CDKN2A is not the principal target of deletions on the short arm of chromosome 9 in neuroendocrine (Merkel cell) carcinoma of the skin

The majority of small-cell lung cancers (SCLCs) express p16 but not pRb, Given our previous study showing loss of pRb in Merkel cell carcinoma (MCC)/neuroendocrine carcinoma of the skin and the clinicopathological similarities between SCLC acid MCC, we wished to determine if this was also the case in MCC, Twenty-nine MCC specimens from 23 patients were examined for deletions at 10 loci on 9p and I on 9p. No loss of heterozygosity (LO H) was peen in 9 patients including 2 for which tumour and cell line DNAs were examined. Four patients had LOH for all informative loci on 9p, Ten tumours showed more limited regions of loss on 9p, and from these 2 common regions of deletion were determined, Half of all informative cases had LOH at D95168, the most telomeric marker examined, and 3 specimens showed loss of only D9S168, A second region (InFNA-D9S126) showed L0H in 10(44%) cases, and case MCC26 showed LOH for only D9S126, implicating genes centromeric of the CDKN2A locus. No mutations in the coding regions of p16 were seen in 7 cell lines tested, and reactivity to anti-p16 antibody was seen in all Il tumour specimens examined and in 6 of 7 cell lines from 6 patients. Furthermore, all cell lines examined reacted with anti-p 14' antibody, These results suggest that neither transcript of the CDKN2A locus is the target of deletions on 9p in MCC and imply the existence of tumour-suppressor genes mapping both centromeric and telomeric of this locus. (C) 2001 Wiley-Liss, Inc.

Mice with genetic deletion of the heparin-binding growth factor midkine exhibit early preclinical features of Parkinson`s disease

There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson`s disease (PD) begin many years before the appearance of the characteristic motor symptoms and that impairments in olfactory, cognitive and motor functions are associated with time-dependent disruption of dopaminergic neurotransmission in different brain areas. Midkine is a 13-kDa retinoic acid-induced heparin-binding growth factor involved in many biological processes in the central nervous system such as cell migration, neurogenesis and tissue repair. The abnormal midkine expression may be associated with neurochemical dysfunction in the dopaminergic system and cognitive impairments in rodents. Here, we employed adult midkine knockout mice (Mdk(-/-)) to further investigate the relevance of midkine in dopaminergic neurotransmission and in olfactory, cognitive and motor functions. Mdk(/-) mice displayed pronounced impairments in their olfactory discrimination ability and short-term social recognition memory with no gross motor alterations. Moreover, the genetic deletion of midkine decreased the expression of the enzyme tyrosine hydroxylase in the substantia nigra reducing partially the levels of dopamine and its metabolites in the olfactory bulb and striatum of mice. These findings indicate that the genetic deletion of midkine causes a partial loss of dopaminergic neurons and depletion of dopamine, resulting in olfactory and memory deficits with no major motor impairments. Therefore, Mdk(-/-) mice may represent a promising animal model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.

Effects of estrogen receptor alpha and beta gene deletion on estrogenic induction of progesterone receptors in the locus coeruleus in female mice

Locus coeruleus (LC) is involved in the LHRH regulation by gonadal steroids. We investigated the expression of progesterone and estrogen receptors (PR; ER) in LC neurons of ER alpha (alpha ERKO) or ER beta (beta ERKO) knockout mice, and their wild-type (alpha WT and beta WT). Immunocytochemical studies showed that LC expresses PR and both ERs, although ER beta was more abundant. Estradiol benzoate (EB) decreased ER alpha-positive cells in WT and beta ERKO mice, and progesterone caused a further reduction, whereas none of the steroids influenced ER beta expression. ER beta deletion increased ER alpha while ER alpha deletion did not alter ER beta expression. In both WT mice, EB increased PR expression, which was diminished by progesterone. These steroid effects were also observed in alpha ERKO animals but to a lesser extent, suggesting that ER alpha is partially responsible for the estrogenic induction of PR in LC. Steroid effects on PR in beta ERKO mice were similar to those in the alpha ERKO but to a lesser extent, probably because PR expression was already high in the oil-treated group. This expression seems to be specific of LC neurons, since it was not observed in other areas studied, the preoptic area and ventromedial nucleus of hypothalamus. These findings show that LC in mice expresses alpha ER, beta ER, and PR, and that a balance between them may be critical for the physiological control of reproductive function.

A novel approach to antigen-specific deletion of CTL with minimal cellular activation using alpha 3 domain mutants of MHC class I/peptide complex

In this study, we have compared the effector functions and fate of a number of human CTL clones in vitro or ex vivo following contact with variant peptides presented either on the cell surface or in a soluble multimeric format. In the presence of CD8 coreceptor binding, there is a good correlation between TCR signaling, killing of the targets, and Fast-mediated CTL apoptosis. Blocking CD8 binding using (alpha3 domain mutants of MHC class I results in much reduced signaling and reduced killing of the targets. Surprisingly, however, Fast expression is induced to a similar degree on these CTLs, and apoptosis of CTL is unaffected. The ability to divorce these events may allow the deletion of antigen-specific and pathological CTL populations without the deleterious effects induced by full CTL activation.

Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636del9 common mutation exhibit a variant phenotype

ATM, the gene mutated in the human immunodeficiency disorder ataxia-telangiectasia (A-T), plays a central role in recognizing ionizing radiation damage in DNA and in controlling several cell cycle checkpoints. We describe here a murine model in which a nine-nucleotide in-frame deletion has been introduced into the Atm gene by homologous recombination followed by removal of the selectable marker cassette by Cre-loxP site-specific, recombination-mediated excision. This mouse, Abm-Delta SRI, was designed as a model of one of the most common deletion mutations (7636de19) found in A-T patients. The murine Atm deletion results in the loss of three amino acid residues (SRI; 2556-2558) but produces near full-length detectable Atm protein that lacks protein kinase activity. Radiosensitivity was observed in Atm-Delta SRI mice, whereas the immunological profile of these mice showed greater heterogeneity of T-cell subsets than observed in Atm(-/-) mice. The life span of Atm-Delta SRI mice was significantly longer than that of Atm(-/-) mice when maintained under nonspecific pathogen-free conditions. This can be accounted for by a lower incidence of thymic lymphomas in Atm-Delta SRI mice up to 40 weeks, after which time the animals died of other causes. The thymic lymphomas in Atm-Delta SRI mice were characterized by extensive apoptosis, which appears to be attributable to an increased number of cells expressing Fas ligand. A variety of other tumors including B-cell lymphomas, sarcomas, and carcinomas not seen in Atm(-/-) mice were observed in older Atm-Delta SRI animals. Thus, expression of mutant protein in Atm-Delta SRI knock-in mice gives rise to a discernibly different phenotype to Atm(-/-) mice, which may account for the heterogeneity seen in A-T patients with different mutations.

Deletion of 8p: a report of a child with normal intelligence

The case is presented of a female infant with a distal deletion of 8p (8p23.1 --> pter) whose development was monitored over a 5-year period from 12 months of age. Although previous literature has suggested that 8p deletion is associated with mild to moderate intellectual disability, the child reported here has normal intelligence. Despite initial delays in gross motor and language skills, cognitive development (assessed with the Bayley Scales of Infant Development) and intellectual ability (measured on the Stanford-Binet Intelligence Scale) were within average range. It is argued that the small number of previous case reports may have created a misleading impression of intellectual development in individuals with distal deletions of 8p.

Apoptotic deletion of Th cells specific for the 19-kDa carboxyl-terminal fragment of merozoite surface protein 1 during malaria infection

Immunity induced by the 19-kDa fragment of merozoite surface protein 1 is dependent on CD4(+) Th cells. However, we found that adoptively transferred CFSE-labeled Th cells specific for an epitope on Plasmodium yoelii 19-kDa fragment of merozoite surface protein 1 (peptide (p)24), but not OVA-specific T cells, were deleted as a result of P. yoelii infection. As a result of infection, spleen cells recovered from infected p24-specific T cell-transfused mice demonstrated reduced response to specific Ag. A higher percentage of CFSE-labeled p24-specific T cells stained positive with annexin and anti-active caspase-3 in infected compared with uninfected mice, suggesting that apoptosis contributed to deletion of p24-specific T cells during infection. Apoptosis correlated with increased percentages of p24-specific T cells that stained positive for Fas from infected mice, suggesting that P. yoelii-induced apoptosis is, at least in part, mediated by Fas. However, bystander cells of other specificities also showed increased Fas expression during infection, suggesting that Fas expression alone is not sufficient for apoptosis. These data have implications for the development of immunity in the face of endemic parasite exposure.

Germline BRCA1 promoter deletions in UK and Australian familial breast cancer patients: Identification of a novel deletion consistent with BRCA1 :psi VBRCA1 recombination

Inherited susceptibility to breast cancer results from germline mutations in one of a number of genes including BRCA1. A significant number of BRCA1-linked familial breast cancer patients, however, have no detectable BRCA1 mutation. This could be due in part to the inability of commonly used mutation-detection techniques to identify mutations outside the BRCA1 coding region. This paper addresses the hypothesis that non coding region mutations, specifically in the BRCA1 promoter, account for some of these cases. We describe a new and detailed restriction map of the 5' region of the BRCA1 gene including the nearby NBR2, psiBRCA1, and NBR1 genes and the isolation of a number of new informative hybridization probes suitable for Southern analysis. Using this information we screened DNA from lymphoblastoid cell-lines made from 114 UK familial breast cancer patients and detected one large deletion in the 5' region of BRCA1. We show that the breakpoints for this deletion are in BRCA1 intron 2 and between NBR2 and exon 2 of psiBRCA1, raising the possibility that this deletion arose via a novel mechanism involving BRCA1:psiBRCA1 recombination. We have also screened 60 familial breast cancer patients from the Australian population, using an amplification refractory mutation system (ARMS) technique described previously by our group, and found one patient with a genotype consistent with a BRCA1 promoter deletion. These findings indicate that germline BRCA1 promoter deletions are a rare and yet significant mutation event and that they could arise via a novel genetic mechanism. Hum Mutat 19:435-442, 2002. (C) 2002 Wiley-Liss, Inc.

Fast neutron mutagenesis of soybean (Glycine soja L.) produces a supernodulating mutant containing a large deletion in linkage group H

We describe for the first time the application of fast neutron mutagenesis to the genetic dissection of root nodulation in legumes. We demonstrate the utility of chromosomal deletion mutations through production of a soybean supernodulation mutant FN37 that lacks the internal autoregulation of nodulation mechanism. After inoculation with microsymbiont Bradyrhizobium japonicum, FN37 forms at least 10 times more nodules than the wild type G. soja parent and has a phenotype identical to that of chemically induced allelic mutants nts382 and nts1007 (NTS-1 locus). Reciprocal grafting of shoots and roots confirmed systemic shoot control of the FN37 nodulation phenotype. RFLP/PCR marker pUTG132a and AFLP marker UQC-IS1 which are tightly linked to NTS-1 allowed the isolation of BAC contigs delineating both ends of the deletion. The genetic/physical distance ratio in the NTS-1 region is 279 kb/cM. The deletion is estimated to be about 460 kb based on the absence of markers and bacterial artificial chromosomes (BAC) ends as well as genetic and physical mapping. Deletion break points were determined physically and placed within flanking BAC contigs.

Texto para discuss??o 23: reforma administrativa e direito adquirido

A Constitui????o n??o se interpreta mediante a lei ordin??ria; a lei ?? que tem a sua interpreta????o condicionada pela Constitui????o. A garantia constitucional inscrita no art. 5o, XXXVI, por expressa determina????o constitucional, tem aplica????o imediata (art. 5o, ??1o, CF), independendo de preceito legal regulador. Se o conceito de direito adquirido constitu??sse mat??ria de car??ter ordin??rio, a garantia constitucional do direito adquirido estaria de modo indireto ?? disposi????o do legislador, subordinada aos seus humores, esvaziada enquanto norma de prote????o individual. Al??m disso, ter??amos de admitir o paradoxo de um limite ao legislador depender da atua????o do pr??prio legislador

Fauna de Dissomphalus Ashmead (Hymenoptera, Bethylidae) da Mata Atlântica Brasileira, com descrição de 23 espécies novas

Foram realizadas coletas padronizadas em 18 pontos ao longo da Mata Atlântica Brasileira no escopo do Programa BIOTA/FAPESP usando-se varredura de vegetação, e armadilhas Malaise e Möricke. Foi coletado um total de 2.811 exemplares de Dissomphalus. Foram reconhecidas 30 espécies descritas, a saber: Dissomphalus conicus Azevedo, 2003, D. h-ramus Redighieri & Azevedo, 2004, D. laminaris Redighieri & Azevedo, 2004, D. manus Azevedo, 2003, D. umbilicus Azevedo, 2003, D. verrucosus Redighieri & Azevedo, 2004, D. alticlypeatus Azevedo, 2003, D. bicerutus Azevedo, 2003, D. gilvipes Evans, 1979, D. krombeini Azevedo, 1999, D. gordus Azevedo, 2003, D. undatus Azevedo, 2003, D. cristatus Redighieri & Azevedo, 2004, D. laticephalus Azevedo, 2003, D. lobicephalus Azevedo, 2003, D. completus Azevedo, 1999, D. gigantus Azevedo, 1999, D. scamatus Azevedo, 1999, D. napo Evans, 1979, D. punctatus (Kieffer, 1910), D. infissus Evans, 1969, D. plaumanni Evans, 1964, D. concavatus Azevedo, 1999, D. rectilineus Azevedo, 1999, D. bifurcatus Azevedo, 1999, D. extrarramis Azevedo, 1999, D. strictus Azevedo, 1999, D. connubialis Evans, 1966, D. microstictus Evans, 1969, D. scopatus Redighieri & Azevedo, 2004. Além disso, foram descritas e ilustradas 23 espécies novas: Dissomphalus inclinatus sp. nov., D. divisus sp. nov., D. distans sp. nov., D. crassus sp. nov., D. filiformis sp. nov., D. inflexus sp. nov., D. spissus sp. nov., D. firmus sp. nov., D. setosus sp. nov., D. tubulatus sp. nov., D. differens sp. nov., D. lamellatus sp. nov., D. fimbriatus sp. nov., D. magnus sp. nov., D. trilobatus sp. nov., D. amplifoveatus sp. nov., D. personatus sp. nov., D. excellens sp. nov., D. peculiaris sp. nov., D. bahiensis sp. nov., D. amplexus sp. nov., D. elegans sp. nov. e D. amplus sp. nov.. Foram propostos 2 grupos novos de espécies, brasiliensis com duas espécies e setosus com oito espécies. Dissomphalus connubialis Evans, 1966 foi revalidado a partir de D. brasiliensis Kieffer, 1910. Dissomphalus bispinulatus Evans, 1969 foi considerado sinônimo junior de D. brasiliensis. Foi proposto para o gênero uma chave de espécies Neotropicais baseada em machos. Algumas espécies como Dissomphalus rectilineus, D. plaumanni, D. connubialis e D. gigantus são amplamente distribuídos ao longo deste bioma. Por outro lado, espécies como Dissomphalus completus, D. bifurcatus, D. napo, D. gilvipes, D. microstictus, D. brasiliensis, D. scamatus, D. strictus, D. undatus, D. alticlypeatus, D. laticephalus, D. verrucosus, D. extrarramis, D. concavatus, D. krombeini, D. gordus, D. lobicephalus e 13 espécies novas são restritas a regiões específicas, apresentando congruência com os subcentros deste bioma.

Norma internacional de contabilidade [NIC 23]: custos de empréstimos obtidos

Revista Fiscal, Junho 2007

Números curiosos: os intrigantes 11, 17 e 23

(...) Desde logo, salienta-se um aspeto curioso. Estamos na presença de três números primos (significa que são divisíveis apenas por eles próprios e pela unidade) separados uns dos outros por seis unidades: 11+6=17 e 17+6=23. Ou seja, o 6 volta aqui a estar em destaque! (...) Destacam-se algumas ocorrências do número 11 associadas a vários acontecimentos históricos. Em 1998, um avião da Swissair, com 229 pessoas a bordo, despenhou-se no Oceano Atlântico sem sobreviventes. Era um modelo McDonnell Douglas MD-11 com número de voo SWR111. Todos nos recordamos da tragédia decorrente do sismo e tsunami de Sendai, no Japão. Estima-se que este sismo, que assolou a costa japónica a 11 de março de 2011, tenha sido o maior sismo a atingir o Japão e um dos cinco maiores do mundo desde que os registros modernos começaram a ser compilados. (...) O 17 é considerado por muitos povos um número tão azarento como o 13, como acontece, por exemplo, em Itália. Uma das justificações para esta triste fama prende-se com a escrita do 17 em numeração romana, XVII, e com um dos seus anagramas, VIXI, que significa “vivi”. E se “vivi” é porque estou morto! A aversão a este número em Itália é tal que levou a Renault, marca francesa de automóveis, a mudar a designação do seu modelo R17 para R177, para que o pudesse vender em território italiano. Ainda hoje não se encontra facilmente em Itália prédios com andares 17 e hotéis com quartos 17, nem tão pouco assentos de aviões italianos com esse número. Terminamos com algumas curiosidades relativas ao 23, um dos números favoritos em muitas teorias da conspiração: 2/3 é aproximadamente igual a 0,666, sendo 666 o número da Besta; quando foi assassinado, Júlio César terá sido esfaqueado 23 vezes; William Shakespeare nasceu a 23 de abril de 1564 e morreu a 23 de abril de 1616; o famoso Titanic afundou-se na madrugada do dia 15 de abril de 1912 (1+5+4+1+9+1+2=23); a bomba atómica foi lançada sobre Hiroshima pelas 8h15 (8+15=23); (...)