Absence of MyD88 results in enhanced TLR3-dependent phosphorylation of IRF3 and increased IFN-(beta) and RANTES production

Toll-like receptors are a group of pattern-recognition receptors that play a crucial role in "danger" recognition and induction of the innate immune response against bacterial and viral infections. TLR3 has emerged as a key sensor of viral dsRNA, resulting in the induction of the anti-viral molecule, IFN- . Thus, a clearer understanding of the biological processes that modulate TLR3 signaling is essential. Previous studies have shown that the TLR adaptor, Mal/TIRAP, an activator of TLR4, inhibits TLR3-mediated IFN- induction through a mechanism involving IRF7. In this study, we sought to investigate whether the TLR adaptor, MyD88, an activator of all TLRs except TLR3, has the ability to modulate TLR3 signaling. Although MyD88 does not significantly affect TLR3 ligand-induced TNF- induction, MyD88 negatively regulates TLR3-, but not TLR4-, mediated IFN- and RANTES production; this process is mechanistically distinct from that employed by Mal/TIRAP. We show that MyD88 inhibits IKK -, but not TBK1-, induced activation of IRF3. In doing so, MyD88 curtails TLR3 ligand-induced IFN- induction. The present study shows that while MyD88 activates all TLRs except TLR3, MyD88 also functions as a negative regulator of TLR3. Thus, MyD88 is essential in restricting TLR3 signaling, thereby protecting the host from unwanted immunopathologies associated with the excessive production of IFN- . Our study offers a new role for MyD88 in restricting TLR3 signaling through a hitherto unknown mechanism whereby MyD88 specifically impairs IKK -mediated induction of IRF3 and concomitant IFN- and RANTES production.

Picture Recognition of Food by Macaques (Macaca silenus)

Pictorial representations of three-dimensional objects are often used to investigate animal cognitive abilities; however, investigators rarely evaluate whether the animals conceptualize the two-dimensional image as the object it is intended to represent. We tested for picture recognition in lion-tailed macaques by presenting five monkeys with digitized images of familiar foods on a touch screen. Monkeys viewed images of two different foods and learned that they would receive a piece of the one they touched first. After demonstrating that they would reliably select images of their preferred foods on one set of foods, animals were transferred to images of a second set of familiar foods. We assumed that if the monkeys recognized the images, they would spontaneously select images of their preferred foods on the second set of foods. Three monkeys selected images of their preferred foods significantly more often than chance on their first transfer session. In an additional test of the monkeys' picture recognition abilities, animals were presented with pairs of food images containing a medium-preference food paired with either a high-preference food or a low-preference food. The same three monkeys selected the medium-preference foods significantly more often when they were paired with low-preference foods and significantly less often when those same foods were paired with high-preference foods. Our novel design provided convincing evidence that macaques recognized the content of two-dimensional images on a touch screen. Results also suggested that the animals understood the connection between the two-dimensional images and the three-dimensional objects they represented.

Melody recognition at fast and slow tempos: Effects of age, experience, and familiarity

Eighty-one listeners defined by three age ranges (18–30, 31–59, and over 60 years) and three levels of musical experience performed an immediate recognition task requiring the detection of alterations in melodies. On each trial, a brief melody was presented, followed 5 sec later by a test stimulus that either was identical to the target or had two pitches changed, for a same–different judgment. Each melody pair was presented at 0.6 note/sec, 3.0 notes/sec, or 6.0 notes/sec. Performance was better with familiar melodies than with unfamiliar melodies. Overall performance declined slightly with age and improved substantially with increasing experience, in agreement with earlier results in an identification task. Tempo affected performance on familiar tunes (moderate was best), but not on unfamiliar tunes. We discuss these results in terms of theories of dynamic attending, cognitive slowing, and working memory in aging.

Levels-of-processing effects on "remember" responses in recognition for familiar and unfamiliar tunes

We investigated the effect of level-of-processing manipulations on “remember” and “know” responses in episodic melody recognition (Experiments 1 and 2) and how this effect is modulated by item familiarity (Experiment 2). In Experiment 1, participants performed 2 conceptual and 2 perceptual orienting tasks while listening to familiar melodies: judging the mood, continuing the tune, tracing the pitch contour, and counting long notes. The conceptual mood task led to higher d' rates for “remember” but not “know” responses. In Experiment 2, participants either judged the mood or counted long notes of tunes with high and low familiarity. A level-of-processing effect emerged again in participants’ “remember” d' rates regardless of melody familiarity. Results are discussed within the distinctive processing framework.

Recognition of familiar and unfamiliar music in normal aging and Alzheimer's disease

We tested normal young and elderly adults and elderly Alzheimer’s disease (AD) patients on recognition memory for tunes. In Experiment 1, AD patients and age-matched controls received a study list and an old/new recognition test of highly familiar, traditional tunes, followed by a study list and test of novel tunes. The controls performed better than did the AD patients. The controls showed the “mirror effect” of increased hits and reduced false alarms for traditional versus novel tunes, whereas the patients false-alarmed as often to traditional tunes as to novel tunes. Experiment 2 compared young adults and healthy elderly persons using a similar design. Performance was lower in the elderly group, but both younger and older subjects showed the mirror effect. Experiment 3 produced confusion between preexperimental familiarity and intraexperimental familiarity by mixing traditional and novel tunes in the study lists and tests. Here, the subjects in both age groups resembled the patients of Experiment 1 in failing to show the mirror effect. Older subjects again performed more poorly, and they differed qualitatively from younger subjects in setting stricter criteria for more nameable tunes. Distinguishing different sources of global familiarity is a factor in tune recognition, and the data suggest that this type of source monitoring is impaired in AD and involves different strategies in younger and older adults.

Aging and experience in the recognition of musical transpositions

The authors examined the effects of age, musical experience, and characteristics of musical stimuli on a melodic short-term memory task in which participants had to recognize whether a tune was an exact transposition of another tune recently presented. Participants were musicians and nonmusicians between ages 18 and 30 or 60 and 80. In 4 experiments, the authors found that age and experience affected different aspects of the task, with experience becoming more influential when interference was provided during the task. Age and experience interacted only weakly, and neither age nor experience influenced the superiority of tonal over atonal materials. Recognition memory for the sequences did not reflect the same pattern of results as the transposition task. The implications of these results for theories of aging, experience, and music cognition are discussed.

Crystallization, optimization and preliminary X-ray characterization of a metal-dependent PI-PLC from Streptomyces antibioticus

A recombinant metal-dependent phosphatidylinositol-specific phospholipase C (PI-PLC) from Streptomyces antibioticus has been crystallized by the hanging-drop method with and without heavy metals. The native crystals belonged to the orthorhombic space group P222, with unit-cell parameters a = 41.26, b = 51.86, c= 154.78 A. The X-ray diffraction results showed significant differences in the crystal quality of samples soaked with heavy atoms. Additionally, drop pinning, which increases the surface area of the drops, was also used to improve crystal growth and quality. The combination of heavy-metal soaks and drop pinning was found to be critical for producing high-quality crystals that diffracted to 1.23 A resolution.

Stress and Strain Adaptation in Load-Dependent Remodeling of the Embryonic Left Ventricle

Altered pressure in the developing left ventricle (LV) results in altered morphology and tissue material properties. Mechanical stress and strain may play a role in the regulating process. This study showed that confocal microscopy, three-dimensional reconstruction, and finite element analysis can provide a detailed model of stress and strain in the trabeculated embryonic heart. The method was used to test the hypothesis that end-diastolic strains are normalized after altered loading of the LV during the stages of trabecular compaction and chamber formation. Stage-29 chick LVs subjected to pressure overload and underload at stage 21 were reconstructed with full trabecular morphology from confocal images and analyzed with finite element techniques. Measured material properties and intraventricular pressures were specified in the models. The results show volume-weighted end-diastolic von Mises stress and strain averaging 50–82% higher in the trabecular tissue than in the compact wall. The volume-weighted-average stresses for the entire LV were 115, 64, and 147Pa in control, underloaded, and overloaded models, while strains were 11, 7, and 4%; thus, neither was normalized in a volume-weighted sense. Localized epicardial strains at mid-longitudinal level were similar among the three groups and to strains measured from high-resolution ultrasound images. Sensitivity analysis showed changes in material properties are more significant than changes in geometry in the overloaded strain adaptation, although resulting stress was similar in both types of adaptation. These results emphasize the importance of appropriate metrics and the role of trabecular tissue in evaluating the evolution of stress and strain in relation to pressure-induced adaptation.

Terrestrial feeding in aquatic turtles: environment-dependent feeding behavior modulation and the evolution of terrestrial feeding in Emydidae

Evolutionary transitions between aquatic and terrestrial environments are common in vertebrate evolution. These transitions require major changes in most physiological functions, including feeding. Emydid turtles are ancestrally aquatic, with most species naturally feeding only in water, but some terrestrial species can modulate their feeding behavior appropriately for both media. In addition, many aquatic species can be induced to feed terrestrially. A comparison of feeding in both aquatic and terrestrial environments presents an excellent opportunity to investigate the evolution of terrestrial feeding from aquatic feeding, as well as a system within which to develop methods for studying major evolutionary transitions between environments. Individuals from eight species of emydid turtles (six aquatic, two terrestrial) were filmed while feeding underwater and on land. Bite kinematics were analyzed to determine whether aquatic turtles modulated their feeding behavior in a consistent and appropriate manner between environments. Aquatic turtles showed consistent changes between environments, taking longer bites and using more extensive motions of the jaw and hyoid when feeding on land. However, these motions differ from those shown by species that naturally feed in both environments and mostly do not seem to be appropriate for terrestrial feeding. For example, more extensive motions of the hyoid are only effective during underwater suction feeding. Emydids evolving to feed on land probably would have needed to evolve or learn to overcome many, but not all, aspects of the intrinsic emydid response to terrestrial feeding. Studies that investigate major evolutionary transitions must determine what responses to the new environment are shown by naïve individuals in order to fully understand the evolutionary patterns and processes associated with these transitions.

Corpus-Based Speech Enhancement With Uncertainty Modeling and Cepstral Smoothing

We present a new approach for corpus-based speech enhancement that significantly improves over a method published by Xiao and Nickel in 2010. Corpus-based enhancement systems do not merely filter an incoming noisy signal, but resynthesize its speech content via an inventory of pre-recorded clean signals. The goal of the procedure is to perceptually improve the sound of speech signals in background noise. The proposed new method modifies Xiao's method in four significant ways. Firstly, it employs a Gaussian mixture model (GMM) instead of a vector quantizer in the phoneme recognition front-end. Secondly, the state decoding of the recognition stage is supported with an uncertainty modeling technique. With the GMM and the uncertainty modeling it is possible to eliminate the need for noise dependent system training. Thirdly, the post-processing of the original method via sinusoidal modeling is replaced with a powerful cepstral smoothing operation. And lastly, due to the improvements of these modifications, it is possible to extend the operational bandwidth of the procedure from 4 kHz to 8 kHz. The performance of the proposed method was evaluated across different noise types and different signal-to-noise ratios. The new method was able to significantly outperform traditional methods, including the one by Xiao and Nickel, in terms of PESQ scores and other objective quality measures. Results of subjective CMOS tests over a smaller set of test samples support our claims.

Temperature-Dependent Defect Dynamics in the Network Glass SiO2

We investigate the long time dynamics of a strong glass former, SiO2, below the glass transition temperature by averaging single-particle trajectories over time windows which comprise roughly 100 particle oscillations. The structure on this coarse-grained time scale is very well defined in terms of coordination numbers, allowing us to identify ill-coordinated atoms, which are called defects in the following. The most numerous defects are O-O neighbors, whose lifetimes are comparable to the equilibration time at low temperature. On the other hand, SiO and OSi defects are very rare and short lived. The lifetime of defects is found to be strongly temperature dependent, consistent with activated processes. Single-particle jumps give rise to local structural rearrangements. We show that in SiO2 these structural rearrangements are coupled to the creation or annihilation of defects, giving rise to very strong correlations of jumping atoms and defects.

Yolk Androstenedione in Domestic Chicks (Gallus Gallus Domesticus): Uptake and Sex-Dependent Alteration of Growth and Behavior

In birds, causes and consequences of variation in maternally-derived steroids in egg yolk have been the subject of intense experimentation. Many studies have quantified or manipulated testosterone ("T") and one of its immediate precursors, androstenedione ("A4") - often lumping the two steroids as "androgens" and treating them as functionally equivalent. However, yolk A4 is deposited in substantially higher concentrations than T, binds only weakly to the androgen receptor, and is readily converted into either T or estrone by steroidogenic enzymes present during embryonic development. Thus it may not be appropriate to assume that A4 has the same effect as T. In addition, A4's metabolic fate is likely to differ between females and males. The goals of this study were to examine the sex-specific uptake and metabolism of yolk A4 and consequences of elevated levels of yolk A4 on development and behavior of domestic chicks. Eggs were injected with 2mu Ci of tritiated androstenedione; radioactivity was detected in all tissues of day 7 and day 16 embryos and found in both aqueous and organics phases of day 7 yolk, with no difference between sexes. A second set of eggs was injected with 125ng of A4. A4 increased growth of morphological traits (tarsus, beak) in females, but not males. A4 males had smaller combs than controls; there was no treatment effect in females. A4 reduced tonic immobility behavior in both sexes. The results of this study illustrate the importance of distinguishing both between androgens and between sexes when investigating avian endocrine maternal effects. Copyright 2013 Elsevier Inc. All rights reserved.

THE RESONATE-AND-FIRE NEURON: TIME DEPENDENT AND FREQUENCY SELECTIVE NEURONS IN NEURAL NETWORKS

The means through which the nervous system perceives its environment is one of the most fascinating questions in contemporary science. Our endeavors to comprehend the principles of neural science provide an instance of how biological processes may inspire novel methods in mathematical modeling and engineering. The application ofmathematical models towards understanding neural signals and systems represents a vibrant field of research that has spanned over half a century. During this period, multiple approaches to neuronal modeling have been adopted, and each approach is adept at elucidating a specific aspect of nervous system function. Thus while bio-physical models have strived to comprehend the dynamics of actual physical processes occurring within a nerve cell, the phenomenological approach has conceived models that relate the ionic properties of nerve cells to transitions in neural activity. Further-more, the field of neural networks has endeavored to explore how distributed parallel processing systems may become capable of storing memory. Through this project, we strive to explore how some of the insights gained from biophysical neuronal modeling may be incorporated within the field of neural net-works. We specifically study the capabilities of a simple neural model, the Resonate-and-Fire (RAF) neuron, whose derivation is inspired by biophysical neural modeling. While reflecting further biological plausibility, the RAF neuron is also analytically tractable, and thus may be implemented within neural networks. In the following thesis, we provide a brief overview of the different approaches that have been adopted towards comprehending the properties of nerve cells, along with the framework under which our specific neuron model relates to the field of neuronal modeling. Subsequently, we explore some of the time-dependent neurocomputational capabilities of the RAF neuron, and we utilize the model to classify logic gates, and solve the classic XOR problem. Finally we explore how the resonate-and-fire neuron may be implemented within neural networks, and how such a network could be adapted through the temporal backpropagation algorithm.

Accuracy of Recognition and Diagnosis of Comorbid Depression in the Nursing Home

A variety of research has documented high levels of depression among older adults in the health care setting. Additional research has shown that care providers in health care settings are not very effective at diagnosing comorbid depression.This is a troublesome finding since comorbid depression has been linked to a number of negative outcomes in older adults. Early results have indicated that comorbid depression may be associated with a number of unfavorable consequences ranging from impairments in physical functioning to increased mortality.The health care setting with arguably the highest rate of physical impairment is the nursing home and it is the nursing home where the effects of comorbid depression may be most costly. Therefore, the current analysis uses data from the Institutional Population Component of the NationalMedical Expenditure Survey (US Department of Health and Human Services, 1990) to explore rates of both recognized and unrecognized comorbid depression in the nursing home setting. Using a constructed proxy variable representative of the DSM-III-R diagnosis of depression, results indicate that approximately 8.1% of nursing home residents have an unrecognized potential comorbid depression.

The Role of Features and Context in Recognition of Novel Melodies

WE INVESTIGATED HOW WELL STRUCTURAL FEATURES such as note density or the relative number of changes in the melodic contour could predict success in implicit and explicit memory for unfamiliar melodies. We also analyzed which features are more likely to elicit increasingly confident judgments of "old" in a recognition memory task. An automated analysis program computed structural aspects of melodies, both independent of any context, and also with reference to the other melodies in the testset and the parent corpus of pop music. A few features predicted success in both memory tasks, which points to a shared memory component. However, motivic complexity compared to a large corpus of pop music had different effects on explicit and implicit memory. We also found that just a few features are associated with different rates of "old" judgments, whether the items were old or new. Rarer motives relative to the testset predicted hits and rarer motives relative to the corpus predicted false alarms. This data-driven analysis provides further support for both shared and separable mechanisms in implicit and explicit memory retrieval, as well as the role of distinctiveness in true and false judgments of familiarity.