Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria

Mutations in Pten-induced kinase 1 (PINK1) are linked to early-onset familial Parkinson's disease (FPD). PINK1 has previously been implicated in mitochondrial fission/fusion dynamics, quality control, and electron transport chain function. However, it is not clear how these processes are interconnected and whether they are sufficient to explain all aspects of PINK1 pathogenesis. Here we show that PINK1 also controls mitochondrial motility. In Drosophila, downregulation of dMiro or other components of the mitochondrial transport machinery rescued dPINK1 mutant phenotypes in the muscle and dopaminergic (DA) neurons, whereas dMiro overexpression alone caused DA neuron loss. dMiro protein level was increased in dPINK1 mutant but decreased in dPINK1 or dParkin overexpression conditions. In Drosophila larval motor neurons, overexpression of dPINK1 inhibited axonal mitochondria transport in both anterograde and retrograde directions, whereas dPINK1 knockdown promoted anterograde transport. In HeLa cells, overexpressed hPINK1 worked together with hParkin, another FPD gene, to regulate the ubiquitination and degradation of hMiro1 and hMiro2, apparently in a Ser-156 phosphorylation-independent manner. Also in HeLa cells, loss of hMiro promoted the perinuclear clustering of mitochondria and facilitated autophagy of damaged mitochondria, effects previously associated with activation of the PINK1/Parkin pathway. These newly identified functions of PINK1/Parkin and Miro in mitochondrial transport and mitophagy contribute to our understanding of the complex interplays in mitochondrial quality control that are critically involved in PD pathogenesis, and they may explain the peripheral neuropathy symptoms seen in some PD patients carrying particular PINK1 or Parkin mutations. Moreover, the different effects of loss of PINK1 function on Miro protein level in Drosophila and mouse cells may offer one explanation of the distinct phenotypic manifestations of PINK1 mutants in these two species.     

Immunoreactive EGF in human benign prostatic hyperplasia: relationships with androgen and estrogen receptors

Benign prostatic hyperplasia (BPH) is a sex steroid dependent disease. Estrogens and androgens can modulate in different mammalian tissues epidermal growth factor (EGF) production and/or secretion. In order to clarify the relationships between estrogen and androgen receptor concentrations and those of immunoreactive EGF (irEGF), we have evaluated these parameters in 14 human BPH samples, by means of a dextran-coated charcoal method and radioimmunoassay, respectively. Cytosolic steroid receptors did not seem to correlate with irEGF. A linear significative relationship was evident between nuclear androgen receptor (ARn) levels and endogenous irEGF but not between nuclear estrogen receptors and irEGF: in ARn negative BPH samples, irEGF levels were lower than in ARn positive ones. Therefore, it is possible that androgens act at prostatic tissue level, through their own receptors, by modulating EGF production and/or secretion.     

The CD11a partner in Sus scrofa lymphocyte function-associated antigen-1 (LFA-1): mRNA cloning, structure analysis and comparison with mammalian homologues

Background  

Lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, alphaLbeta2), the most abundant and widely expressed beta2-integrin, is required for many cellular adhesive interactions during the immune response. Many studies have shown that LFA-1 is centrally involved in the pathogenesis of several diseases caused by Repeats-in-toxin (RTX) -producing bacteria.     

The Effect of Transdermal Delivery of Fentanyl on Activity in Growing Pigs

Recently, decreased activity levels have been observed in pigs treated postoperatively with transdermal delivery of fentanyl (TD-fentanyl) after isoflurane anaesthesia. Whether the change in behaviour is related to opioid-induced sedation or to insufficient pain relief remains to be investigated. This study was therefore undertaken to evaluate the effect of TD-fentanyl 50 μg h^-1 on the activity level with and without isoflurane anaesthesia. Eight pigs (25.4 ± 5.2 kg) were submitted to a cross-over study and given two treatments; 1) fentanyl patch applied after 30 minutes of anaesthesia (treatment A/F) and 2) fentanyl patch without anaesthesia (treatment F). The pigs' behaviour was observed from a video recording instantaneously every 10 minutes for 24 h before treatments and up to 72 h after the patch attachment. Venous blood samples were taken 1, 6, 12, 24, 48 and 72 h after the patch application. The behaviour recordings showed that TD-fentanyl did not produce sedation in any pig. No differences were found between the two treatments in activity level, weight gain or serum fentanyl concentration. This concentration measured after 24 h was 0.27 ± 0.11 ng ml^-1 and 0.47 ± 0.40 ng ml^-1 in the A/F and F group, respectively.     

Phase II protocol for the evaluation of new treatments in patients with advanced gastric carcinoma: results of ECOG 5282

The study was a Phase II randomized study to evaluate the efficacy of new agents for the treatment of advanced gastric carcinoma. Patients were randomized to receive single agent chemotherapy with mitoxantrone, etoposide, aclacinomycin-A or spirogermanium. The patients were stratified by prior use of chemotherapy, prior doxorubicin use and ECOG performance status. Patients with a history of cardiac disease or prior doxorubicin exceeding a dose of 400 mg/m² were restrictively randomized to sopirogermanium or etoposide only. One hundred and fourteen patients were registered for the study. Among 98 evaluable patients there were only two partial responses (both in the etoposide arm), and one complete response in the mitoxantrone arm. The median survival on the study was 3.3 months. One hundred and six patients were analyzable for toxicity. There were four treatment-related deaths and four life-threatening toxicities. Because of low response rates and relatively high toxicities the studied compounds were not deemed worth further investigation for advanced gastric cancer.     

Host habitat assessment by a parasitoid using fungal volatiles

Background

The genus Mantella, endemic poison frogs of Madagascar with 16 described species, are known in the field of international pet trade and entered under the CITES control for the last four years. The phylogeny and phylogeography of this genus have been recently subject of study for conservation purposes. Here we report on the studies of the phylogeography of the Mantella cowani group using a fragment of 453 bp of the mitochondrial cytochrome b gene from 195 individuals from 21 localities. This group is represented by five forms: M. cowani, a critically endangered species, a vulnerable species, M. haraldmeieri, and the non-threatened M. baroni, M. aff. baroni, and M. nigricans.

Results

The Bayesian phylogenetic and haplotype network analyses revealed the presence of three separated haplotype clades: (1) M. baroni, M. aff. baroni, M. nigricans, and putative hybrids of M. cowani and M. baroni, (2) M. cowani and putative hybrids of M. cowani and M. baroni, and (3) M. haraldmeieri. The putative hybrids were collected from sites where M. cowani and M. baroni live in sympatry.

Conclusion

These results suggest (a) a probable hybridization between M. cowani and M. baroni, (b) a lack of genetic differentiation between M. baroni/M. aff. baroni and M. nigricans, (c) evidence of recent gene-flow between the northern (M. nigricans), eastern (M. baroni), and south-eastern (M. aff. baroni) forms of distinct coloration, and (d) the existence of at least three units for conservation in the Mantella cowani group.