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Navigation requires integrating sensory information with a stable schema to create a dynamic map of an animal's position using egocentric and allocentric coordinate systems. In the hippocampus, place cells encode allocentric space, but their firing rates may also exhibit directional tuning within egocentric or allocentric reference frames. We compared experimental and simulated data to assess the prevalence of tuning to egocentric bearing (EB) among hippocampal cells in rats foraging in an open field. Using established procedures, we confirmed egocentric modulation of place cell activity in recorded data; however, simulated data revealed a high false-positive rate (FPR). When we accounted for false positives by comparing with shuffled data that retain correlations between the animal's direction and position, only a very low number of hippocampal neurons appeared modulated by EB. Our study highlights biases affecting FPRs and provides insights into the challenges of identifying egocentric modulation in hippocampal neurons., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

The SUNshiners group includes people in the early stages of dementia with an interest in dementia activism and research. The group found that despite the growing awareness of invisible disabilities, there is very limited research into the pros and cons of the invisibility of dementia. Our paper explores the SUNshiners research which stemmed from varied individual experiences of disclosing diagnoses. The group designed and developed a short survey to explore what the public knew about dementia and what they thought about the invisibility of dementia. A mixture of open- and closed-ended questions were used to gain meaningful data. A total of 347 people completed the survey (315 online and 32 paper-based), which was then co-analysed. The findings suggest that the majority of the public felt that the invisibility of dementia was negative; that knowing someone had dementia when first meeting them would be beneficial; that people living with dementia should maintain the right to vote; and that people living with dementia do not automatically require a consistent, regular carer. Common themes from the open-ended answers included capacity, severity of dementia, and access to support. The findings support the disclosure of dementia diagnosis; however, more action is needed to tackle stigmatised views, particularly as the SUNshiners felt that people do not have enough dementia education to support a positive disclosure experience. They shared their experiences of the group and the project's benefits, but also the losses they have faced. Our paper aims to be as accessible as possible.

Objective: Preserving core body temperature across a wide range of ambient temperatures requires adaptive changes of thermogenesis that must be offset by corresponding changes of energy intake if body fat stores are also to be preserved. Among neurons implicated in the integration of thermoregulation with energy homeostasis are those that express both neuropeptide Y (NPY) and agouti-related protein (AgRP) (referred to herein as AgRP neurons). Specifically, cold-induced activation of AgRP neurons was recently shown to be required for cold exposure to increase food intake in mice. Here, we investigated how consuming a high-fat diet (HFD) impacts various adaptive responses to cold exposure as well as the responsiveness of AgRP neurons to cold., Methods: To test this, we used immunohistochemistry, in vivo fiber photometry and indirect calorimetry for continuous measures of core temperature, energy expenditure, and energy intake in both chow- and HFD-fed mice housed at different ambient temperatures., Results: We show that while both core temperature and the thermogenic response to cold are maintained normally in HFD-fed mice, the increase of energy intake needed to preserve body fat stores is blunted, resulting in weight loss. Using both immunohistochemistry and in vivo fiber photometry, we show that although cold-induced AgRP neuron activation is detected regardless of diet, the number of cold-responsive neurons appears to be blunted in HFD-fed mice., Conclusions: We conclude that HFD-feeding disrupts the integration of systems governing thermoregulation and energy homeostasis that protect body fat mass during cold exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

To investigate whether glucoregulatory neurons in the hypothalamus can sense and respond to physiological variation in the blood glucose (BG) level, we combined continuous arterial glucose monitoring with continuous measures of the activity of a specific subset of neurons located in the hypothalamic ventromedial nucleus that express pituitary adenylate cyclase activating peptide (VMNPACAP neurons) obtained using fiber photometry. Data were collected in conscious, free-living mice during a 1-h baseline monitoring period and a subsequent 2-h intervention period during which the BG level was raised either by consuming a chow or a high-sucrose meal or by intraperitoneal glucose injection. Cross-correlation analysis revealed that, following a 60- to 90-s delay, interventions that raise the BG level reliably associate with reduced VMNPACAP neuron activity (P < 0.01). In addition, a strong positive correlation between BG and spontaneous VMNPACAP neuron activity was observed under basal conditions but with a much longer (∼25 min) temporal offset, consistent with published evidence that VMNPACAP neuron activation raises the BG level. Together, these findings are suggestive of a closed-loop system whereby VMNPACAP neuron activation increases the BG level; detection of a rising BG level, in turn, feeds back to inhibit these neurons. To our knowledge, these findings constitute the first evidence of a role in glucose homeostasis for glucoregulatory neurocircuits that, like pancreatic β-cells, sense and respond to physiological variation in glycemia., Article Highlights: By combining continuous arterial glucose monitoring with fiber photometry, studies investigated whether neurons in the murine ventromedial nucleus that express pituitary adenylate cyclase activating peptide (VMNPACAP neurons) detect and respond to changes in glycemia in vivo. VMNPACAP neuron activity rapidly decreases (within <2 min) when the blood glucose level is raised by either food consumption or glucose administration. Spontaneous VMNPACAP neuron activity also correlates positively with glycemia, but with a longer temporal offset, consistent with reports that hyperglycemia is induced by experimental activation of these neurons. Like pancreatic β-cells, neurons in the hypothalamic ventromedial nucleus appear to sense and respond to physiological variation in glycemia., (© 2023 by the American Diabetes Association.)

Examination of cognition has historically been approached from language and introspection. However, human language-dependent definitions ignore the evolutionary roots of brain mechanisms and constrain their study in experimental animals. We promote an alternative view, namely that cognition, including memory, can be explained by exaptation and expansion of the circuits and algorithms serving bodily functions. Regulation and protection of metabolic and energetic processes require time-evolving brain computations enabling the organism to prepare for altered future states. Exaptation of such circuits was likely exploited for exploration of the organism's niche. We illustrate that exploration gives rise to a cognitive map, and in turn, environment-disengaged computation allows for mental travel into the past (memory) and the future (planning). Such brain-body interactions not only occur during waking but also persist during sleep. These exaptation steps are illustrated by the dual, endocrine-homeostatic and memory, contributions of the hippocampal system, particularly during hippocampal sharp-wave ripples.

The current dominant view of the hippocampus is that it is a navigation "device" guided by environmental inputs. Yet, a critical aspect of navigation is a sequence of planned, coordinated actions. We examined the role of action in the neuronal organization of the hippocampus by training rats to jump a gap on a linear track. Recording local field potentials and ensembles of single units in the hippocampus, we found that jumping produced a stereotypic behavior associated with consistent electrophysiological patterns, including phase reset of theta oscillations, predictable global firing-rate changes, and population vector shifts of hippocampal neurons. A subset of neurons ("jump cells") were systematically affected by the gap but only in one direction of travel. Novel place fields emerged and others were either boosted or attenuated by jumping, yet the theta spike phase versus animal position relationship remained unaltered. Thus, jumping involves an action plan for the animal to traverse the same route as without jumping, which is faithfully tracked by hippocampal neuronal activity.

The hippocampus has previously been implicated in both cognitive and endocrine functions 1-15 . We simultaneously measured electrophysiological activity from the hippocampus and interstitial glucose concentrations in the body of freely behaving rats to identify an activity pattern that may link these disparate functions of the hippocampus. Here we report that clusters of sharp wave-ripples recorded from the hippocampus reliably predicted a decrease in peripheral glucose concentrations within about 10 min. This correlation was not dependent on circadian, ultradian or meal-triggered fluctuations, could be mimicked with optogenetically induced ripples in the hippocampus (but not in the parietal cortex) and was attenuated to chance levels by pharmacogenetically suppressing activity of the lateral septum, which is the major conduit between the hippocampus and the hypothalamus. Our findings demonstrate that a function of the sharp wave-ripple is to modulate peripheral glucose homeostasis, and offer a mechanism for the link between sleep disruption and blood glucose dysregulation in type 2 diabetes 16-18 ., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Online education is rapidly expanding in response to rising demand for higher and continuing education, but many online students struggle to achieve their educational goals. Several behavioral science interventions have shown promise in raising student persistence and completion rates in a handful of courses, but evidence of their effectiveness across diverse educational contexts is limited. In this study, we test a set of established interventions over 2.5 y, with one-quarter million students, from nearly every country, across 247 online courses offered by Harvard, the Massachusetts Institute of Technology, and Stanford. We hypothesized that the interventions would produce medium-to-large effects as in prior studies, but this is not supported by our results. Instead, using an iterative scientific process of cyclically preregistering new hypotheses in between waves of data collection, we identified individual, contextual, and temporal conditions under which the interventions benefit students. Self-regulation interventions raised student engagement in the first few weeks but not final completion rates. Value-relevance interventions raised completion rates in developing countries to close the global achievement gap, but only in courses with a global gap. We found minimal evidence that state-of-the-art machine learning methods can forecast the occurrence of a global gap or learn effective individualized intervention policies. Scaling behavioral science interventions across various online learning contexts can reduce their average effectiveness by an order-of-magnitude. However, iterative scientific investigations can uncover what works where for whom., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

A major task in the history of neurophysiology has been to relate patterns of neural activity to ongoing external stimuli. More recently, this approach has branched out to relating current neural activity patterns to external stimuli or experiences that occurred in the past or future. Here, we aim to review the large body of methodological approaches used towards this goal, and to assess the assumptions each makes with reference to the statistics of neural data that are commonly observed. These methods primarily fall into two categories, those that quantify zero-lag relationships without examining temporal evolution, termed reactivation , and those that quantify the temporal structure of changing activity patterns, termed replay . However, no two studies use the exact same approach, which prevents an unbiased comparison between findings. These observations should instead be validated by multiple and, if possible, previously established tests. This will help the community to speak a common language and will eventually provide tools to study, more generally, the organization of neuronal patterns in the brain. This article is part of the Theo Murphy meeting issue 'Memory reactivation: replaying events past, present and future'.

Urban resource models increasingly rely on implicit network formulations. Resource consumption behaviours documented in the existing empirical studies are ultimately by-products of the network abstractions underlying these models. Here, we present an analytical formulation and examination of a generic demand-driven network model that accounts for the effectiveness of resource utilization and its implications for policy levers in addressing resource management in cities. We establish simple limiting boundaries to systems' resource effectiveness. These limits are found not to be a function of system size and to be simply determined by the system's average ability to maintain resource quality through its transformation processes. We also show that resource utilization in itself does not enjoy considerable size efficiencies with larger and more diverse systems only offering increased chances of finding matching demand and supply between existing sectors in the system., Competing Interests: We declare we have no competing interests., (© 2020 The Authors.)

Hippocampal sharp wave-ripples (SWR) are thought to mediate brain-wide reactivation of memory traces in service of memory consolidation. However, rather than the faithful replay of neural activity observed during a specific experience, reactivation in both the hippocampus and downstream regions is more variable. We suggest that variable reactivation is a unifying feature of recurrent brain circuits. In the hippocampus, self-organized activation during offline states is constrained by existing attractor manifolds, or maps, and may be biased toward particular mapped locations by salient experience, which results in the appearance of experience-specific replay. Similarly, the impact of SWR-associated reactivation on downstream regions is not a simple transfer of hippocampal representational content. Rather, the response of downstream regions depends on a transformation function, defined by both the feedforward and local circuit architecture, as well as the 'listening state' of the downstream region. We hypothesize that SWRs act as a multiplexed signal, the mnemonic specificity of which is largely determined by this transformation function, and discuss the implications of this framing for theories of systems consolidation., Competing Interests: Conflict of interest statement Nothing declared.

The mnemonic functions of hippocampal sharp wave ripples (SPW-Rs) have been studied extensively. Because hippocampal outputs affect not only cortical but also subcortical targets, we examined the impact of SPW-Rs on the firing patterns of lateral septal (LS) neurons in behaving rats. A large fraction of SPW-Rs were temporally locked to high-frequency oscillations (HFOs) (120-180 Hz) in LS, with strongest coupling during non-rapid eye movement (NREM) sleep, followed by waking immobility. However, coherence and spike-local field potential (LFP) coupling between the two structures were low, suggesting that HFOs are generated locally within the LS GABAergic population. This hypothesis was supported by optogenetic induction of HFOs in LS. Spiking of LS neurons was largely independent of the sequential order of spiking in SPW-Rs but instead correlated with the magnitude of excitatory synchrony of the hippocampal output. Thus, LS is strongly activated by SPW-Rs and may convey hippocampal population events to its hypothalamic and brainstem targets., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Spiking activity of place cells in the hippocampus encodes the animal's position as it moves through an environment. Within a cell's place field, both the firing rate and the phase of spiking in the local theta oscillation contain spatial information. We propose a position-theta-phase (PTP) model that captures the simultaneous expression of the firing-rate code and theta-phase code in place cell spiking. This model parametrically characterizes place fields to compare across cells, time, and conditions; generates realistic place cell simulation data; and conceptualizes a framework for principled hypothesis testing to identify additional features of place cell activity. We use the PTP model to assess the effect of running speed in place cell data recorded from rats running on linear tracks. For the majority of place fields, we do not find evidence for speed modulation of the firing rate. For a small subset of place fields, we find firing rates significantly increase or decrease with speed. We use the PTP model to compare candidate mechanisms of speed modulation in significantly modulated fields and determine that speed acts as a gain control on the magnitude of firing rate. Our model provides a tool that connects rigorous analysis with a computational framework for understanding place cell activity.

Hippocampal sharp wave ripples (SPW-Rs) have been hypothesized as a mechanism for memory consolidation and action planning. The duration of ripples shows a skewed distribution with a minority of long-duration events. We discovered that long-duration ripples are increased in situations demanding memory in rats. Prolongation of spontaneously occurring ripples by optogenetic stimulation, but not randomly induced ripples, increased memory during maze learning. The neuronal content of randomly induced ripples was similar to short-duration spontaneous ripples and contained little spatial information. The spike content of the optogenetically prolonged ripples was biased by the ongoing, naturally initiated neuronal sequences. Prolonged ripples recruited new neurons that represented either arm of the maze. Long-duration hippocampal SPW-Rs replaying large parts of planned routes are critical for memory., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

UK national guidelines recommend that older people at risk of falling should have their fracture risk assessed and acted upon. People with cognitive impairment are more likely to sustain a fracture than their cognitively intact peers. We assessed the fracture risk of 79 memory clinic attendees and compared their actual management with guidelines. Despite reporting 57 falls in the last year, only 36% of those who would be recommended antiresportive treatment were prescribed it and a dual-energy X-ray absorptiometry (DEXA)scan was performed in only 13% where it would be recommended. These findings highlight an important deficit in fracture risk assessment which should inform future interventions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Massive open online courses (MOOCs) attract diverse student bodies, and course forums could potentially be an opportunity for students with different political beliefs to engage with one another. We test whether this engagement actually takes place in two politically-themed MOOCs, on education policy and American government. We collect measures of students' political ideology, and then observe student behavior in the course discussion boards. Contrary to the common expectation that online spaces often become echo chambers or ideological silos, we find that students in these two political courses hold diverse political beliefs, participate equitably in forum discussions, directly engage (through replies and upvotes) with students holding opposing beliefs, and converge on a shared language rather than talk-ing past one another. Research that focuses on the civic mission of MOOCs helps ensure that open online learning engages the same breadth of purposes that higher education aspires to serve.

Retrosplenial cortex (RSC) is heavily interconnected with a multitude of cortical regions and is directly connected with the hippocampal formation. As such, it is a likely coordinator of information transfer between the hippocampus (HPC) and cortex in the service of spatial cognition and episodic memory. The current work examined three potential temporal frameworks for retrosplenial-hippocampal communication, namely, theta frequency oscillations (6-12 Hz), sharp-wave/ripple events, and repeating, theta phase-locked shifts from low (30-65 Hz) to high (120-160 Hz) gamma frequency oscillations. From simultaneous recordings of single units and local field potentials (LFPs) in RSC and HPC, we report the presence of prominent theta, low-gamma, and high-gamma oscillations in the retrosplenial LFP. Retrosplenial and hippocampal theta rhythms were strongly coherent and subgroups of retrosplenial neurons exhibited either spiking at theta frequencies and/or spike-phase-locking to theta. Retrosplenial neurons were also phase-locked to local low- and high-gamma rhythms, and power in these frequency bands was coupled in a sequential fashion to specific phases of hippocampal and retrosplenial theta rhythms. Coordinated activity between the two regions also occurred during hippocampal sharp-wave/ripple events, where retrosplenial neuron populations were modulated in their spiking and retrosplenial LFPs exhibited sharp-wave-like events that co-occurred with those observed in HPC. These results identify several temporal windows of synchronization between RSC and HPC that may mediate cortico-hippocampal processes related to learning, memory, and spatial representation. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Neural computations are often compared to instrument-measured distance or duration, and such relationships are interpreted by a human observer. However, neural circuits do not depend on human-made instruments but perform computations relative to an internally defined rate-of-change. While neuronal correlations with external measures, such as distance or duration, can be observed in spike rates or other measures of neuronal activity, what matters for the brain is how such activity patterns are utilized by downstream neural observers. We suggest that hippocampal operations can be described by the sequential activity of neuronal assemblies and their internally defined rate of change without resorting to the concept of space or time., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Human workers ensure the functioning of governments around the world. The efficacy of human workers, in turn, is linked to the climatic conditions they face. Here we show that the same weather that amplifies human health hazards also reduces street-level government workers' oversight of these hazards. To do so, we employ US data from over 70 million regulatory police stops between 2000 and 2017, from over 500,000 fatal vehicular crashes between 2001 and 2015, and from nearly 13 million food safety violations across over 4 million inspections between 2012 and 2016. We find that cold and hot temperatures increase fatal crash risk and incidence of food safety violations while also decreasing police stops and food safety inspections. Added precipitation increases fatal crash risk while also decreasing police stops. We examine downscaled general circulation model output to highlight the possible day-to-day governance impacts of climate change by 2050 and 2099. Future warming may augment regulatory oversight during cooler seasons. During hotter seasons, however, warming may diminish regulatory oversight while simultaneously amplifying the hazards government workers are tasked with overseeing., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Complex behaviors demand temporal coordination among functionally distinct brain regions. The basal forebrain's afferent and efferent structure suggests a capacity for mediating this coordination at a large scale. During performance of a spatial orientation task, synaptic activity in this region was dominated by four amplitude-independent oscillations temporally organized by the phase of the slowest, a theta-frequency rhythm. Oscillation amplitudes were also organized by task epoch and positively correlated to the task-related modulation of individual neuron firing rates. For many neurons, spiking was temporally organized through phase precession against theta band field potential oscillations. Theta phase precession advanced in parallel to task progression, rather than absolute spatial location or time. Together, the findings reveal a process by which associative brain regions can integrate independent oscillatory inputs and transform them into sequence-specific, rate-coded outputs that are adaptive to the pace with which organisms interact with their environment.

The hippocampus constructs a map of the environment. How this "cognitive map" is utilized by other brain regions to guide behavior remains unexplored. To examine how neuronal firing patterns in the hippocampus are transmitted and transformed, we recorded neurons in its principal subcortical target, the lateral septum (LS). We observed that LS neurons carry reliable spatial information in the phase of action potentials, relative to hippocampal theta oscillations, while the firing rates of LS neurons remained uninformative. Furthermore, this spatial phase code had an anatomical microstructure within the LS and was bound to the hippocampal spatial code by synchronous gamma frequency cell assemblies. Using a data-driven model, we show that rate-independent spatial tuning arises through the dynamic weighting of CA1 and CA3 cell assemblies. Our findings demonstrate that transformation of the hippocampal spatial map depends on higher-order theta-dependent neuronal sequences. VIDEO ABSTRACT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Studies with non-clinical populations show that nostalgia increases psychological resources, such as self-esteem and social connectedness., Objectives: Our objectives were to find out if the benefits of nostalgia in non-clinical populations generalize to people with dementia and if nostalgia facilitates recall of dementia-related information., Methods: All three experiments recruited participants with mild or moderate levels of dementia. Experiment 1 tested whether nostalgia (compared to control) enhances psychological resources among 27 participants. Experiment 2 used music to induce nostalgia (compared to control) in 29 participants. Experiment 3 compared recall for self-referent dementia statements among 50 participants randomized to either a nostalgia or control condition. Findings across experiments were synthesized with integrative data analysis., Results: Nostalgia (compared to control) significantly increased self-reported social connectedness, meaning in life, self-continuity, optimism, self-esteem, and positive (but not negative) affect (Experiments 1-3). Compared to controls, nostalgic participants also recalled significantly more self-referent dementia-related information (Experiment 3)., Conclusion: This series of experiments extends social psychological research with non-clinical populations into dementia care, providing evidence that nostalgia significantly enhances psychological resources. The finding that nostalgia increased recall of self-referent statements about dementia suggests that this emotion lends participants the fortitude to face the threat posed by their illness. The finding has potentially important clinical implications both for the development of reminiscence therapy and for facilitating adjustment to a diagnosis of dementia.

Cooperation among genetically unrelated individuals can be supported by direct reciprocity. Theoretical models and experiments with adults show that the possibility of future interactions with the same partner can promote cooperation via conditionally cooperative strategies such as tit-for-tat (TFT). Here, we introduce a novel implementation of the repeated Prisoner's Dilemma (PD) designed for children to examine whether repeated interactions can successfully promote cooperation in 10 and 11 year olds. We find that children cooperate substantially more in repeated PDs than in one-shot PDs. We also find that girls cooperate more than boys, and that children with more conduct problems cooperate less. Finally, we find that children use conditional cooperation strategies but that these strategies vary by gender and conduct problem rating. Specifically, girls and children with few conduct problems appear to follow an altruistic version of win-stay, lose-shift (WSLS), attempting to re-establish cooperation after they had defected. Boys and children with more conduct problems appear to follow a Grim strategy, defecting for the duration after the partner defects. Thus we provide evidence that children utilize the power of direct reciprocity to promote cooperation in strategic interactions and that, by late elementary school, distinct strategies of conditional cooperation have emerged.

The basal forebrain comprises several heterogeneous neuronal subgroupings having modular projection patterns to discrete sets of cortical subregions. Each cortical region forms recurrent projections, via prefrontal cortex, that reach the specific basal forebrain subgroups from which they receive afferents. This architecture enables the basal forebrain to selectively modulate cortical responsiveness according to current processing demands. Theoretically, optimal functioning of this distributed network would be enhanced by temporal coordination among coactive basal forebrain neurons, or the emergence of "cell assemblies." The present work demonstrates assembly formation in rat basal forebrain neuronal populations during a selective attention task. Neuron pairs exhibited coactivation patterns organized within beta-frequency time windows (55 ms), regardless of their membership within distinct bursting versus nonbursting basal forebrain subpopulations. Thus, the results reveal a specific temporal framework for integration of information within basal forebrain networks and for the modulation of cortical responsiveness., (Copyright © 2015 the authors 0270-6474/15/352992-09$15.00/0.)

Mediation analysis has been extensively applied in psychological and other social science research. A number of methodologists have recently developed a formal theoretical framework for mediation analysis from a modern causal inference perspective. In Imai, Keele, and Tingley (2010), we have offered such an approach to causal mediation analysis that formalizes identification, estimation, and sensitivity analysis in a single framework. This approach has been used by a number of substantive researchers, and in subsequent work we have also further extended it to more complex settings and developed new research designs. In an insightful article, Pearl (2014) proposed an alternative approach that is based on a set of assumptions weaker than ours. In this comment, we demonstrate that the theoretical differences between our identification assumptions and his alternative conditions are likely to be of little practical relevance in the substantive research settings faced by most psychologists and other social scientists. We also show that our proposed estimation algorithms can be easily applied in the situations discussed in Pearl (2014). The methods discussed in this comment and many more are implemented via mediation, an open-source software (Tingley, Yamamoto, Hirose, Keele, & Imai, 2013)., (PsycINFO Database Record (c) 2014 APA, all rights reserved)

Sapropterin dihydrochloride is used to lower blood phenylalanine levels in tetrahydrobiopterin-responsive phenylketonuria in conjunction with a phenylalanine-restricted diet. This study investigated the solubility and stability of sapropterin tablets and a sapropterin powder formulation when mixed in selected beverages and foods. Solubility was partial for the tablets and complete for the powder. The stability testing showed that 93% or more of active sapropterin dihydrochloride is present at 1 hour after either tablets or powders are mixed with certain foods and beverages. Mixing sapropterin powder with foods and beverages might facilitate its administration in patients who have difficulty swallowing the drug according to prescribing information.

Cortically projecting basal forebrain neurons play a critical role in learning and attention, and their degeneration accompanies age-related impairments in cognition. Despite the impressive anatomical and cell-type complexity of this system, currently available data suggest that basal forebrain neurons lack complexity in their response fields, with activity primarily reflecting only macro-level brain states such as sleep and wake, onset of relevant stimuli and/or reward obtainment. The current study examined the spiking activity of basal forebrain neuron populations across multiple phases of a selective attention task, addressing, in particular, the issue of complexity in ensemble firing patterns across time. Clustering techniques applied to the full population revealed a large number of distinct categories of task-phase-specific activity patterns. Unique population firing-rate vectors defined each task phase and most categories of task-phase-specific firing had counterparts with opposing firing patterns. An analogous set of task-phase-specific firing patterns was also observed in a population of posterior parietal cortex neurons. Thus, consistent with the known anatomical complexity, basal forebrain population dynamics are capable of differentially modulating their cortical targets according to the unique sets of environmental stimuli, motor requirements, and cognitive processes associated with different task phases.

Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD). Genome-wide association studies have provided compelling associations for three loci with COPD. In this study, we aimed to estimate direct, i.e., independent from smoking, and indirect effects of those loci on COPD development using mediation analysis. We included a total of 3,424 COPD cases and 1,872 unaffected controls with data on two smoking-related phenotypes: lifetime average smoking intensity and cumulative exposure to tobacco smoke (pack years). Our analysis revealed that effects of two linked variants (rs1051730 and rs8034191) in the AGPHD1/CHRNA3 cluster on COPD development are significantly, yet not entirely, mediated by the smoking-related phenotypes. Approximately 30% of the total effect of variants in the AGPHD1/CHRNA3 cluster on COPD development was mediated by pack years. Simultaneous analysis of modestly (r (2) = 0.21) linked markers in CHRNA3 and IREB2 revealed that an even larger (~42%) proportion of the total effect of the CHRNA3 locus on COPD was mediated by pack years after adjustment for an IREB2 single nucleotide polymorphism. This study confirms the existence of direct effects of the AGPHD1/CHRNA3, IREB2, FAM13A and HHIP loci on COPD development. While the association of the AGPHD1/CHRNA3 locus with COPD is significantly mediated by smoking-related phenotypes, IREB2 appears to affect COPD independently of smoking.

Evolutionary psychologists have suggested that confidence and conservatism promoted aggression in our ancestral past, and that this may have been an adaptive strategy given the prevailing costs and benefits of conflict. However, in modern environments, where the costs and benefits of conflict can be very different owing to the involvement of mass armies, sophisticated technology, and remote leadership, evolved tendencies toward high levels of confidence and conservatism may continue to be a contributory cause of aggression despite leading to greater costs and fewer benefits. The purpose of this paper is to test whether confidence and conservatism are indeed associated with greater levels of aggression-in an explicitly political domain. We present the results of an experiment examining people's levels of aggression in response to hypothetical international crises (a hostage crisis, a counter-insurgency campaign, and a coup). Levels of aggression (which range from concession to negotiation to military attack) were significantly predicted by subjects' (1) confidence that their chosen policy would succeed, (2) score on a liberal-conservative scale, (3) political party affiliation, and (4) preference for the use of military force in real-world U.S. policy toward Iraq and Iran. We discuss the possible adaptive and maladaptive implications of confidence and conservatism for the prospects of war and peace in the modern world.

Traditionally in the social sciences, causal mediation analysis has been formulated, understood, and implemented within the framework of linear structural equation models. We argue and demonstrate that this is problematic for 3 reasons: the lack of a general definition of causal mediation effects independent of a particular statistical model, the inability to specify the key identification assumption, and the difficulty of extending the framework to nonlinear models. In this article, we propose an alternative approach that overcomes these limitations. Our approach is general because it offers the definition, identification, estimation, and sensitivity analysis of causal mediation effects without reference to any specific statistical model. Further, our approach explicitly links these 4 elements closely together within a single framework. As a result, the proposed framework can accommodate linear and nonlinear relationships, parametric and nonparametric models, continuous and discrete mediators, and various types of outcome variables. The general definition and identification result also allow us to develop sensitivity analysis in the context of commonly used models, which enables applied researchers to formally assess the robustness of their empirical conclusions to violations of the key assumption. We illustrate our approach by applying it to the Job Search Intervention Study. We also offer easy-to-use software that implements all our proposed methods., (PsycINFO Database Record (c) 2010 APA, all rights reserved.)

Monoamine oxidase A gene (MAOA) has earned the nickname "warrior gene" because it has been linked to aggression in observational and survey-based studies. However, no controlled experimental studies have tested whether the warrior gene actually drives behavioral manifestations of these tendencies. We report an experiment, synthesizing work in psychology and behavioral economics, which demonstrates that aggression occurs with greater intensity and frequency as provocation is experimentally manipulated upwards, especially among low activity MAOA (MAOA-L) subjects. In this study, subjects paid to punish those they believed had taken money from them by administering varying amounts of unpleasantly hot (spicy) sauce to their opponent. There is some evidence of a main effect for genotype and some evidence for a gene by environment interaction, such that MAOA is less associated with the occurrence of aggression in a low provocation condition, but significantly predicts such behavior in a high provocation situation. This new evidence for genetic influences on aggression and punishment behavior complicates characterizations of humans as "altruistic" punishers and supports theories of cooperation that propose mixed strategies in the population. It also suggests important implications for the role of individual variance in genetic factors contributing to everyday behaviors and decisions.

Political science, as a discipline, has been reluctant to adopt theories and methodologies developed in fields studying human behavior from an evolutionary standpoint. I ask whether evolutionary concepts are reconcilable with standard political-science theories and whether those concepts help solve puzzles to which these theories classically are applied. I find that evolutionary concepts readily and simultaneously accommodate theories of rational choice, symbolism, interpretation, and acculturation. Moreover, phenomena perennially hard to explain in standard political science become clearer when human interactions are understood in light of natural selection and evolutionary psychology. These phenomena include the political and economic effects of emotion, status, personal attractiveness, and variations in information-processing and decision-making under uncertainty; exemplary is the use of "focal points" in multiple-equilibrium games. I conclude with an overview of recent research by, and ongoing debates among, scholars analyzing politics in evolutionarily sophisticated terms.

PDZ-domain containing proteins of the MAGUK (membrane-associated guanylate kinase) family target, anchor, and cluster receptors and channels to subcellular sites. Among the MAGUK proteins, the members of the PSD-95 family (MAGUKs: PSD-95, PSD-93, SAP-97, and SAP-102) target and anchor glutamate receptors to the synaptic terminals. Associations of glutamate receptors with MAGUKs have been described in the brain but not in the cochlea. In this study, RT-PCR, immunofluorescence microscopy, and immunoelectron microscopy were used to investigate the presence and distribution of MAGUK proteins in the organ of Corti. The presence of the mRNA for PSD-95, PSD-93, SAP-97, and SAP-102 in the organ of Corti was confirmed by RT-PCR. Immunocytochemistry using a "pan-MAGUK" antibody, which recognizes all four MAGUK proteins, and selective antibodies against these proteins revealed that all four MAGUKs are present within the base of inner hair cells while all except SAP-97 are found within the base of the outer hair cells. In addition, PSD-93 and PSD-95 are found in postsynaptic afferent terminals on inner hair cells, while postsynaptic afferent terminals on outer hair cells have PSD-93., (Copyright 2001 Wiley-Liss, Inc.)

Physician Data Query (PDQ) (National Cancer Institute [NCI], Bethesda, MD) and CANCERLIT (NCI, Bethesda, MD) are two online cancer information databases. PDQ summarizes current cancer therapy literature into specific treatment recommendations. CANCERLIT is a bibliographic system similar to MEDLINE (National Library of Medicine [NLM], Bethesda, MD) that provides a comprehensive source of literature citations for the field of cancer. In this report, we discuss linking PDQ and CANCERLIT with PDQ ACCESS (NCI, Bethesda, MD)--a custom software package that makes searching the cancer literature easy for the practicing physician unfamiliar with database searching.

The National Cancer Institute's PDQ database is the most current source of peer-reviewed information available today on state-of-the-art treatment of cancer and AIDS. It can serve the primary care physician as a principal reference point for decisions regarding consultation, referral, and patient care, and it is relatively simple and inexpensive to use. The new PDQ ACCESS microcomputer soft-ware enables untrained searchers automatically to execute current literature searches of the CANCERLIT database, as an adjunct to searching PDQ.

PDQ is an online database that provides information about the prognosis and treatment of all major types of cancer. It represents a major effort by the NCI to communicate advances in cancer treatment using computer technology, and serves as a major component of the Institute's program to reduce cancer mortality nationwide. PDQ utilizes a modern large-scale computer to provide processing speed, a general purpose database management system to provide retrieval and display functions, and commercial telecommunication networks to provide online access to up-to-date information on cancer treatment. A series of user-friendly menus allow searching, browsing, and displaying without having to learn a specialized search language. PDQ is accessible through the National Library of Medicine's computer system via a computer terminal or personal computer and is available to the medical community at over 2000 medical libraries and centers and through individual access codes. PDQ is also available as an online database under a special license agreement with NCI through two medical information systems produced by commercial database vendors: BRS/Saunders' COLLEAGUE and Mead Data Central's MEDIS.

It is the intent of this paper to draw attention to round window tears with the inherent symptomatology that has, for the first time, been documented in two aircrew members. It is also felt important to emphasize that the condition, regardless of etiology, could be catastrophic to the flying pilot and may be an up-recognized cause of otherwise unexplainable accidents. Not all cases of window tears cause vertigo-but some do. Not all vertigo so caused is prostrating--but some is. Because of the findings in two reported cases, it is postulated that round window membrane tear may be a significant cause of pilot disorientation. It may have been the root cause of peculiar and previously unexplained air crashes. The corollary of this hypothesis is the proposition that, in the future, careful attention be paid to the ears of pilots recovered from what would otherwise appear to be a mysterious accident.