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Advanced general visual object tracking models have been drastically developed with the access of large annotated datasets and progressive network architectures. However, a general tracker always suffers domain shift when directly adopting to specific testing scenarios. In this paper, we dedicate to addressing the animal tracking problem by proposing a spatio-temporal inference module and a coarse-to-fine tracking strategy. In terms of tracking animals, non-rigid deformation is a typical challenge. Therefore, we particularly design a novel transformer-based inference structure where the changing animal state is transmitted across continuous frames. By explicitly transmitting the appearance variations, this spatio-temporal module enables adaptive target learning, boosting the animal tracking performance compared to the fixed template matching approaches. Besides, considering the altered contours of animals in different frames, we propose to perform coarse-to-fine tracking to obtain a fine-grained animal bounding box with a dedicated distribution-aware regression module. The coarse tracking phase focuses on distinguishing the target against potential distractors in the background. While the fine-grained tracking phase aims at accurately regressing the final animal bounding box. To facilitate animal tracking evaluation, we captured and annotated 145 video sequences with 20 categories from the zoo, forming a new test set for animal tracking, coined ZOO145. We also collected a dataset, AnimalSOT, with 162 video sequences from existing tracking test benchmarks. The experimental performance on animal tracking datasets, MoCA, ZOO145, and AnimalSOT, demonstrate the merit of the proposed approach against advanced general tracking approaches, providing a baseline for future animal tracking studies. [ABSTRACT FROM AUTHOR]

Spleen tissue segmentation is an essential process for analyzing various immunological diseases as observed in the cryo-imaging data. Because manual labeling of the spleen tissue by human experts is not efficient, an automatic segmentation algorithm is needed. In this study, we developed a novel algorithm for automatically segmenting spleen substructures including white pulp and red pulp for the first time. The algorithm is designed for datasets created by a cryo-imaging system. This unique technology can effectively enable cellular tracking anywhere in the whole mouse with single-cell sensitivity. The proposed algorithm consists of four components: initial spleen mask creation, feature extraction, Supervised Patch-based Fuzzy c-Mean (spFCM) classification, and post-processing. The algorithm accurately and efficiently labeled spleen tissues in all experiment settings. The algorithm also improved the spleen segmentation throughput by 90 folds as compared to the manual segmentation. Moreover, we show that our novel spFCM algorithm outperformed traditional fast-learning classifiers as well as the U-Net deep-learning model in many aspects. Two major contributions of this paper are (1) an explainable algorithm for segmenting spleen tissues in cryo-images for the first time and (2) an spFCM algorithm as a new classifier. We also discussed that our work can be beneficial to researchers who work not only in the fields of graft-versus-host disease (GVHD) mouse models, but also in that of other immunological disease models where spleen analysis is essential. Future work building upon our research may lay the foundations for biomedical studies that utilize cryo-imaging technology. [ABSTRACT FROM AUTHOR]

In this article, we move from sensory physiology to psychology and consider the proverbially lazy drone. I will describe how some simple experiments permitted us to understand why males in the Indian paper wasp Ropalidia marginata do no work in the colony even during the time they live in it. Taking the behaviour of feeding larvae as an example of work, we show that male wasps normally do not feed larvae, not because they are incapable of doing so, but because they do not have access to enough food and also because female wasps are so much better at this job. As a confirmation of this conclusion, we could cure the males of their laziness, i.e., get them to feed the larvae by providing them with excess food and leaving them in the presence of hungry larvae, without the presence of females. [ABSTRACT FROM AUTHOR]

The drug development process involves a variety of drug activity evaluations, which can determine drug efficacy, strictly analyze the biological indicators after the drug action, and use these indicators as the preclinical drug evaluation criteria. At present, most of the screening of preclinical anticancer drugs mainly relies on traditional 2D cell culture. However, this traditional technology cannot simulate the tumor microenvironment in vivo, let alone reflect the characteristics of solid tumors in vivo, and has a relatively poor ability to predict drug activity. 3D cell culture is a technology between 2D cell culture and animal experiments, which can better reflect the biological state in vivo and reduce the consumption of animal experiments. 3D cell culture can link the individual study of cells with the study of the whole organism, reproduce in vitro the biological phenotype of cells in vivo more greatly, and thus predict the activity and resistance of anti-tumor drugs more accurately. In this paper, the common techniques of 3D cell culture are discussed, with emphasis on its main advantages and application in the evaluation of anti-tumor resistance, which can provide strategies for the screening of anti-tumor drugs. [ABSTRACT FROM AUTHOR]

Continuing to explore the intriguing world of the Indian paper wasp Ropalidia marginata for one last time, here we will focus on the function of fighting behaviour in two additional contexts (i) the hyper-aggression of the potential queen during queen succession and (ii) during encounters with non-nestmate wasps. We will see again that the function of fighting is different in different contexts. We have already seen two different functions of fighting in two different contexts—to decide who will be the queen and who will be the worker in the context of founding new nests, and to regulate foraging in mature colonies by conveying colony hunger levels to foragers. Here we will see that the function of the potential queen's hyper-aggression is to boost her own ovarian development and the function of aggression towards non-nestmates is to keep them away, and if necessary, to kill! As before, our primary focus will be on how to design simple experiments that will help answer a direct question, while minimising the need for expensive equipment or other facilities. [ABSTRACT FROM AUTHOR]

Continuing to explore the intriguing world of the Indian paper wasp Ropalidia marginata, here we will focus on their fighting behaviour. When wasps fight, there is, as expected, a winner and a loser. The winner is said to have shown dominance behaviour, and the loser is said to have shown subordinate behaviour. What is the function of such dominance-subordinate behaviour? We saw in the 7th article in this series [1] that in the context of founding new nests, wasps fight to decide who would be the queen and who would be the worker. We then saw in the 8th article in this series [2] that when wasps have to decide who would be their next queen in a mature colony, they do not decide by fighting, although they fight for other reasons. We will see in this article that workers continue to show dominance-subordinate behaviour in mature colonies. What is the function of this aggression displayed by the workers? In this article, I will describe two simple experiments that help us answer this question, and show that the function of wasp aggression can be quite different in different contexts. [ABSTRACT FROM AUTHOR]

Continuing to explore the fascinating world of the Indian paper wasp Ropalidia marginata, in this article, we will ask how wasps choose their queens in another context. In the previous article in this series, we saw how a simple experiment revealed that wasps fight, i.e., indulge in dominance-subordinate interactions, and the winner becomes the queen and the loser becomes the worker. This was in the context of new nest foundation. But context matters. When the same wasps once again have to decide who will be their next queen if the first one dies or is experimentally removed, the same rules do not hold. The wasps in a mature colony continue to show dominance-subordinate interactions and can even be arranged in a dominance hierarchy, but the dominance ranks of the wasps do not predict who their next queen will be. How they choose their next queen in this context continues to be an enduring mystery. In this article, I will describe four simple experiments that have helped us come close to nailing the culprit, although I must confess that we have not yet found the smoking gun—the chase is on, and we are hot on the trail—please join in! [ABSTRACT FROM AUTHOR]

Endoscopic submucosal dissection (ESD) is technically challenging and requires a high level of skill. However, there is no effective method of exposing the submucosal plane during dissection. In this study, the efficacy of robot arm-assisted tissue traction for gastric ESD was evaluated using an in vivo porcine model. The stomach of each pig was divided into eight locations. In the conventional ESD (C-ESD) group, one ESD was performed at each location (N = 8). In the robot arm-assisted ESD (R-ESD) group, two ESDs were performed at each location (N = 16). The primary endpoint was the submucosal dissection speed (mm2/s). The robot arm could apply tissue traction in the desired direction and successfully expose the submucosal plane during submucosal dissection in all lesion locations. The submucosal dissection speed was significantly faster in the R-ESD group than in the C-ESD group (p = 0.005). The blind dissection rate was significantly lower in the R-ESD group (P = 0.000). The robotic arm-assisted traction in ESD enabled a significant improvement in submucosal dissection speed, blind dissection rate which suggests the potential for making ESD easier and enhancing procedural efficiency and safety. [ABSTRACT FROM AUTHOR]

Background: Neurogenic meningeal inflammation is regarded as a key driver of migraine headache. Multiple evidence show importance of inflammatory processes in the dura mater for pain generation but contribution of the leptomeninges is less clear. We assessed effects of cortical spreading depolarization (CSD), the pathophysiological mechanism of migraine aura, on expression of inflammatory mediators in the leptomeninges. Methods: A single CSD event was produced by a focal unilateral microdamage of the cortex in freely behaving rats. Three hours later intact cortical leptomeninges and parenchyma of ipsi-lesional (invaded by CSD) and sham-treated contra-lesional (unaffected by CSD) hemispheres were collected and mRNA levels of genes associated with inflammation (Il1b, Tnf, Ccl2; Cx3cl1, Zc3h12a) and endocannabinoid CB2 receptors (Cnr2) were measured using qPCR. Results: Three hours after a single unilateral CSD, most inflammatory factors changed their expression levels in the leptomeninges, mainly on the side of CSD. The meninges overlying affected cortex increased mRNA expression of all proinflammatory cytokines (Il1b, Tnf, Ccl2) and anti-inflammatory factors Zc3h12a and Cx3cl1. Upregulation of proinflammatory cytokines was found in both meninges and parenchyma while anti-inflammatory markers increased only meningeal expression. Conclusion: A single CSD is sufficient to produce pronounced leptomeningeal inflammation that lasts for at least three hours and involves mostly meninges overlying the cortex affected by CSD. The prolonged post-CSD inflammation of the leptomeninges can contribute to mechanisms of headache generation following aura phase of migraine attack. [ABSTRACT FROM AUTHOR]

The biomedical research community addresses reproducibility challenges in animal studies through standardized nomenclature, improved experimental design, transparent reporting, data sharing, and centralized repositories. The ARRIVE guidelines outline documentation standards for laboratory animals in experiments, but genetic information is often incomplete. To remedy this, we propose the Laboratory Animal Genetic Reporting (LAG-R) framework. LAG-R aims to document animals' genetic makeup in scientific publications, providing essential details for replication and appropriate model use. While verifying complete genetic compositions may be impractical, better reporting and validation efforts enhance reliability of research. LAG-R standardization will bolster reproducibility, peer review, and overall scientific rigor. Reproducibility is key to all fields of research, and in the case of animal research, this can be hampered by inconsistent reporting of animal genetics. Here the authors propose a reporting framework and guidelines designed to discuss the validation and standardise the reporting of genetic backgrounds and genetic alterations in animal models. [ABSTRACT FROM AUTHOR]

The recent outbreak of mpox epidemic, caused by monkeypox virus (MPXV), poses a new threat to global public health. Here, we initially assessed the preexisting antibody level to the MPXV B6 protein in vaccinia vaccinees born before the end of the immunization program and then identified two monoclonal antibodies (MAbs), hMB621 and hMB668, targeting distinct epitopes on B6, from one vaccinee. Binding assays demonstrate that both MAbs exhibit broad binding abilities to B6 and its orthologs in vaccinia (VACV), variola (VARV) and cowpox viruses (CPXV). Neutralizing assays reveal that the two MAbs showed potent neutralization against VACV. Animal experiments using a BALB/c female mouse model indicate that the two MAbs showed effective protection against VACV via intraperitoneal injection. Additionally, we determined the complex structure of B6 and hMB668, revealing the structural feature of B6 and the epitope of hMB668. Collectively, our study provides two promising antibody candidates for the treatment of orthopoxvirus infections, including mpox. There are limited therapeutics available for treatment of mpox. In this study, the authors identify two non-competing human neutralizing monoclonal antibodies with protective effects against orthopoxvirus infection in a mouse model and structurally resolve the targeted epitope within the MPXV B6 protein. [ABSTRACT FROM AUTHOR]

Background: Pain, an evolutionarily conserved warning system, lets us recognize threats and motivates us to adapt to those threats. Headache pain from migraine affects approximately 15% of the global population. However, the identity of any putative threat that migraine or headache warns us to avoid is unknown because migraine pathogenesis is poorly understood. Here, we show that a stress-induced increase in pituitary adenylate cyclase-activating polypeptide-38 (PACAP38), known as an initiator of allosteric load inducing unbalanced homeostasis, causes headache-like behaviour in male mice via mas-related G protein-coupled receptor B2 (MrgprB2) in mast cells. Methods: The repetitive stress model and dural injection of PACAP38 were performed to induce headache behaviours. We assessed headache behaviours using the facial von Frey test and the grimace scale in wild-type and MrgprB2-deficient mice. We further examined the activities of trigeminal ganglion neurons using in vivo Pirt-GCaMP Ca2+ imaging of intact trigeminal ganglion (TG). Results: Repetitive stress and dural injection of PACAP38 induced MrgprB2-dependent headache behaviours. Blood levels of PACAP38 were increased after repetitive stress. PACAP38/MrgprB2-induced mast cell degranulation sensitizes the trigeminovascular system in dura mater. Moreover, using in vivo intact TG Pirt-GCaMP Ca2+ imaging, we show that stress or/and elevation of PACAP38 sensitized the TG neurons via MrgprB2. MrgprB2-deficient mice showed no sensitization of TG neurons or mast cell activation. We found that repetitive stress and dural injection of PACAP38 induced headache behaviour through TNF-a and TRPV1 pathways. Conclusions: Our findings highlight the PACAP38-MrgprB2 pathway as a new target for the treatment of stress-related migraine headache. Furthermore, our results pertaining to stress interoception via the MrgprB2/PACAP38 axis suggests that migraine headache warns us of stress-induced homeostatic imbalance. [ABSTRACT FROM AUTHOR]

Abstract  The paper is concerned with how neo-Lockean accounts of personal identity should respond to the challenge of animalist accounts. Neo-Lockean accounts that hold that persons can change bodies via brain transplants or cerebrum transplants are committed to the prima facie counterintuitive denial that a person is an (biologically individuated) animal. This counterintuitiveness can be defused by holding that a person is biological animal (on neo-Lockean views) if the “is” is the “is” of constitution rather than the “is” of identity, and that a person is identical with an animal in a sense of “animal” different from that which requires the persistence conditions of animals to be biological. Another challenge is the “too many minds problem”: if persons and their coincident biological animals share the same physical properties, and mental properties supervene on physical properties, the biological animal will share the mental properties of the person, and so should itself be a person. The response to this invokes a distinction between “thin” properties, which are shared by coincident entities, and “thick” properties which are not so shared. Mental properties, and their physical realizers, are thick, not thin, so are not properties persons share with their bodies or biological animals. The paper rebuts the objection that neo-Lockean accounts cannot explain how persons can have physical properties. To meet a further problem it is argued that the biological properties of persons and those of biological animals are different because of differences in their causal profiles. [ABSTRACT FROM AUTHOR]

In a previous paper, we reported that juvenile barn swallows (Hirundo rustica) trapped during the autumn migratory season and tested in modified Emlen funnels under overcast conditions can use magnetic information for compass orientation, although they did not orient toward the expected migratory direction. To further investigate this behaviour, in the present paper, we report the results of two series of displacement experiments performed on juvenile barn swallows belonging to two different roost sites [Massaciuccoli Lake (ML) and Terzo Cavone (TC)] and tested using the same protocol as that previously adopted. On the whole, the outcome of the ML and TC experiments was quite different with respect to (a) the degree of bird activity within the funnel (substantially lower for TC) and (b) the effect of the experimental displacement on the directional preferences of the tested subjects (not detectable in TC, while evident in ML swallows). Taken together, these results suggest that migrating swallows could react differently to the experimental tests depending on the roost site where they were caught. Indeed, TC swallows, trapped in southern Italy, close to the seacoast, and characterized by fairly large amounts of fat stores, mainly broke off their migratory activity or reoriented their directional preferences toward inland sites, possibly in search of more profitable habitats. On the other hand, ML swallows, trapped about 660 km to the north and characterized by lower amounts of fat stores, apparently tried to compensate for the experimental displacement. [ABSTRACT FROM AUTHOR]

Descending neural pathways in the mammalian auditory system are known to modulate the function of the peripheral auditory system. These pathways include the medial olivocochlear (MOC) efferent innervation to outer hair cells (OHCs) and the acoustic reflex pathways mediating middle ear muscle (MEM) contractions. Based on measurements in humans (Marks and Siegel, companion paper), we applied a sensitive method to attempt to differentiate MEM and MOC reflexes using contralateral acoustic stimulation in mice under different levels of anesthesia. Separation of these effects is based on the knowledge that OHC-generated transient evoked otoacoustic emissions (TEOAE) are delayed relative to the stimulus, and that the MOC reflex affects the emission through its innervation of OHC. In contrast, the MEM-mediated changes in middle ear reflectance alter both the stimulus (with a short delay) and the emission. Using this approach, time averages to transient stimuli were evaluated to determine if thresholds for a contralateral effect on the delayed emission, indicating potential MOC activation, could be observed in the absence of a change in the stimulus pressure. This outcome was not observed in the majority of cases. There were also no statistically significant differences between MEM and putative MOC thresholds, and variability was high for both thresholds regardless of anesthesia level. Since the two reflex pathways could not be differentiated on the basis of activation thresholds, it was concluded that the MEM reflex dominates changes in TEOAEs induced by contralateral noise. This result complicates the identification of purely MOC-induced changes on OAEs in mice unless the MEM reflex is inactivated surgically or pharmacologically. [ABSTRACT FROM AUTHOR]

Background: CircRNAs play a crucial role in the regulation of various cancers. This study aims to investigate the involvement of circCHSY1 in the development of esophageal squamous cell carcinoma (ESCC). Methods: RNA levels were quantified using qRT-PCR, and protein levels were measured by western blot. The stability of circCHSY1 was analyzed using RNase R. The functional effect of circCHSY1 on cell behavior was evaluated by CCK-8, EdU, flow cytometry, transwell, tube formation, and xenograft tumor model assays. The associations among circCHSY1, miR-1229-3p, and Tectonic-1 (TCTN1) were certified by bioinformatics analysis, dual-luciferase reporter assay, and RNA pull-down assay. Results: CircCHSY1 was up-regulated in both ESCC tissues and cell lines in comparison with the control groups. Knockdown of circCHSY1 inhibited the proliferation, migration, invasion, and tube formation and promoted apoptosis of ESCC cells. Mechanistically, circCHSY1 targeted miR-1229-3p, which was downregulated in ESCC tissues and cells. Inhibition of miR-1229-3p attenuated the effects mediated by circCHSY1 suppression. Besides, miR-1229-3p bound to TCTN1, and TCTN1 overexpression restored miR-1229-3p-induced effects in ESCC cells. Animal experiments revealed that circCHSY1 silencing suppressed tumor tumorigenesis in vivo. Conclusion: CircCHSY1 contributed to ESCC cell malignancy, and the underlying mechanism involved the circCHSY1/miR-1229-3p/TCTN1 axis, providing potential therapeutic targets for ESCC. [ABSTRACT FROM AUTHOR]

Background: The upper cervical dorsal root ganglia (DRG) are important for the transmission of sensory information associated with the back of the head and neck, contributing to head pain. Calcitonin receptor (CTR)-based receptors, such as the amylin 1 (AMY1) receptor, and ligands, calcitonin gene-related peptide (CGRP) and amylin, have been linked to migraine and pain. However, the contribution of this system to nociception involving the cervical DRG is unclear. Therefore, this study aimed to determine the relative distribution of the CTR, CGRP, and amylin in upper cervical DRG. Methods: CTR, CGRP, and amylin immunofluorescence was examined relative to neural markers in C1/2 DRG from male and female mice, rats, and human cases. Immunofluorescence was supported by RNA-fluorescence in situ hybridization examining amylin mRNA distribution in rat DRG. Results: Amylin immunofluorescence was observed in neuronal soma and fibres. Amylin mRNA (Iapp) was also detected. Amylin and CGRP co-expression was observed in 19% (mouse), 17% (rat), and 36% (human) of DRG neurons in distinct vesicle-like neuronal puncta from one another. CTR immunoreactivity was present in DRG neurons, and both peptides produced receptor signalling in primary DRG cell cultures. CTR-positive neurons frequently co-expressed amylin and/or CGRP (66% rat; 84% human), with some sex differences. Conclusions: Amylin and CGRP could both be local peptide agonists for CTR-based receptors in upper cervical DRG, potentially acting through autocrine and/or paracrine signalling mechanisms to modulate neuron function. Amylin and its receptors could represent novel pain targets. [ABSTRACT FROM AUTHOR]

This study aims to test the animal spirits theory by Akerlof and Shiller (Animal spirits - how human psychology drives the economy, and why it matters for global capitalism? Princeton University Press) for ethical stock markets using Islamic and sustainable stock indexes during calm and crisis periods. This question helps determine whether ethical finance is driven more by its specific rules or determined by animal spirits. We used data covering January 1996–September 2021, which includes both calm periods and crisis periods (dot-com bubble of 2000, subprime crisis of 2007, global financial crisis of 2008–2009, and COVID-19 recession). Accordingly, we applied different time series tests, ran a quantile regression, and built an econometric framework to empirically test the animal spirits theory. We provide two key findings. First, investor sentiment and consumer confidence significantly affect the dynamics of both ethical stock returns, suggesting further evidence of animal spirits. This finding supports the assumption that investors' emotions and sentiments affect their behaviors and related feelings, for example, spontaneous instinctive that urge to action than inaction, optimism, and so forth, might help to apprehend some investment actions. Second, and interestingly, animal spirit effects enter asymmetrically and nonlinearly as their effects on ethical stock returns are time-varying and vary with the quantile under consideration. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation, mediated by the activation of microglia, contributes to central sensitization, which is associated with the development of chronic migraine (CM). TREM1 receptors amplify the inflammatory response. However, their relationship to CM is unclear. Thus, this study endeavoured to elucidate the exact role of TREM1 in CM. Methods: Nitroglycerin (NTG) was repeatedly administered intraperitoneally to establish the CM model. Mechanical and thermal sensitivities were assessed using von Frey filaments and hot plate assays. Using Western blotting, TREM1, NF-κB pathway, NLRP3 inflammasome components, and proinflammatory cytokines were all detected. Immunofluorescence was used to examine the cellular distribution of TREM1 and NLRP3, the number of microglia, immunoreactivity, and morphological changes. We examined the effects of TREM1 antagonists (LR12) and NF-κB inhibitors (PDTC) on pain behaviour, as well as the production of c-fos and CGRP. Additionally, we investigated whether LR12 and PDTC affect the activation of microglia and the NLRP3 inflammasome. We synthesized siRNA and TREM1-overexpressing plasmids to transfect BV2 cells treated with LPS and normal BV2 cells and treated TREM1-overexpressing BV2 cells with PDTC. The NF-κB pathway, NLRP3 inflammasome components, and proinflammatory cytokines were quantified using Western blotting. Results: Following NTG administration, the expression of TREM1 was significantly upregulated and exclusively localized in microglia in the TNC, and was well co-localized with NLRP3. Furthermore, activation of the classical NF-κB pathway was observed. Pre-treatment with LR12 and PDTC effectively attenuated mechanical hypersensitivity, suppressed the expression of c-fos and CGRP, and inhibited NF-κB activity in CM mice. Additionally, inhibition of TREM1 and NF-κB activity mitigated NTG-induced microglia and NLRP3 activation, as well as proinflammatory cytokines production. In vitro, knockdown of TREM1 resulted in attenuated activation of the NF-κB pathway following lipopolysaccharide (LPS) treatment and reduced expression of NLRP3 inflammasome components as well as proinflammatory cytokines. After TREM1 overexpression, the NF-κB pathway was activated, NLRP3 inflammasome components and proinflammatory cytokines were upregulated, and PDTC reversed this phenomenon. Conclusions: Our findings suggest that TREM1 regulates microglia and NLRP3 activation via the NF-κB pathway, thereby contributing to central sensitization and implicating its involvement in chronic migraine pathogenesis. [ABSTRACT FROM AUTHOR]

Background/objectives: Insects have been the subject of recent attention as a potentially environmentally sustainable and nutritious alternative to traditional protein sources. The purpose of this paper is to test the hypothesis that insects are nutritionally preferable to meat, using two evaluative tools that are designed to combat over- and under-nutrition. Subjects/methods: We selected 183 datalines of publicly available data on the nutrient composition of raw cuts and offal of three commonly consumed meats (beef, pork and chicken), and six commercially available insect species, for energy and 12 relevant nutrients. We applied two nutrient profiling tools to this data: The Ofcom model, which is used in the United Kingdom, and the Nutrient Value Score (NVS), which has been used in East Africa. We compared the median nutrient profile scores of different insect species and meat types using non-parametric tests and applied Bonferroni adjustments to assess for statistical significance in differences. Results: Insect nutritional composition showed high diversity between species. According to the Ofcom model, no insects were significantly 'healthier' than meat products. The NVS assigned crickets, palm weevil larvae and mealworm a significantly healthier score than beef (P<0.001) and chicken (P<0.001). No insects were statistically less healthy than meat. Conclusions: Insect nutritional composition is highly diverse in comparison with commonly consumed meats. The food category 'insects' contains some foods that could potentially exacerbate diet-related public health problems related to over-nutrition, but may be effective in combating under-nutrition. [ABSTRACT FROM AUTHOR]

Background: In oncology, an emerging paradigm emphasises molecularly targeted approaches for cancer prevention and therapy and the use of adjuvant chemotherapeutics to overcome cisplatin limitations. Owing to their safe use, some polyphenols, such as curcumin, modulate important pathways or molecular targets in cancers. This paper focuses on curcumin as an adjuvant molecule to cisplatin by analysing its potential implications on the molecular targets, signal transducer and activator of transcription 3 (STAT3) and NF-E2 p45-related factor 2 (Nrf-2), in tumour progression and cisplatin resistance in vitro and the adverse effect ototoxicity in vivo.Methods: The effects of curcumin and/or cisplatin treatment have been evaluated in head and neck squamous cell carcinoma as well as in a rat model of cisplatin-induced ototoxicity by using immunofluorescence, western blot, and functional and morphological analysis.Results: This study demonstrates that curcumin attenuates all stages of tumour progression (survival, proliferation) and, by targeting pSTAT3 and Nrf-2 signalling pathways, provides chemosensitisation to cisplatin in vitro and protection from its ototoxic adverse effects in vivo.Conclusions: These results indicate that curcumin can be used as an efficient adjuvant to cisplatin cancer therapy. This treatment strategy in head and neck cancer could mediate cisplatin chemoresistance by modulating therapeutic targets (STAT3 and Nrf2) and, at the same time, reduce cisplatin-related ototoxic adverse effects. [ABSTRACT FROM AUTHOR]

Reports the criticism on the biologists who tried to test the performance of a laboratory genetic analysis in the United States. Use of hair from a captive lynx as a blind control; Reaction of interest groups and congressional critics of US environmental-protection laws; Accusation of conspiring with environmental groups.

Objective:Reactive oxygen species (ROS) are significantly upregulated after spinal cord injury (SCI). MicroRNAs (miRNAs) are reported to be widely involved in regulating gene expression. This paper aims to explore the correlation between ROS-induced cell apoptosis and abnormal miRNA expression after SCI.Methods:To profile the expression of miRNAs after SCI, miRNA microarray was applied and the result was verified by reverse transcription quantitative PCR (RT-qPCR). ROS production following H2O2 stimulation was examined using dihydroethidium staining and flow cytometry. The levels of miR-200c after H2O2 treatment were determined using RT-qPCR. Cell viability and apoptosis were examined in murine BV-2 cells transfected with miR-200c mimics, inhibitor or negative control. Immunofluorescence and western blot were used to further explore the effects of miR-200c on Fas-associated phosphatase-1 (FAP-1) expression.Results:MiR-200c was showed to be significantly increased after SCI by miRNA microassay and RT-qPCR. ROS production enhanced miR-200c expression in a dose-dependent manner and induced significant apoptosis in BV-2 cells. The upregulation of miR-200c reduced cell viability and induced BV-2 cell apoptosis. MiR-200c negatively regulated the expression of FAP-1, thereby inducing FAS signaling-induced apoptosis. RT-qPCR analysis showed that the FAP-1-targeting small interfering RNA (siRNA) did not affect the level of miR-200c in murine BV-2 cells. In addition, suppression of FAP-1 by siRNA promoted apoptosis, even in cells that were co-transfected with the miR-200c inhibitor.Conclusions:The current data suggested that miR-200c contributes to apoptosis in murine BV-2 cells by regulating the expression of FAP-1. This proposes a therapeutic target for enhancing neural cell functional recovery after SCI. [ABSTRACT FROM AUTHOR]

Properly handling animals and understanding their habits are crucial to establish a society where humans and animals coexist. Thus, identifying individual animals, including their possessions, and adequately managing each animal is necessary. Although several conventional identification methods exist, such as the use of ear punch, tattoos, and radio frequency (RF) chips, they require several processes and external apparatus. In this study, we proposed a new biotagging method using a microneedle array for animal identification. Our approach uses dissolvable microneedle arrays as a single patch to deliver dyes directly into the skin layer. Additionally, we developed a new fabrication method for customised female moulds to realise microneedle array patches (MAPs) with patterns of different characters and number. The characteristics and feasibility of the patterned MAPs were confirmed through basic evaluations and animal experiments. Moreover, we confirmed that patterns formed from biotagging using the developed patterned MAPs lasted over one month with clear readability. Finally, we confirmed that our patterned MAPs successfully realised biotagging on rat skin with the designated patterns including characters and number patterns. The proposed method is expected to enable minimally invasive tagging without external equipment or complex processes. In addition, the developed method could be used to embed various tags into the skin of animals and humans in the future. [ABSTRACT FROM AUTHOR]

Cells living in geometrically confined microenvironments are ubiquitous in various physiological processes, e.g., wound closure. However, it remains unclear whether and how spatially geometric constraints on host cells regulate bacteria-host interactions. Here, we reveal that interactions between bacteria and spatially constrained cell monolayers exhibit strong spatial heterogeneity, and that bacteria tend to adhere to these cells near the outer edges of confined monolayers. The bacterial adhesion force near the edges of the micropatterned monolayers is up to 75 nN, which is ~3 times higher than that at the centers, depending on the underlying substrate rigidities. Single-cell RNA sequencing experiments indicate that spatially heterogeneous expression of collagen IV with significant edge effects is responsible for the location-dependent bacterial adhesion. Finally, we show that collagen IV inhibitors can potentially be utilized as adjuvants to reduce bacterial adhesion and thus markedly enhance the efficacy of antibiotics, as demonstrated in animal experiments. Cells in the body live in geometrically constrained microenvironments. Here, Feng at al report that these constraints induce collagen IV expression which is responsible for location dependent bacterial adhesion. [ABSTRACT FROM AUTHOR]

Background: Migraine is a disabling neurological disorder, characterized by recurrent headaches. During migraine attacks, individuals often experience sensory symptoms such as cutaneous allodynia which indicates the presence of central sensitization. This sensitization is prevented by oral administration of propranolol, a common first-line medication for migraine prophylaxis, that also normalized the activation of the locus coeruleus (LC), considered as the main origin of descending noradrenergic pain controls. We hypothesized that the basal modulation of trigeminal sensory processing by the locus coeruleus is shifted towards more facilitation in migraineurs and that prophylactic action of propranolol may be attributed to a direct action in LC through beta-adrenergic receptors. Methods: We used simultaneous in vivo extracellular recordings from the trigeminocervical complex (TCC) and LC of male Sprague–Dawley rats to characterize the relationship between these two areas following repeated meningeal inflammatory soup infusions. Von Frey Hairs and air-puff were used to test periorbital mechanical allodynia. RNAscope and patch-clamp recordings allowed us to examine the action mechanism of propranolol. Results: We found a strong synchronization between TCC and LC spontaneous activities, with a precession of the LC, suggesting the LC drives TCC excitability. Following repeated dural-evoked trigeminal activations, we observed a disruption in coupling of activity within LC and TCC. This suggested an involvement of the two regions' interactions in the development of sensitization. Furthermore, we showed the co-expression of alpha-2A and beta-2 adrenergic receptors within LC neurons. Finally propranolol microinjections into the LC prevented trigeminal sensitization by desynchronizing and decreasing LC neuronal activity. Conclusions: Altogether these results suggest that trigemino-coerulean coupling plays a pivotal role in migraine progression, and that propranolol's prophylactic effects involve, to some extent, the modulation of LC activity through beta-2 adrenergic receptors. This insight reveals new mechanistic aspects of LC control over sensory processing. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer worldwide, with an estimated 2.3 million new cases diagnosed every year. Effective measures for cancer prevention and cancer therapy require a detailed understanding of the individual key disease mechanisms involved and their interactions at the molecular, cellular, tissue, organ, and organism level. In that regard, the rapid progress of biomedical and toxicological research in recent years now allows the pursuit of new approaches based on non-animal methods that provide greater mechanistic insight than traditional animal models and therefore facilitate the development of Adverse Outcome Pathways (AOPs) for human diseases. We performed a systematic review of the current state of published knowledge with regard to breast cancer to identify relevant key mechanisms for inclusion into breast cancer AOPs, i.e. decreased cell stiffness and decreased cell adhesion, and to concurrently map non-animal methods addressing these key events. We conclude that the broader sharing of expertise and methods between biomedical research and toxicology enabled by the AOP knowledge management framework can help to coordinate global research efforts and accelerate the transition to advanced non-animal methods, which, when combined into powerful method batteries, closely mimic human physiology and disease states without the need for animal testing. [ABSTRACT FROM AUTHOR]

Background Several studies have shown that the TGF-β signaling pathway plays a critical role in colorectal cancer (CRC) pathogenesis. The aim of the current study is to investigate the therapeutic potential of Vactosertib (EW-7197), a selective inhibitor of TGF-β receptor type I, either alone or in combination with the standard first-line chemotherapeutic treatment, 5-Fluorouracil (5-FU), in CRC progression in both cellular and animal models. Methods Real-Time PCR, Zymography, enzyme-linked immunosorbent assay (ELISA), Hematoxylin and Eosin (H&E) tissue staining, and Flow cytometry techniques were applied to determine the anti-tumor properties of this novel TGF-β inhibitor in in vitro (CT-26 cell line) and in vivo (inbred BALB/C mice) samples. Results Our findings showed that Vactosertib decreased cell proliferation and induced spheroid shrinkage. Moreover, this inhibitor suppressed the cell cycle and its administration either alone or in combination with 5-FU induced apoptosis by regulating the expression of p53 and BAX proteins. It also improved 5-FU anti-cancer effects by decreasing the tumor volume and weight, increasing tumor necrosis, and regulating tumor fibrosis and inflammation in an animal model. Vactosertib also enhanced the inhibitory effect of 5-FU on invasive behavior of CRC cells by upregulating the expression of E-cadherin and inhibiting MMP-9 enzymatic activity. Conclusion This study demonstrating the potent anti-tumor effects of Vactosertib against CRC progression. Our results clearly suggest that this inhibitor could be a promising agent reducing CRC tumor progression when administered either alone or in combination with standard treatment in CRC patients. [ABSTRACT FROM AUTHOR]

Background Clove volatile oil (CVO) and its major compound, eugenol (EUG), have anxiolytic effects, but their clinical use has been impaired due to their low bioavailability. Thus, their encapsulation in nanosystems can be an alternative to overcome these limitations. Objectives This work aims to prepare, characterize and study the anxiolytic potential of CVO loaded-nanoemulsions (CVONE) against anxious-like behavior in adult zebrafish (Danio rerio). Methods The CVO-NE was prepared using Agaricus blazei Murill polysaccharides as stabilizing agent. The drug-excipient interactions were performed, as well as colloidal characterization of CVO-NE and empty nanoemulsion (B-NE). The acute toxicity and potential anxiolytic activity of CVO, EUG, CVO-NE and B-NE against adult zebrafish models were determined. Results CVO, EUG, CVO-NE and B-NE presented low acute toxicity, reduced the locomotor activity and anxious-like behavior of the zebrafish at 4 -- 20 mg kg--1. CVO-NE reduced the anxious-like behavior of adult zebrafish without affecting their locomotor activity. In addition, it was demonstrated that anxiolytic activity of CVO, EUG and CVO-NE is linked to the involvement of GABAergic pathway. Conclusion Therefore, this study demonstrates the anxiolytic effect of CVO, in addition to providing a new nanoformulation for its administration. [ABSTRACT FROM AUTHOR]

Background Trehalose is a non-reducing disaccharide synthesized by lower organisms. It has recently received special attention because of its neuroprotective properties by stimulating autophagy in Parkinson's disease (PD) models. Therefore, evaluating whether trehalose affects metabolic organs is vital to determine its neurotherapeutic safety. Methods We validated the trehalose neuroprotective dosage in a PD model induced with intraperitoneal paraquat administration twice weekly for 7 weeks. One week before paraquat administration, mice were treated with trehalose in the drinking water and continued along with paraquat treatment. Histological and morphometrical analyses were conducted on the organs involved in trehalose metabolism, including the liver, pancreas, and kidney. Results Paraquat-induced dopaminergic neuronal loss was significantly decreased by trehalose. After trehalose treatment, the liver morphology, the mononucleated/binucleated hepatocytes percentage, and sinusoidal diameter remained unchanged in each liver lobes. Endocrine and exocrine pancreas's histology was not affected, nor was any fibrotic process observed. The islet of Langerhans's structure was preserved when analyzing the area, the largest and smallest diameter, and circularity. Renal morphology remained undamaged, and no changes were identified within the glomerular basement membrane. The renal corpuscle structure did not suffer alterations in the Bowman's space, area, diameter, circularity, perimeter, and cellularity. Besides, the renal tubular structuress luminal area and internal and external diameter were preserved. Conclusion Our study demonstrates that systemic trehalose administration preserved the typical histological architecture of the organs involved in its metabolism, supporting its safety as a potential neuroprotective agent. [ABSTRACT FROM AUTHOR]

A minimal necessary condition for preclinical studies to contribute to risk assessments of e-cigarettes (ECs) is the ability to expose laboratory animals to an appropriate dosage of aerosols. In this study, we examined the fulfilment of this essential consistency condition for the ECX-Joyetech E-Vic Mini (ECX), a piece of computerized exposure equipment manufactured by SCIREQ, which has been employed by numerous in vivo testing. We began by calibrating the customary Evic VTC mini device mod and the 4 coils available, reproducing in the laboratory the operation of the ECX in the power-control and temperature-control modes, using puffing parameters recommended by its documentation. We then conducted the following tests for each coil: (1) verifying whether the generated aerosols satisfy an optimal operational regime, free from overheating, as determined by a linear relation between the mass of vaporized e-liquid vs. supplied power and (2) obtaining the mean yields of aldehydes for each of the tested power settings and coils. The results of these tests show that, under the main conditions used in in vivo testing, the ECX equipment fails to comply with these consistency requirements, especially for coils with low subohm resistance, a shortcoming that can be corrected by applying much larger airflows for these coils. Therefore, the outcomes of preclinical studies using the ECX equipment should be examined with great scepticism and subjected to further testing. [ABSTRACT FROM AUTHOR]

Longitudinal animal experiments in the field of regenerative biology often require repeated use of short-term anesthesia (minutes to a few hours). Regain of consciousness limits the level of acceptable invasiveness of procedures, and it makes it difficult to untangle behavioral changes caused by injury to physiological processes involved in the regenerative response. Therefore, a method to keep a regenerative research animal in a comatose state under continuous anesthesia during regenerative experiments often spanning months, would be ethically and experimentally desirable. Here we report on a method using propofol based anesthesia in an isosmotic environment that allows for continuous anesthesia of regenerating axolotls for 60 days with a 75% survival rate, thus spanning the majority of a full regenerative cycle following limb amputation or cryoinjury to the heart. No differences were detected in the axolotl's ability to regenerate amputated limbs and cardiac cryo-injury while anesthetized, however some regenerative failures in the limb were observed in both anesthetized and unanesthetized control groups, most likely caused by prolonged fasting. Sixty days of anesthesia may be approaching a level were kidney function is affected, but the 75% surviving anesthetized animals recovered well after anesthesia and showed a full behavioral recovery within 17 days. [ABSTRACT FROM AUTHOR]

Animal studies are unavoidable in evaluating chemical and drug safety. Generative Adversarial Networks (GANs) can generate synthetic animal data by learning from the legacy animal study results, thus may serve as an alternative approach to assess untested chemicals. AnimalGAN, a GAN method to simulate 38 rat clinical pathology measures, was developed with significant robustness even for the drugs that vary significantly from these used during training, both in terms of chemical structure, drug class, and the year of FDA approval. AnimalGAN showed comparable results in hepatotoxicity assessment as using the real animal data and outperformed 12 conventional quantitative structure-activity relationship approaches. Using AnimalGAN, a virtual experiment of 100,000 rats ranked hepatotoxicity of three structurally similar drugs in a similar trend that has been observed in human population. AnimalGAN represented a significant step with artificial intelligence towards the global effort in replacement, reduction, and refinement (3Rs) of animal use. Generative AI has the potential to transform the way chemical and drug safety research is conducted. Here the authors show AnimalGAN, a model developed using Generative Adversarial Networks, which simulates virtual animal experiments to generate multidimensional rat clinical pathology measurements. [ABSTRACT FROM AUTHOR]

In the brain, many regions work in a network-like association, yet it is not known how durable these associations are in terms of activity and could survive without structural connections. To assess the association or similarity between brain regions with a generating approach, this study evaluated the similarity of activities of neurons within each region after disconnecting between regions. The "generation" approach here refers to using a multi-layer LSTM (Long Short-Term Memory) model to learn the rules of activity generation in one region and then apply that knowledge to generate activity in other regions. Surprisingly, the results revealed that activity generation from one region to disconnected regions was possible with similar accuracy to generation between the same regions in many cases. Notably, firing rates and synchronization of firing between neuron pairs, often used as neuronal representations, could be reproduced with precision. Additionally, accuracies were associated with the relative angle between brain regions and the strength of the structural connections that initially connected them. This outcome enables us to look into trends governing non-uniformity of the cortex based on the potential to generate informative data and reduces the need for animal experiments. A new approach using a multi-layer LSTM network for generating and evaluating synthetic neural spike data is developed to assess homology between regions, demonstrating that different cortical areas can sometimes generate mutual neural activity. [ABSTRACT FROM AUTHOR]

The significance of hyperactive astrocytes in neuropathic pain is crucial. However, the association between medullary astrocytes and trigeminal neuralgia (TN)-related pain processing is unclear. Here, we examined how optogenetic inhibition of medullary astrocytes in the trigeminal nucleus caudalis (TNC) regulates pain hypersensitivity in an infraorbital nerve (ION) constricted TN model. We used adult Sprague Dawley rats subjected to infraorbital nerve (ION) constriction to mimic TN symptoms, with naive and sham rats serving as controls. For in vivo optogenetic manipulations, rats stereotaxically received AAV8-GFAP-eNpHR3.0-mCherry or AAV8-GFAP-mCherry at the trigeminal nucleus caudalis (TNC). Open field, von Frey, air puff, and acetone tests measured pain behavioral flexibility. In vivo thalamic recordings were obtained simultaneously with optogenetic manipulation in the TNC. Orofacial hyperalgesia and thalamic hyperexcitability were both accompanied by medullary astrocyte hyperactivity, marked by upregulated GFAP. The yellow laser-driven inhibition of TNC astrocytes markedly improved behavioral responses and regulated thalamic neuronal responses. Halorhodopsin-mediated inhibition in medullary astrocytes may modify the nociceptive input transmitted through the trigeminothalamic tract and pain perception. Taken together, these findings imply that this subpopulation in the TNC and its thalamic connections play a significant role in regulating the trigeminal pain circuitry, which might aid in the identification of new therapeutic measures in TN management. [ABSTRACT FROM AUTHOR]

Nowadays, skin cancer is considered a serious disorder in which early identification and treatment of the disease are essential to ensure the stability of the patients. Several existing skin cancer detection methods are introduced by employing deep learning (DL) to perform skin disease classification. Convolutional neural networks (CNNs) can classify melanoma skin cancer images. But, it suffers from an overfitting problem. Therefore, to overcome this problem and to classify both benign and malignant tumors efficiently, the multi-stage faster RCNN-based iSPLInception (MFRCNN-iSPLI) method is proposed. Then, the test dataset is used for evaluating the proposed model performance. The faster RCNN is employed directly to perform image classification. This may heavily raise computation time and network complications. So, the iSPLInception model is applied in the multi-stage classification. In this, the iSPLInception model is formulated using the Inception-ResNet design. For candidate box deletion, the prairie dog optimization algorithm is utilized. We have utilized two skin disease datasets, namely, ISIC 2019 Skin lesion image classification and the HAM10000 dataset for conducting experimental results. The methods' accuracy, precision, recall, and F1 score values are calculated, and the results are compared with the existing methods such as CNN, hybrid DL, Inception v3, and VGG19. With 95.82% accuracy, 96.85% precision, 96.52% recall, and 0.95% F1 score values, the output analysis of each measure verified the prediction and classification effectiveness of the method. [ABSTRACT FROM AUTHOR]

This study concerns large margin nearest neighbors classifier and its multi-metric extension as the efficient approaches for metric learning which aimed to learn an appropriate distance/similarity function for considered case studies. In recent years, many studies in data mining and pattern recognition have demonstrated that a learned metric can significantly improve the performance in classification, clustering and retrieval tasks. The paper describes application of the metric learning approach to in silico assessment of chemical liabilities. Chemical liabilities, such as adverse effects and toxicity, play a significant role in drug discovery process, in silico assessment of chemical liabilities is an important step aimed to reduce costs and animal testing by complementing or replacing in vitro and in vivo experiments. Here, to our knowledge for the first time, a distance-based metric learning procedures have been applied for in silico assessment of chemical liabilities, the impact of metric learning on structure-activity landscapes and predictive performance of developed models has been analyzed, the learned metric was used in support vector machines. The metric learning results have been illustrated using linear and non-linear data visualization techniques in order to indicate how the change of metrics affected nearest neighbors relations and descriptor space. [ABSTRACT FROM AUTHOR]

Study design:Literature review.Objectives:Spinal cord injury (SCI) remains a major public health issue in developed countries as well as worldwide. The pathophysiology of SCI is characterized by an initial primary injury followed by secondary deterioration. Although the etiology and pathogenesis of SCI remain to be fully understood, it has been suggested that reactive oxygen species (ROS) and oxidative stress have a significant role in the pathophysiology of SCI. Thus, alleviating oxidative stress may be an effective strategy for therapeutic intervention of SCI. The aim of this review was to describe (i) the sources of ROS as well as the major antioxidant defenses with particular attention being paid to lipid peroxidation; (ii) the biomarkers of oxidative stress in SCI and (iii) the neuroprotective effects of various compounds with antioxidative properties in animal models of SCI.Methods:PubMed, one of the most comprehensive biomedical databases, was searched from 1976-2011. All relevant papers were read by title, abstract and full-length article.Results:Oxidative stress is considered a hallmark of injury of SCI. Thus, alleviating oxidative stress may be an effective way of therapeutic intervention of SCI. Two of these agents, the glucocorticoid steroid methylprednisolone and the non-glucocorticoid 21-aminosteroid tirilazad, have been shown to possess significant antioxidant activities and improve recovery of SCI patients in clinical trials. Other promising botanical compounds and their molecular targets and mechanisms of action with regard to potential protection against SCI were also described. These include carotenoids and phenolic compounds.Conclusion:ROS and oxidative stress have a significant role in the pathophysiology of SCI. Alleviating oxidative stress is be an effective strategy for therapeutic intervention of SCI. Extensive research over the past several decades has identified numerous bioactive compounds that have antioxidative stress benefits in animal models of SCI. Thus, continued studies on bioactive compounds with ROS-scavenging capacity may lead to the development of effective antioxidant-based modalities for treating SCI in human subjects. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "A Matter of Life and Death" in a 2006 issue.

Taking up the body turn in sociology, this paper discusses scientific practices as embodied action from the perspective of Husserl's phenomenological theory of the 'Body'. Based on ethnographic data on a biology laboratory it will discuss the importance of the scientist's Body for the performance of scientific activities. Successful researchers have to be skilled workers using their embodied knowledge for the process of tinkering towards the material transformation of their objects for data production. The researcher's body then is an instrument of measuring as well as a kind of archive of knowing. Their body becomes a disciplined instrument which has its own place and function inside the laboratory. Furthermore, the appresentational apperception of Bodies (Husserl) is being discussed as a basis for the emotional and ethical concerns towards laboratory-animals. Attitudes towards animals in the laboratory setting (as well as elsewhere) are highly emotional. Nevertheless, following the literature of the sociology of the body, those emotional reactions still follow certain cultural patterns which themselves can be understood as embodied ways of knowing 'right' or 'wrong'. Besides as an instrument, the scientist's body can also be understood as a resource of emotional attachment towards animals. It is an instrument for performing transformation as well as one for caring. [ABSTRACT FROM AUTHOR]

This paper describes results from a stochastic computational neuron model that simulates the effects of rate adaptation on the responses to electrical stimulation in the form of pulse trains. We recently reported results from a single-node computational model that included a novel element that tracks external potassium ion concentration so as to modify membrane voltage and cause adaptation-like responses. Here, we report on an improved version of the model that incorporates the anatomical components of a complete feline auditory nerve fiber (ANF) so that conduction velocity and effects of manipulating the site of excitation can be evaluated. Model results demonstrate rate adaptation and changes in spike amplitude similar to those reported for feline ANFs. Changing the site of excitation from a central to a peripheral axonal site resulted in plausible changes in latency and relative spread (i.e., dynamic range). Also, increasing the distance between a modeled ANF and a stimulus electrode tended to decrease the degree of rate adaptation observed in pulse-train responses. This effect was clearly observed for high-rate (5,000 pulse/s) trains but not low-rate (250 pulse/s) trains. Finally, for relatively short electrode-to-ANF distances, increases in modeled ANF diameter increased the degree of rate adaptation. These results are compared against available feline ANF data, and possible effects of individual parameters are discussed. [ABSTRACT FROM AUTHOR]

The role of innate immunity and macrophage recruitment to the inner ear after hair cell injury is a subject where little is known. In this paper, we demonstrate recruitment of monocytes and macrophages to the inner ear after kanamycin. We also examined the effect of fractalkine receptor (CX3CR1) deletion in kanamycin ototoxicity. We observed more functional and structural damage in CX3CR1 null mice compared to wild-type and heterozygous littermates. In order to determine if increased susceptibility to kanamycin resulted from CX3CR1 deletion from cochlear leukocytes, we created bone marrow chimeras by transplanting CX3CR1-null bone marrow into wild-type mice whose native bone marrow was ablated by lethal irradiation. These mice were then treated with kanamycin sulfate. Auditory brainstem responses (ABR), hair cell counts, and numbers of macrophages recruited to the cochlea were recorded in irradiated mice that received either wild-type, CX3CR1 heterozygous, or CX3CR1 knockout bone marrow. A strong correlation was present between numbers of macrophages and hair cell death in recipients transplanted with CX3CR1 null marrow. No correlation between macrophage number and hair cell loss was present in mice transplanted with wild-type or CX3CR1 heterozygous marrow. We suggest that CX3CR1 plays a role in modulating the detrimental effects of cochlear macrophages after kanamycin ototoxicity. Our data point to the possibility that CX3CR1-deficient cochlear macrophages exacerbate kanamycin ototoxicity while CX3CR1-expressing monocytes do not. [ABSTRACT FROM AUTHOR]

Background: The new European Regulation on chemical safety, REACH, (Registration, Evaluation, Authorisation and Restriction of CHemical substances), is in the process of being implemented. Many chemicals used in industry require additional testing to comply with the REACH regulations. At the same time EU member states are attempting to reduce the number of animals used in experiments under the 3 Rs policy, (refining, reducing, and replacing the use of animals in laboratory procedures). Computational techniques such as QSAR have the potential to offer an alternative for generating REACH data. The FP6 project CAESAR was aimed at developing QSAR models for 5 key toxicological endpoints of which skin sensitisation was one. Results: This paper reports the development of two global QSAR models using two different computational approaches, which contribute to the hybrid model freely available online. Conclusions: The QSAR models for assessing skin sensitisation have been developed and tested under stringent quality criteria to fulfil the principles laid down by the OECD. The final models, accessible from CAESAR website, offer a robust and reliable method of assessing skin sensitisation for regulatory use. [ABSTRACT FROM AUTHOR]

Background: The effect of glycoengineering a membrane specific anti-carcinoembryonic antigen (CEA) (this paper uses the original term CEA for the formally designated CEACAM5) antibody (PR1A3) on its ability to enhance killing of colorectal cancer (CRC) cell lines by human immune effector cells was assessed. In vivo efficacy of the antibody was also tested.Methods: The antibody was modified using EBNA cells cotransfected with beta-1,4-N-acetylglucosaminyltransferase III and the humanised hPR1A3 antibody genes.Results: The resulting alteration of the Fc segment glycosylation pattern enhances the antibody's binding affinity to the FcgammaRIIIa receptor on human immune effector cells but does not alter the antibody's binding capacity. Antibody-dependent cellular cytotoxicity (ADCC) is inhibited in the presence of anti-FcgammaRIII blocking antibodies. This glycovariant of hPR1A3 enhances ADCC 10-fold relative to the parent unmodified antibody using either unfractionated peripheral blood mononuclear or natural killer (NK) cells and CEA-positive CRC cells as targets. NK cells are far more potent in eliciting ADCC than either freshly isolated monocytes or granulocytes. Flow cytometry and automated fluorescent microscopy have been used to show that both versions of hPR1A3 can induce antibody-dependent cellular phagocytosis (ADCP) by monocyte-derived macrophages. However, the glycovariant antibody did not mediate enhanced ADCP. This may be explained by the relatively low expression of FcgammaRIIIa on cultured macrophages. In vivo studies show the efficacy of glycoengineered humanised IgG1 PR1A3 in significantly improving survival in a CRC metastatic murine model.Conclusion: The greatly enhanced in vitro ADCC activity of the glycoengineered version of hPR1A3 is likely to be clinically beneficial. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) 'pulsed' with an appropriate antigen may elicit an antitumour immune response in mouse models. However, while attempting to develop a DC immunotherapy protocol for the treatment of breast cancer based on the tumour-associated MUC1 glycoforms, we found that unpulsed DCs can affect tumour growth. Protection from RMA-MUC1 tumour challenge was achieved in C57Bl/6 MUC1 transgenic mice by immunising with syngeneic DCs pulsed with a MUC1 peptide. However, unpulsed DCs gave a similar level of protection, making it impossible to evaluate the effect of immunisation of mice with DCs pulsed with the specific peptide. Balb/C mice could also be protected from tumour challenge by immunisation with unpulsed DCs prior to challenge with murine mammary tumour cells (410.4) or these cells transfected with MUC1 (E3). Protection was achieved with as few as three injections of 50,000 naïve DCs per mouse per week, was not dependent on injection route, and was not specific to cell lines expressing human MUC1. However, the use of Rag2-knockout mice demonstrated that the adaptive immune response was required for tumour rejection. Injection of unpulsed DCs into mice bearing the E3 tumour slowed tumour growth. In vitro, production of IFN-gamma and IL-4 was increased in splenic cells isolated from mice immunised with DCs. Depleting CD4 T cells in vitro partially decreased cytokine production by splenocytes, but CD8 depletion had no effect. This paper shows that naïve syngeneic DCs may induce an antitumour immune response and has implications for DC immunotherapy preclinical and clinical trials. [ABSTRACT FROM AUTHOR]

Intervertebral disc (IVD) degeneration is an often investigated pathophysiological condition because of its implication in causing low back pain. As human material for such studies is difficult to obtain because of ethical and government regulatory restriction, animal tissue, organs and in vivo models have often been used for this purpose. However, there are many differences in cell population, tissue composition, disc and spine anatomy, development, physiology and mechanical properties, between animal species and human. Both naturally occurring and induced degenerative changes may differ significantly from those seen in humans. This paper reviews the many animal models developed for the study of IVD degeneration aetiopathogenesis and treatments thereof. In particular, the limitations and relevance of these models to the human condition are examined, and some general consensus guidelines are presented. Although animal models are invaluable to increase our understanding of disc biology, because of the differences between species, care must be taken when used to study human disc degeneration and much more effort is needed to facilitate research on human disc material. [ABSTRACT FROM AUTHOR]

The paper presents the LABAQM system developed for the analysis of laboratory animal behaviours. It is based on qualitative modelling of animal motions. We are dealing with the cognitive phase of the laboratory animal behaviour analysis as a part of the pharmacological experiments. The system is based on the quantitative data from the tracking application and incomplete domain background knowledge. The LABAQM system operates in two main phases: behaviour learning and behaviour analysis. The behaviour learning and behaviour analysis phase are based on symbol sequences, obtained by the transformation of the quantitative data. Behaviour learning phase includes supervised learning procedure, unsupervised learning procedure and their combination. We have shown that the qualitative model of behaviour can be modelled by hidden Markov models. The fusion of supervised and unsupervised learning procedures produces more robust models of characteristic behaviours, which are used in the behaviour analysis phase. [ABSTRACT FROM AUTHOR]

The coxsackievirus and adenovirus receptor (CAR) is a membrane glycoprotein with a cytoplasmic domain, a transmembrane domain and an extracellular region consisting of two immunoglobulin-like domains, an amino-terminal immunoglobulin variable (IgV)-related domain (D1), which is distal to the cell surface, and a proximal IgC2 domain (D2). The coxsackievirus and adenovirus receptor has been shown to exhibit tumour suppression activity in human bladder and prostate cancer cells. In the current paper, we demonstrate that CAR is a tumour suppressor in glioma cells and that the extracellular D2 domain is not required for this inhibitory effect. This finding provides a biological basis for the observation that expression of CAR is downregulated in malignant glioma cells. This suggests that strategies to redirect adenoviruses to achieve CAR-independent infection will be necessary to realise the full potential of adenoviral vectors for cancer gene therapy. [ABSTRACT FROM AUTHOR]

Many exciting findings have been reported in the 15 years since monkeys were first demonstrated to have the capacity to perform computerized tasks. The present data indicate that albino rats can also learn to respond to computer-generated stimuli by manipulating a joystick. Although the rat's control of the cursor is not as skillful as has been reported for primate species, it is clearly better than chance and suggests the great potential for comparative investigation afforded by use of the computer test system. [ABSTRACT FROM AUTHOR]