Does "ichthyosis uteri" have malignant potential? : A case report of squamous cell carcinoma of endometrium associated with extensive ichthyosis uteri

This short report discusses a case of solitary colonic polypoid ganglioneuroma associated with melanosis coli in a woman with no systemic manifestations. To our knowledge this is the first ganglioneuroma reported in the literature in association with melanosis coli. The nature and significance of this event remains unclear, although this may be coincidental due to the laxative intake. Further investigation is necessary to clarify this point. The interest of this case lies moreover in the rarity of this entity and its endoscopic and histologic resemblance to sessile polyps frequent in the clinical practice.     

TCRBV20S1 polymorphism does not influence the susceptibility to type 1 diabetes and multiple sclerosis in the Sardinian population

Among the different T-cell receptor (TCR) BV20S1 polymorphisms, nucleotide substitution at position 524 results in the introduction of a stop codon, whose potential functional relevance is still unknown. We have recently showed in Sardinian subjects the most elevated allele frequency ever reported worldwide for this “null allele” (0.44). As this variant generates a gap in the TCR repertoire, this preliminary finding prompted us to further analyze the role of this polymorphism in the susceptibility to type 1 diabetes (T1D) and multiple sclerosis (MS), which are extremely common in this population. With this aim, we evaluated the influence of the TCRBV20S1 polymorphism by assessing it with the transmission disequilibirum test (TDT) in 652 T1D and 616 MS families, without detecting any significant difference. We conclude that the high frequency of this null allele in Sardinia is not directly related to the high incidence of these autoimmune diseases observed in this founder population.     

1-Methyladenine in urine of an adenosine deaminase-deficient adult without immunodeficiency

Procedures are described for the isolation and identification of 1-methyladenine from the urine of an adult female with adenosine deaminase deficiency but no immunodeficiency. Evidence is provided indicating that much of the usual urinary excretion product, 1-methyladenosine, is converted to 1-methyladenine in this subject prior to excretion. Since the nucleoside phosphorylases present in normal individuals do not act on 1-methyladenosine, this suggests that a phosphorylase with unusual properties is present in this adenosine deaminase-deficient subject. A possible role for this phosphorylase in removal of deoxyadenosine in this subject is discussed.     

Theory of cooperative transitions in protein molecules. I. Why denaturation of globular protein is a first-order phase transition

A theory of equilibrium denaturation of proteins is suggested. According to this theory, a cornerstone of protein denaturation is disruption of tight packing of side chains in protein core. Investigation of this disruption is the object of this paper. It is shown that this disruption is an "all-or-none" transition (independent of how compact is the denatured state of a protein and independent of the protein-solvent interactions) because expansion of a globule must exceed some threshold to release rotational isomerization of side chains. Smaller expansion cannot produce entropy compensation of nonbonded energy loss; this is the origin of a free-energy barrier (transition state) between the native and denatured states. The density of the transition state is so high that the solvent cannot penetrate into protein in this state. The results obtained in this paper make it possible to present in the following paper a general phase diagram of protein molecule in solution.     

Sulfoximines as potent RORγ inverse agonists

Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model.     

Purification and characterization of a high-molecular-weight protein induced in rat serum during the development of cardiac hypertrophy

A relatively high-molecular-weight polypeptide was found in rat serum within 6 h after aortic constriction in experimental animals. This polypeptide persists for about 7 days of the postoperative period and disappears at later stage of hypertrophy (40%). Further, fractionation and purification of this protein through DEAE-Sepharose and gel filtration chromatography have revealed that this protein is a single polypeptide and its relative molecular weight is 135 kDa. Immunoprecipitation and immunofluorescence microscopic analysis have indicated the presence of the above polypeptide in the nuclear fraction of heart cells. Studies on phosphorylation in vitro have revealed that this protein is a phosphoprotein. DNase I sensitivity and hybridization using a muscle specific gene probe have indicated the involvement of this protein in template associated changes in heart nuclei. Further the possibility of this protein being synthesized by heart cells indicates that this protein could traverse back and forth between heart cells and the extracellular fluid, suggesting an autocrine/paracrine role for this protein during the development of cardiac hypertrophy.     

Pulmonary dirofilariasis diagnosed by fine needle aspiration biopsy. A case report

A case of pulmonary dirofilariasis in a 62-year-old female was diagnosed by fine needle aspiration biopsy. A review of the literature revealed this to be the first reported case diagnosed by this method. The presence of bilateral lesions in this patient is an uncommon finding for this entity.     

An Atg13 protein-mediated self-association of the Atg1 protein kinase is important for the induction of autophagy

Autophagy pathways in eukaryotic cells mediate the turnover of a diverse set of cytoplasmic components, including damaged organelles and abnormal protein aggregates. Autophagy-mediated degradation is highly regulated, and defects in these pathways have been linked to a number of human disorders. The Atg1 protein kinase appears to be a key site of this control and is targeted by multiple signaling pathways to ensure the appropriate autophagic response to changing environmental conditions. Despite the importance of this kinase, relatively little is known about the molecular details of Atg1 activation. In this study we show that Atg13, an evolutionarily conserved regulator of Atg1, promotes the formation of a specific Atg1 self-interaction in the budding yeast, Saccharomyces cerevisiae. The appearance of this Atg1-Atg1 complex is correlated with the induction of autophagy, and conditions that disrupt this complex result in diminished levels of both autophagy and Atg1 kinase activity. Moreover, the addition of a heterologous dimerization domain to Atg1 resulted in elevated kinase activity both in vivo and in vitro. The formation of this complex appears to be an important prerequisite for the subsequent autophosphorylation of Thr-226 in the Atg1 activation loop. Previous work indicates that this modification is necessary and perhaps sufficient for Atg1 kinase activity. Interestingly, this Atg1 self-association does not require Atg17, suggesting that this second conserved regulator might activate Atg1 in a manner mechanistically distinct from that of Atg13. In all, this work suggests a model whereby this self-association stimulates the autophosphorylation of Atg1 within its activation loop.     

Phytoliths in woody plants from the northern slope of the Changbai Mountain (Northeast China), and their implication

Phytoliths were extracted from 14 woody plants collected on the northern slope of the Changbai Mountain, including 10 broad-leaved species and 4 conifers. A total of 14 morphotypes of phytoliths were identified, including 3 types first examined in this study. Phytoliths in broad-leaved species were mostly silicified epidermal cells, cell walls, and vascular tissues; phytoliths in conifers were mainly silicified epidermal cells, cell walls, hypodermal cells, and parenchyma cells. Phytoliths produced by broad-leaved species in this region were usually not well silicified, and were fragile, whereas those produced by conifers were better silicified; this might be because of the different lengths of the growth periods. Phytoliths were found have potential in studies of fluctuations of the tree line in this region, and this study also provided a reference for further study of phytoliths in this region and the regional contrast of phytolith assemblages.     

The role of a beta-bulge in the folding of the beta-hairpin structure in ubiquitin

It is known that the peptide corresponding to the N-terminal beta-hairpin of ubiquitin, U(1-17), can populate the monomeric beta-hairpin conformation in aqueous solution. In this study, we show that the Gly-10 that forms the bulge of the beta-turn in this hairpin is very important to the stability of the hairpin. The deletion of this residue to desG10(1-16) unfolds the structure of the peptide in water. Even under denaturing conditions, this bulge appears to be important in maintaining the residual structure of ubiquitin, which involves tertiary interactions within the sequence 1 to 34 in the denatured state. We surmise that this residual structure functions as one of the nucleation centers in the folding process and is important in stabilizing the transition state. In accordance with this idea, deleting Gly-10 slows down the refolding and unfolding rate by about one half.     

A mathematical modelling framework for understanding chemorepulsive signal transduction in Dictyostelium

Chemorepulsion is the process by which an organism or a cell moves in the direction of decreasing chemical concentration. While a few experimental studies have been performed, no mathematical models exist for this process. In this paper we have modelled gradient sensing, the first subprocess of chemorepulsion, in Dictyostelium discoideum-a well characterized model eukaryotic system. We take the first steps towards achieving a comprehensive mechanistic understanding of chemorepulsion in this system. We have used, as a basis, the biochemical network of the Keizer-Gunnink et al. (2007) to develop the mathematical modelling framework. This network describes the underlying pathways of chemorepellent gradient sensing in D. discoideum. Working within this modelling framework we address whether the postulated interactions of the pathways and species in this network can lead to a chemorepulsive response. We also analyse the possible role of additional regulatory effects (such as additional receptor regulation of enzymes in this network) and if this is necessary to achieve this behaviour. Thus we have investigated the receptor regulation of important enzymes and feedback effects in the network. This modelling framework generates important insights into and testable predictions regarding the role of key components and feedback loops in regulating chemorepulsive gradient sensing, and what factors might be important for generating a chemorepulsive response; it serves as a first step towards a comprehensive mechanistic understanding of this process.     

在雌不发生交换的鳞翅目类昆虫中使用F2群体作图显隐性分子标记连锁图谱的极大似然(ML)法

在鳞坡目昆虫中,雌性个体的减数分裂细胞不发生遗传重组。这类物种的杂效Ｆ２群体中杂合子基因型的与一般物种中雌雄个体的减数分裂细胞都发生遗传重组的Ｆ２群体杂合子表型不同,由于这个原因,作用这类物种的遗传连锁图谱通常中使用回交群体。但是,用回效群体傻所得的图谱是不完整的,因为图谱上所有的标记都是百轮回亲本提供的,因此 不会超过杂交Ｆ２各体的一半。另外,目前还没有任何方法和软件可以用杂效Ｆ２群体来作图鳞翅     

Description and life cycle of a new Physarum (Myxomycetes) from the Atacama Desert in Chile

A new species of Physarum (Myxomycetes), Physarum atacamense is described in this paper, and details are provided on its life cycle as observed in spore-to-spore culture in agar. The new species was collected during studies of the Atacama Desert in Chile. It has been collected directly in the field and isolated in moist chamber cultures prepared with material from an endemic cactus. The combination of characters that make this species unique in the genus are its large fusiform nodes of the capillitium, its long, bicolored stalk and the very dark brown and densely warted angular spores. The morphology of specimens of this myxomycete was examined with scanning electron microscopy and light microscopy, and micrographs of relevant details and life cycle stages are included in this paper. The importance of resistant stages in the life cycle of this myxomycete is stressed, and the close association of this myxomycete with its plant substrates is discussed.     

Genetic aspects of the organization of legumin genes in pea

We have compared physical and genetic maps of the region around the legJ gene in pea. In this vicinity there are four B-type legumin genes, arranged as two close pairs. The detection of a recombination event within this gene cluster allows the orientation of this group of genes within the surrounding linkage group to be determined. The relationship between physical and genetic distances in this region is discussed, as are the implications of this for relating physical and genetic maps elsewhere in the pea genome.     

Rb(7.17), a rare Robertsonian fusion in wild populations of the house mouse

Robertsonian (Rb) translocation is the largest source of chromosomal diversity in the western European house mouse (Mus musculus domesticus). Recently, the fusion Rb(7.17) was found in the chromosomal polymorphic zone of this subspecies in the north-east of the Iberian Peninsula. This fusion has not been reported in any other European population. Here we give data on the distribution and frequency of this mutation in this region. Results revealed that Rb(7.17) is restricted to a small geographic area, and that, in comparison with other fusions in this polymorphic zone, it occurs at low frequencies. We suggest some possible explanations for the distribution of this translocation.     

Endogenous digoxin-immunoactive factor in human subjects

Endogenous digoxin-like immunoactivity has been detected in the blood of adult patients in renal failure, newborn infants, and pregnant women in the third trimester. Blood levels of this activity increase in pregnant women as gestation progresses, and preliminary data suggest that the activity is increased in hypertensive pregnant women relative to normotensive pregnant women. Similar immunoactivity has also been detected in amniotic fluid and in the urine and serum of normal healthy subjects. The factors giving rise to this immunoactivity cross-react with antibodies used in many commercially available immunoassays for digoxin. The immunoactive factor isolated from human subjects is water soluble and exists tightly but reversibly bound to proteins in serum. The extent of this protein binding is altered in the clinical conditions studied relative to normal adults. This altered protein binding accounts for the detection of this factor by many of the commercially used immunoassays for digoxin. In this article I summarize recent findings related to detecting this activity in the blood of several clinical populations where the accurate measurement of digoxin may be compromised. I also summarize the preliminary isolation and characterization of the factor responsible for this immunoactivity.     

The critical role of alpha‐folate receptor in the resistance of melanoma to methotrexate

Although methotrexate (MTX) is an effective drug for several types of cancer, it is not active against melanoma. Experiments following methotrexate treatment indicated a reduced accumulation of the drug in the cytosolic compartment in melanoma cells, suggesting that the mechanisms that control the transport and retention of this drug could be altered in melanoma. For this reason, we analyzed the presence and function of folate receptor‐α (FRα) in melanoma cells. In this study, we have identified the presence of FRα in normal and pathological melanocytes and demonstrated that MTX is preferentially transported through this receptor in melanoma cells. FRα‐induced endocytic transport of MTX, together with drug melanosomal sequestration and cellular exportation, ensures reduced accumulation of this cytotoxic compound in intracellular compartments. The critical role of FRα in this mechanism of resistance and the therapeutic consequences of these findings are also discussed.     

A novel mutation in the invariant AG of the acceptor splice site of intron 4 of the beta-hexosaminidase alpha-subunit gene in two unrelated American black GM2-gangliosidosis (Tay-Sachs disease) patients.

Samples of genomic DNA from three unrelated American black infants having both biochemical and clinical features of classical infantile Tay-Sachs disease were sequenced following PCR amplification. A G----T transversion was observed in the AG acceptor splice site preceding exon 5 of the beta-hexosaminidase alpha-subunit gene in the first black family. This transversion changed the acceptor splice site from the consensus sequence, AG, to AT, thereby interfering with splicing at this intron 4/exon 5 junction. The proband was homozygous for this mutation; his mother and a brother are heterozygous. The same mutation was found in a second, apparently unrelated, black GM2-gangliosidosis patient. The second patient was a compound heterozygote, as only one allele carried this mutation. The mother and a brother in this second family are carriers for this mutation, while the father and a noncarrier sister are normal for this region of the gene. The third proband did not have this mutation; nor did the mother of a fourth black proband. Eight other independently ascertained non-black, non-Jewish, GM2-gangliosidosis families did not have this mutation. The observation of the same novel mutation in two unrelated black GM2-gangliosidosis patients indicates that the American black population has segregating within it at least one GM2-gangliosidosis mutation which may be specific to this population and not a result of migration.     

Metabolic stereoisomeric inversion of ibuprofen in mammals

Studies on the mechanism and enzymology of metabolic ibuprofen isomerization constituted the focus of this investigation. Comparative in vivo studies revealed that this biotransformation proceeded via a proton abstraction mechanism in all tested species of mammals, which is in agreement with the previous reports. Direct evidence supporting this conclusion stemmed from the in vitro epimerization of ibuprofen-CoA thioester in rat liver homogenates. Chemically synthesized (R)-ibuprofen-CoA thioester was rapidly transformed to its (S)-counterpart by subcellular hepatic preparations. Examination of this epimerase activity in various rat tissue homogenates indicated that this enzyme was highly tissue specific. This biochemical reaction mainly took place in the liver and kidney, whereas low levels of enzyme activity were associated with other tissues. Nevertheless, the liver and kidney homogenates failed to invert (R)-ibuprofen directly even in the presence of all the necessary cofactors. Presumably, the failure to characterize this bioconversion was due to the lack of enzymatic acyl-CoA synthesis in these homogenates. It is noteworthy that the '2-arylpropionyl-CoA epimerase' catalyzed the transformation from either direction and with high turnover rates. The catalytic efficiency of (S)-ibuprofen CoA epimerization appeared to be greater than that of the (R)-counterpart. These in vitro findings suggest that the step of acyl-CoA formation assume a pivotal role in controlling the stereoselectivity and efficiency of the in vivo metabolism. As the responsible acyl-CoA synthetase(s) in different species of animals may exert the reaction with different degrees of enantiomeric preference and efficiency, the resulting stereochemical outcome and metabolic rates of this bioinversion vary accordingly. Consequently, in guinea pigs, this biotransformation proceeds in both directions with nearly equal efficiency, whereas it is virtually unidirectional and slow in humans. Currently, the purification and characterization of this novel '2-arylpropionyl-CoA epimerase' from rat livers constitute the focus of this investigation.