Estrogen has been found to exacerbate disease activity in murine lupus and to induce a lupus-like... more Estrogen has been found to exacerbate disease activity in murine lupus and to induce a lupus-like syndrome in nonspontaneously autoimmune mice. This has led to the consideration that estrogen may be a risk factor for the development of systemic lupus erythematosus (SLE), and selective estrogen receptor modulators (SERM) may serve to ameliorate lupus activity. We evaluated the effects and mechanism of action of the SERM raloxifene in murine lupus. Effects of raloxifene on the development of lupus in NZB/W F1 mice were evaluated in the presence and absence of estrogen by assessing the serum DNA reactivity, glomerular IgG deposition and kidney damage, B cell maturation and selection, and activation status of marginal zone and follicular B cells. Compared to estradiol-treated mice, mice treated with estradiol and raloxifene had significantly lower serum anti-DNA antibody levels and less kidney damage. These effects of raloxifene were due, at least in part, to antagonism of the influence of estrogen on DNA-reactive B cells. Raloxifene was found to prevent estrogen-mediated suppression of autoreactive B cell elimination at the T1/T2 selection checkpoint, to reduce estrogen-induced CD40 overexpression on follicular B cells, making them less responsive to T cell costimulation, and to ameliorate estrogen-mediated CD22 downregulation on marginal zone B cells, thereby decreasing their responsiveness to B cell antigen receptor-mediated stimuli. Raloxifene suppressed estrogen-mediated effects on the survival, maturation, and activation of autoreactive B cells in NZB/W F1 mice.
A nonaqueous reverse-phase liquid chromatographic (LC) method has been developed to determine ele... more A nonaqueous reverse-phase liquid chromatographic (LC) method has been developed to determine elemental sulfur in pesticide formulations. Samples were extracted in 50 mL of stabilized tetrahydrofuran (THF) by gentle swirling while sonicating for 1 min. A 5 microL aliquot was injected into the LC instrument equipped with a Vydac 218 TP 54 column. The mobile phase was methanol-acetonitrile-stabilized tetrahydrofuran (58.5 + 40 + 1.5). Sulfur was monitored at 280 nm. Retention time was approximately 5 min with total analysis time of 7 min. For 6 different products analyzed 12 times each, the coefficients of variations were all less than 3.5%. Purity of each sulfur peak was checked by using a photodiode array detector in the spectrum and absorbance ratio modes. No impurities were observed at the monitoring wavelength.
Cis-acting type I elements regulate the initiation of DNA replication, replication fork movement,... more Cis-acting type I elements regulate the initiation of DNA replication, replication fork movement, and transcription of the Tetrahymena thermophila rDNA minichromosome and are required for cell cycle-controlled replication and developmentally programmed gene amplification. Previous studies identified three in vitro single-stranded type I element binding activities that were proposed to play distinct roles in replication control. Here we describe the cloning of one of these genes, TIF1, and we provide evidence for its association with type I elements in vivo. Furthermore, we show that TIF1 interacts (in vitro and in vivo) with pause site elements (PSE), which co-localize with replication initiation and fork arrest sites, and are shown to be essential. The in vivo accessibility of PSE and type I elements to potassium permanganate suggests that origin regions are frequently unwound in native chromatin. TIF1 contains sequence similarity to the Solanum tuberosum single strand-specific transcription factor, p24, and a related Arabidopsis protein. Antisense inhibition studies suggest that TIF1 competes with other proteins for PSE and type I element binding. TIF1 displays a marked strand bias in vivo, discriminating between origin- and promoter-proximal type I elements. We propose that this bias selectively modulates the binding of a different subset of proteins to the respective regulatory elements.
How genetic and environmental factors interact in Parkinson disease is poorly understood. We have... more How genetic and environmental factors interact in Parkinson disease is poorly understood. We have now compared the patterns of vulnerability and rescue of Caenorhabditis elegans with genetic modifications of three different genetic factors implicated in Parkinson disease (PD). We observed that expressing alpha-synuclein, deleting parkin (K08E3.7), or knocking down DJ-1 (B0432.2) or parkin produces similar patterns of pharmacological vulnerability and rescue. C. elegans lines with these genetic changes were more vulnerable than nontransgenic nematodes to mitochondrial complex I inhibitors, including rotenone, fenperoximate, pyridaben, or stigmatellin. In contrast, the genetic manipulations did not increase sensitivity to paraquat, sodium azide, divalent metal ions (Fe(II) or Cu(II)), or etoposide compared with the nontransgenic nematodes. Each of the PD-related lines was also partially rescued by the antioxidant probucol, the mitochondrial complex II activator, D-beta-hydroxybutyrate, or the anti-apoptotic bile acid tauroursodeoxycholic acid. Complete protection in all lines was achieved by combining d-beta-hydroxybutyrate with tauroursodeoxycholic acid but not with probucol. These results show that diverse PD-related genetic modifications disrupt the mitochondrial function in C. elegans, and they raise the possibility that mitochondrial disruption is a pathway shared in common by many types of familial PD.
Caloric restriction (CR) markedly extends life span and improves the health of a broad number of ... more Caloric restriction (CR) markedly extends life span and improves the health of a broad number of species. Energy metabolism fundamentally contributes to the beneficial effects of CR, but the underlying mechanisms that are responsible for this effect remain enigmatic. A multidisciplinary approach that involves quantitative proteomics, immunochemistry, metabolic quantification, and life span analysis was used to determine how CR, which occurs in the Caenorhabditis elegans eat-2 mutants, modifies energy metabolism of the worm, and whether the observed modifications contribute to the CR-mediated physiological responses. A switch to fatty acid metabolism as an energy source and an enhanced rate of energy metabolism by eat-2 mutant nematodes were detected. Life span analyses validated the important role of these previously unknown alterations of energy metabolism in the CR-mediated longevity of nematodes. As observed in mice, the overexpression of the gene for the nematode analog of the cytosolic form of phosphoenolpyruvate carboxykinase caused a marked extension of the life span in C. elegans, presumably by enhancing energy metabolism via an altered rate of cataplerosis of tricarboxylic acid cycle anions. We conclude that an increase, not a decrease in fuel consumption, via an accelerated oxidation of fuels in the TCA cycle is involved in life span regulation; this mechanism may be conserved across phylogeny.
Pneumonia is the leading cause of mortality in young children globally, and factors that affect t... more Pneumonia is the leading cause of mortality in young children globally, and factors that affect tissue delivery of oxygen may affect outcomes of pneumonia. We studied whether altitude and anemia influence disease severity and outcomes in young children with World Health Organization-defined severe pneumonia. We analyzed data from the SPEAR (Severe Pneumonia Evaluation Antimicrobial Research) study, a World Health Organization- and USAID-sponsored multinational randomized controlled trial of antibiotics for severe pneumonia among children aged 2 to 59 months in resource-poor settings. The trial enrolled 958 children in 8 sites at varying elevations, classified as high (≥ 2000 m) or low (<2000 m) altitude. We compared illness severity and assessed the effect of anemia on treatment outcome at high and low altitudes, adjusting for potential confounders and study site. Children at high altitudes had significantly lower oxygen saturation on presentation, more cyanosis, lower systolic blood pressure, and higher hemoglobin. After adjusting for potential confounders, anemia predicted treatment failure in children living at high altitude (relative risk: 4.07; 95% confidence interval: 2.60-6.38) but not at low altitude (relative risk: 1.12; 95% confidence interval: 0.96-1.30). Children at high altitude took longer to reach normoxemia than did children at lower altitudes (5.25 vs 0.75 days; P < .0001). Children at high altitude present with more severe disease, and children with anemia at high altitude are at greater risk of poor outcome when being treated for severe pneumonia. Given the high global prevalence of anemia among young children, prevention and treatment of anemia should be a priority in children living at high altitude and could improve outcomes of pneumonia.
The objective of this study was to explore the possibility of a recurrent increase in the ovulati... more The objective of this study was to explore the possibility of a recurrent increase in the ovulation rate of Malpura sheep, a non-prolific breed, by immunization against inhibin-based peptide immunogens over a period of 3 years. Adult ewes (4–7 years of age) and weighing between 28 and 38kg were randomly allocated equally to three treatment groups. The immunization of the
Ultrathin (< 10 nm) zirconium oxide (ZrO2) films have been deposited at low temperature (150° ... more Ultrathin (< 10 nm) zirconium oxide (ZrO2) films have been deposited at low temperature (150° C) on strained-Si on relaxed-Si0. 8Ge0. 2 substrates by microwave plasma enhanced chemical vapor deposition (PECVD). Interfacial and electrical properties of Al/ZrO2/strained-Si MOS capacitors have been characterized using capacitance–voltage (C–V) and conductance–voltage (G–V) techniques. It is observed that Dit ranges from 4.93× 1012 eV− 1 cm− 2 in (EC− 0.35) eV to 1.86× 1012 eV− 1 cm− 2 in (EC− 0.82) eV and decays slowly ...
Numerical Heat Transfer, Part A: Applications, 2011
The physical model considered here is a lid-driven enclosure with bottom heating and top cooling ... more The physical model considered here is a lid-driven enclosure with bottom heating and top cooling conditions, and a heat generating circular body is placed at the center. The vertical walls of the cavity are kept thermally insulated, and the top lid moves at a constant speed. The steady two-dimensional governing equations for the physical problem are transformed in a dimensionless
In search of a new Prussian Blue analogue exhibiting fascinating magnetic properties, potassium m... more In search of a new Prussian Blue analogue exhibiting fascinating magnetic properties, potassium manganese hexacyanoferrate, K0.2Mn0.66IIMn1.44III[Fe0.2IIFe0.8III(CN)6]O0.66(CH3COO)1.32], 7.6H2O, has been synthesized. This compound undergoes a paramagnetic to ferrimagnetic transition at 10K. Temperature and magnetic field-dependent magnetization studies of this compound have revealed different spin alignments below and above 3K. The nature of possible magnetic interactions between the nearest neighbor magnetic centers has been discussed in order to explore the origin of the observed magnetic interactions. Mössbauer spectroscopic study at different temperatures demonstrates the presence of both FeIII and FeII in low-spin states in this compound. Quantitative analysis of the FeIII and FeII ions, and their temperature dependence exhibits the existence of an electron transfer phenomenon between Mn and Fe ions [FeIII (t2g5, S=1/2)–CN–MnII (t2g3eg2, S=5/2)]⇔[FeII (t2g6, S=0)–CN–MnIII (t2g3eg1, S=2)]. This electron transfer has been remarkably enhanced in the magnetically ordered region.
The majority of twist drills used in orthopaedics are very similar to chisel pointed metal drilli... more The majority of twist drills used in orthopaedics are very similar to chisel pointed metal drilling bits. Modifications usually observed are reduction of the point angle to 90 deg and sometimes grinding of the entire cutting lip at 0 deg rake angle, which appeared to have been made arbitrarily without any advantage. We have attempted to design a surgical drill bit with the objective of minimization of the drilling thrust and temperature and effective removal of bone chips. Our results showed that the presence of the chisel edge was mainly responsible for increasing the thrust force and the temperature developed. The effects of a constant feed rate and thrust on the peak temperature were also examined. The combined effect of the helix and the point angles on the rake angle which in turn determines the cutting efficiency was analyzed for various types of surgical bits. Based on our results and previously published data from the literature an optimized drill bit was designed with a split point, a point angle of 118 deg, a parabolic flute, and a helix angle of 36 deg and its performance was compared with other existing surgical drill bits. For drilling in compact bone, the new design decreased the thrust load by 45 percent an the peak temperature rise by 41 percent. Similar improvements were also recorded for drilling bone cement. The time of drilling a bone cortex was also significantly reduced and &quot;walking&quot; on the curved bone surface was eliminated and dimensional tolerance on hole sizes was improved. The new design is likely to reduce the time of surgery and also minimize the tissue damage.
Estrogen has been found to exacerbate disease activity in murine lupus and to induce a lupus-like... more Estrogen has been found to exacerbate disease activity in murine lupus and to induce a lupus-like syndrome in nonspontaneously autoimmune mice. This has led to the consideration that estrogen may be a risk factor for the development of systemic lupus erythematosus (SLE), and selective estrogen receptor modulators (SERM) may serve to ameliorate lupus activity. We evaluated the effects and mechanism of action of the SERM raloxifene in murine lupus. Effects of raloxifene on the development of lupus in NZB/W F1 mice were evaluated in the presence and absence of estrogen by assessing the serum DNA reactivity, glomerular IgG deposition and kidney damage, B cell maturation and selection, and activation status of marginal zone and follicular B cells. Compared to estradiol-treated mice, mice treated with estradiol and raloxifene had significantly lower serum anti-DNA antibody levels and less kidney damage. These effects of raloxifene were due, at least in part, to antagonism of the influence of estrogen on DNA-reactive B cells. Raloxifene was found to prevent estrogen-mediated suppression of autoreactive B cell elimination at the T1/T2 selection checkpoint, to reduce estrogen-induced CD40 overexpression on follicular B cells, making them less responsive to T cell costimulation, and to ameliorate estrogen-mediated CD22 downregulation on marginal zone B cells, thereby decreasing their responsiveness to B cell antigen receptor-mediated stimuli. Raloxifene suppressed estrogen-mediated effects on the survival, maturation, and activation of autoreactive B cells in NZB/W F1 mice.
A nonaqueous reverse-phase liquid chromatographic (LC) method has been developed to determine ele... more A nonaqueous reverse-phase liquid chromatographic (LC) method has been developed to determine elemental sulfur in pesticide formulations. Samples were extracted in 50 mL of stabilized tetrahydrofuran (THF) by gentle swirling while sonicating for 1 min. A 5 microL aliquot was injected into the LC instrument equipped with a Vydac 218 TP 54 column. The mobile phase was methanol-acetonitrile-stabilized tetrahydrofuran (58.5 + 40 + 1.5). Sulfur was monitored at 280 nm. Retention time was approximately 5 min with total analysis time of 7 min. For 6 different products analyzed 12 times each, the coefficients of variations were all less than 3.5%. Purity of each sulfur peak was checked by using a photodiode array detector in the spectrum and absorbance ratio modes. No impurities were observed at the monitoring wavelength.
Cis-acting type I elements regulate the initiation of DNA replication, replication fork movement,... more Cis-acting type I elements regulate the initiation of DNA replication, replication fork movement, and transcription of the Tetrahymena thermophila rDNA minichromosome and are required for cell cycle-controlled replication and developmentally programmed gene amplification. Previous studies identified three in vitro single-stranded type I element binding activities that were proposed to play distinct roles in replication control. Here we describe the cloning of one of these genes, TIF1, and we provide evidence for its association with type I elements in vivo. Furthermore, we show that TIF1 interacts (in vitro and in vivo) with pause site elements (PSE), which co-localize with replication initiation and fork arrest sites, and are shown to be essential. The in vivo accessibility of PSE and type I elements to potassium permanganate suggests that origin regions are frequently unwound in native chromatin. TIF1 contains sequence similarity to the Solanum tuberosum single strand-specific transcription factor, p24, and a related Arabidopsis protein. Antisense inhibition studies suggest that TIF1 competes with other proteins for PSE and type I element binding. TIF1 displays a marked strand bias in vivo, discriminating between origin- and promoter-proximal type I elements. We propose that this bias selectively modulates the binding of a different subset of proteins to the respective regulatory elements.
How genetic and environmental factors interact in Parkinson disease is poorly understood. We have... more How genetic and environmental factors interact in Parkinson disease is poorly understood. We have now compared the patterns of vulnerability and rescue of Caenorhabditis elegans with genetic modifications of three different genetic factors implicated in Parkinson disease (PD). We observed that expressing alpha-synuclein, deleting parkin (K08E3.7), or knocking down DJ-1 (B0432.2) or parkin produces similar patterns of pharmacological vulnerability and rescue. C. elegans lines with these genetic changes were more vulnerable than nontransgenic nematodes to mitochondrial complex I inhibitors, including rotenone, fenperoximate, pyridaben, or stigmatellin. In contrast, the genetic manipulations did not increase sensitivity to paraquat, sodium azide, divalent metal ions (Fe(II) or Cu(II)), or etoposide compared with the nontransgenic nematodes. Each of the PD-related lines was also partially rescued by the antioxidant probucol, the mitochondrial complex II activator, D-beta-hydroxybutyrate, or the anti-apoptotic bile acid tauroursodeoxycholic acid. Complete protection in all lines was achieved by combining d-beta-hydroxybutyrate with tauroursodeoxycholic acid but not with probucol. These results show that diverse PD-related genetic modifications disrupt the mitochondrial function in C. elegans, and they raise the possibility that mitochondrial disruption is a pathway shared in common by many types of familial PD.
Caloric restriction (CR) markedly extends life span and improves the health of a broad number of ... more Caloric restriction (CR) markedly extends life span and improves the health of a broad number of species. Energy metabolism fundamentally contributes to the beneficial effects of CR, but the underlying mechanisms that are responsible for this effect remain enigmatic. A multidisciplinary approach that involves quantitative proteomics, immunochemistry, metabolic quantification, and life span analysis was used to determine how CR, which occurs in the Caenorhabditis elegans eat-2 mutants, modifies energy metabolism of the worm, and whether the observed modifications contribute to the CR-mediated physiological responses. A switch to fatty acid metabolism as an energy source and an enhanced rate of energy metabolism by eat-2 mutant nematodes were detected. Life span analyses validated the important role of these previously unknown alterations of energy metabolism in the CR-mediated longevity of nematodes. As observed in mice, the overexpression of the gene for the nematode analog of the cytosolic form of phosphoenolpyruvate carboxykinase caused a marked extension of the life span in C. elegans, presumably by enhancing energy metabolism via an altered rate of cataplerosis of tricarboxylic acid cycle anions. We conclude that an increase, not a decrease in fuel consumption, via an accelerated oxidation of fuels in the TCA cycle is involved in life span regulation; this mechanism may be conserved across phylogeny.
Pneumonia is the leading cause of mortality in young children globally, and factors that affect t... more Pneumonia is the leading cause of mortality in young children globally, and factors that affect tissue delivery of oxygen may affect outcomes of pneumonia. We studied whether altitude and anemia influence disease severity and outcomes in young children with World Health Organization-defined severe pneumonia. We analyzed data from the SPEAR (Severe Pneumonia Evaluation Antimicrobial Research) study, a World Health Organization- and USAID-sponsored multinational randomized controlled trial of antibiotics for severe pneumonia among children aged 2 to 59 months in resource-poor settings. The trial enrolled 958 children in 8 sites at varying elevations, classified as high (≥ 2000 m) or low (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;2000 m) altitude. We compared illness severity and assessed the effect of anemia on treatment outcome at high and low altitudes, adjusting for potential confounders and study site. Children at high altitudes had significantly lower oxygen saturation on presentation, more cyanosis, lower systolic blood pressure, and higher hemoglobin. After adjusting for potential confounders, anemia predicted treatment failure in children living at high altitude (relative risk: 4.07; 95% confidence interval: 2.60-6.38) but not at low altitude (relative risk: 1.12; 95% confidence interval: 0.96-1.30). Children at high altitude took longer to reach normoxemia than did children at lower altitudes (5.25 vs 0.75 days; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .0001). Children at high altitude present with more severe disease, and children with anemia at high altitude are at greater risk of poor outcome when being treated for severe pneumonia. Given the high global prevalence of anemia among young children, prevention and treatment of anemia should be a priority in children living at high altitude and could improve outcomes of pneumonia.
The objective of this study was to explore the possibility of a recurrent increase in the ovulati... more The objective of this study was to explore the possibility of a recurrent increase in the ovulation rate of Malpura sheep, a non-prolific breed, by immunization against inhibin-based peptide immunogens over a period of 3 years. Adult ewes (4–7 years of age) and weighing between 28 and 38kg were randomly allocated equally to three treatment groups. The immunization of the
Ultrathin (< 10 nm) zirconium oxide (ZrO2) films have been deposited at low temperature (150° ... more Ultrathin (< 10 nm) zirconium oxide (ZrO2) films have been deposited at low temperature (150° C) on strained-Si on relaxed-Si0. 8Ge0. 2 substrates by microwave plasma enhanced chemical vapor deposition (PECVD). Interfacial and electrical properties of Al/ZrO2/strained-Si MOS capacitors have been characterized using capacitance–voltage (C–V) and conductance–voltage (G–V) techniques. It is observed that Dit ranges from 4.93× 1012 eV− 1 cm− 2 in (EC− 0.35) eV to 1.86× 1012 eV− 1 cm− 2 in (EC− 0.82) eV and decays slowly ...
Numerical Heat Transfer, Part A: Applications, 2011
The physical model considered here is a lid-driven enclosure with bottom heating and top cooling ... more The physical model considered here is a lid-driven enclosure with bottom heating and top cooling conditions, and a heat generating circular body is placed at the center. The vertical walls of the cavity are kept thermally insulated, and the top lid moves at a constant speed. The steady two-dimensional governing equations for the physical problem are transformed in a dimensionless
In search of a new Prussian Blue analogue exhibiting fascinating magnetic properties, potassium m... more In search of a new Prussian Blue analogue exhibiting fascinating magnetic properties, potassium manganese hexacyanoferrate, K0.2Mn0.66IIMn1.44III[Fe0.2IIFe0.8III(CN)6]O0.66(CH3COO)1.32], 7.6H2O, has been synthesized. This compound undergoes a paramagnetic to ferrimagnetic transition at 10K. Temperature and magnetic field-dependent magnetization studies of this compound have revealed different spin alignments below and above 3K. The nature of possible magnetic interactions between the nearest neighbor magnetic centers has been discussed in order to explore the origin of the observed magnetic interactions. Mössbauer spectroscopic study at different temperatures demonstrates the presence of both FeIII and FeII in low-spin states in this compound. Quantitative analysis of the FeIII and FeII ions, and their temperature dependence exhibits the existence of an electron transfer phenomenon between Mn and Fe ions [FeIII (t2g5, S=1/2)–CN–MnII (t2g3eg2, S=5/2)]⇔[FeII (t2g6, S=0)–CN–MnIII (t2g3eg1, S=2)]. This electron transfer has been remarkably enhanced in the magnetically ordered region.
The majority of twist drills used in orthopaedics are very similar to chisel pointed metal drilli... more The majority of twist drills used in orthopaedics are very similar to chisel pointed metal drilling bits. Modifications usually observed are reduction of the point angle to 90 deg and sometimes grinding of the entire cutting lip at 0 deg rake angle, which appeared to have been made arbitrarily without any advantage. We have attempted to design a surgical drill bit with the objective of minimization of the drilling thrust and temperature and effective removal of bone chips. Our results showed that the presence of the chisel edge was mainly responsible for increasing the thrust force and the temperature developed. The effects of a constant feed rate and thrust on the peak temperature were also examined. The combined effect of the helix and the point angles on the rake angle which in turn determines the cutting efficiency was analyzed for various types of surgical bits. Based on our results and previously published data from the literature an optimized drill bit was designed with a split point, a point angle of 118 deg, a parabolic flute, and a helix angle of 36 deg and its performance was compared with other existing surgical drill bits. For drilling in compact bone, the new design decreased the thrust load by 45 percent an the peak temperature rise by 41 percent. Similar improvements were also recorded for drilling bone cement. The time of drilling a bone cortex was also significantly reduced and &quot;walking&quot; on the curved bone surface was eliminated and dimensional tolerance on hole sizes was improved. The new design is likely to reduce the time of surgery and also minimize the tissue damage.
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