Dr. Larkin will discuss research foci of the NIA Division of Neuroscience. Dr. Larkin will also be available for small group discussion.

People are living longer than ever before, and the world’s population aged 60 and older is expected to increase from 1 billion to 2.1 billion by 2050. As populations get older, they become more susceptible to age-related diseases such as Alzheimer’s Disease and Related Dementias (AD/ADRD), which affects more than 55 million individuals worldwide. The National Institutes of Health (NIH) aims to prevent and treat diseases such as AD/ADRD through generalist and disease-specific data resources that foster findable, interconnected, and interoperable data to accelerate biomedical innovations and medical interventions that improve human health. The goal of this assessment was to understand the value of AD/ADRD secondary data use from NIH genomic and multi-omics data resources: NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), database of Genotypes and Phenotypes (dbGaP), AD Knowledge Portal (ADKP), and Gene Expression Omnibus (GEO). List of AD/ADRD datasets were retrieved through database searches or directly from repository staff (N=183). Citation frequency of data accessions were used to determine utilization of AD/ADRD genomic and multi-omics datasets in published literature. iSearch tool was used to assess secondary use drivers in resulting publications. Query of data accessions in Pubmed Central returned 284 unique publications. iSearch clustering by term showed that genomic datasets were used to study genetic risk factors of AD/ADRD while multi-omics datasets were used to functionally characterize genetic risk variants, identify gene regulatory networks, and biomarkers associated with neurodegenerative diseases. These findings indicate the usefulness of AD/ADRD secondary data to the scientific literature.

As more digital resources are produced by the research community, it is becoming increasingly important to harmonize and organize them for synergistic utilization. The findable, accessible, interoperable, and reusable (FAIR) guiding principles have prompted many stakeholders to consider strategies for tackling this challenge. The FAIRshake toolkit was developed to enable the establishment of community-driven FAIR metrics and rubrics paired with manual and automated FAIR assessments. FAIR assessments are visualized as an insignia that can be embedded within digital-resources-hosting websites. Using FAIRshake, a variety of biomedical digital resources were manually and automatically evaluated for their level of FAIRness.

As more datasets, tools, workflows, APIs, and other digital resources are produced by the research community, it is becoming increasingly difficult to harmonize and organize these efforts for maximal synergistic integrated utilization. The Findable, Accessible, Interoperable, and Reusable (FAIR) guiding principles have prompted many stakeholders to consider strategies for tackling this challenge by making these digital resources follow common standards and best practices so that they can become more integrated and organized. Faced with the question of how to make digital resources more FAIR, it has become imperative to measure what it means to be FAIR. The diversity of resources, communities, and stakeholders have different goals and use cases and this makes assessment of FAIRness particularly challenging. To begin resolving this challenge, the FAIRshake toolkit was developed to enable the establishment of community-driven FAIR metrics and rubrics paired with manual, semi- and fully-automated FAIR assessment capabilities. The FAIRshake toolkit contains a database that lists registered digital resources, with their associated metrics, rubrics, and assessments. The FAIRshake toolkit also has a browser extension and a bookmarklet that enables viewing and submitting assessments from any website. The FAIR assessment results are visualized as an insignia that can be viewed on the FAIRshake website, or embedded within hosting websites. Using FAIRshake, a variety of bioinformatics tools, datasets listed on dbGaP, APIs registered in SmartAPI, workflows in Dockstore, and other biomedical digital resources were manually and automatically assessed for FAIRness. In each case, the assessments revealed room for improvement, which prompted enhancements that significantly upgraded FAIRness scores of several digital resources.

Hibernation is organized in bouts which are discrete episodes of decreased activity, metabolism, and body temperature. The lengths of hibernation bouts depend on various factors including species, body weight, ambient temperature, and time of year. The nature of hibernation bouts has been an enduring question. Most often this question has been framed in terms of the function and the control of periodic arousals. A number of studies of the timing of entrances into and arousals from hibernation have suggested that periodic arousals from hibernation are controlled in part by the circadian system. The circadian studies leave open the questions of why temperature influences the number of circadian cycles expressed in each bout, and what is the function of periodic arousals. electroencephalogram studies of golden-mantled ground squirrels entering hibernation revealed that they were predominantly in non-rapid eye movement sleep with rapid eye movement sleep progressively decreasing until it was not evident at all below a brain temperature of 27 °C.

Understanding the human condition is a Big Data problem. This statement is nicely illustrated by the articles that follow from seven of the Centers for Data Excellence that have been funded by the National Institutes of Health (NIH) Big Data to Knowledge (BD2K) initiative. BD2K is a trans-NIH program, funded by all Institutes and Centers at NIH as well as the NIH Common Fund; it is overseen by the NIH Office of Data Science within the NIH Office of the Director. The beginnings of BD2K have been described previously,1 and the purpose here is to provide an overall context, from …

Biomedical research has and will continue to generate large amounts of data (termed ‘big data’) in many formats and at all levels. Consequently, there is an increasing need to better understand and mine the data to further knowledge and foster new discovery. The National Institutes of Health (NIH) has initiated a Big Data to Knowledge (BD2K) initiative to maximize the use of biomedical big data. BD2K seeks to better define how to extract value from the data, both for the individual investigator and the overall research community, create the analytic tools needed to enhance utility of the data, provide the next generation of trained personnel, and develop data science concepts and tools that can be made available to all stakeholders.

The National Heart, Lung, and Blood Institute (NHLBI) has recognized the importance of the systems biology approach for understanding normal physiology and perturbations associated with heart, lung, blood, and sleep diseases and disorders. In 2006, NHLBI announced the Exploratory Program in Systems Biology program, followed in 2010 by the NHLBI Systems Biology Collaborations program. The goal of these programs is to support collaborative teams of investigators in using experimental and computational strategies to integrate the component parts of biological networks and pathways into computational models that are based firmly on and validated using experimental data. These validated models are then applied to gain insights into the mechanisms of altered system function in disease, to generate novel hypotheses regarding these mechanisms that can be tested experimentally, and to then use the results of experiments to refine the models. This perspective reviews the history of dedicated systems biology programs at NHLBI and reviews some promising directions for future research in this area.

To evaluate the effect of genetic background on antibacterial defense to streptococcal infection, eight genetically diverse strains of mice (A/J, DBA/2J, CAST/Ei, FVB/NJ, BALB/cJ, C57BL/6J, 129/SvImJ, and C3H/HeJ) and tlr2-deficient mice (C57BL/6(tlr2-/-)) were infected with three doses of Streptococcus zooepidemicus (500, 5,000, or 50,000 colony-forming units) by alveolar challenge. There was a range of susceptibility between the strains at each dose and time point (6, 24, and 96 h). At the lowest dose, the 129/SvImJ and C3H/HeJ strains had significantly higher bacterial counts at all time points after infection, when compared to A/J, DBA/2J, CAST/Ei, FVB/NJ, which were resistant to infection at the low dose of innoculum. At the medium dose, 129/SvImJ and C3H/HeJ had higher bacterial counts, while A/J, DBA/2J, and BALB/cJ showed reduced streptococcal growth. After the highest dose of Streptococcus, there were minimal differences between strains, suggesting the protective impact of modifier genes can be overcome. TLR2-deficient animals contained increased bacterial load with reduced cytokines after 96 h when compared to C57BL/6J controls suggesting a role of innate immunity in late antibacterial defense. Overall, we identify vulnerable (129/SvlmJ and C3H/HeJ) and resistant (A/J, FVB, and DBA) mouse strains to streptococcal lung infection, which demonstrate divergent genetic expression profiles. These results demonstrate that innate differences in pulmonary host defense to S. zooepidemicus are dependent on host genetic factors.

Microarrays have been widely used for the analysis of gene expression, but the issue of reproducibility across platforms has yet to be fully resolved. To address this apparent problem, we compared gene expression between two microarray platforms: the short oligonucleotide Affymetrix Mouse Genome 430 2.0 GeneChip and a spotted cDNA array using a mouse model of angiontensin II–induced hypertension. RNA extracted from treated mice was analyzed using Affymetrix and cDNA platforms and then by quantitative RT-PCR (qRT-PCR) for validation of specific genes. For the 11,710 genes present on both arrays, we assessed the relative impact of experimental treatment and platform on measured expression and found that biological treatment had a far greater impact on measured expression than did platform for more than 90% of genes, a result validated by qRT-PCR. In the small number of cases in which platforms yielded discrepant results, qRT-PCR generally did not confirm either set of data, suggesting that sequence-specific effects may make expression predictions difficult to make using any technique.

Sleep is regulated by independent yet interacting circadian and homeostatic processes. The present study used a novel approach to study sleep homeostasis in the absence of circadian influences by exposing Siberian hamsters to a simple phase delay of the photocycle to make them arrhythmic. Because these hamsters lacked any circadian organization, their sleep homeostasis could be studied in the absence of circadian interactions. Control animals retained circadian rhythmicity after the phase shift and re-entrained to the phase-shifted photocycle. These animals displayed robust daily sleep-wake rhythms with consolidated sleep during the light phase beginning about 1 h after light onset. This marked sleep-wake pattern was circadian in that it persisted in constant darkness. The distribution of sleep in the arrhythmic hamsters over 24 h was similar to that in the light phase of rhythmic animals. Therefore, daily sleep amounts were higher in arrhythmic animals compared with rhythmic ones. During 2- and 6-h sleep deprivations (SD), it was more difficult to keep arrhythmic hamsters awake than it was for rhythmic hamsters. Because the arrhythmic animals obtained more non-rapid eye movement sleep (NREMS) during the SD, they showed a diminished compensatory response in NREMS EEG slow-wave activity during recovery sleep. When amounts of sleep during the SD were taken into account, there were no differences in sleep homeostasis between experimental and control hamsters. Thus loss of circadian control did not alter the homeostatic response to SD. This supports the view that circadian and homeostatic influences on sleep regulation are independent processes.

Circadian activity rhythms of most Siberian hamsters (Phodopus sungorus sungorus) fail to reentrain to a 5-h phase shift of the light-dark (LD) cycle. Instead, their rhythms free-run at periods close to 25 h despite the continued presence of the LD cycle. This lack of behavioral reentrainment necessarily means that molecular oscillators in the master circadian pacemaker, the SCN, were unable to reentrain as well. The authors tested the hypothesis that a phase shift of the LD cycle rendered the SCN incapable of responding to photic input. Animals were exposed to a 5-h phase delay of the photocycle, and activity rhythms were monitored until a lack of reentrainment was confirmed. Hamsters were then housed in constant darkness for 24 h and administered a 30-min light pulse 2 circadian hours after activity onset. Brains were then removed, and tissue sections containing the SCN were processed for in situ hybridization. Sections were probed with Siberian hamster c-fos and per1 mRNA probes because light rapidly induces these 2 genes in the SCN during subjective night but not at other circadian phases. Light pulses induced robust expression of both genes in all animals that reentrained to the LD cycle, but no expression was observed in any animal that failed to reentrain. None of the animals exhibited an intermediate response. This finding is the first report of acute shift in a photocycle eliminating photosensitivity in the SCN and suggests that a specific pattern of light exposure may desensitize the SCN to subsequent photic input.

This information is current as of June 4, 2013. http://www. the-aps. org/. 20814-3991. Copyright© 2004 the American Physiological Society. ESSN: 1531-2267. Visit our website at 24 times a year (twice monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD systems with techniques linking genes and pathways to physiology, from prokaryotes to eukaryotes. It is published publishes results of a wide variety of studies from human and from informative model

Exposure of experimental animals to increased angiotensin II (ANG II) induces hypertension associated with cardiac hypertrophy, inflammation, and myocardial necrosis and fibrosis. Some of the most effective antihypertensive treatments are those that antagonize ANG II. We investigated cardiac gene expression in response to acute (24 h) and chronic (14 day) infusion of ANG II in mice; 24-h treatment induces hypertension, and 14-day treatment induces hypertension and extensive cardiac hypertrophy and necrosis. For genes differentially expressed in response to ANG II treatment, we tested for significant regulation of pathways, based on Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Microarray Pathway Profiler (GenMAPP) databases, as well as functional classes based on Gene Ontology (GO) terms. Both acute and chronic ANG II treatments resulted in decreased expression of mitochondrial metabolic genes, notably those for the electron transport chain and Krebs-TCA cycle; chronic ANG II treatment also resulted in decreased expression of genes involved in fatty acid metabolism. In contrast, genes involved in protein translation and ribosomal activity increased expression following both acute and chronic ANG II treatments. Some classes of genes showed differential response between acute and chronic ANG II treatments. Acute treatment increased expression of genes involved in oxidative stress and amino acid metabolism, whereas chronic treatments increased cytoskeletal and extracellular matrix genes, second messenger cascades responsive to ANG II, and amyloidosis genes. Although a functional linkage between Alzheimer disease, hypertension, and high cholesterol has been previously documented in studies of brain tissue, this is the first demonstration of induction of Alzheimer disease pathways by hypertension in heart tissue. This study provides the most comprehensive available survey of gene expression changes in response to acute and chronic ANG II treatment, verifying results from disparate studies, and suggests mechanisms that provide novel insight into the etiology of hypertensive heart disease and possible therapeutic interventions that may help to mitigate its effects.

Arousal from deep hibernation is accompanied by a transient rise of melatonin (Mel) in circulation; there are no comparable analyses of Mel concentrations in species that undergo much shallower, shorter duration episodes of daily torpor. Serum Mel concentrations were determined during arousal from both natural daily torpor and torpor induced by 2‐deoxy‐D‐glucose (2‐DG) treatment (2,500 mg/kg, intraperitoneal [IP]); blood samples were drawn from the retro‐orbital sinus of anesthetized Siberian hamsters. For animals kept in darkness during torpor, Mel concentrations were highest during early arousal when thermogenesis is maximal, and they decreased as body temperature increased during arousal and returned to baseline once euthermia was reestablished. In hamsters kept in the light during the torpor bout, Mel concentrations were elevated above basal values during arousal, but the response was significantly blunted in comparison with values recorded in darkness. Increased Mel concentrations were detected in hamsters only during arousal from torpor (either natural or 2‐DG induced) and were not simply a result of the drug treatment; hamsters that remained euthermic or manifested mild hypothermia after drug treatment maintained basal Mel concentrations. We propose that increased Mel production may reflect enhanced sympathetic activation associated with intense thermogenesis during arousal from torpor rather than an adjustment of the circadian rhythm of Mel secretion.

Siberian hamsters as young as 16 and 28 d displayed torpor in response to treatment with 2,500 mg/kg 2-deoxy-D-glucose and reduced food availability, respectively. In addition, most food-restricted hamsters displayed increased locomotor activity and elevated body temperatures in the 3 h immediately preceding daily food delivery. This anticipatory activity disappeared within a few days of reimposition of ad lib. feeding. Torpor first appeared spontaneously at approximately 13 wk of age in hamsters fed ad lib. and maintained in short day lengths. The onset of this "spontaneous" torpor was unaffected by the hamsters' history of food restriction before age 2 mo. Siberian hamsters born late in the breeding season can conserve energy by undergoing torpor immediately after weaning when they contend with food shortages and concurrent energetic challenges imposed by growth requirements and low ambient temperatures.

We sought to determine whether ambient temperature (T(a)) affects gonadal function by altering the rate at which circadian rhythms entrain to short day lengths. Syrian hamsters were housed in cages where they received 14 h of light per day ("long days," 14L) at 22 degrees C. Hamsters were then transferred to cages to receive 10 h of light per day ("short days," 10L) and kept at 5, 22, or 28 degrees C or were maintained in 14L at 22 degrees C. Body mass and estimated testis volume as well as duration of nocturnal locomotor activity (alpha), previously established as a reliable indicator of the duration of nocturnal melatonin secretion, were determined over the course of 24 wk. Testicular regression in short days was accelerated by 4 wk at 5 degrees C and delayed by 3 wk at 28 degrees C relative to 22 degrees C. The interval between alpha-expansion and initiation of testicular regression was markedly affected by T(a) with delays of 0, 3, and 6 wk at 5, 22, and 28 degrees C, respectively. All hamsters held at 5 and 22 degrees C underwent testicular regression, but 25% of those maintained at 28 degrees C failed to do so. We suggest that T(a) modulates testicular regression primarily by affecting responsiveness of neuroendocrine target tissues to long melatonin signals.

In Siberian hamsters, day length is encoded by the duration of the nocturnal melatonin signal; short and long melatonin signals over the course of several weeks stimulate and inhibit somatic and gonadal development, respectively, in prepubertal males. We sought to determine whether juvenile male Siberian hamsters respond to multiple melatonin signals each day and the manner in. which the sequence of melatonin signals and the duration of the melatonin-free interval between signals affects development. Twenty-one day old male Siberian hamsters, gestated and maintained in a short-day photoperiod of 10 h light/day (10 L), were transferred to constant light to suppress endogenous melatonin secretion and received s.c. infusions of melatonin or saline for 12 days. Hamsters Infused with saline retained small testes, whereas one short melatonin infusion each. day resulted in significant testicular growth. Other hamsters were provided with two melatonin signals each day, one long (9 h) and one short (4 or 5 h); the order in which these signals was administered. and the duration of the melatonin-free interval after each signal varied between groups. In asymmetrical melatonin infusions, the first. and second daily infusions were followed by 3-h and 7-h melatonin-free intervals, respectively, whereas in symmetrical infusions, each melatonin signal was followed by a 5-h melatonin-free interval. In the asymmetrical sequence, the melatonin signal that immediately preceded the longer melatonin-free interval determined the rate gonadal growth. Equal melatonin-free intervals after each of the long and short daily melatonin infusions produced. intermediate increases in gonadal and somatic development. The hypothalamic-pituitary-gonadal axis of Siberian hamsters can respond to multiple melatonin signals each day, with. the rate of testicular growth determined primarily by the duration of the melatonin-free interval following each infusion.

We investigated circadian and homeostatic regulation of nonrapid eye movement (NREM) sleep in golden-mantled ground squirrels during euthermic intervals between torpor bouts. Slow-wave activity (SWA; 1-4 Hz) and sigma activity (10-15 Hz) represent the two dominant electroencephalographic (EEG) frequency components of NREM sleep. EEG sigma activity has a strong circadian component in addition to a sleep homeostatic component, whereas SWA mainly reflects sleep homeostasis [Dijk DJ and Czeisler CA. J Neurosci 15: 3526-3538, 1995; Dijk DJ, Shanahan TL, Duffy JF, Ronda JM, and Czeisler CA. J Physiol (Lond) 505: 851-858, 1997]. Animals maintained under constant conditions continued to display circadian rhythms in both sigma activity and brain temperature throughout euthermic intervals, whereas sleep and wakefulness showed no circadian organization. Instead, sleep and wakefulness were distributed according to a 6-h ultradian rhythm. SWA, NREM sleep bout length, and sigma activity responded homeostatically to the ultradian sleep-wake pattern. We suggest that the loss of sleep-wake consolidation in ground squirrels during the hibernation season may be related to the greatly decreased locomotor activity during the hibernation season and may be necessary for maintenance of multiday torpor bouts characteristic of hibernating species.

Exposure to low ambient temperatures (Ta) accelerates appearance of the winter phenotype in Siberian hamsters transferred from long to short day lengths. Because melatonin transduces the effects of day length on the neuroendocrine axis, the authors assessed whether low Ta promotes the transition to winterlike traits by accelerating the onset of increased nocturnal melatonin secretion or by enhancing responsiveness to melatonin in short day lengths. Male hamsters were transferred from 16L (16 h light/day) to 8L (8 h light/day) photoperiods and held at 5 °C or 22 °C. Locomotor activity was recorded continuously, and body mass, testis size, and pelage color were determined biweekly for 8 weeks. The duration of nocturnal locomotion ([.alpha]), a reliable indicator of the duration of nocturnal melatonin secretion, lengthened significantly earlier in hamsters exposed to a Ta of 5 °C than 22 °C. Cold exposure increased the proportion of hamsters that were photoresponsive: gonadal regression in short days increased from 44% at 22 °C to 81% at 5 °C ( p < 0.05); low Ta did not, however, accelerate testicular regression in animals that were photoresponsive. Nonphotoresponsive animals at 5 °C temporarily had longer [.alpha]s during the first 4 weeks in short days and significant decreases in body mass and testicular size that were reversed during the ensuing weeks when [.alpha] decreased. In a 2nd experiment, pinealectomized male hamsters infused for 10 h/day with melatonin for 2 weeks had significantly lower body and testes masses when maintained at 5 °C but not 22 °C. Low-ambient temperature appears to accelerate the appearance of the winter phenotype primarily by increasing target tissue responsiveness to melatonin and to a lesser extent by augmenting the rate at which the duration of nocturnal melatonin secretion increases in short day lengths.