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The dorsal periaqueductal grey (PAG) is an important site for integrating predatory threats. However, it remains unclear whether predator-related activation in PAG primarily reflects threat itself and thus can distinguish between various degrees of threat, or rather reflects threat-oriented behaviours, with the PAG potentially orchestrating different types of defensive repertoire. To address this issue, we performed extracellular recording of dorsal PAG neurons in freely behaving rats and examined neuronal and behavioural responses to stimulus conditions with distinct levels of predatory threat. Animals were sequentially exposed to a nonthreatening stimulus familiar environment (exposure to habituated environment) and to a novel nonthreatening stimulus (i.e., a toy animal-plush) and to conditions with high (exposure to a live cat), intermediate (exposure to the environment just visited by the cat, with remnant predator scent), and low (exposure on the following day to the predatory context) levels of predatory threat. To test for contributions of both threat stimuli and behaviour to changes in firing rate, we applied a Poisson generalized linear model regression, using the different predator stimulus conditions and defensive repertoires as predictor variables. Analysis revealed that the different predator stimulus conditions were more predictive of changes in firing rate (primarily threat-induced increases) than the different defensive repertoires. Thus, the dorsal PAG may code for different levels of predatory threat, more than it directly orchestrates distinct threat-oriented behaviours. The present results open interesting perspectives to investigate the role of the dorsal PAG in mediating primal emotional and cognitive responses to fear-inducing stimuli.

The cuneiform nucleus (CUN) is a midbrain structure located lateral to the caudal part of the periaqueductal gray. In the present investigation, we first performed a systematic analysis of the afferent and efferent projections of the CUN using FluoroGold and Phaseolus vulgaris leucoagglutinin as retrograde and anterograde neuronal tracers, respectively. Next, we examined the behavioral responses to optogenetic activation of the CUN and evaluated the impact of pharmacological inactivation of the CUN in both innate and contextual fear responses to a predatory threat (i.e., a live cat). The present hodologic evidence indicates that the CUN might be viewed as a caudal component of the periaqueductal gray. The CUN has strong bidirectional links with the dorsolateral periaqueductal gray (PAGdl). Our hodological findings revealed that the CUN and PAGdl share a similar source of inputs involved in integrating information related to life-threatening events and that the CUN provides particularly strong projections to brain sites influencing antipredatory defensive behaviors. Our functional studies revealed that the CUN mediates innate freezing and flight antipredatory responses but does not seem to influence the acquisition and expression of learned fear responses.

We examined the behavioural responses and Fos expression pattern of rats that were exposed to snake threats from shed snakeskin and a live snake. We differentiated the behavioural responses and the pattern of Fos expression in response to the odour cues and mild threat from a live snake. Animals exposed to the snake odour alone or to the confined snake showed a great deal of risk assessment. Conversely, the intensification of odour during exposure to the live snake decreased the threat ambiguity, and the animals froze for a significantly longer period. Our Fos analysis showed that a pathway formed by the posteroventral part of the medial amygdalar nucleus to the central part of the ventromedial hypothalamic nucleus appeared to be solely responsive to odour cues. In addition, we showed increased Fos expression in a parallel circuit comprising the lateral amygdalar nucleus, ventral subiculum, lateral septum, and juxtadorsomedial region of the lateral hypothalamic area that is responsive to both the odour and mild threat from a live snake. This path is likely to process the environmental boundaries of the threat to be avoided. Both paths merge into the dorsal premammillary nucleus and periaqueductal grey sites, which all increase Fos expression in response to the snake threats and are likely to organize the defensive responses. Moreover, we found that the snake threat mobilized the Edinger-Westphal and supraoculomotor nuclei, which are involved in stress adaptation and attentional mechanisms.

Although mice mostly communicate in the ultrasonic range, they also emit audible calls. We demonstrate that mice selectively bred for high anxiety-related behavior (HAB) have a high disposition for emitting sonic calls when caught by the tail. The vocalization was unrelated to pain but sensitive to anxiolytics. As revealed by manganese-enhanced MRI, HAB mice displayed an increased tonic activity of the periaqueductal gray (PAG). Selective inhibition of the dorsolateral PAG not only reduced anxiety-like behavior but also completely abolished sonic vocalization. Calls were emitted at a fundamental frequency of 3.8 kHz, which falls into the hearing range of numerous predators. Indeed, playback of sonic vocalization attracted rats if associated with a stimulus mouse. If played back to HAB mice, sonic calls were repellent in the absence of a conspecific but attractive in their presence. Our data demonstrate that sonic vocalization attracts both predators and conspecifics depending on the context.

To compare the diagnosis of bacterial vaginosis (BV) by Nugent scoring criteria (Nugent-BV) and the diagnosis of BV and/or aerobic vaginitis (AV) using Donders criteria (Donders-BV/AV) for identifying Molecular-BV detected by bacterial 16s rRNA profiling.We enrolled 512 women of reproductive age in Brazil with data available on Nugent and Donders microscopic analysis and 16S rRNA sequencing. We constructed receiver operating characteristic (ROC) curves of Nugent-BV and Donders-BV/AV and calculated their area under the curves (AUCs) and 95% confidence interval (CI) for matching Molecular-BV.A total of 155 (28.7%) participants were positive for Nugent-BV. Donders-BV and -AV were detected in 90 (17.6%) and 75 (14.6%) participants, respectively, while 28 (5.5%) had concurrent Donders-BV and -AV. Molecular-BV was identified in 139 (27.1%) participants. Analysis of ROC curves showed that diagnosis of Nugent-BV more accurately aligned with presence of Molecular-BV (AUC: 0.88, 95% CI: 0.84-0.91) when compared to Donders-AV/BV (AUC: 0.84; CI: 0.80-0.87) (P = 0.005).The use of Nugent-BV is more representative of Molecular-BV than Donders-AV/BV.

The hypothalamus may be viewed as the central piece of the survival circuits and is responsible for organizing endocrine, autonomic and behavioral responses to guarantee the survival of both the individual and the species. The hypothalamus is largely known to control the three basic classes of behavior required for animal survival, namely, ingestive, defensive, and reproductive behaviors. Over the years, a great deal has been learned regarding the hypothalamic circuits organizing these classes of behavior. In this review, we will focus on hypothalamic circuits involved in organizing anti-predatory and social defenses, noting putative interactions with other hypothalamic systems that mediate metabolic control and social responses, and exploring how the hypothalamic defensive circuits may influence emotional memory linked to predatory and social threats.

Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape from innate and conditioned threats. The hypothalamic dorsal premammillary nucleus (PMd) may control escape, as it is activated by escape-inducing threats and projects to the region most implicated in flight, the dorsolateral periaqueductal gray (dlPAG). We show that in mice cholecystokinin (cck)-expressing PMd cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Lastly, human fMRI data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd as a central node of the escape network.

Made available in DSpace on 2022-04-29T08:45:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-08-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The ability to distinguish between threatening (repulsors), neutral and appetitive stimuli (attractors) stimuli is essential for survival. The orexinergic neurons of hypothalamus send projections to the limbic structures, such as different subregions of the medial prefrontal cortex (mPFC), suggesting that the orexinergic mechanism in the prelimbic cortex (PL) is involved in the processing of fear and anxiety. We investigated the role of orexin receptors type 1 (OX1R) and type 2 (OX2R) in the PL in such processes upon confrontation with an erratically moving robo-beetle in mice. The selective blockade of OX1R and OX2R in the PL with SB 334867 (3, 30, 300 nM) and TCS OX2 29 (3, 30, 300 nM), respectively, did not affect general exploratory behavior or reactive fear such as avoidance, jumping or freezing, but significantly enhances tolerance and approach behavior at the highest dose of each antagonist tested (300 nM). We interpret these findings as evidence for an altered cognitive appraisal of the potential threatening stimulus. Consequently, the orexin system seems to bias the perception of stimuli towards danger or threat via OX1R and OX2R in the PL. Department of Biological Sciences School of Sciences Humanities and Languages of the São Paulo State University (UNESP) Neuronal Plasticity Research Group Max Planck Institute of Psychiatry Department of Pharmacology Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP) Department of Anatomy Biomedical Sciences Institute of the University of São Paulo (ICB-USP) Behavioural Neuroscience Institute (INeC) NAP-USP-Neurobiology of Emotions Research Centre (NuPNE) Ribeirão Preto Medical School of the University of São Paulo Central Nervous System Diseases Research Boehringer Ingelheim Pharmaceuticals Die Gesellschaft mit Beschränkter Haftung & Compagnie Kommanditgesellschaft Department of Biological Sciences School of Sciences Humanities and Languages of the São Paulo State University (UNESP)

Predator exposure is a life-threatening experience and elicits learned fear responses to the context in which the predator was encountered. The anterior cingulate area (ACA) occupies a pivotal position in a cortical network responsive to predatory threats, and it exerts a critical role in processing fear memory. Ours results revealed that the ACA is involved in both the acquisition and expression of contextual fear to predatory threat. Overall, the ACA can provide predictive relationships between the context and the predator threat and influences fear memory acquisition through projections to the basolateral amygdala and perirhinal region and the expression of contextual fear through projections to the dorsolateral periaqueductal gray. Our results expand previous studies based on classical fear conditioning and open interesting perspectives for understanding how the ACA is involved in processing contextual fear memory to ethologic threatening conditions that entrain specific medial hypothalamic fear circuits (i.e., predator- and conspecific-responsive circuits).

Animals must balance needs to approach threats for risk assessment and to avoid danger. The dorsal periaqueductal gray (dPAG) controls defensive behaviors, but it is unknown how it represents states associated with threat approach and avoidance. We identified a dPAG threatavoidance ensemble in mice that showed higher activity farther from threats such as the open arms of the elevated plus maze and a predator. These cells were also more active during threat avoidance behaviors such as escape and freezing, even though these behaviors have antagonistic motor output. Conversely, the threat approach ensemble was more active during risk assessment behaviors and near threats. Furthermore, unsupervised methods showed that avoidance/approach states were encoded with shared activity patterns across threats. Lastly, the relative number of cells in each ensemble predicted threat avoidance across mice. Thus, dPAG ensembles dynamically encode threat approach and avoidance states, providing a flexible mechanism to balance risk assessment and danger avoidance.

Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape vigor from innate and conditioned threats. Cholecystokinin (cck)-expressing cells in the hypothalamic dorsal premammillary nucleus (PMd) are necessary for initiating escape from innate threats via a projection to the dorsolateral periaqueductal gray (dlPAG). We now show that in mice PMd-cck cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Intriguingly, PMd-cck and dlPAG activity in mice showed higher mutual information during exposure to innate and conditioned threats. In parallel, human functional magnetic resonance imaging data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd-dlPAG circuit as a central node, controlling escape vigor elicited by both innate and conditioned threats.

Animals must balance needs to approach threats for risk-assessment and to avoid danger. The dorsal periaqueductal gray (dPAG) controls defensive behaviors, but it is unknown how it represents states associated with threat approach and avoidance. We identified a dPAG threat-avoidance ensemble in mice that showed higher activity far from threats such as the open arms of the elevated plus maze and a live predator. These cells were also more active during threat-avoidance behaviors such as escape and freezing, even though these behaviors have antagonistic motor output. Conversely, the threat-approach ensemble was more active during risk-assessment behaviors and near threats. Furthermore, unsupervised methods showed approach/avoidance states were encoded with shared activity patterns across threats. Lastly, the relative number of cells in each ensemble predicted threat-avoidance across mice. Thus, dPAG ensembles dynamically encode threat approach and avoidance states, providing a flexible mechanism to balance risk-assessment and danger avoidance.

Evasion from imminent threats and prey attack are opposite behavioral choices critical to survival. The lateral periaqueductal gray (LPAG) is a key player in these behaviors, it responds to social threats and prey hunting while also driving predatory attacks and active defense. Our results revealed that distinct neuronal populations in the LPAG drive prey hunting and evasion from social threats. We show that the LPAG provides a putative glutamatergic projection to the lateral hypothalamic area (LHA). LPAG > LHA pathway optogenetic inhibition impaired insect predation but did not alter escape/attack ratio during social defeat. The results suggest that the LPAG control over evasion to a social attack may be regarded as a stereotyped response depending probably on descending projections. Conversely, the LPAG control over predatory behavior involves an ascending pathway to the LHA that likely influences LHAGABA neurons driving predatory hunting and may provide an emotional drive for appetitive rewards.

The brainstem dorsal periaqueductal gray (dPAG) has been widely recognized as being a vital node orchestrating the responses to innate threats. Intriguingly, recent evidence also shows that the dPAG mediates defensive responses to fear conditioned contexts. However, it is unknown whether the dPAG displays independent or shared patterns of activation during exposure to innate and conditioned threats. It is also unclear how dPAG ensembles encode and predict diverse defensive behaviors. To address this question, we used miniaturized microscopes to obtain recordings of the same dPAG ensembles during exposure to a live predator and a fear conditioned context in male mice. dPAG ensembles encoded not only distance to threat, but also relevant features, such as predator speed and angular offset between mouse and threat. Furthermore, dPAG cells accurately encoded numerous defensive behaviors, including freezing, stretch-attend postures, and escape. Encoding of behaviors and of distance to threat occurred independently in dPAG cells. dPAG cells also displayed a shared representation to encode these behaviors and distance to threat across innate and conditioned threats. Last, we also show that escape could be predicted by dPAG activity several seconds in advance. Thus, dPAG activity dynamically tracks key kinematic and behavioral variables during exposure to threats, and exhibits similar patterns of activation during defensive behaviors elicited by innate or conditioned threats. These data indicate that a common pathway may be recruited by the dPAG during exposure to a wide variety of threat modalities. SIGNIFICANCE STATEMENT The dorsal periaqueductal gray (dPAG) is critical to generate defensive behaviors during encounters with threats of multiple modalities. Here we use longitudinal calcium transient recordings of dPAG ensembles in freely moving mice to show that this region uses shared patterns of activity to represent distance to an innate threat (a live predator) and a conditioned threat (a shock grid). We also show that dPAG neural activity can predict diverse defensive behaviors. These data indicate the dPAG uses conserved population-level activity patterns to encode and coordinate defensive behaviors during exposure to both innate and conditioned threats.

Evasion from imminent threats and prey attack are opposite behavioral choices critical to survival. Curiously, the lateral periaqueductal gray (LPAG) has been implicated in driving both responses. The LPAG responds to social threats and prey hunting while also drives predatory attacks and active defense. However, the LPAG neural mechanisms mediating these behaviors remain poorly defined. Here, we investigate how the LPAG mediates the choices of predatory hunting and evasion from a social threat. Pharmacogenetic inhibition in Fos DD-Cre mice of neurons responsive specifically to insect predation (IP) or social defeat (SD) revealed that distinct neuronal populations in the LPAG drive the prey hunting and evasion from social threats. We show that the LPAG provides massive glutamatergic projection to the lateral hypothalamic area (LHA). Optogenetic inhibition of the LPAG-LHA pathway impaired IP but did not alter escape/attack ratio during SD. We also found that pharmacogenetic inhibition of LHAGABA neurons impaired IP, but did not change evasion during SD. The results suggest that the LPAG control over evasion to a social attack may be regarded as a stereotyped response depending probably on glutamatergic descending projections. On the other hand, the LPAG control over predatory behavior involves an ascending glutamatergic pathway to the LHA that likely influences LHAGABA neurons driving predatory attack and prey consumption. The LPAG-LHA path supposedly provides an emotional drive for prey hunting and, of relevance, may conceivably have more widespread control on the motivational drive to seek other appetitive rewards.

The architecture, engineering, and construction (AEC) industry is well known for low productivity, with a critical obstacle being the difficulties associated with understanding the mechanism of job performance. This due to established theories being incapable of capturing and dealing with the complexities associated with construction projects, with extant performance studies falling short in the context of complex projects by not grounding the factors involved in a common conceptual model that articulates the mechanics of job performance. In response, this study builds on person-environment (P-E) fit theory using a stimulus-organism-response paradigm, to develop a foundational conceptual model of the performance-related working behaviors of construction professionals. This study emphasizes the mediating role of P-E fit assessment and integrates key P-E relationships in a simplified framework, with a common layer based on P-E fit assessment factors that both accommodates previous studies and lays a coherent foundation for future studies. The model can also be applied in a reverse, diagnostic, capacity to identify corrective approaches and appropriate management strategies, and is easily adaptable to more general situations beyond the construction industry. Concluding remarks concern the major contributions made and prospects for future development.

© 2020 selection and editorial matter, Derek Walker and Steve Rowlinson. All rights reserved. This chapter focuses on the role of emerging digital technology as a disruptive agent, a role that emerging digital technology can play simply as the catalyst of change. It deals with a consideration of the construction industry and why it is ripe for disruptive innovation. The chapter provides an overview of the emerging digital technologies of particular relevance to the construction industry at this time. It proposes a new role for emerging digital technology in the context of integrated project delivery (IPD), in the role as a catalyst for change. The broader impact of Industry 4.0 has also been discussed elsewhere in terms of collaboration and the integration of knowledge, skills and attributes. In order for new technology innovation to provide the necessary catalyst for the substantive, whole-of-industry changes, required to drive IPD and radically improve the performance of the construction industry, a different perspective is required.

How an animal responds to environmental stressors and threats is essential for survival. These responses are governed through an interconnected circuit in the brain dubbed the limbic system. Three main structures of the limbic system are the amygdala, bed nucleus of the stria terminalis (BNST), and hypothalamus. Together these structures define a central stress-threat circuit. This chapter describes the most up to date knowledge of how these structures function in regulating responses to stressors and how each of these structures is formed from embryonic development. This knowledge of the underlying biology of these regions is essential to design rational therapeutic approaches for conditions, such as post-traumatic stress disorder (PTSD) that are characterized by dysregulation of the stress-threat system. In this chapter, we also describe the critical unanswered questions in the field of stress-threat research and potential future research directions.

The basolateral amygdala complex, which includes the lateral, basolateral and basomedial nuclei, has been implicated in innate and contextual fear responses to predator threats. In the basolateral complex, the lateral and posterior basomedial nuclei are able to process predator odor information, and they project to the predator-responsive hypothalamic circuit; lesions in these amygdalar sites reduce innate responses and practically abolish contextual fear responses to predatory threats. In contrast to the lateral and posterior basomedial nuclei, the basolateral nucleus does not receive direct information from predator olfactory cues and has no direct link to the predator-responsive hypothalamic circuit. No attempt has previously been made to determine the specific role of the basolateral nucleus in fear responses to predatory threats, and we currently addressed this question by making bilateral N-methyl-D-aspartate lesions in the anterior basolateral nucleus of the amygdala (BLAa), which is often regarded as being contiguous with the lateral amygdalar nucleus, and tested both innate and contextual fear in response to cat exposure. Accordingly, BLAa lesions decreased both innate and contextual fear responses to predator exposure. Considering the targets of the BLAa, the nucleus accumbens appears to be a potential candidate to influence innate defensive responses to predator threats. The present findings also suggest that the BLAa has a role in fear memory of predator threat. The BLAa is likely involved in memory consolidation, which could potentially engage BLAa projection targets, opening interesting possibilities in the investigation of how these targets could be involved in the consolidation of predator-related fear memory.

Naturalistic escape requires versatile context-specific flight with rapid evaluation of local geometry to identify and use efficient escape routes. It is unknown how spatial navigation and escape circuits are recruited to produce context-specific flight. Using mice, we show that activity in cholecystokinin-expressing hypothalamic dorsal premammillary nucleus (PMd-cck) cells is sufficient and necessary for context-specific escape that adapts to each environment's layout. In contrast, numerous other nuclei implicated in flight only induced stereotyped panic-related escape. We reasoned the dorsal premammillary nucleus (PMd) can induce context-specific escape because it projects to escape and spatial navigation nuclei. Indeed, activity in PMd-cck projections to thalamic spatial navigation circuits is necessary for context-specific escape induced by moderate threats but not panic-related stereotyped escape caused by perceived asphyxiation. Conversely, the PMd projection to the escape-inducing dorsal periaqueductal gray projection is necessary for all tested escapes. Thus, PMd-cck cells control versatile flight, engaging spatial navigation and escape circuits.

Previous studies from our group have shown that risk assessment behaviors are the primary contextual fear responses to predatory and social threats, whereas freezing is the main contextual fear response to physically harmful events. To test contextual fear responses to a predator or aggressive conspecific threat, we developed a model that involves placing the animal in an apparatus where it can avoid the threat-associated environment. Conversely, in studies that use shock-based fear conditioning, the animals are usually confined inside the conditioning chamber during the contextual fear test. In the present study, we tested shock-based contextual fear responses using two different behavioral testing conditions: confining the animal in the conditioning chamber or placing the animal in an apparatus with free access to the conditioning compartment. Our results showed that during the contextual fear test, the animals confined to the shock chamber exhibited significantly more freezing. In contrast, the animals that could avoid the conditioning compartment displayed almost no freezing and exhibited risk assessment responses (i.e., crouch-sniff and stretch postures) and burying behavior. In addition, the animals that were able to avoid the shock chamber had increased Fos expression in the juxtadorsomedial lateral hypothalamic area, the dorsomedial part of the dorsal premammillary nucleus and the lateral and dorsomedial parts of the periaqueductal gray, which are elements of a septo/hippocampal-hypothalamic-brainstem circuit that is putatively involved in mediating contextual avoidance. Overall, the present findings show that testing conditions significantly influence both behavioral responses and the activation of circuits involved in contextual avoidance.

Drug screening models have a vital role in the development of novel antimycobacterial agents which are urgently needed to tackle drug-resistant tuberculosis (TB). We recently established the larvae of the insect Galleria mellonella (greater wax moth) as a novel infection model for the Mycobacterium tuberculosis complex. Here we demonstrate its use as a rapid and reproducible screen to evaluate antimycobacterial drug efficacy using larvae infected with bioluminescent Mycobacterium bovis BCG lux. Treatment improved larval survival outcome and, with the exception of pyrazinamide, was associated with a significant reduction in in vivo mycobacterial bioluminescence over a 96 hour period compared to the untreated controls. Isoniazid and rifampicin displayed the greatest in vivo efficacy and survival outcome. Thus G. mellonella, infected with bioluminescent mycobacteria, can rapidly determine in vivo drug efficacy, and has the potential to significantly reduce and/or replace the number of animals used in TB research.

Mental health indicators are essential for monitoring people's mental health status, developing mental health policies, and evaluating the performance of such policies. The aim of this paper is to describe the development of a web-based tool for mental health indicators capable to support the management of Brazilian mental health care networks. The SISAM is a web information system responsible for management and provision of mental health information in Brazil and it was chosen as the use case of this study. The indicators were developed as a decision support web tool for public health managers. The tool is able to calculate 11 indicators related to inpatient care. A descriptive analysis of all indicators is presented using SISAM data from 2017. The results generated by the tool are promising and could provide improvements on care monitoring, evaluation of possible trends and investments in prevention and promotion in mental health care.

© 2019 Elsevier Ltd Delivering transportation projects to their budgeted cost remains a challenge for many governments worldwide. An issue that has hindered progress being made to address this problem has been the availability of empirical data that reflects the changing nature of cost estimates and their difference from a project's final account. Using a homogenous dataset provided by a public sector authority in Hong Kong, we analyse the differences between the approved budget, pre-tender estimates, contract sum and final accounts for approximately HK$115 billion (≈US$14 billion) worth of transportation projects. We demonstrate that 47% (i.e. ≈ 5 out 10) of the projects deviate from their approved budget. In particular, when we consider the difference between the approved budget and the final contract sum, we reveal there are cases of both over and under estimating. We, therefore, question the Planning Fallacy as an appropriate explanation for describing ‘how large infrastructure projects work’. The fallacy of the Planning Fallacy account revealed in this paper leads us to call upon those agencies that have actively embraced this theory to reconsider their approaches to cost estimating and risk analysis used to deliver their transportation infrastructure to ensure taxpayers are provided with better value for money.

Tuberculosis is the leading global cause of infectious disease mortality and roughly a quarter of the world’s population is believed to be infected with Mycobacterium tuberculosis. Despite decades of research, many of the mechanisms behind the success of M. tuberculosis as a pathogenic organism remain to be investigated, and the development of safer, more effective antimycobacterial drugs are urgently needed to tackle the rise and spread of drug resistant tuberculosis. However, the progression of tuberculosis research is bottlenecked by traditional mammalian infection models that are expensive, time consuming, and ethically challenging. Previously we established the larvae of the insect Galleria mellonella (greater wax moth) as a novel, reproducible, low cost, high-throughput and ethically acceptable infection model for members of the M. tuberculosis complex. Here we describe the maintenance, preparation, and infection of G. mellonella with bioluminescent Mycobacterium bovis BCG lux. Using this infection model, mycobacterial dose dependent virulence can be observed, and a rapid readout of in vivo mycobacterial burden using bioluminescence measurements is easily achievable and reproducible. Although limitations exist, such as the lack of a fully annotated genome for transcriptomic analysis, ontological analysis against genetically similar insects can be carried out. As a low cost, rapid, and ethically acceptable model for tuberculosis, G. mellonella can be used as a pre-screen to determine drug efficacy and toxicity, and to determine comparative mycobacterial virulence prior to the use of conventional mammalian models. The use of the G. mellonella-mycobacteria model will lead to a reduction in the substantial number of animals currently used in tuberculosis research.

Exposure to stressful conditions induces long-lasting neurobiological changes in selected brain areas, which could be associated with the emergence of negative emotional responses. Moreover, the interaction of a stressful experience and the retrieval of an established fear memory trace enhance both fear expression and fear retention. Related to this, the stimulation of the dorsolateral part of the mesencephalic periaqueductal gray matter (dlPAG) prior to retrieval potentiates a fear memory trace previously acquired. Therefore, the question that arises is whether the dlPAG mediates the increased fear expression and fear retention after retrieval. Rats were subjected to a contextual fear conditioning paradigm using a single footshock, and 1 day later, rats were subjected to a stressful situation. As previously reported, there was an increase of freezing response only in those rodents that were re-exposed to the associated context at 1 and 5 days after stress exposure. Muscimol intra-dlPAG prior to the restraint event prevented such increase. Conversely, Muscimol intra-dlPAG infusion immediately after the stress experience had no effect on the resulting fear memory. When the neuroendocrine response to stress was explored, intra-dlPAG infusion of muscimol prior to stress decreased Fos expression in the paraventricular nucleus and serum corticosterone levels. Moreover, this treatment prevented the enhancement of the density of hippocampal "mature" spines associated with fear memory. In conclusion, the present results suggest that the dlPAG is a key neural site for the negative valence instruction necessary to modulate the promoting influence of stress on fear memory.

Background Global variation in human papillomavirus (HPV) prevalence and persistence may be explained by differences in risk factors, such as sexual activity, oral contraceptive use, and behavioral factors. We evaluated determinants of acquisition and clearance of HPV infection among young women previously unexposed to HPV. Methods Five hundred thirty-four women aged 15 to 25 years who were cytology and HPV DNA negative, and seronegative for anti-HPV-16/18 antibodies, were recruited (July 2000–September 2001) from study centers in Brazil, the United States, and Canada (NCT00689741/NCT00120848). They were followed up for 76 months. Cervical samples were HPV genotyped via polymerase chain reaction. We used multivariable (forward stepwise, P = 0.15) Cox proportional hazards regression to estimate rate ratios (RR) and 95% confidence intervals (CI), separately according to length of follow-up time. Results On short-term follow-up (0–27 months), 257 (48%; 8535.80 person-months; incidence rate = 30.11; 95% CI, 26.64–34.02) incident HPV infections were detected. Marital status, lifetime number of sex partners, history of any sexually transmitted disease, and occasional use of oral contraceptives were strongly associated with acquisition of any HPV. Having 2 or more lifetime sex partners (RR, 2.03; 95% CI, 1.37–3.02) and a history of any sexually transmitted disease (RR, 1.98; 95% CI, 1.19–3.29) were the most important determinants of high-risk HPV (hrHPV) incidence. During the entire follow-up (0–76 months), an increased hrHPV clearance was found among women in North America (RR, 1.38; 95% CI, 1.08–1.78) and black women (RR, 1.64; 95% CI, 1.04–2.60). Greater number of lifetime partners was associated with reduced clearance rates for any HPV (RR, 0.65; 95% CI, 0.43–0.98). Conclusions We identified variation in risk of HPV acquisition and clearance among women unexposed to HPV at baseline.

© 2018 World Scientific Publishing Company. Drawing upon diffusion of innovation (DoI) theory, technology acceptance models (TAMs), social network perspective and resistance literature, the study developed and tested a model, named integrated resistance factor model (IRFM), which integrates four key elements i.e. resistance indicators, support network factors, experience and disposition factors and the integration and accessibility factors. The study investigated if the model applies in a selected technology, namely online project information management systems (OPIMS). The IRFM was tested with partial least square (PLS) techniques and results from the R2 analysis of the whole PLS structural model were significant and the data were coherence with the proposed model (R2=0.484). These results indicated that user resistance to technology innovation can be predicted using the IRFM.

Neutrals couple to the non-Maxwellian as well as (drifting-)Maxwellian parts of the ion distribution function, producing a residual stress that can drive intrinsic rotation. Our modelling predicted a steeper slope of the toroidal rotation profile than observed in dedicated AUG discharges, suggesting the presence of opposing transport mechanisms. Losses from neutrals escaping to the wall which are not captured by the short MFP approximation, neoclassical torque from the toroidal ripple field or turbulent transport are all possibilities. Finally, we did not predict or observe a significant change in the measured rotation profiles when changing the gas fuelling location. This may be due to the modest fuelling possible in the low density discharges used.

Previous studies from our group have shown that cytotoxic lesions in the ventral portion of the anteromedial thalamic nucleus (AMv), one of the main targets of the hypothalamic predator-responsive circuit, strongly impairs contextual fear responses to an environment previously associated with a predator. The AMv is in a position to convey information to cortico-hippocampal-amygdalar circuits involved in the processing of fear memory. However, it remains to be determined whether the nucleus is involved in the acquisition or subsequent expression of contextual fear. In the present investigation, we addressed this question by inactivating the rat AMv with muscimol either prior to cat exposure or prior to exposure to the cat-related context. Accordingly, AMv pharmacological inactivation prior to cat exposure did not interfere with innate fear responses, but it drastically reduced contextual conditioning to the predator-associated environment. On the other hand, AMv inactivation prior to exposure to the environment associated with the predator threat did not affect contextual fear responses. The behavioral results were further supported by the demonstration that AMv inactivation prior to cat exposure also blocked the activation of sites critically involved in the expression of anti-predatory contextual defensive responses (i.e., the dorsal premammillary nucleus and the dorsolateral periaqueductal gray) in animals exposed to the predator-associated context. The AMv projections were also examined, and the results of this investigation outline important paths that can influence hippocampal circuitry and raise new ideas for anterior thalamic-hippocampal paths involved in emotional learning.

Melanin-concentrating hormone (MCH) is a hypothalamic peptide that plays a critical role in the regulation of food intake and energy metabolism. In this study, we investigated the potential role of dense hippocampal MCH innervation in the spatially oriented food-seeking component of feeding behavior. Rats were trained for eight sessions to seek food buried in an arena using the working memory version of the food-seeking behavior (FSB) task. The testing day involved a bilateral anti-MCH injection into the hippocampal formation followed by two trials. The anti-MCH injection did not interfere with the performance during the first trial on the testing day, which was similar to the training trials. However, during the second testing trial, when no food was presented in the arena, the control subjects exhibited a dramatic increase in the latency to initiate digging. Treatment with an anti-MCH antibody did not interfere with either the food-seeking behavior or the spatial orientation of the subjects, but the increase in the latency to start digging observed in the control subjects was prevented. These results are discussed in terms of a potential MCH-mediated hippocampal role in the integration of the sensory information necessary for decision-making in the pre-ingestive component of feeding behavior.

In the present study, we examined behavioral and brain regional activation changes of rats). To a nonmammalian predator, a wild rattler snake (Crotalus durissus terrificus). Accordingly, during snake threat, rat subjects showed a striking and highly significant behavioral response of freezing, stretch attend, and, especially, spatial avoidance of this threat. The brain regional activation patterns for these rats were in broad outline similar to those of rats encountering other predator threats, showing Fos activation of sites in the amygdala, hypothalamus, and periaqueductal gray matter. In the amygdala, only the lateral nucleus showed significant activation, although the medial nucleus, highly responsive to olfaction, also showed higher activation. Importantly, the hypothalamus, in particular, was somewhat different, with significant Fos increases in the anterior and central parts of the ventromedial hypothalamic nucleus (VMH), in contrast to patterns of enhanced Fos expression in the dorsomedial VMH to cat predators, and in the ventrolateral VMH to an attacking conspecific. In addition, the juxtodorsalmedial region of the lateral hypothalamus showed enhanced Fos activation, where inputs from the septo-hippocampal system may suggest the potential involvement of hippocampal boundary cells in the very strong spatial avoidance of the snake and the area it occupied. Notably, these two hypothalamic paths appear to merge into the dorsomedial part of the dorsal premammillary nucleus and dorsomedial and lateral parts of the periaqueductal gray, all of which present significant increases in Fos expression and are likely to be critical for the expression of defensive behaviors in responses to the snake threat.

The ventral part of the anteromedial thalamic nucleus (AMv) receives substantial inputs from hypothalamic sites that are highly responsive to a live predator or its odor trace and represents an important thalamic hub for conveying predatory threat information to the cerebral cortex. In the present study, we begin by examining the cortico-amygdalar-hippocampal projections of the main AMv cortical targets, namely, the caudal prelimbic, rostral anterior cingulate, and medial visual areas, as well as the rostral part of the ventral retrosplenial area, one of the main targets of the anterior cingulate area. We observed that these areas form a clear cortical network. Next, we revealed that in animals exposed to a live cat, all of the elements of this circuit presented a differential increase in Fos, supporting the idea of a predator threat-responsive cortical network. Finally, we showed that bilateral cytotoxic lesions in each element of this cortical network did not change innate fear responses but drastically reduced contextual conditioning to the predator-associated environment. Overall, the present findings suggest that predator threat has an extensive representation in the cerebral cortex and revealed a cortical network that is responsive to predatory threats and exerts a critical role in processing fear memory.

Motivation: The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene. Main types of variables included: The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record. Spatial location and grain: BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km(2) (158 cm(2)) to 100 km(2) (1,000,000,000,000 cm(2)). Time period and grainBio: TIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year. Major taxa and level of measurement: BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.

The ventral part of the anteromedial thalamic nucleus (AMv) is heavily targeted by the dorsal premammillary nucleus (PMd), which is the main hypothalamic site that is responsive to both predator and conspecific aggressor threats. This PMd-AMv pathway is likely involved in modulating memory processing, and previous findings from our group have shown that cytotoxic lesions or pharmacological inactivation of the AMv drastically reduced contextual fear responses to predator-associated environments. In the present study, we investigated the role of the AMv in both unconditioned (i.e., fear responses during social defeat) and contextual fear responses (i.e., during exposure to a social defeat-associated context). We addressed this question by placing N-methyl-d-aspartate (NMDA) lesions in the AMv and testing unconditioned fear responses during social defeat and contextual fear responses during exposure to a social defeat-associated context. Accordingly, bilateral AMv lesions did not change unconditioned responses, but decreased contextual conditioning related to social defeat. Notably, our bilateral AMv lesions also included, to a certain degree, the nucleus reuniens (RE), but single RE lesions did not affect innate or contextual fear responses. Overall, our results support the idea that the AMv works as a critical hub, receiving massive inputs from a hypothalamic site that is largely responsive to social threats and transferring social threat information to circuits involved in the processing of contextual fear memories.

The Derbyshire Archaeological Journal, 86, 1-30

The periaqueductal gray (PAG) has been commonly recognized as a downstream site in neural networks for the expression of a variety of behaviors and is thought to provide stereotyped responses. However, a growing body of evidence suggests that the PAG may exert more complex modulation of a number of behavioral responses and work as a unique hub supplying primal emotional tone to influence prosencephalic sites mediating complex aversive and appetitive responses. Of particular relevance, we review how the PAG is involved in influencing complex forms of defensive responses, such as circa-strike and risk assessment responses in animals. In addition, we discuss putative dorsal PAG ascending paths that are likely to convey information related to threatening events to cortico-hippocampal-amygdalar circuits involved in the processing of fear learning. Finally, we discuss the evidence supporting the role of the PAG in reward seeking and note that the lateral PAG is part of the circuitry related to goal-oriented responses mediating the motivation to hunt and perhaps drug seeking behavior.