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\"Xenophon (ca. 430 to ca. 354 BCE), a member of a wealthy but politically quietist Athenian family and an admirer of Socrates, left Athens in 401 BCE to serve as a mercenary commander for Cyrus the Younger of Persia, then joined the staff of King Agesilaus II of Sparta before settling in Elis and, in the aftermath of the battle of Leuctra in 371 BCE, retiring to Corinth. His historical and biographical works, Socratic dialogues and reminiscences, and short treatises on hunting, horsemanship, economics, and the Spartan constitution are richly informative about his own life and times. This volume collects Xenophon's portrayals of his associate, Socrates. In Memorabilia (or Memoirs of Socrates) and in Oeconomicus, a dialogue about household management, we see the philosopher through Xenophon's eyes. Here, as in the accompanying Symposium, we also obtain insight on life in Athens. The volume concludes with Xenophon's Apology, an interesting complement to Plato's account of Socrates's defense at his trial.\" -- Publisher website.

Pneumonia resulting from infection is one of the leading causes of death worldwide. Pulmonary infection by the respiratory syncytial virus (RSV) is a large burden on human health, for which there are few therapeutic options 1 . RSV targets ciliated epithelial cells in the airways, but how viruses such as RSV interact with receptors on these cells is not understood. Nucleolin is an entry coreceptor for RSV 2 and also mediates the cellular entry of influenza, the parainfluenza virus, some enteroviruses and the bacterium that causes tularaemia 3 , 4 . Here we show a mechanism of RSV entry into cells in which outside-in signalling, involving binding of the prefusion RSV-F glycoprotein with the insulin-like growth factor-1 receptor, triggers the activation of protein kinase C zeta (PKCζ). This cellular signalling cascade recruits nucleolin from the nuclei of cells to the plasma membrane, where it also binds to RSV-F on virions. We find that inhibiting PKCζ activation prevents the trafficking of nucleolin to RSV particles on airway organoid cultures, and reduces viral replication and pathology in RSV-infected mice. These findings reveal a mechanism of virus entry in which receptor engagement and signal transduction bring the coreceptor to viral particles at the cell surface, and could form the basis of new therapeutics to treat RSV infection. Respiratory syncytial virus enters cells by binding to cell-surface IGFR1, which activates PKCζ and induces trafficking of the NCL coreceptor to the RSV particles at the cell surface.

Matrix metalloproteinases (MMPs) normally act extracellularly. Now Marchant et al . report an unexpected nuclear activity for MMP-12 in virus-infected cells in regulating transcription of the gene encoding IκBα and affecting secretion of interferon-α. Interferon-α (IFN-α) is essential for antiviral immunity, but in the absence of matrix metalloproteinase-12 (MMP-12) or IκBα (encoded by NFKBIA ) we show that IFN-α is retained in the cytosol of virus-infected cells and is not secreted. Our findings suggest that activated IκBα mediates the export of IFN-α from virus-infected cells and that the inability of cells in Mmp12 −/− but not wild-type mice to express IκBα and thus export IFN-α makes coxsackievirus type B3 infection lethal and renders respiratory syncytial virus more pathogenic. We show here that after macrophage secretion, MMP-12 is transported into virus-infected cells. In HeLa cells MMP-12 is also translocated to the nucleus, where it binds to the NFKBIA promoter, driving transcription. We also identified dual-regulated substrates that are repressed both by MMP-12 binding to the substrate's gene exons and by MMP-12–mediated cleavage of the substrate protein itself. Whereas intracellular MMP-12 mediates NFKBIA transcription, leading to IFN-α secretion and host protection, extracellular MMP-12 cleaves off the IFN-α receptor 2 binding site of systemic IFN-α, preventing an unchecked immune response. Consistent with an unexpected role for MMP-12 in clearing systemic IFN-α, treatment of coxsackievirus type B3–infected wild-type mice with a membrane-impermeable MMP-12 inhibitor elevates systemic IFN-α levels and reduces viral replication in pancreas while sparing intracellular MMP-12. These findings suggest that inhibiting extracellular MMP-12 could be a new avenue for the development of antiviral treatments.

Group housing of gestating sows benefits their welfare by allowing them freedom of movement and the opportunity for social interaction. However, social life could also bring disadvantages for individuals who receive direct aggression or are displaced from the feeder. The aim of this study was to investigate associations between social behaviour, body condition and live weight. Gestating sows (n=298) were investigated on a commercial farm. Sows were housed in mixed parity groups where two single space, ad libitum trough feeders served 12 animals. Sows were weighed, body condition scored and had their back fat layer measured at mixing, 4 weeks after insemination and again before farrowing. Social status was estimated based on the numbers of won and lost agonistic interactions at mixing and at the end of gestation. In addition, tear staining was scored before the farrowing and reproductive performance data were collected. With the aid of video recordings, 100 to 150 interactions per group were observed. Winning percentage at mixing and at the end of gestation were associated (P<0.05) and appeared relatively stable within individuals. Tear staining scores and litter sizes were not associated with winning percentage at the end of gestation. However, live weight, relative weight, body condition and back fat thickness were associated with winning percentage (P<0.05), giving heavier animals an advantage. Low winning percentage related to lower live weight gain, probably due to poorer success in competition for feed. Live weight within a mixed parity group could be used as a proxy measure for social status. Sows with low body condition score and submissive sows might need special attention with regard to group dynamics and housing to alleviate the effects of competition in group housing.

Results from clinical studies suggest that drug relapse and craving are often provoked by exposure to drug-associated contexts. Since 2002, this phenomenon has been modeled in laboratory animals using the ABA renewal model. In the classical version of this model, rats with a history of drug self-administration in one context (A) undergo extinction in a different context (B) and reinstate (or relapse to) drug seeking after exposure to the original drug-associated context (A). In a more recent version of the model introduced in 2013, the experimental conditions in context A are identical to those used in the classical model, but drug-reinforced responding in context B is suppressed by probabilistic punishment. The punishment-based ABA renewal model is proposed to resemble abstinence in humans, which is often initiated by the desire to avoid the negative consequences of drug use. The goal of our review is to discuss similarities and differences in mechanisms that play a role in suppression of drug seeking in context B and context-induced relapse to drug seeking in context A in the two models. We first describe psychological mechanisms that mediate extinction and punishment of drug-reinforced responding in context B. We then summarize recent findings on brain mechanisms of context-induced relapse of drug seeking after extinction, or punishment-imposed abstinence. These findings demonstrate both similarities and differences in brain mechanisms underlying relapse in the two variations of the ABA renewal model. We conclude by briefly discussing clinical implications of the preclinical studies.

Tear staining or chromodacryorrhea refers to a dark stain below the inner corner of the eye, caused by porphyrin-pigmented secretion from the Harderian gland. It has been shown to be a consistent indicator of stress in rats and to correlate with social stress and a barren environment in pigs. The current study was, to our knowledge, the first to test it on commercial pig farms as a potential welfare indicator. The study was carried out on three commercial farms in Finland, in connection to a larger study on the effects of different types of manipulable objects on tail and ear biting and other behavioural parameters. Farm A was a fattening farm, on which 768 growing-finishing pigs were studied in 73 pens. Farm B had a fattening unit, in which 656 growing-finishing pigs were studied in 44 pens, and a farrowing unit, in which 29 sows and their litters totalling 303 piglets were studied in 29 pens. Farm C was a piglet-producing farm, on which 167 breeder gilts were studied in 24 pens. Data collection included individual-level scoring of tear staining; scoring of tail and ear damage in the growing-finishing pigs and breeder gilts; a novel object test for the piglets; and a novel person test for the growing-finishing pigs on Farm B and the breeder gilts on Farm C. On Farm A, tear staining was found to correlate with tail damage scores (n=768, r s =0.14, P<0.001) and ear damage scores (n=768, r s =0.16, P<0.001). In the growing-finishing pigs on Farm B, tear staining of the left eye correlated with tail damage (n=656, r s =0.12, P<0.01) and that of the right eye correlated with ear damage (n=656, r s =0.10, P<0.01). On Farm A, tear-staining sores were lower in the treatment with three different types of manipulable objects as compared with controls (mean scores 3.3 and 3.9, respectively, n=31, F 29=4.2, P<0.05). In the suckling piglets on Farm B, tear staining correlated with the latency to approach a novel object (n=29, r p =0.41, P<0.05). Although correlations with tail and ear damage were low, it was concluded that tear staining has promising potential as a new, additional welfare indicator for commercial pig farming. Further research is needed on the mechanisms of tear staining.

In a rat model of drug craving and relapse, cue-induced drug seeking progressively increases after withdrawal from methamphetamine and other drugs, a phenomenon termed 'incubation of drug craving'. However, current experimental procedures used to study incubation of drug craving do not incorporate negative consequences of drug use, which is a common factor promoting abstinence in humans. Here, we studied whether incubation of methamphetamine craving is observed after suppression of drug seeking by adverse consequences (punishment). We trained rats to self-administer methamphetamine or palatable food for 9 h per day for 14 days; reward delivery was paired with a tone-light cue. Subsequently, for one group within each reward type, 50% of the lever-presses were punished by mild footshock for 9-10 days, whereas for the other group lever-presses were not punished. Shock intensity was gradually increased over time. Next, we assessed cue-induced reward seeking in 1-h extinction sessions on withdrawal days 2 and 21. Response-contingent punishment suppressed extended-access methamphetamine or food self-administration; surprisingly, food-trained rats showed greater resistance to punishment than methamphetamine-trained rats. During the relapse tests, both punished and unpunished methamphetamine- and food-trained rats showed significantly higher cue-induced reward seeking on withdrawal day 21 than on day 2. These results demonstrate that incubation of both methamphetamine and food craving occur after punishment-induced suppression of methamphetamine or palatable food self-administration. Our procedure can be used to investigate mechanisms of relapse to drug and palatable food seeking under conditions that more closely approximate the human condition.

Tear staining (TS) in the pig has been related to different stressors and may be a useful tool for assessing animal welfare on farm. The aim of the current study was to investigate TS across the finisher period and its possible relation to age, growth, sex and experimentally induced stressors. The study included 80 finisher pens divided between three batches. Within each batch, the pens either included pigs with docked or undocked tails, had straw provided (150 g/pig/day) or not and had a low (1.21 m2/pig, 11 pigs) or high stocking density (0.73 m2/pig, 18 pigs). Tear staining (scores 1 to 4; from smaller to larger tear stain area, respectively) and tail damage were scored on each individual pig three times per week over the 9-week study period, and the individual maximum TS score within each week was chosen for further analysis. Data were analysed using logistic regression separately for each of the four possible TS score levels. The TS scores 1 and 2 decreased with weeks into the study period and were negatively related to the average daily gain (ADG) of the pigs, whereas the TS score 4 increased with weeks into the study period and was positively related to ADG. None of the TS scores differed between females and castrated males, and neither straw provision nor lowering the stocking density affected the TS scores. However, the TS score 1 decreased the last week before an event of tail damage (at least one pig in the pen with a bleeding tail wound), whereas the TS score 4 increased. The results of the current study advocates for a relation between TS and the factors such as age, growth and stress in the pig, while no relation was found between TS and the environmental factors straw provision and lowered stocking density. The relations to age and growth are important to take into consideration if using TS as a welfare assessment measure in the pig in the future.

In the past decade, novel methods using engineered receptors have enabled researchers to manipulate neuronal activity with increased spatial and temporal specificity. One widely used chemogenetic method in mice and rats is the DREADD (designer receptors exclusively activated by designer drugs) system in which a mutated muscarinic G protein-coupled receptor is activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). Recently, the Roth laboratory developed a novel inhibitory DREADD in which a mutated kappa-opioid receptor (KORD) is activated by the pharmacologically inert drug salvinorin B (SalB; Vardy et al, 2015). They demonstrated the feasibility of using KORD to study brain circuits involved in motivated behavior in mice. Here, we used behavioral, electrophysiological, and neuroanatomical methods to demonstrate the feasibility of using the novel KORD to study brain circuits involved in motivated behavior in rats. In Exp. 1, we show that SalB dose-dependently decreased spontaneous and cocaine-induced locomotor activity in rats expressing KORD to midbrain (ventral tegmental area/substantia nigra). In Exp. 2, we show that SalB completely inhibited tonic firing in KORD-expressing putative dopamine neurons in midbrain. In Exp. 3, we used a 'retro-DREADD' dual-virus approach to restrict expression of KORD in ventral subiculum neurons that project to nucleus accumbens shell. We show that KORD activation selectively decreased novel context-induced Fos expression in this projection. Our results indicate that the novel KORD is a promising tool to selectively inactivate brain areas and neural circuits in rat studies of motivated behavior.

Viruses are diverse pathogens that use host factors to enter cells and cause disease. Imaging the entry and replication phases of viruses and their interactions with host factors is key to fully understanding viral infections. This review will discuss how confocal microscopy and imaging flow cytometry are used to investigate virus entry and replication mechanisms in fixed and live cells. Quantification of viral images and the use of cryo-electron microscopy to gather structural information of viruses is also explored. Using imaging to understand how viruses replicate and interact with host factors, we gain insight into cellular processes and identify novel targets to develop antiviral therapeutics and vaccines.