The Caenorhabditis elegans Elongator Complex Regulates Neuronal α-tubulin Acetylation

Although acetylated α-tubulin is known to be a marker of stable microtubules in neurons, precise factors that regulate α-tubulin acetylation are, to date, largely unknown. Therefore, a genetic screen was employed in the nematode Caenorhabditis elegans that identified the Elongator complex as a possible regulator of α-tubulin acetylation. Detailed characterization of mutant animals revealed that the acetyltransferase activity of the Elongator is indeed required for correct acetylation of microtubules and for neuronal development. Moreover, the velocity of vesicles on microtubules was affected by mutations in Elongator. Elongator mutants also displayed defects in neurotransmitter levels. Furthermore, acetylation of α-tubulin was shown to act as a novel signal for the fine-tuning of microtubules dynamics by modulating α-tubulin turnover, which in turn affected neuronal shape. Given that mutations in the acetyltransferase subunit of the Elongator (Elp3) and in a scaffold subunit (Elp1) have previously been linked to human neurodegenerative diseases, namely Amyotrophic Lateral Sclerosis and Familial Dysautonomia respectively highlights the importance of this work and offers new insights to understand their etiology.     

A survey of entodiniomorphid ciliates in chimpanzees and bonobos

Intestinal entodiniomorphid ciliates are commonly diagnosed in the feces of wild apes of the genera Pan and Gorilla. Although some authors previously considered entodiniomorphid ciliates as possible pathogens, a symbiotic function within the intestinal ecosystem and their participation in fiber fermentation has been proposed. Previous studies have suggested that these ciliates gradually disappear under captive conditions. We studied entodiniomorphid ciliates in 23 captive groups of chimpanzees, three groups of captive bonobos and six populations of wild chimpanzees. Fecal samples were examined using Sheather's flotation and Merthiolate‐Iodine‐Formaldehyde Concentration (MIFC) methods. We quantified the number of ciliates per gram of feces. The MIFC method was more sensitive for ciliate detection than the flotation method. Ciliates of genus Troglodytella were detected in 13 groups of captive chimpanzees, two groups of bonobos and in all wild chimpanzee populations studied. The absence of entodiniomorphids in some captive groups might be because of the extensive administration of chemotherapeutics in the past or a side‐effect of the causative or prophylactic administration of antiparasitic or antibiotic drugs. The infection intensities of ciliates in captive chimpanzees were higher than in wild ones. We suppose that the over‐supply of starch, typical in captive primate diets, might induce an increase in the number of ciliates. In vitro studies on metabolism and biochemical activities of entodiniomorphids are needed to clarify their role in ape digestion. Am J Phys Anthropol 2010. © 2009 Wiley‐Liss, Inc.     

The IGF1 small dog haplotype is derived from Middle Eastern grey wolves: a closer look at statistics,sampling, and the alleged Middle Eastern origin of small dogs

This paper is a response to Gray MM, Sutter NB, Ostrander EA, Wayne RK: The IGF1 small dog haplotype is derived from Middle Eastern grey wolves. BMC Biology 2010, 8:16.     

Should laboratory mice be anaesthetized for tail biopsy?

Tail biopsies are routinely taken to genotype genetically modified mice. However, the effect of this procedure on the wellbeing of the animals has rarely been investigated. Thus, it has not yet been clearly demonstrated to what extent the mice suffer from tail biopsy (TB) and for how long. The aim of our study was to assess the impact of a single TB on the physiological and behavioural parameters of adult mice and to investigate whether or not anaesthesia can be beneficial. Body weight (BW) curves, daily food/water consumption and telemetric measurements of heart rate, body core temperature, and locomotor activity were recorded for three days following TB, both with and without anaesthesia with methoxyflurane (MOF) or diethylether (ether). Additionally, the impact of anaesthesia alone was characterized. TB without anaesthesia induced an increase in heart rate and locomotor activity for 1 h. Body core temperature was elevated for 2 h. In contrast, heart rate was increased for up to 4 h after anaesthesia. Body core temperature remained altered for up to 20 h after exposure to ether and for 44 h after exposure to MOF. BW was slightly reduced after MOF. Cases of death occurred exclusively under ether at a rate of 7%. Our results indicate a short-lived impact of a TB, whereas anaesthesia with either MOF or ether induced remarkable alterations in the parameters analysed. In conclusion, these types of anaesthesia did not improve mouse wellbeing following tail biopsy.     

Expression of AGR2 in non small cell lung cancer

We aimed to evaluate immunohistochemically the expression of the human Anterior Gradient-2 (AGR2), a gene which has recently been proposed as an oncogene for lung carcinoma development, in non small cell lung cancer and to correlate the findings to clinico-pathological data including patient survival. 95 cases of NSCLC were immunostained using a polyclonal AGR2 antibody and statistical analyses were applied to test for prognostic and diagnostic associations. AGR2 was expressed in 66.3% of cases, preferentially adenocarcinomas. There were no relevant associations with clinico-pathological parameters. A prognostic value of AGR2 could not be demonstrated neither in multivariate nor in univariate analyses. Interestingly, this is the first study to demonstrate AGR2 expression in squamous cell carcinomas. Although a prognostic value of AGR2 seems unlikely further studies are warranted to investigate the biological role of AGR2 in NSCLC and its differential expression according to histology.     

Structure-activity relationships of novel N-acyloxy-1,4-dihydropyridines as P-glycoprotein inhibitors

Series of novel N-acyloxy-1,4-dihydropyridines have been synthesized and evaluated as P-glycoprotein inhibitors in an in vitro assay to estimate their potential to act as multidrug resistance modulators in cancer cells. Structure-activity relationships are discussed and prove a significant and regiospecific influence of certain functional groups.     

Increased level of cytokines and matrix metalloproteinases in osteoarthritic subchondral bone

OBJECTIVE: The aim of this study was to investigate the expression of several cytokines, matrix metalloproteinases (MMPs), and tissue inhibitor of matrix metalloproteinases (TIMP)-1 in osteoarthritis (OA) and control sera and different joint tissues. METHODS: Serum, synovial fluid, cartilage, synovial and subchondral bone tissues were examined in OA and control subjects. The protein level of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, IL-8, IL-10 and MMP-2, MMP-3, MMP-9, and TIMP-1 were measured by immunoanalysis. RESULTS: Serum levels of TNF-alpha, MMP-3 and -9 were significantly higher in OA patients than in controls. Conversely, serum IL-10 was decreased in OA patients. CRP was elevated when compared to healthy controls and decreased significantly 6 months after the surgery. In contrast to control samples, OA cartilage and synovium revealed significantly higher MMP-2, -3, -9 and IL-10. IL-1alpha was significantly higher in OA cartilage and IL-8 in OA synovium. Interestingly, MMP-3, -9, TIMP-1 and all tested cytokines were up-regulated in OA subchondral bone. DISCUSSION: This study demonstrates pro-inflammatory condition of OA pathology and supports the idea that vascularized subchondral region may increase the synthesis of cytokines and MMPs leading to degradation of adjacent cartilage.     

microRNA‐379 couples glucocorticoid hormones to dysfunctional lipid homeostasis

In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)‐379/410 genomic cluster as a key component of GC/GR‐driven metabolic dysfunction. Particularly, miR‐379 was up‐regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR‐dependent manner. Hepatocyte‐specific silencing of miR‐379 substantially reduced circulating very‐low‐density lipoprotein (VLDL)‐associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR‐379 effects on key receptors in hepatic TG re‐uptake. As hepatic miR‐379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR‐controlled miRNA cluster not only defines a novel layer of hormone‐dependent metabolic control but also paves the way to alternative miRNA‐based therapeutic approaches in metabolic dysfunction.