Adaptive Physiological Response to Perceived Scarcity as a Mechanism of Sensory Modulation of Life Span.

Chemosensation is a potent modulator of organismal physiology and longevity. In Drosophila, loss of recognition of diverse tastants has significant and bidirectional life-span effects. Recently published results revealed that when flies were unable to taste water, they increased its internal generation, which may have subsequently altered life span. To determine whether similar adaptive responses occur in other contexts, we explored the impact of sensory deficiency of other metabolically important molecules. Trehalose is a major circulating carbohydrate in the fly that is recognized by the gustatory receptor Gr5a. Gr5a mutant flies are short lived, and we found that they specifically increased whole-body and circulating levels of trehalose, but not other carbohydrates, likely through upregulation of de novo synthesis. dILP2 transcript levels were increased in Gr5a mutants, a possible response intended to reduce hypertrehalosemia, and likely a contributing factor to their reduced life span. Together, these data suggest that compensatory physiological responses to perceived environmental scarcity, which are designed to alleviate the ostensive shortage, may be a common outcome of sensory manipulation. We suggest that future investigations into the mechanisms underlying sensory modulation of aging may benefit by focusing on direct or indirect consequences of physiological changes that are designed to correct perceived disparity with the environment.

Positive and negative gustatory inputs affect Drosophila lifespan partly in parallel to dFOXO signaling.

In Caenorhabditis elegans, a subset of gustatory neurons, as well as olfactory neurons, shortens lifespan, whereas a different subset of gustatory neurons lengthens it. Recently, the lifespan-shortening effect of olfactory neurons has been reported to be conserved in Drosophila. Here we show that the Drosophila gustatory system also affects lifespan in a bidirectional manner. We find that taste inputs shorten lifespan through inhibition of the insulin pathway effector dFOXO, whereas other taste inputs lengthen lifespan in parallel to this pathway. We also note that the gustatory influence on lifespan does not necessarily depend on food intake levels. Finally, we identify the nature of some of the taste inputs that could shorten versus lengthen lifespan. Together our data suggest that different gustatory cues can modulate the activities of distinct signaling pathways, including different insulin-like peptides, to promote physiological changes that ultimately affect lifespan.

Maternal low-protein diet alters the expression of real-time quantitative polymerase chain reaction reference genes in an age-, sex-, and organ-dependent manner in rat offspring.

Altered perinatal environment, often manifested as low birth weight, is thought to contribute to greater susceptibility for hypertension, hyperlipidemia, and diabetes as a result of epigenetic modifications and alteration of transcriptional activity for key genes. Real-time polymerase chain reaction is a useful technique for the quantitative determination of differences in transcriptional activity. Real-time quantitative polymerase chain reaction data analyses require normalization of transcriptional activity of target genes to an endogenous control, usually a reference gene. In response to reports of altered expression of reference genes in various experimental models, we hypothesized that adverse perinatal environment alters reference gene expression. We examined the expression of the following reference genes in the offspring of a rodent maternal low-protein diet model: ß-actin, hypoxanthine phosphoribosyltransferase 1, TATA-box-binding protein, glyceraldehyde-3-phosphate dehydrogenase, and glucuronidase-ß in brain, heart, kidneys, and intestines. We found altered expression in brain, heart, and kidneys for each of the reference genes measured; these effects were age, organ, and sex dependent. Glyceraldehyde-3-phosphate dehydrogenase and glucuronidase-ß were found to be the least affected by these variables, whereas hypoxanthine phosphoribosyltransferase 1 was the most inconsistent. Our findings underscore the importance of empirical determination of a reliable reference gene for real-time polymerase chain reaction studies in the low-protein diet model.

Process indicators of quality clinical pharmacy services during transitions of care.

The American College of Clinical Pharmacy charged the Public and Professional Relations Committee to develop a short white paper describing quality measures of clinical pharmacists' patient care services in transitional care settings. Transitional care describes patient movement from one health care setting or service to another. Care transitions are associated with an increased risk of adverse events for patients. Pharmacists play an important role in ensuring that medication errors and adverse events are minimized during these transitions, largely through the reconciliation of medications and assurance of continuity of care. Quality measures are often divided into three domains: structure, process, and outcome. Given the typical nature of the pharmacist's role, process indicators are best suited to evaluate quality clinical pharmacist services. However, process indicators relevant to pharmacists' activities are not yet fully described in the literature. The committee searched available literature describing quality measures that are directly influenced by the pharmacist during care transitions. This white paper describes these process indicators as quality measures of clinical pharmacists' services, identifies the transitional settings and activities to which they are most applicable, and provides the published sources from which indicators were derived. For process indicators that could not be found in published sources, we propose relevant measures that can be adapted for use in a given setting. As pharmacists become more involved in diverse and emerging patient care areas such as transitional care, it will be critical that they use these types of measures to document the quality of new services and reinforce the need for pharmacist participation during transitions of care.

Re-patterning sleep architecture in Drosophila through gustatory perception and nutritional quality.

Organisms perceive changes in their dietary environment and enact a suite of behavioral and metabolic adaptations that can impact motivational behavior, disease resistance, and longevity. However, the precise nature and mechanism of these dietary responses is not known. We have uncovered a novel link between dietary factors and sleep behavior in Drosophila melanogaster. Dietary sugar rapidly altered sleep behavior by modulating the number of sleep episodes during both the light and dark phase of the circadian period, independent of an intact circadian rhythm and without affecting total sleep, latency to sleep, or waking activity. The effect of sugar on sleep episode number was consistent with a change in arousal threshold for waking. Dietary protein had no significant effect on sleep or wakefulness. Gustatory perception of sugar was necessary and sufficient to increase the number of sleep episodes, and this effect was blocked by activation of bitter-sensing neurons. Further addition of sugar to the diet blocked the effects of sweet gustatory perception through a gustatory-independent mechanism. However, gustatory perception was not required for diet-induced fat accumulation, indicating that sleep and energy storage are mechanistically separable. We propose a two-component model where gustatory and metabolic cues interact to regulate sleep architecture in response to the quantity of sugar available from dietary sources. Reduced arousal threshold in response to low dietary availability may have evolved to provide increased responsiveness to cues associated with alternative nutrient-dense feeding sites. These results provide evidence that gustatory perception can alter arousal thresholds for sleep behavior in response to dietary cues and provide a mechanism by which organisms tune their behavior and physiology to environmental cues.

Sensory perception and aging in model systems: from the outside in.

Sensory systems provide organisms from bacteria to humans with the ability to interact with the world. Numerous senses have evolved that allow animals to detect and decode cues from sources in both their external and internal environments. Recent advances in understanding the central mechanisms by which the brains of simple organisms evaluate different cues and initiate behavioral decisions, coupled with observations that sensory manipulations are capable of altering organismal lifespan, have opened the door for powerful new research into aging. Although direct links between sensory perception and aging have been established only recently, here we discuss these initial discoveries and evaluate the potential for different forms of sensory processing to modulate lifespan across taxa. Harnessing the neurobiology of simple model systems to study the biological impact of sensory experiences will yield insights into the broad influence of sensory perception in mammals and may help uncover new mechanisms of healthy aging.

DRE-1: an evolutionarily conserved F box protein that regulates C. elegans developmental age.

During metazoan development, cells acquire both positional and temporal identities. The Caenorhabditis elegans heterochronic loci are global regulators of larval temporal fates. Most encode conserved transcriptional and translational factors, which affect stage-appropriate programs in various tissues. Here, we describe dre-1, a heterochronic gene, whose mutant phenotypes include precocious terminal differentiation of epidermal stem cells and altered temporal patterning of gonadal outgrowth. Genetic interactions with other heterochronic loci place dre-1 in the larval-to-adult switch. dre-1 encodes a highly conserved F box protein, suggesting a role in an SCF ubiquitin ligase complex. Accordingly, RNAi knockdown of the C. elegans SKP1-like homolog SKR-1, the cullin CUL-1, and ring finger RBX homologs yielded similar heterochronic phenotypes. DRE-1 and SKR-1 form a complex, as do the human orthologs, hFBXO11 and SKP1, revealing a phyletically ancient interaction. The identification of core components involved in SCF-mediated modification and/or proteolysis suggests an important level of regulation in the heterochronic hierarchy.

An interactive visualization-based approach for high throughput screening information management in drug discovery.

While high throughput screening (HTS) techniques are capable of generating large amounts of biologically significant data, assimilating and mining this information can be extremely complex and potentially crucial information patterns can easily be lost in the mounds of data. The predominantly life-science oriented scientific training of the researchers in this area furthermore, precludes their using complex querying or data-mining algorithms. Keeping in account these challenges, our goal in this paper is to provide a highly intuitive environment for storing and interacting with large amounts of HTS assay data. The principal modes of user-data interactions supported in the proposed paradigm are interaction and visualization rich. Moreover, they span the heterogeneous data modalities common to drug discovery, including but not limited to chemical structures, high-throughput assay formats, graphical information, and alpha-numeric data types. Case studies and experiments demonstrate the efficacy of the proposed approach in terms of its ease of use as well as its capability to discern complex information patterns in the data.

Hypoxic incubation creates differential morphological effects during specific developmental critical windows in the embryo of the chicken (Gallus gallus).

Hypoxia inhibits vertebrate development, but the magnitude and timing of organ-specific effects are poorly understood. Chick embryos were exposed continuously to hypoxia (15% O2) throughout Days 1-6, 6-12, 12-18 or Days 1-18 of development, followed by morphometric measurements of major organ systems. Early hypoxic exposure reduced eye mass and beak length when measured in middle development. Liver, brain, heart, kidneys, stomach, intestines and skeletal long bones were not affected by hypoxia at any developmental stage. The chorioallantoic membrane (CAM) mass was unchanged by hypoxic exposure in early or mid-development, but CAM mass on Day 18 increased strikingly (40 and 60% in late and continuous populations, respectively) in response to hypoxic exposure. The increase in CAM mass presumably enhances oxygen delivery, thus minimizing the detrimental effects of hypoxia on development and growth. Hypoxic exposure at key critical windows in development thus results in differential effects on organ development, some of which can subsequently be repaired through additional incubation (yolk mass, eye mass, beak length).