1,358 research outputs found

    The Role of Leptin Action in States of Obesity

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    Over the last century, the United States has experienced a shift from underweight malnutrition maladies to obesity-associated complications. Today, over 70% of US adults are overweight and are at increased risk for various chronic diseases including diabetes, cardiovascular disease and cancer. The ubiquitous nature of obesity and its costs on the individual and societal level have elevated it to one of the most impactful diseases of the 21st century. The adipokine leptin is produced in proportion to adipose tissue and binds to its receptor (LepRb) in the CNS to provide a snapshot of energy stores, resulting in the regulation of energy balance. Due to leptin’s role in communicating fat stores and the hyperphagic obesity that results from its absence, leptin is clearly central to the homeostatic systems that regulate energy balance. And, while leptin replacement is an effective anti-obesity treatment in the few cases of obesity from leptin-deficiency, it fails to produce weight loss in diet-induced obese (DIO) individuals who express high levels of leptin (hyperleptinemia) commensurate with their elevated adipose content. Despite this, recent advances in genetic and sequencing technologies have allowed for a closer examination of DIO. We first examined the hypothalamic transcriptome of LepRb neurons and characterized DIO as a state of increased leptin signaling. Additional region-specific analyses confirm this understanding of DIO, and when coupled to immunohistochemical and phenotypic findings, broaden our understanding of the role DIO-hyperleptinemia plays in LepRb neurons and neighboring glial cells. These transcriptome findings additionally revealed STAT1 to be not only another LepRb-dependent signal, but to also significantly increase when STAT3 was ablated in neurons. This increase in Stat1, however, did not functionally compensate for the absence of STAT3. Moreover, we found STAT3 to be both necessary and sufficient in LepRb neurons for energy balance. However, while increased STAT3 activity does decrease weight in normoleptinemic mice (mimicking hyperleptinemia in lean animals) it does not produce weight loss in already hyperleptinemic DIO animals. Thus, the diminishing returns of additional STAT3/leptin action with increasing endogenous leptin levels were demonstrated transcriptionally, phenotypically and genetically. Our further investigation into the overlap between leptin and other metabolic hormones like calcitonin and amylin has broadened our understanding of leptin action and has identified potential molecular targets and locations for the already-proven synergistic amylin-leptin weight loss therapy. Together, these varied approaches underscore the complexity and importance of leptin action and paves a path for the discovery of novel anti-obesity therapies.PHDCellular & Molec Biology PhDUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/155141/1/warrenp_1.pd

    nuID: a universal naming scheme of oligonucleotides for Illumina, Affymetrix, and other microarrays

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    <p>Abstract</p> <p>Background</p> <p>Oligonucleotide probes that are sequence identical may have different identifiers between manufacturers and even between different versions of the same company's microarray; and sometimes the same identifier is reused and represents a completely different oligonucleotide, resulting in ambiguity and potentially mis-identification of the genes hybridizing to that probe.</p> <p>Results</p> <p>We have devised a unique, non-degenerate encoding scheme that can be used as a universal representation to identify an oligonucleotide across manufacturers. We have named the encoded representation 'nuID', for nucleotide universal identifier. Inspired by the fact that the raw sequence of the oligonucleotide is the true definition of identity for a probe, the encoding algorithm uniquely and non-degenerately transforms the sequence itself into a compact identifier (a lossless compression). In addition, we added a redundancy check (checksum) to validate the integrity of the identifier. These two steps, encoding plus checksum, result in an nuID, which is a unique, non-degenerate, permanent, robust and efficient representation of the probe sequence. For commercial applications that require the sequence identity to be confidential, we have an encryption schema for nuID. We demonstrate the utility of nuIDs for the annotation of Illumina microarrays, and we believe it has universal applicability as a source-independent naming convention for oligomers.</p> <p>Reviewers</p> <p>This article was reviewed by Itai Yanai, Rong Chen (nominated by Mark Gerstein), and Gregory Schuler (nominated by David Lipman).</p

    Effects of correlation between merging steps on the global halo formation

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    The excursion set theory of halo formation is modified by adopting the fractional Brownian motion, to account for possible correlation between merging steps. We worked out analytically the conditional mass function, halo merging rate and formation time distribution in the spherical collapse model. We also developed an approximation for the ellipsoidal collapse model and applied it to the calculation of the conditional mass function and the halo formation time distribution. For models in which the steps are positively correlated, the halo merger rate is enhanced when the accreted mass is less than 25M\sim 25M^*, while for the negatively correlated case this rate is reduced. Compared with the standard model in which the steps are uncorrelated, the models with positively correlated steps produce more aged population in small mass halos and more younger population in large mass halos, while for the models with negatively correlated steps the opposite is true. An examination of simulation results shows that a weakly positive correlation between successive merging steps appears to fit best. We have also found a systematic effect in the measured mass function due to the finite volume of simulations. In future work, this will be included in the halo model to accurately predict the three point correlation function estimated from simulations.Comment: 8 pages, submitted to MNRA

    Voltage-independent SK-channel dysfunction causes neuronal hyperexcitability in the hippocampus of Fmr1 knock-out mice

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    Neuronal hyperexcitability is one of the major characteristics of fragile X syndrome (FXS), yet the molecular mechanisms of this critical dysfunction remain poorly understood. Here we report a major role of voltage-independent potassium (

    Cloud Forensics Investigations Relationship: A Model And Instrument

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    Cloud computing is one of the most important advances in computing in recent history. cybercrime has developed side by side and rapidly in recent years. Previous studies had confirmed the existing gap between cloud service providers (CSPs) and law enforcement agencies (LEAs), and LEAs cannot work without the cooperation of CSPs. Their relationship is influenced by legal, organisational and technical dimensions, which affect the investigations. Therefore, it is essential to enhance the cloud forensics relationship between LEAs and CSPs. This research addresses the need for a unified collaborative model to facilitate proper investigations and explore and evaluate existing different models involved in the relationship between Omani LEAs and local CSPs as a participant in investigations. Further, it proposes a validated research instrument that can be cloud forensics survey. It can also be used as an evaluation tool to identify, measure, and manage cloud forensic investigations

    A collection of bioconductor methods to visualize gene-list annotations

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    <p>Abstract</p> <p>Background</p> <p>Gene-list annotations are critical for researchers to explore the complex relationships between genes and functionalities. Currently, the annotations of a gene list are usually summarized by a table or a barplot. As such, potentially biologically important complexities such as one gene belonging to multiple annotation categories are difficult to extract. We have devised explicit and efficient visualization methods that provide intuitive methods for interrogating the intrinsic connections between biological categories and genes.</p> <p>Findings</p> <p>We have constructed a data model and now present two novel methods in a Bioconductor package, "GeneAnswers", to simultaneously visualize genes, concepts (a.k.a. annotation categories), and concept-gene connections (a.k.a. annotations): the "Concept-and-Gene Network" and the "Concept-and-Gene Cross Tabulation". These methods have been tested and validated with microarray-derived gene lists.</p> <p>Conclusions</p> <p>These new visualization methods can effectively present annotations using Gene Ontology, Disease Ontology, or any other user-defined gene annotations that have been pre-associated with an organism's genome by human curation, automated pipelines, or a combination of the two. The gene-annotation data model and associated methods are available in the Bioconductor package called "GeneAnswers " described in this publication.</p

    A Leptin-regulated Circuit Controls Glucose Mobilization During Noxious Stimuli

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    Adipocytes secrete the hormone leptin to signal the sufficiency of energy stores. Reductions in circulating leptin concentrations reflect a negative energy balance, which augments sympathetic nervous system (SNS) activation in response to metabolically demanding emergencies. This process ensures adequate glucose mobilization despite low energy stores. We report that leptin receptor–expressing neurons (LepRb neurons) in the periaqueductal gray (PAG), the largest population of LepRb neurons in the brain stem, mediate this process. Application of noxious stimuli, which often signal the need to mobilize glucose to support an appropriate response, activated PAG LepRb neurons, which project to and activate parabrachial nucleus (PBN) neurons that control SNS activation and glucose mobilization. Furthermore, activating PAG LepRb neurons increased SNS activity and blood glucose concentrations, while ablating LepRb in PAG neurons augmented glucose mobilization in response to noxious stimuli. Thus, decreased leptin action on PAG LepRb neurons augments the autonomic response to noxious stimuli, ensuring sufficient glucose mobilization during periods of acute demand in the face of diminished energy stores
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