Orexins (hypocretins) are two peptides (orexin A and B) produced from the pre-pro-orexin precursor and expressed in a limited region of dorsolateral hypothalamus. Orexins were originally thought to ...specifically mediate feeding and promote wakefulness, but it is now clear that they participate in a wide range of behavioral and physiological processes under select circumstances. Orexins primarily mediate behavior under situations of high motivational relevance, such as during physiological need states, exposure to threats or reward opportunities. We hypothesize that many behavioral functions of orexins (including regulation of sleep/wake cycling) reflect a fundamentally integrated function for orexins in translating motivational activation into organized suites of psychological and physiological processes supporting adaptive behaviors. We also discuss how numerous forms of neural heterogeneity modulate this function, allowing orexin neurons to organize diverse, adaptive responses in a variety of motivationally relevant situations. Thus, the involvement of orexins in diverse behaviors may reflect a common underlying function for this peptide system.
Hominin reliance on Oldowan stone tools-which appear from 2.5 mya and are believed to have been socially transmitted-has been hypothesized to have led to the evolution of teaching and language. Here ...we present an experiment investigating the efficacy of transmission of Oldowan tool-making skills along chains of adult human participants (N=184) using five different transmission mechanisms. Across six measures, transmission improves with teaching, and particularly with language, but not with imitation or emulation. Our results support the hypothesis that hominin reliance on stone tool-making generated selection for teaching and language, and imply that (i) low-fidelity social transmission, such as imitation/emulation, may have contributed to the ~700,000 year stasis of the Oldowan technocomplex, and (ii) teaching or proto-language may have been pre-requisites for the appearance of Acheulean technology. This work supports a gradual evolution of language, with simple symbolic communication preceding behavioural modernity by hundreds of thousands of years.
Globally, increasing acquired antimicrobial resistance among pathogenic bacteria presents an urgent challenge to human and animal health. As a result, significant efforts, such as the One Health ...Initiative, are underway to curtail and optimize the use of critically important antimicrobials for human medicine in all applications, including food animal production. This review discusses the rationale behind multiple and competing “critically important antimicrobial” lists and their contexts as created by international, regional, and national organizations; identifies discrepancies among these lists; and describes issues surrounding risk management recommendations that have been made by regulatory organizations on the use of antibiotics in food animal production. A more harmonized approach to defining criticality in its various contexts (e.g., for human versus animal health, enteric diseases versus other systemic infections, and direct versus indirect selection of resistance) is needed in order to identify shared contextual features, aid in their translation into risk management, and identify the best ways to maintain the health of food animals, all while keeping in mind the wider risks of antimicrobial resistance, environmental impacts, and animal welfare considerations.
Most of the antibiotics sold for animal use in the US are either not considered medically important by the FDA (e.g., ionophores) or else are not included in the list of critically important antimicrobials for human medicine by the WHO (e.g., tetracyclines). Most of the highest priority critically important antimicrobials (HPCIA) have relatively low sales volumes (e.g., fluoroquinolones and cephalosporins), the exception to this being the macrolide class.
•We examine the effect of missing more/less central nodes on network measurement.•We look at measures of centrality, topology, homophily and centralization.•Measurement bias is generally worse when ...central nodes are missing.•The effect of missing central nodes varies by measure and network type.•Researchers can estimate bias in their own network using our web-based calculator.
Missing data is an important, but often ignored, aspect of a network study. Measurement validity is affected by missing data, but the level of bias can be difficult to gauge. Here, we describe the effect of missing data on network measurement across widely different circumstances. In Part I of this study (Smith and Moody, 2013), we explored the effect of measurement bias due to randomly missing nodes. Here, we drop the assumption that data are missing at random: what happens to estimates of key network statistics when central nodes are more/less likely to be missing? We answer this question using a wide range of empirical networks and network measures. We find that bias is worse when more central nodes are missing. With respect to network measures, Bonacich centrality is highly sensitive to the loss of central nodes, while closeness centrality is not; distance and bicomponent size are more affected than triad summary measures and behavioral homophily is more robust than degree-homophily. With respect to types of networks, larger, directed networks tend to be more robust, but the relation is weak. We end the paper with a practical application, showing how researchers can use our results (translated into a publically available java application) to gauge the bias in their own data.
We examine the radiation emitted by high-energy positrons channeled into silicon crystal samples. The positrons are modeled as semiclassical vector currents coupled to an Unruh-DeWitt detector to ...incorporate any local change in the energy of the positron. In the subsequent accelerated QED analysis, we discover a Larmor formula and power spectrum that are both thermalized by the acceleration. Thus, these systems explicitly exhibit thermalization of the detector energy gap at the celebrated Fulling-Davies-Unruh (FDU) temperature. Our derived power spectrum, with a nonzero energy gap, is then shown to have an excellent statistical agreement with high-energy channeling experiments and also provides a method to directly measure the FDU temperature. We also investigate the Rindler horizon dynamics and confirm that the Bekenstein-Hawking area-entropy law is satisfied in these experiments. As such, we present the evidence for the first observation of acceleration-induced thermality in a nonanalog system.
Glutamate inputs to nucleus accumbens (NAc) facilitate conditioned drug-seeking behavior and primarily originate from medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral ...subiculum of the hippocampus (vSub). These regions express Fos (a marker of neural activity) during cue-induced reinstatement of cocaine seeking, but only subpopulations of neurons within these regions drive drug seeking. One way to identify and functionally distinguish neural subpopulations activated during drug-seeking is to examine their projection targets. In rats, we examined Fos expression during cue-induced reinstatement of cocaine- and sucrose-seeking in prelimbic cortex (PL), infralimbic cortex (IL), BLA, and vSub neurons that project to NAc core (NAcC) or NAc shell (NAcSh). Neurons in PL, BLA, and vSub that project to NAcC, but not NAcSh, expressed Fos during cue-induced cocaine seeking, but not sucrose seeking. However, only activation of the PL-NAcC pathway positively correlated with cocaine reinstatement behavior, unlike BLA or vSub inputs to NAcC. To confirm a functional role for the PL-NAcC pathway, and to test the hypothesis that this pathway is recruited in a dopamine-dependent manner, we used a pharmacological disconnection approach whereby dopamine signaling was blocked in PL and glutamate signaling was blocked in the contralateral NAcC. This disconnection attenuated cue-induced reinstatement of cocaine seeking but had no effect on reinstatement of sucrose seeking. Our results highlight a role for the PL-NAcC pathway in cocaine seeking and show that these glutamatergic projections are recruited in a dopamine-dependent manner to drive reinstatement.
Relapse represents a significant barrier to the successful treatment of cocaine addiction. Here, we characterize the relative activation of glutamatergic inputs to nucleus accumbens during cued reinstatement of cocaine seeking versus sucrose seeking. Prelimbic cortex (PL) projections to nucleus accumbens core (NAcC) uniquely expressed Fos in a manner that positively correlated with cocaine-seeking, but not sucrose-seeking, behavior. Additional functional experiments showed that the PL-NAcC pathway was recruited by drug-associated cues in a dopamine-dependent manner to drive cocaine-seeking, but not sucrose-seeking, behavior. These data highlight PL neurons that project to NAcC, and their regulation by dopamine, as potential targets for therapeutics designed to treat cocaine relapse that do not affect natural reward seeking.
The orexin system is a potential treatment target for drug addiction. Orexin-1 receptor (OxR1) antagonism reduces demand for cocaine and remifentanil, indicating that orexin-based therapies may ...reduce demand for many classes of abused drugs. However, pharmacokinetics vary greatly among opioids and it is unclear if OxR1 antagonism would reduce demand for all opioids, particularly ones with high abuse liability. Here, we established a behavioral economics (BE) procedure to assess the effects of OxR1 antagonism on demand for the highly abused opioid fentanyl. We also investigated the utility of our procedure to predict OxR1 antagonism efficacy and relapse propensity. Demand parameters α (demand elasticity or price sensitivity of consumption, an inverse measure of drug motivation) and Q
(drug consumption at null cost) were assessed. The OxR1 antagonist SB-334867 (SB) decreased motivation (increased α) for fentanyl without affecting Q
. Baseline α values predicted SB efficacy, such that SB was most effective at reducing motivation (increasing α) in highly motivated rats. Baseline α values predicted the amount of cued reinstatement of fentanyl seeking; this reinstatement behavior was attenuated by SB administration. These results highlight the promise of the orexin system as a treatment target for opioid addiction and emphasize the usefulness of BE procedures in the study of opioid abuse.
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