Genetic epidemiology of Down's syndrome in Shetland

Summary Pedigrees of all known cases, on Shetland, of Down's syndrome, cytogenetically confirmed as trisomy 21, and of a control for each patient matched by birth date, sex and birth place, were traced over a minimum of eight generations. Mean kinship coefficients in all pairs of Down's syndrome patients and in all pairs of controls were similar. The kinship between the father and mother of each case shows that the parents are more closely related than the general level of relationship in the population, suggesting some recessive element in the etiology. It is argued that the effect of the resulting increased homozygosity would be to prevent the loss of the conceptus that occurs in the majority of trisomy 21 conceptions.     

Using Complete Genome Comparisons to Identify Sequences Whose Presence Accurately Predicts Clinically Important Phenotypes

In clinical settings it is often important to know not just the identity of a microorganism, but also the danger posed by that particular strain. For instance, Escherichia coli can range from being a harmless commensal to being a very dangerous enterohemorrhagic (EHEC) strain. Determining pathogenic phenotypes can be both time consuming and expensive. Here we propose a simple, rapid, and inexpensive method of predicting pathogenic phenotypes on the basis of the presence or absence of short homologous DNA segments in an isolate. Our method compares completely sequenced genomes without the necessity of genome alignments in order to identify the presence or absence of the segments to produce an automatic alignment of the binary string that describes each genome. Analysis of the segment alignment allows identification of those segments whose presence strongly predicts a phenotype. Clinical application of the method requires nothing more that PCR amplification of each of the set of predictive segments. Here we apply the method to identifying EHEC strains of E. coli and to distinguishing E. coli from Shigella. We show in silico that with as few as 8 predictive sequences, if even three of those predictive sequences are amplified the probability of being EHEC or Shigella is >0.99. The method is thus very robust to the occasional amplification failure for spurious reasons. Experimentally, we apply the method to screening a set of 98 isolates to distinguishing E. coli from Shigella, and EHEC from non-EHEC E. coli strains and show that all isolates are correctly identified.     

A Langmuir film balance study of the interactions of ionic and polar solutes with glycolipid monolayers

Using a Langmuir film balance experiments have been conducted to discover if dissolved salts or carbohydrates interact with glycolipid monolayers. Two types of glycolipid were studied, simple glycosides made by ether linking monosaccharides to fatty alcohols and cerebrosides extracted from natural sources. It was found that salts or carbohydrates in the subphase expanded glycolipid monolayers. That is, a monolayer spread on a solution occupied a greater area at a given pressure than it would have spread on pure water. Of the carbohydrates galactose and glucose, galactose caused a markedly greater expansion of monolayers than glucose. However, the magnitude of the expansions measured for stearyl glucoside, mannoside and galactoside films on solutions of a particular sugar were not significantly different, demonstrating that this phenomenon is independent of the glycolipid sugar residue. As with carbohydrates, salts also have differing effects on glycolipid monolayers. Although the effect an individual ion has on a monolayer cannot be directly measured, comparisons between salts indicate that there is a correlation between the size of an ion and the extent of the monolayer expansion it causes. To explain these observations two different mechanisms are proposed. In the case of salts it is suggested that large ions which have a low charge density disrupt water structure in such a way that monolayers spread on the surface of their solutions are expanded. The ability of carbohydrates to expand monolayers is explained in terms of the carbohydrate replacing water molecules bound to the polar groups of the monolayer and in so doing increasing the effective area of the lipid molecules. It is suggested that the molecular mechanisms involved in the interactions of ions and carbohydrates with glycolipid monolayers may also operate in the interactions of glycolipids and glycoproteins with extracellular agents and surfaces.     

Urinary cytodiagnosis of renal involvement in disseminated histiocytic lymphoma

Two cases of patients with disseminated histiocytic lymphoma are presented in which positive urine cytology provided evidence of renal involvement. In addition to malignant cells, the urine sediment characteristics included renal tubular epithelial cell exfoliation, renal epithelial fragments and pathologic cast formation, which distinguished renal from lower urinary tract involvement. Such cytologic observations may be useful in differentiating among the various causes of renal disease in patients with malignant lymphomas.     

Network Translation and Steady-State Properties of Chemical Reaction Systems

Network translation has recently been used to establish steady-state properties of mass action systems by corresponding the given system to a generalized one which is either dynamically or steady-state equivalent. In this work, we further use network translation to identify network structures which give rise to the well-studied property of absolute concentration robustness in the corresponding mass action systems. In addition to establishing the capacity for absolute concentration robustness, we show that network translation can often provide a method for deriving the steady-state value of the robust species. We furthermore present a MILP algorithm for the identification of translated chemical reaction networks that improves on previous approaches, allowing for easier application of the theory.     

Microcystins: Synthesis and structure–activity relationship studies toward PP1 and PP2A

Microcystins are highly toxic cyanotoxins responsible for plant, animal and human poisoning. Exposure to microcystins, mainly through drinkable water and contaminated food, is a current world health concern. Although it is quite challenging, the synthesis of these potent cyanotoxins, analogs and derivatives helps to evaluate their toxicological properties and to elucidate their binding mechanisms to their main targets Protein Phosphatase-1 (PP1) and -2A (PP2A). This review focuses on synthetic approaches to prepare microcystins and analogs and compiles structure–activity relationship (SAR) studies that describe the unique features of microcystins that make them so potent.     

Src kinase activation by nitric oxide promotes resistance to anoikis in tumour cell lines

Tumour progression involves the establishment of tumour metastases at distant sites. Resistance to anoikis, a form of cell death that occurs when cells lose contact with the extracellular matrix and with neighbouring cells, is essential for metastases. NO has been associated with anoikis. NO treated HeLa cells and murine melanoma cells in suspension triggered a nitric oxide (NO)-Src kinase signalling circuitry that enabled resistance to anoikis. Two NO donors, sodium nitroprusside (SNP) (500 µM) and DETANO (125 µM), protected against cell death derived from detachment of a growth permissive surface (experimental anoikis). Under conditions of NO-mediated Src activation the following were observed: (a) down-regulation of the pro-apoptotic proteins Bim and cleaved caspase-3 and the cell surface protein, E-cadherin, (b) up-regulation of caveolin-1, and (c) the dissociation of cell aggregates formed when cells are detached from a growth permissive surface. Efficiency of reattachment of tumour cells in suspension and treated with different concentrations of an NO donor, was dependent on the NO concentration. These findings indicate that NO-activated Src kinase triggers a signalling circuitry that provides resistance to anoikis, and allows for metastases.