Permutation pattern discovery in biosequences.

Functionally related genes often appear in each other's neighborhood on the genome; however, the order of the genes may not be the same. These groups or clusters of genes may have an ancient evolutionary origin or may signify some other critical phenomenon and may also aid in function prediction of genes. Such gene clusters also aid toward solving the problem of local alignment of genes. Similarly, clusters of protein domains, albeit appearing in different orders in the protein sequence, suggest common functionality in spite of being nonhomologous. In the paper, we address the problem of automatically discovering clusters of entities, be they genes or domains: we formalize the abstract problem as a discovery problem called the (pi)pattern problem and give an algorithm that automatically discovers the clusters of patterns in multiple data sequences. We take a model-less approach and introduce a notation for maximal patterns that drastically reduces the number of valid cluster patterns, without any loss of information, We demonstrate the automatic pattern discovery tool on motifs on E. Coli protein sequences.     

Genetic variation in vitamin D receptor gene (Fok1:rs2228570) is associated with risk of coronary artery disease

Objective: The Fok1 polymorphism (rs2228570) in vitamin D receptor gene appears to be the only polymorphism influencing size of translated protein. Investigations into its association with coronary artery disease (CAD) are sparse.

Methods: Male patients (n?=?98) with verified CAD were recruited alongside age- and sex-matched controls (n?=?55). Genotyping was performed by PCR-RFLP and plasma 25-Hydroxyvitamin D levels were assessed by HPLC-UV.

Results: The C-variant (mutant) was predominantly expressed in patients compared to controls (68.9% versus 55.5%; p?=?0.025). The observed genotypes were not associated with 25-Hydroxyvitamin D levels.

Conclusion: This study presents Fok1 polymorphism as a potential genetic marker for CAD.     

Allopurinol Resistance in Leishmania infantum from Dogs with Disease Relapse

Background

Visceral leishmaniasis caused by the protozoan Leishmania infantum is a zoonotic, life threatening parasitic disease. Domestic dogs are the main peridomestic reservoir, and allopurinol is the most frequently used drug for the control of infection, alone or in combination with other drugs. Resistance of Leishmania strains from dogs to allopurinol has not been described before in clinical studies.

Methodology/Principal Findings

Following our observation of clinical disease relapse in dogs under allopurinol treatment, we tested susceptibility to allopurinol of L. infantum isolated from groups of dogs pre-treatment, treated in remission, and with disease relapse during treatment. Promastigote isolates obtained from four treated relapsed dogs (TR group) showed an average half maximal inhibitory concentration (IC50) of 996 μg/mL. A significantly lower IC50 (P = 0.01) was found for isolates from ten dogs before treatment (NT group, 200 μg/mL), as well as for five isolates obtained from treated dogs in remission (TA group, 268 μg/mL). Axenic amastigotes produced from isolates of the TR group also showed significantly higher (P = 0.002) IC50 compared to the NT group (1678 and 671 μg/mL, respectively). The lower sensitivity of intracellular amastigotes from the TR group relative to those from the NT group (P = 0.002) was confirmed using an infected macrophage model (6.3% and 20% growth inhibition, respectively at 300 μg/mL allopurinol).

Conclusions

This is the first study to demonstrate allopurinol resistance in L. infantum and to associate it with disease relapse in the canine host. These findings are of concern as allopurinol is the main drug used for long term control of the disease in dogs, and resistant L. infantum strains may enhance uncontrolled transmission to humans and to other dogs.     

Histochemical localization of ornithine decarboxylase with a labelled suicidal enzyme inhibitor

We describe a new technique for cytochemical localization of ornithine decarboxylase by the use of a synthesized conjugate of rhodamine bound to α-difluoromethylornithine a suicidal inhibitor of the enzyme. The labelled inhibitor retained its specificity and irreversibility towards ornithine decarboxylase inhibition. Using this technique we have localized the enzyme in specific regions of the developing rat cerebellum. This novel technique may be generally applicable to other enzymes.     

Familial Leydig cell hypoplasia as a cause of male pseudohermaphroditism

A case of familial Leydig cell hypoplasia as a cause of male pseudohermaphroditism is described in two 46,XY female sibs. Biochemical and histologic evidence for such diagnosis is presented.     

Hydrolysis of retinyl palmitate by enzymes of rat pancreas and liver. Differentiation of bile salt-dependent and bile salt-independent, neutral retinyl ester hydrolases in rat liver

Previous studies have demonstrated that homogenates of the livers of rats contain a neutral retinyl ester hydrolase activity that requires millimolar concentrations of bile salts for maximal in vitro activity. The enzymatic properties of this neutral, bile salt-dependent retinyl ester hydrolase activity in liver homogenates are nearly identical to those observed in the present report for the in vitro hydrolysis of retinyl palmitate by purified rat pancreatic cholesteryl ester hydrolase (EC 3.1.1.13). Moreover, anti-rat pancreatic cholesteryl ester hydrolase IgG completely inhibits the bile salt-dependent retinyl ester hydrolase activity of rat liver homogenates whereas normal rabbit IgG does not. We also show that liver homogenates contain a neutral, bile salt-independent retinyl ester hydrolase activity that differs from the bile salt-dependent activity in that 1) its absolute activity does not vary markedly among individual rats, 2) it is not inhibited by antibodies to pancreatic cholesteryl ester hydrolase, and 3) it is localized in the microsomal fraction of liver homogenates. Subfractionation of microsomes demonstrates that the neutral, bile salt-independent retinyl ester hydrolase activity is associated with liver cell plasma membranes and thus may play a role in the hydrolysis of retinyl esters delivered to the liver by chylomicron remnants.