Features, Causes and Consequences of Splanchnic Sequestration of Amino Acid in Old Rats

RATIONALE: In elderly subjects, splanchnic extraction of amino acids (AA) increases during meals in a process known as splanchnic sequestration of amino acids (SSAA). This process potentially contributes to the age-related progressive decline in muscle mass via reduced peripheral availability of dietary AA. SSAA mechanisms are unknown but may involve an increased net utilization of ingested AA in the splanchnic area. OBJECTIVES: Using stable isotope methodology in fed adult and old rats to provide insight into age-related SSAA using three hypotheses: 1) an increase in protein synthesis in the gut and/or the liver, 2) an increase in AA oxidation related to an increased ureagenesis, and 3) Kupffer cell (KC) activation consequently to age-related low-grade inflammation. FINDINGS: Splanchnic extraction of Leu (SPELeu) was doubled in old rats compared to adult rats and was not changed after KC inactivation. No age-related effects on gut and liver protein synthesis were observed, but urea synthesis was lower in old rats and negatively correlated to liver Arg utilization. Net whole-body protein synthesis and arterial AA levels were lower in old rats and correlated negatively with SPELeu. CONCLUSION: SSAA is not the consequence of age-related alterations in ureagenesis, gut or liver protein synthesis or of KC activity. However, SSAA may be related to reduced net whole-body protein synthesis and consequently to the reduced lean body mass that occurs during aging

Correct use of non-indexed eGFR for drug dosing and renal drug-related problems at hospital admission

PURPOSE Two to seven percent of the German adult population has a renal impairment (RI) with an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2. This often remains unrecognized and adjustment of drug therapy is lacking. To determine renal function in clinical routine, the CKD-EPI equation is used to calculate an indexed eGFR (ml/min/1.73m2). For drug dosing, it has to be individualized to a non-indexed eGFR (ml/min) by the patient's body surface area. Here, we investigated the number of patients admitted to urological wards of a teaching hospital with RI between July and December 2016. Additionally, we correctly used the eGFRnon-indexed for drug and dosage adjustments and to analyse the use of renal risk drugs (RRD) and renal drug-related problems (rDRP). METHODS In a retrospective observational study, urological patients with pharmacist-led medication reconciliation at hospital admission and eGFRindexed (CKD-EPI) of 15-59 ml/min/1.73m2 were identified. Indexed eGFR (ml/min/1.73m2) was recalculated with body surface area to non-indexed eGFR (ml/min) for correct drug dosing. Medication at admission was reviewed for RRD and based on the eGFRnon-indexed for rDRP, e.g. inappropriate dose or contraindication. RESULTS Of 1320 screened patients, 270 (20.5%) presented with an eGFRindexed of 15–59 ml/min/1.73m2. After readjustment, 203 (15.4%) patients had an eGFRnon-indexed of 15–59 ml/min. Of these, 190 (93.6%) used ≥ 1 drugs at admission with 660 of 1209 (54.7%) drugs classified as RRD. At least one rDRP was identified in 115 (60.5%) patients concerning 264 (21.8%) drugs. CONCLUSION Renal impairment is a common risk factor for medication safety in urologic patients admitted to a hospital. Considerable shifts were seen in eGFR-categories when correctly calculating eGFRnon-indexed for drug dosing purposes. The fact that more than half of the study patients showed rDRP at hospital admission underlines the need to consider this risk factor appropriately

The first small-molecule inhibitors of members of the ribonuclease E family

The Escherichia coli endoribonuclease RNase E is central to the processing and degradation of all types of RNA and as such is a pleotropic regulator of gene expression. It is essential for growth and was one of the first examples of an endonuclease that can recognise the 5′-monophosphorylated ends of RNA thereby increasing the efficiency of many cleavages. Homologues of RNase E can be found in many bacterial families including important pathogens, but no homologues have been identified in humans or animals. RNase E represents a potential target for the development of new antibiotics to combat the growing number of bacteria that are resistant to antibiotics in use currently. Potent small molecule inhibitors that bind the active site of essential enzymes are proving to be a source of potential drug leads and tools to dissect function through chemical genetics. Here we report the use of virtual high-throughput screening to obtain small molecules predicted to bind at sites in the N-terminal catalytic half of RNase E. We show that these compounds are able to bind with specificity and inhibit catalysis of Escherichia coli and Mycobacterium tuberculosis RNase E and also inhibit the activity of RNase G, a paralogue of RNase E

Induction of the interleukin 6/ signal transducer and activator of transcription pathway in the lungs of mice sub-chronically exposed to mainstream tobacco smoke

<p>Abstract</p> <p>Background</p> <p>Tobacco smoking is associated with lung cancer and other respiratory diseases. However, little is known about the global molecular changes that precede the appearance of clinically detectable symptoms. In this study, the effects of mainstream tobacco smoke (MTS) on global transcription in the mouse lung were investigated.</p> <p>Methods</p> <p>Male C57B1/CBA mice were exposed to MTS from two cigarettes daily, 5 days/week for 6 or 12 weeks. Mice were sacrificed immediately, or 6 weeks following the last cigarette. High density DNA microarrays were used to characterize global gene expression changes in whole lung. Microarray results were validated by Quantitative real-time RT-PCR. Further analysis of protein synthesis and function was carried out for a select set of genes by ELISA and Western blotting.</p> <p>Results</p> <p>Globally, seventy nine genes were significantly differentially expressed following the exposure to MTS. These genes were associated with a number of biological processes including xenobiotic metabolism, redox balance, oxidative stress and inflammation. There was no differential gene expression in mice exposed to smoke and sampled 6 weeks following the last cigarette. Moreover, cluster analysis demonstrated that these samples clustered alongside their respective controls. We observed simultaneous up-regulation of <it>interleukin 6 </it>(<it>IL-6</it>) and its antagonist, <it>suppressor of cytokine signalling </it>(<it>SOCS3</it>) mRNA following 12 weeks of MTS exposure. Analysis by ELISA and Western blotting revealed a concomitant increase in total IL-6 antigen levels and its downstream targets, including phosphorylated signal transducer and activator of transcription 3 (Stat3), basal cell-lymphoma extra large (BCL-XL) and myeloid cell leukemia 1 (MCL-1) protein, in total lung tissue extracts. However, in contrast to gene expression, a subtle decrease in total SOCS3 protein was observed after 12 weeks of MTS exposure.</p> <p>Conclusion</p> <p>Global transcriptional analysis identified a set of genes responding to MTS exposure in mouse lung. These genes returned to basal levels following smoking cessation, providing evidence to support the benefits of smoking cessation. Detailed analyses were undertaken for IL-6 and its associated pathways. Our results provide further insight into the role of these pathways in lung injury and inflammation induced by MTS.</p

Frequency fluctuations in silicon nanoresonators

Frequency stability is key to performance of nanoresonators. This stability is thought to reach a limit with the resonator's ability to resolve thermally-induced vibrations. Although measurements and predictions of resonator stability usually disregard fluctuations in the mechanical frequency response, these fluctuations have recently attracted considerable theoretical interest. However, their existence is very difficult to demonstrate experimentally. Here, through a literature review, we show that all studies of frequency stability report values several orders of magnitude larger than the limit imposed by thermomechanical noise. We studied a monocrystalline silicon nanoresonator at room temperature, and found a similar discrepancy. We propose a new method to show this was due to the presence of frequency fluctuations, of unexpected level. The fluctuations were not due to the instrumentation system, or to any other of the known sources investigated. These results challenge our current understanding of frequency fluctuations and call for a change in practices

Old lineage on an old island : Pixibinthus, a new cricket genus endemic to New Caledonia shed light on gryllid diversification in a hotspot of biodiversity

Few studies have focused on the early colonization of New Caledonia by insects, after the re-emergence of the main island, 37 Myr ago. Here we investigate the mode and tempo of evolution of a new endemic cricket genus, Pixibinthus, recently discovered in southern New Caledonia. First we formally describe this new monotypic genus found exclusively in the open shrubby vegetation on metalliferous soils, named 'maquis minier', unique to New Caledonia. We then reconstruct a dated molecular phylogeny based on five mitochondrial and four nuclear loci in order to establish relationships of Pixibinthus within Eneopterinae crickets. Pixibinthus is recovered as thesister clade of the endemic genus Agnotecous, mostly rainforest-dwellers. Dating results show that the island colonization by their common ancestor occurred around 34.7 Myr, shortly after New Caledonia re-emergence. Pixibinthus and Agnotecous are then one of the oldest insect lineages documented so far for New Caledonia. This discovery highlights for the first time two clear-cut ecological specializations between sister clades, as Agnotecous is mainly found in rainforests with 19 species, whereas Pixibinthus is found in open habitats with a single documented species. The preference of Pixibinthus for open habitats and of Agnotecous for forest habitats nicely fits an acoustic specialization, either explained by differences in body size or in acoustic properties of their respective habitats. We hypothesize that landscape dynamics, linked to major past climatic events and recent change in fire regimes are possible causes for both present-day low diversity and rarity in genus Pixibinthus. The unique evolutionary history of this old New Caledonian lineage stresses the importance to increase our knowledge on the faunal biodiversity of 'maquis minier', in order to better understand the origin and past dynamics of New Caledonian biota

Social network analysis resolves temporal dynamics of male dominance relationships

Social organization is often studied through point estimates of individual association or interaction patterns, which does not account for temporal changes in the course of familiarization processes and the establishment of social dominance. Here, we present new insights on short-term temporal dynamics in social organization of mixed-sex groups that have the potential to affect sexual selection patterns. Using the live-bearing Atlantic molly (Poecilia mexicana), a species with pronounced male size polymorphism, we investigated social network dynamics of mixed sex experimental groups consisting of eight females and three different-sized males over a period of 5 days. Analyzing association-based social networks as well as direct measures of spatial proximity, we found that large males tended to monopolize most females, while excluding small- and medium-bodied males from access to females. This effect, however, emerged only gradually over time, and different-sized males had equal access to females on day 1 as well as day 2, though to a lesser extent. In this highly aggressive species with strong social dominance stratifications, the observed temporal dynamics in male-female association patterns may balance the presumed reproductive skew among differentially competitive male phenotypes when social structures are unstable (i.e., when individual turnover rates are moderate to high). Ultimately, our results point toward context-dependent sexual selection arising from temporal shifts in social organization. © 2014 Springer-Verlag Berlin Heidelberg