A Transcription Elongation Factor That Links Signals from the Reproductive System to Lifespan Extension in Caenorhabditis elegans

In Caenorhabditis elegans and Drosophila melanogaster, the aging of the soma is influenced by the germline. When germline-stem cells are removed, aging slows and lifespan is increased. The mechanism by which somatic tissues respond to loss of the germline is not well-understood. Surprisingly, we have found that a predicted transcription elongation factor, TCER-1, plays a key role in this process. TCER-1 is required for loss of the germ cells to increase C. elegans' lifespan, and it acts as a regulatory switch in the pathway. When the germ cells are removed, the levels of TCER-1 rise in somatic tissues. This increase is sufficient to trigger key downstream events, as overexpression of tcer-1 extends the lifespan of normal animals that have an intact reproductive system. Our findings suggest that TCER-1 extends lifespan by promoting the expression of a set of genes regulated by the conserved, life-extending transcription factor DAF-16/FOXO. Interestingly, TCER-1 is not required for DAF-16/FOXO to extend lifespan in animals with reduced insulin/IGF-1 signaling. Thus, TCER-1 specifically links the activity of a broadly deployed transcription factor, DAF-16/FOXO, to longevity signals from reproductive tissues

Huntington's disease and its therapeutic target genes: a global functional profile based on the HD Research Crossroads database.

BACKGROUND: Huntington's disease (HD) is a fatal progressive neurodegenerative disorder caused by the expansion of the polyglutamine repeat region in the huntingtin gene. Although the disease is triggered by the mutation of a single gene, intensive research has linked numerous other genes to its pathogenesis. To obtain a systematic overview of these genes, which may serve as therapeutic targets, CHDI Foundation has recently established the HD Research Crossroads database. With currently over 800 cataloged genes, this web-based resource constitutes the most extensive curation of genes relevant to HD. It provides us with an unprecedented opportunity to survey molecular mechanisms involved in HD in a holistic manner. METHODS: To gain a synoptic view of therapeutic targets for HD, we have carried out a variety of bioinformatical and statistical analyses to scrutinize the functional association of genes curated in the HD Research Crossroads database. In particular, enrichment analyses were performed with respect to Gene Ontology categories, KEGG signaling pathways, and Pfam protein families. For selected processes, we also analyzed differential expression, using published microarray data. Additionally, we generated a candidate set of novel genetic modifiers of HD by combining information from the HD Research Crossroads database with previous genome-wide linkage studies. RESULTS: Our analyses led to a comprehensive identification of molecular mechanisms associated with HD. Remarkably, we not only recovered processes and pathways, which have frequently been linked to HD (such as cytotoxicity, apoptosis, and calcium signaling), but also found strong indications for other potentially disease-relevant mechanisms that have been less intensively studied in the context of HD (such as the cell cycle and RNA splicing, as well as Wnt and ErbB signaling). For follow-up studies, we provide a regularly updated compendium of molecular mechanism, that are associated with HD, at http://hdtt.sysbiolab.eu Additionally, we derived a candidate set of 24 novel genetic modifiers, including histone deacetylase 3 (HDAC3), metabotropic glutamate receptor 1 (GRM1), CDK5 regulatory subunit 2 (CDK5R2), and coactivator 1ß of the peroxisome proliferator-activated receptor gamma (PPARGC1B). CONCLUSIONS: The results of our study give us an intriguing picture of the molecular complexity of HD. Our analyses can be seen as a first step towards a comprehensive list of biological processes, molecular functions, and pathways involved in HD, and may provide a basis for the development of more holistic disease models and new therapeutics

Presidential Election Campaigns and American Democracy: The Relationship Between Communication Use and Normative Outcomes

There is very little research about the relative influence of campaign communication forms or venues on normative outcomes concerning the extent to which campaign communication promotes or degrades basic democratic values. This investigation assesses the relative impact of 17 communication forms on three normative outcomes: political expertise, which embodies people’s awareness, knowledge, and interest in politics; attitude about the process used to elect candidates; and likelihood of participating in the political process. Data are based on results of two national surveys conducted in different phases of the 2004 presidential campaign. Hierarchical regression analyses are used to evaluate the relative influence of the 17 communication forms on normative outcomes, controlling for sociodemographic variables.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder–Robinson syndrome

Abstract Snyder–Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the only treatment. Reduced SMS activity causes spermidine accumulation while spermine levels are reduced. The resulting exaggerated spermidine:spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this imbalance as a therapeutic strategy for SRS. Here we report the repurposing of 2‐difluoromethylornithine (DFMO), an FDA‐approved inhibitor of polyamine biosynthesis, in rebalancing spermidine:spermine ratios in SRS patient cells. Mechanistic in vitro studies demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of spermidine into spermine in hypomorphic SMS cells and induces uptake of exogenous spermine, altogether reducing the aberrant ratios. In a Drosophila SRS model characterized by reduced lifespan, DFMO improves longevity. As nearly all SRS patient mutations are hypomorphic, these studies form a strong foundation for translational studies with significant therapeutic potential

Development and testing of an integrated signal validation system for nuclear power plants

The approach for signal validation, instrument fault isolation and characterization incorporates some of the methods used in the past, and new techniques developed under this project. The general architecture consists of parallel signal processing modules. Each of the modules performs a specific task. The current architecture consists of seven signal processing modules. There is no direct communication between the modules. Any cross information desired must be requested at the system executive level. 26 refs., 102 figs., 39 tabs

Vascular injuries in laparoscopic cholecystectomy: An underestimated problem

Background: Bile duct injury is a severe complication of laparoscopic cholecystectomy and many reports focus on this topic, especially regarding the long- term success of repair of these injuries. There is some concern, however, as to whether concomitant vascular injuries can jeopardize reconstruction of a bile duct injury following laparoscopic cholecystectomy. Methods: A review of the current literature on the clinical significance and management of a concomitant vascular injury to the outcome of reconstruction of bile duct injuries following laparoscopic cholecystectomy. Relevant articles were extracted through PubMed, with secondary references obtained from key articles. Results: Although the relevant literature is generally poor, there is a trend of appearance of relatively large series on the topic over the last five years, as opposed to case reports or small series during the previous decade. Conclusion: The disruption of the hepatic arterial flow during laparoscopic cholecystectomy is usually well tolerated in an otherwise healthy patient. There is strong evidence that concomitant vascular injuries do not have any impact on mortality after biliary reconstruction. There is also evidence that does increase overall morbidity, but when it comes specifically to long-term anastomotic stricture formation, there is no strong evidence to support a negative impact of a concomitant vascular injury; this is especially true for centers/ surgeons with HPB interest. Copyright (c) 2006 S. Karger AG, Basel