Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer

High androgen receptor (AR) level in primary tumour predicts increased prostate cancer-specific mortality. However, the mechanisms that regulate AR function in prostate cancer are poorly known. We report here a new paradigm for the forkhead protein FoxA1 action in androgen signalling. Besides pioneering the AR pathway, FoxA1 depletion elicited extensive redistribution of AR-binding sites (ARBs) on LNCaP-1F5 cell chromatin that was commensurate with changes in androgen-dependent gene expression signature. We identified three distinct classes of ARBs and androgen-responsive genes: (i) independent of FoxA1, (ii) pioneered by FoxA1 and (iii) masked by FoxA1 and functional upon FoxA1 depletion. FoxA1 depletion also reprogrammed AR binding in VCaP cells, and glucocorticoid receptor binding and glucocorticoid-dependent signalling in LNCaP-1F5 cells. Importantly, FoxA1 protein level in primary prostate tumour had significant association to disease outcome; high FoxA1 level was associated with poor prognosis, whereas low FoxA1 level, even in the presence of high AR expression, predicted good prognosis. The role of FoxA1 in androgen signalling and prostate cancer is distinctly different from that in oestrogen signalling and breast cancer.     

Genome-wide LORE1 retrotransposon mutagenesis and high-throughput insertion detection in Lotus japonicus

Use of insertion mutants facilitates functional analysis of genes, but it has been difficult to identify a suitable mutagen and to establish large populations for reverse genetics in most plant species. The main challenge is developing efficient high-throughput procedures for both mutagenesis and identification of insertion sites. To date, only floral-dip T-DNA transformation of Arabidopsis has produced independent germinal insertions, thereby allowing generation of mutant populations from seeds of single plants. In addition, advances in insertion detection have been hampered by a lack of protocols, including software for automated data analysis, that take full advantage of high-throughput next-generation sequencing. We have addressed these challenges by developing the FSTpoolit protocol and software package, and here we demonstrate its efficacy by detecting 8935 LORE1 insertions in 3744 Lotus japonicus plants. The identified insertions show that the endogenous LORE1 retrotransposon is well suited for insertion mutagenesis due to homogenous gene targeting and exonic insertion preference. As LORE1 transposition occurs in the germline, harvesting seeds from a single founder line and cultivating progeny generates a complete mutant population. This ease of LORE1 mutagenesis, combined with the efficient FSTpoolit protocol, which exploits 2D pooling, Illumina sequencing and automated data analysis, allows highly cost-efficient development of a comprehensive reverse genetic resource.     

Metabolism of palmitate in perfused rat liver. Computer models of subcellular triacylglycerol metabolism

1. In the preceding paper [Kondrup (1979) Biochem. J.184, 63-71] the separation of two major fractions of hepatic triacylglycerol was described. One fraction contained triacylglycerol from the endoplasmic reticulum and from the Golgi apparatus. The other fraction contained triacylglycerol from the cytoplasmic lipid droplets. In the present paper possible precursor-product relationships between the two fractions were investigated by means of computer models. 2. The fatty acids present in di- and tri-acylglycerol in the fractions isolated in the time studies were analysed by gas chromatography. From this analysis the relative specific radioactivities, and contents, of palmitate in acylglycerols in the two fractions at the various time points were calculated. 3. A computer was used to predict relative specific radioactivities of pools in defined models of hepatic triacylglycerol metabolism. The acceptability of the models was evaluated by comparing predicted with measured relative specific radioactivities. 4. It is suggested that triacylglycerol in cytoplasmic lipid droplets does not originate (a) directly from triacylglycerol in the endoplasmic reticulum, (b) from a sub-pool of it or (c) directly from non-esterified fatty acids entering the cell. Rather, it is formed from diacylglycerol (and acyl-CoA) in the endoplasmic reticulum. Diacylglycerol, on the other hand, is furnished in part by hydrolysis of triacylglycerol in the endoplasmic reticulum. 5. This suggestion is discussed in relation to previous models of hepatic fatty acid metabolism.     

Elevation of Proteasomal Substrate Levels Sensitizes Cells to Apoptosis Induced by Inhibition of Proteasomal Deubiquitinases

Inhibitors of the catalytic activity of the 20S proteasome are cytotoxic to tumor cells and are currently in clinical use for treatment of multiple myeloma, whilst the deubiquitinase activity associated with the 19S regulatory subunit of the proteasome is also a valid target for anti-cancer drugs. The mechanisms underlying the therapeutic efficacy of these drugs and their selective toxicity towards cancer cells are not known. Here, we show that increasing the cellular levels of proteasome substrates using an inhibitor of Sec61-mediated protein translocation significantly increases the extent of apoptosis that is induced by inhibition of proteasomal deubiquitinase activity in both cancer derived and non-transformed cell lines. Our results suggest that increased generation of misfolded proteasome substrates may contribute to the mechanism(s) underlying the increased sensitivity of tumor cells to inhibitors of the ubiquitin-proteasome system.     

Age-related differences in the serum prolactin response during standardized surgery

The aim with the present study was to assess possible age-related differences in the serum prolactin, cortisol and blood glucose responses to standardized surgical stress in humans. Relatively healthy men suffering from inguinal hernias were selected. The subjects were divided into a group of younger people (M=36.4 years, r=13–45, n=7) and one of older people (M=66.5 years, r=56–75, n=9). Surgery was carried out under general anesthesia. Blood was drawn before, during and following the operation. Blood pressure and pulse rate were also monitored. No differences were noticed in plasma prolactin, cortisol, and blood glucose during basal conditions. Even though plasma prolactin increased significantly in both groups during surgery, it was higher in the younger group (M= 56.2 μg/1) as compared with 28.7 μg/1 for the older group, p<.01. Plasma prolactin during surgery, but not under basal conditions, correlated inversely with age. No differences between groups were found during surgery in blood glucose and serum cortisol. This study indicates a diminished stress response in older subjects, possibly due to age-related neuroendocrine changes.     

Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling

DNA damage is believed to be the main cause of the antiproliferative effect of cisplatin, a cornerstone agent in anticancer therapy. However, cisplatin can be expected to react also with nucleophiles other than DNA. Using enucleated cells (cytoplasts) we demonstrate here that cisplatin-induced apoptotic signaling may occur independently of DNA damage. Cisplatin-induced caspase-3 activation in cytoplasts required calcium and the activity of the calcium-dependent protease calpain. It is known that calpain activation may be associated with endoplasmic reticulum (ER) stress, suggesting that the ER is a cytosolic target of cisplatin. Consistent with this hypothesis, cisplatin induced calpain-dependent activation of the ER-specific caspase-12 in cytoplasts as well as in intact cells. Cisplatin also induced increased expression of Grp78/BiP, another marker of ER stress. By contrast, the DNA-damaging topoisomerase II inhibitor etoposide did not induce apoptotic signaling in cytoplasts nor ER stress in intact cells. We have thus identified a novel mechanism of action of cisplatin. The results have implications for the understanding of resistance mechanisms as well as the unique efficiency of this drug.     

The genetic and environmental effects on depressive symptoms among older female twins.

The aim of the present study was to examine the contribution of genetic and environmental factors to depressive symptoms among older women. The participants were 102 monozygotic and 115 dizygotic female twin pairs aged 64 to 76 years. Depressive symptoms were assessed by the Center for the Epidemiologic Studies Depression Scale. The contribution of genetic and environmental effects was estimated for the constructed depressiveness factor and for the subscales which were depressed mood, psychomotor retardation, lack of wellbeing and interpersonal difficulties. Of the variance in depressiveness, shared environmental influences accounted for 39% and nonshared environmental influences 61%. For the subscales, 24% to 62% of the variance was explained by individual, and 13% to 23% by shared, environmental factors. Lack of wellbeing had its own moderate additive genetic effect explaining 30% of the variance. This study showed that in older women predominantly environmental factors underlay individual differences in depressiveness; however, the factors varied to some extent between dimensions measured by the subscales.     

A model of enhancement and inhibition of HIV infection of monocytes by antibodies against HIV

Antibodies (Ab) specific for epitopes on HIV glycoprotein gp120 or gp41 can inhibit or enhance HIV infection of human cellsin vitro. These effects may have significant implications both for the pathogenesis of chronic HIV infection and for vaccine development. A particularly puzzling findingin vitro is antibody dependent enhancement (ADE) at low concentrations of Ab while high concentrations of the same antibody inhibit infection. Similar phenomena have been observed for other enveloped viruses. Antibodies can inhibit infection by several mechanisms. However, by binding to receptors on target cells, virus bound antibodies can also enhance adhesion to these cells and thereby facilitate infection. We propose a mathematical model that describes how these two processes interact and hereby provide an explanation for the observed enhancement/neutralization phenomena. Simulation results were validated with good agreement against empirical data from antibody dependent enhancement of HIV infection of monocytoid (U937) cellsin vitro, and the model should be applicable to otherin vitro systems involving different cells and viruses.The model indicates that for the common type of HIV neutralizing antibody, acting at a post-CD4-binding step, there is a neutralizing window defined by the affinity and concentration of antibody.     

Maya and Altaic

Evolution and Human Behavior. Alexander Alland. Social Science Paperbacks. No. 49. Tavistock Publications. London 1969. 243 pp. 37 figs. Price 18/‐.

The Two Worlds of the Washo. An indian Tribe of California &; Nevada. (Case Studies in Cultural Anthropology.) James F. Downs, Holt, Rine‐hart and Winston, Inc., New York 1966. 113 pages, 1 map, 1 pl.

West African Kingdoms in the Nineteenth Century. Ed. with an Introduction by Daryll Forde and P. M. Kaberry. Published for the International African Institute by Oxford University Press. Oxford 1967. 289 pp. Price 50 s.net.

Francisco de Avila. Hermann Trimborn und Antje Kelm. Quellenwerke zur Alten Geschichte Amerikas aufgezeichnet in den Sprachen der Eingeborenen. Herausgegeben vom Ibero‐Amerikanischen Institut Berlin der Stiftung Preussischer Kulturbesitz. Band VIII. Gebr. Mann Verlag, Berlin, 1967. 308 pp. Price DM 105: ‐ (I, "Francisco de Avila” by Hermann Trimborn, pp. 1–198; II, "Götter und Kulte in Huarochirí” by Antje Kelm, pp. 199–307).

The Individual and Culture. Mary Ellen Goodman. The Dorsey Press. Homewood, Illinois 1967. 265 pp. Price $ 4.95.

Mythologie du Masque en Nouvelle‐Calédonie. Jean Guiart. Publications de la Société des Océanistes, No. 18. Paris 1966. 150 pp., 22 pls., 1 map.

Goldgewichte aus Ghana. Brigitte Menzel. Veröffentlichungen des Museums für Völkerkunde, Berlin. Neue Folge 12, Abteilung Afrika III, Berlin 1968. 242 S. Reich illustriert.

La division du temps et le calendrier rituel des peuples lagunaires de Côte d'Ivoire. Georges Niangoran‐Bouah. Université de Paris. Travaux et Mémoires de l'Institut d'Ethnologie. LXVIII. Paris 1964. 164 S., 12 Abbildungen.

Boum‐le‐Grand, village d'Iro: Claude Pairault. Université de Paris. Travaux et Mémoires de l'Institut d'Ethnologie. LXXIII. Paris 1966. 470 S., 225 Abb.

The Social Organization of the Western Apache. Grenville Goodwin. With a Preface by Keith H. Basso. The University of Arizona Press, Tucson, Arizona, 1969 (2nd edition), xxii+701 pp. Price $ 10.

The Gurage. A People of the Ensete Culture. William A. Shack. Published for the International African Institute by Oxford University Press, London 1966. 222 pp. Ill. Price 50 s.net.

Die Erde in Vorstellungswelt und Kulturpraktiken der sudanischen Völker. Jürgen Zwernemann. (Habilitationsschrift.) Dietrich Reimer Verlag, Berlin 1968. 545 S., 1 Karte. DM 80: ‐, broschiert.

The Medicine Man, Swifa Ya Nguvumali. Hasani Bin Ismail. Edited and translated by Peter Lienhardt. Oxford Library of African Literature. Clarendon Press. Oxford University Press. Oxford 1968. 208 pp. Price 42 s.

Das Rind in den Felsbilddarstellungen Nordafrikas. Walther F. E. Resch. Studien zur Kulturkunde, Band 20. Franz Steiner Verlag, Wiesbaden 1967. 105 S., 24 Tafeln und 4 Abbildungen. Broschiert DM 20:‐.

Social Anthropology. Godfrey Lienhardt. 2nd edition. Oxford Paperbacks University Series Opus 15. London 1966. 177 pp. Price 7/6 net.

Churches at the Grass‐Roots. A Study in Congo/Brazzaville. Efraim Andersson. World Studies of Churches in Mission. Lutherworth Press. London 1968. 296 pp. Price 30/‐.

Os Macomdes de Moçambique. Vol. I‐II. Junta de Investigates do Ultramar. Centro de Estudos de Antropología Cultural. Lisboa 1964.

I. Aspectos históricos e económicos. Jorge Dias. 180 S., 109 Abb., 17 Zeichnungen, 7 Karten.

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