fitted which differed on the relationship matrix: an IBS model (GIBS), an IBD (defined within the known pedigree) model (GIBD), and a pedigree model (A22). In 9 of 20 traits, the range of increase for the estimates of σu2 and h2 was 1.2–2.9 times greater with GIBS and GIBD models than with A22. Whereas for all traits, both parameters were similar between genomic models. The r̂y,ŷ of the genomic models was higher compared to A22. A scarce increment in r̂y,ŷ was found with GIBS when compared to GIBD, most likely due to the former recovering sizeable relationships among founder F0 animals. [ABSTRACT FROM AUTHOR]

Chronic rotator cuff tears (RCTs) are one of the most common injuries of shoulder pain. Despite the recent advances in surgical techniques and improved clinical outcomes of arthroscopically repaired rotator cuffs (RCs), complete functional recovery-without retear-of the RC tendon through tendon-to-bone interface (TBI) regeneration remains a key clinical goal to be achieved. Inspired by the highly organized nanostructured extracellular matrix in RC tendon tissue, we propose herein a tissue-engineered tendon nano-construct (TNC) for RC tendon regeneration. When compared with two currently used strategies (i.e., transosseous sutures and stem cell injections), our nano-construct facilitated more significant healing of all parts of the TBI (i.e., tendon, fibrocartilages, and bone) in both rabbit and pig RCT models owing to its enhancements in cell proliferation and differentiation, protein expression, and growth factor secretion. Overall, our findings demonstrate the high potential of this transplantable tendon nano-construct for clinical repair of chronic RCTs. [ABSTRACT FROM AUTHOR]

Aim: There are growing evidences linking chronic apical periodontitis (CAP) to atherosclerosis. Gut microbiota is found to be involved in the development of atherosclerosis. Recent studies have shown that CAP could change the diversity and composition of the gut microbiota. It was therefore, we hypothesized that gut microbiota and its metabolites could mediate the impact of CAP on atherosclerosis. Methodology: Twenty‐four 5‐week‐old lipoprotein E knockout (apoE−/−) mice were randomly divided into four groups: the CAP group, Con group, Co‐CAP (cohoused with CAP) and Co‐Con (cohoused with Con) group. In the CAP group, sterile cotton wool containing P. gingivalis was placed into the exposed pulp chamber, followed by coronal resin‐based composite restoration of the bilateral maxillary first and second molars. In the Con group, a sham operation was performed. Biweekly, mice in the CAP group were anaesthetised to check the sealing of coronal access. Meanwhile, the animals in the Con group were anaesthetised. The cohousing approach was used to introduce gut microbiota from the CAP and Con groups into the Co‐CAP and Co‐Con groups, respectively. Alterations in the abundance and diversity of the gut microbiota were detected using 16S rRNA sequencing, Oil‐red O staining was used to demonstrate the extent of lesions, and serum levels of trimethylamine N‐oxide (TMAO), and immunohistochemistry of flavin‐containing monooxygenase 3 (FMO3) in liver were used to assess TMAO‐related metabolic alterations. Results: Alterations of alpha and beta diversity were shown both in the CAP and the Co‐CAP groups. Moreover, the percentage of atherosclerotic lesion area increased in the CAP and Co‐CAP groups (p <.05). Linear discriminant analysis effect size (LEfSe) at the family level found the increases of Lachnospiraceae and Ruminococcaceae (p <.05), which were positively correlated with serum TMAO levels (p <.05). In the redundancy analysis technique (RDA), serum levels of TMAO were positively associated with the atherosclerotic lesions. Co‐occurrence analysis revealed that the relative abundances of Lachnospiraceae and Porphyromonadacae were positively correlated with both the percentage of lesion area and TMAO level (p <.05). Conclusion: Thus, within the limitations of this study, the data suggest that the gut microbiota can mediate the effects of CAP on atherosclerosis. [ABSTRACT FROM AUTHOR]

The incidence of respiratory diseases such as chronic obstructive pulmonary disease and pulmonary cancer is growing significantly around the world, making pulmonary disease one of the leading causes of mortality. However, the development of effective therapeutics for pulmonary diseases has been hindered by the lack of human‐mimetic physiological models that reliably emulate patient responses. Recent advances in technology and cell culture have led to the development of organoids and organ‐on‐a‐chip models that allow us to recapitulate the structure, cellular organization, and organ‐level responses of the target tissue in vitro. Here, we review the advances and milestones of lung organoid and lung‐on‐a‐chip models in the past decade and highlight their applications in mimicking pulmonary system development, physiology, disease, and regeneration. In addition, we discuss the ongoing challenges and the future prospects of integrating lung organoids and lung‐on‐a‐chip models to overcome current limitations and to enhance their physiological relevance. These human‐centric models are likely to provide important insights into pulmonary physiology and pathophysiology for drug discovery that complement and potentially replace traditional animal models. [ABSTRACT FROM AUTHOR]

It is well established that epilepsy is associated with numerous neurobehavioral comorbidities, with a bidirectional relationship; people with epilepsy have an increased incidence of depression, anxiety, learning and memory difficulties, and numerous other psychosocial challenges, and the occurrence of epilepsy is higher in individuals with those comorbidities. Although the cause‐and‐effect relationship is uncertain, a fuller understanding of the mechanisms of comorbidities within the epilepsies could lead to improved therapeutics. Here, we review recent data on epilepsy and its neurobehavioral comorbidities, discussing mainly rodent models, which have been studied most extensively, and emphasize that clinically relevant information can be gained from preclinical models. Furthermore, we explore the numerous potential factors that may confound the interpretation of emerging data from animal models, such as the specific seizure induction method (e.g., chemical, electrical, traumatic, genetic), the role of species and strain, environmental factors (e.g., laboratory environment, handling, epigenetics), and the behavioral assays that are chosen to evaluate the various aspects of neural behavior and cognition. Overall, the interplay between epilepsy and its neurobehavioral comorbidities is undoubtedly multifactorial, involving brain structural changes, network‐level differences, molecular signaling abnormalities, and other factors. Animal models are well poised to help dissect the shared pathophysiological mechanisms, neurological sequelae, and biomarkers of epilepsy and its comorbidities. [ABSTRACT FROM AUTHOR]

The authors comment on a report by Seong Min Kim and colleagues on the effects of selective cyclooxygenase (COX)-2 inhibitor meloxicam on an experimental animal model of chronic liver damage, bile duct ligation (BDL) with rats. It is noted that the paper is the first to examine the effects of the selective COX-2 inhibitor on chronic cholestatic liver injury. They point out that COX-2 has both pro- and anti-cell death and fibrogenic effects in animal experimental models.

Comments on "Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia," a paper published in "Nature Genetics" by Yu and colleagues. Identification of the cancerous blasts of acute leukemia; Study of the methylation sites to identify the corresponding effect on gene expression and examined for patterns; Enhanced promoter methylation and the distribution of the sites; Identification of a specific promoter as a putative tumor-suppressor gene methylated in acute lymphoblastic leukemia.

This study aimed to conduct a detailed study on murine model testing of bacteriophage against Acinetobacter baumannii. These bacteriophages were tested not only for their efficacy in healing wound of murine models infected with multidrug resistant A. baumannii but were also studied for any derangement in hematological parameters as well as liver and kidney function. The study also included any histological changes observed in hepatic and renal tissues of the bacteriophage treated murine animals. This experimental study was conducted at Institute of Basic Medical Sciences, Khyber Medical University, Peshawar and Institute of Pure and Applied Biology, Department of Microbiology and Molecular Genetics, Bahauddin Zakariya University, Multan. A. baumannii isolates were obtained from the Microbiology Department, Armed Forces Institute of Pathology, Rawalpindi. Antimicrobial susceptibility was done by using standard procedures and as per Clinical Laboratory Standards Institute guidelines. Bacteriophages were isolated from sewage water samples collected from different hospitals in Multan. These bacteriophages were characterized and finally used for treating the murine model and efficacy of phage as a therapeutic option was determined by using superficial rat wound model. In this study, the isolated lytic bacteriophage was effective in relatively faster wound healing of the infected animals. Moreover, there were no significant hematological or renal and hepatic profile changes in treated animals. Histology of renal and hepatic tissues was also normal as compared to control animals. Our study concluded that the isolated phage could serve as an attractive therapeutic candidate to combat the deadly multidrug resistant A. baumannii. [ABSTRACT FROM AUTHOR]

The local inflammatory impact of different reaming protocols in intramedullary nailing has been sparsely investigated. We examined the effect of different reaming protocols on fracture hematoma (FH) immunological characteristics in pigs. To do so, a standardized midshaft femur fracture was induced in adult male pigs. Fractures were treated with conventional reamed femoral nailing (group RFN, n = 6); unreamed femoral nailing (group UFN, n = 6); reaming with a Reamer Irrigator Aspirator device (group RIA, n = 12). Animals were observed for 6 h and FH was collected. FH‐cell apoptosis and neutrophil receptor expression (Mac‐1/CD11b and FcγRIII/CD16) were studied by flow cytometry and local temperature changes were analyzed. The study demonstrates that apoptosis‐rates of FH‐immune cells were significantly lower in group RIA (3.50 ± 0.53%) when compared with non‐RIA groups: (group UFN 12.50 ± 5.22%, p = 0.028 UFN vs. RIA), (group RFN 13.30 ± 3.18%, p < 0.001, RFN vs. RIA). Further, RIA‐FH showed lower neutrophil CD11b/CD16 expression when compared with RFN (mean difference of 43.0% median fluorescence intensity (MFI), p = 0.02; and mean difference of 35.3% MFI, p = 0.04, respectively). Finally, RIA induced a transient local hypothermia and hypothermia negatively correlated with both FH‐immune cell apoptosis and neutrophil activation. In conclusion, immunologic changes observed in FH appear to be modified by certain reaming techniques. Irrigation during reaming was associated with transient local hypothermia, decreased apoptosis, and reduced neutrophil activation. Further study is warranted to examine whether the rinsing effect of RIA, specific tissue removal by reaming, or thermal effects predominantly determine local inflammatory changes during reaming. [ABSTRACT FROM AUTHOR]

Telomeres are protective caps at the end of eukaryotic chromosomes that shorten with age and in response to stressful or resource‐demanding conditions. Their length predicts individual health and lifespan across a wide range of animals, but whether the observed positive association between telomere length and lifespan is environmentally induced, or set at conception due to a shared genetic basis, has not been tested in wild animals. We applied quantitative genetic "animal models" to longitudinal telomere measurements collected over a 10‐year period from individuals of a wild seabird (common tern; Sterna hirundo) with known pedigree. We found no variation in telomere shortening with age among individuals at the phenotypic and genetic level, and only a small permanent environmental effect on adult telomere length. Instead, we found telomere length to be highly heritable and strongly positively genetically correlated with lifespan. Such heritable differences between individuals that are set at conception may present a hitherto underappreciated component of variation in somatic state. [ABSTRACT FROM AUTHOR]

Surgical resection of lesions and closed‐loop suppression are the two main treatment options for patients with refractory epilepsy whose symptoms cannot be managed with medicines. Unfortunately, failures in foci localization and seizure prediction are constraining these treatments. Electrical impedance tomography (EIT), sensitive to impedance changes caused by blood flow or cell swelling, is a potential new way to locate epileptic foci and predict seizures. Animal validation is a necessary research process before EIT can be used in clinical practice, but it is unclear which among the many animal epilepsy models is most suited to this task. The selection of an animal model of epilepsy that is similar to human seizures and can be adapted to EIT is important for the accuracy and reliability of EIT research results. This study provides an overview of the animal models of epilepsy that have been used in research on the use of EIT to locate the foci or predict seizures; discusses the advantages and disadvantages of these models regarding inducement by chemical convulsant and electrical stimulation; and finally proposes optimal animal models of epilepsy to obtain more convincing research results for foci localization and seizure prediction by EIT. The ultimate goal of this study is to facilitate the development of new treatments for patients with refractory epilepsy. This article is categorized under:Neuroscience > Clinical NeurosciencePsychology > Brain Function and Dysfunction [ABSTRACT FROM AUTHOR]

To investigate photoactivated disinfection (PAD) to treat acute pseudomembranous stomatitis, an animal model was established. Six‐week‐old male ICR mice were inoculated with Candida albicans under immunosuppression then divided into three groups (15 mice per group). Pseudomembranous area was measured, then mice had 1 mg mL−1 toluidine blue solution spread on the area, left for 1 min (PAD‐1 group) or 2 min (PAD‐2 group), then irradiated with a 750 mW LED red light for 1 min, a control group received no treatment. Fungal load was measured immediately; after 48 h of observation pseudomembranous area and fungal load were measured. The mice were sacrificed and histopathological examination was performed. Before treatment, pseudomembranous area scores were similar (3 to 4 points) in all groups; 48 h after treatment, the treatment groups' scores were lower (1 to 2 points) than the control group (3 to 4 points, P < 0.05). Immediately after treatment and 48 h later, the fungal loads of the treatment groups were lower than the control group (both P < 0.05). Histopathology of the treatment groups improved more than controls. The treatment groups' results were similar. Therefore, this method of PAD, with short treatment time, reduced the fungal load and pseudomembranous area scores in a mouse model of acute pseudomembranous stomatitis and may have clinical potential. [ABSTRACT FROM AUTHOR]

Backgorund: Prior data suggest pre‐diagnostic aspirin use impacts breast tumour biology and patient outcome. Here, we employed faithful surgical resection models of HER2+ and triple‐negative breast cancer (TNBC), to study outcome and response mechanisms across breast cancer subtypes. Method: NOD/SCID mice were implanted with HER2+ MDA‐MB‐231/LN/2‐4/H2N, trastuzumab‐resistant HER2+ HCC1954 or a TNBC patient‐derived xenograft (PDX). A daily low‐dose aspirin regimen commenced until primary tumours reached ~250 mm3 and subsequently resected. MDA‐MB‐231/LN/2‐4/H2N mice were monitored for metastasis utilising imaging. To interrogate the survival benefit of pre‐treatment aspirin, 3 weeks post‐resection, HCC1954/TNBC animals received standard‐of‐care (SOC) chemotherapy for 6 weeks. Primary tumour response to aspirin was interrogated using immunohistochemistry. Results: Aspirin delayed time to metastasis in MDA‐MB‐231/LN/2‐4/H2N xenografts and decreased growth of HER2+/TNBC primary tumours. Lymphangiogenic factors and lymph vessels number were decreased in HER2+ tumours. However, no survival benefit was seen in aspirin pre‐treated animals (HCC1954/TNBC) that further received adjuvant SOC, compared with animals treated with SOC alone. In an effort to study mechanisms responsible for the observed reduction in lymphangiogenesis in HER2+ BC we utilised an in vitro co‐culture system of HCC1954 tumour cells and mesenchymal stromal cells (MSC). Aspirin abrogated the secretion of VEGF‐C in MSCs and also decreased the lymph/angiogenic potential of the MSCs and HCC1954 by tubule formation assay. Furthermore, aspirin decreased the secretion of uPA in HCC1954 cells potentially diminishing its metastatic capability. Conclusion: Our data employing clinically relevant models demonstrate that aspirin alters breast tumour biology. However, aspirin may not represent a robust chemo‐preventative agent in the HER2+ or TNBC setting. [ABSTRACT FROM AUTHOR]

Spatial capture–recapture (SCR) models have emerged as a robust method to estimate the population density of mobile animals. However, model evaluation has generally been based on data simulated from simplified representations of animal space use. Here, we generated data from animal movement simulated from a mechanistic individual‐based model, in which movement emerges from the individual's response to a changing environment (i.e., from the bottom‐up), driven by key ecological processes (e.g., resource memory and territoriality). We drew individual detection data from simulated movement trajectories and fitted detection data sets to a basic, resource selection and transience SCR model, as well as their variants accounting for resource‐driven heterogeneity in density and detectability. Across all SCR models, abundance estimates were robust to multiple, but low‐degree violations of the specified movement processes (e.g., resource selection). SCR models also successfully captured the positive effect of resource quality on density. However, covariate models failed to capture the finer scale effect of resource quality on detectability and space use, which may be a consequence of the low temporal resolution of SCR data sets and/or model misspecification. We show that home‐range size is challenging to infer from the scale parameter alone, compounded by reliance on conventional measures of "true" home‐range size that are highly sensitive to sampling regime. Additionally, we found the transience model challenging to fit, probably due to data sparsity and violation of the assumption of normally distributed inter‐occasion movement of activity centers, suggesting that further development of the model is required for general applicability. Our results showed that further integration of complex movement into SCR models may not be necessary for population estimates of abundance when the level of individual heterogeneity induced by the underlying movement process is low, but appears warranted in terms of accurately revealing finer scale patterns of ecological and movement processes. Further investigation into whether this holds true in populations with other types of realistic movement characteristics is merited. Our study provides a framework to generate realistic SCR data sets to develop and evaluate more complex movement processes in SCR models. [ABSTRACT FROM AUTHOR]

Background: Topical exogenous lipase has been approved for cosmetic use and has been used to mobilize fat from adipocytes. The objective of this study was to determine the effects of exogenous lipase in the subcutaneous adipose tissue. Methods: Three different concentrations of exogenous lipase 1× (2 Units per ml), 5× (10 units per ml), and 10× (20 units per ml) were applied in a porcine model. Normal saline (NS) solution (as negative control) and phosphatidylcholine (as positive control) were also injected. Skin and subcutaneous tissue biopsies, up to the fascia, were obtained from each injection site on the 3rd day after injection. The number of cells per 20× field was counted as an indirect measurement of the size of the adipocytes. Results: For 1× lipase, the number of cells per field was 47.80 (±7.63) versus 27.26 (±4.93), and 34.66 (±6.84) for NS, and phosphatidylcholine, respectively. For 5× lipase, the count was 36.06 (±4.74) versus 24.13 (±5.18), and 33.2 (±9.34). For 10× lipase, it was 40.06 (±4.35) versus 29.26 (±2.34) and 32.66 (±6.30) (p <.05 for all groups). Conclusions: A higher number of cells per field were observed in the lipase samples, inferring a decreased volume of adipocytes. No inflammation and/or loss of cell architecture were evidenced in the exogenous lipase groups. [ABSTRACT FROM AUTHOR]

Gaucher disease is a lysosomal storage disorder caused by mutations which destabilize the native folded form of GCase, triggering degradation and ultimately resulting in low enzyme activity. Pharmacological chaperones (PCs) which stabilize mutant GCase have been used to increase lysosomal activity through improving trafficking efficiency. By engineering their inherent basicity, we have synthesized PCs that change conformation between the ER and the lysosomal environment, thus weakening binding to GCase after its successful trafficking to the lysosome. NMR studies confirmed the conformational change while X‐ray data reveal bound conformations and binding modes. These results were further corroborated by cell studies showing increases in GCase activity when using the pH‐switchable probe at low dosing. Preliminary in vivo assays with humanized mouse models of Gaucher showed enhanced GCase activity levels in relevant tissues, including the brain, further supporting their potential. [ABSTRACT FROM AUTHOR]

1. Cancer is an understudied but important process in wildlife that is predicted to have a significant effect on the evolution of metazoan species due to negative effects on host fitness. However, gaining understanding of the impact of cancer on species and ecosystems is currently relatively slow as the development of both animal models in which cancer can be induced and experiments that can be performed in an ecological setting are required. Invertebrates, because they are widely available and relatively easy to manipulate, are promising animal models. 2. In this review we examine how tumours can be induced in invertebrates to use them as experimental models to study the effects of cancer on the ecology and evolution of species. We identified four main groups of invertebrates (planarian, bivalves, hydra and drosophila) in which such inductions are performed. We then reviewed the types and effectiveness of the methods employed to induce tumours in those groups. 3. Cancer alters the phenotype of the host. We review how experiments using invertebrate models can be used to investigate the impact of cancer on tumour-bearing individuals for their movement, reproduction, feeding behaviours, social interactions, holobiont and predation risk. 4. We provide recommendations to facilitate the development of new invertebrate models. We also highlight a series of key questions on the ecology and evolution of cancer that could be answered with the use of invertebrate models. [ABSTRACT FROM AUTHOR]

Anterior cruciate ligament (ACL) injuries are common knee ligament injuries. While generally successful, ACL reconstruction that uses a tendon graft to stabilize the knee is still associated with a notable percentage of failures and long‐term morbidities. Preclinical research that uses small laboratory species (i.e., mice, rats, and rabbits) to model ACL reconstruction are important to evaluate factors that can impact graft incorporation or posttraumatic osteoarthritis after ACL reconstruction. Small animal ACL reconstruction models are also used for proof‐of‐concept studies for the development of emerging biological strategies aimed at improving ACL reconstruction healing. The objective of this review is to provide an overview on the use of common small animal laboratory species to model ACL reconstruction. The review includes a discussion on comparative knee anatomy, technical considerations including types of tendon grafts employed amongst the small laboratory species (i.e., mice, rats, and rabbits), and common laboratory evaluative methods used to study healing and outcomes after ACL reconstruction in small laboratory animals. The review will also highlight common research questions addressed with small animal models of ACL reconstruction. [ABSTRACT FROM AUTHOR]

XBD173 and etifoxine are translocator protein (TSPO) ligands that modulate inflammatory responses in preclinical models. Limited human pharmacokinetic data is available for either molecule, and the binding affinity of etifoxine for human TSPO is unknown. To allow for design of human challenge experiments, we derived pharmacokinetic data for orally administered etifoxine (50 mg 3 times daily) and XBD173 (90 mg once daily) and determined the binding affinity of etifoxine for TSPO. For XBD173, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 1.0 nM, which is similar to XBD173 binding affinity. For etifoxine, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 0.31 nM, substantially lower than the Ki for etifoxine in human brain derived here (7.8 μM, 95% CI 4.5–14.6 μM). We conclude that oral XBD173 dosing at 90 mg once daily will achieve pharmacologically relevant TSPO occupancy. However, the occupancy is too low for TSPO mediated effects after oral dosing of etifoxine at 50 mg 3 times daily. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the potential of hydrogen peroxide-generated oxygen gas-based phase contrast imaging (PCI) for visualizing mouse hepatic portal veins. The O2 gas was made from the reaction between H2O2 and catalase. The gas production was imaged by PCI in real time. The H2O2 was injected into the enteric cavity of the lower sigmoid colon to produce O2 in the submucosal venous plexus. The generated O2 gas could be finally drained into hepatic portal veins. Absorption contrast imaging (ACI) and PCI of O2-filled portal veins were performed and compared. PCI offers high resolution and real-time visualization of the O2 gas production. Compared with O2-based ACI, O2-based PCI significantly enhanced the revealing of the portal vein in vivo. It is concluded that O2-based PCI is a novel and promising imaging modality for future studies of portal venous disorders in mice models. [ABSTRACT FROM AUTHOR]

The ARRIVE guidelines have been implemented in BJP for 4 years with the aim of increasing transparency in reporting experiments involving animals. BJP has assessed our success in implementing them and concluded that we could do better. This editorial discusses the issues and explains how we are changing our requirements for authors to report their findings in experiments involving animals. This is one of a series of discussing updates to the BJP Linked Editorials This Editorial is part of a series. To view the other Editorials in this series, visit: ; ; and . Video To view the video on the ARRIVE guidelines, visit: [ABSTRACT FROM AUTHOR]

Populations often contain discrete classes or morphs (e.g., sexual dimorphisms, wing dimorphisms, trophic dimorphisms) characterized by distinct patterns of trait expression. In quantitative genetic analyses, the different morphs can be considered as different environments within which traits are expressed. Genetic variances and covariances can then be estimated independently for each morph or in a combined analysis. In the latter case, morphs can be considered as separate environments in a bivariate analysis or entered as fixed effects in a univariate analysis. Although a common approach, we demonstrate that the latter produces downwardly biased estimates of additive genetic variance and heritability unless the quantitative genetic architecture of the traits concerned is perfectly correlated between the morphs. This result is derived for four widely used quantitative genetic variance partitioning methods. Given that theory predicts the evolution of genotype-by-environment (morph) interactions as a consequence of selection favoring different trait combinations in each morph, we argue that perfect correlations between the genetic architectures of the different morphs are unlikely. A sampling of the recent literature indicates that the majority of researchers studying traits expressed in different morphs recognize this and do estimate morph-specific quantitative genetic architecture. However, ca. 16% of the studies in our sample utilized only univariate, fixed-effects models. We caution against this approach and recommend that it be used only if supported by evidence that the genetic architectures of the different morphs do not differ. [ABSTRACT FROM AUTHOR]

Presents a reply to the comments on the research about the importance of animal dispersal to the outcomes of spatially explicit population models. Views on the error rates used for dispersal mortality; Calculation of the percentage of the prediction error; Opinions regarding the simplicity and practical applications of the models.

Points out that the six articles included in this issue of the "American Journal of Primatology" address the role of psychosocial stressors as immune modulators in macaques. Psychoneuroimmunology, the field of study that examines the interrelationship among behavior and the nervous, endocrine and immune systems; Nonhuman primates as excellent subjects for studying the behavior-immune link.

Background and Purpose: Pore‐forming α subunits of the voltage‐ and Ca2+‐activated K+ channel with large conductance (BKα) promote malignant phenotypes of breast tumour cells. Auxiliary subunits such as the leucine‐rich repeat containing 26 (LRRC26) protein, also termed BKγ1, may be required to permit activation of BK currents at a depolarized resting membrane potential that frequently occur in non‐excitable tumour cells. Experimental Approach Anti‐tumour effects of BKα loss were investigated in breast tumour‐bearing MMTV‐PyMT transgenic BKα knockout (KO) mice, primary MMTV‐PyMT cell cultures, and in a syngeneic transplantation model of breast cancer derived from these cells. The therapeutic relevance of BK channels in the context of endocrine treatment was assessed in human breast cancer cell lines expressing either low (MCF‐7) or high (MDA‐MB‐453) levels of BKα and BKγ1, as well as in BKα‐negative MDA‐MB‐157. Key Results: BKα promoted breast cancer onset and overall survival in preclinical models. Conversely, lack of BKα and/or knockdown of BKγ1 attenuated proliferation of murine and human breast cancer cells in vitro. At low concentrations, tamoxifen and its major active metabolites stimulated proliferation of BKα/γ1‐positive breast cancer cells, independent of the genomic signalling controlled by the oestrogen receptor. Finally, tamoxifen increased the relative survival time of BKα KO but not of wild‐type tumour cell recipient mice. Conclusion and Implications: Breast cancer initiation, progression, and tamoxifen sensitivity depend on functional BK channels thereby providing a rationale for the future exploration of the oncogenic actions of BK channels in clinical outcomes with anti‐oestrogen therapy. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc [ABSTRACT FROM AUTHOR]

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and intellectual disability (ID), are pervasive, often lifelong disorders, lacking evidence‐based interventions for core symptoms. With no established biological markers, diagnoses are defined by behavioral criteria. Thus, preclinical in vivo animal models of NDDs must be optimally utilized. For this reason, experts in the field of behavioral neuroscience convened a workshop with the goals of reviewing current behavioral studies, reports, and assessments in rodent models. Goals included: (a) identifying the maximal utility and limitations of behavior in animal models with construct validity; (b) providing recommendations for phenotyping animal models; and (c) guidelines on how in vivo models should be used and reported reliably and rigorously while acknowledging their limitations. We concluded by recommending minimal criteria for reporting in manuscripts going forward. The workshop elucidated a consensus of potential solutions to several problems, including revisiting claims made about animal model links to ASD (and related conditions). Specific conclusions included: mice (or other rodent or preclinical models) are models of the neurodevelopmental insult, not specifically any disorder (e.g., ASD); a model that perfectly recapitulates a disorder such as ASD is untenable; and greater attention needs be given to validation of behavioral testing methods, data analysis, and critical interpretation. [ABSTRACT FROM AUTHOR]

Summary: Obesity is associated with hypothalamic–pituitary–testicular axis dysregulation in males. Here, we summarize recent evidence derived from clinical trials and studies in preclinical animal models regarding the role of androgen receptor (AR) signaling in the pathophysiology of males with obesity. We also discuss therapeutic strategies targeting the AR for the treatment of obesity and their limitations and provide insight into the future research necessary to advance this field. [ABSTRACT FROM AUTHOR]

Epilepsy is a common neurological disease characterized by the enduring predisposition of the brain to generate seizures. Among the recognized causes, a role played by the gut microbiota in epilepsy has been hypothesized and supported by new investigative approaches. To dissect the microbiota‐gut‐brain (MGB) axis involvement in epilepsy, in vitro modeling approaches arouse interest among researchers in the field. This review summarizes, first of all, the evidence of a role of the MGB axis in epilepsy by providing an overview of the recent clinical and preclinical studies and showing how dietary modification, microbiome supplementations, and hence, microbiota alterations may have an impact on seizures. Subsequently, the currently available strategies to study epilepsy on animal and in vitro models are described, focusing attention on these latter and the technological challenges for integration with already existing MGB axis models. Finally, the implementation of existing epilepsy in vitro systems is discussed, offering a complete overview of the available technological tools which may improve reliability and clinical translation of the results towards the development of innovative therapeutic approaches, taking advantage of complementary technologies. [ABSTRACT FROM AUTHOR]

Models are useful tools for understanding and predicting ecological patterns and processes. Under ongoing climate and biodiversity change, they can greatly facilitate decision‐making in conservation and restoration and help designing adequate management strategies for an uncertain future. Here, we review the use of spatially explicit models for decision support and to identify key gaps in current modelling in conservation and restoration. Of 650 reviewed publications, 217 publications had a clear management application and were included in our quantitative analyses. Overall, modelling studies were biased towards static models (79%), towards the species and population level (80%) and towards conservation (rather than restoration) applications (71%). Correlative niche models were the most widely used model type. Dynamic models as well as the gene‐to‐individual level and the community‐to‐ecosystem level were underrepresented, and explicit cost optimisation approaches were only used in 10% of the studies. We present a new model typology for selecting models for animal conservation and restoration, characterising model types according to organisational levels, biological processes of interest and desired management applications. This typology will help to more closely link models to management goals. Additionally, future efforts need to overcome important challenges related to data integration, model integration and decision‐making. We conclude with five key recommendations, suggesting that wider usage of spatially explicit models for decision support can be achieved by 1) developing a toolbox with multiple, easier‐to‐use methods, 2) improving calibration and validation of dynamic modelling approaches and 3) developing best‐practise guidelines for applying these models. Further, more robust decision‐making can be achieved by 4) combining multiple modelling approaches to assess uncertainty, and 5) placing models at the core of adaptive management. These efforts must be accompanied by long‐term funding for modelling and monitoring, and improved communication between research and practise to ensure optimal conservation and restoration outcomes. [ABSTRACT FROM AUTHOR]

The imidazodiazepine, (5‐(8‐ethynyl‐6‐(pyridin‐2‐yl)‐4H‐benzo [f]imidazole[1,5‐α][1,4]diazepin‐3‐yl) oxazole or KRM‐II‐81) is a new α2/3‐selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half‐life of KRM‐II‐81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities. Incubation of KRM‐II‐81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5‐KRM‐II‐81) that could be evaluated as a potentially longer‐acting analog. In contrast to computer predictions, peak plasma concentrations of D5‐KRM‐II‐81 in rats were not significantly greater than those produced by KRM‐II‐81 after oral administration. Furthermore, brain disposition of KRM‐II‐81 was higher than that of D5‐KRM‐II‐81. The half‐life of the two compounds in either plasma or brain did not statistically differ from one another but the tmax for D5‐KRM‐II‐81 occurred slightly earlier than for KRM‐II‐81. Non‐metabolic considerations might be relevant to the lack of increases in exposure by D5‐KRM‐II‐81. Alternative sites of metabolism on KRM‐II‐81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5‐KRM‐II‐81, like KRM‐II‐81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5‐KRM‐II‐81. [ABSTRACT FROM AUTHOR]

While [11C]palmitate continues to be a promising tracer for cardiovascular Positron Emission Tomography (PET) imaging, unfavourable logistics due to the short half-life of 11C (20 min) and cumbersome labeling methodologies are the major impediments that limit its widespread use. In order to circumvent such limitations, an attempt has been made to explore the potential of 68Ga-labeled fatty acid analogs for metabolic imaging owing to the availability of 68Ga through a 68Ge/68Ga generator on an on-demand basis. In this study, two fatty acid conjugates were synthesized by conjugation of p-SCN-benzyl NOTA with the ω-amino group of 11-amino undecanoic acid and 12-amino dodecanoic acid, respectively, under alkaline conditions. Both derivatives were radiolabeled in high yields with 68Ga obtained from an in-house 68Ge/68Ga generator. Biodistribution studies in Swiss mice showed reasonable myocardial uptake at 2 min for both derivatives (7.4 ± 2.8% ID/g for 11-carbon fatty acid-NOTA conjugate and 6.4 ± 2.1% ID/g for 12-carbon fatty acid-NOTA conjugate), which cleared rapidly over 30 min. However, significant activity was found in blood for both tracers, with heart/blood ratios observed to be below 0.5 at all time points, diminishing the potential of the synthesized complexes for cardiac imaging. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Summary: Antibodies that bind complement components were first identified over 30 years ago. Investigations into their functions in animal models motivated clinical studies that have now generated licensed products and a strong pipeline of future therapeutics. Despite this, the mechanisms of action of one of the first effective C5‐binding antibodies, BB5.1, were not known. Here, we report a new study that reveals these mechanisms, enabling new approaches for designing C5‐binding molecules for therapeutic use. [ABSTRACT FROM AUTHOR]