Autonomic cardiovascular dysregulation as a potential mechanism underlying depression and coronary artery bypass grafting surgery outcomes.

BACKGROUND: Coronary artery bypass grafting (CABG) is often used to treat patients with significant coronary heart disease (CHD). To date, multiple longitudinal and cross-sectional studies have examined the association between depression and CABG outcomes. Although this relationship is well established, the mechanism underlying this relationship remains unclear. The purpose of this study was twofold. First, we compared three markers of autonomic nervous system (ANS) function in four groups of patients: 1) Patients with coronary heart disease and depression (CHD/Dep), 2) Patients without CHD but with depression (NonCHD/Dep), 3) Patients with CHD but without depression (CHD/NonDep), and 4) Patients without CHD and depression (NonCHD/NonDep). Second, we investigated the impact of depression and autonomic nervous system activity on CABG outcomes. METHODS: Patients were screened to determine whether they met some of the study's inclusion or exclusion criteria. ANS function (i.e., heart rate, heart rate variability, and plasma norepinephrine levels) were measured. Chi-square and one-way analysis of variance were performed to evaluate group differences across demographic, medical variables, and indicators of ANS function. Logistic regression and multiple regression analyses were used to assess impact of depression and autonomic nervous system activity on CABG outcomes. RESULTS: The results of the study provide some support to suggest that depressed patients with CHD have greater ANS dysregulation compared to those with only CHD or depression. Furthermore, independent predictors of in-hospital length of stay and non-routine discharge included having a diagnosis of depression and CHD, elevated heart rate, and low heart rate variability. CONCLUSIONS: The current study presents evidence to support the hypothesis that ANS dysregulation might be one of the underlying mechanisms that links depression to cardiovascular CABG surgery outcomes. Thus, future studies should focus on developing and testing interventions that targets modifying ANS dysregulation, which may lead to improved patient outcomes.

Structure, function, and phylogeny of the mating locus in the Rhizopus oryzae complex.

The Rhizopus oryzae species complex is a group of zygomycete fungi that are common, cosmopolitan saprotrophs. Some strains are used beneficially for production of Asian fermented foods but they can also act as opportunistic human pathogens. Although R. oryzae reportedly has a heterothallic (+/-) mating system, most strains have not been observed to undergo sexual reproduction and the genetic structure of its mating locus has not been characterized. Here we report on the mating behavior and genetic structure of the mating locus for 54 isolates of the R. oryzae complex. All 54 strains have a mating locus similar in overall organization to Phycomyces blakesleeanus and Mucor circinelloides (Mucoromycotina, Zygomycota). In all of these fungi, the minus (-) allele features the SexM high mobility group (HMG) gene flanked by an RNA helicase gene and a TP transporter gene (TPT). Within the R. oryzae complex, the plus (+) mating allele includes an inserted region that codes for a BTB/POZ domain gene and the SexP HMG gene. Phylogenetic analyses of multiple genes, including the mating loci (HMG, TPT, RNA helicase), ITS1-5.8S-ITS2 rDNA, RPB2, and LDH genes, identified two distinct groups of strains. These correspond to previously described sibling species R. oryzae sensu stricto and R. delemar. Within each species, discordant gene phylogenies among multiple loci suggest an outcrossing population structure. The hypothesis of random-mating is also supported by a 50:50 ratio of plus and minus mating types in both cryptic species. When crossed with tester strains of the opposite mating type, most isolates of R. delemar failed to produce zygospores, while isolates of R. oryzae produced sterile zygospores. In spite of the reluctance of most strains to mate in vitro, the conserved sex locus structure and evidence for outcrossing suggest that a normal sexual cycle occurs in both species.

Minding metals: tailoring multifunctional chelating agents for neurodegenerative disease.

Neurodegenerative diseases like Alzheimer's and Parkinson's disease are associated with elevated levels of iron, copper, and zinc and consequentially high levels of oxidative stress. Given the multifactorial nature of these diseases, it is becoming evident that the next generation of therapies must have multiple functions to combat multiple mechanisms of disease progression. Metal-chelating agents provide one such function as an intervention for ameliorating metal-associated damage in degenerative diseases. Targeting chelators to adjust localized metal imbalances in the brain, however, presents significant challenges. In this perspective, we focus on some noteworthy advances in the area of multifunctional metal chelators as potential therapeutic agents for neurodegenerative diseases. In addition to metal chelating ability, these agents also contain features designed to improve their uptake across the blood-brain barrier, increase their selectivity for metals in damage-prone environments, increase antioxidant capabilities, lower Abeta peptide aggregation, or inhibit disease-associated enzymes such as monoamine oxidase and acetylcholinesterase.

Genomics research: world survey of public funding.

BACKGROUND: Over the past two decades, genomics has evolved as a scientific research discipline. Genomics research was fueled initially by government and nonprofit funding sources, later augmented by private research and development (R&D) funding. Citizens and taxpayers of many countries have funded much of the research, and have expectations about access to the resulting information and knowledge. While access to knowledge gained from all publicly funded research is desired, access is especially important for fields that have broad social impact and stimulate public dialogue. Genomics is one such field, where public concerns are raised for reasons such as health care and insurance implications, as well as personal and ancestral identification. Thus, genomics has grown rapidly as a field, and attracts considerable interest. RESULTS: One way to study the growth of a field of research is to examine its funding. This study focuses on public funding of genomics research, identifying and collecting data from major government and nonprofit organizations around the world, and updating previous estimates of world genomics research funding, including information about geographical origins. We initially identified 89 publicly funded organizations; we requested information about each organization's funding of genomics research. Of these organizations, 48 responded and 34 reported genomics research expenditures (of those that responded but did not supply information, some did not fund such research, others could not quantify it). The figures reported here include all the largest funders and we estimate that we have accounted for most of the genomics research funding from government and nonprofit sources. CONCLUSION: Aggregate spending on genomics research from 34 funding sources averaged around $2.9 billion in 2003-2006. The United States spent more than any other country on genomics research, corresponding to 35% of the overall worldwide public funding (compared to 49% US share of public health research funding for all purposes). When adjusted to genomics funding intensity, however, the United States dropped below Ireland, the United Kingdom, and Canada, as measured both by genomics research expenditure per capita and per Gross Domestic Product.

Increasing arousal enhances inhibitory control in calm but not excitable dogs

© 2015, Springer-Verlag Berlin Heidelberg.The emotional-reactivity hypothesis proposes that problem-solving abilities can be constrained by temperament, within and across species. One way to test this hypothesis is with the predictions of the Yerkes–Dodson law. The law posits that arousal level, a component of temperament, affects problem solving in an inverted U-shaped relationship: Optimal performance is reached at intermediate levels of arousal and impeded by high and low levels. Thus, a powerful test of the emotional-reactivity hypothesis is to compare cognitive performance in dog populations that have been bred and trained based in part on their arousal levels. We therefore compared a group of pet dogs to a group of assistance dogs bred and trained for low arousal (N = 106) on a task of inhibitory control involving a detour response. Consistent with the Yerkes–Dodson law, assistance dogs, which began the test with lower levels of baseline arousal, showed improvements when arousal was artificially increased. In contrast, pet dogs, which began the test with higher levels of baseline arousal, were negatively affected when their arousal was increased. Furthermore, the dogs’ baseline levels of arousal, as measured in their rate of tail wagging, differed by population in the expected directions. Low-arousal assistance dogs showed the most inhibition in a detour task when humans eagerly encouraged them, while more highly aroused pet dogs performed worst on the same task with strong encouragement. Our findings support the hypothesis that selection on temperament can have important implications for cognitive performance.

The frontal eye field sends predictively remapped visual signals to the superior colliculus

We perceive a stable visual world even though saccades often move our retinas. One way the brain may achieve a stable visual percept is through predictive remapping of visual receptive fields: just before a saccade, the receptive field of many neurons moves from its current location ("current receptive field") to the location it is expected to occupy after the saccade ("future receptive field"). Goldberg and colleagues found such remapping in cortical areas, e.g. in the frontal eye field (FEF), as well as in the intermediate layers of the superior colliculus (SC). In the present study we investigated the source of the SC's remapped visual signals. Do some of them come from the FEF? We identified FEF neurons that project to the SC using antidromic stimulation. For neurons with a visual response, we tested whether the receptive field shifted just prior to making a saccade. Saccadic amplitudes were chosen to be as small as possible while clearly separating the current and future receptive fields; they ranged from 5-30 deg. in amplitude and were directed contraversively. The saccadic target was a small red spot. We probed visual responsiveness at the current and future receptive field locations using a white spot flashed at various times before or after the saccade. Predictive remapping was indicated by a visual response to a probe flashed in the future receptive field just before the saccade began. We found that many FEF neurons projecting to the SC exhibited predictive remapping. Moreover, the remapping was as fast and strong as any previously reported for FEF or SC. It is clear, therefore, that remapped visual signals are sent from FEF to SC, providing direct evidence that the FEF is one source of the SC's remapped visual signals. Because remapping requires information about an imminent saccade, we hypothesize that remapping in FEF depends on corollary discharge signals such as those ascending from the SC through MD thalamus (Sommer and Wurtz 2002).

Influence of the thalamus on spatial visual processing in frontal cortex.

Each of our movements activates our own sensory receptors, and therefore keeping track of self-movement is a necessary part of analysing sensory input. One way in which the brain keeps track of self-movement is by monitoring an internal copy, or corollary discharge, of motor commands. This concept could explain why we perceive a stable visual world despite our frequent quick, or saccadic, eye movements: corollary discharge about each saccade would permit the visual system to ignore saccade-induced visual changes. The critical missing link has been the connection between corollary discharge and visual processing. Here we show that such a link is formed by a corollary discharge from the thalamus that targets the frontal cortex. In the thalamus, neurons in the mediodorsal nucleus relay a corollary discharge of saccades from the midbrain superior colliculus to the cortical frontal eye field. In the frontal eye field, neurons use corollary discharge to shift their visual receptive fields spatially before saccades. We tested the hypothesis that these two components-a pathway for corollary discharge and neurons with shifting receptive fields-form a circuit in which the corollary discharge drives the shift. First we showed that the known spatial and temporal properties of the corollary discharge predict the dynamic changes in spatial visual processing of cortical neurons when saccades are made. Then we moved from this correlation to causation by isolating single cortical neurons and showing that their spatial visual processing is impaired when corollary discharge from the thalamus is interrupted. Thus the visual processing of frontal neurons is spatiotemporally matched with, and functionally dependent on, corollary discharge input from the thalamus. These experiments establish the first link between corollary discharge and visual processing, delineate a brain circuit that is well suited for mediating visual stability, and provide a framework for studying corollary discharge in other sensory systems.

What the brain stem tells the frontal cortex. II. Role of the SC-MD-FEF pathway in corollary discharge.

One way we keep track of our movements is by monitoring corollary discharges or internal copies of movement commands. This study tested a hypothesis that the pathway from superior colliculus (SC) to mediodorsal thalamus (MD) to frontal eye field (FEF) carries a corollary discharge about saccades made into the contralateral visual field. We inactivated the MD relay node with muscimol in monkeys and measured corollary discharge deficits using a double-step task: two sequential saccades were made to the locations of briefly flashed targets. To make second saccades correctly, monkeys had to internally monitor their first saccades; therefore deficits in the corollary discharge representation of first saccades should disrupt second saccades. We found, first, that monkeys seemed to misjudge the amplitudes of their first saccades; this was revealed by systematic shifts in second saccade end points. Thus corollary discharge accuracy was impaired. Second, monkeys were less able to detect trial-by-trial variations in their first saccades; this was revealed by reduced compensatory changes in second saccade angles. Thus corollary discharge precision also was impaired. Both deficits occurred only when first saccades went into the contralateral visual field. Single-saccade generation was unaffected. Additional deficits occurred in reaction time and overall performance, but these were bilateral. We conclude that the SC-MD-FEF pathway conveys a corollary discharge used for coordinating sequential saccades and possibly for stabilizing vision across saccades. This pathway is the first elucidated in what may be a multilevel chain of corollary discharge circuits extending from the extraocular motoneurons up into cerebral cortex.

A pathway in primate brain for internal monitoring of movements.

It is essential to keep track of the movements we make, and one way to do that is to monitor correlates, or corollary discharges, of neuronal movement commands. We hypothesized that a previously identified pathway from brainstem to frontal cortex might carry corollary discharge signals. We found that neuronal activity in this pathway encodes upcoming eye movements and that inactivating the pathway impairs sequential eye movements consistent with loss of corollary discharge without affecting single eye movements. These results identify a pathway in the brain of the primate Macaca mulatta that conveys corollary discharge signals.