Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice.

Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site- and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1(tm1a)) that reduces mRNA to ∼10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1(tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1(tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.

A link between FXYD3 (Mat-8)-mediated Na,K-ATPase regulation and differentiation of Caco-2 intestinal epithelial cells.

FXYD3 (Mat-8) proteins are regulators of Na,K-ATPase. In normal tissue, FXYD3 is mainly expressed in stomach and colon, but it is also overexpressed in cancer cells, suggesting a role in tumorogenesis. We show that FXYD3 silencing has no effect on cell proliferation but promotes cell apoptosis and prevents cell differentiation of human colon adenocarcinoma cells (Caco-2), which is reflected by a reduction in alkaline phosphatase and villin expression, a change in several other differentiation markers, and a decrease in transepithelial resistance. Inhibition of cell differentiation in FXYD3-deficient cells is accompanied by an increase in the apparent Na+ and K+ affinities of Na,K-ATPase, reflecting the absence of Na,K-pump regulation by FXYD3. In addition, we observe a decrease in the maximal Na,K-ATPase activity due to a decrease in its turnover number, which correlates with a change in Na,K-ATPase isozyme expression that is characteristic of cancer cells. Overall, our results suggest an important role of FXYD3 in cell differentiation of Caco-2 cells. One possibility is that FXYD3 silencing prevents proper regulation of Na,K-ATPase, which leads to perturbation of cellular Na+ and K+ homeostasis and changes in the expression of Na,K-ATPase isozymes, whose functional properties are incompatible with Caco-2 cell differentiation.

Respostas do cacaueiro à aplicação de N, P e K em dois solos da Amazônia Brasileira

A cacauicultura da Amazônia está implantada em solos eutróficos, com predominância da Terra Roxa Estruturada, e em Latossolos ou Podzólicos distróficos, sendo desconhecidas as limitações nutricionais desses solos na fase produtiva do cacaueiro. As respostas do cacaueiro à aplicação de N, P e K foram determinadas em dois experimentos instalados nos municípios de Medicilândia, ao longo da Rodovia Transamazônica, e Benevides, Pará, em solos das unidades Terra Roxa Estrutura eutrófica (TR) e Latossolo Amarelo (LA), respectivamente. As lavouras de cacau do híbrido Sca 6 x Be 10 foram implantadas após o corte e queima da mata primária, utilizando-se, como esquema experimental, um fatorial NPK 2³ com tratamentos adicionais de P. Os resultados obtidos demonstraram que o P foi o principal nutriente que limitou a produção, provocando incrementos de produtividade (P < 0,01) da ordem de 13,7% (110 kg ha-1) e 44,3% (214 kg ha-1) nos solos TR e LA, respectivamente, na média do período 1987 a 1993. O K também aumentou (P < 0,01) o rendimento de amêndoas secas de cacau no solo LA, verificando-se, ainda, interações significativas (P < 0,05) entre N x K e P x K neste solo. A resposta linear do cacaueiro ao P e o aumento ou diminuição da taxa de infecção de vassoura-de-bruxa ao N, P e K evidenciam a necessidade de novas pesquisas para definir a dosagem econômica de P, de K e o efeito da interação dos nutrientes com a enfermidade.

[Archives de la Parole]. , Parable of the prodigal son : in Kodaku, from Surguja / [Sir George Grierson], éd. ; Linguistic survey of India ; [Jūthan Koḍākū], voix

[Traditions. Asie. Inde. Madhya Pradesh. Chhattisgarh]

[Archives de la Parole]. , Parable of the prodigal son : in Korwa, from Surguja (C.P.) [i.e. Central Provinces] / [Sir George Grierson], éd. ; Linguistic survey of India ; [Nathu Kōrwā], voix

[Traditions. Asie. Inde. Madhya Pradesh. Chhattisgarh]

[Archives de la Parole]. , Parable of the Prodigal Son : in Kolami, from Yeotmal (Berar) - Dravidien - Ling[uistic] survey of India / [Sir George Grierson], éd. ; Linguistic survey of India ; [Rakma Kōlām], voix

[Traditions. Asie. Inde. Madhya Pradesh. Maharashtra]

Myocardial impairment in chronic hypoxia is abolished by short aeration episodes: involvement of K+ATP channels.

In vivo exposure to chronic hypoxia is considered to be a cause of myocardial dysfunction, thereby representing a deleterious condition, but repeated aeration episodes may exert some cardioprotection. We investigated the possible role of ATP-sensitive potassium channels in these mechanisms. First, rats (n = 8/group) were exposed for 14 days to either chronic hypoxia (CH; 10% O(2)) or chronic hypoxia with one episode/day of 1-hr normoxic aeration (CH+A), with normoxia (N) as the control. Second, isolated hearts were Langendorff perfused under hypoxia (10% O(2), 30 min) and reoxygenated (94% O(2), 30 min) with or without 3 microM glibenclamide (nonselective K(+)(ATP) channel-blocker) or 100 microM diazoxide (selective mitochondrial K(+)(ATP) channel-opener). Blood gasses, hemoglobin concentration, and plasma malondialdehyde were similar in CH and CH+A and in both different from normoxic (P < 0.01), body weight gain and plasma nitrate/nitrite were higher in CH+A than CH (P < 0.01), whereas apoptosis (number of TUNEL-positive nuclei) was less in CH+A than CH (P < 0.05). During in vitro hypoxia, the efficiency (ratio of ATP production/pressure x rate product) was the same in all groups and diazoxide had no measurable effects on myocardial performance, whereas glibenclamide increased end-diastolic pressure more in N and CH than in CH+A hearts (P < 0.05). During reoxgenation, efficiency was markedly less in CH with respect to N and CH+A (P < 0.0001), and ratex pressure product remained lower in CH than N and CH+A hearts (P < 0.001), but glibenclamide or diazoxide abolished this difference. Glibenclamide, but not diazoxide, decreased vascular resistance in N and CH (P < 0.005 and < 0.001) without changes in CH+A. We hypothesize that cardioprotection in chronically hypoxic hearts derive from cell depolarization by sarcolemmal K(+)(ATP) blockade or from preservation of oxidative phosphorylation efficiency (ATP turnover/myocardial performance) by mitochondrial K(+)(ATP) opening. Therefore K(+)(ATP) channels are involved in the deleterious effects of chronic hypoxia and in the cardioprotection elicited when chronic hypoxia is interrupted with short normoxic aeration episodes.