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Gail Willsky

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The University of Winnipeg

Fernando Luís Barroso da Silva

Universidade de São Paulo

Johns Hopkins University

University of Karachi

AlAzhar University cairo

University of Debrecen

University of Toronto

Universidad de Buenos Aires

Universidad Peruana Cayetano Heredia

Sergio D Bergese

SUNY: Stony Brook University

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Papers by Gail Willsky

Utilization of two sample -test statistics from redundant probe sets to evaluate different probe set algorithms in GeneChip studies-5

<b>Copyright information:</b>Taken from "Utilization of two sample -test statist... more <b>Copyright information:</b>Taken from "Utilization of two sample -test statistics from redundant probe sets to evaluate different probe set algorithms in GeneChip studies"BMC Bioinformatics 2006;7():12-12.Published online 10 Jan 2006PMCID:PMC1361777.Copyright © 2006 Hu and Willsky; licensee BioMed Central Ltd.rom different probe set algorithms. The same analysis procedures as in Figure 4 were applied. (a) Comparison of normalization options at the probe set level. (b) Comparison of expression summary options. (c) Comparison of normalization options. (d) Comparison of PM correction options. (e) Comparison of background correction options. (f) Comparison of the selected 10 expression summary datasets to all others.

Aqueous Reactions and NMR Spectroscopy of Hydroxamidovanadate

Vanadium, 2007

Integrating Traditional and Modern Medicine: Perspectives from Ethnobotany, Medical Anthropology, Microbiology, and Pharmacy

Transforming Global Health, 2020

Coordination of Vanadate by Hydrogen Peroxide and Hydroxylamines

Vanadium, 2007

Vanadium Salts in the Treatment of Human Diabetes Mellitus

ACS Symposium Series, 1998

Inorganic Phosphate Transport in Escherichia coli: Involvement of Two Genes Which Play a Role in Alkaline Phosphatase Regulation

Journal of Bacteriology, 1973

Two classes of alkaline phosphatase constitutive mutations which comprise the original phoS locus... more Two classes of alkaline phosphatase constitutive mutations which comprise the original phoS locus (genes phoS and phoT ) on the Escherichia coli genome have been implicated in the regulation of alkaline phosphatase synthesis. When these mutations were introduced into a strain dependent on a single system, the pst system, for inorganic phosphate (P i ) transport, profound changes in P i transport were observed. The phoT mutations led to a complete P i − phenotype in this background, and no activity of the pst system could be detected. The introduction of the phoS mutations changed the specificity of the pst system so that arsenate became growth inhibitory. Changes in the phosphate source led to changes in the levels of constitutive alkaline phosphatase synthesis found in phoS and phoT mutants. When glucose-6-phosphate or l -α-glycerophosphate was supplied as the sole source of phosphate, phoT mutants showed a 3- to 15- fold reduction in constitutive alkaline phosphatase synthesis whe...

Control of the synthesis of alkaline phosphatase and the phosphate-binding protein in Escherichia coli

Journal of Bacteriology, 1976

Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunological techniques, we ... more Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunological techniques, we have compared the synthesis of the phoA protein (alkaline phosphatase) and the phoS protein (phosphate-binding protein) in response to the level of phosphate in the medium in different genetic backgrounds containing the known alkaline phosphatase control mutations. Both proteins are produced in excess phosphate media in a phoR1a- strain, whereas neither protein is produced in a phoB- strain even under derepression conditions. In four different phoR1c- strains, however, the phoA product cannot be detected in extracts of cells obtained from any growth condition, whereas the phoS product is produced in both excess and limiting phosphate media. It is not yet known if phoR1c- mutants are a special class of mutations within the phoB gene or whether they occur in a separate cistron involved in alkaline phosphatase regulation. From these results we conclude that the expression of the phoA gene i...

Alteration of protein synthesis in Saccharomyces cerevisiae caused by transition metals

The effects of transition metals and metal oxides (Co/sup 2 +/, Cu/sup 2 +/, Ni/sup 2 +/, Zn/sup ... more The effects of transition metals and metal oxides (Co/sup 2 +/, Cu/sup 2 +/, Ni/sup 2 +/, Zn/sup 2 +/, arsenite (AsOââ»), arsenate (AsOâ/sup 3 -/) and vanadate (VOâ/sup 3 -/)) on protein synthesis and cellular thermotolerance in Saccharomyces cerevisiae have been examined. Arsenate and vanadate differ in that they are known to be physiologic phosphate analogues, e.g. in yeast,

Utilization of two sample t-test statistics from redundant probe sets to evaluate different probe set algorithms in GeneChip studies

BMC bioinformatics, 2006

The choice of probe set algorithms for expression summary in a GeneChip study has a great impact ... more The choice of probe set algorithms for expression summary in a GeneChip study has a great impact on subsequent gene expression data analysis. Spiked-in cRNAs with known concentration are often used to assess the relative performance of probe set algorithms. Given the fact that the spiked-in cRNAs do not represent endogenously expressed genes in experiments, it becomes increasingly important to have methods to study whether a particular probe set algorithm is more appropriate for a specific dataset, without using such external reference data. We propose the use of the probe set redundancy feature for evaluating the performance of probe set algorithms, and have presented three approaches for analyzing data variance and result bias using two sample t-test statistics from redundant probe sets. These approaches are as follows: 1) analyzing redundant probe set variance based on t-statistic rank order, 2) computing correlation of t-statistics between redundant probe sets, and 3) analyzing ...

Renal drug metabolism

Pharmacological reviews, 1998

### A. History The kidneys have important physiological functions including maintenance of water ... more

Comparing Administration Route in Rats with Streptozocin-Induced Diabetes and Inhibition of Myoblast Growth of Vanadium [V(III), V(IV), and V(V)] Dipicolinic Acid Complexes

ACS Symposium Series, 2007

The V(V) dipicolinic acid complex was the most potent complex in two administration routes for re... more The V(V) dipicolinic acid complex was the most potent complex in two administration routes for reducing diabetic hyperglycemia or hyperlipidemia. After V(V) dipic treatment in both routes an inverse correlation of the blood/serum vanadium pool versus blood/plasma glucose pool was found. This is the first vanadium complex to show such a correlation in any diabetic population. The distribution in blood of V(V) and V (IV) dipic complexes was best modeled with a 2-compartment model after acute administration. Only the V(III) and V(V) dipic complexes stimulated myoblast growth at 1 μM complex, while all complexes inhibited growth at higher concentrations. These experiments show that the oxidation state of the vanadium in dipic complexes affects biological efficacy and that processing of the V(V) dipic complex is different fom that of the lower oxidation states. These results also show that effects of vanadium complexes on rat myoblasts are similar to those observed in diabetic animals administered compounds intraperitoneally.

Vanadium–phosphatase complexes: Phosphatase inhibitors favor the trigonal bipyramidal transition state geometries

Coordination Chemistry Reviews, 2015

Over the past two decades increasing information about the function and structural detail of phos... more Over the past two decades increasing information about the function and structural detail of phosphatases has become available detailing the interaction with vanadate or other vanadium compounds. Considering the importance of the phosphorylation reaction in signal transductions the structural details of the interaction of vanadate or other vanadium species with many phosphatases are used to provide information on the nature of successful inhibitors of these enzymes. Analysis shows that most of the available X-ray structures of vanadium-phosphatase complexes contain vanadium with five coordinating atoms in trigonal bipyramidal coordination geometries even though corresponding small molecule analogue compounds may have square pyramidal geometries. This finding for the static structures in their solid state documents the fact that the variety of phosphatases all stabilize a vanadium geometry that is closer to the trigonal Highlights  Vanadate and vanadium compounds are potent inhibitors of phosphatases.  Five-coordinate vanadium covalently attached to the protein is most common  Vanadium-protein complexes usually have vanadium in a trigonal bipyramidal geometry  The potency of V inhibitors are not likely to change much as the ligand changes

Tetravanadate, Decavanadate, Keggin and Dawson Oxotungstates Inhibit Growth of S. cerevisiae

Nanostructure Science and Technology, 2002

ABSTRACT

Vanadium metabolism in wild type and respiratory-deficient strains ofS. cerevisiae

Yeast, 1986

Vanadium metabolism was studied in a wild type and respiratory-deficient strain of S. cerevisiae.... more Vanadium metabolism was studied in a wild type and respiratory-deficient strain of S. cerevisiae. Inhibition of growth by vanadate [V(+ 5)], vanadate accumulation, and conversion of medium vanadate [V(+ 5)] to both cell-associated and medium vanadyl [V(+4)] and vanadate [V(+5)] were compared. The growth of both the parental and respiratory-deficient strains was inhibited by vanadate at concentrations greater than or equal to 1 mM. Both parental and respiratory-deficient strains accumulated vanadate and converted medium vanadate to cellular vanadyl as detected using electron spin resonance (ESR). The accumulation of cell-associated vanadyl was correlated with the loss of medium vanadate in both strains using a chemical assay. In contrast, the respiratory-deficient strain showed a greater amount of a cell-associated vanadate compound, as detected with vanadium-5 1 nuclear magnetic resonance (5 'V-NMR), than the wild type strain or a representative respiratory-competent vanadate-resistant mutant. These data imply that mitochondria1 function may be directly involved in vanadium metabolism.

Effect of vanadium(IV) compounds in the treatment of diabetes: in vivo and in vitro studies with vanadyl sulfate and bis(maltolato)oxovandium(IV)

Journal of Inorganic Biochemistry, 2001

Vanadyl sulfate (VOSO) was given orally to 16 subjects with type 2 diabetes mellitus for 6 weeks ... more Vanadyl sulfate (VOSO) was given orally to 16 subjects with type 2 diabetes mellitus for 6 weeks at a dose of 25, 50, or 100 mg 4 vanadium (V) daily [Goldfine et al., Metabolism 49 (2000) 1-12]. Elemental V was determined by graphite furnace atomic absorption spectrometry (GFAAS). There was no correlation of V in serum with clinical response, determined by reduction of mean fasting blood glucose or increased insulin sensitivity during euglycemic clamp. To investigate the effect of administering a coordinated V, plasma glucose levels were determined in streptozotocin (STZ)-induced diabetic rats treated with the salt (VOSO) or the coordinated V 4 compound bis(maltolato)oxovandium(IV) (abbreviated as VO(malto)) administered by intraperitoneal (i.p.) injection. There was no 2 relationship of blood V concentration with plasma glucose levels in the animals treated with VOSO , similar to our human diabetic 4 patients. However, with VO(malto) treatment, animals with low plasma glucose tended to have high blood V. To determine if V binding 2 to serum proteins could diminish biologically active serum V, binding of both VOSO and VO(malto) to human serum albumin (HSA), 4 2 human apoTransferrin (apoHTf) and pig immunoglobulin (IgG) was studied with EPR spectroscopy. Both VOSO and VO(malto) bound 4 2 to HSA and apoHTf forming different V-protein complexes, while neither V compound bound to the IgG. VOSO and VO(malto) showed 4 2 differences when levels of plasma glucose and blood V in diabetic rodents were compared, and in the formation of V-protein complexes with abundant serum proteins. These data suggest that binding of V compounds to ligands in blood, such as proteins, may affect the available pool of V for biological effects.

$Fig. 3. Response of type 2 diabetic patients orally dosed with VOSO, for mean fasting blood glucose and euglycemic clamp at two insulin levels. (A) Mean fasting blood glucose. (B) Euglycemic clamp at high insulin concentration. (C) Euglycemic clamp at low insulin concentration. (O) Indicates the five patients who showed an improved response for two of the three variables and is located on each graph for which the response improved for that patient (25V-1, 50V-4, 100V-1, 5 and 7). (+) Indicates the five patients who showed an improved response for all three clinical variables and is located on all three graphs for that patient (SO0V-1 and 5, 100V-2, 6, and 8). The clinical responses in (A-C) were measured as described in Section 2, and are given as fractional responses as described in the text.$

Chloro-substituted dipicolinate vanadium complexes: Synthesis, solution, solid-state, and insulin-enhancing properties

Journal of Inorganic Biochemistry, 2009

Three vanadium complexes of chlorodipicolinic acid (4-chloro-2,6-dipicolinic acid) in oxidation s... more Three vanadium complexes of chlorodipicolinic acid (4-chloro-2,6-dipicolinic acid) in oxidation states III, IV, and V were prepared and their properties characterized across the oxidation states. In addition, the series of hydroxylamido, methylhydroxylamido, dimethylhydroxylamido, and diethylhydroxylamido complexes were prepared from the chlorodipicolinato dioxovanadium(V) complex. The vanadium(V) compounds were characterized in solution by 51 V and 1 H NMR and in the solid-state by X-ray diffraction and 51 V NMR. Density Functional Theory (DFT) calculations were performed to evaluate the experimental parameters and further describes the electronic structure of the complex. The small structural changes that do occur in bond lengths and angles and partial charges on different atoms are minor compared to the charge features that are responsible for the majority of the electric field gradient tensor. The EPR parameters of the vanadium(IV) complex were characterized and compared to the corresponding dipicolinate complex. The chemical properties of the chlorodipicolinate compounds are discussed and correlated with their insulin-enhancing activity in streptozoticin (STZ) induced diabetic Wistar rats. The effect of the chloro-substitution on lowering diabetic hyperglycemia was evaluated and differences were found depending on the compounds oxidation state similar as was observed for the vanadium III, IV and V dipicolinate complexes (P.

Effects of vanadium (III, IV, V)-chlorodipicolinate on glycolysis and antioxidant status in the liver of STZ-induced diabetic rats

Journal of Inorganic Biochemistry, 2014

Vanadium compounds exert various insulin-mimetic and anti-diabetic effects both in vitro and in v... more Vanadium compounds exert various insulin-mimetic and anti-diabetic effects both in vitro and in vivo. Vanadium(III, IV, V)-chlorodipicolinate (Vdipic-Cl) compounds, including H[V III (dipic-Cl) 2 ] • 5H 2 O (V 3 dipic-Cl), V IV O(dipic-Cl)(H 2 O) 2 (V 4 dipic-Cl) and K[V V O 2 (dipic-Cl)] (V 5 dipic-Cl), were synthesized with the indicated oxidation states. The present study was conducted to investigate if chemical valence and anti-oxidation effects of vanadium compounds are involved in the anti-diabetic effects observed in streptozotocin (STZ)-induced diabetic rats treated with these vanadium compounds. V 3 dipic-Cl, V 4 dipic-Cl, V 5 dipic-Cl, inorganic vanadium salts vanadyl sulfate (VOSO 4) or sodium metavanadate (NaVO 3) were orally administered in drinking water (50 μgV/ml) to STZ-induced diabetic rats for 28 days. The results showed that Vdipic-Cl treatment significantly improved hyperglycemia and glucose intolerance, as well as increased hepatic glycogen synthesis in diabetic rats. The mRNA levels of key glycolytic enzymes in liver, phosphoenolpyruvate carboxykinase (PEPCK), glucokinase (GK), and L-pyruvate kinase (L-PK) altered in diabetic animals were significantly restored towards normal values by treatment with some of the vanadium compounds. Moreover, the diabetes elevated activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in serum were significantly decreased after treatment with Vdipic-Cl complexes. Furthermore, treatment of diabetic rats with V 4 dipic-Cl and V 5 dipic-Cl compounds significantly reduced malondialdehyde (MDA) production and increased glutathione peroxidase (GSH-Px) and catalase (CAT) activities. These data suggest that vanadium compounds with the indicated chemical valence promote glycogen synthesis and recover suppressed glycolysis in the liver of diabetic rats due to their capacity to reduce oxidative stress by stimulating antioxidant enzymes.

Vanadate induction of pancreatic amylase mRNA in diabetic rats

Diabetes, 1990

Amylase activity and mRNA abundance are reduced to < 1 % of normal levels in diabetic rat pancrea... more Amylase activity and mRNA abundance are reduced to < 1 % of normal levels in diabetic rat pancreas. Administration of vanadate in drinking water restored normal amylase activity and amylase mRNA levels. These results demonstrate an effect of vanadate on pancreatic acinar cells and suggest that vanadate can mimic the effect of insulin on transcription of the pancreatic amylase gene. Diabetes 39:757-59,1990 I norganic vanadate has the remarkable property of reproducing several of the biological effects of insulin in cultured cells and intact animals (for review, see refs. 1-3). In diabetic rats, oral administration of vanadate results in normalized blood glucose levels (1,4). The correction of hyperglycemia is accompanied by vanadate-stimulated glucose uptake in muscle and liver (5). In the liver of diabetic rats, vanadate mimics the effect of insulin on levels of glucokinase and fructose-2,6-bisphosphate activity (6,7). Molecular characterization of the insulinlike activities of vanadate is the subject of active investigation in several laboratories. The induction of pancreatic amylase in diabetic rodents is one of the well-characterized responses to insulin (8,9). Amylase transcripts account for 20% of total mRNA in the normal pancreas. When animals are given streptozocin or other diabetogenic agents, the abundance of the amylase mRNA is reduced to < 1 % of normal (10-12). Normal levels of amylase mRNA can be restored by administration of insulin. The response to insulin is dependent on an enhancer element in the 5'-flanking region of the amylase gene (13; unpublished observations). The induction of amylase mRNA

Anti-diabetic effects of vanadium(III, IV, V)–chlorodipicolinate complexes in streptozotocin-induced diabetic rats

BioMetals, 2009

Vanadium(III, IV, V)-chlorodipicolinate (dipic-Cl) complexes, including H[VIII(dipic-Cl)2] · 5H2O... more Vanadium(III, IV, V)-chlorodipicolinate (dipic-Cl) complexes, including H[VIII(dipic-Cl)2] · 5H2O (V3dipic-Cl), VIVO(dipic-Cl)(H2O)2 (V4dipic-Cl) and K[VVO2(dipic-Cl)] (V5dipic-Cl), were prepared with the indicated oxidation states. Our aim was to evaluate the anti-diabetic effects of V3dipic-Cl, V4dipic-Cl and V5dipic-Cl in streptozotocin-induced diabetic rats. Vanadium complexes were orally administered to diabetic rats at concentrations of 0.1-0.3 mg/ml in the drinking water. We found that vanadium-chlorodipicolinate (V-dipic-Cl) complexes at the concentration of 0.1 mg/ml did not exhibit blood glucose-lowering effects when administered to diabetic rats for 20 days. However, the levels of fasting blood glucose in diabetic rats were decreased after treatment with 0.3 mg/ml of V4dipic-Cl and V5dipic-Cl complexes for the following 20 days. Although administration of both V4dipic-Cl and V5dipic-Cl significantly lowered diabetic hyperglycemia, the vanadium intake from administration of V4dipic-Cl is nearly 1.5-fold greater compared to that of V5dipic-Cl. Treatment with the H2dipic-Cl ligand and all three V-dipic-Cl complexes significantly lowered serum cholesterol, while administration of the V5dipic-Cl complex lowered serum cholesterol significantly more than administration of the ligand alone. Treatment with ligand alone did not have an effect on serum triglyceride, while administration of the V4dipic-Cl and V5dipic-Cl significantly lowered the elevated serum triglyceride associated with diabetes. Oral administration of the ligand and all V-dipic-Cl complexes did significantly lower diabetes elevated serum alkaline phosphatase. Treatment with H2dipic-Cl ligand and V4dipic-Cl and V5dipicCl significantly lowered diabetes elevated aspartate amino transferase. These results indicate that the health of the treated animals did not seem to be further compromised compared to that of diabetic animals. In addition, oral administration of H2dipic-Cl, V3dipic-Cl, V4dipic-Cl and V5dipic-Cl did not alter diabetic serum creatinine and blood urea nitrogen levels, suggesting no significant side effects of vanadium treatment on renal functions at the dose of 0.3 mg/ml in diabetic rats. The results presented here suggest that the anti-diabetic effects of treatment with V-dipic-Cl complexes were likely associated in part with the oxidation state of vanadium.

The loss of the phoS periplasmic protein leads to a change in the specificity of a constitutive inorganic phosphate transport system in

Biochemical and Biophysical Research Communications, 1974

ABSTRACT

Utilization of two sample -test statistics from redundant probe sets to evaluate different probe set algorithms in GeneChip studies-5

<b>Copyright information:</b>Taken from "Utilization of two sample -test statist... more <b>Copyright information:</b>Taken from "Utilization of two sample -test statistics from redundant probe sets to evaluate different probe set algorithms in GeneChip studies"BMC Bioinformatics 2006;7():12-12.Published online 10 Jan 2006PMCID:PMC1361777.Copyright © 2006 Hu and Willsky; licensee BioMed Central Ltd.rom different probe set algorithms. The same analysis procedures as in Figure 4 were applied. (a) Comparison of normalization options at the probe set level. (b) Comparison of expression summary options. (c) Comparison of normalization options. (d) Comparison of PM correction options. (e) Comparison of background correction options. (f) Comparison of the selected 10 expression summary datasets to all others.

Aqueous Reactions and NMR Spectroscopy of Hydroxamidovanadate

Vanadium, 2007

Integrating Traditional and Modern Medicine: Perspectives from Ethnobotany, Medical Anthropology, Microbiology, and Pharmacy

Transforming Global Health, 2020

Coordination of Vanadate by Hydrogen Peroxide and Hydroxylamines

Vanadium, 2007

Vanadium Salts in the Treatment of Human Diabetes Mellitus

ACS Symposium Series, 1998

Inorganic Phosphate Transport in Escherichia coli: Involvement of Two Genes Which Play a Role in Alkaline Phosphatase Regulation

Journal of Bacteriology, 1973

Two classes of alkaline phosphatase constitutive mutations which comprise the original phoS locus... more Two classes of alkaline phosphatase constitutive mutations which comprise the original phoS locus (genes phoS and phoT ) on the Escherichia coli genome have been implicated in the regulation of alkaline phosphatase synthesis. When these mutations were introduced into a strain dependent on a single system, the pst system, for inorganic phosphate (P i ) transport, profound changes in P i transport were observed. The phoT mutations led to a complete P i − phenotype in this background, and no activity of the pst system could be detected. The introduction of the phoS mutations changed the specificity of the pst system so that arsenate became growth inhibitory. Changes in the phosphate source led to changes in the levels of constitutive alkaline phosphatase synthesis found in phoS and phoT mutants. When glucose-6-phosphate or l -α-glycerophosphate was supplied as the sole source of phosphate, phoT mutants showed a 3- to 15- fold reduction in constitutive alkaline phosphatase synthesis whe...

Control of the synthesis of alkaline phosphatase and the phosphate-binding protein in Escherichia coli

Journal of Bacteriology, 1976

Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunological techniques, we ... more Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunological techniques, we have compared the synthesis of the phoA protein (alkaline phosphatase) and the phoS protein (phosphate-binding protein) in response to the level of phosphate in the medium in different genetic backgrounds containing the known alkaline phosphatase control mutations. Both proteins are produced in excess phosphate media in a phoR1a- strain, whereas neither protein is produced in a phoB- strain even under derepression conditions. In four different phoR1c- strains, however, the phoA product cannot be detected in extracts of cells obtained from any growth condition, whereas the phoS product is produced in both excess and limiting phosphate media. It is not yet known if phoR1c- mutants are a special class of mutations within the phoB gene or whether they occur in a separate cistron involved in alkaline phosphatase regulation. From these results we conclude that the expression of the phoA gene i...

Alteration of protein synthesis in Saccharomyces cerevisiae caused by transition metals

The effects of transition metals and metal oxides (Co/sup 2 +/, Cu/sup 2 +/, Ni/sup 2 +/, Zn/sup ... more The effects of transition metals and metal oxides (Co/sup 2 +/, Cu/sup 2 +/, Ni/sup 2 +/, Zn/sup 2 +/, arsenite (AsOââ»), arsenate (AsOâ/sup 3 -/) and vanadate (VOâ/sup 3 -/)) on protein synthesis and cellular thermotolerance in Saccharomyces cerevisiae have been examined. Arsenate and vanadate differ in that they are known to be physiologic phosphate analogues, e.g. in yeast,

Utilization of two sample t-test statistics from redundant probe sets to evaluate different probe set algorithms in GeneChip studies

BMC bioinformatics, 2006

The choice of probe set algorithms for expression summary in a GeneChip study has a great impact ... more The choice of probe set algorithms for expression summary in a GeneChip study has a great impact on subsequent gene expression data analysis. Spiked-in cRNAs with known concentration are often used to assess the relative performance of probe set algorithms. Given the fact that the spiked-in cRNAs do not represent endogenously expressed genes in experiments, it becomes increasingly important to have methods to study whether a particular probe set algorithm is more appropriate for a specific dataset, without using such external reference data. We propose the use of the probe set redundancy feature for evaluating the performance of probe set algorithms, and have presented three approaches for analyzing data variance and result bias using two sample t-test statistics from redundant probe sets. These approaches are as follows: 1) analyzing redundant probe set variance based on t-statistic rank order, 2) computing correlation of t-statistics between redundant probe sets, and 3) analyzing ...

Renal drug metabolism

Pharmacological reviews, 1998

### A. History The kidneys have important physiological functions including maintenance of water ... more

Comparing Administration Route in Rats with Streptozocin-Induced Diabetes and Inhibition of Myoblast Growth of Vanadium [V(III), V(IV), and V(V)] Dipicolinic Acid Complexes

ACS Symposium Series, 2007

The V(V) dipicolinic acid complex was the most potent complex in two administration routes for re... more The V(V) dipicolinic acid complex was the most potent complex in two administration routes for reducing diabetic hyperglycemia or hyperlipidemia. After V(V) dipic treatment in both routes an inverse correlation of the blood/serum vanadium pool versus blood/plasma glucose pool was found. This is the first vanadium complex to show such a correlation in any diabetic population. The distribution in blood of V(V) and V (IV) dipic complexes was best modeled with a 2-compartment model after acute administration. Only the V(III) and V(V) dipic complexes stimulated myoblast growth at 1 μM complex, while all complexes inhibited growth at higher concentrations. These experiments show that the oxidation state of the vanadium in dipic complexes affects biological efficacy and that processing of the V(V) dipic complex is different fom that of the lower oxidation states. These results also show that effects of vanadium complexes on rat myoblasts are similar to those observed in diabetic animals administered compounds intraperitoneally.

Vanadium–phosphatase complexes: Phosphatase inhibitors favor the trigonal bipyramidal transition state geometries

Coordination Chemistry Reviews, 2015

Over the past two decades increasing information about the function and structural detail of phos... more Over the past two decades increasing information about the function and structural detail of phosphatases has become available detailing the interaction with vanadate or other vanadium compounds. Considering the importance of the phosphorylation reaction in signal transductions the structural details of the interaction of vanadate or other vanadium species with many phosphatases are used to provide information on the nature of successful inhibitors of these enzymes. Analysis shows that most of the available X-ray structures of vanadium-phosphatase complexes contain vanadium with five coordinating atoms in trigonal bipyramidal coordination geometries even though corresponding small molecule analogue compounds may have square pyramidal geometries. This finding for the static structures in their solid state documents the fact that the variety of phosphatases all stabilize a vanadium geometry that is closer to the trigonal Highlights  Vanadate and vanadium compounds are potent inhibitors of phosphatases.  Five-coordinate vanadium covalently attached to the protein is most common  Vanadium-protein complexes usually have vanadium in a trigonal bipyramidal geometry  The potency of V inhibitors are not likely to change much as the ligand changes

Tetravanadate, Decavanadate, Keggin and Dawson Oxotungstates Inhibit Growth of S. cerevisiae

Nanostructure Science and Technology, 2002

ABSTRACT

Vanadium metabolism in wild type and respiratory-deficient strains ofS. cerevisiae

Yeast, 1986

Vanadium metabolism was studied in a wild type and respiratory-deficient strain of S. cerevisiae.... more Vanadium metabolism was studied in a wild type and respiratory-deficient strain of S. cerevisiae. Inhibition of growth by vanadate [V(+ 5)], vanadate accumulation, and conversion of medium vanadate [V(+ 5)] to both cell-associated and medium vanadyl [V(+4)] and vanadate [V(+5)] were compared. The growth of both the parental and respiratory-deficient strains was inhibited by vanadate at concentrations greater than or equal to 1 mM. Both parental and respiratory-deficient strains accumulated vanadate and converted medium vanadate to cellular vanadyl as detected using electron spin resonance (ESR). The accumulation of cell-associated vanadyl was correlated with the loss of medium vanadate in both strains using a chemical assay. In contrast, the respiratory-deficient strain showed a greater amount of a cell-associated vanadate compound, as detected with vanadium-5 1 nuclear magnetic resonance (5 'V-NMR), than the wild type strain or a representative respiratory-competent vanadate-resistant mutant. These data imply that mitochondria1 function may be directly involved in vanadium metabolism.

Effect of vanadium(IV) compounds in the treatment of diabetes: in vivo and in vitro studies with vanadyl sulfate and bis(maltolato)oxovandium(IV)

Journal of Inorganic Biochemistry, 2001

Vanadyl sulfate (VOSO) was given orally to 16 subjects with type 2 diabetes mellitus for 6 weeks ... more Vanadyl sulfate (VOSO) was given orally to 16 subjects with type 2 diabetes mellitus for 6 weeks at a dose of 25, 50, or 100 mg 4 vanadium (V) daily [Goldfine et al., Metabolism 49 (2000) 1-12]. Elemental V was determined by graphite furnace atomic absorption spectrometry (GFAAS). There was no correlation of V in serum with clinical response, determined by reduction of mean fasting blood glucose or increased insulin sensitivity during euglycemic clamp. To investigate the effect of administering a coordinated V, plasma glucose levels were determined in streptozotocin (STZ)-induced diabetic rats treated with the salt (VOSO) or the coordinated V 4 compound bis(maltolato)oxovandium(IV) (abbreviated as VO(malto)) administered by intraperitoneal (i.p.) injection. There was no 2 relationship of blood V concentration with plasma glucose levels in the animals treated with VOSO , similar to our human diabetic 4 patients. However, with VO(malto) treatment, animals with low plasma glucose tended to have high blood V. To determine if V binding 2 to serum proteins could diminish biologically active serum V, binding of both VOSO and VO(malto) to human serum albumin (HSA), 4 2 human apoTransferrin (apoHTf) and pig immunoglobulin (IgG) was studied with EPR spectroscopy. Both VOSO and VO(malto) bound 4 2 to HSA and apoHTf forming different V-protein complexes, while neither V compound bound to the IgG. VOSO and VO(malto) showed 4 2 differences when levels of plasma glucose and blood V in diabetic rodents were compared, and in the formation of V-protein complexes with abundant serum proteins. These data suggest that binding of V compounds to ligands in blood, such as proteins, may affect the available pool of V for biological effects.

$Fig. 3. Response of type 2 diabetic patients orally dosed with VOSO, for mean fasting blood glucose and euglycemic clamp at two insulin levels. (A) Mean fasting blood glucose. (B) Euglycemic clamp at high insulin concentration. (C) Euglycemic clamp at low insulin concentration. (O) Indicates the five patients who showed an improved response for two of the three variables and is located on each graph for which the response improved for that patient (25V-1, 50V-4, 100V-1, 5 and 7). (+) Indicates the five patients who showed an improved response for all three clinical variables and is located on all three graphs for that patient (SO0V-1 and 5, 100V-2, 6, and 8). The clinical responses in (A-C) were measured as described in Section 2, and are given as fractional responses as described in the text.$

Chloro-substituted dipicolinate vanadium complexes: Synthesis, solution, solid-state, and insulin-enhancing properties

Journal of Inorganic Biochemistry, 2009

Three vanadium complexes of chlorodipicolinic acid (4-chloro-2,6-dipicolinic acid) in oxidation s... more Three vanadium complexes of chlorodipicolinic acid (4-chloro-2,6-dipicolinic acid) in oxidation states III, IV, and V were prepared and their properties characterized across the oxidation states. In addition, the series of hydroxylamido, methylhydroxylamido, dimethylhydroxylamido, and diethylhydroxylamido complexes were prepared from the chlorodipicolinato dioxovanadium(V) complex. The vanadium(V) compounds were characterized in solution by 51 V and 1 H NMR and in the solid-state by X-ray diffraction and 51 V NMR. Density Functional Theory (DFT) calculations were performed to evaluate the experimental parameters and further describes the electronic structure of the complex. The small structural changes that do occur in bond lengths and angles and partial charges on different atoms are minor compared to the charge features that are responsible for the majority of the electric field gradient tensor. The EPR parameters of the vanadium(IV) complex were characterized and compared to the corresponding dipicolinate complex. The chemical properties of the chlorodipicolinate compounds are discussed and correlated with their insulin-enhancing activity in streptozoticin (STZ) induced diabetic Wistar rats. The effect of the chloro-substitution on lowering diabetic hyperglycemia was evaluated and differences were found depending on the compounds oxidation state similar as was observed for the vanadium III, IV and V dipicolinate complexes (P.

Effects of vanadium (III, IV, V)-chlorodipicolinate on glycolysis and antioxidant status in the liver of STZ-induced diabetic rats

Journal of Inorganic Biochemistry, 2014

Vanadium compounds exert various insulin-mimetic and anti-diabetic effects both in vitro and in v... more Vanadium compounds exert various insulin-mimetic and anti-diabetic effects both in vitro and in vivo. Vanadium(III, IV, V)-chlorodipicolinate (Vdipic-Cl) compounds, including H[V III (dipic-Cl) 2 ] • 5H 2 O (V 3 dipic-Cl), V IV O(dipic-Cl)(H 2 O) 2 (V 4 dipic-Cl) and K[V V O 2 (dipic-Cl)] (V 5 dipic-Cl), were synthesized with the indicated oxidation states. The present study was conducted to investigate if chemical valence and anti-oxidation effects of vanadium compounds are involved in the anti-diabetic effects observed in streptozotocin (STZ)-induced diabetic rats treated with these vanadium compounds. V 3 dipic-Cl, V 4 dipic-Cl, V 5 dipic-Cl, inorganic vanadium salts vanadyl sulfate (VOSO 4) or sodium metavanadate (NaVO 3) were orally administered in drinking water (50 μgV/ml) to STZ-induced diabetic rats for 28 days. The results showed that Vdipic-Cl treatment significantly improved hyperglycemia and glucose intolerance, as well as increased hepatic glycogen synthesis in diabetic rats. The mRNA levels of key glycolytic enzymes in liver, phosphoenolpyruvate carboxykinase (PEPCK), glucokinase (GK), and L-pyruvate kinase (L-PK) altered in diabetic animals were significantly restored towards normal values by treatment with some of the vanadium compounds. Moreover, the diabetes elevated activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in serum were significantly decreased after treatment with Vdipic-Cl complexes. Furthermore, treatment of diabetic rats with V 4 dipic-Cl and V 5 dipic-Cl compounds significantly reduced malondialdehyde (MDA) production and increased glutathione peroxidase (GSH-Px) and catalase (CAT) activities. These data suggest that vanadium compounds with the indicated chemical valence promote glycogen synthesis and recover suppressed glycolysis in the liver of diabetic rats due to their capacity to reduce oxidative stress by stimulating antioxidant enzymes.

Vanadate induction of pancreatic amylase mRNA in diabetic rats

Diabetes, 1990

Amylase activity and mRNA abundance are reduced to < 1 % of normal levels in diabetic rat pancrea... more Amylase activity and mRNA abundance are reduced to < 1 % of normal levels in diabetic rat pancreas. Administration of vanadate in drinking water restored normal amylase activity and amylase mRNA levels. These results demonstrate an effect of vanadate on pancreatic acinar cells and suggest that vanadate can mimic the effect of insulin on transcription of the pancreatic amylase gene. Diabetes 39:757-59,1990 I norganic vanadate has the remarkable property of reproducing several of the biological effects of insulin in cultured cells and intact animals (for review, see refs. 1-3). In diabetic rats, oral administration of vanadate results in normalized blood glucose levels (1,4). The correction of hyperglycemia is accompanied by vanadate-stimulated glucose uptake in muscle and liver (5). In the liver of diabetic rats, vanadate mimics the effect of insulin on levels of glucokinase and fructose-2,6-bisphosphate activity (6,7). Molecular characterization of the insulinlike activities of vanadate is the subject of active investigation in several laboratories. The induction of pancreatic amylase in diabetic rodents is one of the well-characterized responses to insulin (8,9). Amylase transcripts account for 20% of total mRNA in the normal pancreas. When animals are given streptozocin or other diabetogenic agents, the abundance of the amylase mRNA is reduced to < 1 % of normal (10-12). Normal levels of amylase mRNA can be restored by administration of insulin. The response to insulin is dependent on an enhancer element in the 5'-flanking region of the amylase gene (13; unpublished observations). The induction of amylase mRNA

Anti-diabetic effects of vanadium(III, IV, V)–chlorodipicolinate complexes in streptozotocin-induced diabetic rats

BioMetals, 2009

Vanadium(III, IV, V)-chlorodipicolinate (dipic-Cl) complexes, including H[VIII(dipic-Cl)2] · 5H2O... more Vanadium(III, IV, V)-chlorodipicolinate (dipic-Cl) complexes, including H[VIII(dipic-Cl)2] · 5H2O (V3dipic-Cl), VIVO(dipic-Cl)(H2O)2 (V4dipic-Cl) and K[VVO2(dipic-Cl)] (V5dipic-Cl), were prepared with the indicated oxidation states. Our aim was to evaluate the anti-diabetic effects of V3dipic-Cl, V4dipic-Cl and V5dipic-Cl in streptozotocin-induced diabetic rats. Vanadium complexes were orally administered to diabetic rats at concentrations of 0.1-0.3 mg/ml in the drinking water. We found that vanadium-chlorodipicolinate (V-dipic-Cl) complexes at the concentration of 0.1 mg/ml did not exhibit blood glucose-lowering effects when administered to diabetic rats for 20 days. However, the levels of fasting blood glucose in diabetic rats were decreased after treatment with 0.3 mg/ml of V4dipic-Cl and V5dipic-Cl complexes for the following 20 days. Although administration of both V4dipic-Cl and V5dipic-Cl significantly lowered diabetic hyperglycemia, the vanadium intake from administration of V4dipic-Cl is nearly 1.5-fold greater compared to that of V5dipic-Cl. Treatment with the H2dipic-Cl ligand and all three V-dipic-Cl complexes significantly lowered serum cholesterol, while administration of the V5dipic-Cl complex lowered serum cholesterol significantly more than administration of the ligand alone. Treatment with ligand alone did not have an effect on serum triglyceride, while administration of the V4dipic-Cl and V5dipic-Cl significantly lowered the elevated serum triglyceride associated with diabetes. Oral administration of the ligand and all V-dipic-Cl complexes did significantly lower diabetes elevated serum alkaline phosphatase. Treatment with H2dipic-Cl ligand and V4dipic-Cl and V5dipicCl significantly lowered diabetes elevated aspartate amino transferase. These results indicate that the health of the treated animals did not seem to be further compromised compared to that of diabetic animals. In addition, oral administration of H2dipic-Cl, V3dipic-Cl, V4dipic-Cl and V5dipic-Cl did not alter diabetic serum creatinine and blood urea nitrogen levels, suggesting no significant side effects of vanadium treatment on renal functions at the dose of 0.3 mg/ml in diabetic rats. The results presented here suggest that the anti-diabetic effects of treatment with V-dipic-Cl complexes were likely associated in part with the oxidation state of vanadium.

The loss of the phoS periplasmic protein leads to a change in the specificity of a constitutive inorganic phosphate transport system in

Biochemical and Biophysical Research Communications, 1974

ABSTRACT