Change in plasma acylation stimulating protein during euglycaemic-hyperinsulinaemic clamp in overweight and obese postmenopausal women: a MONET study.

PubMed

St-Pierre, David H; Cianflone, Katherine; Smith, Jessica; Coderre, Lise; Karelis, Antony D; Imbeault, Pascal; Lavoie, Jean-Marc; Rabasa-Lhoret, Rémi

2009-04-01

Acylation-stimulating protein (ASP) has been shown to positively stimulate fatty acid esterification and glucose uptake in adipocytes. In vitro studies demonstrate that insulin stimulates ASP secretion from adipocytes. Individuals with obesity and/or metabolic disturbances (insulin resistance and type 2 diabetes) have increased plasma ASP. The present study was designed to evaluate whether ASP levels are influenced by the metabolic profiles of overweight and obese postmenopausal women during a euglycaemic/hyperinsulinaemic clamp (EHC). Patients The study population consisted of 76 overweight and obese sedentary postmenopausal women. We evaluated insulin sensitivity, plasma ASP levels, body composition including visceral adipose tissue area, blood lipid profiles, liver enzymes, peak aerobic capacity, resting metabolic rate (RMR) and total energy expenditure (TEE). We observed wide interindividual variations of ASP levels during the EHC. Therefore, subjects were divided into three groups based on ASP changes. Negative ASP Responders (NAR; n = 24) showed a -20% or greater decrease in ASP levels while Positive ASP Responders (PAR; n = 42) displayed ASP fluctuations superior to +20%. Ten subjects had little or no ASP change and were considered as Zero ASP responders (ZAR). PAR women displayed a worse metabolic profile than NAR women, including higher BMI, visceral adipose tissue, fasting insulin levels, lean body mass, and alanine aminotransferase (ALT), a marker of impaired liver function. After adjustment for BMI, only ALT remained significantly different, while lean body mass (P = 0.08) and visceral adipose tissue (P = 0.07) remained marginally higher. Correlation analysis of all subjects demonstrated that fasting ASP levels correlated positively with albumin and VO(2 peak) and this association remained significant after adjustments for the effect of BMI. In addition, the percentage maximal change in ASP levels during the EHC was positively associated with BMI, lean body mass, visceral adipose tissue, fasting insulin, HOMA, TEE, RMR, ALT and AST. Overall these results suggest that an elevated ASP response during the EHC is associated with metabolic disturbances in overweight and obese postmenopausal women.

eNOS Glu298Asp polymorphism and hypertension in a cohort study in Japanese.

PubMed

Kishimoto, Takuji; Misawa, Yumiko; Kaetu, Akihiko; Nagai, Maria; Osaki, Yoneatsu; Okamoto, Mikizoh; Yoshida, Soiti; Kurosawa, Yoichi; Fukumoto, Soji

2004-11-01

Some recent case-control association studies have suggested negative and positive relationship between Glu298Asp (the substitution of aspartic acid for glutamic acid at amino acid position 298) polymorphism of the endothelial nitric oxide synthase (eNOS) gene and hypertension. To investigate whether the Glu298Asp polymorphism of the eNOS gene affects the incidence of hypertension, a retrospective cohort study was performed. The baseline data among Japanese workers in Shimane Prefecture, Japan, were obtained at regular health examination in 1992, and a retrospective cohort study was performed to analyze the influence of Glu298Asp polymorphism on the incidence of hypertension in 1998. The incidences of Glu298Glu, Glu298Asp, and Asp298Asp genotypes in the subjects were 86.4%, 12.6% and 1.1%, respectively. The risk ratios of Glu298Asp and Asp298Asp against Glu298Glu for the incidence of hypertension by single variance analysis were 0.830 in total subjects [95% confidence interval (CI) 0.474-1.452], 0.596 in subjects 20-39 years old (95% CI; 0.207-1.717), and 0.915 in subjects 40-59 years old (95% CI; 0.464-1.805). The risk ratios of Glu298Asp and Asp298Asp against Glu298Glu for the incidence of hypertension by multiple variance analysis adjusted for sex, BMI, serum total cholesterol, serum high-density lipoprotein (HDL) cholesterol, fasting glucose, cigarette smoking, drinking habits, eating habits, and exercise in 1992 were 0.750 in total subjects (95% CI; 0.421-1.335), 0.505 in subjects 20-39 years old (95% CI; 0.170-1.496), and 0.873 in subjects 40-59 years old (95% CI; 0.434-1.757). These results suggested no association between the Glu298Asp gene polymorphism and the incidence of hypertension in this selected population.

The effects of acylation stimulating protein supplementation VS antibody neutralization on energy expenditure in wildtype mice.

PubMed

Paglialunga, Sabina; Fisette, Alexandre; Munkonda, Mercedes; Gao, Ying; Richard, Denis; Cianflone, Katherine

2010-04-23

Acylation stimulating protein (ASP) is an adipogenic hormone that stimulates triglyceride (TG) synthesis and glucose transport in adipocytes. Previous studies have shown that ASP-deficient C3 knockout mice are hyperphagic yet lean, as they display increased oxygen consumption and fatty acid oxidation compared to wildtype mice. In the present study, antibodies against ASP (Anti-ASP) and human recombinant ASP (rASP) were tested in vitro and in vivo. Continuous administration for 4 weeks via osmotic mini-pump of Anti-ASP or rASP was evaluated in wildtype mice on a high-fat diet (HFD) to examine their effects on body weight, food intake and energy expenditure. In mature murine adipocytes, rASP significantly stimulated fatty acid uptake (+243% vs PBS, P < 0.05) while Anti-ASP neutralized the rASP response. Mice treated with Anti-ASP showed elevated energy expenditure (P < 0.0001), increased skeletal muscle glucose oxidation (+141%, P < 0.001), reduced liver glycogen (-34%, P < 0.05) and glucose-6-phosphate content (-64%, P = 0.08) compared to control mice. There was no change in body weight, food intake, fasting insulin, adiponectin, CRP or TG levels compared to controls. Interestingly, HFD mice treated with rASP showed the opposite phenotype with reduced energy expenditure (P < 0.0001) and increased body weight (P < 0.05), cumulative food intake (P < 0.0001) and liver glycogen content (+59%, P < 0.05). Again, there was no change in circulating insulin, adiponectin, CRP or TG levels, however, plasma free fatty acids were reduced (-48%, P < 0.05). In vitro, Anti-ASP effectively neutralized ASP stimulated fatty acid uptake. In vivo, Anti-ASP treatment increased whole body energy utilization while rASP increased energy storage. Therefore, ASP is a potent anabolic hormone that may also be a mediator of energy expenditure.

Aversive Startle Potentiation and Fear Pathology: Mediating Role of Threat Sensitivity and Moderating Impact of Depression

PubMed Central

Yancey, James R.; Vaidyanathan, Uma; Patrick, Christopher J.

2015-01-01

Enhanced startle during exposure to unpleasant cues (aversive startle potentiation; ASP) appears in the RDoC matrix as a physiological index of acute threat response. Increased ASP has been linked to focal fear disorders and to scale measures of dispositional fearfulness (i.e., threat sensitivity; THT+). However, some studies have reported reduced ASP for fear pathology accompanied by major depressive disorder (MDD) or pervasive distress. The current study evaluated whether (a) THT+ as indexed by reported dispositional fearfulness mediates the relationship between fear disorders (when unaccompanied by depression) and ASP, and (b) depression moderates relations of THT+ and fear disorders with ASP. Fear disorder participants without MDD showed enhanced ASP whereas those with MDD (or other distress conditions) showed evidence of reduced ASP. Continuous THT+ scores also predicted ASP, and this association: (a) was likewise moderated by depression/distress, and (b) accounted for the relationship between ASP and fear pathology without MDD. These findings point to a role for the RDoC construct of acute threat, operationalized dispositionally, in enhanced ASP shown by individuals with fear pathology unaccompanied by distress pathology. PMID:25448265

[Experimental study on aging effect of Angelica sinensis polysaccharides combined with cytarabine on human leukemia KG1alpha cell lines].

PubMed

Xu, Chun-Yan; Geng, Shan; Liu, Jun; Zhu, Jia-Hong; Zhang, Xian-Ping; Jiang, Rong; Wang, Ya-Ping

2014-04-01

The latest findings of our laboratory showed that Angelica sinensis polysaccharide (ASP) showed a definite effect in regulating the aging of hematopoietic stem cells. Leukemia is a type of malignant hematopoietic tumor in hematopoietic stem cells. There have been no relevant reports about ASP's effect in regulating the aging of leukemia cells. In this study, human acute myeloid leukemia (AML) KG1alpha cell lines in logarithmic growth phase were taken as the study object, and were divided into the ASP group, the cytarabine (Ara-C) group, the ASP + Ara-C group and the control group. The groups were respectively treated with different concentration of ASP, Ara-C and ASP + Ara-C for different periods, with the aim to study the effect of ASP combined with Ara-C in regulating the aging of human acute myeloid leukemia KG1alpha cell lines and its relevant mechanism. The results showed that ASP, Ara-C and ASP + Ara-C could obviously inhibit KG1alpha cell proliferation in vitro, block the cells in G0/G1 phase. The cells showed the aging morphological feature. The percentage of positive stained aging cells was dramatically increased, and could significantly up-regulate the expression of aging-related proteins P16 and RB, which were more obvious in the ASP + Ara-C group. In conclusion, the aging mechanism of KG1alpha cell induced by ASP and Ara-C may be related to the regulation of the expression of aging-related proteins, suggesting that the combined administration of ASP and anticancer drugs plays a better role in the treatment of leukemia .

77 FR 47839 - Environmental Impacts Statements; Notice of Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-10

... electronic reporting site-- https://cdx.epa.gov/epa_home.asp EIS No. 20120257, Final EIS, BR, CA, San Joaquin... No. 20120262, Draft EIS, BR, CA, San Luis Reservoir State Recreation Area Resource Management Plan...

Metrics for the NASA Airspace Systems Program

NASA Technical Reports Server (NTRS)

Smith, Jeremy C.; Neitzke, Kurt W.

2009-01-01

This document defines an initial set of metrics for use by the NASA Airspace Systems Program (ASP). ASP consists of the NextGen-Airspace Project and the NextGen-Airportal Project. The work in each project is organized along multiple, discipline-level Research Focus Areas (RFAs). Each RFA is developing future concept elements in support of the Next Generation Air Transportation System (NextGen), as defined by the Joint Planning and Development Office (JPDO). In addition, a single, system-level RFA is responsible for integrating concept elements across RFAs in both projects and for assessing system-wide benefits. The primary purpose of this document is to define a common set of metrics for measuring National Airspace System (NAS) performance before and after the introduction of ASP-developed concepts for NextGen as the system handles increasing traffic. The metrics are directly traceable to NextGen goals and objectives as defined by the JPDO and hence will be used to measure the progress of ASP research toward reaching those goals. The scope of this document is focused on defining a common set of metrics for measuring NAS capacity, efficiency, robustness, and safety at the system-level and at the RFA-level. Use of common metrics will focus ASP research toward achieving system-level performance goals and objectives and enable the discipline-level RFAs to evaluate the impact of their concepts at the system level.

Lauroyl-L-aspartate decreased food intake and body temperature in neonatal chicks.

PubMed

Erwan, E; Chowdhury, V S; Ito, K; Furuse, M

2013-11-15

We hypothesized that the effects of L- and D-amino acids might be influenced when conjugated with fatty acid. Thus, the effects of oral administration of lauroyl-L-aspartate (Lau-L-Asp) as well as lauroyl-D-aspartate (Lau-D-Asp) were examined. In Experiment 1, oral administration of both Lau-L-Asp and Lau-D-Asp decreased food intake while L- or D-Asp did not influence food intake. Interestingly, only Lau-L-Asp decreased body temperature. Experiment 2 was conducted to determine whether non-conjugated mixture of L-Asp plus lauric acid has same effects under ad libitum feeding conditions. Lau-L-Asp decreased food intake and body temperature, but L-Asp plus lauric acid did not show any effect studied. In Experiment 3, we found that Lau-L-Asp declined food intake as well as time-dependently suppressed the body temperature in fasted chicks. However, L-Asp plus lauric acid did not show any effect. These results suggest that Lau-L-Asp may exert anorexigenic and hypothermic actions in chicks. © 2013.

Evaluation of Ga-DOTA-(D-Asp)n as bone imaging agents: D-aspartic acid peptides as carriers to bone.

PubMed

Ogawa, Kazuma; Ishizaki, Atsushi; Takai, Kenichiro; Kitamura, Yoji; Makino, Akira; Kozaka, Takashi; Kiyono, Yasushi; Shiba, Kazuhiro; Odani, Akira

2017-10-25

67 Ga-DOTA-(L-Asp) 11 and 67 Ga-DOTA-(L-Asp) 14 , which have been developed as bone imaging agents, showed a high accumulation in bone and a rapid blood clearance in mice. However, peptides composed of D-amino acids are more stable in vivo than those composed of their L-equivalents. In this study, 67 Ga-DOTA-(D-Asp) n (n = 2, 5, 8, 11, or 14) were synthesized using the Fmoc-based solid-phase methodology and evaluated. In hydroxyapatite binding assay, binding of 67 Ga-DOTA-(D-Asp) n tended to increase with increasing length of the amino acid chain. 67 Ga-DOTA-(D-Asp) 11 and 67 Ga-DOTA-(D-Asp) 14 caused a high accumulation of radioactivity in the bones of the mice. However, the results for 67 Ga-DOTA-(D-Asp) n and 67 Ga-DOTA-(L-Asp) n were comparable. In urine analyses, the proportion of intact complex after injection of 67 Ga-DOTA-(D-Asp) 14 was significantly higher than that of 67 Ga-DOTA-(L-Asp) 14 . Although 67 Ga-DOTA-(D-Asp) 14 was more stable than 67 Ga-DOTA-(L-Asp) 14 , the properties of 67 Ga-DOTA-(D-Asp) n and 67 Ga-DOTA-(L-Asp) n as bone imaging agents may be comparable.

A Review of Quality Measures for Assessing the Impact of Antimicrobial Stewardship Programs in Hospitals

PubMed Central

Akpan, Mary Richard; Ahmad, Raheelah; Shebl, Nada Atef; Ashiru-Oredope, Diane

2016-01-01

The growing problem of antimicrobial resistance (AMR) has led to calls for antimicrobial stewardship programs (ASP) to control antibiotic use in healthcare settings. Key strategies include prospective audit with feedback and intervention, and formulary restriction and preauthorization. Education, guidelines, clinical pathways, de-escalation, and intravenous to oral conversion are also part of some programs. Impact and quality of ASP can be assessed using process or outcome measures. Outcome measures are categorized as microbiological, patient or financial outcomes. The objective of this review was to provide an overview of quality measures for assessing ASP and the reported impact of ASP in peer-reviewed studies, focusing particularly on patient outcomes. A literature search of papers published in English between 1990 and June 2015 was conducted in five databases using a combination of search terms. Primary studies of any design were included. A total of 63 studies were included in this review. Four studies defined quality metrics for evaluating ASP. Twenty-one studies assessed the impact of ASP on antimicrobial utilization and cost, 25 studies evaluated impact on resistance patterns and/or rate of Clostridium difficile infection (CDI). Thirteen studies assessed impact on patient outcomes including mortality, length of stay (LOS) and readmission rates. Six of these 13 studies reported non-significant difference in mortality between pre- and post-ASP intervention, and five reported reductions in mortality rate. On LOS, six studies reported shorter LOS post intervention; a significant reduction was reported in one of these studies. Of note, this latter study reported significantly (p < 0.001) higher unplanned readmissions related to infections post-ASP. Patient outcomes need to be a key component of ASP evaluation. The choice of metrics is influenced by data and resource availability. Controlling for confounders must be considered in the design of evaluation studies to adequately capture the impact of ASP and it is important for unintended consequences to be considered. This review provides a starting point toward compiling standard outcome metrics for assessing ASP. PMID:27025520

The relationship of Asperger's syndrome to autism: a preliminary EEG coherence study.

PubMed

Duffy, Frank H; Shankardass, Aditi; McAnulty, Gloria B; Als, Heidelise

2013-07-31

It has long been debated whether Asperger's Syndrome (ASP) should be considered part of the Autism Spectrum Disorders (ASD) or whether it constitutes a unique entity. The Diagnostic and Statistical Manual, fourth edition (DSM-IV) differentiated ASP from high functioning autism. However, the new DSM-5 umbrellas ASP within ASD, thus eliminating the ASP diagnosis. To date, no clear biomarkers have reliably distinguished ASP and ASD populations. This study uses EEG coherence, a measure of brain connectivity, to explore possible neurophysiological differences between ASP and ASD. Voluminous coherence data derived from all possible electrode pairs and frequencies were previously reduced by principal components analysis (PCA) to produce a smaller number of unbiased, data-driven coherence factors. In a previous study, these factors significantly and reliably differentiated neurotypical controls from ASD subjects by discriminant function analysis (DFA). These previous DFA rules are now applied to an ASP population to determine if ASP subjects classify as control or ASD subjects. Additionally, a new set of coherence based DFA rules are used to determine whether ASP and ASD subjects can be differentiated from each other. Using prior EEG coherence based DFA rules that successfully classified subjects as either controls or ASD, 96.2% of ASP subjects are classified as ASD. However, when ASP subjects are directly compared to ASD subjects using new DFA rules, 92.3% ASP subjects are identified as separate from the ASD population. By contrast, five randomly selected subsamples of ASD subjects fail to reach significance when compared to the remaining ASD populations. When represented by the discriminant variable, both the ASD and ASD populations are normally distributed. Within a control-ASD dichotomy, an ASP population falls closer to ASD than controls. However, when compared directly with ASD, an ASP population is distinctly separate. The ASP population appears to constitute a neurophysiologically identifiable, normally distributed entity within the higher functioning tail of the ASD population distribution. These results must be replicated with a larger sample given their potentially immense clinical, emotional and financial implications for affected individuals, their families and their caregivers.

The relationship of Asperger’s syndrome to autism: a preliminary EEG coherence study

PubMed Central

2013-01-01

Background It has long been debated whether Asperger’s Syndrome (ASP) should be considered part of the Autism Spectrum Disorders (ASD) or whether it constitutes a unique entity. The Diagnostic and Statistical Manual, fourth edition (DSM-IV) differentiated ASP from high functioning autism. However, the new DSM-5 umbrellas ASP within ASD, thus eliminating the ASP diagnosis. To date, no clear biomarkers have reliably distinguished ASP and ASD populations. This study uses EEG coherence, a measure of brain connectivity, to explore possible neurophysiological differences between ASP and ASD. Methods Voluminous coherence data derived from all possible electrode pairs and frequencies were previously reduced by principal components analysis (PCA) to produce a smaller number of unbiased, data-driven coherence factors. In a previous study, these factors significantly and reliably differentiated neurotypical controls from ASD subjects by discriminant function analysis (DFA). These previous DFA rules are now applied to an ASP population to determine if ASP subjects classify as control or ASD subjects. Additionally, a new set of coherence based DFA rules are used to determine whether ASP and ASD subjects can be differentiated from each other. Results Using prior EEG coherence based DFA rules that successfully classified subjects as either controls or ASD, 96.2% of ASP subjects are classified as ASD. However, when ASP subjects are directly compared to ASD subjects using new DFA rules, 92.3% ASP subjects are identified as separate from the ASD population. By contrast, five randomly selected subsamples of ASD subjects fail to reach significance when compared to the remaining ASD populations. When represented by the discriminant variable, both the ASD and ASD populations are normally distributed. Conclusions Within a control-ASD dichotomy, an ASP population falls closer to ASD than controls. However, when compared directly with ASD, an ASP population is distinctly separate. The ASP population appears to constitute a neurophysiologically identifiable, normally distributed entity within the higher functioning tail of the ASD population distribution. These results must be replicated with a larger sample given their potentially immense clinical, emotional and financial implications for affected individuals, their families and their caregivers. PMID:23902729

Fungal extracellular polysaccharides in house dust as a marker for exposure to fungi: relations with culturable fungi, reported home dampness, and respiratory symptoms.

PubMed

Douwes, J; van der Sluis, B; Doekes, G; van Leusden, F; Wijnands, L; van Strien, R; Verhoeff, A; Brunekreef, B

1999-03-01

Epidemiologic studies have demonstrated an association between indoor fungal growth and respiratory symptoms. However, in only a few studies was fungal exposure actually measured. The purpose of this study was to evaluate the measurement by enzyme immunoassay of extracellular polysaccharides of Aspergillus and Penicillium species (EPS-Asp/Pen ) in house dust as a marker for fungal exposure and to study the relations between EPS-Asp/Pen levels and home dampness and respiratory symptoms in children. Extracts of house dust samples from bedroom and living room floors and mattresses from homes of 31 children with chronic respiratory symptoms and 29 children with no chronic respiratory symptoms were analyzed for EPS-Asp/Pen. EPS-Asp/Pen were readily detectable (40 to 46,513 nanogram equivalent/g dust) in 161 house dust extracts, with highest concentrations in living room floor dust. EPS-Asp/Pen levels were 2 to 3 times higher on carpeted floors than on smooth floors. EPS-Asp/Pen were significantly correlated with total culturable fungi (r = 0.3 to 0.5) and with house dust mite allergens (r = 0.3 to 0.5). EPS-Asp/Pen levels in living room floor dust were positively associated with occupant-reported home dampness. This was not observed for EPS-Asp/Pen in bedroom floor and mattress dust. EPS-Asp/Pen levels in living room floor dust were positively associated with respiratory symptoms. EPS-Asp/Pen in bedroom floor and mattress dust showed a reversed association with respiratory symptoms, possibly because of allergen-avoidance measures taken in the bedroom. The enzyme immunoassay for fungal EPS-Asp/Pen may be a useful method for exposure assessment of indoor fungi.

Clinical Utility of Ammonia Concentration as a Diagnostic Test in Monitoring of the Treatment with L-Asparaginase in Children with Acute Lymphoblastic Leukemia

PubMed Central

Czogała, Małgorzata; Balwierz, Walentyna; Sztefko, Krystyna; Rogatko, Iwona

2014-01-01

L-asparaginase (ASP) is an enzyme used as one of the basic regimens in the acute lymphoblastic leukemia (ALL) therapy. Because of the possibility of the enzyme inactivation by antibodies, monitoring of ASP activity is essential. The aim of the study was to examine if plasma concentration of ammonia, a direct product of the reaction catalyzed by ASP, can be used in the assessment of ASP activity. A group of 87 patients with acute lymphoblastic leukemia treated in the Department of Pediatric Oncology and Hematology in Krakow was enrolled to the study. ASP activity and ammonia concentration were measured after ASP administrations during induction. A positive correlation was found between the ammonia concentration and ASP activity (R = 0.44; P < 0.0001) and between the medium values of ammonia concentration and ASP activity (R = 0.56; P < 0.0001). The analysis of ROC curves revealed the moderate accuracy of the ammonia concentration values in the ASP activity assessment. It was also found that the medium value of ammonia concentrations can be useful in identification of the patients with low (<100 IU/L) and undetectable (<30 IU/L) ASP activity. The plasma ammonia concentration may reflect ASP activity and can be useful when a direct measurement of the activity is unavailable. PMID:25157375

The role of collagen charge clusters in the modulation of matrix metalloproteinase activity.

PubMed

Lauer, Janelle L; Bhowmick, Manishabrata; Tokmina-Roszyk, Dorota; Lin, Yan; Van Doren, Steven R; Fields, Gregg B

2014-01-24

Members of the matrix metalloproteinase (MMP) family selectively cleave collagens in vivo. Several substrate structural features that direct MMP collagenolysis have been identified. The present study evaluated the role of charged residue clusters in the regulation of MMP collagenolysis. A series of 10 triple-helical peptide (THP) substrates were constructed in which either Lys-Gly-Asp or Gly-Asp-Lys motifs replaced Gly-Pro-Hyp (where Hyp is 4-hydroxy-L-proline) repeats. The stabilities of THPs containing the two different motifs were analyzed, and kinetic parameters for substrate hydrolysis by six MMPs were determined. A general trend for virtually all enzymes was that, as Gly-Asp-Lys motifs were moved from the extreme N and C termini to the interior next to the cleavage site sequence, kcat/Km values increased. Additionally, all Gly-Asp-Lys THPs were as good or better substrates than the parent THP in which Gly-Asp-Lys was not present. In turn, the Lys-Gly-Asp THPs were also always better substrates than the parent THP, but the magnitude of the difference was considerably less compared with the Gly-Asp-Lys series. Of the MMPs tested, MMP-2 and MMP-9 most greatly favored the presence of charged residues with preference for the Gly-Asp-Lys series. Lys-Gly-(Asp/Glu) motifs are more commonly found near potential MMP cleavage sites than Gly-(Asp/Glu)-Lys motifs. As Lys-Gly-Asp is not as favored by MMPs as Gly-Asp-Lys, the Lys-Gly-Asp motif appears advantageous over the Gly-Asp-Lys motif by preventing unwanted MMP hydrolysis. More specifically, the lack of Gly-Asp-Lys clusters may diminish potential MMP-2 and MMP-9 collagenolytic activity. The present study indicates that MMPs have interactions spanning the P23-P23' subsites of collagenous substrates.

Dansylated octapeptide Dns-Glu-Asp-Asp-Ser-Asp-Glu-Glu-Asn inhibits the proliferation rate of HL-60 cells.

PubMed

Marsili, V; Nardicchi, V; Lupidi, G; Brozzetti, A; Gianfranceschi, G L

1996-12-01

Small acidic phosphorylated chromatin peptides show regulatory activity on gene expression. The peptide pyroGlu-Asp-Asp-Ser-Asp-Glu-Glu-Asn, synthesized on the basis of structural and biochemical studies, shows functional properties in vitro (phosphorylation by casein kinase II, control of DNA transcription by RNA polymerase II, inhibition of proliferation and promotion of differentiation in some cell lines) very similar to those of native chromatin peptides. In this report we show that the dansylated octapeptide Dns-Glu-Asp-Asp-Ser-Asp-Glu-Glu-Asn remarkably inhibits cell growth of the HL-60 cell line. The biological effect of the peptide seems to be considerably higher than that shown by the nondansylated peptide, and it cannot be attributed to a toxic effect of the Dns group. The measurement of uptake of 3H-labelled Glu-Asp-Asp-Ser-Asp-Glu-Glu-Asn demonstrates that it is unable to pass through the HL-60 cell membrane. It is our considered opinion that the addition of hydrophobic groups to the peptide N-terminus should increase the biological activity by improving its transport through the cellular membrane.

Structural basis of potassium activation in plant asparaginases.

PubMed

Ajewole, Ebenezer; Santamaria-Kisiel, Liliana; Pajak, Agnieszka; Jaskolski, Mariusz; Marsolais, Frédéric

2018-04-01

l-asparaginases (EC 3.5.1.1) play an important role in nitrogen mobilization in plants. Here, we investigated the biochemical and biophysical properties of potassium-dependent (PvAspG1) and potassium-independent (PvAspG-T2) l-asparaginases from Phaseolus vulgaris. Our previous studies revealed that PvAspG1 requires potassium for catalytic activation and its crystal structure suggested that Ser-118 in the activation loop plays a critical role in coordinating the metal cation. This amino acid residue is replaced by isoleucine in PvAspG-T2. Reciprocal mutants of the enzymes were produced and the effect of the amino acid substitution on the kinetic parameters, allosteric effector binding, secondary structure conformation, and pH profile were studied. Introduction of the serine residue conferred potassium activation in PvAspG-T2. Conversely, the PvAspG1-S118I mutant could no longer be activated by potassium. PvAspG1 and the PvAspG-T2-I117S mutant had a similar half-maximal effective concentration (EC 50 ) value for potassium activation, between 0.1 and 0.3 mm. Potassium binding elicited a similar conformational change in PvAspG1 and PvAspG-T2-I117S, as studied by circular dichroism. However, no change in conformation was observed for PvAspG-T2 and PvAspG1-S118I. Analysis of kinetic parameters in function of pH indicated that potassium activation mediated by Ser-118 influences the ionization of specific functional groups in the enzyme-substrate complex. Together, the results indicate that Ser-118 of PvAspG1 is essential and sufficient for potassium activation in plant l-asparaginases. ENZYME: l-Asparaginase (EC 3.5.1.1). © 2018 Federation of European Biochemical Societies.

Prediction of binding modes between protein L-isoaspartyl (D-aspartyl) O-methyltransferase and peptide substrates including isomerized aspartic acid residues using in silico analytic methods for the substrate screening.

PubMed

Oda, Akifumi; Noji, Ikuhiko; Fukuyoshi, Shuichi; Takahashi, Ohgi

2015-12-10

Because the aspartic acid (Asp) residues in proteins are occasionally isomerized in the human body, not only l-α-Asp but also l-β-Asp, D-α-Asp and D-β-Asp are found in human proteins. In these isomerized aspartic acids, the proportion of D-β-Asp is the largest and the proportions of l-β-Asp and D-α-Asp found in human proteins are comparatively small. To explain the proportions of aspartic acid isomers, the possibility of an enzyme able to repair l-β-Asp and D-α-Asp is frequently considered. The protein L-isoaspartyl (D-aspartyl) O-methyltransferase (PIMT) is considered one of the possible repair enzymes for l-β-Asp and D-α-Asp. Human PIMT is an enzyme that recognizes both l-β-Asp and D-α-Asp, and catalyzes the methylation of their side chains. In this study, the binding modes between PIMT and peptide substrates containing l-β-Asp or D-α-Asp residues were investigated using computational protein-ligand docking and molecular dynamics simulations. The results indicate that carboxyl groups of both l-β-Asp and D-α-Asp were recognized in similar modes by PIMT and that the C-terminal regions of substrate peptides were located in similar positions on PIMT for both the l-β-Asp and D-α-Asp peptides. In contrast, for peptides containing l-α-Asp or D-β-Asp residues, which are not substrates of PIMT, the computationally constructed binding modes between PIMT and peptides greatly differed from those between PIMT and substrates. In the nonsubstrate peptides, not inter- but intra-molecular hydrogen bonds were observed, and the conformations of peptides were more rigid than those of substrates. Thus, the in silico analytical methods were able to distinguish substrates from nonsubstrates and the computational methods are expected to complement experimental analytical methods. Copyright © 2015 Elsevier B.V. All rights reserved.

Quantitative determination of free D-Asp, L-Asp and N-methyl-D-aspartate in mouse brain tissues by chiral separation and Multiple Reaction Monitoring tandem mass spectrometry.

PubMed

Fontanarosa, Carolina; Pane, Francesca; Sepe, Nunzio; Pinto, Gabriella; Trifuoggi, Marco; Squillace, Marta; Errico, Francesco; Usiello, Alessandro; Pucci, Piero; Amoresano, Angela

2017-01-01

Several studies have suggested that free d-Asp has a crucial role in N-methyl d-Asp receptor-mediated neurotransmission playing very important functions in physiological and pathological processes. This paper describes the development of an analytical procedure for the direct and simultaneous determination of free d-Asp, l-Asp and N-methyl d-Asp in specimens of different mouse brain tissues using chiral LC-MS/MS in Multiple Reaction Monitoring scan mode. After comparing three procedures and different buffers and extraction solvents, a simple preparation procedure was selected the analytes of extraction. The method was validated by analyzing l-Asp, d-Asp and N-methyl d-Asp recovery at different spiked concentrations (50, 100 and 200 pg/μl) yielding satisfactory recoveries (75-110%), and good repeatability. Limits of detection (LOD) resulted to be 0.52 pg/μl for d-Asp, 0.46 pg/μl for l-Asp and 0.54 pg/μl for NMDA, respectively. Limits of quantification (LOQ) were 1.57 pg/μl for d-Asp, 1.41 pg/μl for l-Asp and 1.64 pg/μl for NMDA, respectively. Different concentration levels were used for constructing the calibration curves which showed good linearity. The validated method was then successfully applied to the simultaneous detection of d-Asp, l-Asp and NMDA in mouse brain tissues. The concurrent, sensitive, fast, and reproducible measurement of these metabolites in brain tissues will be useful to correlate the amount of free d-Asp with relevant neurological processes, making the LC-MS/MS MRM method well suited, not only for research work but also for clinical analyses.

Fidelity in After-School Program Intervention Research: A Systematic Review

ERIC Educational Resources Information Center

Maynard, Brandy R.; Peters, Kristen E.; Vaughn, Michael G.; Sarteschi, Christine M.

2014-01-01

Over the past 2 decades, the number of after-school programs (ASP) and the number of students attending ASPs has markedly increased. Although several reviews and meta-analyses have examined the outcomes of ASPs, ASP intervention study reviews have not specifically examined intervention fidelity. Establishing intervention fidelity is critically…

Cerebral venous thrombosis in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma during induction chemotherapy with l-asparaginase: The GRAALL experience.

PubMed

Couturier, Marie-Anne; Huguet, Françoise; Chevallier, Patrice; Suarez, Felipe; Thomas, Xavier; Escoffre-Barbe, Martine; Cacheux, Victoria; Pignon, Jean-Michel; Bonmati, Caroline; Sanhes, Laurence; Bories, Pierre; Daguindau, Etienne; Dorvaux, Véronique; Reman, Oumedaly; Frayfer, Jamile; Orvain, Corentin; Lhéritier, Véronique; Ifrah, Norbert; Dombret, Hervé; Hunault-Berger, Mathilde; Tanguy-Schmidt, Aline

2015-11-01

Central nervous system (CNS) thrombotic events are a well-known complication of acute lymphoblastic leukemia (ALL) induction therapy, especially with treatments including l-asparaginase (l-ASP). Data on risk factors and clinical evolution is still lacking in adult patients. We report on the clinical evolution of 22 CNS venous thrombosis cases occurring in 708 adults treated for ALL or lymphoblastic lymphoma (LL) with the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-induction protocol, which included eight L-ASP (6,000 IU/m(2) ) infusions. The prevalence of CNS thrombosis was 3.1%. CNS thrombosis occurred after a median of 18 days (range: 11-31) when patients had received a median of three l-ASP injections (range: 2-7). Patients with CNS thrombosis exhibited a median antithrombin (AT) nadir of 47.5% (range: 36-67%) at Day 17 (range: D3-D28), and 95% of them exhibited AT levels lower than 60%. There were no evident increase in hereditary thrombotic risk factors prevalence, and thrombosis occurred despite heparin prophylaxis which was performed in 90% of patients. Acquired AT deficiency was frequently detected in patients with l-ASP-based therapy, and patients with CNS thrombosis received AT prophylaxis (45%) less frequently than patients without CNS thrombosis (83%), P = 0.0002). CNS thrombosis was lethal in 5% of patients, while 20% had persistent sequelae. One patient received all planned l-ASP infusions without recurrence of CNS thrombotic whereas l-ASP injections were discontinued in 20 patients during the management of thrombosis without a significant impact on overall survival (P = 0.4). © 2015 Wiley Periodicals, Inc.

Platelet inhibition during ticagrelor monotherapy versus ticagrelor plus aspirin in patients with coronary artery disease (TEMPLATE study): study protocol for a randomised controlled trial.

PubMed

Baos, Sarah; Underwood, Wendy; Culliford, Lucy; Reeves, Barnaby C; Rogers, Chris A; Bowles, Ruth; Johnson, Tom; Baumbach, Andreas; Mumford, Andrew

2017-11-09

Dual antiplatelet therapy (DAPT) with aspirin (ASP) and a P2Y 12 blocker is currently standard care after percutaneous coronary intervention (PCI) with stent insertion, and aims to inhibit platelet function in order to prevent stent thrombosis. The P2Y 12 blocker ticagrelor (TIC) has greater antiplatelet effect than the previously used members of this class, such as clopidogrel. In healthy volunteers, TIC is sufficient to cause strong platelet inhibition, with little additional effect from ASP. Omission of ASP may improve the safety of antiplatelet regimes by reducing bleeding. However, the effect of single antiplatelet treatment with TIC, compared to DAPT with TIC + ASP, has not been studied in detail in patients with coronary artery disease. To compare TIC with TIC + ASP, we have initiated a single centre, open-label randomised controlled trial (TEMPLATE study) in adults receiving DAPT following PCI with a sample size of 110 patients. Patients are invited to join the study when, as part of standard care, they are due to switch from DAPT (ASP + any P2Y 12 blocker) to single antiplatelet treatment with ASP alone after 6-12 months. Patients are randomised to receive either TIC or TIC + ASP for 4 weeks. All patients then revert to standard care with ASP alone. Blood samples and clinical data are collected at three study visits: at baseline during treatment with ASP + any P2Y 12 blocker (visit 1); approximately 4 weeks after visit 1 during treatment with either TIC or TIC + ASP (visit 2); and approximately 8 weeks after visit 1 when treatment has reverted to ASP alone (visit 3). The primary outcome is the extent of platelet inhibition, measured by light transmission aggregation, flow cytometry, flow chamber and plasma biomarker tests. The primary analysis will compare the extent of platelet inhibition between the TIC and TIC + ASP groups at visit 2, adjusted for baseline platelet reactivity. Secondary analyses will compare the extent of platelet inhibition at visit 2 with that at visit 3. This is the first study to compare in detail the extent of platelet inhibition in patients who are receiving TIC compared with TIC + ASP. The study findings will complement larger-scale trials of the clinical efficacy and safety of TIC compared to TIC + ASP. ISRCTN registry, identifier ISRCTN84335288 . Registered on 23 June 2014.

Racemization at the Asp 58 residue in αA-crystallin from the lens of high myopic cataract patients.

PubMed

Zhu, Xiang-Jia; Zhang, Ke-Ke; He, Wen-Wen; Du, Yu; Hooi, Michelle; Lu, Yi

2018-02-01

Post-translational modifications in lens proteins are key causal factors in cataract. As the most abundant post-translational modification in the lens, racemization may be closely related to the pathogenesis of cataract. Racemization of αA-crystallin, a crucial structural and heat shock protein in the human lens, could significantly influence its structure and function. In previous studies, elevated racemization from l-Asp 58 to d-isoAsp58 in αA-crystallin has been found in age-related cataract (ARC) lenses compared to normal aged human lenses. However, the role of racemization in high myopic cataract (HMC), which is characterized by an early onset of nuclear cataract, remains unknown. In the current study, apparently different from ARC, significantly increased racemization from l-Asp 58 to d-Asp 58 in αA-crystallin was identified in HMC lenses. The average racemization rates for each Asp isoform were calculated in ARC and HMC group. In ARC patients, the conversion of l-Asp 58 to d-isoAsp 58, up to 31.89%, accounted for the main proportion in racemization, which was in accordance with the previous studies. However, in HMC lenses, the conversion of l-Asp 58 to d-Asp 58, as high as 35.44%, accounted for the largest proportion of racemization in αA-crystallin. The different trend in the conversion of αA-crystallin by racemization, especially the elevated level of d-Asp 58 in HMC lenses, might prompt early cataractogenesis and a possible explanation of distinct phenotypes of cataract in HMC. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

A conserved hydrogen-bond network in the catalytic centre of animal glutaminyl cyclases is critical for catalysis.

PubMed

Huang, Kai-Fa; Wang, Yu-Ruei; Chang, En-Cheng; Chou, Tsung-Lin; Wang, Andrew H-J

2008-04-01

QCs (glutaminyl cyclases; glutaminyl-peptide cyclotransferases, EC 2.3.2.5) catalyse N-terminal pyroglutamate formation in numerous bioactive peptides and proteins. The enzymes were reported to be involved in several pathological conditions such as amyloidotic disease, osteoporosis, rheumatoid arthritis and melanoma. The crystal structure of human QC revealed an unusual H-bond (hydrogen-bond) network in the active site, formed by several highly conserved residues (Ser(160), Glu(201), Asp(248), Asp(305) and His(319)), within which Glu(201) and Asp(248) were found to bind to substrate. In the present study we combined steady-state enzyme kinetic and X-ray structural analyses of 11 single-mutation human QCs to investigate the roles of the H-bond network in catalysis. Our results showed that disrupting one or both of the central H-bonds, i.e., Glu(201)...Asp(305) and Asp(248)...Asp(305), reduced the steady-state catalysis dramatically. The roles of these two COOH...COOH bonds on catalysis could be partly replaced by COOH...water bonds, but not by COOH...CONH(2) bonds, reminiscent of the low-barrier Asp...Asp H-bond in the active site of pepsin-like aspartic peptidases. Mutations on Asp(305), a residue located at the centre of the H-bond network, raised the K(m) value of the enzyme by 4.4-19-fold, but decreased the k(cat) value by 79-2842-fold, indicating that Asp(305) primarily plays a catalytic role. In addition, results from mutational studies on Ser(160) and His(319) suggest that these two residues might help to stabilize the conformations of Asp(248) and Asp(305) respectively. These data allow us to propose an essential proton transfer between Glu(201), Asp(305) and Asp(248) during the catalysis by animal QCs.

ASP archiving solution of regional HUSpacs.

PubMed

Pohjonen, Hanna; Kauppinen, Tomi; Ahovuo, Juhani

2004-09-01

The application service provider (ASP) model is not novel, but widely used in several non-health care-related business areas. In this article, ASP is described as a potential solution for long-term and back-up archiving of the picture archiving and communication system (PACS) of the Hospital District of Helsinki and Uusimaa (HUS). HUSpacs is a regional PACS for 21 HUS hospitals serving altogether 1.4 million citizens. The ultimate goal of this study was to define the specifications for the ASP archiving service and to compare different commercial options for archiving solutions (costs derived by unofficial requests for proposal): in-house PACS components, the regional ASP concept and the hospital-based ASP concept. In conclusion, the large scale of the HUS installation enables a cost-effective regional ASP archiving, resulting in a four to five times more economical solution than hospital-based ASP.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Loew, G.H.; Axe, F.U.; Collins, J.R.

In this study, we have investigated the plausibility of a key postulated transformation of the proximal imidazole ligand (His 175) to an imidazolate by proton transfer to a nearby aspartate (Asp 235) absent in Mb. The proton relay system studied included not only models for the His 175 and Asp 235 residues but also for a nearby Trp 191 residue that could also interact with Asp 235 through hydrogen bonding and polarization. Two semiempirical quantum mechanical methods, Am1 and MNDO/H, with improved capabilities of describing H-bonded systems, were used to calculate the enthalpies of the three tautomeric forms of themore » proton relay system corresponding to the proton on the His, Asp, and Trp, respectively. These calculations were made for several models of the effect of the iron. Relative tautomeric enthalpies were calculated both with H-atom only optimization, keeping the heavy atoms fixed in their X-ray positions, and additional optimization that allowed the model Asp residue to relax. Transition-state enthalpies for the proton transfer from His to Asp were also calculated. The results of these studies suggest that the crucial postulated proton transfer from His to Asp is energetically favored, but only in the presence of the interaction of the iron with the imidazole ligand. Another stable form of the cluster, with competing proton transfer from the Trp to the Asp, was found only when the Asp position was allowed to optimize.« less

NbN A/D Conversion of IR Focal Plane Sensor Signal at 10 K

NASA Technical Reports Server (NTRS)

Eaton, L.; Durand, D.; Sandell, R.; Spargo, J.; Krabach, T.

1994-01-01

We are implementing a 12 bit SFQ counting ADC with parallel-to-serial readout using our established 10 K NbN capability. This circuit provides a key element of the analog signal processor (ASP) used in large infrared focal plane arrays. The circuit processes the signal data stream from a Si:As BIB detector array. A 10 mega samples per second (MSPS) pixel data stream flows from the chip at a 120 megabit bit rate in a format that is compatible with other superconductive time dependent processor (TDP) circuits being developed. We will discuss our planned ASP demonstration, the circuit design, and test results.

IgE binding to peanut allergens is inhibited by combined D-aspartic and D-glutamic acids.

PubMed

Chung, Si-Yin; Reed, Shawndrika

2015-01-01

The objective of this study was to determine if D-amino acids (D-aas) bind and inhibit immunoglobulin E (IgE) binding to peanut allergens. D-aas such as D-Asp (aspartic acid), D-Glu (glutamic acid), combined D-[Asp/Glu] and others were each prepared in a cocktail of 9 other D-aas, along with L-amino acids (L-aas) and controls. Each sample was mixed with a pooled plasma from peanut-allergic donors, and tested by ELISA (enzyme-linked immunosorbent assay) and Western blots for IgE binding to peanut allergens. Results showed that D-[Asp/Glu] (4 mg/ml) inhibited IgE binding (75%) while D-Glu, D-Asp and other D-aas had no inhibitory effect. A higher inhibition was seen with D-[Asp/Glu] than with L-[Asp/Glu]. We concluded that IgE was specific for D-[Asp/Glu], not D-Asp or D-Glu, and that D-[Asp/Glu] was more reactive than was L-[Asp/Glu] in IgE inhibition. The finding indicates that D-[Asp/Glu] may have the potential for removing IgE or reducing IgE binding to peanut allergens in vitro. Published by Elsevier Ltd.

Ingested d-Aspartate Facilitates the Functional Connectivity and Modifies Dendritic Spine Morphology in Rat Hippocampus.

PubMed

Kitamura, Akihiko; Hojo, Yasushi; Ikeda, Muneki; Karakawa, Sachise; Kuwahara, Tomomi; Kim, Jonghyuk; Soma, Mika; Kawato, Suguru; Tsurugizawa, Tomokazu

2018-05-30

d-Aspartate (d-Asp), the stereoisomer of l-aspartate, has a role in memory function in rodents. However, the mechanism of the effect of d-Asp has not been fully understood. In this study, we hypothesized that ingested d-Asp directly reaches the hippocampal tissues via the blood circulation and modifies the functional connectivity between hippocampus and other regions through spinogenesis in hippocampal CA1 neurons. The spinogenesis induced by the application of d-Asp was investigated using rat acute hippocampal slices. The density of CA1 spines was increased following 21 and 100 μM d-Asp application. The nongenomic spine increase pathway involved LIM kinase. In parallel to the acute slice study, brain activation was investigated in awake rats using functional MRI following the intragastric administration of 5 mM d-Asp. Furthermore, the concentration of d-Asp in the blood serum and hippocampus was significantly increased 15 min after intragastric administration of d-Asp. A functional connectivity by awake rat fMRI demonstrated increased slow-frequency synchronization in the hippocampus and other regions, including the somatosensory cortex, striatum, and the nucleus accumbens, 10-20 min after the start of d-Asp administration. These results suggest that ingested d-Asp reaches the brain through the blood circulation and modulates hippocampal neural networks through the modulation of spines.

Studies on Aspirin Crystals Generated by a Modified Vapor Diffusion Method.

PubMed

Mittal, Amit; Malhotra, Deepak; Jain, Preeti; Kalia, Anupama; Shunmugaperumal, Tamilvanan

2016-08-01

The objectives of the current investigation were (1) to study the influence of selected two different non-solvents (diethylether and dichloromethane) on the drug crystal formation of a model drug, aspirin (ASP-I) by the modified vapor diffusion method and (2) to characterize and compare the generated crystals (ASP-II and ASP-III) using different analytical techniques with that of unprocessed ASP-I. When compared to the classical vapor diffusion method which consumes about 15 days to generate drug crystals, the modified method needs only 12 h to get the same. Fourier transform-infrared spectroscopy (FT-IR) reveals that the internal structures of ASP-II and ASP-III crystals were identical when compared with ASP-I. Although the drug crystals showed a close similarity in X-ray diffraction patterns, the difference in the relative intensities of some of the diffraction peaks (especially at 2θ values of around 7.7 and 15.5) could be attributed to the crystal habit or crystal size modification. Similarly, the differential scanning calorimetry (DSC) study speculates that only the crystal habit modifications might occur but without involving any change in internal structure of the generated drug polymorphic form I. This is further substantiated from the scanning electron microscopy (SEM) pictures that indicated the formation of platy shape for the ASP-II crystals and needle shape for the ASP-III crystals. In addition, the observed slow dissolution of ASP crystals should indicate polymorph form I formation. Thus, the modified vapor diffusion method could routinely be used to screen and legally secure all possible forms of other drug entities too.

Xeroderma pigmentosum group D polymorphisms and esophageal cancer susceptibility: a meta-analysis based on case-control studies.

PubMed

Yang, Rong; Zhang, Chong; Malik, Armah; Shen, Zhi-Da; Hu, Jian; Wu, Yi-He

2014-11-28

To clarify the effects of the xeroderma pigmentosum group D (XPD) Asp312Asn and Lys751Gln gene polymorphisms on the risk of esophageal cancer (EC). A computerised literature search was conducted to identify the relevant studies from the PUBMED and EMBASE databases, reviews, and reference lists of relevant articles. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the associations between the XPD Asp312Asn and/or Lys751Gln polymorphisms and EC susceptibility. Statistical analyses were performed using the software Stata 12.0. A fixed or random effects model was selected based on a heterogeneity test. Publication bias was estimated using funnel plots and Egger's linear regression method. Subgroup analyses were performed based on histological type and ethnicity. Thirteen case-control studies with a total of 10 comparisons for the Asp312Asn polymorphism, including 2373 cases and 3175 controls, and 15 comparisons for the Lys751Gln polymorphism, including 3226 cases and 5237 controls, were recruited for the meta-analysis. In terms of the XPD Asp312Asn polymorphism, significantly increased EC risks were identified in the Asp/Asn vs Asp/Asp comparison (OR = 1.17, 95%CI: 1.02-1.33, P = 0.03) and in the dominant-model comparison (Asn/Asn+Asp/Asn vs Asp/Asp: OR = 1.18, 95%CI: 1.04-1.34, P = 0.01). However, no significant associations were found in the Asn/Asn vs Asp/Asp comparison (OR = 1.30, 95%CI: 1.00-1.70, P = 0.05) or in the recessive-model comparison (Asn/Asn vs Asp/Asn + Asp/Asp: OR = 1.17, 95%CI: 0.91-1.50, P = 0.22). In terms of the XPD Lys751Gln polymorphism, a significant association with EC susceptibility was found under the recessive model (Gln/Gln vs Lys/Gln+Lys/Lys: OR = 1.21, 95%CI: 1.02-1.43, P = 0.03). However, no associations were identified in the other comparisons (co-dominant model: Lys/Gln vs Lys/Lys: OR = 1.11, 95%CI: 0.94-1.31, P = 0.20; Gln/Gln vs Lys/Lys: OR = 1.31, 95%CI: 0.98-1.75, P = 0.07; dominant model: OR = 1.14, 95%CI: 0.96-1.35, P = 0.14). The results of this meta-analysis suggest that the XPD Asp312Asn and Lys751Gln gene polymorphisms are associated with a significantly increased risk for EC.

Strategies for improving antibiotic use in Qatar: a survey of pharmacists' perceptions and experiences.

PubMed

Pawluk, Shane; Black, Emily; El-Awaisi, Alla

2015-02-01

The objectives of this study were to identify antimicrobial stewardship activities in Qatar, identify pharmacist involvement in activities and summarize perceived barriers for implementation of antimicrobial stewardship programs (ASPs). A cross-sectional survey was developed based on study objectives and completed by pharmacists in Qatar. Most hospital settings have implemented components of ASP. Lack of infectious disease specialists and training of healthcare providers was the most common barrier to implementation or expansion of ASP identified in the hospital and community settings respectively. Pharmacists report some components of ASP have been implemented; however, barriers must be overcome to further expand ASPs. © 2014 Royal Pharmaceutical Society.

Coordination ability determined transition metal ions substitution of Tb in Tb-Asp fluorescent nanocrystals and a facile ions-detection approach.

PubMed

Duan, Jiazhi; Ma, Baojin; Liu, Feng; Zhang, Shan; Wang, Shicai; Kong, Ying; Du, Min; Han, Lin; Wang, Jianjun; Sang, Yuanhua; Liu, Hong

2018-04-26

Although the synthesis and fluorescent properties of lanthanide-amino acid complex nanostructures have been investigated extensively, limited studies have been reported on metal ions' substitution ability for the lanthanide ions in the complex and their effect on the fluorescent property. In this study, taking biocompatible Tb-aspartic acid (Tb-Asp) complex nanocrystals as a model, the substitution mechanism of metal ions, particularly transition metals, for Tb ions in Tb-Asp nanocrystals and the change in the fluorescent property of the Tb-Asp nanocrystals after substitution were systematically investigated. The experimental results illustrated that metal ions with higher electronegativity, higher valence, and smaller radius possess stronger ability for Tb ions' substitution in Tb-Asp nanocrystals. Based on the effect of substituting ions' concentration on the fluorescent property of Tb-Asp, a facile method for copper ions detection with high sensitivity was proposed by measuring the fluorescent intensity of Tb-Asp nanocrystals' suspensions containing different concentrations of copper ions. The good biocompatibility, great convenience of synthesis and sensitive detection ability make Tb-Asp nanocrystals a very low cost and effective material for metal ions detection, which also opens a new door for practical applications of metal-Asp coordinated nanocrystals.

Structural elucidation of the DFG-Asp in and DFG-Asp out states of TAM kinases and insight into the selectivity of their inhibitors.

PubMed

Messoussi, Abdellah; Peyronnet, Lucile; Feneyrolles, Clémence; Chevé, Gwénaël; Bougrin, Khalid; Yasri, Aziz

2014-10-10

Structural elucidation of the active (DFG-Asp in) and inactive (DFG-Asp out) states of the TAM family of receptor tyrosine kinases is required for future development of TAM inhibitors as drugs. Herein we report a computational study on each of the three TAM members Tyro-3, Axl and Mer. DFG-Asp in and DFG-Asp out homology models of each one were built based on the X-ray structure of c-Met kinase, an enzyme with a closely related sequence. Structural validation and in silico screening enabled identification of critical amino acids for ligand binding within the active site of each DFG-Asp in and DFG-Asp out model. The position and nature of amino acids that differ among Tyro-3, Axl and Mer, and the potential role of these residues in the design of selective TAM ligands, are discussed.

In vitro activity of almond skin polyphenols for scavenging free radicals and inducing quinone reductase.

PubMed

Chen, C-Y Oliver; Blumberg, Jeffrey B

2008-06-25

Observational studies and clinical trials suggest nut intake, including almonds, is associated with an enhancement in antioxidant defense and a reduction in the risk of cancer and cardiovascular disease. Almond skins are rich in polyphenols (ASP) that may contribute to these putative benefits. To assess their potential mechanisms of action, we tested the in vitro effect of ASP extracted with methanol (M) or a gastrointestinal juice mimic (GI) alone or in combination with vitamins C (VC) or E (VE) (1-10 micromol/L) on scavenging free radicals and inducing quinone reductase (QR). Flavonoid profiles from ASP-M and -GI extracts were different from one another. ASP-GI was more potent in scavenging HOCl and ONOO (-) radicals than ASP-M. In contrast, ASP-M increased and ASP-GI decreased QR activity in Hepa1c1c7 cells. Adding VC or VE to ASP produced a combination- and dose-dependent action on radical scavenging and QR induction. In comparison to their independent actions, ASP-M plus VC were less potent in scavenging DPPH, HOCl, ONOO (-), and O 2 (-) (*). However, the interaction between ASP-GI plus VC promoted their radical scavenging activity. Combining ASP-M plus VC resulted in a synergistic interaction, inducing QR activity, but ASP-GI plus VC had an antagonistic effect. On the basis of their total phenolic content, the measures of total antioxidant activity of ASP-M and -GI were comparable. Thus, in vitro, ASP act as antioxidants and induce QR activity, but these actions are dependent upon their dose, method of extraction, and interaction with antioxidant vitamins.

Determination of ASPS performance for large payloads in the shuttle orbiter disturbance environment. [digital simulation

NASA Technical Reports Server (NTRS)

Keckler, C. R.; Kibler, K. S.; Powell, L. F.

1979-01-01

A high fidelity simulation of the annular suspension and pointing system (ASPS), its payload, and the shuttle orbiter was used to define the worst case orientations of the ASPS and its payload for the various vehicle disturbances, and to determine the performance capability of the ASPS under these conditions. The most demanding and largest proposed payload, the Solar Optical Telescope was selected for study. It was found that, in all cases, the ASPS more than satisfied the payload's requirements. It is concluded that, to satisfy facility class payload requirements, the ASPS or a shuttle orbiter free-drift mode (control system off) should be utilized.

Absorption kinetics and action profiles of subcutaneously administered insulin analogues (AspB9GluB27, AspB10, AspB28) in healthy subjects.

PubMed

Kang, S; Brange, J; Burch, A; Vølund, A; Owens, D R

1991-11-01

The subcutaneous absorption and resulting changes in plasma insulin or analogue, glucose, C-peptide, and blood intermediary metabolite concentrations after subcutaneous bolus injection of three soluble human insulin analogues (AspB9GluB27, monomeric; AspB28, mixture of monomers and dimers; and AspB10, dimeric) and soluble human insulin were evaluated. Fasting healthy male volunteers (n = 7) were studied on five occasions 1 wk apart randomly receiving 0.6 nmol.kg-1 s.c. 125I-labeled AspB10 or soluble human insulin (Novolin R, Novo, Copenhagen); 1st study and 0.6 nmol.kg-1 s.c. 125I-labeled AspB28, AspB9GluB27 or soluble human insulin (2nd study). Residual radioactivity at the injection site was measured over 8 h with frequent venous sampling for plasma immunoreactive insulin or analogue, glucose, C-peptide, and blood intermediary metabolite concentrations. The three analogues were absorbed 2-3 times faster than human insulin. The mean +/- SE time to 50% residual radioactivity was 94 +/- 6 min for AspB10 compared with 184 +/- 10 min for human insulin (P less than 0.001), 83 +/- 8 min for AspB28 (P less than 0.005), and 63 +/- 9 min for AspB9GluB27 (P less than 0.001) compared with 182 +/- 21 min for human insulin. delta Peak plasma insulin analogue levels were significantly higher after each analogue than after human insulin (P less than 0.005). With all three analogues, the mean hypoglycemic nadir occurred earlier at 61-65 min postinjection compared with 201-210 min for the reference human insulins (P less than 0.005). The magnitude of the hypoglycemic nadir was greater after AspB9GluB27 (P less than 0.05) and AspB28 (P less than 0.001) compared with human insulin. There was a significantly faster onset and offset of responses in C-peptide and intermediary metabolite levels after the analogues than after human insulin (P less than 0.05). The rapid absorption and biological actions of these analogues offer potential therapeutic advantages over the current short-acting neutral soluble insulins.

Phosphate-Catalyzed Succinimide Formation from Asp Residues: A Computational Study of the Mechanism.

PubMed

Kirikoshi, Ryota; Manabe, Noriyoshi; Takahashi, Ohgi

2018-02-24

Aspartic acid (Asp) residues in proteins and peptides are prone to the non-enzymatic reactions that give biologically uncommon l-β-Asp, d-Asp, and d-β-Asp residues via the cyclic succinimide intermediate (aminosuccinyl residue, Suc). These abnormal Asp residues are known to have relevance to aging and pathologies. Despite being non-enzymatic, the Suc formation is thought to require a catalyst under physiological conditions. In this study, we computationally investigated the mechanism of the Suc formation from Asp residues that were catalyzed by the dihydrogen phosphate ion, H₂PO₄ - . We used Ac-l-Asp-NHMe (Ac = acetyl, NHMe = methylamino) as a model compound. The H₂PO₄ - ion (as a catalyst) and two explicit water molecules (as solvent molecules stabilizing the negative charge) were included in the calculations. All of the calculations were performed by density functional theory with the B3LYP functional. We revealed a phosphate-catalyzed two-step mechanism (cyclization-dehydration) of the Suc formation, where the first step is predicted to be rate-determining. In both steps, the reaction involved a proton relay mediated by the H₂PO₄ - ion. The calculated activation barrier for this mechanism (100.3 kJ mol -1 ) is in reasonable agreement with an experimental activation energy (107 kJ mol -1 ) for the Suc formation from an Asp-containing peptide in a phosphate buffer, supporting the catalytic mechanism of the H₂PO₄ - ion that is revealed in this study.

Glu298Asp eNOS gene polymorphism causes attenuation in nonexercising muscle vasodilatation.

PubMed

Dias, Rodrigo G; Alves, Maria-Janieire N N; Pereira, Alexandre C; Rondon, Maria Urbana P B; Dos Santos, Marcelo R; Krieger, José E; Krieger, Marta H; Negrão, Carlos E

2009-04-10

The influence of Glu298Asp endothelial nitric oxide synthase (eNOS) polymorphism in exercise-induced reflex muscle vasodilatation is unknown. We hypothesized that nonexercising forearm blood flow (FBF) responses during handgrip isometric exercise would be attenuated in individuals carrying the Asp298 allele. In addition, these responses would be mediated by reduced eNOS function and NO-mediated vasodilatation or sympathetic vasoconstriction. From 287 volunteers previously genotyped, we selected 33 healthy individuals to represent three genotypes: Glu/Glu [n = 15, age 43 +/- 3 yr, body mass index (BMI) 22.9 +/- 0.3 kg/m(2)], Glu/Asp (n = 9, age 41 +/- 3 yr, BMI 23.7 +/- 1.0 kg/m(2)), and Asp/Asp (n = 9, age 40 +/- 4 yr, BMI 23.5 +/- 0.9 kg/m(2)). Heart rate (HR), mean blood pressure (MBP), and FBF (plethysmography) were recorded for 3 min at baseline and 3 min during isometric handgrip exercise. Baseline HR, MBP, FBF, and forearm vascular conductance (FVC) were similar among genotypes. FVC responses to exercise were significantly lower in Asp/Asp when compared with Glu/Asp and Glu/Glu (Delta = 0.07 +/- 0.14 vs. 0.64 +/- 0.20 and 0.57 +/- 0.09 units, respectively; P = 0.002). Further studies showed that intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA) did not change FVC responses to exercise in Asp/Asp, but significantly reduced FVC in Glu/Glu (Delta = 0.79 +/- 0.14 vs. 0.14 +/- 0.09 units). Thus the differences between Glu/Glu and Asp/Asp were no longer observed (P = 0.62). l-NMMA + phentolamine increased similarly FVC responses to exercise in Glu/Glu and Asp/Asp (P = 0.43). MBP and muscle sympathetic nerve activity increased significant and similarly throughout experimental protocols in Glu/Glu and Asp/Asp. Individuals who are homozygous for the Asp298 allele of the eNOS enzyme have attenuated nonexercising muscle vasodilatation in response to exercise. This genotype difference is due to reduced eNOS function and NO-mediated vasodilatation, but not sympathetic vasoconstriction.

TREATMENT INTENSIFICATION WITH INSULIN DEGLUDEC/INSULIN ASPART TWICE DAILY: RANDOMIZED STUDY TO COMPARE SIMPLE AND STEP-WISE TITRATION ALGORITHMS.

PubMed

Gerety, Gregg; Bebakar, Wan Mohamad Wan; Chaykin, Louis; Ozkaya, Mesut; Macura, Stanislava; Hersløv, Malene Lundgren; Behnke, Thomas

2016-05-01

This 26-week, multicenter, randomized, open-label, parallel-group, treat-to-target trial in adults with type 2 diabetes compared the efficacy and safety of treatment intensification algorithms with twice-daily (BID) insulin degludec/insulin aspart (IDegAsp). Patients randomized 1:1 to IDegAsp BID used either a 'Simple' algorithm (twice-weekly dose adjustments based on a single prebreakfast and pre-evening meal self-monitored plasma glucose [SMPG] measurement; IDegAsp[BIDSimple], n = 136) or a 'Stepwise' algorithm (once-weekly dose adjustments based on the lowest of 3 pre-breakfast and 3 pre-evening meal SMPG values; IDegAsp[BIDStep-wise], n = 136). After 26 weeks, mean change from baseline in glycated hemoglobin (HbA1c) with IDegAsp[BIDSimple] was noninferior to IDegAsp[BIDStep-wise] (-15 mmol/mol versus -14 mmol/mol; 95% confidence interval [CI] upper limit, <4 mmol/mol) (baseline HbA1c: 66.3 mmol/mol IDegAsp[BIDSimple] and 66.6 mmol/mol IDegAsp[BIDStep-wise]). The proportion of patients who achieved HbA1c <7.0% (<53 mmol/mol) at the end of the trial was 66.9% with IDegAsp[BIDSimple] and 62.5% with IDegAsp[BIDStep-wise]. Fasting plasma glucose levels were reduced with each titration algorithm (-1.51 mmol/L IDegAsp[BIDSimple] versus -1.95 mmol/L IDegAsp[BIDStep-wise]). Weight gain was 3.8 kg IDegAsp[BIDSimple] versus 2.6 kg IDegAsp[BIDStep-wise], and rates of overall confirmed hypoglycemia (5.16 episodes per patient-year of exposure [PYE] versus 8.93 PYE) and nocturnal confirmed hypoglycemia (0.78 PYE versus 1.33 PYE) were significantly lower with IDegAsp[BIDStep-wise] versus IDegAsp[BIDSimple]. There were no significant differences in insulin dose increments between groups. Treatment intensification with IDegAsp[BIDSimple] was noninferior to IDegAsp[BIDStep-wise]. Both titration algorithms were well tolerated; however, the more conservative step-wise algorithm led to less weight gain and fewer hypoglycemic episodes. Clinicaltrials.gov: NCT01680341.

L-Asp is a useful tool in the purification of the ionotropic glutamate receptor A2 ligand-binding domain.

PubMed

Krintel, Christian; Frydenvang, Karla; Ceravalls de Rabassa, Anna; Kaern, Anne M; Gajhede, Michael; Pickering, Darryl S; Kastrup, Jette S

2014-05-01

In purification of the ionotropic glutamate receptor A2 (GluA2) ligand-binding domain (LBD), L-Glu-supplemented buffers have previously been used for protein stabilization during the procedure. This sometimes hampers structural studies of low-affinity ligands, because L-Glu is difficult to displace, despite extensive dialysis. Here, we show that L-Asp binds to full-length GluA2 with low affinity (Ki = 0.63 mM) and to the GluA2 LBD with even lower affinity (Ki = 2.6 mM), and we use differential scanning fluorimetry to show that L-Asp is able to stabilize the isolated GluA2 LBD. We also show that L-Asp can replace L-Glu during purification, providing both equal yields and purity of the resulting protein sample. Furthermore, we solved three structures of the GluA2 LBD in the presence of 7.5, 50 and 250 mM L-Asp. Surprisingly, with 7.5 mM L-Asp, the GluA2 LBD crystallized as a mixed dimer, with L-Glu being present in one subunit, and neither L-Asp nor L-Glu being present in the other subunit. Thus, residual L-Glu is retained from the expression medium. On the other hand, only L-Asp was found at the binding site when 50 or 250 mM L-Asp was used for crystallization. The binding mode observed for L-Asp at the GluA2 LBD is very similar to that described for L-Glu. Taking our findings together, we have shown that L-Asp can be used instead of L-Glu for ligand-dependent stabilization of the GluA2 LBD during purification. This will enable structural studies of low-affinity ligands for lead optimization in structure-based drug design. Structural data are available in the Protein Data Bank under accession numbers 4O3B (7.5 mM L-Asp), 4O3C (50 mM L-Asp), and 4O3A (250 mM L-Asp). © 2014 FEBS.

Prevalence, Characteristics, and Perception of Nursery Antibiotic Stewardship Coverage in the United States.

PubMed

Cantey, Joseph B; Vora, Niraj; Sunkara, Mridula

2017-09-01

Prolonged or unnecessary antibiotic use is associated with adverse outcomes in infants. Antibiotic stewardship programs (ASPs) aim to prevent these adverse outcomes and optimize antibiotic prescribing. However, data evaluating ASP coverage of nurseries are limited. The objectives of this study were to describe the characteristics of nurseries with and without ASP coverage and to determine perceptions of and barriers to nursery ASP coverage. The 2014 American Hospital Association annual survey was used to randomly select a level III neonatal intensive care unit from all 50 states. A level I and level II nursery from the same city as the level III nursery were then randomly selected. Hospital, nursery, and ASP characteristics were collected. Nursery and ASP providers (pharmacists or infectious disease providers) were interviewed using a semistructured template. Transcribed interviews were analyzed for themes. One hundred forty-six centers responded; 104 (71%) provided nursery ASP coverage. In multivariate analysis, level of nursery, university affiliation, and number of full-time equivalent ASP staff were the main predictors of nursery ASP coverage. Several themes were identified from interviews: unwanted coverage, unnecessary coverage, jurisdiction issues, need for communication, and a focus on outcomes. Most providers had a favorable view of nursery ASP coverage. Larger, higher-acuity nurseries in university-affiliated hospitals are more likely to have ASP coverage. Low ASP staffing and a perceived lack of importance were frequently cited as barriers to nursery coverage. Most nursery ASP coverage is viewed favorably by providers, but nursery providers regard it as less important than ASP providers. © The Author 2016. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Human mass balance, metabolite profile and identification of metabolic enzymes of [¹⁴C]ASP015K, a novel oral janus kinase inhibitor.

PubMed

Oda, Kazuo; Cao, Ying J; Sawamoto, Taiji; Nakada, Naoyuki; Fisniku, Ogert; Nagasaka, Yasuhisa; Sohda, Kin-Ya

2015-01-01

1. The human mass balance of (14)C-labelled ASP015K ([(14)C]ASP015K), an orally bioavailable Janus kinase (JAK) inhibitor, was characterized in six healthy male subjects after a single oral dose of [(14)C]ASP015K (100 mg, 3.7 MBq) in solution. [(14)C]ASP015K was rapidly absorbed with tmax of 1.6 and 1.8 h for ASP015K and total radioactivity in plasma, respectively. Mean recovery in urine and feces amounted to 36.8% and 56.6% of the administered dose, respectively. The main components of radioactivity in plasma and urine were ASP015K and M2 (5'-O-sulfo ASP015K). In feces, ASP015K and M4 (7-N-methyl ASP015K) were the main components. 2. In vitro study of ASP015K metabolism showed that the major isozyme contributing to the formation of M2 was human sulfotransferase (SULT) 2A1 and of M4 was nicotinamide N-methyltransferase (NNMT). 3. The in vitro intrinsic clearance (CLint_in vitro) of M4 formation from ASP015K in human liver cytosol (HLC) was 11-fold higher than that of M2. The competitive inhibitory effect of nicotinamide on M4 formation in the human liver was considered the reason for high CLint_in vitro of M4 formation, while each metabolic pathway made a near equal contribution to the in vivo elimination of ASP015K. ASP015K was cleared by multiple mechanisms.

Mechanism research on starting residual oil migration in ASP flooding with different Alkali concentration

NASA Astrophysics Data System (ADS)

Xia, Huifen; Pan, Junliang; Niu, Lijuan; Xu, Tianhan

2018-02-01

The results illustrate that under the condition of the same viscosity of ASP system, oil displacement efficiency is different while the ASP system with different alkali concentration has the same order of magnitude as the interfacial tension of oil. In this paper, the microscopic simulation visual model is used to study the mechanism of starting migration of residual oil by doing ASP flooding experiments with different alkali concentration. The results indicate that the migration of residual oil is different from that in the ASP systems with different alkali concentration. ASP system with high alkali concentration can start the migration by means of emulsifying residual oil into oil droplets and oil threads, on this account, increasing the alkali concentration can make the recovery degree of ASP system higher, which will finally be beneficial to the oil recovery.

Oral administration of D-aspartate, but not L-aspartate, depresses rectal temperature and alters plasma metabolites in chicks.

PubMed

Erwan, Edi; Chowdhury, Vishwajit Sur; Nagasawa, Mao; Goda, Ryosei; Otsuka, Tsuyoshi; Yasuo, Shinobu; Furuse, Mitsuhiro

2014-07-25

L-Aspartate (L-Asp) and D-aspartate (D-Asp) are physiologically important amino acids in mammals and birds. However, the functions of these amino acids have not yet been fully understood. In this study, we therefore examined the effects of L-Asp and D-Asp in terms of regulating body temperature, plasma metabolites and catecholamines in chicks. Chicks were first orally administered with different doses (0, 3.75, 7.5 and 15 mmol/kg body weight) of L- or D-Asp to monitor the effects of these amino acids on rectal temperature during 120 min of the experimental period. Oral administration of D-Asp, but not of L-Asp, linearly decreased the rectal temperature in chicks. Importantly, orally administered D-Asp led to a significant reduction in body temperature in chicks even under high ambient temperature (HT) conditions. However, centrally administered D-Asp did not significantly influence the body temperature in chicks. As for plasma metabolites and catecholamines, orally administered D-Asp led to decreased triacylglycerol and uric acid concentrations and increased glucose and chlorine concentrations but did not alter plasma catecholamines. These results suggest that oral administration of D-Asp may play a potent role in reducing body temperature under both normal and HT conditions. The alteration of plasma metabolites further indicates that D-Asp may contribute to the regulation of metabolic activity in chicks. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparison of subcutaneous soluble human insulin and insulin analogues (AspB9, GluB27; AspB10; AspB28) on meal-related plasma glucose excursions in type I diabetic subjects.

PubMed

Kang, S; Creagh, F M; Peters, J R; Brange, J; Vølund, A; Owens, D R

1991-07-01

To compare postprandial glucose excursions and plasma free insulin-analogue levels after subcutaneous injection of three novel human insulin analogues (AspB10; AspB9, GluB27; and AspB28) with those after injection of soluble human insulin (Actrapid HM U-100). Six male subjects with insulin-dependent diabetes, at least 1 wk apart and after an overnight fast and basal insulin infusion, received 72 nmol (approximately 12 U) s.c. of soluble human insulin 30 min before, or 72 nmol of each of the three analogues immediately before, a standard 500-kcal meal. Mean basal glucoses were similar on the 4 study days. Compared to human insulin (6.3 +/- 0.8 mM), mean +/- SE peak incremental glucose rises were similar after analogues AspB10 (5.4 +/- 0.8 mM) and AspB9, GluB27 (5.4 +/- 0.7 mM) and significantly lower after analogue AspB28 (3.6 +/- 1.2 mM, P less than 0.02). Relative to soluble human insulin (100% +/- SE21), incremental areas under the glucose curve between 0 and 240 min were 79% +/- 34 (AspB10, NS), 70% +/- 29 (AspB9, GluB27, NS), and 43% +/- 23 (AspB28, P less than 0.02). Basal plasma free insulin levels were similar on the 4 study days. Plasma free insulin-analogue levels rose rapidly to peak 30 min after injection at 308 +/- 44 pM (AspB10); 1231 +/- 190 pM (AspB9, GluB27) and 414 +/- 42 pM (AspB28) and were significantly higher than corresponding (i.e., 30 min postmeal) plasma free insulin levels of 157 +/- 15 pM (P less than 0.02 in each case). Plasma profiles of the insulin analogues were more physiological than that of human insulin after subcutaneous injection. All three analogues given immediately before the meal are at least as effective as soluble human insulin given 30 min earlier. These analogues are promising potential candidates for short-acting insulins of the future.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takata, Takumi; Shimo-Oka, Tadashi; Kojima, Masami

Although proteins are generally composed of L-{alpha}-amino acids, D-{beta}-aspartic acid (Asp)-containing proteins have been reported in various elderly tissues. Our previous study detected several D-{beta}-Asp-containing proteins in a rabbit lens derived from epithelial cell line by Western blot analysis of a 2D-gel using a polyclonal antibody that is highly specific for D-{beta}-Asp-containing proteins. The identity of each spot was subsequently determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and the Ms-Fit online database searching algorithm. In this study, we discovered novel D-{beta}-Asp-containing proteins from rabbit lens. The results indicate that {beta}-crystallin A3, {beta}-crystallin A4, {beta}-crystallin B1, {beta}-crystallin B2, {beta}-crystallin B3,more » {gamma}-crystallin C, {gamma}-crystallin D, and {lambda}-crystallin in rabbit lens contain D-{beta}-Asp residues. Furthermore, the occurrence of D-{beta}-Asp residues increases with infrared ray (IR) irradiation. Additionally, some D-{beta}-Asp-containing proteins only appear after IR irradiation. One such protein is the {alpha}-enolase, which shows homology to {tau}-crystallin.« less

GLU298ASP and 4G/5G Polymorphisms and the Risk of Ischemic Stroke in Young Individuals.

PubMed

Esparza-García, Juan Carlos; Santiago-Germán, David; Guadalupe Valades-Mejía, María; Hernández-Juárez, Jesus; Aguilar-Sosa, Eberth; Leaños-Miranda, Alfredo; Alvarado-Moreno, Antonio; Majluf-Cruz, Abraham; Isordia-Salas, Irma

2015-09-01

Polymorphisms in the endothelial nitric oxide synthase (eNOS) and in the plasminogen activator inhibitor -1 (PAI-1) genes have been implicated in stroke pathogenesis but results are still controversial. The aim of this study was to examine the possible contribution of Glu298Asp in the eNOS and 4G/5G in the PAI-1polymorphisms with ischemic stroke in a young Mexican population. In a case-control study, conducted between January 2006 and June 2010, 204 patients ≤45 years of age with ischemic stroke and 204 controls matched by age and gender, were recruited. The Glu298Asp and 4G/5G polymorphisms were determined in all participants by polymerase chain reaction-restriction fragment length polymorphism. There was a significant difference in the Glu298Asp genotype distribution (P=0.001) and allele frequency between the two groups (P=0.001). The 4G/5G genotype distribution (P=0.40) and the allele frequency was similar between groups; (P=0.13). There were independent factors for ischemic stroke: Asp carriage (GluAsp+AspAsp) (P=0.02); smoking (P=0.01); hypertension (P=0.03), and familial history of atherothrombotic disease (P=0.04). The Asp allele from the Gu298Asp gene represents an independent risk factor for ischemic stroke in a young Mexican population. In contrast, the 4G/5G was not associated with an increased risk for this disease in the same group of patients, as previously has been demonstrated in other populations.

Molecular characterization of 45 kDa aspartic protease of Trichinella spiralis.

PubMed

Park, Jong Nam; Park, Sang Kyun; Cho, Min Kyoung; Park, Mi-Kyung; Kang, Shin Ae; Kim, Dong-Hee; Yu, Hak Sun

2012-12-21

In a previous study, we identified an aspartic protease gene (Ts-Asp) from the Trichinella spiralis muscle stage larva cDNA library. The gene sequence of Ts-Asp was 1281 bp long and was found to encode a protein consisting of 405 amino acids, with a molecular mass of 45.248 kD and a pI of 5.95. The deduced Ts-Asp has a conserved catalytic motif with catalytic aspartic acid residues in the active site, a common characteristic of aspartic proteases. In addition, the deduced amino acid sequence of Ts-Asp was found to possess significant homology (above 50%) with aspartic proteases from nematode parasites. Results of phylogenetic analysis indicated a close relationship of Ts-Asp with cathepsin D aspartic proteases. For production of recombinant Ts-Asp (rTs-Asp), the pGEX4T expression system was used. Like other proteases, the purified rTs-Asp was able to digest collagen matrix in vitro. Abundant expression of Ts-Asp was observed in muscle stage larva. Ts-Asp was detected in ES proteins, and was able to elicit the production of specific antibodies. It is the first report of molecular characterization of aspartic protease isolated from T. spiralis. Copyright © 2012 Elsevier B.V. All rights reserved.

Two Salt Bridges Differentially Contribute to the Maintenance of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channel Function*

PubMed Central

Cui, Guiying; Freeman, Cody S.; Knotts, Taylor; Prince, Chengyu Z.; Kuang, Christopher; McCarty, Nael A.

2013-01-01

Previous studies have identified two salt bridges in human CFTR chloride ion channels, Arg352-Asp993 and Arg347-Asp924, that are required for normal channel function. In the present study, we determined how the two salt bridges cooperate to maintain the open pore architecture of CFTR. Our data suggest that Arg347 not only interacts with Asp924 but also interacts with Asp993. The tripartite interaction Arg347-Asp924-Asp993 mainly contributes to maintaining a stable s2 open subconductance state. The Arg352-Asp993 salt bridge, in contrast, is involved in stabilizing both the s2 and full (f) open conductance states, with the main contribution being to the f state. The s1 subconductance state does not require either salt bridge. In confirmation of the role of Arg352 and Asp993, channels bearing cysteines at these sites could be latched into a full open state using the bifunctional cross-linker 1,2-ethanediyl bismethanethiosulfonate, but only when applied in the open state. Channels remained latched open even after washout of ATP. The results suggest that these interacting residues contribute differently to stabilizing the open pore in different phases of the gating cycle. PMID:23709221

Effects of long-term administration of aspartame on biochemical indices, lipid profile and redox status of cellular system of male rats.

PubMed

Adaramoye, Oluwatosin A; Akanni, Olubukola O

2016-01-01

Aspartame (N-L-α-aspartyl-L-phenylalanine-1-methyl ester) (ASP) is a synthetic sweetener used in foods and its safety remains controversial. The study was designed to investigate the effects of long-term administration of aspartame on redox status, lipid profile and biochemical indices in tissues of male Wistar rats. Rats were assigned into four groups and given distilled water (control), aspartame at doses of 15 mg/kg (ASP 1), 35 mg/kg (ASP 2) and 70 mg/kg (ASP 3) daily by oral gavage for consecutive 9 weeks. Administration of ASP 2 and ASP 3 significantly increased the weight of liver and brain, and relative weight of liver of rats. Lipid peroxidation products significantly increased in the kidney, liver and brain of rats at all doses of ASP with concomitant depletion of antioxidant parameters, viz. glutathione-s-transferase, glutathione peroxidase, superoxide dismutase, catalase and reduced glutathione. Furthermore, ASP 2 and ASP 3 significantly increased the levels of gamma glutamyl transferase by 70% and 85%; alanine aminotransferase by 66% and 117%; aspartate aminotransferase by 21% and 48%; urea by 72% and 58% and conjugated bilirubin by 63% and 64%, respectively. Also, ASP 2 and ASP 3 significantly increased the levels of total cholesterol, triglycerides and low-density lipoprotein cholesterol in the rats. Histological findings showed that ASP 2 and ASP 3 caused cyto-architectural changes such as degeneration, monocytes infiltration and necrotic lesions in brain, kidney and liver of rats. Aspartame may induce redox and lipid imbalance in rats via mechanism that involves oxidative stress and depletion of glutathione-dependent system.

76 FR 40912 - Agency Information Collection Request. 30-Day Public Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-12

... primary care services into publicly-funded community mental health and other community-based behavioral... Secretary for Planning and Evaluation (ASPE) and the Substance Abuse and Mental Health Services Administration are funding an independent evaluation of the Substance Abuse and Mental Health Services...

Effects of aspartic acid and potassium chloride on arginine kinase from shrimp.

PubMed

Tang, Hong-min; Yang, Yin-ye; Zhang, Song-fu

2006-12-15

The aspartic acid (Asp)-induced unfolding and the salt-induced folding of arginine kinase (AK) were studied in terms of enzyme activity, intrinsic fluorescence emission spectra, 1-anilino-8-naphthalenesulfonate (ANS) fluorescence spectra and far-UV circular dichroism (CD) spectra. The results showed that Asp caused inactivation and unfolding of AK with no aggregation during AK denaturation. The unfolding of the whole molecule and the inactivation of AK in different Asp concentrations were compared. Much lower Asp concentration was required to induce inactivation than to produce significant conformational changes of the enzyme molecule. However, with further addition of Asp, the molar ellipticity at 222 and 208 nm, the wavelength shift and the emission intensity of ANS hardly changed. Asp denatured AK was reactivated by dilution. In addition, potassium chloride (KCl) induced the molten globule state with a compact structure after AK was denatured with 7.5 mM Asp. These results collectively elucidate the osmotic effect of Asp anions for the molten globule formed during unfolding process. They also suggest that the effect of Asp differed from that of other denaturants such as guanidine hydrochloride or urea during AK folding. The molten globule state indicates that intermediates exist during AK folding.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Metz, G.; Siebert, F.; Engelhard, M.

Solid state {sup 13}C nuclear magnetic resonance measurements of bacteriorhodopsin labeled with (4-{sup 13}C)Asp show that resonances of single amino acids can be resolved. In order to assign and characterize the resonances of specific Asp residues, three different approaches were used. (1) Determination of the chemical shift anisotropy from side-band intensities provides information about the protonation state of Asp residues; (2) relaxation studies and T{sub 1} filtering allow one to discriminate between resonances with different mobility; (3) a comparison of the spectra of light- and dark-adapted bacteriorhodopsin provides evidence for resonances from aspartic acid residues in close neighborhood of themore » chromophore. In agreement with other investigations, four resonances are assigned to internal residues. Two of them are protonated in the ground state up to pH 10 (Asp{sub 96} and Asp{sub 115}). All other detected resonance, including Asp{sub 85} and Asp{sub 212}, are due to deprotonated aspartic acid. Two lines due to the two internal deprotonated groups change upon dark and light adaptation, whereas the protonated Asp residues are unaffected.« less

Biodegradation of phenanthrene in bioaugmented microcosm by consortium ASP developed from coastal sediment of Alang-Sosiya ship breaking yard.

PubMed

Patel, Vilas; Patel, Janki; Madamwar, Datta

2013-09-15

A phenanthrene-degrading bacterial consortium (ASP) was developed using sediment from the Alang-Sosiya shipbreaking yard at Gujarat, India. 16S rRNA gene-based molecular analyses revealed that the bacterial consortium consisted of six bacterial strains: Bacillus sp. ASP1, Pseudomonas sp. ASP2, Stenotrophomonas maltophilia strain ASP3, Staphylococcus sp. ASP4, Geobacillus sp. ASP5 and Alcaligenes sp. ASP6. The consortium was able to degrade 300 ppm of phenanthrene and 1000 ppm of naphthalene within 120 h and 48 h, respectively. Tween 80 showed a positive effect on phenanthrene degradation. The consortium was able to consume maximum phenanthrene at the rate of 46 mg/h/l and degrade phenanthrene in the presence of other petroleum hydrocarbons. A microcosm study was conducted to test the consortium's bioremediation potential. Phenanthrene degradation increased from 61% to 94% in sediment bioaugmented with the consortium. Simultaneously, bacterial counts and dehydrogenase activities also increased in the bioaugmented sediment. These results suggest that microbial consortium bioaugmentation may be a promising technology for bioremediation. Copyright © 2013 Elsevier Ltd. All rights reserved.

75 FR 41867 - Request for Information on Development of an Inventory of Comparative Effectiveness Research

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-19

... Comparative Effectiveness Research AGENCY: Office of the Assistant Secretary for Planning and Evaluation... (ASPE) is developing a national inventory of comparative effectiveness research (CER) and CER-related... Federal Coordinating Council for Comparative Effectiveness Research, which defined CER as the: Conduct and...

75 FR 65340 - Agency Emergency Information Collection Clearance Request for Public Comment

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-22

.... Proposed Project: Healthy Living Innovation Awards--OMB No. 0990- NEW--Emergency Information Collection... Secretary for Planning and Evaluation (ASPE) is requesting emergency approval from the Office of Management... Living Innovation Awards. The project will provide an opportunity for HHS to increase public awareness of...

Additive antithrombotic effect of ASP6537, a selective cyclooxygenase (COX)-1 inhibitor, in combination with clopidogrel in guinea pigs.

PubMed

Sakata, Chinatsu; Suzuki, Ken-Ichi; Morita, Yoshiaki; Kawasaki, Tomihisa

2017-03-05

Clopidogrel (Plavix ® , Sanofi-Aventis), the adenosine diphosphate P2Y 12 receptor antagonist, is reported to be effective in the prevention of cardiovascular events and is often used in combination with aspirin, particularly in high-risk patients. ASP6537 is a reversible cyclooxygenase (COX)-1 inhibitor that is under investigation as an anti-platelet agent. First, we investigated the reversibility of the antiplatelet effect of ASP6537 and its interaction with ibuprofen to compare the usability of ASP6537 with that of aspirin. We then evaluated the antithrombotic effect of ASP6537 in combination with clopidogrel using a FeCl 3 -induced thrombosis model in guinea pigs. ASP6537 exerted reversible antiplatelet activity, and no pharmacodynamic interaction with ibuprofen was noted. When administered as monotherapy, ASP6537 exerted a significant antithrombotic effect at ≥3mg/kg, while aspirin inhibited thrombosis at 100mg/kg. ASP6537 exerted significant additive effects in combination with clopidogrel, and the minimum antithrombotic dose was reduced by concomitant administration of clopidogrel. Our study showed that ASP6537 did not interact with ibuprofen and has clear additive effects in combination with clopidogrel. ASP6537 may therefore represent a promising antiplatelet agent for use in clinical settings in combination with clopidogrel. Copyright © 2017 Elsevier B.V. All rights reserved.

Framework for the design and delivery of organized physical activity sessions for children and adolescents: rationale and description of the 'SAAFE' teaching principles.

PubMed

Lubans, David R; Lonsdale, Chris; Cohen, Kristen; Eather, Narelle; Beauchamp, Mark R; Morgan, Philip J; Sylvester, Benjamin D; Smith, Jordan J

2017-02-23

The economic burden of inactivity is substantial, with conservative estimates suggesting the global cost to health care systems is more than US$50 billion. School-based programs, including physical education and school sport, have been recommended as important components of a multi-sector, multi-system approach to address physical inactivity. Additionally, community sporting clubs and after-school programs (ASPs) offer further opportunities for young people to be physically active outside of school. Despite demonstrating promise, current evidence suggests school-based physical activity programs, community sporting clubs and ASPs are not achieving their full potential. For example, physical activity levels in physical education (PE) and ASP sessions are typically much lower than recommended. For these sessions to have the strongest effects on young people's physical activity levels and their on-going physical literacy, they need to improve in quality and should be highly active and engaging. This paper presents the Supportive, Active, Autonomous, Fair, Enjoyable (SAAFE) principles, which represent an evidence-based framework designed to guide the planning, delivery and evaluation of organized physical activity sessions in school, community sport and ASPs. In this paper we provide a narrative and integrative review of the conceptual and empirical bases that underpin this framework and highlight implications for knowledge translation and application.

The Networks Of The Astronomical Society Of The Pacific And The International Year Of Astronomy

NASA Astrophysics Data System (ADS)

Fraknoi, Andrew; Manning, J.; Gurton, S.; Gibbs, M.; Hurst, A.; White, V.; Berendsen, M.

2007-12-01

Serious planning has begun for the International Year of Astronomy (IYA) in 2009, which will also be the 120th anniversary of the Astronomical Society of the Pacific (ASP). A key element required for IYA's success in reaching the maximum number of people in the U.S. will be to find effective ways of disseminating the programs and materials that are being developed. The ASP's national networks of educational intermediaries can play a major role in training, dissemination, and organization for IYA. These networks include: the Project ASTRO National Site Network (13 regional sites training professional and amateur astronomers to work with local teachers and families), the Night Sky Network (over 200 amateur astronomy clubs engaged in active outreach), the Astronomy from the Ground Up Network (smaller science and nature centers increasing their offerings in astronomy), and the Cosmos in the Classroom Network (hundreds of instructors of introductory astronomy in community, state, and liberal arts colleges). The ASP also offers "The Universe in the Classroom", a quarterly newsletter for those teaching astronomy in grades 3-12, an extensive web site of educational resources, podcasts, workshops, national conferences, and awards to help improve the public understanding of astronomy. At the Summer 2008 AAS meeting, the ASP will sponsor a major symposium and workshops on preparing for IYA (and working with a range of different audiences.)

Design of polyaspartic acid peptide-poly (ethylene glycol)-poly (ε-caprolactone) nanoparticles as a carrier of hydrophobic drugs targeting cancer metastasized to bone

PubMed Central

Liu, Jinsong; Zeng, Youyun; Shi, Shuai; Xu, Lihua; Zhang, Hualin; Pathak, Janak L; Pan, Yihuai

2017-01-01

Treatment of cancer metastasized to bone is still a challenge due to hydrophobicity, instability, and lack of target specificity of anticancer drugs. Poly (ethylene glycol)-poly (ε-caprolactone) polymer (PEG-PCL) is an effective, biodegradable, and biocompatible hydrophobic drug carrier, but lacks bone specificity. Polyaspartic acid with eight peptide sequences, that is, (Asp)8, has a strong affinity to bone surface. The aim of this study was to synthesize (Asp)8-PEG-PCL nanoparticles as a bone-specific carrier of hydrophobic drugs to treat cancer metastasized to bone. 1H nuclear magnetic resonance, Fourier transform infrared spectroscopy, and transmission electron microscopy data showed that (Asp)8-PEG-PCL nanoparticles (size 100 nm) were synthesized successfully. (Asp)8-PEG-PCL nanoparticles did not promote erythrocyte aggregation. Fluorescence microscopy showed clear uptake of Nile red-loaded (Asp)8-PEG-PCL nanoparticles by cancer cells. (Asp)8-PEG-PCL nanoparticles did not show cytotoxic effect on MG63 and human umbilical vein endothelial cells at the concentration of 10–800 μg/mL. (Asp)8-PEG-PCL nanoparticles bound with hydroxyapatite 2-fold more than PEG-PCL. Intravenously injected (Asp)8-PEG-PCL nanoparticles accumulated 2.7-fold more on mice tibial bone, in comparison to PEG-PCL. Curcumin is a hydrophobic anticancer drug with bone anabolic properties. Curcumin was loaded in the (Asp)8-PEG-PCL. (Asp)8-PEG-PCL showed 11.07% loading capacity and 95.91% encapsulation efficiency of curcumin. The curcumin-loaded (Asp)8-PEG-PCL nanoparticles gave sustained release of curcumin in high dose for >8 days. The curcumin-loaded (Asp)8-PEG-PCL nanoparticles showed strong antitumorigenic effect on MG63, MCF7, and HeLa cancer cells. In conclusion, (Asp)8-PEG-PCL nanoparticles were biocompatible, permeable in cells, a potent carrier, and an efficient releaser of hydrophobic anticancer drug and were bone specific. The curcumin-loaded (Asp)8-PEG-PCL nanoparticles showed strong antitumorigenic ability in vitro. Therefore, (Asp)8-PEG-PCL nanoparticles could be a potent carrier of hydrophobic anticancer drugs to treat the cancer metastasized to bone. PMID:28507436

Design of polyaspartic acid peptide-poly (ethylene glycol)-poly (ε-caprolactone) nanoparticles as a carrier of hydrophobic drugs targeting cancer metastasized to bone.

PubMed

Liu, Jinsong; Zeng, Youyun; Shi, Shuai; Xu, Lihua; Zhang, Hualin; Pathak, Janak L; Pan, Yihuai

2017-01-01

Treatment of cancer metastasized to bone is still a challenge due to hydrophobicity, instability, and lack of target specificity of anticancer drugs. Poly (ethylene glycol)-poly (ε-caprolactone) polymer (PEG-PCL) is an effective, biodegradable, and biocompatible hydrophobic drug carrier, but lacks bone specificity. Polyaspartic acid with eight peptide sequences, that is, (Asp) 8 , has a strong affinity to bone surface. The aim of this study was to synthesize (Asp) 8 -PEG-PCL nanoparticles as a bone-specific carrier of hydrophobic drugs to treat cancer metastasized to bone. 1 H nuclear magnetic resonance, Fourier transform infrared spectroscopy, and transmission electron microscopy data showed that (Asp) 8 -PEG-PCL nanoparticles (size 100 nm) were synthesized successfully. (Asp) 8 -PEG-PCL nanoparticles did not promote erythrocyte aggregation. Fluorescence microscopy showed clear uptake of Nile red-loaded (Asp) 8 -PEG-PCL nanoparticles by cancer cells. (Asp) 8 -PEG-PCL nanoparticles did not show cytotoxic effect on MG63 and human umbilical vein endothelial cells at the concentration of 10-800 μg/mL. (Asp) 8 -PEG-PCL nanoparticles bound with hydroxyapatite 2-fold more than PEG-PCL. Intravenously injected (Asp) 8 -PEG-PCL nanoparticles accumulated 2.7-fold more on mice tibial bone, in comparison to PEG-PCL. Curcumin is a hydrophobic anticancer drug with bone anabolic properties. Curcumin was loaded in the (Asp) 8 -PEG-PCL. (Asp) 8 -PEG-PCL showed 11.07% loading capacity and 95.91% encapsulation efficiency of curcumin. The curcumin-loaded (Asp) 8 -PEG-PCL nanoparticles gave sustained release of curcumin in high dose for >8 days. The curcumin-loaded (Asp) 8 -PEG-PCL nanoparticles showed strong antitumorigenic effect on MG63, MCF7, and HeLa cancer cells. In conclusion, (Asp) 8 -PEG-PCL nanoparticles were biocompatible, permeable in cells, a potent carrier, and an efficient releaser of hydrophobic anticancer drug and were bone specific. The curcumin-loaded (Asp) 8 -PEG-PCL nanoparticles showed strong antitumorigenic ability in vitro. Therefore, (Asp) 8 -PEG-PCL nanoparticles could be a potent carrier of hydrophobic anticancer drugs to treat the cancer metastasized to bone.

DOE Office of Scientific and Technical Information (OSTI.GOV)

French, Troy

Le Norman Energy Company conducted research on field application of alkaline-surfactant-polymer (ASP) flooding as a part of the U.S. Department of Energy's plan to maximize the production of our domestic oil resources. In addition to having substantial technical merit, the process uses chemicals that are environmentally acceptable. Le Norman's field project is located in the Sho-Vel-Tum (OK) oil field, which was a major producer of crude oil in past years, but has since been extensively waterflooded. This reservoir in this portion of the field is typical of many shallow reservoirs in the Oklahoma-Kansas area and is a good demonstration sitemore » for that area. The pay zones are located approximately 700 ft. deep, and this project is the shallowest field test for ASP flooding.« less

Neutropenia associated with vincristine and L-asparaginase induction chemotherapy for canine lymphoma.

PubMed

Northrup, Nicole C; Rassnick, Kenneth M; Snyder, Laura A; Stone, Michael S; Kristal, Orna; Cotter, Susan M; Moore, Antony S

2002-01-01

Vincristine (VCR) and L-asparaginase (L-ASP) are commonly used to treat canine lymphoma. As single agents, these drugs are not myelosuppressive. However, in combination, VCR and L-ASP cause severe neutropenia in some dogs. It has been recommended that L-ASP be administered 12-24 hours after VCR to minimize toxicity. The purpose of this retrospective study was to determine the prevalence of neutropenia after VCR/L-ASP induction therapy for canine lymphoma and to evaluate risk factors for myelosuppression, especially the interval between VCR and L-ASP administration. Medical records of 147 dogs were reviewed. L-ASP was given 0 (n = 50), 6 (n = 23), 18 (n = 20), or 24 (n = 54) hours after VCR. Forty percent of the dogs were neutropenic 7 days after VCR/L-ASP, and 18% had neutrophil counts of <1,000 cells/microL. The median neutrophil count was 3,712 cells/microL (range 0-30,968 cells/microL). No correlation was found between administration interval and day 7 neutrophil count (P = .84) or development of gastrointestinal signs, including vomiting (P = .80), diarrhea (P = .52), and decreased appetite (P = .30). No significant predictors of neutropenia were identified. Higher clinical stage and substage b were associated with decreased appetite after treatment (P = .04 and .01, respectively). Sixteen percent of the dogs were hospitalized. This study demonstrates that VCR/L-ASP induction for canine lymphoma may result in neutropenia but that separation of VCR and L-ASP administration may not be necessary to avoid toxicity.

Interface design and reinforced features of arrowroot (Maranta arundinacea) starch/polyester-based membranes: Preparation, antioxidant activity, and cytocompatibility.

PubMed

Wu, Chin-San; Liao, Hsin-Tzu

2017-01-01

The structural, mechanical, antioxidant, and cytocompatibility properties of membranes prepared from the polyhydroxyalkanoate (PHA) and arrowroot (Maranta arundinacea) starch powder (ASP) blend (PHA/ASP) were studied. The acrylic acid-grafted PHA (PHA-g-AA) and the coupling agent treated ASP (TASP) were used to enhance the desired characteristics of these membranes. The PHA-g-AA/TASP membranes had better mechanical properties than the PHA/ASP membrane. This effect was attributed to greater compatibility between the grafted PHA and TASP. The water resistance of the PHA-g-AA/TASP membranes was greater than that of the PHA/ASP membranes, and a cytocompatibility evaluation with human foreskin fibroblasts (FBs) indicated that both materials were nontoxic. Moreover, both ASP and TASP enhanced the polyphenol content and antioxidant properties of the membranes. PHA-g-AA/TASP and PHA/ASP membranes had better antioxidant activity than the control group. Copyright © 2016 Elsevier B.V. All rights reserved.

Biomass characterization of laboratory-scale thermophilic-mesophilic wastewater treatment processes.

PubMed

Suvilampi, J; Lehtomäki, A; Rintala, J

2006-01-01

Two thermophilic-mesophilic wastewater treatment processes, one as the combination of the thermophilic activated sludge process (ASP), followed by the mesophilic ASP and the other as thermophilic suspended carrier biofilm process (SCBP), followed by the mesophilic ASP, were used to study sludge characteristics and floc formation. Thermophilic bacteria in both ASP and SCBP were able to form flocs, which were <50 microm in size and had a weak structure and irregular shape. Flocs in both the mesophilic ASPs were larger in size (50-500 microm) and had more compact structures. Filamentous bacteria played an important role in both the thermophilic and mesophilic processes by forming bridges between small flocs. Both thermophilic processes showed a high density of dispersed particles, such as free bacteria. When hydraulic retention time (HRT) was decreased the biofilm was retained in the thermophilic SCBP better than the flocs in the thermophilic ASP. The mesophilic ASPs efficiently removed dispersed particles originating from the thermophilic processes.

[Effects of Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly peptides on hormonal activity and thyroid morphology in hypophysectomized mature and old birds].

PubMed

Kuznik, B I; Pateiuk, A V; Rusaeva, N S; Baranchugova, L M; Obydenko, V I

2011-01-01

The aim of the paper was to investigate effects of Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly peptides which were designed and synthesized on the basis of amino acid study of the hypophyseal anterior and posterior lobe peptides on the thyroid morphology and hormonal activity in mature chicken and old birds. Hypophysectomy was established to produce atrophic changes in the thyroid gland and development of secondary hypothyrosis. Administration of Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly tetrapeptides significantly prevented these impairments by increasing the levels of the thyroid-stimulating hormone (TSH) as well as T3 and T4. Restoration of the thyroid functions and morphology was registered to be greater in one-year-old chicken as compared to five-year-old ones.

Genetic polymorphisms of xeroderma pigmentosum group D gene Asp312Asn and Lys751Gln and susceptibility to prostate cancer: a systematic review and meta-analysis.

PubMed

Ma, Qingtong; Qi, Can; Tie, Chong; Guo, Zhanjun

2013-11-10

Many studies have reported the role of xeroderma pigmentosum group D (XPD) with prostate cancer risk, but the results remained controversial. To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between XPD Asp312Asn and Lys751Gln polymorphisms and prostate cancer risk. A total of 8 studies including 2620 cases and 3225 controls described Asp312Asn genotypes, among which 10 articles involving 3230 cases and 3582 controls described Lys751Gln genotypes and were also involved in this meta-analysis. When all the eligible studies were pooled into this meta-analysis, a significant association between prostate cancer risk and XPD Asp312Asn polymorphism was found. For Asp312Asn polymorphism, in the stratified analysis by ethnicity and source of controls, prostate cancer risk was observed in co-dominant, dominant and recessive models, while no evidence of any associations of XPD Lys751Gln polymorphism with prostate cancer was found in the overall or subgroup analyses. Our meta-analysis supports that the XPD Asp312Asn polymorphism contributed to the risk of prostate cancer from currently available evidence. However, a study with a larger sample size is needed to further evaluate gene-environment interaction on XPD Asp312Asn and Lys751Gln polymorphisms and prostate cancer risk. © 2013.

Host protective ASP-based vaccine against the parasitic nematode Ostertagia ostertagi triggers NK cell activation and mixed IgG1-IgG2 response.

PubMed

González-Hernández, Ana; Van Coppernolle, Stefanie; Borloo, Jimmy; Van Meulder, Frederik; Paerewijck, Oonagh; Peelaers, Iris; Leclercq, Georges; Claerebout, Edwin; Geldhof, Peter

2016-07-11

The mucus-dwelling parasite Ostertagia ostertagi is one of the most important gastrointestinal nematodes in cattle. Our group has previously demonstrated the protective capacity of a vaccine against this parasite based on a native activation-associated secreted protein ASP1 (nASP) in combination with the saponin adjuvant QuilA. The aim of the current study was to analyse the effect of both antigen and adjuvant on the cellular and humoral vaccine-induced immune responses by comparing the native ASP to a recombinant version expressed in Pichia pastoris (pASP) and replacing QuilA by Al(OH)3. Immunization of cattle with the protective nASP+QuilA vaccine was associated with antigen-induced proliferation of natural killer (NK) cells combined with IFN-γ secretion and the induction of a mixed IgG1/IgG2 antibody response. ASP-specific activation and proliferation of NK cells was also observed in mice following the same vaccination regime. Replacing QuilA by Al(OH)3 or nASP by pASP significantly decreased the capacity of the vaccines to trigger both NK cell activation and antibody responses and failed to induce protection against a challenge infection. Reduction of the structurally anchoring disulphide bonds of the nASP completely abolished its ability to induce NK cell activation and antibody responses, highlighting the importance of protein conformation for the immunostimulatory activity.

The dipeptide Pro-Asp promotes IGF-1 secretion and expression in hepatocytes by enhancing JAK2/STAT5 signaling pathway.

PubMed

Wang, Songbo; Wang, Guoqing; Zhang, Mengyuan; Zhuang, Lu; Wan, Xiaojuan; Xu, Jingren; Wang, Lina; Zhu, Xiaotong; Gao, Ping; Xi, Qianyun; Zhang, Yongliang; Shu, Gang; Jiang, Qingyan

2016-11-15

It has been implicated that IGF-1 secretion can be regulated by dietary protein. However, whether the dipeptides, one of digested products of dietary protein, have influence on IGF-1 secretion remain largely unknown. Our study aimed to investigate the effects of the dipeptide Pro-Asp on IGF-1 secretion and expression in hepatocytes and to explore the possible underlying mechanisms. Our findings demonstrated that Pro-Asp promoted the secretion and gene expression of IGF-1 in HepG2 cells and primary porcine hepatocytes. Meanwhile, Pro-Asp activated the ERK and Akt signaling pathways, downstream of IGF-1. In addition, Pro-Asp enhanced GH-mediated JAK2/STAT5 signaling pathway, while inhibition of JAK2/STAT5 blocked the promotive effect of Pro-Asp on IGF-1 secretion and expression. Moreover, acute injection of Pro-Asp stimulated IGF-1 expression and activated JAK2/STAT5 signaling pathway in mice liver. Together, these results suggested that the dipeptide Pro-Asp promoted IGF-1 secretion and expression in hepatocytes by enhancing GH-mediated JAK2/STAT5 signaling pathway. Copyright © 2016. Published by Elsevier Ireland Ltd.

Comparative study of (Asp)7-CHOL-modified liposome prepared using pre-insertion and post-insertion methods for bone targeting in vivo.

PubMed

Zhang, Lijing; Cao, Hua; Zhang, Jiaxin; Yang, Chengli; Hu, Tingting; Li, Huili; Yang, Wu; He, Gu; Song, Xiangrong; Tong, Aiping; Guo, Gang; Li, Rui; Jiang, Yu; Liu, Jiyan; Cai, Lulu; Zheng, Yu

2017-02-01

Specific delivery of drugs to bone tissue is very challenging due to the architecture and structure of bone tissue. A seven-repeat sequence of aspartate, a representative bone-targeting oligopeptide, is preferentially used for targeted therapy for bone diseases. In this study, Asp7-cholesterol((Asp)7-CHOL) was synthesized and (Asp)7-CHOL-modified liposome loaded with doxorubicin (DOX) was successfully prepared using both pre-insertion (pre-L) and post-insertion (post-L) methods. The formulation was optimized according to particle size, zeta potential and the drug-loading efficiency of the liposome. In addition, the bone affinity of the (Asp)7-CHOL-modified liposome was evaluated using a hydroxyapatite (HA) absorption method. The results suggested that (Asp)7-CHOL-modified liposome show excellent HA absorption; pre-L showed slightly higher HA binding than post-L. However, post-L had a higher DOX entrapment efficiency than pre-L. In vivo imaging further demonstrated that pre-L showed a higher bone-targeting efficiency than post-L, which was consistent with in vitro results. In all, (Asp)7-CHOL-modified liposome showed excellent bone-targeting activity, suggesting their potential for use as a drug delivery system for bone disease-targeted therapies.

Gender differences in D-aspartic acid content in skull bone.

PubMed

Torikoshi-Hatano, Aiko; Namera, Akira; Shiraishi, Hiroaki; Arima, Yousuke; Toubou, Hirokazu; Ezaki, Jiro; Morikawa, Masami; Nagao, Masataka

2012-12-01

In forensic medicine, the personal identification of cadavers is one of the most important tasks. One method of estimating age at death relies on the high correlation between racemization rates in teeth and actual age, and this method has been applied successfully in forensic odontology for several years. In this study, we attempt to facilitate the analysis of racemized amino acids and examine the determination of age at death on the basis of the extent of aspartic acid (Asp) racemization in skull bones. The specimens were obtained from 61 human skull bones (19 females and 42 males) that underwent judicial autopsy from October 2010 to May 2012. The amount of D-Asp and L-Asp, total protein, osteocalcin, and collagen I in the skull bones was measured. Logistic regression analysis was performed for age, sex, and each measured protein. The amount of D-Asp in the female skull bones was significantly different from that in the male skull bones (p = 0.021), whereas the amount of L-Asp was similar. Thus, our study indicates that the amount of D-Asp in skull bones is different between the sexes.

De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy.

PubMed

Fassio, Anna; Esposito, Alessandro; Kato, Mitsuhiro; Saitsu, Hirotomo; Mei, Davide; Marini, Carla; Conti, Valerio; Nakashima, Mitsuko; Okamoto, Nobuhiko; Olmez Turker, Akgun; Albuz, Burcu; Semerci Gündüz, C Nur; Yanagihara, Keiko; Belmonte, Elisa; Maragliano, Luca; Ramsey, Keri; Balak, Chris; Siniard, Ashley; Narayanan, Vinodh; Ohba, Chihiro; Shiina, Masaaki; Ogata, Kazuhiro; Matsumoto, Naomichi; Benfenati, Fabio; Guerrini, Renzo

2018-06-01

V-type proton (H+) ATPase (v-ATPase) is a multi-subunit proton pump that regulates pH homeostasis in all eukaryotic cells; in neurons, v-ATPase plays additional and unique roles in synapse function. Through whole exome sequencing, we identified de novo heterozygous mutations (p.Pro27Arg, p.Asp100Tyr, p.Asp349Asn, p.Asp371Gly) in ATP6V1A, encoding the A subunit of v-ATPase, in four patients with developmental encephalopathy with epilepsy. Early manifestations, observed in all patients, were developmental delay and febrile seizures, evolving to encephalopathy with profound delay, hypotonic/dyskinetic quadriparesis and intractable multiple seizure types in two patients (p.Pro27Arg, p.Asp100Tyr), and to moderate delay with milder epilepsy in the other two (p.Asp349Asn, p.Asp371Gly). Modelling performed on the available prokaryotic and eukaryotic structures of v-ATPase predicted p.Pro27Arg to perturb subunit interaction, p.Asp100Tyr to cause steric hindrance and destabilize protein folding, p.Asp349Asn to affect the catalytic function and p.Asp371Gly to impair the rotation process, necessary for proton transport. We addressed the impact of p.Asp349Asn and p.Asp100Tyr mutations on ATP6V1A expression and function by analysing ATP6V1A-overexpressing HEK293T cells and patients' lymphoblasts. The p.Asp100Tyr mutant was characterized by reduced expression due to increased degradation. Conversely, no decrease in expression and clearance was observed for p.Asp349Asn. In HEK293T cells overexpressing either pathogenic or control variants, p.Asp349Asn significantly increased LysoTracker® fluorescence with no effects on EEA1 and LAMP1 expression. Conversely, p.Asp100Tyr decreased both LysoTracker® fluorescence and LAMP1 levels, leaving EEA1 expression unaffected. Both mutations decreased v-ATPase recruitment to autophagosomes, with no major impact on autophagy. Experiments performed on patients' lymphoblasts using the LysoSensor™ probe revealed lower pH of endocytic organelles for p.Asp349Asn and a reduced expression of LAMP1 with no effect on the pH for p.Asp100Tyr. These data demonstrate gain of function for p.Asp349Asn characterized by an increased proton pumping in intracellular organelles, and loss of function for p.Asp100Tyr with decreased expression of ATP6V1A and reduced levels of lysosomal markers. We expressed p.Asp349Asn and p.Asp100Tyr in rat hippocampal neurons and confirmed significant and opposite effects in lysosomal labelling. However, both mutations caused a similar defect in neurite elongation accompanied by loss of excitatory inputs, revealing that altered lysosomal homeostasis markedly affects neurite development and synaptic connectivity. This study provides evidence that de novo heterozygous ATP6V1A mutations cause a developmental encephalopathy with a pathomechanism that involves perturbations of lysosomal homeostasis and neuronal connectivity, uncovering a novel role for v-ATPase in neuronal development.

Neural network versus activity-specific prediction equations for energy expenditure estimation in children.

PubMed

Ruch, Nicole; Joss, Franziska; Jimmy, Gerda; Melzer, Katarina; Hänggi, Johanna; Mäder, Urs

2013-11-01

The aim of this study was to compare the energy expenditure (EE) estimations of activity-specific prediction equations (ASPE) and of an artificial neural network (ANNEE) based on accelerometry with measured EE. Forty-three children (age: 9.8 ± 2.4 yr) performed eight different activities. They were equipped with one tri-axial accelerometer that collected data in 1-s epochs and a portable gas analyzer. The ASPE and the ANNEE were trained to estimate the EE by including accelerometry, age, gender, and weight of the participants. To provide the activity-specific information, a decision tree was trained to recognize the type of activity through accelerometer data. The ASPE were applied to the activity-type-specific data recognized by the tree (Tree-ASPE). The Tree-ASPE precisely estimated the EE of all activities except cycling [bias: -1.13 ± 1.33 metabolic equivalent (MET)] and walking (bias: 0.29 ± 0.64 MET; P < 0.05). The ANNEE overestimated the EE of stationary activities (bias: 0.31 ± 0.47 MET) and walking (bias: 0.61 ± 0.72 MET) and underestimated the EE of cycling (bias: -0.90 ± 1.18 MET; P < 0.05). Biases of EE in stationary activities (ANNEE: 0.31 ± 0.47 MET, Tree-ASPE: 0.08 ± 0.21 MET) and walking (ANNEE 0.61 ± 0.72 MET, Tree-ASPE: 0.29 ± 0.64 MET) were significantly smaller in the Tree-ASPE than in the ANNEE (P < 0.05). The Tree-ASPE was more precise in estimating the EE than the ANNEE. The use of activity-type-specific information for subsequent EE prediction equations might be a promising approach for future studies.

Effects of Asp-179 mutations in TEMpUC19 beta-lactamase on susceptibility to beta-lactams.

PubMed Central

Vakulenko, S B; Tóth, M; Taibi, P; Mobashery, S; Lerner, S A

1995-01-01

To examine the effect of disruption of the salt bridge (between Arg-164 and Asp-179 [numbering of Ambler et al. (Biochem J. 267:269-272, 1991)]) that anchors the conserved omega-loop in class A beta-lactamases, we obtained mutant enzymes with each of the 19 other amino acid residues replacing Asp-179 in the TEM beta-lactamase encoded by pUC19 and studied the level of resistance to various beta-lactams conferred by each enzyme. All mutations of Asp-179 compromised the level of resistance to ampicillin, but most of them enhanced resistance to ceftazidime. In contrast, mutations of Asp-179 generally impaired the low levels of resistance to cefepime and aztreonam. One might expect to find clinical isolates with mutant TEM beta-lactamases with replacements of Asp-179 that express an expanded spectrum of resistance to beta-lactams including ceftazidime. PMID:7486939

Impact of Iron-Enriched Aspergillus oryzae on Iron Bioavailability, Safety, and Gut Microbiota in Rats.

PubMed

Reddy, Manju B; Armah, Seth M

2018-06-20

Iron deficiency is a leading global nutritional problem. Ferrous sulfate (FeSO 4 ) is the most common iron source used for supplementation. Because of many side effects associated with its consumption, it is important to identify new forms of iron. The objectives of this study were to assess the bioavailability of iron-enriched Aspergillus oryzae, Aspiron (ASP), evaluate the toxicity of high-dose iron supplementation with ASP, and determine the ASP impact on gut microbiota in rats. In this study, we investigated iron bioavailability using the hemoglobin repletion test. Aspartate aminotransferase, alanine aminotransferase, and blood urea nitrogen levels were determined to evaluate the effect on liver and kidney functions. Protein carbonyls were measured to assess oxidative damage to proteins. Fecal samples at the end of the 14 day repletion period were used for 16S rRNA sequencing for gut microbiota analysis. The slope ratio method using a common intercept linear regression model was used to compare the bioavailability of ASP to FeSO 4 . Iron repletion increased hemoglobin concentrations with both ASP and FeSO 4 treatments compared to the control group, except in the lowest ASP group. The slope ratio indicated that relative iron bioavailability of ASP was 60% of that of FeSO 4 when hemoglobin change was compared to iron in the diet. Similar results were obtained when absolute iron intake was compared on the basis of food consumption. In comparison to the control, protein carbonyl concentrations were significantly ( p < 0.05) higher in the FeSO 4 group but not with the ASP group. Supplementation with both sources of iron reduced the Enterobacteriaceae population in the gut microbiota of the rats. A higher relative abundance of bacteria from the phylum Verrucomicrobia was also observed with the highest dose of ASP. Iron-enriched A. oryzae with 60% relative bioavailability of FeSO 4 did not show any signs of adverse effects after 14 days of iron supplementation. Future human studies are needed to understand the ASP detailed effect on gut microbiota.

Impact of antimicrobial stewardship programme on hospitalized patients at the intensive care unit: a prospective audit and feedback study.

PubMed

Khdour, Maher R; Hallak, Hussein O; Aldeyab, Mamoon A; Nasif, Mowaffaq A; Khalili, Aliaa M; Dallashi, Ahamad A; Khofash, Mohammad B; Scott, Michael G

2018-04-01

Inappropriate use of antibiotics is one of the most important factors contributing to the emergence of drug resistant pathogens. The purpose of this study was to measure the clinical impact of antimicrobial stewardship programme (ASP) interventions on hospitalized patients at the Intensive care unit at Palestinian Medical Complex. A prospective audit with intervention and feedback by ASP team within 48-72 h of antibiotic administration began in September 2015. Four months of pre-ASP data were compared with 4 months of post-ASP data. Data collected included clinical and demographic data; use of antimicrobials measured by defined daily doses, duration of therapy, length of stay, readmission and all-cause mortality. Overall, 176 interventions were made the ASP team with an average acceptance rate of 78.4%. The most accepted interventions were dose optimization (87.0%) followed by de-escalation based on culture results with an acceptance rate of 84.4%. ASP interventions significantly reduces antimicrobial use by 24.3% (87.3 defined daily doses/100 beds vs. 66.1 defined daily doses/100 beds P < 0.001). The median (interquartile range) of length of stay was significantly reduced post ASP [11 (3-21) vs. 7 (4-19) days; P < 0.01]. Also, the median (interquartile range) of duration of therapy was significantly reduced post-ASP [8 (5-12) days vs. 5 (3-9); P = 0.01]. There was no significant difference in overall 30-day mortality or readmission between the pre-ASP and post-ASP groups (26.9% vs. 23.9%; P = 0.1) and (26.1% vs. 24.6%; P = 0.54) respectively. Our prospective audit and feedback programme was associated with positive impact on antimicrobial use, duration of therapy and length of stay. © 2017 The British Pharmacological Society.

Earth Observations to Assess Impact of Hurricane Katrina on John C. Stennis Space Center

NASA Technical Reports Server (NTRS)

Graham, William D.; Ross, Kenton W.

2007-01-01

The peril from hurricanes to Space Operations Centers is real and is forecast to continue; Katrina, Rita, and Wilma of 2005 and Charley, Frances, Ivan, and Jeanne of 2004 are sufficient motivation for NASA to develop a multi-Center plan for preparedness and response. As was demonstrated at SSC (Stennis Space Center) in response to Hurricane Katrina, NASA Centers are efficiently activated as local command centers, playing host to Federal and State agencies and first responders to coordinate and provide evacuation, relocation, response, and recovery activities. Remote sensing decision support provides critical insight for managing NASA infrastructure and for assisting Center decision makers. Managers require geospatial information to manage the federal city. Immediately following Katrina, SSC s power and network connections were disabled, hardware was inoperative, technical staff was displaced and/or out of contact, and graphical decision support tools were non-existent or less than fully effective. Despite this circumstance, SSC EOC (Emergency Operations Center) implemented response operations to assess damage and to activate recovery plans. To assist Center Managers, the NASA ASP (Applied Sciences Program) made its archive of high-resolution data over the site available. In the weeks and months after the immediate crisis, NASA supplemented this data with high-resolution, post-Katrina imagery over SSC and much of the affected coastal areas. Much of the high-resolution imagery was made available through the Department of Defense Clear View contract and was distributed through U.S. Geological Survey Center for Earth Resources Observation and Science "Hurricane Katrina Disaster Response" Web site. By integrating multiple image data types with other information sources, ASP applied an all-source solutions approach to develop decision support tools that enabled managers to respond to critical issues, such as expedient access to infrastructure and deployment of resources, provision of temporary shelter, logistical control of critical supplies, and the mobilization and coordination of assets from ground crews to aircraft/airspace management. Furthermore, ASP developed information products that illustrate risks to SSC's infrastructure from surge, inundation, and flood. Current plans include developing wind-risk prototype products for refinement and adoption into EOC plans.

Incremental Value of Live/Real Time Three-Dimensional over Two-Dimensional Transesophageal Echocardiography in the Assessment of Atrial Septal Pouch.

PubMed

Elsayed, Mahmoud; Hsiung, Ming C; Meggo-Quiroz, L David; Elguindy, Mostafa; Uygur, Begum; Tandon, Rohit; Guvenc, Tolga; Keser, Nurgul; Vural, Mustafa G; Bulur, Serkan; Chahwala, Jugal R; Abtahi, Firoozeh; Nanda, Navin C

2015-12-01

An atrial septal pouch (ASP) results from partial fusion of the septum primum and the septum secundum, and depending on the site of fusion, the pouch can be left-sided (LASP) or right-sided (RASP). LASPs have been described in association with thrombi found in patients admitted with acute strokes, raising awareness of its potential cardioembolic role, especially in those with no other clearly identifiable embolic source. We retrospectively studied 39 patients in whom the presence of an ASP had been identified by three-dimensional transesophageal echocardiography (3DTEE) and who had a two-dimensional transesophageal echocardiogram (2DTEE) performed during the same clinical encounter. The incremental value provided by 3DTEE over 2DTEE included the detection of six ASPs not found by 2DTEE; the detection of two ASPs in the same subject (in four patients) not identified by 2DTEE; larger ASP measurements of length and height in over 80% of the cases; and measurement of the ASP width (elevational axis) for the calculation of the area of the ASP opening, because of its unique capability to view the pouch en face. In addition, the volume of ASP and of the echogenic masses contained in the ASP (four of 39 patients) could be calculated by 3DTEE, which is a superior parameter of size characterization when compared to individual dimensions. One of these patients who presented with ischemic stroke diagnosed by magnetic resonance imaging had a large (>2 cm) mass in a LASP, with echolucencies similar to those seen in thrombi and associated with clot lysis and resolution. This mass completely disappeared on anticoagulant therapy lending credence that it was most likely a thrombus. There was no history of stroke or any other type of embolic event in the other three patients with masses in ASP. In conclusion, this retrospective study highlights the incremental value of 3DTEE over 2DTEE in the comprehensive assessment and characterization of ASPs, which can aid in the clarification of their role in cryptogenic stroke patients. © 2015, Wiley Periodicals, Inc.

Active Play in After-school Programmes: development of an intervention and description of a matched-pair cluster-randomised trial assessing physical activity play in after-school programmes.

PubMed

Riiser, Kirsti; Helseth, Sølvi; Ellingsen, Hanna; Fallang, Bjørg; Løndal, Knut

2017-08-04

Interventions delivered in after-school programmes (ASPs) have the potential to become a means of ensuring adequate physical activity among schoolchildren. This requires a motivational climate, allowing for self-determined play. If trained, ASP staff may represent a valuable resource for supporting such play. Increasing knowledge and supportive skills among ASP staff may also potentially increase their motivation for work. The purpose of this article is to describe the development of the 'Active Play in ASP' intervention, which aims to promote physical activity among first graders attending ASP, and to present a protocol for a matched-pair cluster-randomised trial to evaluate the intervention. Informed by experiences from practice, evidence-based knowledge and theory, the intervention was developed in a stepwise process including focus group meetings and a small-scale pilot test. The intervention contains a course programme for ASP staff to increase their skills in how to support physical activity through play. In a cluster randomised controlled trial, the ASPs will be matched and randomly allocated to receive the 7-month intervention or to a control group. Outcomes will be assessed at baseline, after 7 and 19 months. First graders attending the ASPs included are eligible. The primary outcome will be accelerometer-determined minutes in moderate to vigorous physical activity in the ASP. The study uses a mixed methods approach including observations and interviews to provide rich descriptions of the concept of children's physical activity in ASP. Moreover, the trial will assess whether the ASP staff benefits from participation in the intervention in terms of increased work motivation. Lastly, process evaluations of programme fidelity, satisfaction and suggestions on improvement will be performed. The study is approved by the Data Protection Official for Research (reference no 46008). Results will be presented in conferences and peer-reviewed journals. Clinical Trials (NCT02954614), pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Antimicrobial Stewardship in Inpatient Settings in the Asia Pacific Region: A Systematic Review and Meta-analysis.

PubMed

Honda, Hitoshi; Ohmagari, Norio; Tokuda, Yasuharu; Mattar, Caline; Warren, David K

2017-05-15

An antimicrobial stewardship program (ASP) is one of the core elements needed to optimize antimicrobial use. Although collaboration at the national level to address the importance of ASPs and antimicrobial resistance has occurred in the Asia Pacific region, hospital-level ASP implementation in this region has not been comprehensively evaluated. We conducted a systematic review and meta-analysis to assess the efficacy of ASPs in inpatient settings in the Asia Pacific region from January 2005 through March 2016. The impact of ASPs on various outcomes, including patient clinical outcomes, antimicrobial prescription outcomes, microbiological outcomes, and expenditure were assessed. Forty-six studies were included for a systematic review and meta-analysis. The pooled risk ratio for mortality from ASP before-after trials and 2-group comparative studies were 1.03 (95% confidence interval [CI], .88-1.19) and 0.69 (95% CI, .56-.86), respectively. The pooled effect size for change in overall antimicrobial and carbapenem consumption (% difference) was -9.74% (95% CI, -18.93% to -.99%) and -10.56% (95% CI, -19.99% to -3.03%), respectively. Trends toward decreases in the incidence of multidrug-resistant organisms and antimicrobial expenditure (range, 9.7%-58.1% reduction in cost in the intervention period/arm) were also observed. ASPs in inpatient settings in the Asia Pacific region appear to be safe and effective to reduce antimicrobial consumption and improve outcomes. However, given the significant variations in assessing the efficacy of ASPs, high-quality studies using standardized surveillance methodology for antimicrobial consumption and similar metrics for outcome measurement are needed to further promote antimicrobial stewardship in this region. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Astragalus polysaccharide enhanced antitumor effects of Apatinib in gastric cancer AGS cells by inhibiting AKT signalling pathway.

PubMed

Wu, Jun; Yu, Junxian; Wang, Jing; Zhang, Chenguang; Shang, Kun; Yao, Xiaojun; Cao, Bangwei

2018-04-01

Apatinib has been proved effective in the treatment of advanced gastric cancer. Traditional Chinese medicine is often considered as adjuvants which could increase the effects and counteract the side effects of chemotherapy. The present study aims to explore the antitumor effects of Astragalus polysaccharide (AsPs) in combination with Apatinib in gastric cancer AGS cells. Our results demonstrated that the expression of VEGFR-2 was observed in human gastric cancer line AGS. Both Apatinib and AsPs could significantly inhibit the proliferation of AGS cells in a dose-dependent manner and Apatinib in combination with AsPs showed enhanced inhibitory effects on cell proliferation, migration and invasion compared with Apatinib monotherapy. Moreover, there was a remarkable increase in apoptosis following Apatinib treatment which could be enhanced by the addition of AsPs. Western blotting showed that the combination of Apatinib and AsPs could inhibit the expression of phosphorylated AKT (p-AKT) and MMP-9 expression. In addition, both Apatinib alone and Apatinib in combination with AsPs induced celluar autophagy which could be attenuated by the autophagy inhibitor 3-MA. The suppression of autophagy leaded to further apoptosis induction and cell proliferation suppression. In conclusion, the current study showed AsPs enhanced antitumor effects of Apatinib on AGS cells by the mechanism which includes inhibition of AKT signaling pathway. Apatinib-induced autophagy could be attenuated by 3-MA, which subsequently increased the apoptosis rate. On the basis of our study, the combination of Apatinib and AsPs could be considered as a potential candidate in the gastric cancer treatment. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Bacterial communities and enzymatic activities in the vegetation-activated sludge process (V-ASP) and related advantages by comparison with conventional constructed wetland.

PubMed

Yuan, Jiajia; Dong, Wenyi; Sun, Feiyun; Zhao, Ke; Du, Changhang; Shao, Yunxian

2016-11-01

A new-developed vegetation-activated sludge process (V-ASP) was implemented for decentralized domestic wastewater treatment, and studied in lab-scale and full-scale. The main purpose of this work was the investigation of biomass activities and microbial communities in V-ASP by comparison with conventional constructed wetland (CW), to unveil the causations of its consistently higher pollutants removal efficiencies. Compared with CWs, V-ASP has greater vegetation nitrogen and phosphorus uptake rates, higher biomass and enzymatic activities, and more bacteria community diversity. The microbial community structure was comprehensively analyzed by using high-throughput sequencing. It was observed that Proteobacteria was dominated in both CWs and V-ASPs, while their subdivisions distribution was rather different. V-ASPs contained a higher nitrite-oxidizing bacteria (Nitrospira) abundances that resulted in a consistently better nitrogen removal efficiency. Hence, a long-term experiment of full-scale V-ASP displayed stably excellent capability in resistance of influent loading shocks and seasonal temperature effect. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparative analysis of the immune responses induced by native versus recombinant versions of the ASP-based vaccine against the bovine intestinal parasite Cooperia oncophora.

PubMed

González-Hernández, Ana; Borloo, Jimmy; Peelaers, Iris; Casaert, Stijn; Leclercq, Georges; Claerebout, Edwin; Geldhof, Peter

2018-01-01

The protective capacities of a native double-domain activation-associated secreted protein (ndd-ASP)-based vaccine against the cattle intestinal nematode Cooperia oncophora has previously been demonstrated. However, protection analysis upon vaccination with a recombinantly produced antigen has never been performed. Therefore, the aim of the current study was to test the protective potential of a Pichia-produced double-domain ASP (pdd-ASP)-based vaccine against C. oncophora. Additionally, we aimed to compare the cellular and humoral mechanisms underlying the vaccine-induced responses by the native (ndd-ASP) and recombinant vaccines. Immunisation of cattle with the native C. oncophora vaccine conferred significant levels of protection after an experimental challenge infection, whereas the recombinant vaccine did not. Moreover, vaccination with ndd-ASP resulted in a higher proliferation of CD4-T cells both systemically and in the small intestinal mucosa when compared with animals vaccinated with the recombinant antigen. In terms of humoral response, although both native and recombinant vaccines induced similar levels of antibodies, animals vaccinated with the native vaccine were able to raise antibodies with greater specificity towards ndd-ASP in comparison with antibodies raised by vaccination with the recombinant vaccine, suggesting a differential immune recognition towards the ndd-ASP and pdd-ASP. Finally, the observation that animals displaying antibodies with higher percentages of recognition towards ndd-ASP also exhibited the lowest egg counts suggests a potential relationship between antibody specificity and protection. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

R76 in transmembrane domain 3 of the aspartate:alanine transporter AspT is involved in substrate transport.

PubMed

Suzuki, Satomi; Nanatani, Kei; Abe, Keietsu

2016-01-01

The L-aspartate:L-alanine antiporter of Tetragenococcus halophilus (AspT) possesses an arginine residue (R76) within the GxxxG motif in the central part of transmembrane domain 3 (TM3)-a residue that has been estimated to transport function. In this study, we carried out amino acid substitutions of R76 and used proteoliposome reconstitution for analyzing the transport function of each substitution. Both l-aspartate and l-alanine transport assays showed that R76K has higher activity than the AspT-WT (R76), whereas R76D and R76E have lower activity than the AspT-WT. These results suggest that R76 is involved in AspT substrate transport.

Brief Report: Insight into Illness and Social Attributional Style in Asperger's Syndrome

ERIC Educational Resources Information Center

Didehbani, Nyaz; Shad, Mujeeb U.; Kandalaft, Michelle R.; Allen, Tandra T.; Tamminga, Carol A.; Krawczyk, Daniel C.; Chapman, Sandra B.

2012-01-01

A number of psychiatric illnesses have been recognized to have some level of insight deficits, including developmental disorders, such as Asperger's Syndrome (ASP). However insight into illness has not been empirically investigated in ASP and little research has examined how individuals with ASP view their deficits. This is the first study to…

Community Partnership to Address Snack Quality and Cost in After-School Programs

ERIC Educational Resources Information Center

Beets, Michael W.; Tilley, Falon; Turner-McGrievy, Gabrielle; Weaver, Robert G.; Jones, Sonya

2014-01-01

Background: Policies call on after-school programs (ASPs) to serve more nutritious snacks. A major barrier for improving snack quality is cost. This study describes the impact on snack quality and expenditures from a community partnership between ASPs and local grocery stores. Methods: Four large-scale ASPs (serving ~500 children, aged 6-12?years,…

A meta-analysis of differences in IQ profiles between individuals with Asperger's disorder and high-functioning autism.

PubMed

Chiang, Hsu-Min; Tsai, Luke Y; Cheung, Ying Kuen; Brown, Alice; Li, Huacheng

2014-07-01

A meta-analysis was performed to examine differences in IQ profiles between individuals with Asperger's disorder (AspD) and high-functioning autism (HFA). Fifty-two studies were included for this study. The results showed that (a) individuals with AspD had significantly higher full-scale IQ, verbal IQ (VIQ), and performance IQ (PIQ) than did individuals with HFA; (b) individuals with AspD had significantly higher VIQ than PIQ; and (c) VIQ was similar to PIQ in individuals with HFA. These findings seem to suggest that AspD and HFA are two different subtypes of Autism. The implications of the present findings to DSM-5 Autism Spectrum Disorder are discussed.

Opposing effects of D-aspartic acid and nitric oxide on tuning of testosterone production in mallard testis during the reproductive cycle.

PubMed

Di Fiore, Maria M; Lamanna, Claudia; Assisi, Loredana; Botte, Virgilio

2008-07-04

D-Aspartic acid (D-Asp) and nitric oxide (NO) play an important role in tuning testosterone production in the gonads of male vertebrates. In particular, D-Asp promotes either the synthesis or the release of testosterone, whereas NO inhibits it. In this study, we have investigated for the first time in birds the putative effects of D-Asp and NO on testicular testosterone production in relation to two phases of the reproductive cycle of the adult captive wild-strain mallard (Anas platyrhynchos) drake. It is a typical seasonal breeder and its cycle consists of a short reproductive period (RP) in the spring (April-May) and a non reproductive period (NRP) in the summer (July), a time when the gonads are quiescent. The presence and the localization of D-Asp and NO in the testis and the trends of D-Asp, NO and testosterone levels were assessed during the main phases of the bird's reproductive cycle. Furthermore, in vitro experiments revealed the direct effect of exogenously administered D-Asp and NO on testosterone steroidogenesis. By using immunohistochemical (IHC) techniques, we studied the presence and the distributional pattern of D-Asp and NO in the testes of RP and NRP drakes. D-Asp levels were evaluated by an enzymatic method, whereas NO content, via nitrite, was assessed using biochemical measurements. Finally, immunoenzymatic techniques determined testicular testosterone levels. IHC analyses revealed the presence of D-Asp and NO in Leydig cells. The distributional pattern of both molecules was in some way correlated to the steroidogenic pathway, which is involved in autocrine testosterone production. Indeed, whereas NO was present only during the NRP, D-Asp was almost exclusively present during the RP. Consistently, the high testosterone testicular content occurring during RP was coupled to a high D-Asp level and a low NO content in the gonad. By contrast, in sexually inactive drakes (NRP), the low testosterone content in the gonad was coupled to a low D-Asp content and to a relatively high NO level. Consequently, to determine the exogenous effects of the two amino acids on testosterone synthesis, we carried out in vitro experiments using testis sections deriving from both the RP and NRP. When testis slices were incubated for 60 or 120 min with D-Asp, testosterone was enhanced, whereas in the presence of L-Arg, a precursor of NO, it was inhibited. Our results provide new insights into the involvement of D-Asp and NO in testicular testosterone production in the adult captive wild-strain mallard drake. The localization of these two molecules in the Leydig cells in different periods of the reproductive cycle demonstrates that they play a potential role in regulating local testosterone production.

Enhancing and Promoting Recovery In Attentionally Impaired People Diagnosed With Schizophrenia: Results From A Randomized Controlled Trial Of Attention Shaping In A Partial Hospital Program.

PubMed

Silverstein, Steven M; Roché, Matthew W; Khan, Zaynab; Carson, Sarah J; Malinovsky, Igor; Newbill, William A; Menditto, Anthony A; Wilkniss, Sandra M

2014-01-01

The attentional impairments associated with schizophrenia are well-documented and profound. Psychopharmacological and most psychosocial interventions have been shown to have limited effect in improving attentional capacity. That said, one form of psychosocial treatment, attention shaping procedures (ASP), has been repeatedly demonstrated to produce significant and meaningful change in various aspects of participant attentiveness behaviors. To date, studies of ASP have been limited in that they have been conducted primarily with inpatients, have not assessed the generalizability of ASP's effects, and have not explored whether reinforcement is required to be contingent on performance of attentive behaviors. To address these limitations we conducted the first randomized clinical trial of ASP with people diagnosed with schizophrenia who are being treated in a partial hospital program. Our results indicate that ASP is effective in improving attention in people with schizophrenia in these types of programs, the effects of ASP generalize outside of the immediate treatment context to both other treatment groups and real world functioning, and contingent reinforcement is a critical ingredient of ASP. This project provides further evidence for the benefits of use of ASP in the recovery-oriented treatment of people diagnosed with schizophrenia who have significant attentional impairments.

Impact of Antimicrobial Stewardship on Physician Practice in a Geriatric Facility

PubMed Central

Kassett, Nina; Sham, Rosalind; Aleong, Rosanne; Yang, Daisy; Kirzner, Michael; Craft, Aidlee

2016-01-01

Background There is a paucity of literature describing the implementation of antimicrobial stewardship programs (ASPs) in long-term care (LTC) facilities. The current study evaluated the impact of an ASP that was implemented across a geriatric facility, which included an inpatient specialty hospital and an LTC facility. The program included prospective audits with feedback, multidisciplinary education, information technology interventions, and guideline development. Objective To investigate the impact of the ASP on physicians’ prescribing practices in this geriatric facility. Methods Utilization data for antibiotics commonly used to treat urinary tract infections were retrieved for the period September 1, 2011, to August 31, 2013. The study examined whether there were significant changes in overall antibiotic use, ciprofloxacin use, and physician prescribing behaviour after program implementation in September 2012. Results There was no significant change in the total number of antibiotic prescriptions for urinary tract infections in the hospital or the LTC facility after ASP implementation. Significant reductions were seen in the average days of therapy initially prescribed and the actual days of therapy after ASP implementation in the LTC facility but not the hospital. Across both facilities, significant reductions were seen in the number of ciprofloxacin prescriptions. Conclusions The current study showed that an ASP can affect physicians’ antibiotic prescribing behaviour and antibiotic usage in an LTC environment. PMID:28123192

Association of single Nucleotide Missence Polymorphism Val109Asp of Omentin-1 gene and coronary artery disease in Pakistani population: Multicenter study

PubMed Central

Nazar, Shazia; Zehra, Sitwat; Azhar, Abid

2017-01-01

Background & Objective: Coronary artery disease (CAD) is a most important cause of morbidity and mortality worldwide as well as in Pakistan. Recent studies have shown that the combination of obesity, insulin resistance and fluctuation in circulating adipocytokines levels is associated with the pathogenesis of coronary artery disease. Omentin-1 is recently found adipocytokine that is highly expressed in visceral adipose tissue. It has anti- inflammatory properties and is negatively correlated with ischemic heart disease. Therefore, this study was designed to investigate the relationship between omentin-1 Val109Asp polymorphism and CAD in Pakistani population. Methods: A total of 350 subjects were included in the study. Two hundred fifty were diagnosed with coronary artery disease while 100 served as healthy controls. PCR-RFLP was performed at Dr. A Q. Khan Institute of Biotechnology (KIBGE) to analyze Val109Asp polymorphism. In this, case control study SPSS software version 16 (Chicago, IL, USA) was used for data analysis. Continuous variables and categorical variables were presented as mean±SD or in percentage. Independent sample test and chi-square test was performed to compare the differences in means between cases and controls. Genotype distribution was analyzed by chi-square test and results were presented as percentage and frequency. Multivarible regression analysis indicated that Val109Asp SNP might be an independent risk factor for CAD susceptibility after adjustment for some well- known CAD risk factors including age, gender, body mass index, smoking, hypertension, diabetes mellitus and lipid abnormalities. There was estimation of odd ratios (OR) and 95% confidence intervals (CIs) to determine the correlation between genotypes and the risk of CAD. (p> 0.05). Genotype frequencies were compared by Chi-square test. Results: There was prevalence of Omentin-1 Val109Asp polymorphism in both case and control groups. However, Val/Asp (heterozygous mutant) genotype was detected more frequently in patients with CAD, OR(95%)=1.921; CI=1.173-3.1469 in comparison of Asp/Asp and Val/Val genotypes. Conclusion: Individuals having Val/Asp heterozygous gemotype of omentin-1 gene polymorphism are at more risk of developing CAD in Pakistani population, further studies are required in different populations and ethnicities to confirm our findings. PMID:29142551

[Comparison of the Effectiveness and Safety of Combined Chemotherapy with PEG-Asp for Treatment of ALL and T-NHL Patients].

PubMed

Xu, Yan; Wang, Jin; Yang, Nan; Bai, Ju; Zhang, Peng-Yu; Gu, Liu-Fang; Lei, Bo; Liu, Jie; Wang, Fang-Xia; Huang, Bing-Qiao; Zhang, Wang-Gang; He, Ai-Li; Cao, Xing-Mei; Chen, Yin-Xia; Ma, Xiao-Rong

2016-04-01

To explore the effectiveness and safety of combined chemotherapy with pegasparaginase (PEG-Asp) for treatment of patients with acute lymphoblastic leukemia (ALL) and T cell non-Hodgkin's lymphoma (T-NHL) patients. A total of 62 ALL or T-NHL patients were diagnosed and treated in our department and were enrolled in this study. Among them, 22 patients received the combined chemotherapy with PEG-Asp, while the other 40 patients received the standard chemotherapy with L-asparaginase (L-Asp) as the control. Therapeutic effectiveness, adverse effects, duration and expense of hospitalization, treatment-related mortality and survival were evaluated and compared in 2 different groups. In group of combined chemotherapy with PEG-Asp, the overall response rate was 90.91% (20 cases), among them CR rate and PR rate are 77.27% (17 cases) and 13.64% (3 cases), respectively. In the group of standard chemotherapy with L-Asp, the overall response rate was 87.5% (35 cases), among them CR rate and PR rate were 72.5% (29 cases) and 15% (6 cases), respectively. The difference neither between PEG-Asp and L-Asp chemotherapy groups nor between ALL and T-NHL subgroups was significant (P > 0.05). The 6-month and 12-month overall survival rates were not significantly different between the PEG-Asp and L-Asp chemotherapy groups, respectively (P > 0.05). The adverse effects were identified as degree 1-2 according to the WHO criteria of drug toxicity. Neither the adverse effects identified as degree 3-4 nor the treatment-related death were observed. Expect for allergy and hyperglycaemia, the difference of side-effect incidence between the two groups were not significant (P > 0.05). The treatment for all the patients in PEG-Asp chemotherapy group was completed, while the treatment with L-Asp was completed only in 29 cases. Moreover, both average duration and expense of hospitalization after the combined chemotherapy were less than the control. With higher response rate, lower drug toxicity and allergy incidence, the combined chemotherapy with PEG-Asp can replace the standard chemotherapy with L-Asp in the treatment of ALL and T-NHL. The optimization of the combined chemotheropeutic protocols for more cases and long-term survival rates need to further and deeply explorate.

Colloidal aggregation and structural assembly of aspect ratio variant goethite (α-FeOOH) with nC60 fullerene in environmental media.

PubMed

Ghosh, Saikat; Pradhan, Nihar R; Mashayekhi, Hamid; Zhang, Qiu; Pan, Bo; Xing, Baoshan

2016-12-01

Environmental mobility of C 60 fullerene can be significantly affected in the presence of naturally abundant α-FeOOH. However, α-FeOOH vary significantly in sizes, shapes and associated properties that can greatly influence the fate and transport of C 60 fullerene in environmental media. Therefore, colloidal hetero-association between well crystallized low aspect (L Asp ) α-FeOOH and nC 60 fullerene may differ substantially to weakly crystallized high-aspect (H Asp ) counterpart. In contrast to L Asp α-FeOOH, inherent crystal defects and surface charge generation in H Asp α-FeOOH facilitated strong Coulombic attraction and aggregation with fullerene in acidic pH. However, L Asp α-FeOOH demonstrated subtle entropic depletion mediated interaction with fullerene prevalent in hard rods. Humic acid (HA) encapsulation of H Asp α-FeOOH substantially blocked fullerene attachment. Minute enhancement in colloidal stability was detected for HA-coated H Asp α-FeOOH and fullerene mixture to HA-coated H Asp α-FeOOH alone. To investigate the interfacial assembly of α-FeOOH with fullerene "in situ" differential interference contrast (DIC) microscopic investigations were employed. This study showed significantly different interface behavior of the binary mixtures of fullerene and H Asp α-FeOOH NPs, and L Asp particles. On air-water interface, bare H Asp α-FeOOH displayed liquid crystalline packing. However, addition of fullerene to H Asp α-FeOOH suspension at pH5 produced closed-loop polygonal and circular ring structures. Head-to-tail alignment of magnetic dipoles as well as fullerene hydrophobicity facilitated such assembly formation. "Ex situ" AFM investigation revealed further the presence of magnetically derived ring structure which asserts that the formed "in situ" ensembles were not transient, hence, may abate fullerene transport through environmental interfaces. Barring hydrophobicity assisted attachment of fullerene to L Asp α-FeOOHs, the absence of any close-packed structures may unlikely abate fullerene transport as envisaged in case of H Asp α-FeOOH. Thus, aspect ratio variation and associated material properties of naturally abundant α-FeOOH may significantly impact fullerene transport through environmental media. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ecological Forecasting Project Management with Examples

NASA Technical Reports Server (NTRS)

Skiles, J. W.; Schmidt, Cindy; Estes, Maury; Turner, Woody

2017-01-01

Once scientists publish results of their projects and studies, all too often they end up on the shelf and are not otherwise used. The NASA Earth Science Division established its Applied Sciences Program (ASP) to apply research findings to help solve and manage real-world problems and needs. ASP-funded projects generally produce decision support systems for operational applications which are expected to last beyond the end of the NASA funding. Because of NASAs unique perspective of looking down on the Earth from space, ASP studies involve the use of remotely sensed information consisting of satellite data and imagery as well as information from sub-orbital platforms. ASP regularly solicits Earth science proposals that address one or more focus areas; disasters mitigation, ecological forecasting, health and air quality, and water resources. Reporting requirements for ASP-funded projects are different from those typical for research grants from NASA and other granting agencies, requiring management approaches different from other programs. This presentation will address the foregoing in some detail and give examples of three ASP-funded ecological forecasting projects that include: 1) the detection and survey of chimpanzee habitat in Africa from space, 2) harmful algal blooms (HABs) in the California Current System affecting aquaculture facilities and marine mammal populations, and 3) a call for the public to identify North America wildlife in Wisconsin using trail camera photos. Contact information to propose to ASP solicitations for those PIs interested is also provided.

75 FR 19977 - Office of the Assistant Secretary for Planning and Evaluation; Statement of Organization...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-16

... reorganization is to realign the functions of ASPE's Office of Science and Data Policy to reflect the current... and Data Policy (AEJ),'' in its entirety and replace with the following: E. The Office of Science and Data Policy (AEJ) The Office of Science and Data Policy (SDP) is responsible for policy development...

D-aspartic acid supplementation combined with 28 days of heavy resistance training has no effect on body composition, muscle strength, and serum hormones associated with the hypothalamo-pituitary-gonadal axis in resistance-trained men.

PubMed

Willoughby, Darryn S; Leutholtz, Brian

2013-10-01

It was hypothesized that D-aspartic acid (D-ASP) supplementation would not increase endogenous testosterone levels or improve muscular performance associated with resistance training. Therefore, body composition, muscle strength, and serum hormone levels associated with the hypothalamo-pituitary-gonadal axis were studied after 28 days of resistance training and D-ASP supplementation. Resistance-trained men resistance trained 4 times/wk for 28 days while orally ingesting either 3 g of placebo or 3 g of D-ASP. Data were analyzed with 2 × 2 analysis of variance (P < .05). Before and after resistance training and supplementation, body composition and muscle strength, serum gonadal hormones, and serum D-ASP and d-aspartate oxidase (DDO) were determined. Body composition and muscle strength were significantly increased in both groups in response to resistance training (P < .05) but not different from one another (P > .05). Total and free testosterone, luteinizing hormone, gonadotropin-releasing hormone, and estradiol were unchanged with resistance training and D-ASP supplementation (P > .05). For serum D-ASP and DDO, D-ASP resulted in a slight increase compared with baseline levels (P > .05). For the D-ASP group, the levels of serum DDO were significantly increased compared with placebo (P < .05). The gonadal hormones were unaffected by 28 days of D-ASP supplementation and not associated with the observed increases in muscle strength and mass. Therefore, at the dose provided, D-ASP supplementation is ineffective in up-regulating the activity of the hypothalamo-pituitary-gonadal axis and has no anabolic or ergogenic effects in skeletal muscle. © 2013 Elsevier Inc. All rights reserved.

Methodology for the systematic reviews on an adjacent segment pathology.

PubMed

Norvell, Daniel C; Dettori, Joseph R; Skelly, Andrea C; Riew, K Daniel; Chapman, Jens R; Anderson, Paul A

2012-10-15

A systematic review. To provide a detailed description of the methods undertaken in the systematic search and analytical summary of adjacent segment pathology (ASP) issues and to describe the process used to develop consensus statements and clinical recommendations regarding factors associated with the prevention and treatment of ASP. We present methods used in conducting the systematic, evidence-based reviews and development of expert panel consensus statements and clinical recommendations on the classification, natural history, risk factors, and treatment of radiographical and clinical ASP. Our intent is that clinicians will combine the information from these reviews with an understanding of their own capacities and experience to better manage patients at risk of ASP and consider future research for the prevention and treatment of ASP. A systematic search and critical review of the English-language literature was undertaken for articles published on the classification, risk, risk factors, and treatment of radiographical and clinical ASP. Articles were screened for relevance using a priori criteria, and relevant articles were critically reviewed. Whether an article was included for review depended on whether the study question was descriptive, one of therapy, or one of prognosis. The strength of evidence for the overall body of literature in each topic area was determined by 2 independent reviewers considering risk of bias, consistency, directness, and precision of results using a modification of the Grades of Recommendation Assessment, Development and Evaluation (GRADE) criteria. Disagreements were resolved by consensus. Findings from articles meeting inclusion criteria were summarized. From these summaries, consensus statements or clinical recommendations were formulated among subject experts through a modified Delphi process using the GRADE approach. A total of 3382 articles were identified and screened on 14 topics relating to the classification, risks, risk factors, and treatment of radiographical and clinical ASP. Of these, 127 met our predetermined inclusion criteria and were used to answer specific clinical questions within each topic. Lack of precision in the terminology related to adjacent segment disease and critical evaluation of definitions used across included articles led to a consensus to use ASP and suggest it as a standard. No validated comprehensive classification system for ASP currently exists. The expert panel developed a consensus definition of radiographical and clinical ASP (RASP and CASP). Some of the highlights from the analyses included the annual, 5- and 10-year risks of developing cervical and lumbar ASP after surgery, several important risk factors associated with the development of cervical and lumbar ASP, and the possibility that some motion sparing procedures may be associated with a lower risk of ASP compared with fusion despite kinematic studies demonstrating similar adjacent segment mobility following these procedures. Other highlights included a high risk of proximal junctional kyphosis (PJK) following long fusions for deformity correction, postsurgical malalignment as a potential risk factor for RASP and the paucity of studies on treatment of cervical and lumbar ASP. Systematic reviews were undertaken to understand the classification, risks, risk factors, and treatment of RASP and CASP and to provide consensus statements and clinical recommendations. This article reports the methods used in the reviews.

Correlation of Specific Mutations in Line Probe Assay (LPA) and Drug Susceptibility Test (DST) with respect to Fluoroquinolone Resistance in Drug Resistant Mycobacterium tuberculosis

PubMed Central

Agrawal, Umang; Savaj, Pratik; Davda, Kanishka; Rodrigues, Camilla; Soman, Rajeev

2017-01-01

Abstract Background This study was done to investigate the utility of specific fluoroquinolone mutations in LPA in predicting the susceptibility in DST at WHO recommended Critical Concentrations of 0.5 and 2 µg/dL of moxifloxacin within a short time frame as provided by LPA. Methods In a retrospective study performed at a tertiary care hospital of Mumbai, India from October 2015 to February 2017, consecutive samples demonstrating fluoroquinolone resistance by LPA were selected. The LPA kit used was Hain Lifescience Genotype MTBDRsl (Version 1). It detects the following mutations in gyrA gene: MUT1: Ala90Val, MUT2: Ser91Pro, MUT3A: Asp94Ala, MUT3B: Asp94Asn/Tyr, MUT3C: Asp94Gly, MUT3D: Asp94His. The causal mutation was noted. For 89 of these samples, DST had been requested and results with Critical Concentration of 0.5µg/dL and 2µg/dL for moxifloxacin were available Results The 89 samples studied were as follows: Sputum (n = 60), paravertebral soft tissue (n = 2), bronchoalveolar fluid (n = 2), cerebrospinal fluid (n = 1), endotracheal tube secretion (n = 1), pleural fluid (n = 1) and site not recorded (22). 3 of these samples had double mutations. Results are as follows. Mutation in gyrA gene Number of samples (n) Susceptible at 0.5 µg/dL [n (%)] Susceptible at 2 µg/dL [n (%)] MUT1 (Ala90Val) 18 6(33.33) 16(88.89) MUT2 (Ser91Pro) 2 0(0) 1(50) MUT3A (Asp94Asn) 13 3(23.07) 11(84.61) MUT3B (Asp94Asn/Tyr) 6 1(16.67) 4(66.67) MUT3C (Asp94Gly) 51 4(8) 43(84.31) MUT3D (Asp94His) 2 0(0) 2(100) Conclusion This study showed a higher proportion of M. tuberculosis susceptibility at 2 µg/dL rather than at 0.5 µg/dL, to moxifloxacin for gyrA mutations Ala90Val (MUT1), Asp94Ala (MUT3A), Asp94Gly (MUT3C), Asp94His (MUT3D) but not for Ser91Pro (MUT2) and Asp94Asn/Tyr (MUT3B). However, the number of samples with Ser91Pro (MUT2) and Asp94Asn/Tyr (MUT3B) mutations was too small for meaningful conclusion. This susceptibility at a higher critical concentration of moxifloxacin may have clinical implications for use of high dose moxifloxacin. Since this information is available within a short time frame as provided by LPA, a more effective regimen could be devised 4 to 8 weeks earlier than after results of DST. This may result in faster sputum conversion and prevent amplification of resistance. Disclosures All authors: No reported disclosures.

Substitution of Asp-309 by Asn in the Arg-Asp-Pro (RDP) motif of Acetobacter diazotrophicus levansucrase affects sucrose hydrolysis, but not enzyme specificity.

PubMed Central

Batista, F R; Hernández, L; Fernández, J R; Arrieta, J; Menéndez, C; Gómez, R; Támbara, Y; Pons, T

1999-01-01

beta-Fructofuranosidases share a conserved aspartic acid-containing motif (Arg-Asp-Pro; RDP) which is absent from alpha-glucopyranosidases. The role of Asp-309 located in the RDP motif of levansucrase (EC 2.4.1.10) from Acetobacter diazotrophicus SRT4 was studied by site-directed mutagenesis. Substitution of Asp-309 by Asn did not affect enzyme secretion. The kcat of the mutant levansucrase was reduced 75-fold, but its Km was similar to that of the wild-type enzyme, indicating that Asp-309 plays a major role in catalysis. The two levansucrases showed optimal activity at pH 5.0 and yielded similar product profiles. Thus the mutation D309N affected the efficiency of sucrose hydrolysis, but not the enzyme specificity. Since the RDP motif is present in a conserved position in fructosyltransferases, invertases, levanases, inulinases and sucrose-6-phosphate hydrolases, it is likely to have a common functional role in beta-fructofuranosidases. PMID:9895294

Face-selective crystal growth behavior of L-aspartic acid in the presence of L-asparagine

NASA Astrophysics Data System (ADS)

Sato, Hiroyasu; Doki, Norihito; Yoshida, Saki; Yokota, Masaaki; Shimizu, Kenji

2016-02-01

The kinetic mechanism of L-asparagine (L-Asn) action on L-aspartic acid (L-Asp) crystal growth, namely the face-selective effect of L-Asn on the L-Asp crystal growth rate in each direction, was examined. In the a-axis direction, the effect of L-Asn on the L-Asp crystal growth rate was small. Enhancement and inhibition of L-Asp crystal growth, and interestingly the dissolution of the L-Asp crystal face, were observed in the b-axis direction, depending on the amount of L-Asn added. In the c-axis direction, the L-Asp crystal growth rate decreased with the increase in the amount of L-Asn added, and the experimental results were well fitted with a Langmuir adsorption isotherm. The study showed that there were crystal growth conditions where enhancement and inhibition, as well as inhibition and dissolution, coexisted in the presence of an additive with a structure similar to the growing crystal.

Lack of association between the APEX1 Asp148Glu polymorphism and sporadic amyotrophic lateral sclerosis.

PubMed

Coppedè, Fabio; Lo Gerfo, Annalisa; Carlesi, Cecilia; Piazza, Selina; Mancuso, Michelangelo; Pasquali, Livia; Murri, Luigi; Migliore, Lucia; Siciliano, Gabriele

2010-02-01

Impairments in DNA repair enzymes have been observed in amyotrophic lateral sclerosis (ALS) tissues, particularly in the activity of the apurinic/apyrimidinic endonuclease 1 (APEX1). Moreover, it was suggested that the common APEX1 Asp148Glu polymorphism might be associated with ALS risk. To further address this question we performed the present study aimed at evaluating the contribution of the APEX1 Asp148Glu polymorphism in sporadic ALS (sALS) risk and clinical presentation, including age and site of onset and disease progression. We screened 134 sALS Italian patients and 129 matched controls for the presence of the APEX1 Asp148Glu polymorphism. No difference in APEX1 Asp148Glu allele and genotype frequencies was found between the groups, nor was the polymorphism associated with age and site of onset or disease progression. Present results do not support a role for the APEX1 Asp148Glu polymorphism in sALS pathogenesis in the Italian population.

Efficacy and safety of once-daily insulin degludec/insulin aspart compared with once-daily insulin glargine in participants with Type 2 diabetes: a randomized, treat-to-target study.

PubMed

Kumar, S; Jang, H C; Demirağ, N G; Skjøth, T V; Endahl, L; Bode, B

2017-02-01

To investigate, in a 26-week, open-label, randomized, treat-to-target trial, the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) once daily vs insulin glargine (IGlar) once daily in adults with Type 2 diabetes, inadequately controlled on basal insulin. Participants were randomized (1:1) to IDegAsp once daily or IGlar once daily in combination with existing oral antidiabetic drugs. IDegAsp once daily was administered with the main evening meal or the largest meal of the day (agreed at baseline); dosing time was maintained throughout the trial. Participants titrated their insulin dose weekly to a mean pre-breakfast self-measured plasma glucose target [3.9-4.9 mmol/l (70-89 mg/dl)]. IDegAsp once daily was non-inferior to IGlar once daily in reducing HbA 1c after 26 weeks [mean estimated treatment difference IDegAsp once daily - IGlar once daily: -0.03% (95% CI -0.20, 0.14)]. The evening meal glucose increment was significantly lower with IDegAsp once daily vs IGlar once daily [estimated treatment difference IDegAsp once daily - IGlar once daily: -1.32 mmol/l (95% CI -1.93, -0.72); P < 0.05]. The overall confirmed hypoglycaemia rate was higher with IDegAsp once daily (estimated rate ratio 1.43; 95% CI 1.07, 1.92; P < 0.05). The rate of nocturnal hypoglycaemia did not significantly differ between the IDegAsp and IGlar groups [estimated rate ratio 0.80 (95% CI 0.49, 1.30); not significant]. In participants with Type 2 diabetes inadequately controlled on basal insulin, IDegAsp once daily improved glycaemic control and was non-inferior to IGlar once daily. IDegAsp led to higher rates of overall hypoglycaemia than IGlar, with no significant difference in rates of nocturnal hypoglycaemia. © 2016 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

Angelica sinensis polysaccharides promotes apoptosis in human breast cancer cells via CREB-regulated caspase-3 activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Wei-Jie; Wang, Sheng; Hu, Zhuang, E-mail: zhuanghu475000@sina.com

Angelica sinensis polysaccharide (ASP) is purified from the fresh roots of Angelica sinensis (AS). This traditional Chinese medicine has been used for thousands of years for treating gynecological diseases and used in functional foods for the prevention and treatment of various diseases, such as inflammation and cancer. The antitumor activity of ASP is related to its biological activities, because it suppresses a variety of pro-proliferative or anti-apoptotic factors that are dramatically expressed in cancer cells of given types. In this study, we show that angelica sinensis polysaccharide induced apoptosis in breast cancer cells of T47D over-expressing the Cyclic AMP responsemore » element binding protein (CREB), inducing apoptosis-related signaling pathway activity. The result also found that ASP caused cell death was linked to caspase activity, accompanied by the loss of mitochondrial membrane potential, cytochrome c release, and Bax translocation from the cytosol to the mitochondria. We found that ASP significantly affected the poly-ADP-ribose polymerase (PARP), Bcl-2 Associated X Protein (Bax), Bcl-2, Bcl-xL and apoptotic protease activating facter-1 (Apaf1) protein expression in a dose- and time-dependent manner. DAPI staining and Flow cytometry were used to analyze apoptosis. The nude mice xenograft model was used to evaluate the antitumor effect of ASP in vivo. ASP has profound antitumor effect on T47D cells, probably by inducing apoptosis through CREB signaling pathway. Thus, these results suggest that ASP would be a promising therapeutic agent for breast cancer. - Highlights: • CREB and Caspase-3 signaling pathways are involved in the ASP induced breast cancer cells apoptosis. • ROCK1/Mlc signaling pathway plays a critical role in this ASP-mediated apoptosis. • Angelica sinensis polysaccharide (ASP) affected the PARP, Bax, Bcl-2, Bcl-xL and Apaf1 protein expression. • The activation of CREB and ROCK1 promotes caspase-3 activation and apoptosis induced by ASP.« less

Topology of AspT, the aspartate:alanine antiporter of Tetragenococcus halophilus, determined by site-directed fluorescence labeling.

PubMed

Nanatani, Kei; Fujiki, Takashi; Kanou, Kazuhiko; Takeda-Shitaka, Mayuko; Umeyama, Hideaki; Ye, Liwen; Wang, Xicheng; Nakajima, Tasuku; Uchida, Takafumi; Maloney, Peter C; Abe, Keietsu

2007-10-01

The gram-positive lactic acid bacterium Tetragenococcus halophilus catalyzes the decarboxylation of L-aspartate (Asp) with release of L-alanine (Ala) and CO(2). The decarboxylation reaction consists of two steps: electrogenic exchange of Asp for Ala catalyzed by an aspartate:alanine antiporter (AspT) and intracellular decarboxylation of the transported Asp catalyzed by an L-aspartate-beta-decarboxylase (AspD). AspT belongs to the newly classified aspartate:alanine exchanger family (transporter classification no. 2.A.81) of transporters. In this study, we were interested in the relationship between the structure and function of AspT and thus analyzed the topology by means of the substituted-cysteine accessibility method using the impermeant, fluorescent, thiol-specific probe Oregon Green 488 maleimide (OGM) and the impermeant, nonfluorescent, thiol-specific probe [2-(trimethylammonium)ethyl]methanethiosulfonate bromide. We generated 23 single-cysteine variants from a six-histidine-tagged cysteineless AspT template. A cysteine position was assigned an external location if the corresponding single-cysteine variant reacted with OGM added to intact cells, and a position was assigned an internal location if OGM labeling required cell lysis. The topology analyses revealed that AspT has a unique topology; the protein has 10 transmembrane helices (TMs), a large hydrophilic cytoplasmic loop (about 180 amino acids) between TM5 and TM6, N and C termini that face the periplasm, and a positively charged residue (arginine 76) within TM3. Moreover, the three-dimensional structure constructed by means of the full automatic modeling system indicates that the large hydrophilic cytoplasmic loop of AspT possesses a TrkA_C domain and a TrkA_C-like domain and that the three-dimensional structures of these domains are similar to each other even though their amino acid sequences show low similarity.

Topology of AspT, the Aspartate:Alanine Antiporter of Tetragenococcus halophilus, Determined by Site-Directed Fluorescence Labeling▿ †

PubMed Central

Nanatani, Kei; Fujiki, Takashi; Kanou, Kazuhiko; Takeda-Shitaka, Mayuko; Umeyama, Hideaki; Ye, Liwen; Wang, Xicheng; Nakajima, Tasuku; Uchida, Takafumi; Maloney, Peter C.; Abe, Keietsu

2007-01-01

The gram-positive lactic acid bacterium Tetragenococcus halophilus catalyzes the decarboxylation of l-aspartate (Asp) with release of l-alanine (Ala) and CO2. The decarboxylation reaction consists of two steps: electrogenic exchange of Asp for Ala catalyzed by an aspartate:alanine antiporter (AspT) and intracellular decarboxylation of the transported Asp catalyzed by an l-aspartate-β-decarboxylase (AspD). AspT belongs to the newly classified aspartate:alanine exchanger family (transporter classification no. 2.A.81) of transporters. In this study, we were interested in the relationship between the structure and function of AspT and thus analyzed the topology by means of the substituted-cysteine accessibility method using the impermeant, fluorescent, thiol-specific probe Oregon Green 488 maleimide (OGM) and the impermeant, nonfluorescent, thiol-specific probe [2-(trimethylammonium)ethyl]methanethiosulfonate bromide. We generated 23 single-cysteine variants from a six-histidine-tagged cysteineless AspT template. A cysteine position was assigned an external location if the corresponding single-cysteine variant reacted with OGM added to intact cells, and a position was assigned an internal location if OGM labeling required cell lysis. The topology analyses revealed that AspT has a unique topology; the protein has 10 transmembrane helices (TMs), a large hydrophilic cytoplasmic loop (about 180 amino acids) between TM5 and TM6, N and C termini that face the periplasm, and a positively charged residue (arginine 76) within TM3. Moreover, the three-dimensional structure constructed by means of the full automatic modeling system indicates that the large hydrophilic cytoplasmic loop of AspT possesses a TrkA_C domain and a TrkA_C-like domain and that the three-dimensional structures of these domains are similar to each other even though their amino acid sequences show low similarity. PMID:17660287

ASP6537, a novel highly selective cyclooxygenase-1 inhibitor, exerts potent antithrombotic effect without "aspirin dilemma".

PubMed

Sakata, Chinatsu; Kawasaki, Tomihisa; Kato, Yasuko; Abe, Masaki; Suzuki, Ken-ichi; Ohmiya, Makoto; Funatsu, Toshiyuki; Morita, Yoshiaki; Okada, Masamichi

2013-07-01

Aspirin inhibits both the cyclooxygenase (COX)-1-dependent production of thromboxane A2 (TXA2) in platelets and COX-2-dependent production of anti-aggregatory prostaglandin I2 (PGI2) in vessel walls, resulting in "aspirin dilemma." Our objective is to investigate whether ASP6537 can overcome aspirin dilemma and exert a potent antithrombotic effect without a concurrent ulcerogenic effect. We evaluated the inhibitory effects of ASP6537 on recombinant human COX-1 (rhCOX-1) and rhCOX-2 activities using a COX-1/2 selectivity test. To determine whether ASP6537 induces aspirin dilemma, we examined the effects of ASP6537 on in vitro TXA2 and PGI2 metabolite production from platelets and isolated aorta of guinea pigs, and on plasma concentrations of TXA2 and PGI2 metabolites in aged rats. Finally, we evaluated the antithrombotic effects and ulcerogenic activity of ASP6537 using an electrically induced carotid arterial thrombosis model and a gastric ulcer model in guinea pigs. The IC50 ratios of rhCOX-2 to rhCOX-1 for ASP6537 and aspirin were >142,000 and 1.63 fold, respectively. ASP6537 inhibited TXA2 production more selectively than aspirin in in vitro and in vivo TXA2/PGI2 production studies. ASP6537 exerted a significant antithrombotic effect at ≥3 mg/kg, while aspirin tended to inhibit thrombosis at 300 mg/kg but it was not statistically significant. Further, ASP6537 did not induce ulcer formation at 100 mg/kg, whereas aspirin exhibited an ulcerogenic effect at doses of ≥100 mg/kg. ASP6537 functions as a highly selective COX-1 inhibitor with a superior ability to aspirin for normalizing TXA2/PGI2 balance, and exerts antithrombotic effect without ulcerogenic effect. Copyright © 2013 Elsevier Ltd. All rights reserved.

A randomized, phase 2 study of ASP0113, a DNA-based vaccine, for the prevention of CMV in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor.

PubMed

Vincenti, Flavio; Budde, Klemens; Merville, Pierre; Shihab, Fuad; Peddi, V Ram; Shah, Malay; Wyburn, Kate; Cassuto-Viguier, Elisabeth; Weidemann, Alexander; Lee, Misun; Flegel, Teresa; Erdman, Jay; Wang, Xuegong; Lademacher, Christopher

2018-05-09

Cytomegalovirus (CMV) is a latent infection in most infected individuals, but can be pathogenic in immunocompromised kidney transplant recipients. ASP0113 is a DNA-based vaccine for the prevention of CMV-related mortality and end-organ disease in transplant recipients. The efficacy, safety, and immunogenicity of ASP0113 was assessed in a phase 2, double-blind, placebo-controlled study in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor. Transplant recipients were randomized (1:1) to receive five doses of ASP0113 (5 mg; n=75) or placebo (n=74) on Days 30/60/90/120/180 post transplant, and received prophylactic valganciclovir/ganciclovir 10-100 days post transplant. The primary endpoint was the proportion of transplant recipients with CMV viremia ≥1000 IU/mL from Day 100 through to 1 year after first study vaccine injection. There was no statistically significant difference in the primary endpoint between the ASP0113 and placebo groups (odds ratio 0.79, 95% confidence interval 0.43-1.47; p=0.307). There were similar numbers of transplant recipients with treatment-emergent adverse events between groups; however, more transplant recipients reported injection site pain in the ASP0113 group compared with placebo. ASP0113 did not demonstrate efficacy in the prevention of CMV viremia in this CMV-seronegative kidney transplant population, but demonstrated a safety profile similar to placebo. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Association between adherence to an antimicrobial stewardship program and mortality among hospitalised cancer patients with febrile neutropaenia: a prospective cohort study

PubMed Central

2014-01-01

Background Initial management of chemotherapy-induced febrile neutropaenia (FN) comprises empirical therapy with a broad-spectrum antimicrobial. Currently, there is sufficient evidence to indicate which antibiotic regimen should be administered initially. However, no randomized trial has evaluated whether adherence to an antimicrobial stewardship program (ASP) results in lower rates of mortality in this setting. The present study sought to assess the association between adherence to an ASP and mortality among hospitalised cancer patients with FN. Methods We conducted a prospective cohort study in a single tertiary hospital from October 2009 to August 2011. All adult patients who were admitted to the haematology ward with cancer and FN were followed up for 28 days. ASP adherence to the initial antimicrobial prescription was determined. The mortality rates of patients who were treated with antibiotics according to the ASP protocol were compared with those of patients treated with other antibiotic regimens. The multivariate Cox proportional hazards model and propensity score were used to estimate 28-day mortality risk. Results A total of 307 FN episodes in 169 subjects were evaluated. The rate of adherence to the ASP was 53%. In a Cox regression analysis, adjusted for propensity scores and other potential confounding factors, ASP adherence was independently associated with lower mortality (hazard ratio, 0.36; 95% confidence interval, 0.14–0.92). Conclusions Antimicrobial selection is important for the initial management of patients with FN, and adherence to the ASP, which calls for the rational use of antibiotics, was associated with lower mortality rates in this setting. PMID:24884397

Association between adherence to an antimicrobial stewardship program and mortality among hospitalised cancer patients with febrile neutropaenia: a prospective cohort study.

PubMed

Rosa, Regis G; Goldani, Luciano Z; dos Santos, Rodrigo P

2014-05-23

Initial management of chemotherapy-induced febrile neutropaenia (FN) comprises empirical therapy with a broad-spectrum antimicrobial. Currently, there is sufficient evidence to indicate which antibiotic regimen should be administered initially. However, no randomized trial has evaluated whether adherence to an antimicrobial stewardship program (ASP) results in lower rates of mortality in this setting. The present study sought to assess the association between adherence to an ASP and mortality among hospitalised cancer patients with FN. We conducted a prospective cohort study in a single tertiary hospital from October 2009 to August 2011. All adult patients who were admitted to the haematology ward with cancer and FN were followed up for 28 days. ASP adherence to the initial antimicrobial prescription was determined. The mortality rates of patients who were treated with antibiotics according to the ASP protocol were compared with those of patients treated with other antibiotic regimens. The multivariate Cox proportional hazards model and propensity score were used to estimate 28-day mortality risk. A total of 307 FN episodes in 169 subjects were evaluated. The rate of adherence to the ASP was 53%. In a Cox regression analysis, adjusted for propensity scores and other potential confounding factors, ASP adherence was independently associated with lower mortality (hazard ratio, 0.36; 95% confidence interval, 0.14-0.92). Antimicrobial selection is important for the initial management of patients with FN, and adherence to the ASP, which calls for the rational use of antibiotics, was associated with lower mortality rates in this setting.

The Effect of Arthrospira platensis Capsules on CD4 T-Cells and Antioxidative Capacity in a Randomized Pilot Study of Adult Women Infected with Human Immunodeficiency Virus Not under HAART in Yaoundé, Cameroon

PubMed Central

Winter, Frank Stéphane; Emakam, Francois; Kfutwah, Anfumbom; Hermann, Johannes; Azabji-Kenfack, Marcel; Krawinkel, Michael B.

2014-01-01

Dietary supplements are often used to improve the nutritional status of people living with HIV/AIDS (PLHIV). Arthrospira platensis (Asp), also known as Spirulina, is a cyanobacterium rich in proteins and micronutrients. Cell and animal trials described immune-modulating, antiretroviral and antioxidant activities. This pilot study describes the effects of the supplementation of 5 g/day of Asp on a pre-highly-active antiretroviral therapy (pre-HAART), HIV-infected, adult female population. It was conducted as a three-month randomized controlled trial (RCT) that compared a cup supplementation of five grams/day of Asp with a placebo of equal protein content and energy. The study included 73 HIV-infected women. The immediate outcome variables were CD4 T-cells, viral load and immune activation by CD8 T-cells expressing CD38. The antioxidant status was assessed by way of the total antioxidant capacity of the serum (TAOS). The renal function was documented by way of creatinine, urea and the calculated glomerular filtration rate. Statistical analyses were carried out with non-parametric tests, and the effect size of each interaction was calculated. No differences in the immunological and virological markers between the Asp and the placebo group could be observed. In the placebo group, 21 of 30 patients (70%) developed concomitant events, while in the Asp group, only 12 of 28 patients (43%) did. Both groups registered a significant weight increase; 0.5 kg (p < 0.05) in the Asp group and 0.65 kg (p < 0.05) in the placebo group. The antioxidant capacity increase of 56 (1–98) µM for Asp was significantly different from the decrease observed in the placebo group (p < 0.001). A slight increase in the creatinine level of 0.1 g/dL (p < 0.001) was observed in the Asp group, and no effect was observed in the urea levels. The improvement of the antioxidant capacity under Asp, shown for the first time on PLHIV, could become a focus for future research on the nutritional and health effects of Spirulina. The observed slight, but significant increase of serum creatinine needs further evaluation, especially with varying doses of Asp. PMID:25057105

Clinical experiences with an ASP model backup archive for PACS images

NASA Astrophysics Data System (ADS)

Liu, Brent J.; Cao, Fei; Documet, Luis; Huang, H. K.; Muldoon, Jean

2003-05-01

Last year we presented a Fault-Tolerant Backup Archive using an Application Service Provider (ASP) model for disaster recovery. The purpose of this paper is to update and provide clinical experiences related towards implementing the ASP model archive solution for short-term backup of clinical PACS image data as well as possible applications other than disaster recovery. The ASP backup archive provides instantaneous, automatic backup of acquired PACS image data and instantaneous recovery of stored PACS image data all at a low operational cost and with little human intervention. This solution can be used for a variety of scheduled and unscheduled downtimes that occur on the main PACS archive. A backup archive server with hierarchical storage was implemented offsite from the main PACS archive location. Clinical data from a hospital PACS is sent to this ASP storage server in parallel to the exams being archived in the main server. Initially, connectivity between the main archive and the ASP storage server is established via a T-1 connection. In the future, other more cost-effective means of connectivity will be researched such as the Internet 2. We have integrated the ASP model backup archive with a clinical PACS at Saint John's Health Center and has been operational for over 6 months. Pitfalls encountered during integration with a live clinical PACS and the impact to clinical workflow will be discussed. In addition, estimations of the cost of establishing such a solution as well as the cost charged to the users will be included. Clinical downtime scenarios, such as a scheduled mandatory downtime and an unscheduled downtime due to a disaster event to the main archive, were simulated and the PACS exams were sent successfully from the offsite ASP storage server back to the hospital PACS in less than 1 day. The ASP backup archive was able to recover PACS image data for comparison studies with no complex operational procedures. Furthermore, no image data loss was encountered during the recovery. During any clinical downtime scenario, the ASP backup archive server can repopulate a clinical PACS quickly with the majority of studies available for comparison during the interim until the main PACS archive is fully recovered.

Inhibition of the gut enzyme intestinal alkaline phosphatase may explain how aspartame promotes glucose intolerance and obesity in mice

PubMed Central

Gul, Sarah S.; Hamilton, A. Rebecca L.; Munoz, Alexander R.; Phupitakphol, Tanit; Liu, Wei; Hyoju, Sanjiv K.; Economopoulos, Konstantinos P.; Morrison, Sara; Hu, Dong; Zhang, Weifeng; Gharedaghi, Mohammad Hadi; Huo, Haizhong; Hamarneh, Sulaiman R.; Hodin, Richard A.

2017-01-01

Diet soda consumption has not been associated with tangible weight loss. Aspartame (ASP) commonly substitutes sugar and one of its breakdown products is phenylalanine (PHE), a known inhibitor of intestinal alkaline phosphatase (IAP), a gut enzyme shown to prevent metabolic syndrome in mice. We hypothesized that ASP consumption might contribute to the development of metabolic syndrome based on PHE’s inhibition of endogenous IAP. The design of the study was such that for the in vitro model, IAP was added to diet and regular soda, and IAP activity was measured. For the acute model, a closed bowel loop was created in mice. ASP or water was instilled into it and IAP activity was measured. For the chronic model, mice were fed chow or high-fat diet (HFD) with/without ASP in the drinking water for 18 weeks. The results were that for the in vitro study, IAP activity was lower (p < 0.05) in solutions containing ASP compared with controls. For the acute model, endogenous IAP activity was reduced by 50% in the ASP group compared with controls (0.2 ± 0.03 vs 0.4 ± 0.24) (p = 0.02). For the chronic model, mice in the HFD + ASP group gained more weight compared with the HFD + water group (48.1 ± 1.6 vs 42.4 ± 3.1, p = 0.0001). Significant difference in glucose intolerance between the HFD ± ASP groups (53 913 ± 4000.58 (mg·min)/dL vs 42 003.75 ± 5331.61 (mg·min)/dL, respectively, p = 0.02). Fasting glucose and serum tumor necrosis factor-alpha levels were significantly higher in the HFD + ASP group (1.23- and 0.87-fold increases, respectively, p = 0.006 and p = 0.01). In conclusion, endogenous IAP’s protective effects in regard to the metabolic syndrome may be inhibited by PHE, a metabolite of ASP, perhaps explaining the lack of expected weight loss and metabolic improvements associated with diet drinks. PMID:27997218

Inhibition of the gut enzyme intestinal alkaline phosphatase may explain how aspartame promotes glucose intolerance and obesity in mice.

PubMed

Gul, Sarah S; Hamilton, A Rebecca L; Munoz, Alexander R; Phupitakphol, Tanit; Liu, Wei; Hyoju, Sanjiv K; Economopoulos, Konstantinos P; Morrison, Sara; Hu, Dong; Zhang, Weifeng; Gharedaghi, Mohammad Hadi; Huo, Haizhong; Hamarneh, Sulaiman R; Hodin, Richard A

2017-01-01

Diet soda consumption has not been associated with tangible weight loss. Aspartame (ASP) commonly substitutes sugar and one of its breakdown products is phenylalanine (PHE), a known inhibitor of intestinal alkaline phosphatase (IAP), a gut enzyme shown to prevent metabolic syndrome in mice. We hypothesized that ASP consumption might contribute to the development of metabolic syndrome based on PHE's inhibition of endogenous IAP. The design of the study was such that for the in vitro model, IAP was added to diet and regular soda, and IAP activity was measured. For the acute model, a closed bowel loop was created in mice. ASP or water was instilled into it and IAP activity was measured. For the chronic model, mice were fed chow or high-fat diet (HFD) with/without ASP in the drinking water for 18 weeks. The results were that for the in vitro study, IAP activity was lower (p < 0.05) in solutions containing ASP compared with controls. For the acute model, endogenous IAP activity was reduced by 50% in the ASP group compared with controls (0.2 ± 0.03 vs 0.4 ± 0.24) (p = 0.02). For the chronic model, mice in the HFD + ASP group gained more weight compared with the HFD + water group (48.1 ± 1.6 vs 42.4 ± 3.1, p = 0.0001). Significant difference in glucose intolerance between the HFD ± ASP groups (53 913 ± 4000.58 (mg·min)/dL vs 42 003.75 ± 5331.61 (mg·min)/dL, respectively, p = 0.02). Fasting glucose and serum tumor necrosis factor-alpha levels were significantly higher in the HFD + ASP group (1.23- and 0.87-fold increases, respectively, p = 0.006 and p = 0.01). In conclusion, endogenous IAP's protective effects in regard to the metabolic syndrome may be inhibited by PHE, a metabolite of ASP, perhaps explaining the lack of expected weight loss and metabolic improvements associated with diet drinks.

The Global Epidemiology of Syphilis in the Past Century - A Systematic Review Based on Antenatal Syphilis Prevalence.

PubMed

Kenyon, Chris Richard; Osbak, Kara; Tsoumanis, Achilleas

2016-05-01

How can we explain the uneven decline of syphilis around the world following the introduction of penicillin? In this paper we use antenatal syphilis prevalence (ASP) to investigate how syphilis prevalence varied worldwide in the past century, and what risk factors correlate with this variance. 1) A systematic review using PubMed and Google Scholar was conducted to identify countries with published data relating to ASP estimates from before 1952 until the present. Eleven countries were identified (Canada, Denmark, Finland, India, Japan, Norway, Singapore, South Africa, United States of America (USA), United Kingdom (UK) and Zimbabwe). The ASP epidemic curve for each population was depicted graphically. In South Africa and the USA, results are reported separately for the black and white populations. 2) National antenatal syphilis prevalence estimates for 1990 to 1999 and 2008 were taken from an Institute for Health Metrics and Evaluation database on the prevalence of syphilis in low risk populations compiled for the Global Burden of Diseases study and from a recent review paper respectively. National ASPs were depicted graphically and regional median ASPs were calculated for both time periods. 3) Linear regression was used to test for an association between ASP in 1990-1999 and 2008 and four risk factors (efficacy of syphilis screening/treatment, health expenditure, GDP per capita and circumcision prevalence). WHO world regions were included as potential explanatory variables. In most populations, ASP dropped to under 1% before 1960. In Zimbabwe and black South Africans, ASP was high in the pre-penicillin period, dropped in the post-penicillin period, but then plateaued at around 6% until the end of the 20th century when ASP dropped to just above 1%. In black Americans, ASP declined in the post penicillin period, but plateaued at 3-5% thereafter. ASP was statistically significantly higher in sub-Saharan Africa in 1990-1999 and 2008 than in the other world regions (P < 0.001). On multivariate analysis in both time periods, ASP was only associated with residence in sub-Saharan Africa. Further research is necessary to elucidate the reasons for the higher prevalence of syphilis in sub-Saharan Africa.

A functional nonsynonymous toll-like receptor 4 gene polymorphism is associated with metabolic syndrome, surrogates of insulin resistance, and syndromes of lipid accumulation.

PubMed

Steinhardt, Alberto Penas; Aranguren, Florencia; Tellechea, Mariana L; Gómez Rosso, Leonardo A; Brites, Fernando D; Martínez-Larrad, Maria T; Serrano-Ríos, Manuel; Frechtel, Gustavo D; Taverna, Mariano J

2010-05-01

Toll-like receptor 4 (TLR4) plays a key role in the activation of innate immune responses. Loss-of-function mutations in TLR4 prevent diet-induced obesity and insulin resistance (IR). We conducted a population cross-sectional study to evaluate whether Asp299Gly (rs4986790) TLR4 gene polymorphism is associated with metabolic syndrome (MS), surrogates of IR, and syndromes of lipid accumulation (SLAs) in Argentinean healthy male subjects. rs4986790 was genotyped in 621 healthy unrelated male blood donors. National Cholesterol Education Program/Adult Treatment Panel III-MS (NCEP/ATP III-MS); SLAs such as enlarged waist elevated triglyceride syndrome (EWET), hypertriglyceridemic waist (HW), and overweight-lipid syndrome (OLS); and surrogates of IR were assessed. The prevalence of MS, OLS, and EWET was significantly higher among Asp299Asp carriers (P < .05). These findings were confirmed using 32 000 bootstrap samples. Surrogate markers of IR were also significantly higher in Asp299Asp carriers (P < .05). Most findings were especially strengthened among individuals with C-reactive protein below the 95th percentile and/or total cholesterol to high-density lipoprotein cholesterol ratio >or=5. This is the first report to find, in Argentinean healthy male blood donors, associations between the Asp299Asp genotype of rs4986790 TLR4 gene polymorphism and high risk for NCEP/ATP III-MS, SLAs, and surrogates of IR. These findings are consistent with previous functional and observational studies showing that Asp299 allele, in comparison with Gly299, is associated with increased TLR4 activation, higher levels of inflammatory cytokines, acute-phase reactants and soluble adhesion molecules, and higher risk of atherosclerosis.

Antimicrobial resistance of Enterococcus isolates in Turkey: A meta-analysis of current studies.

PubMed

Kilbas, Imdat; Ciftci, Ihsan Hakki

2018-03-01

In this study, a meta-analysis of Enterococcus isolates collected in 2000-2015 in Turkey and their susceptibility/resistance to antibiotics, clinical indications for initial drug treatment, and identification of alternative treatments was conducted. The meta-analysis examined antibiotic susceptibility/resistance in Enterococcus spp. isolates. The study was planned and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Statements on antimicrobial resistance were grouped according to the antimicrobial stewardship programme (ASP). The mean resistance rates of Enterococcus faecalis to vancomycin (VAN) and linezolid (LNZ) were 1.0±2.2% and 1.9±2.6%, respectively, whereas the mean resistance rates of Enterococcus faecium to VAN and LNZ were 10.3±11.3% and 2.4±0%, respectively. This study is the first meta-analysis of the resistance of clinical Enterococcus isolates in Turkey to antimicrobial agents, which is a major problem stemming from the excessive usage of antibiotics. The development of antibiotic resistance in Turkey has changed over time. To support the practice of evidence-based medicine, more notifications about Enterococcus resistance status are needed, especially notifications following ASP rules. Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

Different profile of thrombin generation in children with acute lymphoblastic leukaemia treated with native or pegylated asparaginase: A cohort study.

PubMed

Rozen, Laurence; Noubouossie, Denis; Dedeken, Laurence; Huybrechts, Sophie; Lê, Phu Quoc; Ferster, Alina; Demulder, Anne

2017-02-01

Asparaginase (Asp) and corticosteroid (CS) treatment in patients with acute lymphoblastic leukaemia (ALL) is associated with an increased risk of thrombotic events. Characterization of global haemostatic phenotypes of patients with ALL during Asp therapy. Thrombin generation (TG) was monitored in platelet-poor plasma of 56 children treated for a B lineage ALL (36 with native, 20 with PEG Asp) using 1 pM tissue factor and 4 μM phospholipids, with and without thrombomodulin. Protein C activity (PC), free protein S (PS), antithrombin (AT) and fibrinogen levels were also measured. Elevated endogenous thrombin potential (ETP) and peak of TG were noted at diagnosis, throughout the Induction phase and Late Intensification but was significantly less for PEG than for native Asp (P < 0.001), while age, sex, type of corticosteroid during Induction and molecular response had no significant effect. The reduction of ETP after addition of thrombomodulin was significantly lower in ALL children compared with that in controls, suggesting impairment in PS/PC pathway. Three patients experienced thrombosis: two treated with native and one with PEG Asp. The two patients with native Asp had, at the time of thrombosis, a prothrombotic profile. Treatment with Asp, in combination with CS, enhances TG in children with ALL, more significantly with native than PEG Asp, which is present early at diagnosis, persists during Induction and reappears during Late Intensification. This is consistent with the high incidence of thrombotic events described during these phases of therapy. The less pronounced effect of PEG Asp remains to be elucidated. © 2016 Wiley Periodicals, Inc.

Antimicrobial stewardship program in a Malaysian district hospital: First year experience

PubMed Central

Sing, Diana Yap Fui; Boo, Yang Liang; Mukhlis, Roshalina; Chin, Pek Woon; Hoo, Fan Kee

2016-01-01

Backgrounds & Objective: Antimicrobial resistance is an alarming public health threat that requires urgent global solution. Implementation of antimicrobial stewardship program (ASP) is an essential practice element for healthcare institutions in gate-keeping judicious antimicrobial use. This study highlighted the development, first year experience, and result of the implementation of ASP utilizing persuasive and restrictive approaches in a Malaysian district hospital. Methods: An observational study was conducted between January 2015 to December 2015 on implementation of ASP among hospitalized inpatients age 12 years old and above. Results: Recommendations were provided for 60% of cases (110 patients) with the average acceptance rate of 83.33%. Majority of the interventions were to stop the antimicrobial therapy (30.3%), and the most common audited antimicrobials was Piperacillin/Tazobactam (25.5%), followed by Meropenem (11.82%), Amoxicillin/Clavulanate and Vancomycin (8.18%) respectively. The concordance rate towards authorization policy was increased in 2015 (71.59% of cases) as compared before the implementation of ASP in 2014 (60.6% of cases). Restrictive enforcement under ASP had been shown to improve significantly adherence rate towards antimicrobials authorization policy (p-value: 0.004). Conclusion: ASP was successfully implemented in a district hospital. Future studies on its clinical outcomes are important to evaluate its effectiveness as well as focus on the improvement to the pre-existing strategies and measures. PMID:27648056

ASPsiRNA: A Resource of ASP-siRNAs Having Therapeutic Potential for Human Genetic Disorders and Algorithm for Prediction of Their Inhibitory Efficacy

PubMed Central

Monga, Isha; Qureshi, Abid; Thakur, Nishant; Gupta, Amit Kumar; Kumar, Manoj

2017-01-01

Allele-specific siRNAs (ASP-siRNAs) have emerged as promising therapeutic molecules owing to their selectivity to inhibit the mutant allele or associated single-nucleotide polymorphisms (SNPs) sparing the expression of the wild-type counterpart. Thus, a dedicated bioinformatics platform encompassing updated ASP-siRNAs and an algorithm for the prediction of their inhibitory efficacy will be helpful in tackling currently intractable genetic disorders. In the present study, we have developed the ASPsiRNA resource (http://crdd.osdd.net/servers/aspsirna/) covering three components viz (i) ASPsiDb, (ii) ASPsiPred, and (iii) analysis tools like ASP-siOffTar. ASPsiDb is a manually curated database harboring 4543 (including 422 chemically modified) ASP-siRNAs targeting 78 unique genes involved in 51 different diseases. It furnishes comprehensive information from experimental studies on ASP-siRNAs along with multidimensional genetic and clinical information for numerous mutations. ASPsiPred is a two-layered algorithm to predict efficacy of ASP-siRNAs for fully complementary mutant (Effmut) and wild-type allele (Effwild) with one mismatch by ASPsiPredSVM and ASPsiPredmatrix, respectively. In ASPsiPredSVM, 922 unique ASP-siRNAs with experimentally validated quantitative Effmut were used. During 10-fold cross-validation (10nCV) employing various sequence features on the training/testing dataset (T737), the best predictive model achieved a maximum Pearson’s correlation coefficient (PCC) of 0.71. Further, the accuracy of the classifier to predict Effmut against novel genes was assessed by leave one target out cross-validation approach (LOTOCV). ASPsiPredmatrix was constructed from rule-based studies describing the effect of single siRNA:mRNA mismatches on the efficacy at 19 different locations of siRNA. Thus, ASPsiRNA encompasses the first database, prediction algorithm, and off-target analysis tool that is expected to accelerate research in the field of RNAi-based therapeutics for human genetic diseases. PMID:28696921

Biaxial tensile strain tuned up-and-down behavior on lattice thermal conductivity in β-AsP monolayer

NASA Astrophysics Data System (ADS)

Guo, San-Dong; Dong, Jun

2018-07-01

Various two-dimensional (2D) materials with a graphene-like buckled structure have emerged, and the β-phase AsP monolayer has been recently proposed to be thermodynamically stable from first-principles calculations. The studies of thermal transport are very useful for these 2D materials-based nano-electronics devices. Motivated by this, a comparative study of strain-dependent phonon transport of AsP monolayers is performed by solving the linearized phonon Boltzmann equation within the single-mode relaxation time approximation (RTA). It is found that the lattice thermal conductivity () of the AsP monolayer is very close to the one of As monolayer with a similar buckled structure, which is due to neutralization between the reduction of phonon lifetimes and group velocity enhancement from As to AsP monolayer. The corresponding room-temperature sheet thermal conductance of AsP monolayer is 152.5 . It is noted that the increasing tensile strain can harden a long wavelength out-of-plane (ZA) acoustic mode, and soften the in-plane longitudinal acoustic (LA) and transversal acoustic (TA) modes. Calculated results show that of AsP monolayer presents a nonmonotonic up-and-down behavior with increased strain. The unusual strain dependence is due to the competition among the reduction of phonon group velocities, improved phonon lifetimes of ZA mode and nonmonotonic up-and-down phonon lifetimes of TA/LA mode. It is found that acoustic branches dominate the in the considered strain range, and the contribution from ZA branch increases with increased strain, while it is opposite for TA/LA branch. By analyzing cumulative with respect to phonon mean free path, tensile strain can modulate effectively the size effects on in the AsP monolayer. Our work enriches the studies of thermal transports of 2D materials with graphene-like buckled structures, and strengthens the idea to engineer thermal transport properties by simple mechanical strain, and stimulates further experimental works to synthesize AsP monolayers.

Utility of recombinant Aspergillus fumigatus antigens in the diagnosis of allergic bronchopulmonary aspergillosis: a systematic review and diagnostic test accuracy meta-analysis.

PubMed

Muthu, Valliappan; Sehgal, Inderpaul Singh; Dhooria, Sahajal; Aggarwal, Ashutosh N; Agarwal, Ritesh

2018-06-21

The role of recombinant A.fumigatus (rAsp) antigens in the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) has not been systematically evaluated. Herein, we evaluate the utility of recombinant A.fumigatus (rAsp) antigens in diagnosing ABPA. We systematically reviewed the PubMed, EmBase, and Scopus databases for studies evaluating rAsp antigens in ABPA. The QUADAS-2 tool and the GRADE approach were used to assess the risk of bias and the quality of evidence, respectively. The diagnostic performance of IgE or skin test against rAsp f1, f2, f3, f4, f6, and their combination was evaluated separately for ABPA complicating asthma or cystic fibrosis (CF), using an HSROC model. The reference standard for diagnosing ABPA was the composite (clinical, radiological, immunological) criteria. Our search yielded 26 studies (n=1,694) and 17 studies (n=1,131) for inclusion in the systematic review and meta-analysis, respectively. In asthmatics, the pooled sensitivity for diagnosing ABPA was best for IgE against a combination of rAsp f1 or f3 (96.7%; 95% confidence interval [CI], 87.6-99.2). The pooled specificity for diagnosing ABPA was highest (99.2%; 95% CI, 88.2-99.9) for IgE against a combination of f4 or f6. In CF patients, the pooled sensitivity of rAsp f1 or f3 was 93.3% (95% CI, 55.2-99.9) while the pooled specificity of rAsp f4 or f6 was 93.9% (95% CI, 68.8-99.9). The quality of evidence was low as per the GRADE approach. A combination of IgE against rAsp antigens (f1, f2, f3, f4, f6) are likely to be helpful in the diagnosis of ABPA. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Cleavage of the actin-capping protein alpha -adducin at Asp-Asp-Ser-Asp633-Ala by caspase-3 is preceded by its phosphorylation on serine 726 in cisplatin-induced apoptosis of renal epithelial cells.

PubMed

van de Water, B; Tijdens, I B; Verbrugge, A; Huigsloot, M; Dihal, A A; Stevens, J L; Jaken, S; Mulder, G J

2000-08-18

Decreased phosphorylation of focal adhesion kinase and paxillin is associated with loss of focal adhesions and stress fibers and precedes the onset of apoptosis (van de Water, B., Nagelkerke, J. F., and Stevens, J. L. (1999) J. Biol. Chem. 274, 13328-13337). The cortical actin cytoskeletal network is also lost during apoptosis, yet little is known about the temporal relationship between altered phosphorylation of proteins that are critical in the regulation of this network and their potential cleavage by caspases during apoptosis. Adducins are central in the cortical actin network organization. Cisplatin caused apoptosis of renal proximal tubular epithelial cells, which was associated with the cleavage of alpha-adducin into a 74-kDa fragment; this was blocked by a general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk). Hemagglutinin-tagged human alpha-adducin was cleaved into a similar 74-kDa fragment by caspase-3 in vitro but not by caspase-6 or -7. Asp-Arg-Val-Asp(29)-Glu, Asp-Ile-Val-Asp(208)-Arg, and Asp-Asp-Ser-Asp(633)-Ala were identified as the principal caspase-3 cleavage sites; Asp-Asp-Ser-Asp(633)-Ala was key in the formation of the 74-kDa fragment. Cisplatin also caused an increased phosphorylation of alpha-adducin and gamma-adducin in the MARCKS domain that preceded alpha-adducin cleavage and was associated with loss of adducins from adherens junctions; this was not affected by z-VAD-fmk. In conclusion, the data support a model in which increased phosphorylation of alpha-adducin due to cisplatin leads to dissociation from the cytoskeleton, a situation rendered irreversible by caspase-3-mediated cleavage of alpha-adducin at Asp-Asp-Ser-Asp(633)-Ala.

New technique for fertilizing eggs of burbot, asp and ide under hatchery conditions.

PubMed

Kucharczyk, Dariusz; Nowosad, Joanna; Łuczyński, Marek J; Targońska, Katarzyna

2016-09-01

The development of a new protocol for egg fertilization may increase embryo survival and benefit the aquaculture process. In the present study, a new technique of partially adding sperm to activated eggs in the artificial fertilization of burbot (Lota lota), ide (Leuciscus idus) and asp (Aspius aspius) eggs was evaluated. If the same volume of sperm was divided into two or three parts and added to eggs in 30-60s intervals, it significantly improved embryo survival at the eyed-egg-stage of development. In the present study, the periodic addition of spermatozoa to eggs affected fertilization (ide and asp) and embryo survival rates (ide, asp and burbot) and might be successfully applied under hatchery conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

Characteristics of Antimicrobial Stewardship Programs at Veterans Affairs Hospitals: Results of a Nationwide Survey.

PubMed

Chou, Ann F; Graber, Christopher J; Jones, Makoto; Zhang, Yue; Goetz, Matthew Bidwell; Madaras-Kelly, Karl; Samore, Matthew; Kelly, Allison; Glassman, Peter A

2016-06-01

BACKGROUND Antimicrobial stewardship programs (ASPs) are variably implemented. OBJECTIVE To characterize variations of antimicrobial stewardship structure and practices across all inpatient Veterans Affairs facilities in 2012 and correlate key characteristics with antimicrobial usage. DESIGN A web-based survey regarding stewardship activities was administered to each facility's designated contact. Bivariate associations between facility characteristics and inpatient antimicrobial use during 2012 were determined. SETTING Total of 130 Veterans Affairs facilities with inpatient services. RESULTS Of 130 responding facilities, 29 (22%) had a formal policy establishing an ASP, and 12 (9%) had an approved ASP business plan. Antimicrobial stewardship teams were present in 49 facilities (38%); 34 teams included a clinical pharmacist with formal infectious diseases (ID) training. Stewardship activities varied across facilities, including development of yearly antibiograms (122 [94%]), formulary restrictions (120 [92%]), stop orders for antimicrobial duration (98 [75%]), and written clinical pathways for specific conditions (96 [74%]). Decreased antimicrobial usage was associated with having at least 1 full-time ID physician (P=.03), an ID fellowship program (P=.003), and a clinical pharmacist with formal ID training (P=.006) as well as frequency of systematic patient-level reviews of antimicrobial use (P=.01) and having a policy to address antimicrobial use in the context of Clostridium difficile infection (P=.01). Stop orders for antimicrobial duration were associated with increased use (P=.03). CONCLUSIONS ASP-related activities varied considerably. Decreased antibiotic use appeared related to ID presence and certain select practices. Further statistical assessments may help optimize antimicrobial practices. Infect Control Hosp Epidemiol 2016;37:647-654.

Anaerobic-aerobic treatment of purified terephthalic acid (PTA) effluent; a techno-economic alternative to two-stage aerobic process.

PubMed

Pophali, G R; Khan, R; Dhodapkar, R S; Nandy, T; Devotta, S

2007-12-01

This paper addresses the treatment of purified terephthalic acid (PTA) effluent using anaerobic and aerobic processes. Laboratory studies were carried out on flow proportionate composite wastewater generated from the manufacturing of PTA. An activated sludge process (ASP-two stage and single stage) and an upflow anaerobic fixed film fixed bed reactor (AFFFBR) were used, individually and in combination. The performance of a full-scale ETP under existing operating conditions was also studied. Full scale ETP studies revealed that the treatment of PTA effluent using a two-stage ASP alone does not meet treated effluent quality within the prescribed Indian Standards. The biomass produced in the two stage ASP was very viscous and fluffy and the sludge volume index (SVI) was very high (200-450 ml/g). However, pretreatment of PTA effluent using an upflow AFFFBR ensured substantial reduction in BOD (63%) and COD (62%) with recovery of biogas at 1.8-1.96 l/l effluent treated at a volumetric loading rate (VLR) 4-5 kg COD/m(3) d. The methane content in the biogas varied between 55% and 60%. The pretreated effluent from the upflow AFFFBR was then treated through a single stage ASP. The biomass produced in the ASP after anaerobic treatment had very good settlability (SVI: 75-90 ml/g) as compared to the two stage ASP and the treated effluent quality with respect to BOD, COD and SS was within the prescribed Indian Standards. The alternative treatment process comprising an upflow AFFFBR and a single stage ASP ensured net power saving of 257 kW and in addition generated 442 kW of power through the AFFFBR.

The Aspergillus fumigatus septins play pleiotropic roles in septation, conidiation, and cell wall stress, but are dispensable for virulence.

PubMed

Vargas-Muñiz, José M; Renshaw, Hilary; Richards, Amber D; Lamoth, Frédéric; Soderblom, Erik J; Moseley, M Arthur; Juvvadi, Praveen R; Steinbach, William J

2015-08-01

Septins are a conserved family of GTPases that regulate important cellular processes such as cell wall integrity, and septation in fungi. The requirement of septins for virulence has been demonstrated in the human pathogenic yeasts Candida albicans and Cryptococcus neoformans, as well as the plant pathogen Magnaporthe oryzae. Aspergillus spp. contains five genes encoding for septins (aspA-E). While the importance of septins AspA, AspB, AspC, and AspE for growth and conidiation has been elucidated in the filamentous fungal model Aspergillus nidulans, nothing is known on the role of septins in growth and virulence in the human pathogen Aspergillus fumigatus. Here we deleted all five A. fumigatus septins, and generated certain double and triple septin deletion strains. Phenotypic analyses revealed that while all the septins are dispensable in normal growth conditions, AspA, AspB, AspC and AspE are required for regular septation. Furthermore, deletion of only the core septin genes significantly reduced conidiation. Concomitant with the absence of an electron-dense outer conidial wall, the ΔaspB strain was also sensitive to anti-cell wall agents. Infection with the ΔaspB strain in a Galleria mellonella model of invasive aspergillosis showed hypervirulence, but no virulence difference was noted when compared to the wild-type strain in a murine model of invasive aspergillosis. Although the deletion of aspB resulted in increased release of TNF-α from the macrophages, no significant inflammation differences in lung histology was noted between the ΔaspB strain and the wild-type strain. Taken together, these results point to the importance of septins in A. fumigatus growth, but not virulence in a murine model. Copyright © 2015 Elsevier Inc. All rights reserved.

Cardioprotection activity and mechanism of Astragalus polysaccharide in vivo and in vitro.

PubMed

Liu, Debin; Chen, Lei; Zhao, Jianye; Cui, Kang

2018-05-01

Astragalus polysaccharides (ASP) is extracted from Astragalus, and is the main active ingredient of Astragalus membranaceus. The purpose of this study was to investigate the protective effect of ASP on rat cardiomyocytes damage induced by myocardial ischemia and reperfusion injury (MVRI) and isoprenaline(ISO) in vivo and in vitro. The model of cardiomyocytes damage was induced using MVRI in a rat in vivo and also using ISO in cell. After ASP intervention, the protective effect of ASP on cardiomyocytes was evaluated by animal experimental and cell experimental. The results show that ASP can relieve the increase of cell volume in myocardium, reduce the apoptosis of cell in myocardial tissue caused by MVRI in vivo. At the cellular level, ASP can reverse the decrease of cell activity induced by ISO, inhibit the apoptosis, and decrease the levels of intracellular reactive oxygen species. Mechanistically at the molecular level, these effects are elicited via down-regulation of the protein levels of caspase-3 and bax and up-regulation of the protein levels of bcl-2 in both in vivo and in vitro. These results demonstrate that ASP has a protective efficacy in MVRI/ISO-treated cardiomyocytes by inhibiting the apoptosis. Copyright © 2018 Elsevier B.V. All rights reserved.

Chronic administration of Angelica sinensis polysaccharide effectively improves fatty liver and glucose homeostasis in high-fat diet-fed mice.

PubMed

Wang, Kaiping; Cao, Peng; Wang, Hanxiang; Tang, Zhuohong; Wang, Na; Wang, Jinglin; Zhang, Yu

2016-05-18

This study aimed to investigate the therapeutic effects of Angelica sinensis polysaccharide (ASP), an active component derived from a water extract of Angelica sinensis, in high-fat diet (HFD)-fed BALB/c mice. The potential mechanisms underlying the activity of this compound were also considered. Specifically, serum and hepatic biochemical parameters were evaluated, and key proteins involved in the lipid/glucose metabolism were analyzed. Long-term feeding with a HFD induced severe fatty liver and hyperglycemia. Histological examination clearly showed that ASP reduced lipid accumulation in the liver and attenuated hepatic steatosis in HFD-fed mice. In addition, ASP markedly alleviated serum and liver lipid disorders and fatty liver via the upregulation of PPARγ expression and the activation of adiponectin-SIRT1-AMPK signaling. Furthermore, ASP also significantly relieved severe oxidative stress, demonstrating that ASP might attenuate nonalcoholic fatty liver disease via a "two-hit" mechanism. In addition, ASP reduced blood glucose levels and ameliorated insulin resistance via the regulation of related metabolic enzymes and by activating the PI3K/Akt pathway in HFD-fed mice. Our findings revealed that ASP might be used as an alternative dietary supplement or health care product to ameliorate metabolic syndrome in populations that consistently consume HFDs.

Prooxidative effects of aspartame on antioxidant defense status in erythrocytes of rats.

PubMed

Prokic, Marko D; Paunovic, Milica G; Matic, Milos M; Djordjevic, Natasa Z; Ognjanovic, Branka I; Stajn, Andras S; Saicic, Zorica S

2014-12-01

Since aspartame (L-aspartyl-L-phenylalanine methyl ester, ASP) is one of the most widely used artificial sweeteners, the aim of the present study was to investigate its effects on serum glucose and lipid levels as well as its effects on oxidative/antioxidative status in erythrocytes of rats. The experiment included two groups of animals: the control group was administered with water only, while the experimental group was orally administered with ASP (40 mg/kg b.w.) daily, for a period of six weeks. When compared with the control group, the group administrated with ASP indicated higher values of serum glucose, cholesterol and triglycerides. Significantly increased concentrations of superoxide anion (O2 .-), hydrogen peroxide (H2O2), peroxynitrite (?N??-) and lipid peroxides (LPO) were recorded in the erythrocytes of ASP treated group in comparison to the control group. In the course of chronic ASP administration, the following was observed: the concentration of reduced glutathione (GSH) and the activity of catalase (CAT) increased. Thus, these findings suggest that long-term consumption of ASP leads to hyperglycemia and hyperlipidemia, as well as to oxidative stress in erythrocytes.

Making Healthy Eating Policy Practice: A Group Randomized Controlled Trial on Changes in Snack Quality, Costs, and Consumption in After-School Programs.

PubMed

Beets, Michael W; Weaver, R Glenn; Turner-McGrievy, Gabrielle; Huberty, Jennifer; Ward, Dianne S; Freedman, Darcy; Hutto, Brent; Moore, Justin B; Beighle, Aaron

2016-09-01

The aim of this study was to evaluate an intervention designed to assist after-school programs (ASPs) in meeting snack nutrition policies that specify that a fruit or vegetable be served daily and sugar-sweetened beverages/foods and artificially flavored foods eliminated. The study used a 1-year group-randomized controlled trial. The study took place in ASPs operating in South Carolina, United States. Twenty ASPs serving over 1700 children were recruited, match-paired postbaseline on enrollment size and days fruits/vegetables were served per week, and randomized to either intervention (n = 10) or control (n = 10) groups. The study used Strategies To Enhance Practice for Healthy Eating (STEPs-HE), a multistep adaptive intervention framework that assists ASP leaders and staff to serve snacks that meet nutrition policies while maintaining cost. Direct observation of snacks served and consumed and monthly snack expenditures as determined by receipts were used. The study used nonparametric and mixed-model repeated measures. By postassessment, intervention ASPs increased serving of fruits/vegetables to 3.9 ± 2.1 vs. 0.7 ± 1.7 d/wk and decreased serving sugar-sweetened beverages to 0.1 ± 0.7 vs. 1.8 ± 2.4 d/wk and sugar-sweetened foods to 0.3 ± 1.1 vs. 2.7 ± 2.5 d/wk compared to controls, respectively. Cost of snacks increased by $0.02/snack in the intervention ASPs ($0.36 to $0.38) compared to a $0.01 per snack decrease in the control group ($0.39 to $0.38). Across both assessments and groups, 80% to 100% of children consumed FVs. The STEPs-HE intervention can assist ASPs in meeting nationally endorsed nutrition policies with marginal increases in cost. © 2016 by American Journal of Health Promotion, Inc.

The antimicrobial stewardship program in Gulf Cooperation Council (GCC) states: insights from a regional survey.

PubMed

Enani, Mushira A

2016-01-01

The purpose of the current study is to describe the prevalence and characteristics of antimicrobial stewardship programs (ASP) in Gulf Cooperation Council (GCC) states to explore opportunities and overcome barriers to effective ASP implementation. A cross-sectional questionnaire survey was used to evaluate the current status of ASP: major stewardship components, barriers of implementation and program impact in acute care hospitals of GCC states. Forty-seven healthcare professionals responded from four GCC states, the majority from Saudi Arabia (81%). Twenty-nine (62%) participating hospitals had ASP in place. Of these established programs, 35 (75%) reported lack of funding and personnel as major barriers to program implementation. The top three objectives cited for the hospital ASP were to reduce resistance (72.3%), improve clinical outcomes (70.2%) and reduce costs (44.7%). The reported impact of existing ASP was reduction of inappropriate prescribing (68%), reduction of broad spectrum antibiotic use (63.8%), reduction of healthcare-associated infections (61.7%), reduction of length of stay or mortality metrics (59.6%), reduction in direct antibiotic cost (57.4%) and reduction of reported antibiotic resistance (55.3%). Survey participants from GCC states who have implemented ASP report significant impacts in the reduction of broad spectrum antibiotic use, hospital-acquired infection, inappropriate prescribing and antimicrobial resistance. These findings suggest a promising opportunity to enhance existing ASP through sharing of best practices and support the development of regional guidelines across GCC states.

The antimicrobial stewardship program in Gulf Cooperation Council (GCC) states: insights from a regional survey

PubMed Central

2015-01-01

Objectives: The purpose of the current study is to describe the prevalence and characteristics of antimicrobial stewardship programs (ASP) in Gulf Cooperation Council (GCC) states to explore opportunities and overcome barriers to effective ASP implementation. Methods: A cross-sectional questionnaire survey was used to evaluate the current status of ASP: major stewardship components, barriers of implementation and program impact in acute care hospitals of GCC states. Results: Forty-seven healthcare professionals responded from four GCC states, the majority from Saudi Arabia (81%). Twenty-nine (62%) participating hospitals had ASP in place. Of these established programs, 35 (75%) reported lack of funding and personnel as major barriers to program implementation. The top three objectives cited for the hospital ASP were to reduce resistance (72.3%), improve clinical outcomes (70.2%) and reduce costs (44.7%). The reported impact of existing ASP was reduction of inappropriate prescribing (68%), reduction of broad spectrum antibiotic use (63.8%), reduction of healthcare-associated infections (61.7%), reduction of length of stay or mortality metrics (59.6%), reduction in direct antibiotic cost (57.4%) and reduction of reported antibiotic resistance (55.3%). Conclusion: Survey participants from GCC states who have implemented ASP report significant impacts in the reduction of broad spectrum antibiotic use, hospital-acquired infection, inappropriate prescribing and antimicrobial resistance. These findings suggest a promising opportunity to enhance existing ASP through sharing of best practices and support the development of regional guidelines across GCC states. PMID:28989448

Engineering acidic Streptomyces rubiginosus D-xylose isomerase by rational enzyme design.

PubMed

Waltman, Mary Jo; Yang, Zamin Koo; Langan, Paul; Graham, David E; Kovalevsky, Andrey

2014-02-01

To maximize bioethanol production from lignocellulosic biomass, all sugars must be utilized. Yeast fermentation can be improved by introducing the d-xylose isomerase enzyme to convert the pentose sugar d-xylose, which cannot be fermented by Saccharomyces cerevisiae, into the fermentable ketose d-xylulose. The low activity of d-xylose isomerase, especially at the low pH required for optimal fermentation, limits its use. A rational enzyme engineering approach was undertaken, and seven amino acid positions were replaced to improve the activity of Streptomyces rubiginosus d-xylose isomerase towards its physiological substrate at pH values below 6. The active-site design was guided by mechanistic insights and the knowledge of amino acid protonation states at low pH obtained from previous joint X-ray/neutron crystallographic experiments. Tagging the enzyme with 6 or 12 histidine residues at the N-terminus resulted in a significant increase in the active-site affinity towards substrate at pH 5.8. Substituting an asparagine at position 215, which hydrogen bonded to the metal-bound Glu181 and Asp245, with an aspartate gave a variant with almost an order of magnitude lower KM than measured for the native enzyme, with a 4-fold increase in activity. Other studied variants showed similar (Asp57Asn, Glu186Gln/Asn215Asp), lower (Asp57His, Asn247Asp, Lys289His, Lys289Glu) or no (Gln256Asp, Asp287Asn, ΔAsp287) activity in acidic conditions relative to the native enzyme.

Ameliorative effect of Pimpinella anisum oil on immunohistochemical and ultrastuctural changes of cerebellum of albino rats induced by aspartame.

PubMed

Abdul-Hamid, Manal; Gallaly, Sanaa Rida

2014-05-01

The study aims to investigate the protective effect of Pimpinella anisum oil on aspartame (ASP) which resulted in cerebellar changes. The rats were divided into four equal groups: Group 1: (control group): served as control animals. Group 2: control P. anisum oil received .5 mL/kg/d/b wt. once daily. Group 3 (ASP group): received daily 250 mg/kg/b wt. of ASP dissolved in distilled water and given orally to the animals by intra-gastric tube for 2 months. Group 4: received .5 mL/kg/b wt. of prophylactic P. anisum oil once daily, followed by ASP after 2 h for 2 months. The histopathological approach revealed marked changes in the Purkinje cells, myleinated nerve fibers and granular cells of ASP-treated animals. Some of these cells appeared with deeply stained cytoplasm. Ultrastructural examination showed Purkinje cells with dilated rough endoplasmic reticulum and condensed mitochondria. Granular cells appeared with less c nuclei and surrounded by dissolution of most Mossy rosettes structures. Most myelinated nerve fibers showed thickening of myelinated sheath and others showed splitting of their myelin sheath. The histopathological, immunohistochemical and ultrastructural alterations were much less observed in concomitant use of P. anisum oil with ASP. Cerebellar cortex is considered target areas of ASP neurotoxicity, while P. anisum oil, when used in combination with ASP displays a protective action against neurotoxicity.

77 FR 15370 - Agency Information Collection Request. 60-Day Public Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-15

.... Proposed Project: Teen Pregnancy Prevention Replication Evaluation Study: Follow-up Data Collection--OMB No... Evaluation (ASPE), the Centers for Disease Control and Prevention (CDC), and the Administration for Children... with ASPE the Teen Pregnancy Prevention Replication Evaluation Study (TPP Replication Study). The TPP...

D-Aspartic acid and nitric oxide as regulators of androgen production in boar testis.

PubMed

Lamanna, Claudia; Assisi, Loredana; Vittoria, Alfredo; Botte, Virgilio; Di Fiore, Maria Maddalena

2007-01-15

D-Aspartic acid (D-Asp) and nitric oxide (NO) are two biologically active molecules playing important functions as neurotransmitters and neuromodulators of nerve impulse and as regulators of hormone production by endocrine organs. We studied the occurrence of D-Asp and NO as well as their effects on testosterone synthesis in the testis of boar. This model was chosen for our investigations because it contains more Leydig cells than other mammals. Indirect immunofluorescence applied to cryostat sections was used to evaluate the co-localization of D-Asp and of the enzyme nitric oxide synthase (NOS) in the same Leydig cells. D-Asp and NOS often co-existed in the same Leydig cells and were found, separately, in many other testicular cytotypes. D-Asp level was dosed by an enzymatic method performed on boar testis extracts and was 40+/-3.6 nmol/g of fresh tissue. NO measurement was carried out using a biochemical method by NOS activity determination and expressed as quantity of nitrites produced: it was 155.25+/-21.9 nmol/mg of tissue. The effects of the two molecules on steroid hormone production were evaluated by incubating testis homogenates, respectively with or without D-Asp and/or the NO-donor L-arginine (L-Arg). After incubation, the testosterone presence was measured by immunoenzymatic assay (EIA). These in vitro experiments showed that the addition of D-Asp to incubated testicular homogenates significantly increased testosterone concentration, whereas the addition of L-Arg decreased the hormone production. Moreover, the inclusion of L-Arg to an incubation medium of testicular homogenates with added D-Asp, completely inhibited the stimulating effects of this enantiomer. Our results suggest an autocrine action of both D-Asp and NO on the steroidogenetic activity of the Leydig cell.

Aspartic acid functions as carbonyl trapper to inhibit the formation of advanced glycation end products by chemical chaperone activity.

PubMed

Prasanna, Govindarajan; Saraswathi, N T

2016-05-01

Advanced glycation end products (AGEs) were implicated in pathology of numerous diseases. In this study, we present the bioactivity of aspartic acid (Asp) to inhibit the AGEs. Hemoglobin and bovine serum albumin (BSA) were glycated with glucose, fructose, and ribose in the presence and absence of Asp (100-200 μM). HbA1c inhibition was investigated using human blood and characterized by micro-column ion exchange chromatography. The effect of methyl glyoxal (MG) on hemoglobin and BSA was evaluated by fluorescence spectroscopy and gel electrophoresis. The effect of MG on red blood cells morphology was characterized by scanning electron micrographs. Molecular docking was performed on BSA with Asp. Asp is capable of inhibiting the formation of fluorescent AGEs by reacting with the reducing sugars. The presence of Asp as supplement in whole blood reduced the HbA1c% from 8.8 to 6.1. The presence of MG showed an increase in fluorescence and the presence of Asp inhibited the glycation thereby the fluorescence was quenched. MG also affected the electrophoretic mobility of hemoglobin and BSA by forming high molecular weight aggregates. Normal RBCs showed typical biconcave shape. MG modified RBCs showed twisted and elongated shape whereas the presence of ASP tends to protect RBC from twisting. Asp interacted with arginine residues of bovine serum albumin particularly ARG 194, ARG 198, and ARG 217 thereby stabilized the protein complex. We conclude that Asp has dual functions as a chemical chaperone to stabilize protein and as a dicarbonyl trapper, and thereby it can prevent the complications caused by glycation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colantonio, Patrizia; Leboffe, Loris; Bolli, Alessandro

Caspase-3 is responsible for the cleavage of several proteins including the nuclear enzyme poly(ADP-ribose) polymerase (PARP). Designed on the cleavage site of PARP, Ac-Asp-Glu-Val-Asp-H has been reported as a highly specific inhibitor. To overcome the susceptibility to proteolysis, the intrinsic instability, and the scarce membrane permeability of tetra-peptidyl aldehydes, di- and tri-peptidyl caspase-3 inhibitors have been synthesized. Here, the synthesis and the inhibition properties of peptidyl aldehydes Z-tLeu-Asp-H, Z-tLeu-Val-Asp-H, and Z-Val-tLeu-Asp-H are reported. Z-tLeu-Asp-H, Z-tLeu-Val-Asp-H, and Z-Val-tLeu-Asp-H inhibit competitively human caspase-3 activity in vitro with K{sub i}{sup 0} = 3.6 nM, 18.2 nM, and 109 nM, respectively (pH 7.4 andmore » 25 deg. C). Moreover, Z-tLeu-Asp-H impairs apoptosis in human DLD-1 colon adenocarcinoma cells without affecting caspase-8. Therefore, Ac-Asp-Glu-Val-Asp-H can be truncated to Z-tLeu-Asp-H retaining nanomolar inhibitory activity in vitro and displaying action in whole cells, these properties reflect the unprecedented introduction of the bulky and lipophilic tLeu residue at the P{sub 2} position.« less

An increase level of acylation stimulating protein is correlated with metabolic risk markers in North Indian obese women.

PubMed

Mishra, Supriya; Gupta, Vani; Mishra, Sameeksha; Gupta, Vandana; Mahdi, Abbas Ali; Sachan, Rekha

2017-12-01

The present study was to investigate the association between serum acylation stimulating protein (ASP) level with metabolic risk factors in North Indian obese women. This is a case control study, total n=322 women aged between 20 and 45 years (n=162 with metabolic syndrome & n=160 without metabolic syndrome) were recruited for the study according to National Cholesterol Education Program Treatment Panel (NCEPATP) guidelines. Serum ASP level were determined by enzyme linked immunosorbent assay. Results indicated that circulating ASP and other metabolic risk factors (waist circumference, triglycerides, fasting plasma glucose etc) were significantly higher in women with metabolic syndrome (WmetS) than in women without syndrome (WometS) (p<0.001). Furthermore circulating ASP was significantly higher possitively correlated with waist circumference (r=0.51, p<0.001), triglyceride (r=0.56, p<0.001), glucose (r=0.70, p<0.001), and negatively correlated with high density lipoprotein(r=-0.56, p<0.001) in women with metabolic syndrome. Conclusively circulating ASP was found to be significantly associated with hyperlipidemia, obesity and obesity related disorders in North Indian obese women. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Association between Toll-like receptor 4 Asp299Gly polymorphism and coronary heart disease susceptibility.

PubMed

Wu, B W; Zhu, J; Shi, H M; Jin, B; Wen, Z C

2017-08-07

Published data on the association between Toll-like receptor 4 (TLR4) Asp299Gly polymorphism and coronary heart disease (CHD) susceptibility are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. English-language studies were identified by searching PubMed and Embase databases (up to November 2016). All epidemiological studies were regarding Caucasians because no TLR4 Asp/Gly and Gly/Gly genotypes have been detected in Asians. A total of 20 case-control studies involving 14,416 cases and 10,764 controls were included in the meta-analysis. Overall, no significant associations were found between TLR4 Asp299Gly polymorphism and CHD susceptibility in the dominant model (OR=0.89; 95%CI=0.74 to 1.06; P=0.20) pooled in the meta-analysis. In the subgroup analysis by CHD, non-significant associations were found in cases compared to controls. When stratified by control source, no significantly decreased risk was found in the additive model or dominant model. The present meta-analysis suggests that the TLR4 Asp299Gly polymorphism was not associated with decreased CHD risk in Caucasians.

Substrate specificity of the aspartate:alanine antiporter (AspT) of Tetragenococcus halophilus in reconstituted liposomes.

PubMed

Sasahara, Ayako; Nanatani, Kei; Enomoto, Masaru; Kuwahara, Shigefumi; Abe, Keietsu

2011-08-19

The aspartate:alanine antiporter (AspT) of the lactic acid bacterium Tetragenococcus halophilus is a member of the aspartate:alanine exchanger (AAEx) transporter family. T. halophilus AspT catalyzes the electrogenic exchange of L-aspartate(1-) with L-alanine(0). Although physiological functions of AspT were well studied, L-aspartate(1-):L-alanine(0) antiport mechanisms are still unsolved. Here we report that the binding sites of L-aspartate and L-alanine are independently present in AspT by means of the kinetic studies. We purified His(6)-tagged T. halophilus AspT and characterized its kinetic properties when reconstituted in liposomes (K(m) = 0.35 ± 0.03 mm for L-aspartate, K(m) = 0.098 ± 0 mm for D-aspartate, K(m) = 26 ± 2 mm for L-alanine, K(m) = 3.3 ± 0.2 mm for D-alanine). Competitive inhibition by various amino acids of L-aspartate or L-alanine in self-exchange reactions revealed that L-cysteine selectively inhibited L-aspartate self-exchange but only weakly inhibited L-alanine self-exchange. Additionally, L-serine selectively inhibited L-alanine self-exchange but barely inhibited L-aspartate self-exchange. The aspartate analogs L-cysteine sulfinic acid, L-cysteic acid, and D-cysteic acid competitively and strongly inhibited L-aspartate self-exchange compared with L-alanine self-exchange. Taken together, these kinetic data suggest that the putative binding sites of L-aspartate and L-alanine are independently located in the substrate translocation pathway of AspT.

The Global Epidemiology of Syphilis in the Past Century – A Systematic Review Based on Antenatal Syphilis Prevalence

PubMed Central

Kenyon, Chris Richard; Osbak, Kara; Tsoumanis, Achilleas

2016-01-01

Background How can we explain the uneven decline of syphilis around the world following the introduction of penicillin? In this paper we use antenatal syphilis prevalence (ASP) to investigate how syphilis prevalence varied worldwide in the past century, and what risk factors correlate with this variance. Methods 1) A systematic review using PubMed and Google Scholar was conducted to identify countries with published data relating to ASP estimates from before 1952 until the present. Eleven countries were identified (Canada, Denmark, Finland, India, Japan, Norway, Singapore, South Africa, United States of America (USA), United Kingdom (UK) and Zimbabwe). The ASP epidemic curve for each population was depicted graphically. In South Africa and the USA, results are reported separately for the black and white populations. 2) National antenatal syphilis prevalence estimates for 1990 to 1999 and 2008 were taken from an Institute for Health Metrics and Evaluation database on the prevalence of syphilis in low risk populations compiled for the Global Burden of Diseases study and from a recent review paper respectively. National ASPs were depicted graphically and regional median ASPs were calculated for both time periods. 3) Linear regression was used to test for an association between ASP in 1990–1999 and 2008 and four risk factors (efficacy of syphilis screening/treatment, health expenditure, GDP per capita and circumcision prevalence). WHO world regions were included as potential explanatory variables. Results In most populations, ASP dropped to under 1% before 1960. In Zimbabwe and black South Africans, ASP was high in the pre-penicillin period, dropped in the post-penicillin period, but then plateaued at around 6% until the end of the 20th century when ASP dropped to just above 1%. In black Americans, ASP declined in the post penicillin period, but plateaued at 3–5% thereafter. ASP was statistically significantly higher in sub-Saharan Africa in 1990–1999 and 2008 than in the other world regions (P < 0.001). On multivariate analysis in both time periods, ASP was only associated with residence in sub-Saharan Africa. Conclusions Further research is necessary to elucidate the reasons for the higher prevalence of syphilis in sub-Saharan Africa. PMID:27167068

An Evaluation of μ-Opioid Receptor (OPRM1) as a Predictor of Naltrexone Response in the Treatment of Alcohol Dependence

PubMed Central

Anton, Raymond F.; Oroszi, Gabor; O'Malley, Stephanie; Couper, David; Swift, Robert; Pettinati, Helen; Goldman, David

2008-01-01

Context: Naltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the μ-opioid receptor gene (OPRM1), might predict naltrexone response. Objective: To evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone. Design: Pharmacogenetic analysis conducted between January 1, 2001, and January 31, 2004. Setting: Eleven academic sites in the COMBINE Study. Participants: Recently abstinent volunteers who met all 3 of the following conditions: (1) DSM-IV criteria for primary alcohol dependence; (2) participation in the COMBINE Study; and (3) availability of DNA. Interventions: Alcoholic subjects were treated for 16 weeks with 100 mg of naltrexone hydrochloride (234 Asn40 homozygotes and 67 with at least 1 copy of the Asp40 allele) or placebo (235 Asn40 homozygotes and 68 with at least 1 copy of the Asp40 allele). All participants received medical management (MM) alone or with combined behavioral intervention (CBI). Main Outcome Measures: Time trends in percentage of days abstinent, percentage of heavy drinking days, and rates of good clinical outcome. Results: Alcoholic subjects with an Asp40 allele receiving MM alone (no CBI) had an increased percentage of days abstinent (P=.07) and a decreased percentage of heavy drinking days (P=.04) if treated with naltrexone vs placebo, while those with the Asn40/Asn40 genotype showed no medication differences. If treated with MM alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of individuals with the Asn40/Asn40 genotype (odds ratio, 5.75; confidence interval, 1.88-17.54), while, if treated with placebo, 48.6% of Asp40 carriers and 54.0% of individuals with the Asn40/Asn40 genotype had a good clinical outcome (interaction between medication and genotype, P=.005). No gene×medication interactions were observed in those treated with both MM and CBI. Conclusions: These results confirm and extend the observation that the functionally significant OPRM1 Asp40 allele predicts naltrexone treatment response in alcoholic individuals. This relationship might be obscured, however, by other efficacious treatments. OPRM1 geno-typing in alcoholic individuals might be useful to assist in selecting treatment options. PMID:18250251

Conformational Change in the Active Site of Streptococcal Unsaturated Glucuronyl Hydrolase Through Site-Directed Mutagenesis at Asp-115.

PubMed

Nakamichi, Yusuke; Oiki, Sayoko; Mikami, Bunzo; Murata, Kousaku; Hashimoto, Wataru

2016-08-01

Bacterial unsaturated glucuronyl hydrolase (UGL) degrades unsaturated disaccharides generated from mammalian extracellular matrices, glycosaminoglycans, by polysaccharide lyases. Two Asp residues, Asp-115 and Asp-175 of Streptococcus agalactiae UGL (SagUGL), are completely conserved in other bacterial UGLs, one of which (Asp-175 of SagUGL) acts as a general acid and base catalyst. The other Asp (Asp-115 of SagUGL) also affects the enzyme activity, although its role in the enzyme reaction has not been well understood. Here, we show substitution of Asp-115 in SagUGL with Asn caused a conformational change in the active site. Tertiary structures of SagUGL mutants D115N and D115N/K370S with negligible enzyme activity were determined at 2.00 and 1.79 Å resolution, respectively, by X-ray crystallography. The side chain of Asn-115 is drastically shifted in both mutants owing to the interaction with several residues, including Asp-175, by formation of hydrogen bonds. This interaction between Asn-115 and Asp-175 probably prevents the mutants from triggering the enzyme reaction using Asp-175 as an acid catalyst.

Terbium-Aspartic Acid Nanocrystals with Chirality-Dependent Tunable Fluorescent Properties.

PubMed

Ma, Baojin; Wu, Yu; Zhang, Shan; Wang, Shicai; Qiu, Jichuan; Zhao, Lili; Guo, Daidong; Duan, Jiazhi; Sang, Yuanhua; Li, Linlin; Jiang, Huaidong; Liu, Hong

2017-02-28

Terbium-aspartic acid (Tb-Asp) nanocrystals with chirality-dependent tunable fluorescent properties can be synthesized through a facile synthesis method through the coordination between Tb and Asp. Asp with different chirality (dextrorotation/d and levogyration/l) changes the stability of the coordination center following fluorescent absorption/emission ability differences. Compared with l-Asp, d-Asp can coordinate Tb to form a more stable center, following the higher quantum yield and longer fluorescence life. Fluorescence intensity of Tb-Asp linearly increases with increase ratio of d-Asp in the mixed chirality Tb-Asp system, and the fluorescent properties of Tb-Asp nanocrystals can be tuned by adjusting the chirality ratio. Tb-Asp nanocrystals possess many advantage, such as high biocompatibility, without any color in visible light irradiation, monodispersion with very small size, and long fluorescent life. Those characteristics will give them great potential in many application fields, such as low-cost antifake markers and advertisements using inkjet printers or for molds when dispersed in polydimethylsiloxane. In addition, europium can also be used to synthesize Eu-Asp nanoparticles. Importantly, the facile, low-cost, high-yield, mass-productive "green" process provides enormous advantages for synthesis and application of fluorescent nanocrystals, which will have great impact in nanomaterial technology.

Substitution of amino acids Asp-85, Asp-212, and Arg-82 in bacteriorhodopsin affects the proton release phase of the pump and the pK of the Schiff base.

PubMed

Otto, H; Marti, T; Holz, M; Mogi, T; Stern, L J; Engel, F; Khorana, H G; Heyn, M P

1990-02-01

Photocycle and flash-induced proton release and uptake were investigated for bacteriorhodopsin mutants in which Asp-85 was replaced by Ala, Asn, or Glu; Asp-212 was replaced by Asn or Glu; Asp-115 was replaced by Ala, Asn, or Glu; Asp-96 was replaced by Ala, Asn, or Glu; and Arg-82 was replaced by Ala or Gln in dimyristoylphosphatidylcholine/3-[(3-cholamidopropyl)dimethylammonio]-1- propanesulfonate micelles at pH 7.3. In the Asp-85----Ala and Asp-85----Asn mutants, the absence of the charged carboxyl group leads to a blue chromophore at 600 and 595 nm, respectively, and lowers the pK of the Schiff base deprotonation to 8.2 and 7, respectively, suggesting a role for Asp-85 as counterion to the Schiff base. The early part of the photocycles of the Asp-85----Ala and Asp-85----Asn mutants is strongly perturbed; the formation of a weak M-like intermediate is slowed down about 100-fold over wild type. In both mutants, proton release is also slower but clearly precedes the rise of M. The amplitude of the early (less than 0.2 microseconds) reversed photovoltage component in the Asp-85----Asn mutant is very large, and the net charge displacement is close to zero, indicating proton release and uptake on the cytoplasmic side of the membrane. The data suggest an obligatory role for Asp-85 in the efficient deprotonation of the Schiff base and in the proton release phase, probably as proton acceptor. In the Asp-212----Asn mutant, the rise of the absorbance change at 410 nm is slowed down to 220 microsecond, its amplitude is small, and the release of protons is delayed to 1.9 ms. The absorbance changes at 650 nm indicate perturbations in the early time range with a slow K intermediate. Thus Asp-212 also participates in the early events of charge translocation and deprotonation of the Schiff base. In the Arg-82----Gln mutant, no net transient proton release was observed, whereas, in the Arg-82----Ala mutant, uptake and release were reversed. The pK shift of the purple-to-blue transition in the Asp-85----Glu, Arg-82----Ala, and Arg-82----Gln mutants and the similarity in the photocycle and photoelectrical signals of the Asp-85----Ala, Asp-85----Asn, and Asp-212----Asn mutants suggest the interaction between Asp-85, Arg-82, Asp-212, and the Schiff base as essential for proton release.

Dynamic characterization of HLA-B*44 Alleles: A comparative molecular dynamics simulation study.

PubMed

Ozbek, Pemra

2016-06-01

Human Leukocyte Antigens (HLA) are highly polymorphic proteins that play a key role in the immune system. HLA molecule is present on the cell membrane of antigen-presenting cells of the immune system and presents short peptides, originating from the proteins of invading pathogens or self-proteins, to the T-cell Receptor (TCR) molecule of the T-cells. In this study, peptide-binding characteristics of HLA-B*44:02, 44:03, 44:05 alleles bound to three nonameric peptides were studied using molecular dynamics simulations. Polymorphisms among these alleles (Asp116Tyr and Asp156Leu) result in major differences in the allele characteristics. While HLA-B*44:02 (Asp116, Asp156) and HLA-B*44:03 (Asp116, Leu156) depend on tapasin for efficient peptide loading, HLA-B*44:05 (Tyr116, Asp156) is tapasin independent. On the other hand, HLA-B*44:02 and HLA-B*44:03 mismatch is closely related to transplant rejection and acute-graft-versus-host disease. In order to understand the dynamic characteristics, the simulation trajectories were analyzed by applying Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) calculations and hydrogen bonding analysis. Binding dynamics of the three HLA-B*44 alleles and peptide sequences are comparatively discussed. In general, peptide binding stability is found to depend on the peptide rather than the allele type for HLA-B*44 alleles. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pure detection of the acoustic spin pumping in Pt/YIG/PZT structures

NASA Astrophysics Data System (ADS)

Uchida, Ken-ichi; Qiu, Zhiyong; Kikkawa, Takashi; Saitoh, Eiji

2014-11-01

The acoustic spin pumping (ASP) stands for the generation of a spin voltage from sound waves in a ferromagnet/paramagnet junction. In this letter, we propose and demonstrate a method for pure detection of the ASP, which enables the separation of sound-wave-driven spin currents from the spin Seebeck effect due to the heating of a sample caused by a sound-wave injection. Our demonstration using a Pt/YIG/PZT sample shows that the ASP signal in this structure measured by a conventional method is considerably offset by the heating signal and that the pure ASP signal is one order of magnitude greater than that reported in the previous study.

Does mental illness stigma contribute to adolescent standardized patients' discomfort with simulations of mental illness and adverse psychosocial experiences?

PubMed

Hanson, Mark D; Johnson, Samantha; Niec, Anne; Pietrantonio, Anna Marie; High, Bradley; MacMillan, Harriet; Eva, Kevin W

2008-01-01

Adolescent mental illness stigma-related factors may contribute to adolescent standardized patients' (ASP) discomfort with simulations of psychiatric conditions/adverse psychosocial experiences. Paradoxically, however, ASP involvement may provide a stigma-reduction strategy. This article reports an investigation of this hypothetical association between simulation discomfort and mental illness stigma. ASPs were randomly assigned to one of two simulation conditions: one was associated with mental illness stigma and one was not. ASP training methods included carefully written case simulations, educational materials, and active teaching methods. After training, ASPs completed the adapted Project Role Questionnaire to rate anticipated role discomfort with hypothetical adolescent psychiatric conditions/adverse psychosocial experiences and to respond to open-ended questions regarding this discomfort. A mixed design ANOVA was used to compare comfort levels across simulation conditions. Narrative responses to an open-ended question were reviewed for relevant themes. Twenty-four ASPs participated. A significant effect of simulation was observed, indicating that ASPs participating in the simulation associated with mental illness stigma anticipated greater comfort with portraying subsequent stigma-associated roles than did ASPs in the simulation not associated with stigma. ASPs' narrative responses regarding their reasons for anticipating discomfort focused upon the role of knowledge-related factors. ASPs' work with a psychiatric case simulation was associated with greater anticipated comfort with hypothetical simulations of psychiatric/adverse psychosocial conditions in comparison to ASPs lacking a similar work experience. The ASPs provided explanations for this anticipated discomfort that were suggestive of stigma-related knowledge factors. This preliminary research suggests an association between ASP anticipated role discomfort and mental illness stigma, and that ASP work may contribute to stigma reduction.

A comparative study of occurrence and fate of endocrine disruptors: diethyl phthalate and dibutyl phthalate in ASP- and SBR-based wastewater treatment plants.

PubMed

Saini, Gita; Pant, Shalini; Singh, Shri Om; Kazmi, A A; Alam, Tanveer

2016-11-01

Phthalates are endocrine-disrupting chemicals which affect endocrine system by bio-accumulation in aquatic organisms and produce adverse health effects in aquatic organisms as well as human beings, when come in contact. Present study focuses on occurrence and removal of two phthalates: diethylphthalate (DEP) and dibutylphthalate (DBP) in two full-scale wastewater treatment plants (WWTPs) i.e. sewage treatment plants (STPs) based on well-adopted technologies, activated sludge process (ASP) and sequencing batch reactor (SBR).Gas chromatography-mass spectrometry (GC-MS) analysis was performed for both wastewater and sludge sample for determination and identification of the concentration of these compounds in both STPs by monitoring the STPs for 9 months. It was observed that the concentration of DEP was less than DBP in the influent of ASP and SBR. Average concentrations of DEP and DBP in sludge sample of ASP were found to be 2.15 and 2.08 ng/g, whereas in SBR plant, these values were observed as 1.71 and 2.01 ng/g, respectively. Concerning the removal efficiency of DEP, SBR and ASP plants were found effective with removal efficiency of 91.51 and 91.03 %, respectively. However, in the case of DBP, SBR showed lower removal efficiency (85.42 %) as compared to ASP (92.67 %). Comparative study of both plants proposed that in ASP plant, DBP reduction was higher than the SBR. Fourier transformation infrared (FTIR) analysis also confirmed the same result of sludge analysis for both STPs. Sludge disposal studied with scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX) and thermo-gravimetric analysis (TGA) techniques confirmed that sludge of both STPs have high calorific value and can be used as fuel to make fuel-briquettes and bottom ash to make firebricks.

Lack of association between the Glu298Asp polymorphism of endothelial nitric oxide synthase and slow coronary flow in the Turkish population

PubMed Central

Caglayan, Ahmet Okay; Kalay, Nihat; Saatci, Cetin; Yalcın, Arif; Akalın, Hilal; Dundar, Munis

2009-01-01

BACKGROUND: Coronary endothelial dysfunction plays an important pathogenetic role in patients with slow coronary flow (SCF). No data exist regarding the possible contribution of the Glu298Asp polymorphism genotype of the endothelial nitric oxide synthase (eNOS) gene to human SCF in the literature. OBJECTIVE: To investigate the association between SCF and the Glu298Asp polymorphism of the eNOS gene. METHODS: The study population consisted of 85 consecutive patients. The patient group included 66 patients with angiographically proven normal coronary arteries with SCF, and 19 subjects with normal coronary arteries with no SCF. The thrombolysis in myocardial infarction frame count was used for the diagnosis of SCF. The Glu298Asp polymorphism was determined by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: The baseline characteristics were similar between the two groups, except for high-density lipoprotein cholesterol, which was higher in the SCF group than in the controls. The genotype distribution of Glu298Asp was as follows: GG 26%, GT 56% and TT 12%, where G is guanine and T is thymine. There was no difference in the frequency of the various genotypes or the alleles in patients with SCF versus normal controls. CONCLUSIONS: The Glu298Asp polymorphism genotype of the eNOS gene is not a risk factor for SCF in the present study population. PMID:19279989

Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period.

PubMed

Saleh, J; Summers, L K; Cianflone, K; Fielding, B A; Sniderman, A D; Frayn, K N

1998-04-01

The objective of this study was to determine whether Acylation Stimulating Protein (ASP) is generated in vivo by human adipose tissue during the postprandial period. After a fat meal, samples from 12 subjects were obtained (up to 6 h) from an arterialized hand vein and an anterior abdominal wall vein that drains adipose tissue. Veno-arterial (V-A) gradients across the subcutaneous adipose tissue bed were calculated. The data demonstrate that ASP is produced in vivo (positive V-A gradient) With maximal production at 3-5 h postprandially. The plasma triacylglycerol (TAG) clearance was evidenced by a negative V-A gradient. It increased substantially after 3 h and remained prominent until the final time point. There was, therefore, a close temporal coordination between ASP generation and TAG clearance. In contrast, plasma insulin and non-esterified fatty acid (NEFA) had an early (1-2 h) postprandial change. Fatty acid incorporation into adipose tissue (FIAT) was calculated from V-A glycerol and non-esterified fatty acid (NEFA) differences postprandially. FIAT was negative during the first hour, implying net fat mobilization. FIAT then became increasingly positive, implying net fat deposition, and overall followed the same time course as ASP and TAG clearance. There was a direct positive correlation between total ASP production and total FIAT (r = 0.566, P < 0.05). These data demonstrate that ASP is generated in vivo by human adipocytes and that this process is accentuated postprandially, supporting the concept that ASP plays an important role in clearance of TAG from plasma and fatty acid storage in adipose tissue.

Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r

PubMed Central

Le Pape, Elodie; Passeron, Thierry; Giubellino, Alessio; Valencia, Julio C.; Wolber, Rainer; Hearing, Vincent J.

2009-01-01

The melanocortin-1 receptor (MC1R) is a key regulator of pigmentation in mammals and is tightly linked to an increased risk of skin cancers, including melanoma, in humans. Physiologically activated by α-melanocyte stimulating hormone (αMSH), MC1R function can be antagonized by a secreted factor, agouti signal protein (ASP), which is responsible for the lighter phenotypes in mammals (including humans), and is also associated with increased risk of skin cancer. It is therefore of great interest to characterize the molecular effects elicited by those MC1R ligands. In this study, we determined the gene expression profiles of murine melan-a melanocytes treated with ASP or αMSH over a 4-day time course using genome-wide oligonucleotide microarrays. As expected, there were significant reductions in expression of numerous melanogenic proteins elicited by ASP, which correlates with its inhibition of pigmentation. ASP also unexpectedly modulated the expression of genes involved in various other cellular pathways, including glutathione synthesis and redox metabolism. Many genes up-regulated by ASP are involved in morphogenesis (especially in nervous system development), cell adhesion, and extracellular matrix-receptor interactions. Concomitantly, ASP enhanced the migratory potential and the invasiveness of melanocytic cells in vitro. These results demonstrate the role of ASP in the dedifferentiation of melanocytes, identify pigment-related genes targeted by ASP and by αMSH, and provide insights into the pleiotropic molecular effects of MC1R signaling that may function during development and may affect skin cancer risk. PMID:19174519

Physical and antibacterial properties of açaí edible films formulated with thyme essential oil and apple skin polyphenols.

PubMed

Espitia, Paula J P; Avena-Bustillos, Roberto J; Du, Wen-Xian; Chiou, Bor-Sen; Williams, Tina G; Wood, Delilah; McHugh, Tara H; Soares, Nilda F F

2014-05-01

Thyme essential oil (TEO) and apple skin polyphenols (ASP) are natural compounds considered as generally recognized as safe by FDA, with biological effects against bacteria and fungi. This work aimed to evaluate physical and antimicrobial properties of açaí edible films formulated with TEO and ASP at 3% and 6% (w/w) individually or combined at 3% (w/w) each. Physical properties studied include mechanical resistance, water vapor permeability (WVP), color, and thermal resistance. Antimicrobial activity against Listeria monocytogenes was determined using the overlay diffusion test. Addition of ASP resulted in improved mechanical properties. TEO at 6% (w/w) resulted in increased elongation. ASP films had significant higher WVP than control film. ASP films were lighter and had more red color than other films. Incorporation of ASP resulted in improved film thermal stability, whereas TEO caused rapid thermal decomposition. Presence of clusters was observed on the surface of films. Addition of ASP resulted in a smoother surface, whereas addition of TEO led to the formation of crater-like pits on the film surface. Açaí edible film incorporated with 6% (w/w) TEO presented the highest antimicrobial activity. However, both antimicrobials are necessary in the açaí films in order to obtain edible films with suitable physical-mechanical properties. The results of the present study showed that TEO and ASP can be used to prepare açaí edible films with adequate physical-mechanical properties and antimicrobial activity for food applications by direct contact. Developed açaí edible films presented antimicrobial activity against L. monocytogenes and good physical-mechanical properties, showing the potential use of açaí edible films in food preservation. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Attenuated-Signal Plaque Progression Predicts Long-Term Mortality After Heart Transplantation: IVUS Assessment of Cardiac Allograft Vasculopathy.

PubMed

Okada, Kozo; Fearon, William F; Luikart, Helen; Kitahara, Hideki; Otagiri, Kyuhachi; Tanaka, Shigemitsu; Kimura, Takumi; Yock, Paul G; Fitzgerald, Peter J; Yeung, Alan C; Valantine, Hannah A; Khush, Kiran K; Honda, Yasuhiro

2016-07-26

Although cardiac allograft vasculopathy (CAV) is typically characterized by diffuse coronary intimal thickening with pathological vessel remodeling, plaque instability may also play an important role in CAV. Previous studies of native coronary atherosclerosis have demonstrated associations between attenuated-signal plaque (ASP), plaque instability, and adverse clinical events. This study's aim was to characterize the association between ASP and long-term mortality post-heart transplantation. In 105 heart transplant recipients, serial (baseline and 1-year post-transplant) intravascular ultrasound was performed in the first 50 mm of the left anterior descending artery. The ASP score was calculated by grading the measured angle of attenuation from grades 0 to 4 (specifically, 0°, 1° to 90°, 91° to 180°, 181° to 270°, and >270°) at 1-mm intervals. The primary endpoint was all-cause death or retransplantation. At 1-year post-transplant, 10.5% of patients demonstrated ASP progression (newly developed or increased ASP). Patients with ASP progression had a higher incidence of acute cellular rejection during the first year (63.6% vs. 22.3%; p = 0.006) and tendency for greater intimal growth (percent intimal volume: 9.2 ± 9.3% vs. 4.4 ± 5.3%; p = 0.07) than those without. Over a median follow-up of 4.6 years, there was a significantly lower event-free survival rate in patients with ASP progression at 1-year post-transplant compared with those without. In contrast, maximum intimal thickness did not predict long-term mortality. ASP progression appears to reflect chronic inflammation related to acute cellular rejection and is an independent predictor of long-term mortality after heart transplantation. Serial assessments of plaque instability may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Aeromonas sobria serine protease (ASP): a subtilisin family endopeptidase with multiple virulence activities.

PubMed

Imamura, Takahisa; Murakami, Yoji; Nitta, Hidetoshi

2017-09-26

Aeromonas sobria serine protease (ASP) is secreted from Aeromonas sobria, a pathogen causing gastroenteritis and sepsis. ASP resembles Saccharomyces cerevisiae Kex2, a member of the subtilisin family, and preferentially cleaves peptide bonds at the C-terminal side of paired basic amino acid residues; also accepting unpaired arginine at the P1 site. Unlike Kex2, however, ASP lacks an intramolecular chaperone N-terminal propeptide, instead utilizes the external chaperone ORF2 for proper folding, therefore, ASP and its homologues constitute a new subfamily in the subtilisin family. Through activation of the kallikrein/kinin system, ASP induces vascular leakage, and presumably causes edema and septic shock. ASP accelerates plasma clotting by α-thrombin generation from prothrombin, whereas it impairs plasma clottability by fibrinogen degradation, together bringing about blood coagulation disorder that occurs in disseminated intravascular coagulation, a major complication of sepsis. From complement C5 ASP liberates C5a that induces neutrophil recruitment and superoxide release, and mast cell degranulation, which are associated with pus formation, tissue injury and diarrhea, respectively. Nicked two-chain ASP also secreted from A. sobria is more resistant to inactivation by α2-macroglobulin than single-chain ASP, thereby raising virulence activities. Thus, ASP is a potent virulence factor and may participate in the pathogenesis of A. sobria infection.

Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298→Asp polymorphism) to the presence, extent, and severity of coronary artery disease

PubMed Central

Colombo, M G; Andreassi, M G; Paradossi, U; Botto, N; Manfredi, S; Masetti, S; Rossi, G; Clerico, A; Biagini, A

2002-01-01

Background: Genetic variants of endothelial nitric oxide synthase (eNOS) could influence individual susceptibility to coronary artery disease. Objective: To assess whether Glu298→Asp polymorphism of the eNOS gene is associated with the occurrence and severity of angiographically defined coronary artery disease in the Italian population. Methods: Polymerase chain reaction/restriction fragment length polymorphism analysis was done to detect the Glu298→Asp variant of the eNOS gene in 201 patients with coronary artery disease and 114 controls. The severity of coronary artery disease was expressed by the number of affected vessels and by the Duke scoring system. Results: The frequencies of the eNOS Glu/Glu, Glu/Asp, and Asp/Asp genotypes in the coronary artery disease group were significantly different from those of controls (45.3%, 38.8%, and 15.9% v 42.1%, 51.8%, and 6.1%, respectively; χ2 = 8.589, p = 0.0136). In comparison with subjects who had a Glu298 allele in the eNOS gene, the risk of coronary artery disease was increased among Asp/Asp carriers (odds ratio 2.9, 95% confidence interval 1.2 to 6.8, p = 0.01) and was independent of the other common risk factors (p = 0.04). There was a significant association between the eNOS Glu298→Asp variant and both the number of stenosed vessels (mean (SEM), 2.3 (0.1) for Asp/Asp v 1.9 (0.1) and 1.8 (0.1) for Glu/Glu and Glu/Asp, respectively; p = 0.01) and the Duke score (56.1 (3.1) for Asp/Asp v 46.7 (2.0) and 46.1 (1.9) for Glu/Glu and Glu/Asp, respectively; p = 0.02). Conclusions: Glu298→Asp polymorphism of the eNOS gene appears to be associated with the presence, extent, and severity of angiographically assessed coronary artery disease. PMID:12010932

Comparison of laboratory-scale thermophilic biofilm and activated sludge processes integrated with a mesophilic activated sludge process.

PubMed

Suvilampi, J; Lehtomäki, A; Rintala, J

2003-07-01

A combined thermophilic-mesophilic wastewater treatment was studied using a laboratory-scale thermophilic activated sludge process (ASP) followed by mesophilic ASP or a thermophilic suspended carrier biofilm process (SCBP) followed by mesophilic ASP, both systems treating diluted molasses (dilution factor 1:500 corresponding GF/A-filtered COD (COD(filt)) of 1900+/-190 mgl(-1)). With hydraulic retention times (HRTs) of 12-18 h the thermophilic ASP and thermophilic SCBP removed 60+/-13% and 62+/-7% of COD(filt), respectively, with HRT of 8 h the removals were 48+/-1% and 69+/-4%. The sludge volume index (SVI) was notably lower in the thermophilic SCBP (measured from suspended sludge) than in the thermophilic ASP. Under the lowest HRT the mesophilic ASP gave better performance (as SVI, COD(filt), and COD(tot) removals) after the thermophilic SCBP than after the thermophilic ASP. Measured sludge yields were low (less than 0.1 kg suspended solids (SS) kg COD(filt removed)(-1)) in all processes. Both thermophilic treatments removed 80-85% of soluble COD (COD(sol)) whereas suspended COD (COD(susp)) and colloidal COD (COD(col)) were increased. Both mesophilic post-treatments removed all COD(col) and most of the COD(susp) from the thermophilic effluents. In conclusion, combined thermophilic-mesophilic treatment appeared to be easily operable and produced high effluent quality.

Variants in Several Genomic Regions Associated with Asperger Disorder

PubMed Central

Salyakina, D.; Ma, D.Q.; Jaworski, J.M.; Konidari, I.; Whitehead, P.L.; Henson, R.; Martinez, D.; Robinson, J.L.; Sacharow, S.; Wright, H.H.; Abramson, R.K.; Gilbert, J.R.; Cuccaro, M.L.; Pericak-Vance, M.A.

2010-01-01

Asperger disorder (ASP) is one of the autism spectrum disorders (ASD) and is differentiated from autism largely on the absence of clinically significant cognitive and language delays. Analysis of a homogenous subset of families with ASP may help to address the corresponding effect of genetic heterogeneity on identifying ASD genetic risk factors. To examine the hypothesis that common variation is important in ASD, we performed a genome-wide association study (GWAS) in 124 ASP families in a discovery data set and 110 ASP families in a validation data set. We prioritized the top 100 association results from both cohorts by employing a ranking strategy. Novel regions on 5q21.1 (P = 9.7 × 10−7) and 15q22.1–q22.2 (P = 7.3 × 10−6) were our most significant findings in the combined data set. Three chromosomal regions showing association, 3p14.2 (P = 3.6 × 10−6), 3q25–26 (P = 6.0 × 10−5) and 3p23 (P = 3.3 × 10−4) overlapped linkage regions reported in Finnish ASP families, and eight association regions overlapped ASD linkage areas. Our findings suggest that ASP shares both ASD-related genetic risk factors, as well as has genetic risk factors unique to the ASP phenotype. PMID:21182207

ASPsiRNA: A Resource of ASP-siRNAs Having Therapeutic Potential for Human Genetic Disorders and Algorithm for Prediction of Their Inhibitory Efficacy.

PubMed

Monga, Isha; Qureshi, Abid; Thakur, Nishant; Gupta, Amit Kumar; Kumar, Manoj

2017-09-07

Allele-specific siRNAs (ASP-siRNAs) have emerged as promising therapeutic molecules owing to their selectivity to inhibit the mutant allele or associated single-nucleotide polymorphisms (SNPs) sparing the expression of the wild-type counterpart. Thus, a dedicated bioinformatics platform encompassing updated ASP-siRNAs and an algorithm for the prediction of their inhibitory efficacy will be helpful in tackling currently intractable genetic disorders. In the present study, we have developed the ASPsiRNA resource (http://crdd.osdd.net/servers/aspsirna/) covering three components viz (i) ASPsiDb , (ii) ASPsiPred , and (iii) analysis tools like ASP-siOffTar ASPsiDb is a manually curated database harboring 4543 (including 422 chemically modified) ASP-siRNAs targeting 78 unique genes involved in 51 different diseases. It furnishes comprehensive information from experimental studies on ASP-siRNAs along with multidimensional genetic and clinical information for numerous mutations. ASPsiPred is a two-layered algorithm to predict efficacy of ASP-siRNAs for fully complementary mutant (Eff mut ) and wild-type allele (Eff wild ) with one mismatch by ASPsiPred SVM and ASPsiPred matrix , respectively. In ASPsiPred SVM , 922 unique ASP-siRNAs with experimentally validated quantitative Eff mut were used. During 10-fold cross-validation (10nCV) employing various sequence features on the training/testing dataset (T737), the best predictive model achieved a maximum Pearson's correlation coefficient (PCC) of 0.71. Further, the accuracy of the classifier to predict Eff mut against novel genes was assessed by leave one target out cross-validation approach (LOTOCV). ASPsiPred matrix was constructed from rule-based studies describing the effect of single siRNA:mRNA mismatches on the efficacy at 19 different locations of siRNA. Thus, ASPsiRNA encompasses the first database, prediction algorithm, and off-target analysis tool that is expected to accelerate research in the field of RNAi-based therapeutics for human genetic diseases. Copyright © 2017 Monga et al.

Compliance with the Healthy Eating Standards in YMCA afterschool programs

PubMed Central

Beets, Michael W.; Weaver, R. Glenn; Turner-McGrievy, Brie; Beighle, Aaron; Moore, Justin B.; Webster, Collin; Khan, Mahmud; Saunders, Ruth

2016-01-01

Objective In 2011, the YMCA of the USA adopted Healthy Eating (HE) Standards for all their afterschool programs (ASPs). The extent to which YMCA-ASPs comply with the standards is unknown. Methods Twenty ASPs from all YMCA-ASPs across SC (N=102) were invited to participate. Direct observation of the foods/beverages served and staff behaviors were collected on four non-consecutive days/ASP. Results One ASP did not serve a snack. Of the remaining, a total of 26% ASPs served a fruit/vegetable and 32% served water every day; 26% served sugar-sweetened beverages, 47% served sugar-added foods, and only 11% served whole grains, when grains were served. Staff were sitting with the children (65%) or verbally promoting healthy eating (15%) on at least one observation day. Staff where drinking non-approved drinks (25%) or foods (45%) on at least one observation day. No ASPs served snacks family-style every day. Conclusions/Implications Additional efforts are required to assist YMCA-operated ASPs in achieving these important nutrition standards. PMID:27372234

β-Cyclodextrin inclusion complex: preparation, characterization, and its aspirin release in vitro

NASA Astrophysics Data System (ADS)

Zhou, Hui-Yun; Jiang, Ling-Juan; Zhang, Yan-Ping; Li, Jun-Bo

2012-09-01

In this work, the optimal clathration condition was investigated for the preparation of aspirin-β-cyclodextrin (Asp-β-CD) inclusion complex using design of experiment (DOE) methodology. A 3-level, 3-factor Box-Behnken design with a total of 17 experimental runs was used. The Asp-β-CD inclusion complex was prepared by saturated solution method. The influence on the embedding rate was investigated, including molar ratio of β-CD to Asp, clathration temperature and clathration time, and the optimum values of such three test variables were found to be 0.82, 49°C and 2.0 h, respectively. The embedding rate could be up to 61.19%. The formation of the bonding between -COOH group of Asp and O-H group of β-CD might play an important role in the process of clathration according to FT-IR spectra. Release kinetics of Asp from inclusion complex was studied for the evaluation of drug release mechanism and diffusion coefficients. The results showed that the drug release from matrix occurred through Fickian diffusion mechanism. The cumulative release of Asp reached only 40% over 24 h, so the inclusion complex could potentially be applied as a long-acting delivery system.

The modeling and design of the Annular Suspension and Pointing System /ASPS/. [for Space Shuttle

NASA Technical Reports Server (NTRS)

Kuo, B. C.; Lin, W. C. W.

1979-01-01

The Annular Suspension and Pointing System (ASPS) is a payload auxiliary pointing device of the Space Shuttle. The ASPS is comprised of two major subassemblies, a vernier and a coarse pointing subsystem. The three functions provided by the ASPS are related to the pointing of the payload, centering the payload in the magnetic actuator assembly, and tracking the payload mounting plate and shuttle motions by the coarse gimbals. The equations of motion of a simplified planar model of the ASPS are derived. Attention is given to a state diagram of the dynamics of the ASPS with position-plus-rate controller, the nonlinear spring characteristic for the wire-cable torque of the ASPS, the design of the analog ASPS through decoupling and pole placement, and the time response of different components of the continuous control system.

The ASP3 locus in Saccharomyces cerevisiae originated by horizontal gene transfer from Wickerhamomyces.

PubMed

League, Garrett P; Slot, Jason C; Rokas, Antonis

2012-11-01

The asparagine degradation pathway in the S288c laboratory strain of Saccharomyces cerevisiae is comprised of genes located at two separate loci. ASP1 is located on chromosome IV and encodes for cytosolic l-asparaginase I, whereas ASP3 contains a gene cluster located on chromosome XII comprised of four identical genes, ASP3-1, ASP3-2, ASP3-3, and ASP3-4, which encode for cell wall-associated l-asparaginase II. Interestingly, the ASP3 locus appears to be only present, in variable copy number, in S. cerevisiae strains isolated from laboratory or industrial environments and is completely absent from the genomes of 128 diverse fungal species. Investigation of the evolutionary history of ASP3 across these 128 genomes as well as across the genomes of 43 S. cerevisiae strains shows that ASP3 likely arose in a S. cerevisiae strain via horizontal gene transfer (HGT) from, or a close relative of, the wine yeast Wickerhamomyces anomalus, which co-occurs with S. cerevisiae in several biotechnological processes. Thus, because the ASP3 present in the S288c laboratory strain of S. cerevisiae is induced in response to nitrogen starvation, its acquisition may have aided yeast adaptation to artificial environments. Our finding that the ASP3 locus in S. cerevisiae originated via HGT further highlights the importance of gene sharing between yeasts in the evolution of their remarkable metabolic diversity. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

A comparison of repetitive behaviors in Aspergers Disorder and high functioning autism.

PubMed

Cuccaro, Michael L; Nations, Laura; Brinkley, Jason; Abramson, Ruth K; Wright, Harry H; Hall, Alicia; Gilbert, John; Pericak-Vance, Margaret A

2007-04-01

In this study we compared 33 IQ and age matched pairs of individuals with Aspergers Disorder (ASP) and high functioning autism (HFA) on measures of repetitive behavior. On the Repetitive Behavior Scale-Revised (RBS-R), the ASP and HFA groups showed no differences in RBS-R Intensity score (severity) score or Frequency score (number of problems present). This suggests that the two groups are similar with respect to the intensity or severity of repetitive behaviors and the presence of repetitive behaviors. At the item level there were no differences on scales typically associated with autism (Stereotyped Behavior) and ASP (Restricted Interests). Similarly, there were no differences between the groups on the Aberrant Behavior Checklist Stereotypy scale. These findings add to the body of literature showing that HFA and ASP fail to differ with respect to repetitive behaviors. The implications of the findings for neurobiologic and genetic studies are discussed.

Surface proton transport of fully protonated poly(aspartic acid) thin films on quartz substrates

NASA Astrophysics Data System (ADS)

Nagao, Yuki; Kubo, Takahiro

2014-12-01

Thin film structure and the proton transport property of fully protonated poly(aspartic acid) (P-Asp100) have been investigated. An earlier study assessed partially protonated poly(aspartic acid), highly oriented thin film structure and enhancement of the internal proton transport. In this study of P-Asp100, IR p-polarized multiple-angle incidence resolution (P-MAIR) spectra were measured to investigate the thin film structure. The obtained thin films, with thicknesses of 120-670 nm, had no oriented structure. Relative humidity dependence of the resistance, proton conductivity, and normalized resistance were examined to ascertain the proton transport property of P-Asp100 thin films. The obtained data showed that the proton transport of P-Asp100 thin films might occur on the surface, not inside of the thin film. This phenomenon might be related with the proton transport of the biological system.

Electrospun PLA: PCL composites embedded with unmodified and 3-aminopropyltriethoxysilane (ASP) modified halloysite nanotubes (HNT)

NASA Astrophysics Data System (ADS)

Haroosh, Hazim J.; Dong, Yu; Chaudhary, Deeptangshu S.; Ingram, Gordon D.; Yusa, Shin-ichi

2013-02-01

Electrospinning is a simple and versatile fiber synthesis technique in which a high-voltage electric field is applied to a stream of polymer melt or polymer solution, resulting in the formation of continuous micro/nanofibers. Halloysite nanotubes (HNT) have been found to achieve improved structural and mechanical properties when embedded into various polymer matrices. This research work focuses on blending poly( ɛ-caprolactone) (PCL) (9 and 15 wt%/v) and poly(lactic acid) (PLA) (fixed at 8 wt%/v) solutions with HNT at two different concentrations 1 and 2 wt%/v. Both unmodified HNT and HNT modified with 3-aminopropyltriethoxysilane (ASP) were utilized in this study. Fiber properties have been shown to be strongly related to the solution viscosity and electrical conductivity. The addition of HNT increased the solution viscosity, thus resulting in the production of uniform fibers. For both PCL concentrations, the average fiber diameter increased with the increasing of HNT concentration. The average fiber diameters with HNT-ASP were reduced considerably in comparison to those with unmodified HNT when using 15 wt%/v PCL. Slightly better dispersion was obtained for PLA: PCL composites embedded with HNT-ASP compared to unmodified HNT. Furthermore, the addition of HNT-ASP to the polymeric blends resulted in a moderate decrease in the degree of crystallinity, as well as slight reductions of glass transition temperature of PCL, the crystallization temperature and melting temperature of PLA within composite materials. The infrared spectra of composites confirmed the successful embedding of HNT-ASP into PLA: PCL nanofibers relative to unmodified HNT due to the premodification using ASP to reduce the agglomeration behavior. This study provides a new material system that could be potentially used in drug delivery, and may facilitate good control of the drug release process.

Effects of protonation state of Asp181 and position of active site water molecules on the conformation of PTP1B.

PubMed

Ozcan, Ahmet; Olmez, Elif Ozkirimli; Alakent, Burak

2013-05-01

In protein tyrosine phosphatase 1B (PTP1B), the flexible WPD loop adopts a closed conformation (WPDclosed ) in the active state of PTP1B, bringing the catalytic Asp181 close to the active site pocket, while WPD loop is in an open conformation (WPDopen ) in the inactive state. Previous studies showed that Asp181 may be protonated at physiological pH, and ordered water molecules exist in the active site. In the current study, molecular dynamics simulations are employed at different Asp181 protonation states and initial positions of active site water molecules, and compared with the existing crystallographic data of PTP1B. In WPDclosed conformation, the active site is found to maintain its conformation only in the protonated state of Asp181 in both free and liganded states, while Asp181 is likely to be deprotonated in WPDopen conformation. When the active site water molecule network that is a part of the free WPDclosed crystal structure is disrupted, intermediate WPD loop conformations, similar to that in the PTPRR crystal structure, are sampled in the MD simulations. In liganded PTP1B, one active site water molecule is found to be important for facilitating the orientation of Cys215 and the phosphate ion, thus may play a role in the reaction. In conclusion, conformational stability of WPD loop, and possibly catalytic activity of PTP1B, is significantly affected by the protonation state of Asp181 and position of active site water molecules, showing that these aspects should be taken into consideration both in MD simulations and inhibitor design. Copyright © 2013 Wiley Periodicals, Inc.

Assembly of the Type II Secretion System such as Found in Vibrio cholerae Depends on the Novel Pilotin AspS

PubMed Central

Dunstan, Rhys A.; Heinz, Eva; Wijeyewickrema, Lakshmi C.; Pike, Robert N.; Purcell, Anthony W.; Evans, Timothy J.; Praszkier, Judyta; Robins-Browne, Roy M.; Strugnell, Richard A.; Korotkov, Konstantin V.; Lithgow, Trevor

2013-01-01

The Type II Secretion System (T2SS) is a molecular machine that drives the secretion of fully-folded protein substrates across the bacterial outer membrane. A key element in the machinery is the secretin: an integral, multimeric outer membrane protein that forms the secretion pore. We show that three distinct forms of T2SSs can be distinguished based on the sequence characteristics of their secretin pores. Detailed comparative analysis of two of these, the Klebsiella-type and Vibrio-type, showed them to be further distinguished by the pilotin that mediates their transport and assembly into the outer membrane. We have determined the crystal structure of the novel pilotin AspS from Vibrio cholerae, demonstrating convergent evolution wherein AspS is functionally equivalent and yet structurally unrelated to the pilotins found in Klebsiella and other bacteria. AspS binds to a specific targeting sequence in the Vibrio-type secretins, enhances the kinetics of secretin assembly, and homologs of AspS are found in all species of Vibrio as well those few strains of Escherichia and Shigella that have acquired a Vibrio-type T2SS. PMID:23326233

Characterization of the functional role of Asp141, Asp194, and Asp464 residues in the Mn2+-L-malate binding of pigeon liver malic enzyme.

PubMed

Chou, W Y; Chang, H P; Huang, C H; Kuo, C C; Tong, L; Chang, G G

2000-02-01

Pigeon liver malic enzyme was inactivated and cleaved at Asp141, Asp194, and Asp464 by the Cu2+-ascorbate system in acidic environment. Site-specific mutagenesis was performed at these putative metal-binding sites. Three point mutants, D141N, D194N, and D464N; three double mutants, D(141,194)N, D(194,464)N, and D(141,464)N; and a triple mutant, D(141,194,464)N; as well as the wild-type malic enzyme (WT) were successfully cloned and expressed in Escherichia coli cells. All recombinant enzymes, except the triple mutant, were purified to apparent homogeneity by successive Q-Sepharose and adenosine-2',5'-bisphosphate-agarose columns. The mutants showed similar apparent Km,NADP values to that of the WT. The Km,Mal value was increased in the D141N and D194N mutants. The Km,Mn value, on the other hand, was increased only in the D141N mutant by 14-fold, corresponding to approximately 1.6 kcal/mol for the Asp141-Mn2+ binding energy. Substrate inhibition by L-malate was only observed in WT, D464N, and D(141,464)N. Initial velocity experiments were performed to derive the various kinetic parameters. The possible interactions between Asp141, Asp194, and Asp464 were analyzed by the double-mutation cycles and triple-mutation box. There are synergistic weakening interactions between Asp141 and Asp194 in the metal binding that impel the D(141,194)N double mutant to an overall specificity constant [k(cat)/(Kd,Mn Km,Mal Km,NADP)] at least four orders of magnitude smaller than the WT value. This difference corresponds to an increase of 6.38 kcal/mol energy barrier for the catalytic efficiency. Mutation at Asp464, on the other hand, has partial additivity on the mutations at Asp141 and Asp194. The overall specificity constants for the double mutants D(194,464)N and D(141,464)N or the triple mutant D(141,194,464)N were decreased by only 10- to 100-fold compared to the WT. These results strongly suggest the involvement of Asp141 in the Mn2+-L-malate binding for the pigeon liver malic enzyme. The Asp194 and Asp464, which may be oxidized by nonspecific binding of Cu2+, are involved in the Mn2+-L-malate binding or catalysis indirectly by modulating the binding affinity of Asp141 with the Mn2+.

Argon Shrouded Plasma Spraying of Tantalum over Titanium for Corrosion Protection in Fluorinated Nitric Acid Media

NASA Astrophysics Data System (ADS)

Vetrivendan, E.; Jayaraj, J.; Ningshen, S.; Mallika, C.; Kamachi Mudali, U.

2018-02-01

Argon shrouded plasma spraying (ASPS) was used to deposit a Ta coating on commercially pure Ti (CP-Ti) under inert argon, for dissolver vessel application in the aqueous spent fuels reprocessing plant with high plutonium content. Oxidation during plasma spraying was minimized by shrouding argon system. Porosity and oxide content were controlled by optimizing the spraying parameters, to obtain a uniform and dense Ta coating. The Ta particle temperature and velocity were optimized by judiciously controlling the spray parameters, using a spray diagnostic charge-coupled device camera. The corrosion resistance of the Ta coatings developed by ASPS was investigated by electrochemical studies in 11.5 M HNO3 and 11.5 M HNO3 + 0.05 M NaF. Similarly, the durability of the ASPS Ta coating/substrate was evaluated as per ASTM A262 Practice-C test in boiling nitric acid and fluorinated nitric acid for 240 h. The ASPS Ta coating exhibited higher corrosion resistance than the CP-Ti substrate, as evident from electrochemical studies, and low corrosion rate with excellent coating stability in boiling nitric, and fluorinated nitric acid. The results of the present study revealed that tantalum coating by ASPS is a promising strategy for improving the corrosion resistance in the highly corrosive reprocessing environment.

Fidelity of Automatic Speech Processing for Adult and Child Talker Classifications.

PubMed

VanDam, Mark; Silbert, Noah H

2016-01-01

Automatic speech processing (ASP) has recently been applied to very large datasets of naturalistically collected, daylong recordings of child speech via an audio recorder worn by young children. The system developed by the LENA Research Foundation analyzes children's speech for research and clinical purposes, with special focus on of identifying and tagging family speech dynamics and the at-home acoustic environment from the auditory perspective of the child. A primary issue for researchers, clinicians, and families using the Language ENvironment Analysis (LENA) system is to what degree the segment labels are valid. This classification study evaluates the performance of the computer ASP output against 23 trained human judges who made about 53,000 judgements of classification of segments tagged by the LENA ASP. Results indicate performance consistent with modern ASP such as those using HMM methods, with acoustic characteristics of fundamental frequency and segment duration most important for both human and machine classifications. Results are likely to be important for interpreting and improving ASP output.

Fidelity of Automatic Speech Processing for Adult and Child Talker Classifications

PubMed Central

2016-01-01

Automatic speech processing (ASP) has recently been applied to very large datasets of naturalistically collected, daylong recordings of child speech via an audio recorder worn by young children. The system developed by the LENA Research Foundation analyzes children's speech for research and clinical purposes, with special focus on of identifying and tagging family speech dynamics and the at-home acoustic environment from the auditory perspective of the child. A primary issue for researchers, clinicians, and families using the Language ENvironment Analysis (LENA) system is to what degree the segment labels are valid. This classification study evaluates the performance of the computer ASP output against 23 trained human judges who made about 53,000 judgements of classification of segments tagged by the LENA ASP. Results indicate performance consistent with modern ASP such as those using HMM methods, with acoustic characteristics of fundamental frequency and segment duration most important for both human and machine classifications. Results are likely to be important for interpreting and improving ASP output. PMID:27529813

Acidic Polysaccharide from Angelica sinensis Reverses Anemia of Chronic Disease Involving the Suppression of Inflammatory Hepcidin and NF-κB Activation.

PubMed

Wang, Kaiping; Wu, Jun; Cheng, Fang; Huang, Xiao; Zeng, Fang; Zhang, Yu

2017-01-01

Anemia of chronic disease (ACD) is the second most prevalent anemia and frequently occurs in patients with acute or chronic immune activation. In the current study, we evaluated the therapeutic efficacy of Angelica sinensis polysaccharide (ASP) against ACD in rats and the potential mechanisms involved. The results showed that ASP inhibited inflammatory hepcidin in both HepG2 cells and ACD rats by blocking the IL-6/STAT3 and BMP/SMAD pathways. In ACD rats, the administration of ASP increased ferroportin expression, mobilized iron from the liver and spleen, increased serum iron levels, caused an elevation of serum EPO, and effectively relieved the anemia. Furthermore, ASP inhibited NF- κ B p65 activation via the I κ B kinases- (IKKs-) I κ B α pathway, thereby reducing the secretion of interleukin-6 (IL-6) and TNF- α , which is known to inhibit erythropoiesis. Our findings indicate that ASP is a potential treatment option for patients suffering from ACD.

Study of Water-Oil Emulsion Breaking by Stabilized Solution Consisting of Anionic Surface Acting Agent - Soda Ash - Polymer (ASP)

NASA Astrophysics Data System (ADS)

Kulichkov, S. V.; Avtomonov, E. G.; Andreeva, L. V.; Solomennik, S. F.; Nikitina, A. V.

2018-01-01

The paper provides a laboratory research of breaking natural water-oil emulsions: - by non-stabilized ASP; by stabilized ASP; by mixture of stabilized and non-stabilized ASP in different proportions and production of refinery water of the required quality with the use of IronGuard 2495 as flocculant. Oil-in-water emulsion is stable. Classic methods are not suitable for residual water treatment: sediment gravity flow; filtration; centrifuge test. Microemulsion formed after ASP application has low boundary tension and high pH. It contributes to transfer of oil phase into a water one, forming oil-in-water emulsion. Alkaline condition has adverse effect on demulsifying ability of agents, flocculation and boundary tension. For breaking of water-oil emulsion at EBU before the interchanger water or water-oil emulsion from the wells that were not APS-treated in ratio of 1:9 shall be delivered. Residual water after EBU must be prepared in water tanks by dilution in great volume.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berkowitz, Carl M.; Berg, Larry K.; Ogren, J. A.

This white paper presents the scientific motivation and preliminary logistical plans for a proposed ASP field campaign to be carried out in the summer of 2007. The primary objective of this campaign is to use the DOE Gulfstream-1 aircraft to make measurements characterizing the chemical, physical and optical properties of aerosols below, within and above large fields of fair weather cumulus and to use the NASA Langley Research Center’s High Spectral Resolution Lidar (HSRL) to make independent measurements of aerosol backscatter and extinction profiles in the vicinity of these fields. Separate from the science questions to be addressed by thesemore » observations will be information to add in the development of a parameterized cumulus scheme capable of including multiple cloud fields within a regional or global scale model. We will also be able to compare and contrast the cloud and aerosol properties within and outside the Oklahoma City plume to study aerosol processes within individual clouds. Preliminary discussions with the Cloud and Land Surface Interaction Campaign (CLASIC) science team have identified overlap between the science questions posed for the CLASIC Intensive Operation Period (IOP) and the proposed ASP campaign, suggesting collaboration would benefit both teams.« less

Establishment of a nested-ASP-PCR method to determine the clarithromycin resistance of Helicobacter pylori.

PubMed

Luo, Xiao-Feng; Jiao, Jian-Hua; Zhang, Wen-Yue; Pu, Han-Ming; Qu, Bao-Jin; Yang, Bing-Ya; Hou, Min; Ji, Min-Jun

2016-07-07

To investigate clarithromycin resistance positions 2142, 2143 and 2144 of the 23SrRNA gene in Helicobacter pylori (H. pylori) by nested-allele specific primer-polymerase chain reaction (nested-ASP-PCR). The gastric tissue and saliva samples from 99 patients with positive results of the rapid urease test (RUT) were collected. The nested-ASP-PCR method was carried out with the external primers and inner allele-specific primers corresponding to the reference strain and clinical strains. Thirty gastric tissue and saliva samples were tested to determine the sensitivity of nested-ASP-PCR and ASP-PCR methods. Then, clarithromycin resistance was detected for 99 clinical samples by using different methods, including nested-ASP-PCR, bacterial culture and disk diffusion. The nested-ASP-PCR method was successfully established to test the resistance mutation points 2142, 2143 and 2144 of the 23SrRNA gene of H. pylori. Among 30 samples of gastric tissue and saliva, the H. pylori detection rate of nested-ASP-PCR was 90% and 83.33%, while the detection rate of ASP-PCR was just 63% and 56.67%. Especially in the saliva samples, nested-ASP-PCR showed much higher sensitivity in H. pylori detection and resistance mutation rates than ASP-PCR. In the 99 RUT-positive gastric tissue and saliva samples, the H. pylori-positive detection rate by nested-ASP-PCR was 87 (87.88%) and 67 (67.68%), in which there were 30 wild-type and 57 mutated strains in gastric tissue and 22 wild-type and 45 mutated strains in saliva. Genotype analysis showed that three-points mixed mutations were quite common, but different resistant strains were present in gastric mucosa and saliva. Compared to the high sensitivity shown by nested-ASP-PCR, the positive detection of bacterial culture with gastric tissue samples was 50 cases, in which only 26 drug-resistant strains were found through analyzing minimum inhibitory zone of clarithromycin. The nested-ASP-PCR assay showed higher detection sensitivity than ASP-PCR and drug sensitivity testing, which could be performed to evaluate clarithromycin resistance of H. pylori.

Establishment of a nested-ASP-PCR method to determine the clarithromycin resistance of Helicobacter pylori

PubMed Central

Luo, Xiao-Feng; Jiao, Jian-Hua; Zhang, Wen-Yue; Pu, Han-Ming; Qu, Bao-Jin; Yang, Bing-Ya; Hou, Min; Ji, Min-Jun

2016-01-01

AIM: To investigate clarithromycin resistance positions 2142, 2143 and 2144 of the 23SrRNA gene in Helicobacter pylori (H. pylori) by nested-allele specific primer-polymerase chain reaction (nested-ASP-PCR). METHODS: The gastric tissue and saliva samples from 99 patients with positive results of the rapid urease test (RUT) were collected. The nested-ASP-PCR method was carried out with the external primers and inner allele-specific primers corresponding to the reference strain and clinical strains. Thirty gastric tissue and saliva samples were tested to determine the sensitivity of nested-ASP-PCR and ASP-PCR methods. Then, clarithromycin resistance was detected for 99 clinical samples by using different methods, including nested-ASP-PCR, bacterial culture and disk diffusion. RESULTS: The nested-ASP-PCR method was successfully established to test the resistance mutation points 2142, 2143 and 2144 of the 23SrRNA gene of H. pylori. Among 30 samples of gastric tissue and saliva, the H. pylori detection rate of nested-ASP-PCR was 90% and 83.33%, while the detection rate of ASP-PCR was just 63% and 56.67%. Especially in the saliva samples, nested-ASP-PCR showed much higher sensitivity in H. pylori detection and resistance mutation rates than ASP-PCR. In the 99 RUT-positive gastric tissue and saliva samples, the H. pylori-positive detection rate by nested-ASP-PCR was 87 (87.88%) and 67 (67.68%), in which there were 30 wild-type and 57 mutated strains in gastric tissue and 22 wild-type and 45 mutated strains in saliva. Genotype analysis showed that three-points mixed mutations were quite common, but different resistant strains were present in gastric mucosa and saliva. Compared to the high sensitivity shown by nested-ASP-PCR, the positive detection of bacterial culture with gastric tissue samples was 50 cases, in which only 26 drug-resistant strains were found through analyzing minimum inhibitory zone of clarithromycin. CONCLUSION: The nested-ASP-PCR assay showed higher detection sensitivity than ASP-PCR and drug sensitivity testing, which could be performed to evaluate clarithromycin resistance of H. pylori. PMID:27433095

A fluorescently labeled undecapeptide derived from a protein in royal jelly of the honeybee-royalisin-for specific detection of oxidized low-density lipoprotein.

PubMed

Sato, Akira; Unuma, Hiroto; Yamazaki, Yoji; Ebina, Keiichi

2018-06-01

The probes for detection of oxidized low-density lipoprotein (ox-LDL) in plasma and in atherosclerotic plaques are expected to facilitate the diagnosis, prevention, and treatment of atherosclerosis. Recently, we have reported that a heptapeptide (Lys-Trp-Tyr-Lys-Asp-Gly-Asp, KP6) coupled through the ε-amino group of N-terminal Lys to fluorescein isothiocyanate (FITC), (FITC)KP6, can be useful as a fluorescent probe for specific detection of ox-LDL. In the present study, to develop a novel fluorescent peptide for specific detection of ox-LDL, we investigated the interaction (with ox-LDL) of an undecapeptide corresponding to positions 41 to 51 of a potent antimicrobial protein (royalisin, which consists of 51 residues; from royal jelly of honeybees), conjugated at the N-terminus to FITC in the presence of 6-amino-n-caproic acid (AC) linker, (FITC-AC)-royalisin P11, which contains both sequences, Phe-Lys-Asp and Asp-Lys-Tyr, similar to Tyr-Lys-Asp in (FITC)KP6. The (FITC-AC)-royalisin P11 bound with high specificity to ox-LDL in a dose-dependent manner, through the binding to major lipid components in ox-LDL (lysophosphatidylcholine and oxidized phosphatidylcholine). In contrast, a (FITC-AC)-shuffled royalisin P11 peptide, in which sequences Phe-Lys-Asp and Asp-Lys-Tyr were modified to Lys-Phe-Asp and Asp-Tyr-Lys, respectively, hardly bound to LDL and ox-LDL. These findings strongly suggest that (FITC-AC)-royalisin P11 may be an effective fluorescent probe for specific detection of ox-LDL and that royalisin from the royal jelly of honeybees may play a role in the treatment of atherosclerosis through the specific binding of the region at positions 41 to 51 to ox-LDL. Copyright © 2018 European Peptide Society and John Wiley & Sons, Ltd.

Automated Sequence Processor: Something Old, Something New

NASA Technical Reports Server (NTRS)

Streiffert, Barbara; Schrock, Mitchell; Fisher, Forest; Himes, Terry

2012-01-01

High productivity required for operations teams to meet schedules Risk must be minimized. Scripting used to automate processes. Scripts perform essential operations functions. Automated Sequence Processor (ASP) was a grass-roots task built to automate the command uplink process System engineering task for ASP revitalization organized. ASP is a set of approximately 200 scripts written in Perl, C Shell, AWK and other scripting languages.. ASP processes/checks/packages non-interactive commands automatically.. Non-interactive commands are guaranteed to be safe and have been checked by hardware or software simulators.. ASP checks that commands are non-interactive.. ASP processes the commands through a command. simulator and then packages them if there are no errors.. ASP must be active 24 hours/day, 7 days/week..

Impact of a Prospective Audit and Feedback Antimicrobial Stewardship Program at a Veterans Affairs Medical Center: A Six-Point Assessment

PubMed Central

Morrill, Haley J.; Caffrey, Aisling R.; Gaitanis, Melissa M.; LaPlante, Kerry L.

2016-01-01

Background Prospective audit and feedback is a core antimicrobial stewardship program (ASP) strategy; however its impact is difficult to measure. Methods Our quasi-experimental study measured the effect of an ASP on clinical outcomes, antimicrobial use, resistance, costs, patient safety (adverse drug events [ADE] and Clostridium difficile infection [CDI]), and process metrics pre- (9/10–10/11) and post-ASP (9/12–10/13) using propensity adjusted and matched Cox proportional-hazards regression models and interrupted time series (ITS) methods. Results Among our 2,696 patients, median length of stay was 1 day shorter post-ASP (5, interquartile range [IQR] 3–8 vs. 4, IQR 2–7 days, p<0.001). Mortality was similar in both periods. Mean broad-spectrum (-11.3%), fluoroquinolone (-27.0%), and anti-pseudomonal (-15.6%) use decreased significantly (p<0.05). ITS analyses demonstrated a significant increase in monthly carbapenem use post-ASP (trend: +1.5 days of therapy/1,000 patient days [1000PD] per month; 95% CI 0.1–3.0). Total antimicrobial costs decreased 14%. Resistance rates did not change in the one-year post-ASP period. Mean CDI rates/10,000PD were low pre- and post-ASP (14.2 ± 10.4 vs. 13.8 ± 10.0, p = 0.94). Fewer patients experienced ADEs post-ASP (6.0% vs. 4.4%, p = 0.06). Conclusions Prospective audit and feedback has the potential to improve antimicrobial use and outcomes, and contain bacterial resistance. Our program demonstrated a trend towards decreased length of stay, broad-spectrum antimicrobial use, antimicrobial costs, and adverse events. PMID:26978263

Neuroprotective and Ameliorating Impacts of Omega-3 Against Aspartame-induced Neuronal and Astrocytic Degeneration.

PubMed

Ali, Eyad M T; Sonpol, Hany M A

2017-07-01

Aspartame (ASP) is one of the commonest artificial sweetener used all over the world and considered as an extremely risky compound and raises a lot of controversy. Therefore, this study was designed to investigate cellular damage of the anterior horn cells in the spinal cord of albino male rats and the possibility of hindering these changes by using omega-3 (OM3).Thirty seven adult male albino rats were divided into three groups: Control, ASP-treated and ASP + OM3-treated groups. Spinal cord sections were prepared and stained with Hx&E, caspase-3 and GFAP immunostaining. All data were morphometrically and statistically analyzed. In ASP-treated group, the cell body of some degenerated neurons was swollen and its cytoplasm was vacuolated. Their nuclei were eccentric and pyknotic. Moreover, other neurons were of a heterogeneous pattern in the form of cell body shrinkage, loss of Nissl substance, intensely stained eosinophilic cytoplasm and a small darkly stained nucleus that may eventually fragment. However, the cells were apparently normal in ASP+ OM3-treated group. Strong +ve caspase-3 stained neurons were detected in ASP-treated group. Furthermore, the immunoreaction was faint on treating the rats with both ASP and OM3. Few number of +ve GFAP- stained astrocytes were observed in ASP-treated rats. On the other hand, the immunoreactivity for GFAP was found to be intense in the ASP + OM3-treated group. Additionally, there was a significant decrease in the surface area percentage of the +ve GFAP-stained astrocytes of the ASP-treated group compared to the control and the ASP + OM3-treated groups. Anat Rec, 300:1290-1298, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

ASP-G: an ASP-based method for finding attractors in genetic regulatory networks

PubMed Central

Mushthofa, Mushthofa; Torres, Gustavo; Van de Peer, Yves; Marchal, Kathleen; De Cock, Martine

2014-01-01

Motivation: Boolean network models are suitable to simulate GRNs in the absence of detailed kinetic information. However, reducing the biological reality implies making assumptions on how genes interact (interaction rules) and how their state is updated during the simulation (update scheme). The exact choice of the assumptions largely determines the outcome of the simulations. In most cases, however, the biologically correct assumptions are unknown. An ideal simulation thus implies testing different rules and schemes to determine those that best capture an observed biological phenomenon. This is not trivial because most current methods to simulate Boolean network models of GRNs and to compute their attractors impose specific assumptions that cannot be easily altered, as they are built into the system. Results: To allow for a more flexible simulation framework, we developed ASP-G. We show the correctness of ASP-G in simulating Boolean network models and obtaining attractors under different assumptions by successfully recapitulating the detection of attractors of previously published studies. We also provide an example of how performing simulation of network models under different settings help determine the assumptions under which a certain conclusion holds. The main added value of ASP-G is in its modularity and declarativity, making it more flexible and less error-prone than traditional approaches. The declarative nature of ASP-G comes at the expense of being slower than the more dedicated systems but still achieves a good efficiency with respect to computational time. Availability and implementation: The source code of ASP-G is available at http://bioinformatics.intec.ugent.be/kmarchal/Supplementary_Information_Musthofa_2014/asp-g.zip. Contact: Kathleen.Marchal@UGent.be or Martine.DeCock@UGent.be Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25028722

Compliance With the Healthy Eating Standards in YMCA After-School Programs.

PubMed

Beets, Michael W; Weaver, R Glenn; Turner-McGrievy, Gabrielle; Beighle, Aaron; Moore, Justin B; Webster, Collin; Khan, Mahmud; Saunders, Ruth

2016-09-01

In 2011, the YMCA of the US adopted Healthy Eating standards for all of their after-school programs (ASPs). The extent to which YMCA ASPs comply with the standards is unknown. Twenty ASPs from all YMCA ASPs across South Carolina (N = 102) were invited to participate. Direct observation of the food and beverages served and staff behaviors were collected on 4 nonconsecutive days per ASP. One ASP did not serve a snack. Of the remaining ASPs, a total of 26% served a fruit or vegetable and 32% served water every day; 26% served sugar-sweetened beverages, 47% served sugar-added foods, and only 11% served whole grains when grains were served. Staff members sat with the children (65%) or verbally promoted healthy eating (15%) on at least 1 observation day. Staff drank non-approved drinks (25%) or foods (45%) on at least 1 observation day. No ASPs served snacks family-style every day. Additional efforts are required to assist YMCA-operated ASPs in achieving these important nutrition standards. Copyright © 2016 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.

Analysis of Arg-Gly-Asp mimetics and soluble receptor of tumour necrosis factor as therapeutic modalities for concanavalin A induced hepatitis in mice.

PubMed Central

Bruck, R; Shirin, H; Hershkoviz, R; Lider, O; Kenet, G; Aeed, H; Matas, Z; Zaidel, L; Halpern, Z

1997-01-01

BACKGROUND/AIMS: It has been shown that synthetic non-peptidic analogues of Arg-Gly-Asp, a major cell adhesive ligand of extracellular matrix, prevented an increase in serum aminotransferase activity, as a manifestation of concanavalin A induced liver damage in mice. This study examined the effects of an Arg-Gly-Asp mimetic on liver histology and cytokine release in response to concanavalin A administration, and the efficacy of soluble receptor of tumour necrosis factor (TNF) alpha in preventing hepatitis in this model of liver injury. METHODS: Mice were pretreated with either the Arg-Gly-Asp mimetic SF-6,5 or recombinant soluble receptor of TNF alpha before their inoculation with 10 mg/kg concanavalin A. Liver enzymes, histology, and the serum values of TNF alpha and interleukin (IL)6 were examined. RESULTS: The histopathological damage in the liver, and the concanavalin A induced release of TNF alpha and IL6 were significantly inhibited by the synthetic Arg-Gly-Asp mimetic (p < 0.001). Liver injury, manifested by the increase in serum aminotransferase and cytokines, as well as by histological manifestations of hepatic damage, was effectively prevented by pretreatment of the mice with the soluble TNF receptor (p < 0.001). CONCLUSIONS: This study confirms the efficacy of a synthetic Arg-Gly-Asp mimetic and soluble TNF receptor in the prevention of immune mediated liver damage in mice. Images PMID:9155591

The asparagine-transamidosome from Helicobacter pylori: a dual-kinetic mode in non-discriminating aspartyl-tRNA synthetase safeguards the genetic code.

PubMed

Fischer, Frédéric; Huot, Jonathan L; Lorber, Bernard; Diss, Guillaume; Hendrickson, Tamara L; Becker, Hubert D; Lapointe, Jacques; Kern, Daniel

2012-06-01

Helicobacter pylori catalyzes Asn-tRNA(Asn) formation by use of the indirect pathway that involves charging of Asp onto tRNA(Asn) by a non-discriminating aspartyl-tRNA synthetase (ND-AspRS), followed by conversion of the mischarged Asp into Asn by the GatCAB amidotransferase. We show that the partners of asparaginylation assemble into a dynamic Asn-transamidosome, which uses a different strategy than the Gln-transamidosome to prevent the release of the mischarged aminoacyl-tRNA intermediate. The complex is described by gel-filtration, dynamic light scattering and kinetic measurements. Two strategies for asparaginylation are shown: (i) tRNA(Asn) binds GatCAB first, allowing aminoacylation and immediate transamidation once ND-AspRS joins the complex; (ii) tRNA(Asn) is bound by ND-AspRS which releases the Asp-tRNA(Asn) product much slower than the cognate Asp-tRNA(Asp); this kinetic peculiarity allows GatCAB to bind and transamidate Asp-tRNA(Asn) before its release by the ND-AspRS. These results are discussed in the context of the interrelation between the Asn and Gln-transamidosomes which use the same GatCAB in H. pylori, and shed light on a kinetic mechanism that ensures faithful codon reassignment for Asn.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qasim, Mohammad A., E-mail: qasimm@ipfw.edu; Song, Jikui; Markley, John L.

Research highlights: {yields} Large pK shifts in ionizable groups when buried in the protein interior. {yields} Substrate dependent shifts in pH optimum for serine proteases. {yields} Lys side chain is a stronger acid in serine protease S{sub 1} pocket than Asp side chain. -- Abstract: Enzymatic hydrolysis of the synthetic substrate succinyl-Ala-Ala-Pro-Xxx-pNA (where Xxx = Leu, Asp or Lys) catalyzed by bovine chymotrypsin (CHYM) or Streptomyces griseus protease B (SGPB) has been studied at different pH values in the pH range 3-11. The pH optima for substrates having Leu, Asp, and Lys have been found to be 7.5-8.0, 5.5-6.0, andmore » {approx}10, respectively. At the normally reported pH optimum (pH 7-8) of CHYM and SGPB, the substrate with Leu at the reactive site is more than 25,000-fold more reactive than that with Asp. However, when fully protonated, Asp is nearly as good a substrate as Leu. The pK values of the side chains of Asp and Lys in the hydrophobic S{sub 1} pocket of CHYM and SGPB have been calculated from pH-dependent hydrolysis data and have been found to be about 9 for Asp and 7.4 and 9.7 for Lys for CHYM and SGPB, respectively. The results presented in this communication suggest a possible application of CHYM like enzymes in cleaving peptide bonds contributed by acidic amino acids between pH 5 and 6.« less

Effect of Communication Errors During Calls to an Antimicrobial Stewardship Program

PubMed Central

Linkin, Darren R.; Fishman, Neil O.; Landis, J. Richard; Barton, Todd D.; Gluckman, Steven; Kostman, Jay; Metlay, Joshua P.

2011-01-01

Objective To determine the effect of inaccurate communication of patient data—from clinicians caring for inpatients to prior-approval antimicrobial stewardship programs (ASP) staff (practitioners)—on the incidence of inappropriate antimicrobial recommendations by ASP practitioners Design A retrospective cohort design was utilized. The accuracy of communicated patient data was evaluated against patients’ medical records for pre-determined, clinically significant inaccuracies. Inappropriate antimicrobial recommendations were defined when an expert panel unanimously rated the actual recommendations as inappropriate after reviewing vignettes derived from inpatients’ medical records. Setting The setting was an academic medical center with a prior-approval ASP. Patients All inpatient subjects of ASP prior-approval calls were eligible for inclusion. Results The panel agreed on whether the antimicrobial recommendation was inappropriate or not in 163 (82%) of 200 ASP calls; the 163 calls were then the basis for further analyses. After controlling for confounders, inaccurate communications were associated with inappropriate antimicrobial recommendations with an odds ratio (OR) of 2.2 (p=0.03). In secondary analyses of specific data types, only inaccuracies of microbiological data were associated with the study outcome (OR 7.5, p=0.002). The most common reason given by panelists for an inappropriate rating was that antimicrobials were not indicated. Conclusions Inaccurate communication of patient data, particularly microbiological data, during prior-approval calls is associated with an increased risk of inappropriate antimicrobial recommendations from the ASP. Clinicians and ASP practitioners should work to confirm critical communicated data prior to use in prescribing decisions. PMID:17994518

Tetrapod-type [Asp1] angiotensin is present in a holostean fish, Amia calva.

PubMed

Takei, Y; Itahara, Y; Butler, D G; Watanabe, T X; Oudit, G Y

1998-05-01

The renin-angiotensin system has been identified in various vertebrates, from elasmobranchs to mammals. Tetrapod (amphibians to mammals) angiotensin (ANG) has Asp at the N-terminus, but Asp is replaced by Asn in elasmobranch and teleost fish. ANG I has been isolated from incubates of plasma and kidney extracts of the bowfin Amia calva, a holostean fish, using the eel vasopressor activity as an assay system; its sequence was found to be H-Asp-Arg-Val-Tyr-Val-His-Pro-Phe-Asn-Leu-OH after sequence analysis, mass spectrometry, and comparison with the synthetic peptide. This sequence is identical to bullfrog ANG I. [Asn1] ANG I was not detected. Thus the bowfin is the first fish species which contains only [Asp1] ANG I. The bowfin ANG I and II were no more vasopressor than eel peptides in the bowfin, indicating that bowfin ANG II receptors do not distinguish between [Asp1] and [Asn1] peptides. In the rat, bowfin ANG I and rat [Ile5, His9] ANG I have equipressor activities when examined in different animals, but the vasopressor activity of bowfin ANG I decreased following rat ANG I in the same animals, although the activity of rat ANG I was unaffected after bowfin ANG I. The present study directly demonstrates the presence of the renin-angiotensin system in a holostean fish and showed that its ANG II receptors have not yet fully coevolved with the homologous [Asp1] peptide.

Characterization of angiotensin receptors on bovine adrenal fasciculata cells.

PubMed Central

Vallotton, M B; Capponi, A M; Grillet, C; Knupfer, A L; Hepp, R; Khosla, M C; Bumpus, F M

1981-01-01

We have further characterized angiotensin receptors on bovine adrenal fasciculata cells whose presence was previously demonstrated by the intrinsic agonistic activity of angiotensin II (AII), dex-Asp1-AII, angiotensin I (AI), and des-ASp1-AI on steroidogenesis. The specific binding of AII and des-Asp1-AII labeled with 125I to dispersed bovine fasciculata cells was studied. For both peptides, a single class of binding sites accounted for the data with a mean (+/- SEM) Ka value of 0.23 +/- 0.123 X 10(8) liters/mol for AII and 0.68 X 10(8) liters/mol for des-Asp1-AII. The concentration at which unlabeled AII and des-Asp1-AII displaced 50% of the tracers (Kd) was similar to that at which they induced half-maximal stimulation of steroidogenesis (Kact). For AI and des-Asp1-AI, Kd greater than Kact. Analogs of AII or des-Asp1-AII with antagonistic properties upon steroidogenesis competed also with binding of the tracers. Corticotropin (ACTH) did not inhibit binding. Although ACTH stimulated the formation of cyclic AMP, none of the angiotensins with intrinsic activity did so. Calcium, but not potassium, appeared to potentiate the steroidogenic activity of AII. These data suggest that there is a single class of receptors for angiotensins and analogs in zona fasciculata. These receptors show characteristics that differentiate them from ACTH receptors in zona fasciculata or angiotensin receptors in zona glomerulosa cells. PMID:6264451

Subgroups of Paediatric Acute Lymphoblastic Leukaemia Might Differ Significantly in Genetic Predisposition to Asparaginase Hypersensitivity

PubMed Central

Kutszegi, Nóra; Semsei, Ágnes F.; Gézsi, András; Sági, Judit C.; Nagy, Viktória; Csordás, Katalin; Jakab, Zsuzsanna; Lautner-Csorba, Orsolya; Gábor, Krisztina Míta; Kovács, Gábor T.; Erdélyi, Dániel J.; Szalai, Csaba

2015-01-01

L-asparaginase (ASP) is a key element in the treatment of paediatric acute lymphoblastic leukaemia (ALL). However, hypersensitivity reactions (HSRs) to ASP are major challenges in paediatric patients. Our aim was to investigate genetic variants that may influence the risk to Escherichia coli-derived ASP hypersensitivity. Sample and clinical data collection was carried out from 576 paediatric ALL patients who were treated according to protocols from the Berlin—Frankfurt—Münster Study Group. A total of 20 single nucleotide polymorphisms (SNPs) in GRIA1 and GALNT10 genes were genotyped. Patients with GRIA1 rs4958351 AA/AG genotype showed significantly reduced risk to ASP hypersensitivity compared to patients with GG genotype in the T-cell ALL subgroup (OR = 0.05 (0.01–0.26); p = 4.70E-04), while no such association was found in pre-B-cell ALL. In the medium risk group two SNPs of GRIA1 (rs2055083 and rs707176) were associated significantly with the occurrence of ASP hypersensitivity (OR = 0.21 (0.09–0.53); p = 8.48E-04 and OR = 3.02 (1.36–6.73); p = 6.76E-03, respectively). Evaluating the genders separately, however, the association of rs707176 with ASP HSRs was confined only to females. Our results suggest that genetic variants of GRIA1 might influence the risk to ASP hypersensitivity, but subgroups of patients can differ significantly in this respect. PMID:26457809

Project Report: Automatic Sequence Processor Software Analysis

NASA Technical Reports Server (NTRS)

Benjamin, Brandon

2011-01-01

The Mission Planning and Sequencing (MPS) element of Multi-Mission Ground System and Services (MGSS) provides space missions with multi-purpose software to plan spacecraft activities, sequence spacecraft commands, and then integrate these products and execute them on spacecraft. Jet Propulsion Laboratory (JPL) is currently is flying many missions. The processes for building, integrating, and testing the multi-mission uplink software need to be improved to meet the needs of the missions and the operations teams that command the spacecraft. The Multi-Mission Sequencing Team is responsible for collecting and processing the observations, experiments and engineering activities that are to be performed on a selected spacecraft. The collection of these activities is called a sequence and ultimately a sequence becomes a sequence of spacecraft commands. The operations teams check the sequence to make sure that no constraints are violated. The workflow process involves sending a program start command, which activates the Automatic Sequence Processor (ASP). The ASP is currently a file-based system that is comprised of scripts written in perl, c-shell and awk. Once this start process is complete, the system checks for errors and aborts if there are any; otherwise the system converts the commands to binary, and then sends the resultant information to be radiated to the spacecraft.

Different HIV-1 env frames: gp120 and ASP (antisense protein) biosynthesis, and theirs co-variation tropic amino acid signatures in X4- and R5-viruses.

PubMed

Dimonte, Salvatore

2017-01-01

Antisense protein (ASP) is the new actor of viral life of Human Immunodeficiency Virus type 1 (HIV-1) although proposed above 20 years ago. The asp ORF is into complementary strand of the gp120/gp41 junction of env gene. The ASP biological role remains little known. Knowing the Env markers of viral tropism, a dataset of sequences (660 strains) was used to analyze the hypothetical ASP involvement in CCR5 (R5) and/or CXCR4 (X4) co-receptor interaction. Preliminarily, prevalence of ASP and gp120 V3 mutations was performed; following association among mutations were elaborate. The classical V3 tropic-signatures were confirmed, and 36 R5- and 22 X4-tropic ASP mutations were found. Moreover, by analyzing the ASP sequences, 36 out of 179 amino acid positions significantly associated with different co-receptor usage were found. Several statistically significant associations between gp120 V3 and ASP mutations were observed. The dendrogram showed the existence of a cluster associated with R5-usage and a large cluster associated with X4-usage. These results show that gp120 V3 and specific amino acid changes in ASP are associated together with CXCR4 and/or CCR5-usage. These findings implement previous observations on unclear ASP functions. J. Med. Virol. 89:112-122, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Structural Effect of the Asp345a Insertion in Penicillin-Binding Protein 2 from Penicillin-Resistant Strains of Neisseria gonorrhoeae

PubMed Central

2015-01-01

A hallmark of penicillin-binding protein 2 (PBP2) from penicillin-resistant strains of Neisseria gonorrhoeae is insertion of an aspartate after position 345. The insertion resides on a loop near the active site and is immediately adjacent to an existing aspartate (Asp346) that forms a functionally important hydrogen bond with Ser363 of the SxN conserved motif. Insertion of other amino acids, including Glu and Asn, can also lower the rate of acylation by penicillin, but these insertions abolish transpeptidase function. Although the kinetic consequences of the Asp insertion are well-established, how it impacts the structure of PBP2 is unknown. Here, we report the 2.2 Å resolution crystal structure of a truncated construct of PBP2 containing all five mutations present in PBP2 from the penicillin-resistant strain 6140, including the Asp insertion. Commensurate with the strict specificity for the Asp insertion over similar amino acids, the insertion does not cause disordering of the structure, but rather induces localized flexibility in the β2c−β2d loop. The crystal structure resolves the ambiguity of whether the insertion is Asp345a or Asp346a (due to the adjacent Asp) because the hydrogen bond between Asp346 and Ser362 is preserved and the insertion is therefore Asp346a. The side chain of Asp346a projects directly toward the β-lactam-binding site near Asn364 of the SxN motif. The Asp insertion may lower the rate of acylation by sterically impeding binding of the antibiotic or by hindering breakage of the β-lactam ring during acylation because of the negative charge of its side chain. PMID:25403720

Structural effect of the Asp345a insertion in penicillin-binding protein 2 from penicillin-resistant strains of Neisseria gonorrhoeae.

PubMed

Fedarovich, Alena; Cook, Edward; Tomberg, Joshua; Nicholas, Robert A; Davies, Christopher

2014-12-09

A hallmark of penicillin-binding protein 2 (PBP2) from penicillin-resistant strains of Neisseria gonorrhoeae is insertion of an aspartate after position 345. The insertion resides on a loop near the active site and is immediately adjacent to an existing aspartate (Asp346) that forms a functionally important hydrogen bond with Ser363 of the SxN conserved motif. Insertion of other amino acids, including Glu and Asn, can also lower the rate of acylation by penicillin, but these insertions abolish transpeptidase function. Although the kinetic consequences of the Asp insertion are well-established, how it impacts the structure of PBP2 is unknown. Here, we report the 2.2 Å resolution crystal structure of a truncated construct of PBP2 containing all five mutations present in PBP2 from the penicillin-resistant strain 6140, including the Asp insertion. Commensurate with the strict specificity for the Asp insertion over similar amino acids, the insertion does not cause disordering of the structure, but rather induces localized flexibility in the β2c-β2d loop. The crystal structure resolves the ambiguity of whether the insertion is Asp345a or Asp346a (due to the adjacent Asp) because the hydrogen bond between Asp346 and Ser362 is preserved and the insertion is therefore Asp346a. The side chain of Asp346a projects directly toward the β-lactam-binding site near Asn364 of the SxN motif. The Asp insertion may lower the rate of acylation by sterically impeding binding of the antibiotic or by hindering breakage of the β-lactam ring during acylation because of the negative charge of its side chain.

Experimental and Theoretical Investigations of Infrared Multiple Photon Dissociation Spectra of Aspartic Acid Complexes with Zn2+ and Cd2.

PubMed

Boles, Georgia C; Hightower, Randy L; Coates, Rebecca A; McNary, Christopher P; Berden, Giel; Oomens, Jos; Armentrout, P B

2018-04-12

Complexes of aspartic acid (Asp) cationized with Zn 2+ : Zn(Asp-H) + , Zn(Asp-H) + (ACN) where ACN = acetonitrile, and Zn(Asp-H) + (Asp); as well as with Cd 2+ , CdCl + (Asp), were examined by infrared multiple photon dissociation (IRMPD) action spectroscopy using light generated from a free electron laser. A series of low-energy conformers for each complex was found using quantum chemical calculations to identify the structures formed experimentally. The main binding motif observed for the heavy-metal complex, CdCl + (Asp)[N,CO,CO s ], is a charge-solvated, tridentate structure, where the metal center binds to the backbone amino group and carbonyl oxygens of the backbone and side-chain carboxylic acids. Likewise, the deprotonated Zn(Asp-H) + (ACN) and Zn(Asp-H) + (Asp) complexes show comparable [N,CO - ,CO s ](ACN) and [N,CO - ,CO s ][N,CO,CO s ] coordinations, respectively. Interestingly, there was only minor spectral evidence for the analogous Zn(Asp-H) + [N,CO - ,CO s ] binding motif, even though this species is predicted to be the lowest-energy conformer. Instead, rearrangement and partial dissociation of the amino acid are observed, as spectral features most consistent with the experimental spectrum are exhibited by a four-coordinate Zn(Asp-NH 4 ) + [CO 2 - ,CO s ](NH 3 ) complex. Analysis of the mechanistic pathway leading from the predicted lowest-energy conformer to the isobaric deaminated complex is explored theoretically. Further, comparison of the current work to that of Zn 2+ and Cd 2+ complexes of asparagine (Asn) allows additional conclusions regarding populated conformers and effects of carboxamide versus carboxylic acid binding to be drawn.

Role of four conserved aspartic acid residues of EF-loops in the metal ion binding and in the self-assembly of ciliate Euplotes octocarinatus centrin.

PubMed

Liu, Wen; Duan, Lian; Sun, Tijian; Yang, Binsheng

2016-12-01

Ciliate Euplotes octocarinatus centrin (EoCen) is an EF-hand calcium-binding protein closely related to the prototypical calcium sensor protein calmodulin. Four mutants (D37K, D73K, D110K and D146K) were created firstly to elucidate the importance of the first aspartic acid residues (Asp37, Asp73, Asp110 and Asp146) in the beginning of the four EF-loops of EoCen. Aromatic-sensitized Tb 3+ fluorescence indicates that the aspartic acid residues are very important for the metal-binding of EoCen, except for Asp73 (in EF-loop II). Resonance light scattering (RLS) measurements for different metal ions (Ca 2+ and Tb 3+ ) binding proteins suggest that the order of four conserved aspartic acid residues for contributing to the self-assembly of EoCen is Asp37 > Asp146 > Asp110 > Asp73. Cross-linking experiment also exhibits that Asp37 and Asp146 play critical role in the self-assembly of EoCen. Asp37, in site I, which is located in the N-terminal domain, plays the most important role in the metal ion-dependent self-assembly of EoCen, and there is cooperativity between N-terminal and C-terminal domain (especially the site IV). In addition, the dependence of Tb 3+ induced self-assembly of EoCen and the mutants on various factors, including ionic strength and pH, were characterized using RLS. Finally, 2-p-toluidinylnaphthalene-6-sulfonate (TNS) binding, ionic strength and pH control experiments indicate that in the process of EoCen self-assembly, molecular interactions are mediated by both electrostatic and hydrophobic forces, and the hydrophobic interaction has the important status.

Application service provider (ASP) financial models for off-site PACS archiving

NASA Astrophysics Data System (ADS)

Ratib, Osman M.; Liu, Brent J.; McCoy, J. Michael; Enzmann, Dieter R.

2003-05-01

For the replacement of its legacy Picture Archiving and Communication Systems (approx. annual workload of 300,000 procedures), UCLA Medical Center has evaluated and adopted an off-site data-warehousing solution based on an ASP financial with a one-time single payment per study archived. Different financial models for long-term data archive services were compared to the traditional capital/operational costs of on-site digital archives. Total cost of ownership (TCO), including direct and indirect expenses and savings, were compared for each model. Financial parameters were considered: logistic/operational advantages and disadvantages of ASP models versus traditional archiving systems. Our initial analysis demonstrated that the traditional linear ASP business model for data storage was unsuitable for large institutions. The overall cost markedly exceeds the TCO of an in-house archive infrastructure (when support and maintenance costs are included.) We demonstrated, however, that non-linear ASP pricing models can be cost-effective alternatives for large-scale data storage, particularly if they are based on a scalable off-site data-warehousing service and the prices are adapted to the specific size of a given institution. The added value of ASP is that it does not require iterative data migrations from legacy media to new storage media at regular intervals.

Plasma growth hormone (GH), insulin and amino acid responses to arginine with or without aspartic acid in pigs. Effect of the dose.

PubMed

Cochard, A; Guilhermet, R; Bonneau, M

1998-01-01

The aim of the present study was to examine, for the first time in pigs, the dose-dependent effect of arginine (ARG) on growth hormone (GH) and insulin release and the effect of the combined ARG and aspartic acid (ASP) treatment on GH and insulin release. ARG (0.5 or 1 g/kg body weight) with or without an equimolar supplement of ASP (0.38 or 0.76 g/kg, respectively) was administered in piglets via the duodenum. ARG increased plasma arginine, ornithine, urea, proline and branched chain amino acid concentrations. ASP increased specifically plasma aspartic acid, glutamic acid, alanine and citrulline concentrations. Plasma insulin increased with no apparent difference between treatments. Maximum GH level and the area under the GH curve (AUC) were increased in a dose-dependent manner in response to ARG treatment. GH response to the combined ARG and ASP treatment (ARGASP) was delayed compared to ARG alone and was not dose-dependent. AUC for GH after ARGASP treatments were intermediate between those observed after the two ARG doses. Our data suggest that high ASP doses transiently inhibit and delay ARG-induced GH release in pigs and that an equimolar supplement of ASP stimulates or inhibits ARG-induced GH release depending on the dose used.

Effects of mutations of thermolysin, as N116 to asp and asp150 to glu, on salt-induced activation and stabilization.

PubMed

Menach, Evans; Yasukawa, Kiyoshi; Inouye, Kuniyo

2013-01-01

Neutral salts activate and stabilize thermolysin. We previously found that two single mutations, Asn116→Asp and Asp150→Glu, increase the activity of thermolysin. In the present study, we examined their effects on NaCl-induced activation and stabilization. In the hydrolysis of N-[3-(2-furyl)acryloyl]-glycyl-L-leucine amide, the relative activities (the ratios of the specificity constant, kcat/Km, at x M NaCl to that at 0 M NaCl) at 0.5-4.0 M NaCl of D150E and N116D/D150E were lower than those of wild-type thermolysin (WT) and N116D, respectively. In thermal inactivation at 70 °C, the relative stabilities (the ratios of the first-order rate constant, kobs, at 0 M NaCl to that at x M NaCl) at 0.5-4.0 M NaCl of D150E and N116D/D150E were lower than those of WT and N116D, respectively. These results indicate that unlike Asn116→Asp, Asp150→Glu reduced NaCl-induced activation and stabilization, suggesting that the binding of ions with certain residues of thermolysin is involved in the activation and stabilization.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Otto, H.; Marti, T.; Holz, M.

Photocycle and flash-induced proton release and uptake were investigated for bacteriorhodopsin mutants in which Asp-85 was replaced by Ala, Asn, or Glu; Asp-212 was replaced by Asn or Glu; Asp-115 was replaced by Ala, Asn, or Glu; Asp-96 was replaced by Ala, Asn, or Glu; and Arg-82 was replaced by Ala or Gln in dimyristoylphosphatidylcholine/3-((3-cholamidopropyl)dimethylammonio)-1- propanesulfonate micelles at pH 7.3. In the Asp-85----Ala and Asp-85----Asn mutants, the absence of the charged carboxyl group leads to a blue chromophore at 600 and 595 nm, respectively, and lowers the pK of the Schiff base deprotonation to 8.2 and 7, respectively, suggesting amore » role for Asp-85 as counterion to the Schiff base. The early part of the photocycles of the Asp-85----Ala and Asp-85----Asn mutants is strongly perturbed; the formation of a weak M-like intermediate is slowed down about 100-fold over wild type. In both mutants, proton release is also slower but clearly precedes the rise of M. The amplitude of the early reversed photovoltage component in the Asp-85----Asn mutant is very large, and the net charge displacement is close to zero, indicating proton release and uptake on the cytoplasmic side of the membrane. The data suggest an obligatory role for Asp-85 in the efficient deprotonation of the Schiff base and in the proton release phase, probably as proton acceptor. In the Asp-212----Asn mutant, the rise of the absorbance change at 410 nm is slowed down to 220 microsecond, its amplitude is small, and the release of protons is delayed to 1.9 ms. The absorbance changes at 650 nm indicate perturbations in the early time range with a slow K intermediate. Thus Asp-212 also participates in the early events of charge translocation and deprotonation of the Schiff base.« less

Controversies in Antimicrobial Stewardship: Focus on New Rapid Diagnostic Technologies and Antimicrobials

PubMed Central

Wenzler, Eric; Wong, Jordan R.; Goff, Debra A.; Jankowski, Christopher A.; Bauer, Karri A.

2016-01-01

Antimicrobial stewardship programs (ASPs) are challenged with ensuring appropriate antimicrobial use while minimizing expenditures. ASPs have consistently demonstrated improved patient outcomes and significant cost reductions but are continually required to justify the costs of their existence and interventions due to the silo mentality often adopted by hospital administrators. As new technologies and antimicrobials emerge, ASPs are in a constant tug-of-war between providing optimal clinical outcomes and ensuring cost containment. Additionally, robust data on cost-effectiveness of new rapid diagnostic technologies and antimicrobials with subsequent ASP interventions to provide justification are lacking. As the implementation of an ASP will soon be mandatory for acute care hospitals in the United States, ASPs must find ways to justify novel interventions to align themselves with healthcare administrators. This review provides a framework for the justification of implementing a rapid diagnostic test or adding a new antimicrobial to formulary with ASP intervention, reviews approaches to demonstrating cost-effectiveness, and proposes methods for which ASPs may reduce healthcare expenditures via alternative tactics. PMID:27025521

Annular Suspension and Pointing System (ASPS) magnetic rotary joint

NASA Technical Reports Server (NTRS)

Smith, W. E.; Quach, W.; Thomas, W.

1993-01-01

The Annular Suspension and Pointing System (ASPS) is a prototype of flight hardware for a high-accuracy space payload pointing mount. The long term project objective is to perform modifications and implement improvements to the existing ASPS in hopes of recommission. Also, new applications will be investigated for this technology. This report will focus on the first aspect of this overall goal, to establish operation of a single bearing station. Presented is an overview of the system history and bearing operation followed by the processes, results, and status of the single bearing study.

Influence of the magnesium aspartate hydrochloride administration to the maternal circuit on the aspartate concentration of the fetal circuit under in vitro perfusion of human placenta.

PubMed

Malek, A; Leiser, R

2009-01-01

Magnesium aspartate hydrochloride (Magnesiocard, Mg-Asp-HCl) is proposed as a substitute of magnesium sulfate for the treatment of preeclampsia and premature labor. After an i.v. administration of a dose equivalent to that used in the treatment of preeclampsia to nonpregnant volunteers, a 10-fold increase of aspartic acid (Asp) over the physiological level was observed. Animal experiments have demonstrated that highly increased fetal levels of acidic amino acids such as Asp could be associated with neurotoxic damage in the fetal brain. The influence of such an elevation of Asp concentration in the maternal circuit on the fetal level, using the in vitro perfusion model of human placenta, was investigated. After a control phase (2h), a therapeutic dose of Mg combined with Asp (Magnesiocard, Mg-Asp-HCl) was applied to the maternal circuit approaching 10 times the physiological level of Asp. The administration was performed in two different phases simulating either a peak of maximum concentration (bolus application, 2h) or a steady state level (initially added, 4h). In four experiments, during experimental phases (6h) a slow increase in concentration in the fetal circuit was seen for Mg, AIB (alpha-aminoisobutyric acid, artificial amino acid) and creatinine confirming previous observations. In contrast, no net transfer of Asp across the placenta was seen. A continuous decrease in the concentration of Asp on both maternal and fetal side suggests active uptake and metabolization by the placenta. Viability control parameters remained stable indicating the absence of an effect on placental metabolism, permeability and morphology. Elevation of Asp concentration up to 10 times the physiological level by the administration of Mg-Asp-HCl to the maternal circuit under in vitro perfusion conditions of human placenta has no influence on the fetal level of Asp suggesting no transfer of Asp from the maternal to fetal compartment. Therefore, the administration of Mg-Asp-HCl to preeclamptic patients would be beneficial for the patients without any impact on placental or fetal physiology.

Influence of training status and eNOS haplotypes on plasma nitrite concentrations in normotensive older adults: a hypothesis-generating study.

PubMed

da Silva, Roberta Fernanda; Sertório, Jonas Tadeu Cau; Lacchini, Riccardo; Trapé, Atila Alexandre; Tanus-Santos, José Eduardo; Rush, James W E; Amaral, Sandra Lia; Zago, Anderson Saranz

2014-12-01

The purpose of this study was to evaluate the relationship between 3 eNOS gene polymorphisms and training status (TS) in affecting plasma nitrite concentration (NO2) in normotensive adults over 50 years old. Resting blood pressure (BP) was measured in all participants (n = 101). Plasma was taken to analyze: lipid profile, nitrite concentration (NO2) and lipid peroxide levels (T-BARS). Also, genomic DNA was extracted from plasma for genotyping NOS3 polymorphisms (-786T>C; 894G>T; and VNTR in intron 4). TS was determined by one-mile walk test and Functional Fitness Test Battery from AAHPERD (TS1-regular TS; TS2-good TS; and TS3-very good TS). BP was not influenced by TS, but NO2 was 15% higher in TS3 (123 ± 27 nM) compared to TS-2 (106 ± 22 nM). No differences were found in plasma NO2 in the haplotype analyses. However, the presence of the C allele (T-786C) and ASP allele (Glu298Asp) was found to enhance the correlation between TS and NO2 levels (r = 0.492 in C/4b/ASP haplotype and r = 0.855 in C/4a/ASP haplotype). This study thus identifies NOS3 polymorphism-dependent sensitivity to the effects of physical training on plasma NO2. Maintenance of good levels of training status, in carriers of C allele for T-786C polymorphism, combined with ASP allele for Glu298Asp polymorphism, may result in an increase in the NO2 plasma concentrations, which may reflect improved NO bioavailability in older adult normotensive individuals.

Characterization of chicken antisera raised against Aspergillus spp. by enzyme linked immunosorbent assay.

PubMed

Chen, F S; Chen, J W; Zhao, S; Gan, Z B; Luo, X C; Zhou, Q

2000-10-01

Enzyme linked immunosorbent assays of three Aspergillus species have been developed. Laying hens were immunized with the exoantigens from Asp. flavus, Asp. ochreaus and Asp. versicolor. All test chickens except for one produced antisera raised against the exoantigens. The antisera production process and ELISA titer were analysed. Fourteen days after the first injection, the antisera began to produce largely, on the 35th day reached to the peak, and maintained a stable level until the 42nd day. The maximum ELISA titer of the antisera to the exoantigens from Asp. flavus, Asp. ochreaus and Asp. versicolor was 1:8,000, 1:10,000 and 1:10,000, respectively. The cross-reactivities of antisera were determined with seventeen species of Aspergillus, ten species of fungi from other genera and the buffer-extracts of grain. The antisera did not cross-react with the exoantigens from other genera and the buffer-extracts of grain. The antiserum to exoantigen from Asp. ochreaus was species-specific, whereas the antisera against Asp. flavus and Asp. versicolor tended to cross-react with other Aspergillus species to varying degrees. The results suggest that exoantigens immunoassays can be developed to indentify and detect Aspergillus genus in grains.

The potential role of toll-like receptor 4 Asp299Gly polymorphism and its association with recurrent cystic echinococcosis in postoperative patients.

PubMed

Noori, Jafar; Spotin, Adel; Ahmadpour, Ehsan; Mahami-Oskouei, Mahmoud; Sadeghi-Bazargani, Homayoun; Kazemi, Tohid; Sakhinia, Ebrahim; Aghebati-Maleki, Leili; Shahrivar, Firooz

2018-06-01

The study of pathogenesis mechanisms of larval stages in the Taeniidae has recently focused on host genetic factors, particularly toll-like receptor (TLR) variations. However, the potential role of TLR4 polymorphism in hydatidosis has not yet been sufficiently elucidated in postoperative patients. In this case-control investigation, 80 patients from Iran, including 40 with acute hydatidosis (AH) and 40 with recurrent hydatidosis (RH), and 80 ethnically matched controls were evaluated from February 2015 to February 2017. Hydatidosis patients were confirmed using radiological, immunological, and histopathological examinations. Genotyping of Asp299Gly and Thr399Ile of TLR4 single-nucleotide polymorphisms was determined by restriction fragment length polymorphism, sequencing, and phylogenetic strategies. The heterozygous mutant-type TLR4 Asp299Gly genotype indicated a tendency to be associated with the occurrence of RH (P = 0.060) and conferred a 3-fold risk for susceptibility. There was no difference in genotype frequency of Asp299Gly between patients with AH and healthy controls (P = 0.42; OR, 1.82; 95% CI, 0.11-30.1%). Interestingly, a frequency of the G allele (12%: Gly) was observed to be a risk factor for susceptibility to RH patients (P = 0.050; OR, 7.08; 95% CI, 0.97-51.5%). A relative genetic variability of TLR4 Asp299Gly was found in RH patients (haplotype diversity: 0.700) compared to AH patients and healthy controls (Hd: 0.000). The Asp299Gly genotype was dominantly identified in patients with hepatic hydatid cysts. The TLR4 Thr399Ile codon was not detected except in a patient with a pulmonary hydatid cyst. The current findings enhance our knowledge regarding the TLR4 Asp299Gly polymorphism potentially leading to the development of RH, by skewing the immune system towards a Th2 response. Identification of the Asp299Gly codon may be a diagnostic hallmark in RH patients who have undergone unsuccessful postoperative intervention. However, further studies with a higher case number are needed on ethnic population from various geographic regions, in order to confirm this hypothesis.

Polymorphisms in XPD (Asp312Asn and Lys751Gln) genes, sunburn and arsenic-related skin lesions.

PubMed

McCarty, Kathleen M; Smith, Thomas J; Zhou, Wei; Gonzalez, Ernesto; Quamruzzaman, Quazzi; Rahman, Mahmuder; Mahiuddin, Golam; Ryan, Louise; Su, Li; Christiani, David C

2007-08-01

Single-nucleotide polymorphisms in genes related to DNA repair capacity and ultraviolet exposure have not been well investigated in relation to skin lesions associated with arsenic exposure. This population based case-control study, of 600 cases and 600 controls, frequency matched on age and gender in Pabna, Bangladesh, in 2001-2002, investigated the association and potential effect modification between polymorphisms in Xeroderma Pigmentosum complementation group D (XPD) (Lys751Gln and Asp312Asn) genes, tendency to sunburn and arsenic-related skin lesions. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). No significant association was observed between skin lesions and the XPD 312 Asp/Asn (adjusted OR = 0.87, 95% CI = 0.65-1.15) Asn/Asn (adjusted OR = 0.76, 95% CI = 0.50-1.15) (referent Asp/Asp); XPD 751 Lys/Gln (adjusted OR = 0.92, 95% CI = 0.69-1.23) Gln/Gln (adjusted OR = 0.98, 95% CI = 0.66-1.45) (referent Lys/Lys). While we did not observe any evidence of effect modification of these polymorphisms on the association between well arsenic concentration and skin lesions, we did observe effect modification between these polymorphisms and sunburn tendency and arsenic-related skin lesions. Individuals with the heterozygote or homozygote variant forms (Asp/Asn or Asn/Asn) had half the risk of skin lesions (OR = 0.45, 95% CI = 0.29-0.68) compared with those with the wild-type XPDAsp312Asn genotype (Asp/Asp) and individuals with heterozygote or homozygote variant forms (Lys/Gln or Gln/Gln) had half the risk of skin lesions (OR = 0.47, 95% CI = 0.31-0.72) compared with those with the wild-type XPDLys751Gln genotype (Lys/Lys), within the least sensitive strata of sunburn severity. We observed effect modification on the multiplicative scale for XPD 751 and XPD 312. XPD polymorphisms modified the relationship between tendency to sunburn and skin lesions in an arsenic exposed population. Further study is necessary to explore the effect of XPD polymorphisms and sun exposure on risk of arsenic-related skin lesions.

The Crystal Structure of Peroxiredoxin Asp f3 Provides Mechanistic Insight into Oxidative Stress Resistance and Virulence of Aspergillus fumigatus.

PubMed

Hillmann, Falk; Bagramyan, Karine; Straßburger, Maria; Heinekamp, Thorsten; Hong, Teresa B; Bzymek, Krzysztof P; Williams, John C; Brakhage, Axel A; Kalkum, Markus

2016-09-14

Invasive aspergillosis and other fungal infections occur in immunocompromised individuals, including patients who received blood-building stem cell transplants, patients with chronic granulomatous disease (CGD), and others. Production of reactive oxygen species (ROS) by immune cells, which incidentally is defective in CGD patients, is considered to be a fundamental process in inflammation and antifungal immune response. Here we show that the peroxiredoxin Asp f3 of Aspergillus fumigatus inactivates ROS. We report the crystal structure and the catalytic mechanism of Asp f3, a two-cysteine type peroxiredoxin. The latter exhibits a thioredoxin fold and a homodimeric structure with two intermolecular disulfide bonds in its oxidized state. Replacement of the Asp f3 cysteines with serine residues retained its dimeric structure, but diminished Asp f3's peroxidase activity, and extended the alpha-helix with the former peroxidatic cysteine residue C61 by six residues. The asp f3 deletion mutant was sensitive to ROS, and this phenotype was rescued by ectopic expression of Asp f3. Furthermore, we showed that deletion of asp f3 rendered A. fumigatus avirulent in a mouse model of pulmonary aspergillosis. The conserved expression of Asp f3 homologs in medically relevant molds and yeasts prompts future evaluation of Asp f3 as a potential therapeutic target.

C3 Polymorphism Influences Circulating Levels of C3, ASP and Lipids in Schizophrenic Patients.

PubMed

Nsaiba, Mohamed Jalloul; Lapointe, Marc; Mabrouk, Hajer; Douki, Wahiba; Gaha, Lotfi; Pérusse, Louis; Bouchard, Claude; Jrad, Besma Bel Hadj; Cianflone, Katherine

2015-05-01

Excessive activation of complement is associated with many diseases including schizophrenia. Investigation of C3 polymorphisms, circulating C3, cleavage product ASP/C3adesArg, and lipid metabolism. Cross-sectional analysis. C3 genotyping (CC vs GG for R102L) was performed on 434 Tunisian people consisting of 272 schizophrenic (SZ) patients and 162 control subjects. In a age- and gender-matched subgroups of the three genotypes (131 SZ and 112 NOR), plasma triglycerides, total cholesterol (C), LDL-C, HDL-C, ASP, and complement C3 were measured. C3 gene polymorphism influences BMI and plasma C3, ASP, triglyceride, total cholesterol, LDL-C and HDL-C among SZ patients (p < 0.05-0.0001), with increasing values demonstrated from CC (common form) to CG (heterozygote form) to GG (rare homozygote) forms. Significant correlations between plasma C3 and BMI, triglyceride, HDL-C and ASP (p < 0.05-0.0001) were observed, while ASP correlated with BMI and LDL-C (p = 0.005, p = 0.001, respectively) in SZ patients. Further, proportional conversion of C3 to ASP (%ASP/C3) also increased (p < 0.0001, GG>CG>CC). C3 polymorphisms and plasma C3, ASP and %ASP/C3 correlated with lipid parameters in this SZ population, suggesting that factors predisposing patients to schizophrenia are permissive for complement pathway activation and dyslipidemic influences.

A comparative intracellular proteomic profiling of Pseudomonas aeruginosa strain ASP-53 grown on pyrene or glucose as sole source of carbon and identification of some key enzymes of pyrene biodegradation pathway.

PubMed

Mukherjee, Ashis K; Bhagowati, Pabitra; Biswa, Bhim Bahadur; Chanda, Abhishek; Kalita, Bhargab

2017-09-07

Pseudomonas aeruginosa strain ASP-53, isolated from a petroleum oil-contaminated soil sample, was found to be an efficient degrader of pyrene. PCR amplification of selected hydrocarbon catabolic genes (alkB gene, which encodes for monooxygenase, and the C12O, C23O, and PAH-RHDα genes encoding for the dioxygenase enzyme) from the genomic DNA of P. aeruginosa strain ASP-53 suggested its hydrocarbon degradation potential. The GC-MS analysis demonstrated 30.1% pyrene degradation by P. aeruginosa strain ASP-53 after 144h of incubation at pH6.5, 37°C. Expressions of 115 and 196 intracellular proteins were unambiguously identified and quantitated by shotgun proteomics analysis when the isolate was grown in medium containing pyrene and glucose, respectively. The pyrene-induced uniquely expressed and up-regulated proteins in P. aeruginosa strain ASP-53 in addition to substrate (pyrene) metabolism are also likely to be associated with different cellular functions for example-related to protein folding (molecular chaperone), stress response, metabolism of carbohydrate, proteins and amino acids, and fatty acids; transport of metabolites, energy generation such as ATP synthesis, electron transport and nitrate assimilation, and other oxidation-reduction reactions. Proteomic analyses identified some important enzymes involved in pyrene degradation by P. aeruginosa ASP-53 which shows that this bacterium follows the salicylate pathway of pyrene degradation. This study is the first report on proteomic analysis of pyrene biodegradation pathway by Pseudomonas aeruginosa, isolated from a petroleum-oil contaminated soil sample. The pathway displays partial similarity with deduced pyrene degradation mechanisms of Mycobacterium vanbaalenii PYR-1. The GC-MS analysis as well as PCR amplification of hydrocarbon catabolic genes substantiated the potency of the bacterium under study to effectively degrade high molecular weight, toxic PAH such as pyrene for its filed scale bioremediation experiments. The proteomics approach (LC-MS/MS analysis) identified the differentially regulated intracellular proteins of the isolate P. aeruginosa ASP-53 when grown in pyrene medium. This study identified some important pyrene biodegradation enzymes in Pseudomonas aeruginosa ASP-53 and highlights that the bacterium follows salicylate pathway for pyrene degradation. Copyright © 2017 Elsevier B.V. All rights reserved.

Low temperature effects on nitrification and nitrifier community structure in V-ASP for decentralized wastewater treatment and its improvement by bio-augmentation.

PubMed

Yuan, Jiajia; Dong, Wenyi; Sun, Feiyun; Zhao, Ke

2018-03-01

The vegetation-activated sludge process (V-ASP) has been proved to be an environment-friendly decentralized wastewater treatment system with extra esthetic function and less footprint. However, the effects of low temperature on the treatment performance of V-ASP and related improvement methods are rarely investigated, up to now. In this work, the effect of low temperature on nitrification in V-ASP was comprehensively investigated from overall nitrification performance, substrate utilization kinetics, functional enzymatic activities, and microbial community structure shift by comparison with conventional ASP. Bio-augmentation methods in terms of single-time nitrifier-enriched biomass dosage were employed to improve nitrification efficiency in bench- and full-scale systems. The experiment results demonstrated that the NH 4 + -N removal efficiency in V-ASP system decreased when the operational temperature decreased from 30 to 15 °C, and the decreasing extent was rather smaller compared to ASP, as well as ammonium and nitrite oxidation rates and enzymatic activities, which indicated the V-ASP system possesses high resistance to low temperature. With direct dosage of 1.6 mg nitrifier/gSS sludge, the nitrification efficiency in V-ASP was enhanced dramatically from below 50% to above 90%, implying that bio-augmentation was effective for V-ASP whose enzymatic activities and microbial communities were both also improved. The feasibility and effectiveness of bio-augmentation was further confirmed in a full-scale V-ASP system after a long-term experiment which is instructive for the practical application.

The Development of After-School Program Educators through University-Community Partnerships

ERIC Educational Resources Information Center

Mahoney, Joseph L.; Levine, Mark D.; Hinga, Briana

2010-01-01

Participation in after-school programs (ASPs) "can" positively affect the development of young people. However, "whether" ASPs are beneficial depends on program quality. Although many factors influence the quality of a program, the competencies of adult staff who lead ASPs are a critical determinant. Unfortunately, ASP staff…

Neurological soft signs in Chinese adolescents with antisocial personality traits.

PubMed

Wang, Xin; Cai, Lin; Li, Lingyan; Yang, Yanjie; Yao, Shuqiao; Zhu, Xiongzhao

2016-09-30

The current study was designed to explore the specific relationship between neurologic soft signs (NSSs) and characteristics of antisocial personality traits in adolescents, and to investigate particular NSSs linked to certain brain regions in adolescents with antisocial personality traits. The research was conducted on 96 adolescents diagnosed with ASP traits (ASP trait group) using the ASPD subscale of the Personality Diagnostic Questionnaire for the DSM-IV (PDQ-4+) and 96 adolescents without traits of any personality disorder (control group). NSSs were assessed using the soft sign subscales of the Cambridge Neurological Inventory. Adolescents with ASP traits showed more motor coordination, sensory integration, disinhibition, and total NSSs than the control group. Seven NSSs, including stereognosia in right hand, finger agnosia and graphesthesia in both hands, left-right orientation, and go/no go stimulus, were significantly more frequent in teenagers with ASP traits. Sensory integration was positively associated with ASP traits. Adolescents with antisocial personality traits might have abnormalities in the central nervous system, and sensory integration might be the particular indicator of antisocial personality disorder. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

America’s Holy War

DTIC Science & Technology

2006-04-14

Journal. 24 April 2002. http://www.mepc.org/public_asp/journal/ vol10 /0306_alqaeda.asp accessed on 21 Sept 05. 21 “Translation of April 24, 2002 al...Qaeda document”. Middle East Policy Council Journal. 24 April 2002. http://www.mepc.org/public_asp/journal/ vol10 /0306_alqaeda.asp accessed on 21 Sept... vol10 /0306_alqaeda.asp accessed on 21 Sept 05. 23 “Osama bin Laden’s Speech on the Eve of the 2004 US Elections”. The Middle East Media Research

A Pilot Study for Antimicrobial Stewardship Post-Discharge: Avoiding Pitfalls at the Transitions of Care.

PubMed

Jones, Justin M; Leedahl, Nathan D; Losing, Ashley; Carson, Paul J; Leedahl, David D

2018-04-01

Lack of patient follow-up is a major concern during care transitions, and the role of an antimicrobial stewardship program (ASP) in assessing antimicrobial regimens after hospital discharge is not well described. We implemented an expanded ASP to include patients recently discharged from the hospital and measured its impact on inappropriate antimicrobial therapy 72 hours after inpatient culture data were finalized. A prospective cohort study was conducted at a 583-bed tertiary care center in the Upper Midwest of America. All patients discharged from our facility on antimicrobial therapy with pending culture results between February 3, 2016, and March 2, 2016, were included for review. If a pathogen nonsusceptible to all prescribed antimicrobials was identified post-discharge, a recommendation for therapy modification was communicated to the prescriber. Thirty-eight patients discharged from our hospital on antimicrobial therapy with pending culture results were evaluated for intervention. When final culture susceptibilities were considered, 5 of 38 patients had been prescribed an inappropriate antimicrobial agent. An ASP pharmacist intervened on 4 of 5 patients, resulting in 3 of 5 patients transitioning to appropriate antimicrobial therapy. When compared to a historical cohort, our transitions-of-care ASP yielded a 3.6-fold increase in antimicrobial-related interventions among discharged patients while reducing inappropriate outpatient antimicrobial therapy by 39%. We believe this is the first pharmacist-driven ASP represented in the medical literature which evaluated all available inpatient culture data to serve patients discharged from the hospital. Antimicrobial stewardship for patients in care transitions may provide an opportunity to increase ASP interventions and reduce inappropriate antimicrobial therapy.

Polymorphisms in DNA repair genes increase the risk for type 2 diabetes mellitus and hypertension.

PubMed

Das, Sambuddha; Purkayastha, Sukanya; Roy, Hirakjyoti; Sinha, Anima; Choudhury, Yashmin

2018-06-09

We investigated the effect of polymorphisms in four DNA repair genes, viz. RAD18 Arg302Gln (G>A) (rs373572), XPD Asp312Asn (G>A) (rs1799793), APE1 Asp148Glu (T>G) (rs3136820), and OGG1 Ser326Cys (C>G) (rs1052133) on the risk for type 2 diabetes mellitus (T2DM) and hypertension (HT) in association with smoking, tobacco chewing, and alcohol consumption in a population from Northeast India. The study subjects were comprised of 70 patients suffering from both T2DM and HT and 83 healthy controls. Genotyping was performed using ARMS-PCR for XPD Asp312Asn (G>A) and PCR-CTPP for RAD18 Arg302Gln (G>A), APE1 Asp148Glu (T>G) and OGG1 Ser326Cys (C>G). The RAD18 Gln/Gln genotype was found to significantly increase the risk for T2DM and HT by 30 fold. Significant high risk was observed for individuals with XPD Asn/Asn-RAD18 Arg/Gln genotypes. Smoking was found to be the single most important independent risk factor for T2DM and HT. This study concludes that RAD18 Arg302Gln and XPD Asp312Asn polymorphisms might increase the risk for T2DM and HT in association with smoking, tobacco chewing, and/or alcohol consumption, while APE1 Asp148Glu (T>G) and OGG1 Ser326Cys (C>G) polymorphisms do not contribute to such risk.

A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment

PubMed Central

Tang, Qiao; Liu, Yajun; Li, Tao; Yang, Xiang; Zheng, Guirong; Chen, Hongning; Jia, Lee; Shao, Jingwei

2016-01-01

Metastasis currently remains the predominant cause of breast carcinoma treatment failure. The effective targeting of metastasis-related-pathways in cancer holds promise for a new generation of therapeutics. In this study, we developed an novel Asp-UA conjugate, which was composed of classical “old drug” aspirin and low toxicity natural product ursolic acid for targeting breast cancer metastasis. Our results showed that Asp-UA could attenuate the adhesion, migration and invasion of breast cancer MCF-7 and MDA-MB-231 cells in a more safe and effective manner in vitro. Molecular and cellular study demonstrated that Asp-UA significantly down-regulated the expression of cell adhesion and invasion molecules including integrin α6β1, CD44, MMP-2, MMP-9, COX-2, EGFR and ERK proteins, and up-regulated the epithelial markers “E-cadherin” and “β-catenin”, and PTEN proteins. Furthermore, Asp-UA (80 mg/kg) reduced lung metastasis in a 4T1 murine breast cancer metastasis model more efficiently, which was associated with a decrease in the expression of CD44. More importantly, we did not detect side effects with Asp-UA in mice such as weight loss and main viscera tissues toxicity. Overall, our research suggested that co-drug Asp-UA possessed potential metastasis chemoprevention abilities via influencing EMT and EGFR-mediated pathways and could be a more promising drug candidate for the prevention and/or treatment of breast cancer metastasis. PMID:27683033

A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment.

PubMed

Tang, Qiao; Liu, Yajun; Li, Tao; Yang, Xiang; Zheng, Guirong; Chen, Hongning; Jia, Lee; Shao, Jingwei

2016-11-08

Metastasis currently remains the predominant cause of breast carcinoma treatment failure. The effective targeting of metastasis-related-pathways in cancer holds promise for a new generation of therapeutics. In this study, we developed an novel Asp-UA conjugate, which was composed of classical "old drug" aspirin and low toxicity natural product ursolic acid for targeting breast cancer metastasis. Our results showed that Asp-UA could attenuate the adhesion, migration and invasion of breast cancer MCF-7 and MDA-MB-231 cells in a more safe and effective manner in vitro. Molecular and cellular study demonstrated that Asp-UA significantly down-regulated the expression of cell adhesion and invasion molecules including integrin α6β1, CD44 ,MMP-2, MMP-9, COX-2, EGFR and ERK proteins, and up-regulated the epithelial markers "E-cadherin" and "β-catenin", and PTEN proteins. Furthermore, Asp-UA (80 mg/kg) reduced lung metastasis in a 4T1 murine breast cancer metastasis model more efficiently, which was associated with a decrease in the expression of CD44. More importantly, we did not detect side effects with Asp-UA in mice such as weight loss and main viscera tissues toxicity. Overall, our research suggested that co-drug Asp-UA possessed potential metastasis chemoprevention abilities via influencing EMT and EGFR-mediated pathways and could be a more promising drug candidate for the prevention and/or treatment of breast cancer metastasis.

A Quality Assessment of a Collaborative Model of a Pediatric Antimicrobial Stewardship Program.

PubMed

Nguyen-Ha, Phuong-Tan; Howrie, Denise; Crowley, Kelli; Vetterly, Carol G; McGhee, William; Berry, Donald; Ferguson, Elizabeth; Polischuk, Emily; Brooks, Maria Mori; Goff, Jeffrey; Stillwell, Terri; Darville, Toni; Thompson, Ann E; Levin, James E; Michaels, Marian G; Green, Michael

2016-05-01

Infectious Diseases Society of America guidelines recommend that key antimicrobial stewardship program (ASP) personnel include an infectious disease (ID) physician leader and dedicated ID-trained clinical pharmacist. Limited resources prompted development of an alternative model by using ID physicians and service-based clinical pharmacists at a pediatric hospital. The aim of this study was to analyze the effectiveness and impact of this alternative ASP model. The collaborative ASP model incorporated key strategies of education, antimicrobial restriction, day 3 audits, and practice guidelines. High-use and/or high-cost antimicrobial agents were chosen with audits targeting vancomycin, caspofungin, and meropenem. The electronic medical record was used to identify patients requiring day 3 audits and to communicate ASP recommendations. Segmented regression analyses were used to analyze quarterly antimicrobial agent prescription data for the institution and selected services over time. Initiation of ASP and day 3 auditing was associated with blunting of a preexisting increasing trend for caspofungin drug starts and use and a significant downward trend for vancomycin drug starts (relative change -12%) and use (-25%), with the largest reduction in critical care areas. Although meropenem use was already low due to preexisting requirements for preauthorization, a decline in drug use (-31%, P = .021) and a nonsignificant decline in drug starts (-21%, P = .067) were noted. A 3-month review of acceptance of ASP recommendations found rates of 90%, 93%, and 100% for vancomycin, caspofungin, and meropenem, respectively. This nontraditional ASP model significantly reduced targeted drug usage demonstrating acceptance of integration of service-based clinical pharmacists and ID consultants. Copyright © 2016 by the American Academy of Pediatrics.

Characterization of a low-level unknown isomeric degradation product using an integrated online-offline top-down tandem mass spectrometry platform.

PubMed

Yu, Xiang; Warme, Christopher; Lee, Dinah; Zhang, Jing; Zhong, Wendy

2013-10-01

An integrated online-offline platform was developed combining automated online LC-MS fraction collection, continuous accumulation of selected ions (CASI), and offline top-down electron capture dissociation (ECD) tandem mass spectrometry experiments to identify a low-level, unknown isomeric degradant in a formulated drug product during an accelerated stability study. By identifying the diagnostic ions of the isoaspartic acid (isoAsp), the top-down ECD experiment showed that the Asp9 in exenatide was converted to isoAsp9 to form the unknown isomeric degradant. The platform described here provides an accurate, straightforward, and low limit of detection method for the analysis of Asp isomerization as well as other potential low-level degradants in therapeutic polypeptides and proteins. It is especially useful for unstable and time-sensitive degradants and impurities.

Structure-activity relationship of cyclic peptide penta-c[Asp-His(6)-DPhe(7)-Arg(8)-Trp(9)-Lys]-NH(2) at the human melanocortin-1 and -4 receptors: His(6) substitution.

PubMed

Cheung, Adrian Wai-Hing; Danho, Waleed; Swistok, Joseph; Qi, Lida; Kurylko, Grazyna; Rowan, Karen; Yeon, Mitch; Franco, Lucia; Chu, Xin-Jie; Chen, Li; Yagaloff, Keith

2003-04-07

A series of MT-II related cyclic peptides, based on potent but non-selective hMC4R agonist (Penta-c[Asp-His(6)-DPhe(7)-Arg(8)-Trp(9)-Lys]-NH(2)) was prepared in which His(6) residue was systematically substituted. Two of the most interesting peptides identified in this study are Penta-c[Asp-5-ClAtc-DPhe-Arg-Trp-Lys]-NH(2) and Penta-c[Asp-5-ClAtc-DPhe-Cit-Trp-Lys]-NH(2) which are potent hMC4R agonists and are either inactive or weak partial agonists (not tested for their antagonist activities) in hMC1R, hMC3R and hMC5R agonist assays.

Development of a Design Tool for Planning Aqueous Amendment Injection Systems

DTIC Science & Technology

2008-06-01

BIOREMresources.asp) • “Protocol for Enhanced In Situ Bioremediation Using Emulsified Edible Oil” – (search for title at http://docs.serdp-estcp.org...index.cfm) • “Protocol for In Situ Bioremediation of Chlorinated Solvents Using Edible Oil” (http://www.afcee.brooks.af.mil/products/techtrans...and acetate by common subsurface microorganisms . The H2 and acetate are then used as a carbon and energy source for anaerobic biodegradation of the

DETERMINATION OF C1 AND Cx CELLULOLYTIC ACTIVITIES IN ENZYME PREPARATIONS OF MOLD FUNGI (Opredelenie C1 i Cx Tsellyuloliticheskikh Aktivnostei v Fermentnykh Preparatakh iz Plesnevykh Gribov),

DTIC Science & Technology

Trichotecium roseum, Aspergillus awamory, Asp. niger , Asp. flavus. Differences in the distribution of C1 - and Cx - activities in the preparations of various strains of the same fungus (Asp. awamory, Asp. oryzae) are shown. (Author)

Quality-by-design (QbD): effects of testing parameters and formulation variables on the segregation tendency of pharmaceutical powder measured by the ASTM D 6940-04 segregation tester.

PubMed

Xie, Lin; Wu, Huiquan; Shen, Meiyu; Augsburger, Larry L; Lyon, Robbe C; Khan, Mansoor A; Hussain, Ajaz S; Hoag, Stephen W

2008-10-01

The objective of this study was to examine the effects of testing parameters and formulation variables on the segregation tendency of pharmaceutical powders measured by the ASTM D 6940-04 segregation tester using design of experiments (DOE) approaches. The test blends consisted of 4% aspirin (ASP) and 96% microcrystalline cellulose (MCC) with and without magnesium stearate (MgS). The segregation tendency of a blend was determined by measuring the last/first (L/F) ratio, the ratio of aspirin concentrations between the first and last samples discharged from the tester. A 2(2) factorial design was used to determine the effects of measurement parameters [amount of material loaded (W), number of segregation cycles] with number of replicates 6. ANOVA showed that W was a critical parameter for segregation testing. The L/F value deviated further from 1 (greater segregation tendency) with increasing W. A 2(3) full factorial design was used to assess the effects of formulation variables: grade of ASP (unmilled, milled), grade of MCC, and amount of lubricant, MgS. MLR and ANOVA showed that the grade of ASP was the main effect contributing to segregation tendency. Principal Component Regression Analysis established a correlation between L/F and the physical properties of the blend related to ASP and MCC, the ASP/MCC particle size ratio (PSR) and powder cohesion. The physical properties of the blend related to density and flow were not influenced by the grade of ASP and were not related to the segregation tendency of the blend. The direct relationship between L/F and PSR was determined by univariate analysis. Segregation tendency increased as the ASP to MCC particle size increased. This study highlighted critical test parameters for segregation testing and identified critical physical properties of the blends that influence segregation tendency. (c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association

Using Lagrangian Chemical Transport Modeling to Assess the Impact of Biomass Burning on Ozone and PM2.5

NASA Astrophysics Data System (ADS)

Alvarado, M. J.; Lonsdale, C. R.; Brodowski, C. M.

2017-12-01

One of the challenges of using in situ measurements to study the air quality and climate impacts of biomass burning is correctly determining the contribution of biomass burning sources to the measured ambient concentrations. This is especially important for policy purposes, as the ozone (O3) and fine particulate matter (PM2.5) from natural wildfires should not be confused with that from controllable anthropogenic sources. We have developed a Lagrangian chemical transport model called STILT-ASP that is able to quantify the impact of wildfire events on O3 and PM2.5 measurements made at surface monitoring sites, by mobile laboratories, or by aircraft. STILT-ASP is built by coupling the Stochastic Time Inverted Lagrangian Transport (STILT) model with AER's Aerosol Simulation Program (ASP), which has been used in many studies of the gas and aerosol chemistry of biomass burning smoke. Here we present recent revisions made in STILT-ASP v2.0, including the use of more detailed chemical speciation of fire emissions and biogenic emissions calculated using the MEGAN model with meteorological inputs consistent with those used to drive STILT. We will present the results of an evaluation of the performance of STILT-ASP v2.0 using surface, mobile lab, and aircraft data from the 2013 Houston DISCOVER-AQ campaign. STILT-ASP v2.0 showed good average performance for O3 during the peak of the high O3 episodes on Sept. 25-26, 2013, with a mean bias of -4 ppbv. We will also demonstrate the use of STILT-ASP to evaluate the impact of biomass burning on O3 and PM2.5 in urban areas and to assess the impact of remote fires on the boundary conditions used in Eulerian chemical transport models like CAMx.

The asparagine-transamidosome from Helicobacter pylori: a dual-kinetic mode in non-discriminating aspartyl-tRNA synthetase safeguards the genetic code

PubMed Central

Fischer, Frédéric; Huot, Jonathan L.; Lorber, Bernard; Diss, Guillaume; Hendrickson, Tamara L.; Becker, Hubert D.; Lapointe, Jacques; Kern, Daniel

2012-01-01

Helicobacter pylori catalyzes Asn-tRNAAsn formation by use of the indirect pathway that involves charging of Asp onto tRNAAsn by a non-discriminating aspartyl-tRNA synthetase (ND-AspRS), followed by conversion of the mischarged Asp into Asn by the GatCAB amidotransferase. We show that the partners of asparaginylation assemble into a dynamic Asn-transamidosome, which uses a different strategy than the Gln-transamidosome to prevent the release of the mischarged aminoacyl-tRNA intermediate. The complex is described by gel-filtration, dynamic light scattering and kinetic measurements. Two strategies for asparaginylation are shown: (i) tRNAAsn binds GatCAB first, allowing aminoacylation and immediate transamidation once ND-AspRS joins the complex; (ii) tRNAAsn is bound by ND-AspRS which releases the Asp-tRNAAsn product much slower than the cognate Asp-tRNAAsp; this kinetic peculiarity allows GatCAB to bind and transamidate Asp-tRNAAsn before its release by the ND-AspRS. These results are discussed in the context of the interrelation between the Asn and Gln-transamidosomes which use the same GatCAB in H. pylori, and shed light on a kinetic mechanism that ensures faithful codon reassignment for Asn. PMID:22362756

Activity of [des-Aspartyl1]-Angiotensin II in Primary Aldosteronism

PubMed Central

Carey, Robert M.; Ayers, Carlos R.; Vaughan, E. Darracott; Peach, Michael J.; Herf, Steven M.

1979-01-01

This study describes the effects of [des-Aspartyl1]-angiotensin II ([des-Asp]-AII) on blood pressure and aldosterone production in patients with primary aldosteronism due to aldosterone-producing adrenal adenoma (APA) and idiopathic adrenal hyperplasia (IHA), and in normotensive control subjects. 10 patients with primary aldosteronism, 7 with APA and 3 with IHA, and 6 normotensive control subjects were placed on a constant 150-meq sodium diet for 4 days. [des-Asp]-AII was infused for 30 min at 6, 12, and 18 pmol/kg per min. Three groups of patients were identified on the basis of aldosterone response to [des-Asp]-AII. Group I, composed of normotensive control subjects, showed incremental increases in plasma aldosterone concentration from 6±1 to 14±3 ng/100 ml (P < 0.01) with [des-Asp]-AII infusion. Group II, composed of patients with primary aldosteronism, showed incremental increases in plasma aldosterone concentration from 33±8 to 65±13 ng/100 ml (P < 0.05) with 12 pmol/kg per min of [des-Asp]-AII. Group III, also composed of patients with primary aldosteronism, showed no increase of plasma aldosterone concentration with [des-Asp]-AII. Groups I and II showed similar percentage increases in plasma aldosterone concentration (P = NS). Group III showed significantly lower aldosterone responses than group I (P < 0.01). Group II included all patients with IHA and two patients with APA. Group III included only patients with APA. The blood pressure responses to [des-Asp]-AII of subjects in group I did not differ significantly from those of groups II or III. Thus, patients with IHA and a subgroup of patients with APA showed responsiveness to [des-Asp]-AII which was limited to adrenal cortical stimulation of aldosterone biosynthesis. This suggests that adrenal responsiveness to angiotensin is a major control mechanism in some forms of primary aldosteronism. The differential adrenal responsiveness to [des-Asp]-AII in patients with APA indicates either that there are two distinct subpopulations of APA, or that alteration in tumor response to angiotensin occurs during the natural progression of the disease history. PMID:438332

Electron Transport in a Dioxygenase-Ferredoxin Complex: Long Range Charge Coupling between the Rieske and Non-Heme Iron Center

PubMed Central

Jono, Ryota; Shimizu, Kentaro

2016-01-01

Dioxygenase (dOx) utilizes stereospecific oxidation on aromatic molecules; consequently, dOx has potential applications in bioremediation and stereospecific oxidation synthesis. The reactive components of dOx comprise a Rieske structure Cys2[2Fe-2S]His2 and a non-heme reactive oxygen center (ROC). Between the Rieske structure and the ROC, a universally conserved Asp residue appears to bridge the two structures forming a Rieske-Asp-ROC triad, where the Asp is known to be essential for electron transfer processes. The Rieske and ROC share hydrogen bonds with Asp through their His ligands; suggesting an ideal network for electron transfer via the carboxyl side chain of Asp. Associated with the dOx is an itinerant charge carrying protein Ferredoxin (Fdx). Depending on the specific cognate, Fdx may also possess either the Rieske structure or a related structure known as 4-Cys-[2Fe-2S] (4-Cys). In this study, we extensively explore, at different levels of theory, the behavior of the individual components (Rieske and ROC) and their interaction together via the Asp using a variety of density function methods, basis sets, and a method known as Generalized Ionic Fragment Approach (GIFA) that permits setting up spin configurations manually. We also report results on the 4-Cys structure for comparison. The individual optimized structures are compared with observed spectroscopic data from the Rieske, 4-Cys and ROC structures (where information is available). The separate pieces are then combined together into a large Rieske-Asp-ROC (donor/bridge/acceptor) complex to estimate the overall coupling between individual components, based on changes to the partial charges. The results suggest that the partial charges are significantly altered when Asp bridges the Rieske and the ROC; hence, long range coupling through hydrogen bonding effects via the intercalated Asp bridge can drastically affect the partial charge distributions compared to the individual isolated structures. The results are consistent with a proton coupled electron transfer mechanism. PMID:27656882

Correlation between cervical lordosis and adjacent segment pathology after anterior cervical spinal surgery.

PubMed

Lee, Soo Eon; Jahng, Tae-Ahn; Kim, Hyun Jib

2015-12-01

To evaluate the incidence and risk factors for adjacent segment pathology (ASP) after anterior cervical spinal surgery. Fourteen patients (12 male, mean age 47.1 years) who underwent single-level cervical disk arthroplasty (CDA group) and 28 case-matched patients (24 male, mean age 53.6 years) who underwent single-level anterior cervical discectomy and fusion (ACDF group) were included. Presence of radiologic ASP (RASP) was based on observed changes in anterior osteophytes, disks, and calcification of the anterior longitudinal ligament on lateral radiographs. The mean follow-up period was 43.4 months in the CDA group and 44.6 months in the ACDF group. At final follow-up, ASP was observed in 5 (35.7%) CDA patients and 16 (57.1%) ACDF patients (p = 0.272). The interval between surgery and ASP development was 33.8 months in the CDA group and 16.3 months in the ACDF group (p = 0.046). The ASP risk factor analysis indicated postoperative cervical angle at C3-7 being more lordotic in non-ASP patients in both groups. Restoration of lordosis occurred in the CDA group regardless of the presence of ASP, but heterotopic ossification development was associated with the presence of ASP in the CDA group. And the CDA group had significantly greater clinical improvements than those in the ACDF group when ASP was present. In both CDA and ACDF patients, RASP developed, but CDA was associated with a delay in ASP development. A good clinical outcome was expected in CDA group, even when ASP developed. Restoration of cervical lordosis was an important factor in anterior cervical spine surgery.

The Role of the Asn40Asp Polymorphism of the Mu Opioid Receptor Gene (OPRM1) on Alcoholism Etiology and Treatment: A Critical Review

PubMed Central

Ray, Lara A.; Barr, Christina S.; Blendy, Julie A.; Oslin, David; Goldman, David; Anton, Raymond F.

2011-01-01

The endogenous opioid system has been implicated in the pathophysiology of alcoholism as it modulates the neurobehavioral effects of alcohol. A variant in the mu opioid receptor gene (OPRM1), the Asn40Asp polymorphism, has received attention as a functional variant that may influence a host of behavioral phenotypes for alcoholism as well as clinical response to opioid antagonists. This paper will review converging lines of evidence on the effect of the Asn40Asp SNP on alcoholism phenotypes, including: (i) genetic association studies; (ii) behavioral studies of alcoholism; (iii) neuroimaging studies; (iv) pharmacogenetic studies and clinical trials; and (v) preclinical animal studies. Together, these lines of research seek to elucidate the effects of this functional polymorphism on alcoholism etiology and treatment response. PMID:21895723

Insulin degludec/insulin aspart once daily in Type 2 diabetes: a comparison of simple or stepwise titration algorithms (BOOST® : SIMPLE USE).

PubMed

Park, S W; Bebakar, W M W; Hernandez, P G; Macura, S; Hersløv, M L; de la Rosa, R

2017-02-01

To compare the efficacy and safety of two titration algorithms for insulin degludec/insulin aspart (IDegAsp) administered once daily with metformin in participants with insulin-naïve Type 2 diabetes mellitus. This open-label, parallel-group, 26-week, multicentre, treat-to-target trial, randomly allocated participants (1:1) to two titration arms. The Simple algorithm titrated IDegAsp twice weekly based on a single pre-breakfast self-monitored plasma glucose (SMPG) measurement. The Stepwise algorithm titrated IDegAsp once weekly based on the lowest of three consecutive pre-breakfast SMPG measurements. In both groups, IDegAsp once daily was titrated to pre-breakfast plasma glucose values of 4.0-5.0 mmol/l. Primary endpoint was change from baseline in HbA 1c (%) after 26 weeks. Change in HbA 1c at Week 26 was IDegAsp Simple -14.6 mmol/mol (-1.3%) (to 52.4 mmol/mol; 6.9%) and IDegAsp Stepwise -11.9 mmol/mol (-1.1%) (to 54.7 mmol/mol; 7.2%). The estimated between-group treatment difference was -1.97 mmol/mol [95% confidence interval (CI) -4.1, 0.2] (-0.2%, 95% CI -0.4, 0.02), confirming the non-inferiority of IDegAsp Simple to IDegAsp Stepwise (non-inferiority limit of ≤ 0.4%). Mean reduction in fasting plasma glucose and 8-point SMPG profiles were similar between groups. Rates of confirmed hypoglycaemia were lower for IDegAsp Stepwise [2.1 per patient years of exposure (PYE)] vs. IDegAsp Simple (3.3 PYE) (estimated rate ratio IDegAsp Simple /IDegAsp Stepwise 1.8; 95% CI 1.1, 2.9). Nocturnal hypoglycaemia rates were similar between groups. No severe hypoglycaemic events were reported. In participants with insulin-naïve Type 2 diabetes mellitus, the IDegAsp Simple titration algorithm improved HbA 1c levels as effectively as a Stepwise titration algorithm. Hypoglycaemia rates were lower in the Stepwise arm. © 2016 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Subramaniam, S.; Marti, T.; Khorana, H.G.

Previous studies with site-specific mutants of bacteriorhodopsin have demonstrated that replacement of Asp-85 or Arg-82 affects the absorption spectrum. Between pH 5.5 and 7, the Asp-85----Glu and Arg-82----Ala mutants exist in a pH-dependent equilibrium between purple (lambda max approximately 550/540 nm) and blue (lambda max approximately 600/590 nm) forms of the pigment. Measurement of proton transport as a function of wavelength in reconstituted vesicles shows that proton-pumping activities for the above mutants reside exclusively in their respective purple species. For both mutants, formation of the blue form with decreasing pH is accompanied by loss of proton transport activity. The Asp-85----Asnmore » mutant displays a blue chromophore (lambda max approximately 588 nm), is inactive in proton translocation from pH 5 to 7.5, and shows no transition to the purple form. In contrast, the Asp-212----Asn mutant is purple (lambda max approximately 555 nm) and shows no transition to a blue chromophore with decreasing pH. The experiments suggest that (i) the pKa of the purple-to-blue transition is directly influenced by the pKa of the carboxylate at residue 85 and (ii) the relative strengths of interaction between the protonated Schiff base, Asp-85, Asp-212, and Arg-82 make a major contribution to the regulation of color and function of bacteriorhodopsin.« less

Preliminary X-ray crystallographic studies of BthTX-II, a myotoxic Asp49-phospholipase A{sub 2} with low catalytic activity from Bothrops jararacussu venom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Corrêa, L. C.; Marchi-Salvador, D. P.; Cintra, A. C. O.

2006-08-01

A myotoxic Asp49-PLA{sub 2} with low catalytic activity from B. jararacussu (BthTX-II) was crystallized in the monoclinic crystal system; a complete X-ray diffraction data set was collected and a molecular-replacement solution was obtained. The oligomeric structure of BthTX-II resembles those of the Asp49-PLA{sub 2} PrTX-III and all bothropic Lys49-PLA{sub 2}s. For the first time, a complete X-ray diffraction data set has been collected from a myotoxic Asp49-phospholipase A{sub 2} (Asp49-PLA{sub 2}) with low catalytic activity (BthTX-II from Bothrops jararacussu venom) and a molecular-replacement solution has been obtained with a dimer in the asymmetric unit. The quaternary structure of BthTX-II resemblesmore » the myotoxin Asp49-PLA{sub 2} PrTX-III (piratoxin III from B. pirajai venom) and all non-catalytic and myotoxic dimeric Lys49-PLA{sub 2}s. In contrast, the oligomeric structure of BthTX-II is different from the highly catalytic and non-myotoxic BthA-I (acidic PLA{sub 2} from B. jararacussu). Thus, comparison between these structures should add insight into the catalytic and myotoxic activities of bothropic PLA{sub 2}s.« less

The co-formulation of insulin degludec and insulin aspart lowers fasting plasma glucose and rates of confirmed and nocturnal hypoglycaemia, independent of baseline glycated haemoglobin levels, disease duration or body mass index: A pooled meta-analysis of phase III studies in patients with type 2 diabetes.

PubMed

Haluzík, Martin; Fulcher, Greg; Pieber, Thomas R; Bardtrum, Lars; Tutkunkardas, Deniz; Rodbard, Helena W

2018-02-16

To investigate whether the proven benefits of insulin degludec (IDeg) combined with insulin aspart (IAsp), known as IDegAsp, given twice daily, extend across a wide spectrum of patients with diabetes. This was a post hoc pooled analysis of 5 phase III randomized, 26-week, open-label, treat-to-target trials comparing IDegAsp twice daily (n = 1111) with one of two comparators: premixed insulin (biphasic insulin aspart 30 [BIAsp 30]) twice daily (n = 561) or IDeg once daily + IAsp (n = 136). Patient data were stratified according to baseline glycated haemoglobin (HbA1c) or fasting plasma glucose (FPG) categories, as well as by baseline duration of diabetes or body mass index (BMI) categories. We conducted a meta-analysis of 5 clinical trials: NCT01513590, NCT01009580, NCT01059812, NCT01680341 and NCT01713530. End-of-trial results were broadly consistent, with differences between IDegAsp and comparators observed in phase III trials. HbA1c results were similar for IDegAsp and the comparators in all baseline characteristic (HbA1c, duration of diabetes or BMI) and category groups (number ranges). Significantly lower FPG level was observed with IDegAsp vs comparators in all baseline characteristic and most category groups (excluding FPG <5.5 mmol/L). Significantly lower insulin doses were observed with IDegAsp vs comparators in all baseline characteristic and half of the category groups, and significantly lower rates of confirmed and nocturnal confirmed hypoglycaemia were observed with IDegAsp vs comparators in all baseline variable and category groups. IDegAsp retains a consistent safety and efficacy profile in patients with different baseline characteristics. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Evidence for an Elevated Aspartate pKa in the Active Site of Human Aromatase*

PubMed Central

Di Nardo, Giovanna; Breitner, Maximilian; Bandino, Andrea; Ghosh, Debashis; Jennings, Gareth K.; Hackett, John C.; Gilardi, Gianfranco

2015-01-01

Aromatase (CYP19A1), the enzyme that converts androgens to estrogens, is of significant mechanistic and therapeutic interest. Crystal structures and computational studies of this enzyme shed light on the critical role of Asp309 in substrate binding and catalysis. These studies predicted an elevated pKa for Asp309 and proposed that protonation of this residue was required for function. In this study, UV-visible absorption, circular dichroism, resonance Raman spectroscopy, and enzyme kinetics were used to study the impact of pH on aromatase structure and androstenedione binding. Spectroscopic studies demonstrate that androstenedione binding is pH-dependent, whereas, in contrast, the D309N mutant retains its ability to bind to androstenedione across the entire pH range studied. Neither pH nor mutation perturbed the secondary structure or heme environment. The origin of the observed pH dependence was further narrowed to the protonation equilibria of Asp309 with a parallel set of spectroscopic studies using exemestane and anastrozole. Because exemestane interacts with Asp309 based on its co-crystal structure with the enzyme, its binding is pH-dependent. Aromatase binding to anastrozole is pH-independent, consistent with the hypothesis that this ligand exploits a distinct set of interactions in the active site. In summary, we assign the apparent pKa of 8.2 observed for androstenedione binding to the side chain of Asp309. To our knowledge, this work represents the first experimental assignment of a pKa value to a residue in a cytochrome P450. This value is in agreement with theoretical calculations (7.7–8.1) despite the reliance of the computational methods on the conformational snapshots provided by crystal structures. PMID:25425647

DOE Office of Scientific and Technical Information (OSTI.GOV)

French, T.

The Warden ASP project has progressed from the initial planning stage to construction of an injection plant. An ASP chemical system was designed based on laboratory evaluations that included interfacial tension, mobility requirements, rock-alkali interaction, fluid capabilities, and core tests. Field cores were obtained from the Permian No. 5 and No. 6 sands on the Warden lease in Sho-Vel-Tum oil field. A separate tank battery for the pilot pattern area was installed, and a field tracer test is currently being evaluated. Tracer test results to date indicate that there is no major fracturing in the No. 5 sand. There ismore » indication, however, of some channeling through high permeability sand. The field injection plant was designed, and construction is in progress. Several variations of injection plant design have been evaluated. Some plant design details, such as alkali storage, were found to be dependent on the availability of use equipment and project budget. The surfactant storage facility design was shown to be dependent on surfactant rheology.« less

What Difference Does an Hour Make? Examining the Effects of an After School Program

ERIC Educational Resources Information Center

Farmer-Hinton, Raquel L.; Sass, Daniel A.; Schroeder, Mark

2009-01-01

The use and scope of after-school programs (ASPs) have always varied with the local context. Historically, affluent families used ASPs to provide enrichment for their children. During the Civil Rights and Black Nationalist movements, African Americans used ASPs for cultural and educational activities. In recent times, ASPs have been used for…

Anisotropic Dispersion and Partial Localization of Acoustic Surface Plasmons on an Atomically Stepped Surface: Au(788)

NASA Astrophysics Data System (ADS)

Smerieri, M.; Vattuone, L.; Savio, L.; Langer, T.; Tegenkamp, C.; Pfnür, H.; Silkin, V. M.; Rocca, M.

2014-10-01

Understanding acoustic surface plasmons (ASPs) in the presence of nanosized gratings is necessary for the development of future devices that couple light with ASPs. We show here by experiment and theory that two ASPs exist on Au(788), a vicinal surface with an ordered array of monoatomic steps. The ASPs propagate across the steps as long as their wavelength exceeds the terrace width, thereafter becoming localized. Our investigation identifies, for the first time, ASPs coupled with intersubband transitions involving multiple surface-state subbands.

Effect of peptides Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly on the morphology of the thymus in hypophysectomized young and old birds.

PubMed

Pateyk, A V; Baranchugova, L M; Rusaeva, N S; Obydenko, V I; Kuznik, B I

2013-03-01

Investigations were carried out on chicks of different age. It was found that the most pronounced changes in the morphology of the thymus occurred after neonatal hypophysectomy. These changes are least pronounced in old chicks. Peptides Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly synthesized on the basis of amino acid composition of peptide complexes of the anterior and posterior pituitary lobes administered to hypophysectomized birds regardless of age promoted recovery of the morphological structures of the thymus. The anterior pituitary peptide (Lys-Glu-Asp-Gly) had more pronounced effect on the recovery of thymic structure than posterior pituitary peptide (Ala-Glu-Asp-Gly).

Structures of aspartic acid-96 in the L and N intermediates of bacteriorhodopsin: analysis by Fourier transform infrared spectroscopy

NASA Technical Reports Server (NTRS)

Maeda, A.; Sasaki, J.; Shichida, Y.; Yoshizawa, T.; Chang, M.; Ni, B.; Needleman, R.; Lanyi, J. K.

1992-01-01

The light-induced difference Fourier transform infrared spectrum between the L or N intermediate minus light-adapted bacteriorhodopsin (BR) was measured in order to examine the protonated states and the changes in the interactions of carboxylic acids of Asp-96 and Asp-115 in these intermediates. Vibrational bands due to the protonated and unprotonated carboxylic acid were identified by isotope shift and band depletion upon substitution of Asp-96 or -115 by asparagine. While the signal due to the deprotonation of Asp-96 was clearly observed in the N intermediate, this residue remained protonated in L. Asp-115 was partially deprotonated in L. The C = O stretching vibration of protonated Asp-96 of L showed almost no shift upon 2H2O substitution, in contrast to the corresponding band of Asp-96 or Asp-115 of BR, which shifted by 9-12 cm-1 under the same conditions. In the model system of acetic acid in organic solvents, such an absence of the shift of the C = O stretching vibration of the protonated carboxylic acid upon 2H2O substitution was seen only when the O-H of acetic acid is hydrogen-bonded. The non-hydrogen-bonded monomer showed the 2H2O-dependent shift. Thus, the O-H bond of Asp-96 enters into hydrogen bonding upon conversion of BR to L. Its increased hydrogen bonding in L is consistent with the observed downshift of the O-H stretching vibration of the carboxylic acid of Asp-96.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asojo, Oluwatoyin A., E-mail: oasojo@unmc.edu; Loukas, Alex; Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, Brisbane, QLD 4006

In order to clarify the structural basis of the pathogenesis-related-1 domain, Na-ASP-1, the first multi-domain ASP from the human hookworm parasite N. americanus, has been crystallized. 2.2 Å resolution data have been collected from a crystal belonging to the monoclinic space group P2{sub 1}. Human hookworm infection is a major cause of anemia and malnutrition in the developing world. In an effort to control hookworm infection, the Human Hookworm Vaccine Initiative has identified candidate vaccine antigens from the infective larval stage (L3) of the parasite, including a family of pathogenesis-related-1 (PR-1) proteins known as the ancylostoma-secreted proteins (ASPs). The functionsmore » of the ASPs are unknown. In addition, it is unclear why some ASPs have one while others have multiple PR-1 domains. There are no known structures of a multi-domain ASP and in an effort to remedy this situation, recombinant Na-ASP-1 has been expressed, purified and crystallized. Na-ASP-1 is a 406-amino-acid multi-domain ASP from the prevalent human hookworm parasite Necator americanus. Useful X-ray data to 2.2 Å have been collected from a crystal that belongs to the monoclinic space group P2{sub 1} with unit-cell parameters a = 67.7, b = 74.27, c = 84.60 Å, β = 112.12°. An initial molecular-replacement solution has been obtained with one monomer in the asymmetric unit.« less

Caspofungin exposure alters the core septin AspB interactome of Aspergillus fumigatus.

PubMed

Vargas-Muñiz, José M; Renshaw, Hilary; Waitt, Greg; Soderblom, Erik J; Moseley, M Arthur; Palmer, Jonathan M; Juvvadi, Praveen R; Keller, Nancy P; Steinbach, William J

2017-04-01

Aspergillus fumigatus, the main etiological agent of invasive aspergillosis, is a leading cause of death in immunocompromised patients. Septins, a conserved family of GTP-binding proteins, serve as scaffolding proteins to recruit enzymes and key regulators to different cellular compartments. Deletion of the A. fumigatus septin aspB increases susceptibility to the echinocandin antifungal caspofungin. However, how AspB mediates this response to caspofungin is unknown. Here, we characterized the AspB interactome under basal conditions and after exposure to a clinically relevant concentration of caspofungin. While A. fumigatus AspB interacted with 334 proteins, including kinases, cell cycle regulators, and cell wall synthesis-related proteins under basal growth conditions, caspofungin exposure altered AspB interactions. A total of 69 of the basal interactants did not interact with AspB after exposure to caspofungin, and 54 new interactants were identified following caspofungin exposure. We generated A. fumigatus deletion strains for 3 proteins (ArpB, Cyp4, and PpoA) that only interacted with AspB following exposure to caspofungin that were previously annotated as induced after exposure to antifungal agents, yet only PpoA was implicated in the response to caspofungin. Taken together, we defined how the septin AspB interactome is altered in the presence of a clinically relevant antifungal. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of airway protection: Quantitative timing measures versus penetration/aspiration score.

PubMed

Kendall, Katherine A

2017-10-01

Quantitative measures of swallowing function may improve the reliability and accuracy of modified barium swallow (MBS) study interpretation. Quantitative study analysis has not been widely instituted, however, secondary to concerns about the time required to make measures and a lack of research demonstrating impact on MBS interpretation. This study compares the accuracy of the penetration/aspiration (PEN/ASP) scale (an observational visual-perceptual assessment tool) to quantitative measures of airway closure timing relative to the arrival of the bolus at the upper esophageal sphincter in identifying a failure of airway protection during deglutition. Retrospective review of clinical swallowing data from a university-based outpatient clinic. Swallowing data from 426 patients were reviewed. Patients with normal PEN/ASP scores were identified, and the results of quantitative airway closure timing measures for three liquid bolus sizes were evaluated. The incidence of significant airway closure delay with and without a normal PEN/ASP score was determined. Inter-rater reliability for the quantitative measures was calculated. In patients with a normal PEN/ASP score, 33% demonstrated a delay in airway closure on at least one swallow during the MBS study. There was no correlation between PEN/ASP score and airway closure delay. Inter-rater reliability for the quantitative measure of airway closure timing was nearly perfect (intraclass correlation coefficient = 0.973). The use of quantitative measures of swallowing function, in conjunction with traditional visual perceptual methods of MBS study interpretation, improves the identification of airway closure delay, and hence, potential aspiration risk, even when no penetration or aspiration is apparent on the MBS study. 4. Laryngoscope, 127:2314-2318, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

D-Aspartate drinking solution alleviates pain and cognitive impairment in neuropathic mice.

PubMed

Palazzo, Enza; Luongo, Livio; Guida, Francesca; Marabese, Ida; Romano, Rosaria; Iannotta, Monica; Rossi, Francesca; D'Aniello, Antimo; Stella, Luigi; Marmo, Federica; Usiello, Alessandro; de Bartolomeis, Andrea; Maione, Sabatino; de Novellis, Vito

2016-07-01

D-Aspartate (D-Asp) is a free D-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-D-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether D-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a model of neuropathic pain induced by the spared nerve injury (SNI) of the sciatic nerve in mice. SNI mice developed mechanical allodynia and motor coordination impairment 30 days after SNI surgery. SNI mice showed cognitive impairment, anxiety and depression-like behaviour, reduced sociability in the three chamber sociability paradigm, increased expression of NR2B subunit of NMDA receptor and Homer 1a in the medial prefrontal cortex (mPFC). The expression of (post synaptic density) PSD-95 and Shank 1was instead unaffected in the mPFC of the SNI mice. Treatment with D-Asp drinking solution, started right after the SNI (day 0), alleviated mechanical allodynia, improved cognition and motor coordination and increased social interaction. D-Asp also restored the levels of extracellular D-Asp, Homer 1a and NR2B subunit of the NMDA receptor to physiological levels and reduced Shank1 and PSD-95 protein levels in the mPFC. Amitriptyline, a tricyclic antidepressant used also to alleviate neuropathic pain in humans, reverted mechanical allodynia and cognitive impairment, and unlike D-Asp, was effective in reducing depression and anxiety-like behaviour in the SNI mice and increased PSD protein level. Altogether these findings demonstrate that D-Asp improves sensorial, motor and cognitive-like symptoms related to chronic pain possibly through glutamate neurotransmission normalization in neuropathic mice.

Asp 58 modulates lens αA-crystallin oligomer formation and chaperone function.

PubMed

Takata, Takumi; Nakamura-Hirota, Tooru; Inoue, Rintaro; Morishima, Ken; Sato, Nobuhiro; Sugiyama, Masaaki; Fujii, Noriko

2018-06-01

Senile cataract onset is caused by insolubilization of lens proteins. The lens crystallin protein family correctly orders the formation of homo- or hetero-oligomers in lens fiber cells. Because lens fiber cells do not divide, covalent post-translational modifications, such as isomerization of aspartate residues, accumulate with aging. Although many isomerization sites of αA-crystallin have been reported, their structural and functional contributions have never been identified. In this study, αA-crystallin was extracted from aged human lens and separated into each oligomeric state by size exclusion chromatography and electrophoresis. The novel combination methodology of in-solution/gel tryptic digestion with liquid chromatography equipped with mass spectrometry (LC-MS/MS) was used to evaluate the isomerization of Asp 58. The contributions of isomerization to assembly, solubility, and chaperone functions of αA-crystallin were estimated using a series of mutations of Asp 58 in αA-crystallin. The results indicated that the isomerization of Asp 58 depended on the oligomer size and age of the lens. The substitution of Asp 58 for hydrophobic residues increased αA-crystallin oligomer size and decreased solubility. All substitutions decreased the chaperone function of αA-crystallin for aggregates of bovine βL-crystallin and alcohol dehydrogenase. The data indicated that Asp 58 in αA-crystallin was critical for intermolecular interactions in the lens. Our results also suggested that LC-MS/MS-based isomerization analyses of in-gel-digested products could be useful for investigating the isomerization of Asp residues in oligomeric states. This method could also be used to analyze d/l ratios of amino acid residues in soluble protein aggregates. © 2018 Federation of European Biochemical Societies.

Polymorphic trial in oxidative damage of arsenic exposed Vietnamese.

PubMed

Fujihara, Junko; Soejima, Mikiko; Yasuda, Toshihiro; Koda, Yoshiro; Kunito, Takashi; Iwata, Hisato; Tanabe, Shinsuke; Takeshita, Haruo

2011-10-15

Arsenic causes DNA damage and changes the cellular capacity for DNA repair. Genes in the base excision repair (BER) pathway influence the generation and repair of oxidative lesions. Single nucleotide polymorphisms (SNPs) in human 8-oxoguanine DNA glycosylase (hOGG1) Ser326Cys; apurinic/apyrimidinic endonuclease (APE1) Asp148Glu; X-ray and repair and cross-complementing group 1 (XRCC1) Arg280His and Arg399Gln in the BER genes were analyzed, and the relationship between these 4 SNPs and the urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations of 100 Vietnamese population exposed to arsenic was investigated. Individuals with hOGG1 326Cys/Cys showed significantly higher urinary 8-OHdG concentrations than did those with 326 Ser/Cys and Ser/Ser. As for APE1 Asp148Glu, heterozygous subjects showed significantly higher urinary 8-OHdG concentrations than did those homozygous for Asp/Asp. Moreover, global ethnic comparison of the allelic frequencies of the 4SNPs was performed in 10 population and previous reported data. The mutant allele frequencies of hOGG1 Ser326Cys in the Asian populations were higher than those in the African and Caucasian populations. As for APE1 Asp148Glu, Caucasians showed higher mutant frequencies than those shown by African and Asian populations. Among Asian populations, the Bangladeshi population showed relatively higher mutant allele frequencies of the APE1 Asp148Glu polymorphism. This study is the first to demonstrate the existence of genetic heterogeneity in a worldwide distribution of SNPs (hOGG1 Ser326Cys, APE1 Asp148Glu, XRCC1 Arg280His, and XRCC1 Arg399Gln) in the BER genes. Published by Elsevier Inc.

Sodium Cromoglycate Prevents Exacerbation of IgE-Mediated Food-Allergic Reaction Induced by Aspirin in a Rat Model of Egg Allergy.

PubMed

Yokooji, Tomoharu; Matsuo, Hiroaki

2015-01-01

Aspirin (ASP)-facilitated absorption of ingested allergens is considered an exacerbating factor in the development of food allergy. Sodium cromoglycate (SCG) is used for the treatment of atopic dermatitis with food allergy, but the efficacy of SCG in ASP-exacerbated food-allergy reactions is unclear. In this study, we evaluated the effect of SCG on ASP-exacerbated food-allergic reactions, as well as allergen absorption, in egg-allergic model rats. Plasma concentrations of ovalbumin (OVA) and fluorescein isothiocyanate-labeled dextran (FD-40), a marker for nonspecific-absorption pathways, were measured after oral administration of mixtures of OVA and FD-40 in OVA-unsensitized and OVA-sensitized rats. IgE-mediated allergic reactions were evaluated by measuring changes in rectal temperature and Evans blue dye (EBD) extravasation in the intestine and liver after oral challenge with OVA. The effects of ASP and SCG on such absorption and allergic reactions were also evaluated kinetically. In OVA-sensitized rats, plasma concentrations of OVA and FD-40 were significantly higher than those in unsensitized rats after oral administration. ASP increased the intestinal absorption of OVA and FD-40 via the paracellular pathway, and a lower rectal temperature and higher EBD extravasation were detected in the intestine and liver of OVA-sensitized rats. SCG ameliorated these ASP-facilitated absorptions and allergic reactions in a dose-dependent manner. In particular, high-dose SCG (195.2 μmol/kg) completely inhibited these absorptions and reactions. SCG can prevent ASP-exacerbated allergic reactions in patients with food allergy resulting from inhibition of increases in allergen absorption. © 2015 S. Karger AG, Basel.

Crystallization and preliminary X-ray analysis of Na-ASP-1, a multi-domain pathogenesis-related-1 protein from the human hookworm parasite Necator americanus

PubMed Central

Asojo, Oluwatoyin A.; Loukas, Alex; Inan, Mehmet; Barent, Rick; Huang, Jicai; Plantz, Brad; Swanson, Amber; Gouthro, Mark; Meagher, Michael M.; Hotez, Peter J.

2005-01-01

Human hookworm infection is a major cause of anemia and malnutrition in the developing world. In an effort to control hookworm infection, the Human Hookworm Vaccine Initiative has identified candidate vaccine antigens from the infective larval stage (L3) of the parasite, including a family of pathogenesis-related-1 (PR-1) proteins known as the ancylostoma-secreted proteins (ASPs). The functions of the ASPs are unknown. In addition, it is unclear why some ASPs have one while others have multiple PR-1 domains. There are no known structures of a multi-domain ASP and in an effort to remedy this situation, recombinant Na-ASP-1 has been expressed, purified and crystallized. Na-ASP-1 is a 406-amino-acid multi-domain ASP from the prevalent human hookworm parasite Necator americanus. Useful X-ray data to 2.2 Å have been collected from a crystal that belongs to the monoclinic space group P21 with unit-cell parameters a = 67.7, b = 74.27, c = 84.60 Å, β = 112.12°. An initial molecular-replacement solution has been obtained with one monomer in the asymmetric unit. PMID:16511050

Structural Basis for the Kexin-like Serine Protease from Aeromonas sobria as Sepsis-causing Factor*

PubMed Central

Kobayashi, Hidetomo; Utsunomiya, Hiroko; Yamanaka, Hiroyasu; Sei, Yoshihisa; Katunuma, Nobuhiko; Okamoto, Keinosuke; Tsuge, Hideaki

2009-01-01

The anaerobic bacterium Aeromonas sobria is known to cause potentially lethal septic shock. We recently proposed that A. sobria serine protease (ASP) is a sepsis-related factor that induces vascular leakage, reductions in blood pressure via kinin release, and clotting via activation of prothrombin. ASP preferentially cleaves peptide bonds that follow dibasic amino acid residues, as do Kex2 (Saccharomyces cerevisiae serine protease) and furin, which are representative kexin family proteases. Here, we revealed the crystal structure of ASP at 1.65 Å resolution using the multiple isomorphous replacement method with anomalous scattering. Although the overall structure of ASP resembles that of Kex2, it has a unique extra occluding region close to its active site. Moreover, we found that a nicked ASP variant is cleaved within the occluding region. Nicked ASP shows a greater ability to cleave small peptide substrates than the native enzyme. On the other hand, the cleavage pattern for prekallikrein differs from that of ASP, suggesting the occluding region is important for substrate recognition. The extra occluding region of ASP is unique and could serve as a useful target to facilitate development of novel antisepsis drugs. PMID:19654332

Anaerobic antibiotic usage for pneumonia in the medical intensive care unit.

PubMed

Kioka, Mutsumi J; DiGiovine, Bruno; Rezik, Mohamed; Jennings, Jeffrey H

2017-11-01

Pneumonia is a common admitting diagnosis in the intensive care unit (ICU). When aspiration is suspected, antibiotics to cover anaerobes are frequently used, but in the absence of clear risk factors, current guidelines have questioned their role. It is unknown how frequently these guidelines are followed. We conducted a single-centre observational study on practice patterns of anaerobic antibiotic use in consecutive patients admitted to the ICU with aspiration pneumonia (Asp), community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP). A total of 192 patients were studied (Asp: 20, HCAP: 107, CAP: 65). Overall, 59 patients received anaerobic antibiotics (Asp: 90%, HCAP: 28%, CAP 17%) but a significant proportion of these patients did not meet criteria to receive them. Inappropriate anaerobic antibiotic use was 12/20 for Asp, 27/107 for HCAP and 9/65 for CAP. Mortality probability model III at zero hours (MPM0) score and a diagnosis of Asp were predictors of receiving inappropriate anaerobic antibiotics. Receiving inappropriate anaerobic antibiotics was associated with a longer ICU length of stay (LOS; 7 days (interquartile range (IQR): 7-21) vs 4 days (IQR:2-9), P = 0.017). For patients in the ICU admitted with pneumonia, there is a high occurrence of inappropriately prescribed anaerobic antibiotics, the use of which was associated with a longer ICU LOS. © 2017 Asian Pacific Society of Respirology.

Identification of homozygous WFS1 mutations (p.Asp211Asn, p.Gln486*) causing severe Wolfram syndrome and first report of male fertility

PubMed Central

Haghighi, Amirreza; Haghighi, Alireza; Setoodeh, Aria; Saleh-Gohari, Nasrollah; Astuti, Dewi; Barrett, Timothy G

2013-01-01

Wolfram syndrome (WFS) is a neurodegenerative genetic condition characterized by juvenile-onset of diabetes mellitus and optic atrophy. We studied clinical features and the molecular basis of severe WFS (neurodegenerative complications) in two consanguineous families from Iran. A clinical and molecular genetic investigation was performed in the affected and healthy members of two families. The clinical diagnosis of WFS was confirmed by the existence of diabetes mellitus and optic atrophy in the affected patients, who in addition had severe neurodegenerative complications. Sequencing of WFS1 was undertaken in one affected member from each family. Targeted mutations were tested in all members of relevant families. Patients had most of the reported features of WFS. Two affected males in the first family had fathered unaffected children. We identified two homozygous mutations previously reported with apparently milder phenotypes: family 1: c.631G>A (p.Asp211Asn) in exon 5, and family 2: c.1456C>T (p.Gln486*) in exon 8. Heterozygous carriers were unaffected. This is the first report of male Wolfram patients who have successfully fathered children. Surprisingly, they also had almost all the complications associated with WFS. Our report has implications for genetic counseling and family planning advice for other affected families. PMID:22781099

The Glass Ceiling - A Question of Joint Officer Development - Why Only Five USAF Geographic Combatant Commanders?

DTIC Science & Technology

2010-07-26

kit/OEF.asp (accessed March 6, 2011). 19 U.S. Central Command. "US CENTCOM Leadership: General James N. Mattis , Commander,‖ http... Mattis , USMC Commander, USCENTCOM 0 2 Cmdr, Task Force 58 Cmdr, USJFCOM Admiral James G. Stavridis, USN Commander, USEUCOM 1 2 Plans Officer, JCS...U.S. Central Command. "US CENTCOM Leadership." General James N. Mattis . https://slsp.http://www.centcom.mil/en/about-centcom/leadership

Fast and Reliable Thermodynamic Approach for Determining the Protonation State of the Asp Dyad.

PubMed

Huang, Jinfeng; Sun, Bin; Yao, Yuan; Liu, Junjun

2017-09-25

The protonation state of the asp dyad is significantly important in revealing enzymatic mechanisms and developing drugs. However, it is hard to determine by calculating free energy changes between possible protonation states, because the free energy changes due to protein conformational flexibility are usually much larger than those originating from different locations of protons. Sophisticated and computationally expensive methods such as free energy perturbation, thermodynamic integration (TI), and quantum mechanics/molecular mechanics are therefore usually used for this purpose. In the present study, we have developed a simple thermodynamic approach to effectively eliminating the free energy changes arising from protein conformational flexibility and estimating the free energy changes only originated from the locations of protons, which provides a fast and reliable method for determining the protonation state of asp dyads. The test of this approach on a total of 15 asp dyad systems, including BACE-1 and HIV-1 protease, shows that the predictions from this approach are all consistent with experiments or with the computationally expensive TI calculations. It is clear that our thermodynamic approach could be used to rapidly and reliably determine the protonation state of the asp dyad.

[Genetic polymorphism in XPD related to risks of chronic benzene poisoning].

PubMed

Li, Yan; Zhang, Zhongbin; Sun, Pin; Wan, Junxiang; Jin, Xipeng; Xia, Zhaolin

2010-05-01

To explore the relation between genetic polymorphisms in XPD and risks of chronic benzene poisoning (CBP). A case-control study was conducted. 152 CBP patients and 152 NCBP workers occupationally exposed to benzene were investigated. Polymerase chain reaction-restrained fragment length polymorphism technique (PCR-RFLP) was applied to detect the single nucleotide polymorphisms (SNPs) at c. 199, c. 201, c. 312 and c. 751 of XPD gene. No variant alleles was detected at c. 199 and c. 201 of XPD gene. In comparition with the individual genotypes of XPDc. 312Asp/Asp, the risk of CBP suffered from the individual genotype of XPDc. 312Asp/Asn + Asn/Asn decreased a 0.59 fold (ORadj = 0.59, 95% CI = 0.35-0.99, chi2 = 3.99, P < 0.05), when sex, workage and intensity of benzene exposure were adjusted. And in low intensity of benzene exposure group, the risk of CBP suffered from the individual genotypes of XPDc. 312Asp/Asn + Asn/Asn more decreased (ORadj = 0.13, 95% CI = 0.04-0.51, chi2 = 8.93, P < 0.01). Polymorphism of XPD Asp312Asn could contribute to altered risk of CBP.

Computational studies on non-succinimide-mediated stereoinversion mechanism of aspartic acid residues assisted by phosphate

NASA Astrophysics Data System (ADS)

Nakayoshi, Tomoki; Fukuyoshi, Shuichi; Takahashi, Ohgi; Oda, Akifumi

2018-03-01

Although nearly all of the amino acids that constitute proteins are l-amino acids, d-amino acid residues in human proteins have been recently reported. d-amino acid residues cause a change in the three-dimensional structure of proteins, and d-aspartic acid (Asp) residues are considered to be one of the causes of age-related diseases. The stereoinversion of Asp residues in peptides and proteins is thought to proceed via a succinimide intermediate; however, it has been reported that stereoinversion can occur even under conditions where a succinimide intermediate cannot be formed. In order to elucidate the non-succinimide-mediated stereoinversion pathway, we investigated the stereoinversion of l-Asp to d-Asp catalysed by phosphate and estimated the activation barrier using B3LYP/6-31+G(d,p) density functional theory (DFT) calculations. For the DFT calculations, a model compound in which the Asp residue is capped with acetyl and methyl-amino groups on the N- and C-termini, respectively, was used. The calculated activation barrier was not excessively high for the stereoinversion to occur in vivo. Therefore, this stereoinversion mechanism may compete with the succinimide-mediated mechanism.

Asymmetric membranes for destabilization of oil droplets in produced water from alkaline-surfactant-polymer (ASP) flooding

NASA Astrophysics Data System (ADS)

Ramlee, Azierah; Chiam, Chel-Ken; Sarbatly, Rosalam

2018-05-01

This work presents a study of destabilization of oil droplets in the produced water from alkaline-surfactant-polymer (ASP) flooding by using four types of laboratory-fabricated polyvinylidene fluoride (PVDF) membranes. The PVDF membranes were fabricated via immersion precipitation method with ethanol (0 - 30 %, v/v) as the coagulant. The membranes with the effective area of 17.35 cm2 were tested with synthesized ASP solution as the feed in cross-flow microfiltration process. The ASP feed solution initially contained the oil droplets with radius ranged from 40 to 100 nm and the mean radius was 61 nm. Results have shown that the concentration of the ethanol in the coagulation bath affects the formation of the membrane structure and the corresponding porosity, while no significance influence on the membrane thickness. Coalescence of the oil droplets was occurred when the ASP solution permeated through the asymmetric PVDF membranes. Through the coalescence process, the oil droplets were destabilized where the radius of the oil droplets in the permeates increased to 1.5-4 µm with the corresponding mean radius ranged from 2.4 to 2.7 µm.

Determination of the protonation state of the Asp dyad: conventional molecular dynamics versus thermodynamic integration.

PubMed

Huang, Jinfeng; Zhu, Yali; Sun, Bin; Yao, Yuan; Liu, Junjun

2016-03-01

The protonation state of the Asp dyad is important as it can reveal enzymatic mechanisms, and the information this provides can be used in the development of drugs for proteins such as memapsin 2 (BACE-1), HIV-1 protease, and rennin. Conventional molecular dynamics (MD) simulations have been successfully used to determine the preferred protonation state of the Asp dyad. In the present work, we demonstrate that the results obtained from conventional MD simulations can be greatly influenced by the particular force field applied or the values used for control parameters. In principle, free-energy changes between possible protonation states can be used to determine the protonation state. We show that protonation state prediction by the thermodynamic integration (TI) method is insensitive to force field version or to the cutoff for calculating nonbonded interactions (a control parameter). In the present study, the protonation state of the Asp dyad predicted by TI calculations was the same regardless of the force field and cutoff value applied. Contrary to the intuition that conventional MD is more efficient, our results clearly show that the TI method is actually more efficient and more reliable for determining the protonation state of the Asp dyad.

Insights into the functional role of protonation states in the HIV-1 protease-BEA369 complex: molecular dynamics simulations and free energy calculations.

PubMed

Chen, Jianzhong; Yang, Maoyou; Hu, Guodong; Shi, Shuhua; Yi, Changhong; Zhang, Qinggang

2009-10-01

The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method combined with molecular dynamics (MD) simulations were used to investigate the functional role of protonation in human immunodeficiency virus type 1 (HIV-1) protease complexed with the inhibitor BEA369. Our results demonstrate that protonation of two aspartic acids (Asp25/Asp25') has a strong influence on the dynamics behavior of the complex, the binding free energy of BEA369, and inhibitor-residue interactions. Relative binding free energies calculated using the MM-PBSA method show that protonation of Asp25 results in the strongest binding of BEA369 to HIV-1 protease. Inhibitor-residue interactions computed by the theory of free energy decomposition also indicate that protonation of Asp25 has the most favorable effect on binding of BEA369. In addition, hydrogen-bond analysis based on the trajectories of the MD simulations shows that protonation of Asp25 strongly influences the water-mediated link of a conserved water molecule, Wat301. We expect that the results of this study will contribute significantly to binding calculations for BEA369, and to the design of high affinity inhibitors.

The parasite-derived rOv-ASP-1 is an effective antigen-sparing CD4+ T cell-dependent adjuvant for the trivalent inactivated influenza vaccine, and functions in the absence of MyD88 pathway.

PubMed

Jain, Sonia; George, Parakkal Jovvian; Deng, Wanyan; Koussa, Joseph; Parkhouse, Kaela; Hensley, Scott E; Jiang, Jiu; Lu, Jie; Liu, Zhuyun; Wei, Junfei; Zhan, Bin; Bottazzi, Maria Elena; Shen, Hao; Lustigman, Sara

2018-06-14

Vaccination remains the most cost-effective biomedical approach for controlling influenza disease. In times of pandemics, however, these vaccines cannot be produced in sufficient quantities for worldwide use by the current manufacturing capacities and practices. What is needed is the development of adjuvanted vaccines capable of inducing an adequate or better immune response at a decreased antigen dose. Previously we showed that the protein adjuvant rOv-ASP-1 augments influenza-specific antibody titers and survival after virus challenge in both young adult and old-age mice when administered with the trivalent inactivated influenza vaccine (IIV3). In this study we show that a reduced amount of rOv-ASP-1, with 40-times less IIV3 can also induce protection. Apparently the potency of the rOv-ASP-1 adjuvanted IIV3 vaccine is independent of the IIV3-specific Th1/Th2 associated antibody responses, and independent of the presence of HAI antibodies. However, CD4 + T helper cells were indispensable for the protection. Further, rOv-ASP-1 with or without IIV3 elicited the increased level of various chemokines, which are known chemoattractant for immune cells, into the muscle 4 h after immunization, and significantly induced the recruitment of monocytes, macrophages and neutrophils into the muscles. The recruited monocytes had higher expression of the activation marker MHCII on their surface as well as CXCR3 and CCR2; receptors for IP-10 and MCP-1, respectively. These results show that the rOv-ASP-1 adjuvant allows substantial antigen sparing of IIV3 by stimulating at the site of injection the accumulation of chemokines and the recruitment of immune cells that can augment the activation of CD4 + T cell immune responses, essential for the production of antibody responses. Protection elicited by the rOv-ASP-1 adjuvanted IIV3 vaccine also appears to function in the absence of MyD88-signaling. Future studies will attempt to delineate the precise mechanisms by which the rOv-ASP-1 adjuvanted IIV3 vaccine works. Copyright © 2018 Elsevier Ltd. All rights reserved.

Polymorphisms in XPD (Asp312Asn and Lys751Gln) genes, sunburn and arsenic-related skin lesions

PubMed Central

McCarty, Kathleen M.; Smith, Thomas J.; Zhou, Wei; Gonzalez, Ernesto; Quamruzzaman, Quazzi; Rahman, Mahmuder; Mahiuddin, Golam; Ryan, Louise; Su, Li; Christiani, David C.

2013-01-01

Background Single-nucleotide polymorphisms in genes related to DNA repair capacity and ultraviolet exposure have not been well investigated in relation to skin lesions associated with arsenic exposure. This population based case–control study, of 600 cases and 600 controls, frequency matched on age and gender in Pabna, Bangladesh, in 2001–2002, investigated the association and potential effect modification between polymorphisms in Xeroderma Pigmentosum complementation group D (XPD) (Lys751Gln and Asp312Asn) genes, tendency to sunburn and arsenic-related skin lesions. Methods Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Result No significant association was observed between skin lesions and the XPD 312 Asp/Asn (adjusted OR = 0.87, 95% CI = 0.65–1.15) Asn/Asn (adjusted OR = 0.76, 95% CI = 0.50–1.15) (referent Asp/Asp); XPD 751 Lys/Gln (adjusted OR = 0.92, 95% CI = 0.69–1.23) Gln/Gln (adjusted OR = 0.98, 95% CI = 0.66–1.45) (referent Lys/Lys). While we did not observe any evidence of effect modification of these polymorphisms on the association between well arsenic concentration and skin lesions, we did observe effect modification between these polymorphisms and sunburn tendency and arsenic-related skin lesions. Individuals with the heterozygote or homozygote variant forms (Asp/Asn or Asn/Asn) had half the risk of skin lesions (OR = 0.45, 95% CI = 0.29–0.68) compared with those with the wild-type XPDAsp312Asn genotype (Asp/Asp) and individuals with heterozygote or homozygote variant forms (Lys/Gln or Gln/Gln) had half the risk of skin lesions (OR = 0.47, 95% CI = 0.31–0.72) compared with those with the wild-type XPDLys751Gln genotype (Lys/Lys), within the least sensitive strata of sunburn severity. We observed effect modification on the multiplicative scale for XPD 751 and XPD 312. Conclusion XPD polymorphisms modified the relationship between tendency to sunburn and skin lesions in an arsenic exposed population. Further study is necessary to explore the effect of XPD polymorphisms and sun exposure on risk of arsenic-related skin lesions. PMID:17470448

After-School Program Implementation in Urban Environments: Increasing Engagement among Adolescent Youth

ERIC Educational Resources Information Center

Pelcher, Allison; Rajan, Sonali

2016-01-01

Background: After-school programs (ASPs) play a crucial role in supplementing the present school day. However, implementing ASPs in the urban environment and among adolescents (grades 6-12) poses unique challenges. The purpose of this study was to conduct a systematic literature review to identify evidence-based barriers and facilitators to…

Interaction study of aspirin or clopidogrel on pharmacokinetics of donepezil hydrochloride in rats by HPLC-fluorescence detection.

PubMed

Wada, Mitsuhiro; Nishiwaki, Junichiro; Yamane, Tomoko; Ohwaki, Yuichi; Aboul-Enein, Hassan Y; Nakashima, Kenichiro

2007-06-01

The present study aims to investigate the possibility of interaction of aspirin (Asp) or clopidogrel (CG) on donepezil (DP) hydrochloride in rats by HPLC-fluorescence detection. The separation of DP was achieved in ca. 13 min without interference of Asp and CG on the chromatogram. DP levels in rat plasma with a single administration of DP (5 mg/kg, i.p., group I) and those with a co-administration of Asp (200 mg/kg, p.o., group II or 200 mg/kg, i.p., group III) or CG (5 mg/kg, p.o., group IV) were monitored. The DP concentrations determined in rat plasma ranged from 25.0 to 336.1 ng/mL. Pharmacokinetic parameters for these groups were calculated and compared with one another. No significant difference was observed on the comparison of group I with other groups except for the mean resident time of group IV (p = 0.012). These basic findings may help clinical inference when DP is co-administered with Asp and CG to human. Copyright 2007 John Wiley & Sons, Ltd.

Structure-Activity Relationship Studies on a Macrocyclic Agouti-Related Protein (AGRP) Scaffold Reveal Agouti Signaling Protein (ASP) Residue Substitutions Maintain Melanocortin-4 Receptor Antagonist Potency and Result in Inverse Agonist Pharmacology at the Melanocortin-5 Receptor.

PubMed

Ericson, Mark D; Freeman, Katie T; Schnell, Sathya M; Fleming, Katlyn A; Haskell-Luevano, Carrie

2017-10-12

The melanocortin system consists of five reported receptors, agonists from the proopiomelanocortin gene transcript, and two antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP). For both ASP and AGRP, the hypothesized Arg-Phe-Phe pharmacophores are on exposed β-hairpin loops. In this study, the Asn and Ala positions of a reported AGRP macrocyclic scaffold (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) were explored with 14-compound and 8-compound libraries, respectively, to generate more potent, selective melanocortin receptor antagonists. Substituting diaminopropionic acid (Dap), DDap, and His at the Asn position yielded potent MC4R ligands, while replacing Ala with Ser maintained MC4R potency. Since these substitutions correlate to ASP loop residues, an additional Phe to Ala substitution was synthesized and observed to maintain MC4R potency. Seventeen compounds also possessed inverse agonist activity at the MC5R, the first report of this pharmacology. These findings are useful in developing molecular probes to study negative energy balance conditions and unidentified functions of the MC5R.

Methanolic extract of white asparagus shoots activates TRAIL apoptotic death pathway in human cancer cells and inhibits colon carcinogenesis in a preclinical model

PubMed Central

BOUSSEROUEL, SOUAD; LE GRANDOIS, JULIE; GOSSÉ, FRANCINE; WERNER, DALAL; BARTH, STEPHAN W.; MARCHIONI, ERIC; MARESCAUX, JACQUES; RAUL, FRANCIS

2013-01-01

Shoots of white asparagus are a popular vegetable dish, known to be rich in many bioactive phytochemicals reported to possess antioxidant, and anti-inflammatory and antitumor activities. We evaluated the anticancer mechanisms of a methanolic extract of Asparagus officinalis L. shoots (Asp) on human colon carcinoma cells (SW480) and their derived metastatic cells (SW620), and Asp chemopreventive properties were also assessed in a model of colon carcinogenesis. SW480 and SW620 cell proliferation was inhibited by 80% after exposure to Asp (80 μg/ml). We demonstrated that Asp induced cell death through the activation of TRAIL DR4/DR5 death receptors leading to the activation of caspase-8 and caspase-3 and to cell apoptosis. By specific blocking agents of DR4/DR5 receptors we were able to prevent Asp-triggered cell death confirming the key role of DR4/DR5 receptors. We found also that Asp (80 μg/ml) was able to potentiate the effects of the cytokine TRAIL on cell death even in the TRAIL-resistant metastatic SW620 cells. Colon carcinogenesis was initiated in Wistar rats by intraperitoneal injections of azoxymethane (AOM), once a week for two weeks. One week after (post-initiation) rats received daily Asp (0.01%, 14 mg/kg body weight) in drinking water. After 7 weeks of Asp-treatment the colon of rats exhibited a 50% reduction of the number of preneoplastic lesions (aberrant crypt foci). In addition Asp induced inhibition of several pro-inflammatory mediators, in association with an increased expression of host-defense mediators. In the colonic mucosa of Asp-treated rats we also confirmed the pro-apoptotic effects observed in vitro including the activation of the TRAIL death-receptor signaling pathway. Taken together, our data highlight the chemopreventive effects of Asp on colon carcinogenesis and its ability to promote normal cellular homeostasis. PMID:23754197

Development of Novel Radiogallium-Labeled Bone Imaging Agents Using Oligo-Aspartic Acid Peptides as Carriers

PubMed Central

Ogawa, Kazuma; Ishizaki, Atsushi; Takai, Kenichiro; Kitamura, Yoji; Kiwada, Tatsuto; Shiba, Kazuhiro; Odani, Akira

2013-01-01

68Ga (T 1/2 = 68 min, a generator-produced nuclide) has great potential as a radionuclide for clinical positron emission tomography (PET). Because poly-glutamic and poly-aspartic acids have high affinity for hydroxyapatite, to develop new bone targeting 68Ga-labeled bone imaging agents for PET, we used 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) as a chelating site and conjugated aspartic acid peptides of varying lengths. Subsequently, we compared Ga complexes, Ga-DOTA-(Asp)n (n = 2, 5, 8, 11, or 14) with easy-to-handle 67Ga, with the previously described 67Ga-DOTA complex conjugated bisphosphonate, 67Ga-DOTA-Bn-SCN-HBP. After synthesizing DOTA-(Asp)n by a Fmoc-based solid-phase method, complexes were formed with 67Ga, resulting in 67Ga-DOTA-(Asp)n with a radiochemical purity of over 95% after HPLC purification. In hydroxyapatite binding assays, the binding rate of 67Ga-DOTA-(Asp)n increased with the increase in the length of the conjugated aspartate peptide. Moreover, in biodistribution experiments, 67Ga-DOTA-(Asp)8, 67Ga-DOTA-(Asp)11, and 67Ga-DOTA-(Asp)14 showed high accumulation in bone (10.5±1.5, 15.1±2.6, and 12.8±1.7% ID/g, respectively) but were barely observed in other tissues at 60 min after injection. Although bone accumulation of 67Ga-DOTA-(Asp)n was lower than that of 67Ga-DOTA-Bn-SCN-HBP, blood clearance of 67Ga-DOTA-(Asp)n was more rapid. Accordingly, the bone/blood ratios of 67Ga-DOTA-(Asp)11 and 67Ga-DOTA-(Asp)14 were comparable with those of 67Ga-DOTA-Bn-SCN-HBP. In conclusion, these data provide useful insights into the drug design of 68Ga-PET tracers for the diagnosis of bone disorders, such as bone metastases. PMID:24391942

Effect of glutamate, aspartate and related derivatives on cerebellar Purkinje cell dendrites in the rat: an in vitro study

PubMed Central

Crepel, F.; Dhanjal, S. S.; Sears, T. A.

1982-01-01

1. The responses of Purkinje cells to short duration (pulse) ionophoretic applications of L-aspartate (L-asp), L-glutamate (L-glu), N-methyl DL-aspartate (NMDLA) and quisqualic acid in their dendritic fields were studied in vitro on sagittal slices of lobules IX and X of the adult rat cerebellum. 2. Pulse application of L-asp or L-glu evoked transient and dose-dependent increases in the firing rate of the simple spikes recorded extracellularly as single units. When the ionophoretic electrode was positioned in the dendritic field of the Purkinje cells, the lowest thresholds for L-glu and L-asp mediated excitations of the cells were as low as 25 and 35 pC respectively, with a latency for maximal responses as brief as 7 ms. 3. In intracellular recordings these excitatory responses consisted of depolarizations of up to 18 mV in amplitude and with depolarizing slopes up to 0·52 mV/ms. They were generally unaccompanied by changes in cell input resistance in contrast to the marked decrease which occurred in response to steady applications of large doses of L-asp and L-glu. 4. The spatial distribution of the excitatory sites confirmed that the dendritic sensitivity to L-glu was greater than that of the soma and showed that the same was true for L-asp. In 34% of cells the sensitivity for L-asp declined markedly in the upper region of the molecular layer, whereas it remained high for L-glu; no such differential sensitivity was detected in the remaining 66% of cells. 5. Inhibitory responses, antagonized by 10-5 M-bicuculline in the bath, were also induced in Purkinje cells by L-glu and L-asp when the ionophoretic electrode was withdrawn from the excitatory sites by as little as 8 μm and up to 40 μm upward or downward along the track of parallel fibres or positioned as far as 250 μm laterally. 6. Whenever it was applied in the molecular layer, the pulse application of NMDLA elicited no excitatory response in Purkinje cells recorded extra or intracellularly. However, slow depolarizations accompanied by a slight increase in cell input resistance were obtained with steady applications of 20-50 nA of the drug for 20-30 s. 7. In contrast, pulse application of quisqualic acid appeared to have the same type of fast excitatory effect on Purkinje cells as L-asp and L-glu, but its potency was greater and its action more prolonged. Furthermore, its steady application led to an abrupt and marked decrease in cell membrane resistance. 8. The excitatory effects of L-asp, L-glu and quisqualic acid were antagonized by L-glutamic acid diethyl ester more consistently than by D-α-aminoadipate, suggesting together with previous observations that L-asp and L-glu act on Purkinje cells via quisqualic acid rather than via NMDLA receptors. PMID:6754909

Conserved Asp-137 is important for both structure and regulatory functions of cardiac α-tropomyosin (α-TM) in a novel transgenic mouse model expressing α-TM-D137L.

PubMed

Yar, Sumeyye; Chowdhury, Shamim A K; Davis, Robert T; Kobayashi, Minae; Monasky, Michelle M; Rajan, Sudarsan; Wolska, Beata M; Gaponenko, Vadim; Kobayashi, Tomoyoshi; Wieczorek, David F; Solaro, R John

2013-06-07

α-Tropomyosin (α-TM) has a conserved, charged Asp-137 residue located in the hydrophobic core of its coiled-coil structure, which is unusual in that the residue is found at a position typically occupied by a hydrophobic residue. Asp-137 is thought to destabilize the coiled-coil and so impart structural flexibility to the molecule, which is believed to be crucial for its function in the heart. A previous in vitro study indicated that the conversion of Asp-137 to a more typical canonical Leu alters flexibility of TM and affects its in vitro regulatory functions. However, the physiological importance of the residue Asp-137 and altered TM flexibility is unknown. In this study, we further analyzed structural properties of the α-TM-D137L variant and addressed the physiological importance of TM flexibility in cardiac function in studies with a novel transgenic mouse model expressing α-TM-D137L in the heart. Our NMR spectroscopy data indicated that the presence of D137L introduced long range rearrangements in TM structure. Differential scanning calorimetry measurements demonstrated that α-TM-D137L has higher thermal stability compared with α-TM, which correlated with decreased flexibility. Hearts of transgenic mice expressing α-TM-D137L showed systolic and diastolic dysfunction with decreased myofilament Ca(2+) sensitivity and cardiomyocyte contractility without changes in intracellular Ca(2+) transients or post-translational modifications of major myofilament proteins. We conclude that conversion of the highly conserved Asp-137 to Leu results in loss of flexibility of TM that is important for its regulatory functions in mouse hearts. Thus, our results provide insight into the link between flexibility of TM and its function in ejecting hearts.

Conserved Asp-137 Is Important for both Structure and Regulatory Functions of Cardiac α-Tropomyosin (α-TM) in a Novel Transgenic Mouse Model Expressing α-TM-D137L*

PubMed Central

Yar, Sumeyye; Chowdhury, Shamim A. K.; Davis, Robert T.; Kobayashi, Minae; Monasky, Michelle M.; Rajan, Sudarsan; Wolska, Beata M.; Gaponenko, Vadim; Kobayashi, Tomoyoshi; Wieczorek, David F.; Solaro, R. John

2013-01-01

α-Tropomyosin (α-TM) has a conserved, charged Asp-137 residue located in the hydrophobic core of its coiled-coil structure, which is unusual in that the residue is found at a position typically occupied by a hydrophobic residue. Asp-137 is thought to destabilize the coiled-coil and so impart structural flexibility to the molecule, which is believed to be crucial for its function in the heart. A previous in vitro study indicated that the conversion of Asp-137 to a more typical canonical Leu alters flexibility of TM and affects its in vitro regulatory functions. However, the physiological importance of the residue Asp-137 and altered TM flexibility is unknown. In this study, we further analyzed structural properties of the α-TM-D137L variant and addressed the physiological importance of TM flexibility in cardiac function in studies with a novel transgenic mouse model expressing α-TM-D137L in the heart. Our NMR spectroscopy data indicated that the presence of D137L introduced long range rearrangements in TM structure. Differential scanning calorimetry measurements demonstrated that α-TM-D137L has higher thermal stability compared with α-TM, which correlated with decreased flexibility. Hearts of transgenic mice expressing α-TM-D137L showed systolic and diastolic dysfunction with decreased myofilament Ca2+ sensitivity and cardiomyocyte contractility without changes in intracellular Ca2+ transients or post-translational modifications of major myofilament proteins. We conclude that conversion of the highly conserved Asp-137 to Leu results in loss of flexibility of TM that is important for its regulatory functions in mouse hearts. Thus, our results provide insight into the link between flexibility of TM and its function in ejecting hearts. PMID:23609439

Dietary aspartyl-phenylalanine-1-methyl ester delays osteoarthritis and prevents associated bone loss in STR/ORT mice

PubMed Central

Manion, Carl V.; Hochgeschwender, Ute; Edmundson, Allen B.; Hugli, Tony E.

2011-01-01

Objective. STR/ORT mice provide a well-known model for murine idiopathic OA, with histological joint lesions resembling those of human OA. This model was used to investigate protective effects of the dipeptide aspartyl-phenylalanine-1-methyl ester (Asp-Phe-OMe or aspartame) via the oral route vs a regular diet. Methods. STR/ORT mice were housed individually and fed diets with or without Asp-Phe-OMe (4 mg/kg), after weaning at the age of 3 weeks, until 15 months of age (average of 20 animals per group). The study groups were kept blinded to the investigators, who measured food consumption and body weight and performed gait mobility tests. Radiographic scans were also performed at regular time intervals to evaluate differential radiographic anomalies associated with progress of OA in response to oral Asp-Phe-OMe therapy. Results. The Asp-Phe-OMe-fed animals presented a pattern of significantly delayed disease onset. In addition, their muscle and bone mass were highly preserved, even at later time points after OA was established. Moreover, control animals presented a higher variability in gait motility in comparison with the Asp-Phe-OMe-fed animals, suggesting a protective effect from movement limitations associated with advanced OA. Conclusion. Asp-Phe-OMe, given orally, delays OA in the spontaneous STR/ORT model, improves bone cortical density and muscle mass, and may contribute to a better quality of life for these diseased animals. PMID:21372000

Airspace Systems Program: Next Generation Air Transportation System, NextGen Systems Analysis, Integration and Evaluation Project. Version 1.0; Project Plan

NASA Technical Reports Server (NTRS)

Quon, Leighton

2010-01-01

The key objectives of the NASA ASP are to: Improve mobility, capacity efficiency and access of the airspace system. Improve collaboration, predictability, and flexibility for the airspace users. Enable accurate modeling and simulation of air transportation systems. Accommodate operations of all classes of aircraft. Maintain system safety and environmental protection. In support of these program objectives, the major goal of the NextGen-SAIE Project is to enable the transition of key capacity and efficiency improvements to the NAS. Since many aspects of the NAS are unique to specific airport or airspace environments, demand on various parts of the NAS is not expected to increase equally as system demand grows. SAIE will provide systems level analysis of the NAS characteristics, constraints, and demands such that a suite of capacity-increasing concepts and technologies for system solutions are enabled and facilitated. The technical objectives in support of this goal are the following: Integration, evaluation, and transition of more mature concepts and technologies in an environment that faithfully emulates real-world complexities. Interoperability research and analysis of ASP technologies across ATM functions is performed to facilitate integration and take ASP concepts and technologies to higher Technology Readiness Level (TRL). Analyses are conducted on the program s concepts to identify the system benefits or impacts. System level analysis is conducted to increase understanding of the characteristics and constraints of airspace system and its domains.

Efficacy and safety of native versus pegylated Escherichia coli asparaginase for treatment of adults with high-risk, Philadelphia chromosome-negative acute lymphoblastic leukemia.

PubMed

Ribera, Josep-Maria; Morgades, Mireia; Montesinos, Pau; Martino, Rodrigo; Barba, Pere; Soria, Beatriz; Bermúdez, Arancha; Moreno, María-José; González-Campos, José; Vives, Susana; Gil, Cristina; Abella, Eugenia; Guàrdia, Ramon; Martínez-Carballeira, Daniel; Martínez-Sánchez, Pilar; Amigo, María-Luz; Mercadal, Santiago; Serrano, Alfons; López-Martínez, Aurelio; Vall-Llovera, Ferran; Sánchez-Sánchez, María-José; Peñarrubia, María-Jesús; Calbacho, María; Méndez, Jose-Angel; Bergua, Juan; Cladera, Antonia; Tormo, Mar; García-Belmonte, Daniel; Feliu, Evarist; Ciudad, Juana; Orfao, Alberto

2017-11-22

Native or pegylated (PEG) asparaginase (ASP) are commonly used in treatment of acute lymphoblastic leukemia (ALL), but have been scarcely compared in the same trial in adult patients. Native vs. PEG-ASP administered according to availability in each center were prospectively evaluated in adults with high-risk ALL. Ninety-one patients received native ASP and 35 PEG-ASP in induction. No significant differences were observed in complete remission, minimal residual disease levels after induction and after consolidation, disease-free survival, and overall survival. No significant differences in grades 3-4 toxicity were observed in the induction period, although a trend for higher hepatic toxicity was observed in patients receiving PEG-ASP. In this trial the type of ASP did not influence patient response and outcome.

Anaphylactic reaction to polyethylene-glycol conjugated-asparaginase: premedication and desensitization may not be sufficient.

PubMed

Sahiner, Umit M; Yavuz, S Tolga; Gökce, Muge; Buyuktiryaki, Betul; Altan, Ilhan; Aytac, Selin; Tuncer, Murat; Tuncer, Ayfer; Sackesen, Cansin

2013-08-01

In hypersensitive reactions to native L-asparaginase, either premedication and desensitization or substitution with polyethylene glycol conjugated asparaginase (PEG-ASP) is preferred. Anaphylaxis with PEG-ASP is rare. An 8-year-old girl and a 2.5-year-old boy, both diagnosed as having acute lymphoblastic leukemia, presented with native L-asparaginase hypersensitivity and substitution with PEG-ASP was preferred. They received a premedication (methylprednisolone, hydroxyzine and ranitidine) followed by desensitization with PEG-ASP infusion. Both patients developed anaphylaxis with peg-asparaginase. These are the first reported cases of anaphylactic reaction to PEG-ASP, despite the application of both premedication and desensitization. Anaphylaxis with PEG-ASP is very rare and premedication and desensitization protocols may not prevent these hypersensitive reactions. © 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.

Unraveling the sequence of cytosolic reactions in the export of GspB adhesin from Streptococcus gordonii

PubMed Central

Chen, Yu; Bensing, Barbara A.; Seepersaud, Ravin; Mi, Wei; Liao, Maofu; Jeffrey, Philip D.; Shajahan, Asif; Sonon, Roberto N.; Azadi, Parastoo; Sullam, Paul M.; Rapoport, Tom A.

2018-01-01

Many pathogenic bacteria, including Streptococcus gordonii, possess a pathway for the cellular export of a single serine-rich-repeat protein that mediates the adhesion of bacteria to host cells and the extracellular matrix. This adhesin protein is O-glycosylated by several cytosolic glycosyltransferases and requires three accessory Sec proteins (Asp1–3) for export, but how the adhesin protein is processed for export is not well understood. Here, we report that the S. gordonii adhesin GspB is sequentially O-glycosylated by three enzymes (GtfA/B, Nss, and Gly) that attach N-acetylglucosamine and glucose to Ser/Thr residues. We also found that modified GspB is transferred from the last glycosyltransferase to the Asp1/2/3 complex. Crystal structures revealed that both Asp1 and Asp3 are related to carbohydrate-binding proteins, suggesting that they interact with carbohydrates and bind glycosylated adhesin, a notion that was supported by further analyses. We further observed that Asp1 also has an affinity for phospholipids, which is attenuated by Asp2. In summary, our findings support a model in which the GspB adhesin is sequentially glycosylated by GtfA/B, Nss, and Gly and then transferred to the Asp1/2/3 complex in which Asp1 mediates the interaction of the Asp1/2/3 complex with the lipid bilayer for targeting of matured GspB to the export machinery. PMID:29462788

Unraveling the sequence of cytosolic reactions in the export of GspB adhesin from Streptococcus gordonii.

PubMed

Chen, Yu; Bensing, Barbara A; Seepersaud, Ravin; Mi, Wei; Liao, Maofu; Jeffrey, Philip D; Shajahan, Asif; Sonon, Roberto N; Azadi, Parastoo; Sullam, Paul M; Rapoport, Tom A

2018-04-06

Many pathogenic bacteria, including Streptococcus gordonii , possess a pathway for the cellular export of a single serine-rich-repeat protein that mediates the adhesion of bacteria to host cells and the extracellular matrix. This adhesin protein is O -glycosylated by several cytosolic glycosyltransferases and requires three accessory Sec proteins (Asp1-3) for export, but how the adhesin protein is processed for export is not well understood. Here, we report that the S. gordonii adhesin GspB is sequentially O -glycosylated by three enzymes (GtfA/B, Nss, and Gly) that attach N -acetylglucosamine and glucose to Ser/Thr residues. We also found that modified GspB is transferred from the last glycosyltransferase to the Asp1/2/3 complex. Crystal structures revealed that both Asp1 and Asp3 are related to carbohydrate-binding proteins, suggesting that they interact with carbohydrates and bind glycosylated adhesin, a notion that was supported by further analyses. We further observed that Asp1 also has an affinity for phospholipids, which is attenuated by Asp2. In summary, our findings support a model in which the GspB adhesin is sequentially glycosylated by GtfA/B, Nss, and Gly and then transferred to the Asp1/2/3 complex in which Asp1 mediates the interaction of the Asp1/2/3 complex with the lipid bilayer for targeting of matured GspB to the export machinery.

Drug release patterns and cytotoxicity of PEG-poly(aspartate) block copolymer micelles in cancer cells.

PubMed

Eckman, Allison M; Tsakalozou, Eleftheria; Kang, Nayon Y; Ponta, Andrei; Bae, Younsoo

2012-07-01

To test physicochemical and biological properties of PEG-poly(aspartate) [PEG-p(Asp)] block copolymer micelles entrapping doxorubicin hydrochloride (DOX) through ionic interaction. PEG-p(Asp) was synthesized from 5 kDa PEG and 20 Asp units. Carboxyl groups of p(Asp) were present as benzyl ester [PEG-p(Asp/Bz)], sodium salt [PEG-p(Asp/Na)] or free acid [PEG-p(Asp/H)]. Block copolymers and DOX were mixed at various ratios to prepare polymer micelles, which were subsequently characterized to determine particle size, drug loading and release patterns, and cytotoxicity against prostate (PC3 and DU145) and lung (A549) cancer cell lines. PEG-p(Asp/Bz), Na- and H-micelles entrapped 1.1, 56.8 and 40.6 wt.% of DOX, respectively. Na- and H-micelles (<100 nm) showed time-dependent DOX release at pH 7.4, which was accelerated at pH 5.0. Na-micelles were most stable at pH 7.4, retaining 31.8% of initial DOX for 48 h. Cytotoxicity of Na-micelles was 23.2% (A549), 28.5% (PC3) and 45.9% (DU145) more effective than free DOX. Ionic interaction appeared to entrap DOX efficiently in polymer micelles from PEG-p(Asp) block copolymers. Polymer micelles possessing counter ions (Na) of DOX in the core were the most stable, releasing drugs for prolonged time in a pH-dependent manner, and suppressing cancer cells effectively.

Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans.

PubMed

Kang, S; Brange, J; Burch, A; Vølund, A; Owens, D R

1991-11-01

To study the influence of molecular aggregation on rates of subcutaneous insulin absorption and to attempt to elucidate the mechanism of absorption of conventional soluble human insulin in humans. Seven healthy male volunteers aged 22-43 yr and not receiving any drugs comprised the study. This study consisted of a single-blind randomized comparison of equimolar dosages of 125I-labeled forms of soluble hexameric 2 Zn2+ human insulin and human insulin analogues with differing association states at pharmaceutical concentrations (AspB10, dimeric; AspB28, mixture of monomers and dimers; AspB9, GluB27, monomeric). After an overnight fast and a basal period of 1 h, 0.6 nmol/kg of either 125I-labeled human soluble insulin (Actrapid HM U-100) or 125I-labeled analogue was injected subcutaneously on 4 separate days 1 wk apart. Absorption was assessed by measurement of residual radioactivity at the injection site by external gamma-counting. The mean +/- SE initial fractional disappearance rates for the four preparations were 20.7 +/- 1.9 (hexameric soluble human insulin), 44.4 +/- 2.5 (dimeric analogue AspB10), 50.6 +/- 3.9 (analogue AspB28), and 67.4 +/- 7.4%/h (monomeric analogue AspB9, GluB27). Absorption of the dimeric analogue was significantly faster than that of hexameric human insulin (P less than 0.001); absorption of monomeric insulin analogue AspB9, GluB27 was significantly faster than that of dimeric analogue AspB10 (P less than 0.01). There was an inverse linear correlation between association state and the initial fractional disappearance rates (r = -0.98, P less than 0.02). Analysis of the disappearance data on a log linear scale showed that only the monomeric analogue had a monoexponential course throughout. Two phases in the rates of absorption were identified for the dimer and three for hexameric human insulin. The fractional disappearance rates (%/h) calculated by log linear regression analysis were monomer 73.3 +/- 6.8; dimer 44.4 +/- 2.5 from 0 to 2 h and 68.9 +/- 3.5 from 2.5 h onward; and hexameric insulin 20.7 +/- 1.9 from 0 to 2 h, 45.6 +/- 5.0 from 2.5 to 5 h, and 70.6 +/- 6.3 from 5 h onward. Association state is a major determinant of rates of absorption of insulin and insulin analogues. The lag phase and the subsequent increasing rate of subcutaneous soluble insulin absorption can be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process.

Prevention and Control of Multidrug-Resistant Gram-Negative Bacteria in Adult Intensive Care Units: A Systematic Review and Network Meta-analysis.

PubMed

Teerawattanapong, Nattawat; Kengkla, Kirati; Dilokthornsakul, Piyameth; Saokaew, Surasak; Apisarnthanarak, Anucha; Chaiyakunapruk, Nathorn

2017-05-15

This study evaluated the relative efficacy of strategies for the prevention of multidrug-resistant gram-negative bacteria (MDR-GNB) in adult intensive care units (ICUs). A systematic review and network meta-analysis was performed; searches of the Cochrane Library, PubMed, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) included all randomized controlled trials and observational studies conducted in adult patients hospitalized in ICUs and evaluating standard care (STD), antimicrobial stewardship program (ASP), environmental cleaning (ENV), decolonization methods (DCL), or source control (SCT), simultaneously. The primary outcomes were MDR-GNB acquisition, colonization, and infection; secondary outcome was ICU mortality. Of 3805 publications retrieved, 42 met inclusion criteria (5 randomized controlled trials and 37 observational studies), involving 62068 patients (median age, 58.8 years; median APACHE [Acute Physiology and Chronic Health Evaluation] II score, 18.9). The majority of studies reported extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and MDR Acinetobacter baumannii. Compared with STD, a 4-component strategy composed of STD, ASP, ENV, and SCT was the most effective intervention (rate ratio [RR], 0.05 [95% confidence interval {CI}, .01-.38]). When ENV was added to STD+ASP or SCT was added to STD+ENV, there was a significant reduction in the acquisition of MDR A. baumannii (RR, 0.28 [95% CI, .18-.43] and 0.48 [95% CI, .35-.66], respectively). Strategies with ASP as a core component showed a statistically significant reduction the acquisition of ESBL-producing Enterobacteriaceae (RR, 0.28 [95% CI, .11-.69] for STD+ASP+ENV and 0.23 [95% CI, .07-.80] for STD+ASP+DCL). A 4-component strategy was the most effective intervention to prevent MDR-GNB acquisition. As some strategies were differential for certain bacteria, our study highlighted the need for further evaluation of the most effective prevention strategies. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Effect of tetrapeptides Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly on the structure and function of the thyroid gland in neonatally hypophysectomized chickens.

PubMed

Kuznik, B I; Pateyuk, A V; Rusaeva, N S

2008-01-01

Tetrapeptides Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly were synthesized on the basis of amino acid composition of pituitary cytomedins. Administration of these tetrapeptides to hypophysectomized chickens for 40 days was followed by an increase in the concentrations of thyrotropic hormone and thyroid hormones and recovery of thyroid gland structure.

A Meta-Analysis of Differences in IQ Profiles between Individuals with Asperger's Disorder and High-Functioning Autism

ERIC Educational Resources Information Center

Chiang, Hsu-Min; Tsai, Luke Y.; Cheung, Ying Kuen; Brown, Alice; Li, Huacheng

2014-01-01

A meta-analysis was performed to examine differences in IQ profiles between individuals with Asperger's disorder (AspD) and high-functioning autism (HFA). Fifty-two studies were included for this study. The results showed that (a) individuals with AspD had significantly higher full-scale IQ, verbal IQ (VIQ), and performance IQ (PIQ) than did…

Elucidating the Role of Many-Body Forces in Liquid Water. I. Simulations of Water Clusters on the VRT (ASP-W) Potential Surfaces

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldman, N; Saykally, R J

We test the new VRT(ASP-W)II and VRT(ASP-W)III potentials by employing Diffusion Quantum Monte Carlo simulations to calculate the vibrational ground-state properties of water clusters. These potentials are fits of the highly detailed ASP-W ab initio potential to (D{sub 2}O){sub 2} microwave and far-IR data, and along with the SAPT5s potentials, are the most accurate water dimer potential surfaces in the literature. The results from VRT(ASP-W)II and III are compare to those from the original ASP-W potential, the SAPT5s family of potentials, and several bulk water potentials. Only VRT(ASP-W)II and the spectroscopically ''tuned'' SAPT5st (with N-body induction included) accurately reproduce themore » vibrational ground-state structures of water clusters up to the hexamer. Finally, the importance of many-body induction and three-body dispension are examined, and it is shown that the latter can have significant effects on water cluster properties despite its small magnitude.« less

Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter.

PubMed

Schophuizen, Carolien M S; Wilmer, Martijn J; Jansen, Jitske; Gustavsson, Lena; Hilgendorf, Constanze; Hoenderop, Joost G J; van den Heuvel, Lambert P; Masereeuw, Rosalinde

2013-12-01

Several organic cations, such as guanidino compounds and polyamines, have been found to accumulate in plasma of patients with kidney failure due to inadequate renal clearance. Here, we studied the interaction of cationic uremic toxins with renal organic cation transport in a conditionally immortalized human proximal tubule epithelial cell line (ciPTEC). Transporter activity was measured and validated in cell suspensions by studying uptake of the fluorescent substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium-iodide (ASP(+)). Subsequently, the inhibitory potencies of the cationic uremic toxins, cadaverine, putrescine, spermine and spermidine (polyamines), acrolein (polyamine breakdown product), guanidine, and methylguanidine (guanidino compounds) were determined. Concentration-dependent inhibition of ASP(+) uptake by TPA, cimetidine, quinidine, and metformin confirmed functional endogenous organic cation transporter 2 (OCT2) expression in ciPTEC. All uremic toxins tested inhibited ASP(+) uptake, of which acrolein required the lowest concentration to provoke a half-maximal inhibition (IC50 = 44 ± 2 μM). A Dixon plot was constructed for acrolein using three independent inhibition curves with 10, 20, or 30 μM ASP(+), which demonstrated competitive or mixed type of interaction (K i = 93 ± 16 μM). Exposing the cells to a mixture of cationic uremic toxins resulted in a more potent and biphasic inhibitory response curve, indicating complex interactions between the toxins and ASP(+) uptake. In conclusion, ciPTEC proves a suitable model to study cationic xenobiotic interactions. Inhibition of cellular uptake transport was demonstrated for several uremic toxins, which might indicate a possible role in kidney disease progression during uremia.

Poly aspartic acid peptide-linked PLGA based nanoscale particles: potential for bone-targeting drug delivery applications.

PubMed

Jiang, Tao; Yu, Xiaohua; Carbone, Erica J; Nelson, Clarke; Kan, Ho Man; Lo, Kevin W-H

2014-11-20

Delivering drugs specifically to bone tissue is very challenging due to the architecture and structure of bone tissue. Poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) hold great promise for the delivery of therapeutics to bone tissue. The goal of the present research was to formulate a PLGA-based NP drug delivery system for bone tissue exclusively. Since poly-aspartic acids (poly-Asp) peptide sequence has been shown to bind to hydroxyapatite (HA), and has been suggested as a molecular tool for bone-targeting applications, we fabricated PLGA-based NPs linked with poly-Asp peptide sequence. Nanoparticles made of methoxy - poly(ethylene glycol) (PEG)-PLGA and maleimide-PEG-PLGA were prepared using a water-in-oil-in-water double emulsion and solvent evaporation method. Fluorescein isothiocyanate (FITC)-tagged poly-Asp peptide was conjugated to the surface of the nanoparticles via the alkylation reaction between the sulfhydryl groups at the N-terminal of the peptide and the CC double bond of maleimide at one end of the polymer chain to form thioether bonds. The conjugation of FITC-tagged poly-Asp peptide to PLGA NPs was confirmed by NMR analysis and fluorescent microscopy. The developed nanoparticle system is highly aqueous dispersible with an average particle size of ∼80 nm. In vitro binding analyses demonstrated that FITC-poly-Asp NPs were able to bind to HA gel as well as to mineralized matrices produced by human mesenchymal stem cells and mouse bone marrow stromal cells. Using a confocal microscopy technique, an ex vivo binding study of mouse major organ ground sections revealed that the FITC-poly-Asp NPs were able to bind specifically to the bone tissue. In addition, proliferation studies indicated that our FITC-poly-Asp NPs did not induce cytotoxicity to human osteoblast-like MG63 cell lines. Altogether, these promising results indicated that this nanoscale targeting system was able to bind to bone tissue specifically and might have a great potential for bone disease therapy in clinical applications. Copyright © 2014 Elsevier B.V. All rights reserved.

After-School Program Engagement: Links to Child Competence and Program Quality and Content

ERIC Educational Resources Information Center

Mahoney, Joseph L; Parente, Maria E.; Lord, Heather

2007-01-01

This 2-year study assessed program-level differences in after-school program (ASP) engagement in relation to child competencies (effectance motivation, social competence, school grades) and program quality and content. Participants were 141 children (M age = 8.4 years) who attended 9 ASPs in an urban, disadvantaged city in the United States.…

Physical and Social-Motivational Contextual Correlates of Youth Physical Activity in Underresourced Afterschool Programs

ERIC Educational Resources Information Center

Zarrett, Nicole; Sorensen, Carl; Cook, Brittany Skiles

2015-01-01

Afterschool programs (ASPs) have become increasingly recognized as a key context to support youth daily physical activity (PA) accrual. The purpose of the present study was to assess the physical and social-motivational climate characteristics of ASPs associated with youth PA, and variations in contextual correlates of PA by youth sex. Systematic…

Making Healthy Eating and Physical Activity Policy Practice: Process Evaluation of a Group Randomized Controlled Intervention in Afterschool Programs

ERIC Educational Resources Information Center

Weaver, R. Glenn; Beets, Michael W.; Hutto, Brent; Saunders, Ruth P.; Moore, Justin B.; Turner-McGrievy, Gabrielle; Huberty, Jennifer L.; Ward, Dianne S.; Pate, Russell R.; Beighle, Aaron; Freedman, Darcy

2015-01-01

This study describes the link between level of implementation and outcomes from an intervention to increase afterschool programs' (ASPs) achievement of healthy eating and physical activity (HE-PA) Standards. Ten intervention ASPs implemented the Strategies-To-Enhance-Practice (STEPs), a multi-component, adaptive intervention framework identifying…

The Asp(327)Asn polymorphism in the sex hormone-binding globulin gene modifies the association of soy food and tea intake with endometrial cancer risk.

PubMed

Xu, Wang Hong; Zheng, Wei; Cai, Qiuyin; Cheng, Jia-Rong; Cai, Hui; Xiang, Yong-Bing; Shu, Xiao Ou

2008-01-01

We evaluated the interactive effect of polymorphisms in the sex hormone-binding globulin (SHBG) gene with soy isoflavones, tea consumption, and dietary fiber on endometrial cancer risk in a population-based, case-control study of 1,199 endometrial cancer patients and 1,212 controls. Genotyping of polymorphisms was performed by using TaqMan (Applied Biosystems, Foster City, CA) assays (rs6259) or the Affymetrix MegAllele Targeted Genotyping System (Affymetrix, Inc., US) (rs13894, rs858521, and rs2955617). Dietary information was obtained using a validated food frequency questionnaire. A logistic regression model was employed to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs). We found that the Asp(327)Asn (rs6259) polymorphism was associated with decreased risk of endometrial cancer, particularly among postmenopausal women (OR = 0.79, 95% CI = 0.62-1.00). This single nucleotide polymorphism (SNP) modified associations of soy isoflavones and tea consumption but not fiber intake with endometrial cancer, with the inverse association of soy intake and tea consumption being more evident for those with the Asp/Asp genotype of the SHBG gene at Asp(327)Asn (rs6259), particularly premenopausal women (P(interaction) = 0.06 and 0.02, respectively, for soy isoflavones and tea intake). This study suggests that gene-diet interaction may play an important role in the etiology of endometrial cancer risk.

Fatigue and fatigue-related symptoms in patients treated for different causes of hypothyroidism.

PubMed

Louwerens, Marloes; Appelhof, Bente C; Verloop, Herman; Medici, Marco; Peeters, Robin P; Visser, Theo J; Boelen, Anita; Fliers, Eric; Smit, Johannes W A; Dekkers, Olaf M

2012-12-01

Research on determinants of well-being in patients on thyroid hormone replacement therapy is warranted, as persistent fatigue-related complaints are common in this population. In this study, we evaluated the impact of different states of hypothyroidism on fatigue and fatigue-related symptoms. Furthermore, the relationship between fatigue and the TSH receptor (TSHR)-Asp727Glu polymorphism, a common genetic variant of the TSHR, was analyzed. A cross-sectional study was performed in 278 patients (140 patients treated for differentiated thyroid carcinoma (DTC) and 138 with autoimmune hypothyroidism (AIH)) genotyped for the TSHR-Asp727Glu polymorphism. The multidimensional fatigue inventory (MFI-20) was used to assess fatigue, with higher MFI-20 scores indicating more fatigue-related complaints. MFI-20 scores were related to disease status and Asp727Glu polymorphism status. AIH patients scored significantly higher than DTC patients on all five MFI-20 subscales (P<0.001), independent of clinical and thyroid hormone parameters. The frequency of the TSHR-Glu727 allele was 7.2%. Heterozygous DTC patients had more favorable MFI-20 scores than wild-type DTC patients on four of five subscales. The modest effect of the TSHR-Asp727Glu polymorphism on fatigue was found in DTC patients only. AIH patients had significantly higher levels of fatigue compared with DTC patients, which could not be attributed to clinical or thyroid hormone parameters. The modest effect of the TSHR-Asp727Glu polymorphism on fatigue in DTC patients should be confirmed in other cohorts.

β-Lactam Therapy for Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Comparative Review of Cefazolin versus Antistaphylococcal Penicillins.

PubMed

Li, Julius; Echevarria, Kelly L; Traugott, Kristi A

2017-03-01

Methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia is associated with high morbidity and mortality. Traditionally, antistaphylococcal penicillins (ASPs) have been considered the agents of choice for the treatment of MSSA bacteremia. Vancomycin has been demonstrated to have poorer outcomes in several studies and is only recommended for patients with severe penicillin allergies. Although cefazolin is considered as an alternative to the ASPs for patients with nonsevere penicillin allergies, cefazolin offers several pharmacologic advantages over ASPs, such as more convenient dosing regimens, and antimicrobial stewardship programs are increasingly using cefazolin as the preferential agent for MSSA infections as part of cost-saving initiatives. Concerns about susceptibility to hydrolysis by type A β-lactamases, particularly at high inocula seen in deep-seated infections such as endocarditis; selective pressures from unnecessary gram-negative coverage; and lack of comparative clinical data have precluded recommending cefazolin as a first-line therapy for MSSA bacteremia. Recent clinical studies, however, have suggested similar clinical efficacy but better tolerability, with lower rates of discontinuation due to adverse drug reactions, of cefazolin compared with ASPs. Other variables, such as adequate source control (e.g., intravascular catheter removal, debridement, or drainage) and enhanced pharmacodynamics through aggressive cefazolin dosing, may mitigate the role of cefazolin inoculum effect and factor into determining improved clinical outcomes. In this review, we highlight the utility of cefazolin versus ASPs in the treatment of MSSA bacteremia with a focus on clinical efficacy and safety. © 2017 Pharmacotherapy Publications, Inc.

Low acylation stimulating protein levels are associated with cardiometabolic disorders–secondary to autoimmune activation?

PubMed Central

Onat, Altan; Altay, Servet; Yüksel, Murat; Karadeniz, Yusuf; Can, Günay; Yüksel, Hüsniye; Ademoğlu, Evin

2017-01-01

Objective: We investigated the possible association of serum acylation stimulating protein (ASP) with cardiometabolic disorders and the evidence of autoimmune activation. Methods: Population-based randomly selected 1024 participants were cross-sectionally and prospectively analyzed. ASP concentrations were measured with a validated ELISA kit. Correlations were sought separately in subjects with no cardiometabolic disorders (n=427) designated as “healthy.” Results: ASP was positively correlated with total testosterone and inversely correlated with platelet activating factor (PAF), PAF-acetylhydrolase (AH), in each gender, and positively correlated in “healthy” men with lipoprotein [Lp](a) and apolipoprotein B. Correlations of ASP with PAF values ≥22 nmol/L were abolished, contrasted to a strongly inverse one in subjects with PAF <22 nmol/L. In linear regression analyses in the whole sample, ASP was inversely associated independently with PAF and PAF-AH and, in men, positively with Lp(a) and sex hormone-binding globulin. Prevalent and (at 2.0 years’ follow-up) incident metabolic syndrome (MetS, n=393), diabetes (n=154), and coronary heart disease (CHD, n=171) were analyzed by sex-, age-, and Lp(a)-adjusted logistic regression, using tertiles of ASP and PAF. The lower two (<42 nmol/L) ASP tertiles were a risk factor in combined sexes for MetS and diabetes. In women, incident CHD was predicted by either reduced or elevated ASP tertiles. Conclusion: Findings can be explained by the notion of operation of immune responses against both ASP and oxidized PAF-like lipids of Lp(a) to yield for “reduced” values and increased likelihood of cardiometabolic disorders. PMID:27599666

Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles.

PubMed

Terlizzi, Vito; Castaldo, Giuseppe; Salvatore, Donatello; Lucarelli, Marco; Raia, Valeria; Angioni, Adriano; Carnovale, Vincenzo; Cirilli, Natalia; Casciaro, Rosaria; Colombo, Carla; Di Lullo, Antonella Miriam; Elce, Ausilia; Iacotucci, Paola; Comegna, Marika; Scorza, Manuela; Lucidi, Vincenzina; Perfetti, Anna; Cimino, Roberta; Quattrucci, Serena; Seia, Manuela; Sofia, Valentina Maria; Zarrilli, Federica; Amato, Felice

2017-04-01

The effect of complex alleles in cystic fibrosis (CF) is poorly defined for the lack of functional studies. To describe the genotype-phenotype correlation and the results of either in vitro and ex vivo studies performed on nasal epithelial cells (NEC) in a cohort of patients with CF carrying cystic fibrosis transmembrane conductance regulator ( CFTR ) complex alleles. We studied 70 homozygous, compound heterozygous or heterozygous for CFTR mutations: p.[Arg74Trp;Val201Met;Asp1270Asn], n=8; p.[Ile148Thr;Ile1023_Val1024del], n=5; p.[Arg117Leu;Leu997Phe], n=6; c.[1210-34TG[12];1210-12T[5];2930C>T], n=3; p.[Arg74Trp;Asp1270Asn], n=4; p.Asp1270Asn, n=2; p.Ile148Thr, n=6; p.Leu997Phe, n=36. In 39 patients, we analysed the CFTR gating activity on NEC in comparison with patients with CF (n=8) and carriers (n=4). Finally, we analysed in vitro the p.[Arg74Trp;Val201Met;Asp1270Asn] complex allele. The p.[Ile148Thr;Ile1023_Val1024del] caused severe CF in five compound heterozygous with a class I-II mutation. Their CFTR activity on NEC was comparable with patients with two class I-II mutations (mean 7.3% vs 6.9%). The p.[Arg74Trp;Asp1270Asn] and the p.Asp1270Asn have scarce functional effects, while p.[Arg74Trp;Val201Met;Asp1270Asn] caused mild CF in four of five subjects carrying a class I-II mutation in trans , or CFTR-related disorders (CFTR-RD) in three having in trans a class IV-V mutation. The p.[Arg74Trp;Val201Met;Asp1270Asn] causes significantly (p<0.001) higher CFTR activity compared with compound heterozygous for class I-II mutations. Furthermore, five of six compounds heterozygous with the p.[Arg117Leu;Leu997Phe] had mild CF, whereas the p.Leu997Phe, in trans with a class I-II CFTR mutation, caused CFTR-RD or a healthy status (CFTR activity: 21.3-36.9%). Finally, compounds heterozygous for the c.[1210-34TG[12];1210-12T[5];2930C>T] and a class I-II mutation had mild CF or CFTR-RD (gating activity: 18.5-19.0%). The effect of complex alleles partially depends on the mutation in trans . Although larger studies are necessary, the CFTR activity on NEC is a rapid contributory tool to classify patients with CFTR dysfunction. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Microstructure simulation of rapidly solidified ASP30 high-speed steel particles by gas atomization

NASA Astrophysics Data System (ADS)

Ma, Jie; Wang, Bo; Yang, Zhi-liang; Wu, Guang-xin; Zhang, Jie-yu; Zhao, Shun-li

2016-03-01

In this study, the microstructure evolution of rapidly solidified ASP30 high-speed steel particles was predicted using a simulation method based on the cellular automaton-finite element (CAFE) model. The dendritic growth kinetics, in view of the characteristics of ASP30 steel, were calculated and combined with macro heat transfer calculations by user-defined functions (UDFs) to simulate the microstructure of gas-atomized particles. The relationship among particle diameter, undercooling, and the convection heat transfer coefficient was also investigated to provide cooling conditions for simulations. The simulated results indicated that a columnar grain microstructure was observed in small particles, whereas an equiaxed microstructure was observed in large particles. In addition, the morphologies and microstructures of gas-atomized ASP30 steel particles were also investigated experimentally using scanning electron microscopy (SEM). The experimental results showed that four major types of microstructures were formed: dendritic, equiaxed, mixed, and multi-droplet microstructures. The simulated results and the available experimental data are in good agreement.

Antibiotic Stewardship in Small Hospitals: Barriers and Potential Solutions.

PubMed

Stenehjem, Edward; Hyun, David Y; Septimus, Ed; Yu, Kalvin C; Meyer, Marc; Raj, Deepa; Srinivasan, Arjun

2017-08-15

Antibiotic stewardship programs (ASPs) improve antibiotic prescribing. Seventy-three percent of US hospitals have <200 beds. Small hospitals (<200 beds) have similar rates of antibiotic prescribing compared to large hospitals, but the majority of small hospitals lack ASPs that satisfy the Centers for Disease Control and Prevention's core elements. All hospitals, regardless of size, are now required to have ASPs by The Joint Commission, and the Centers for Medicare and Medicaid Services has proposed a similar requirement. Very few studies have described the successful implementation of ASPs in small hospitals. We describe barriers commonly encountered in small hospitals when constructing an antibiotic stewardship team, obtaining appropriate metrics of antibiotic prescribing, implementing antibiotic stewardship interventions, obtaining financial resources, and utilizing the microbiology laboratory. We propose potential solutions that tailor stewardship activities to the needs of the facility and the resources typically available. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Array Simulations Platform (ASP) predicts NASA Data Link Module (NDLM) performance

NASA Technical Reports Server (NTRS)

Snook, Allen David

1993-01-01

Through a variety of imbedded theoretical and actual antenna patterns, the array simulation platform (ASP) enhanced analysis of the array antenna pattern effects for the KTx (Ku-Band Transmit) service of the NDLM (NASA Data Link Module). The ASP utilizes internally stored models of the NDLM antennas and can develop the overall pattern of antenna arrays through common array calculation techniques. ASP expertly assisted in the diagnosing of element phase shifter errors during KTx testing and was able to accurately predict the overall array pattern from combinations of the four internally held element patterns. This paper provides an overview of the use of the ASP software in the solving of array mis-phasing problems.

Effect of short peptides on expression of signaling molecules in organotypic pineal cell culture.

PubMed

Khavinson, V Kh; Linkova, N S; Chalisova, N I; Dudkov, A V; Koncevaya, E A

2011-11-01

We demonstrated the influence of short peptides on the expression of signaling molecules in organotypic culture of the pineal gland from 3-month-old rats. Peptides Ala-Glu-Asp-Gly and Lys-Glu-Asp stimulate the expression of proliferative protein Ki-67 in pineal gland culture. These peptides as well as Glu-Asp-Arg and Lys-Glu do not affect the expression of apoptosis marker AIF. The synthesis of transcription factor CGRP by pinealocytes was stimulated only by Ala-Glu-Asp-Gly. Thus, peptide Ala-Glu-Asp-Gly tissue-specifically stimulates proliferative and secretory activities of pinealocytes, which can be used for recovery of pineal gland functions at the molecular level.

Pilot-scale comparison of thermophilic aerobic suspended carrier biofilm process and activated sludge process in pulp and paper mill effluent treatment.

PubMed

Suvilampi, J E; Rintala, J A

2004-01-01

Thermophilic aerobic treatment of settled pulp and paper mill effluent was studied under mill premises with two comparative pilot processes; suspended carrier biofilm process (SCBP) and activated sludge process (ASP). Full-scale mesophilic activated sludge process was a reference treatment. During the runs (61 days) hydraulic retention times (HRTs) were kept 13+/-5 h and 16+/-6 h for SCBP and ASP, respectively. Corresponding volumetric loadings rates (VLR) were 2.7+/-0.9 and 2.2+/-1.0 kg CODfilt m(-3)d(-1). Temperatures varied between 46 to 60 degrees C in both processes. Mesophilic ASP was operated with HRT of 36 h, corresponding VLR of 0.7 kg CODfilt m(-3)d(-1). Both SCBP and ASP achieved CODfilt (GF/A filtered) removals up to 85%, while the mesophilic ASP removal was 89+/-2%. NTU values were markedly higher (100-300) in thermophilic effluents than in mesophilic effluent (30). Effluent turbidity was highly dependent on temperature; in batch experiment mesophilic effluent sample had NTU values of 30 and 60 at 35 degrees C and 55 degrees C, respectively. As a conclusion, both thermophilic treatments gave high CODfilt removals, which were close to mesophilic process removal and were achieved with less than half of HRT.

Compositional analysis of sulfated polysaccharides from sea cucumber (Stichopus japonicus) released by autolysis reaction.

PubMed

Song, Shuang; Wu, Sufeng; Ai, Chunqing; Xu, Xin; Zhu, Zhenjun; Cao, Chunyang; Yang, Jingfeng; Wen, Chengrong

2018-07-15

Autolysis is not only a major reason for postharvest quality deterioration of sea cucumber, but also a promising alternative for exogenous protease to produce peptides or polysaccharides. However, little has been known about the effects of autolysis on bioactive polysaccharides of sea cucumber. Concerning the quality and safety of sea cucumber products involved autolysis reaction, the present study focused on the chemical composition of sulfated polysaccharides (SPs) released by autolysis reaction. Chemical analysis indicated that after 3-day autolysis 63% of sulfated polysaccharides were liberated but with protein chains at their reducing ends. Then the composition of SP obtained by autolysis (A-SP) was compared with that of total SPs (T-SP) via a series of analysis techniques, including FTIR, 1 H NMR, HPLC and mass spectroscopy. As indicated by the results, fucan to fucosylated chondroitin sulfate ratio was found high in A-SP compared to T-SP, fucan with a lower molecular weight was the major fraction in A-SP, and the di-sulfated Fuc residue observed in T-SP was absent in A-SP. To conclude, A-SP differed greatly from T-SP in the chemical composition, suggesting possible changes on their bioactivities. Copyright © 2018. Published by Elsevier B.V.

Athlete support personnel and anti-doping: Knowledge, attitudes, and ethical stance.

PubMed

Mazanov, J; Backhouse, S; Connor, J; Hemphill, D; Quirk, F

2014-10-01

Athlete support personnel (ASP) failing to meet responsibilities under the World Anti-Doping Code risk sanction. It is unclear whether the poor knowledge of responsibilities seen in sports physicians and coaches applies to other ASP (e.g., administrators, chiropractors, family, nutritionists, physiotherapists, psychologists, and trainers). A purposive sample of Australian ASP (n = 292) responded to a survey on knowledge of anti-doping rules (35 true/false questions), ethical beliefs and practice, and attitudes toward performance enhancement. Some ASP declined to participate, claiming doping was irrelevant to their practice. Physicians were most knowledgeable (30.8/35), with family and trainers the least (26.0/35). ASP reported that improvements were needed to support anti-doping education (e.g., basis for anti-doping) and practice (e.g., rules). ASP also had a slightly negative attitude toward performance enhancement. Linear regression showed that being a sports physician, providing support at the elite level, and 15 years of experience influenced knowledge. The results confirm gaps in knowledge, suggesting that stronger engagement with ASP anti-doping education and practice is needed. Applying the principles of andragogy could help foster active engagement through emphasis on active inquiry, rather than passive reception of content. Future work on the context within which ASP experience anti-doping is needed, exploring acquisition and translation of knowledge into practice. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Insulin Degludec/Insulin Aspart Administered Once Daily at Any Meal, With Insulin Aspart at Other Meals Versus a Standard Basal-Bolus Regimen in Patients With Type 1 Diabetes

PubMed Central

Hirsch, Irl B.; Bode, Bruce; Courreges, Jean-Pierre; Dykiel, Patrik; Franek, Edward; Hermansen, Kjeld; King, Allen; Mersebach, Henriette; Davies, Melanie

2012-01-01

OBJECTIVE To evaluate efficacy and tolerability of a co-formulation of insulin degludec and insulin aspart (IDegAsp) with insulin aspart (IAsp) at other meals compared with basal-bolus therapy using insulin detemir (IDet) and IAsp. RESEARCH DESIGN AND METHODS Adults (n = 548) with type 1 diabetes (A1C 7.0–10.0%; BMI ≤35.0 kg/m2) were randomized 2:1 in a 26-week, multinational, parallel-group, treat-to-target trial to IDegAsp or IDet. IDegAsp was given with a meal, and IDet was given in the evening, with a second (breakfast) dose added if needed. RESULTS Non-inferiority for IDegAsp versus IDet was confirmed; A1C improved by 0.75% with IDegAsp and 0.70% with IDet to 7.6% in both groups (estimated treatment difference IDegAsp − IDet: –0.05% [95% CI –0.18 to 0.08]). There was no statistically significant difference between IDegAsp and IDet in the rates of severe hypoglycemia (0.33 and 0.42 episodes/patient-year, respectively) or overall confirmed (plasma glucose <3.1 mmol/L) hypoglycemia (39.17 and 44.34 episodes/patient-year, respectively). Nocturnal confirmed hypoglycemia rate was 37% lower with IDegAsp than IDet (3.71 vs. 5.72 episodes/patient-year, P < 0.05). Weight gain was 2.3 and 1.3 kg with IDegAsp and IDet, respectively (P < 0.05). Total insulin dose was 13% lower in the IDegAsp group (P < 0.0001). No treatment differences were detected in Health-Related Quality of Life, laboratory measurements, physical examination, vital signs, electrocardiograms, fundoscopy, or adverse events. CONCLUSIONS IDegAsp in basal-bolus therapy with IAsp at additional mealtimes improves overall glycemic control and was non-inferior to IDet, with a reduced risk of nocturnal hypoglycemia and fewer injections in comparison with IDet + IAsp basal-bolus therapy. PMID:22933438

Tumorigenesis of K-ras mutation in human endometrial carcinoma via upregulation of estrogen receptor.

PubMed

Tu, Zheng; Gui, Liming; Wang, Jianliu; Li, Xiaoping; Sun, Pengming; Wei, Lihui

2006-05-01

To investigate the tumorigenesis of mutant [12Asp]-K-ras in endometrial carcinoma and its relationship with ER. We constructed pcDI-[12Asp]K-ras4B by inserting full-length [12Asp]K-ras4B from human endometrial carcinoma Hec-1A cells, into pcDI vector. Cell proliferation of NIH3T3 after transfection with pcDI-[12Asp]K-ras4B was measured by MTT assay. The cell transformation was determined by colony formation and tumor nodule development. [12Asp]-K-ras4B-NIH3T3 cells were transfected with constitutively active pCMV-RafCAAX and dominant-negative pCMV-RafS621A. Cell growth was measured by MTT assay and [3H]thymidine incorporation. After transfected with pcDI-[12Asp]K-ras4B or pCMV-RafS621A, the cells were harvested for Western blot and reporter assay to determine the expression and transcriptional activity of ERalpha and ERbeta, respectively. [12Asp]-K-ras4B enhanced NIH3T3 cells proliferation after 48 h post-transfection (P < 0.05). More colonies were grown 10 days after incubating pcDI-[12Asp]-K-ras4B-NIH3T3 cells (13.48%) than pcDI-NIH3T3 (4.26%) or untreated NIH3T3 (2.33%). The pcDI-[12Asp]-K-ras4B-NIH3T3 cells injected to the nude mice Balb/C developed tumor nodules with poor-differentiated cells after 12 days. An increase of ERalpha and ERbeta was observed in pcDI-[12Asp]-K-ras4B-NIH3T3 cells. RafS621A downregulated ERalpha and ERbeta expression. Estrogen induced the ER transcriptional activity by 5-fold in pcDI-NIH3T3 cells, 13-fold in pcDI-[12Asp]K-ras4B-NIH3T3 and 19-fold in HEC-1A. RafS621A suppressed the ER transcriptional activity. K-ras mutation induces tumorigenesis in endometrium, and this malignant transformation involves Raf signaling pathway and ER.

Effects of aspirin on immobile behavior and endocrine and immune changes in the forced swimming test: comparison to fluoxetine and imipramine.

PubMed

Guan, Xi-ting; Shao, Feng; Xie, Xi; Chen, Lin; Wang, Weiwen

2014-09-01

Aspirin (ASP) is the most commonly used non-steroidal anti-inflammatory drug in the world. Recent clinical and preclinical evidence suggests that ASP may also exert psychoactive effects. It remains unclear whether ASP has antidepressant-like activity, and any molecular mechanisms underlying such activity have yet to be elucidated. Using the forced swimming test (FST), a well-established animal model of depression widely used to screen potential antidepressants in rodents, we investigated the effects of subacute treatment with ASP (0, 6, 12, 25, and 50mg/kg, i.p.) on immobility in the FST, and on FST-induced changes in endocrine and immune parameters in rats, in comparison to the clinical antidepressants imipramine (IMI) and fluoxetine (FLU). Serum levels of corticosterone, pro-inflammatory cytokine interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. ASP dose-dependently decreased immobility in the FST, without altering the locomotor activity in the open-field test. The inhibitory effects of higher doses (25 and 50mg/kg) of ASP on immobility were similar to that of FLU and IMI at a dose of 10mg/kg. In addition, the levels of corticosterone, IL-6, and TNF-α in peripheral blood were significantly increased after the FST exposure. IMI, but not FLU and ASP at any dose tested, significantly attenuated corticosterone responses in the FST. Both FLU and IMI treatment reduced the increase of IL-6 and TNF-α levels following the FST exposure. ASP dose-dependently decreased FST-induced increase of cytokine levels, as manifested by significantly stronger effects on IL-6 and TNF-α levels at higher doses (25 and 50mg/kg) than the lowest dose of ASP (6 mg/kg). In all, these results indicate that ASP treatment dose-dependently decreased the immobility time and the release of pro-inflammatory cytokines in the FST, suggesting that the anti-inflammatory effects of ASP might be involved in the antidepressant-like effect. Copyright © 2014 Elsevier Inc. All rights reserved.

Intercomparison of SOUP, ASP, LPSP, and MDI magnetograms

NASA Astrophysics Data System (ADS)

Berger, T.; Lites, B.; Martinez-Pillet, V.; Tarbell, T.; Title, A.

2001-05-01

We compare simultaneous magnetograms of a solar active region taken by the Advanced Stokes Polarimeter (ASP) and the Solar Optical Universal Polimeter (SOUP) in 1998. In addition we compare magnetograms taken by the La Palma Stokes Polarimeter (LPSP), the Michelson Doppler Imager (MDI) on SOHO, and the SOUP instrument in 2000. The SOUP instrument on the Swedish Vacuum Solar Telescope (SVST) attains the highest spatial resolution but has the least understood calibration; the ASP on the Dunn Solar Telescope (DST) at Sacramento Peak attains the highest magnetic field precision. The goal of the program is to better quantify the SOUP magnetograms and thereby study magnetic element dynamics in the photosphere with higher precision.

Substitution of the Lys Linker with the β-Ala Linker Dramatically Decreased the Renal Uptake of 99mTc-Labeled Arg-X-Asp-Conjugated and X-Ala-Asp-Conjugated α-Melanocyte Stimulating Hormone Peptides

PubMed Central

2015-01-01

The purpose of this study was to examine whether the substitution of the Lys linker with the β-Ala could reduce the renal uptake of 99mTc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated α-melanocyte stimulating hormone (α-MSH) peptides. RSD-β-Ala-(Arg11)CCMSH (1) {c[Arg-Ser-Asp-dTyr-Asp]-β-Ala-Cys-Cys-Glu-His-dPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2}, RTD-β-Ala-(Arg11)CCMSH (2), RVD-β-Ala-(Arg11)CCMSH (3), RAD-β-Ala-(Arg11)CCMSH (4), NAD-β-Ala-(Arg11)CCMSH (5), and EAD-β-Ala-(Arg11)CCMSH (6) peptides were synthesized and evaluated for their melanocortin 1 (MC1) receptor binding affinities in B16/F1 melanoma cells. The biodistribution of their 99mTc-conjugates were determined in B16/F1 melanoma-bearing C57 mice. The substitution of the Lys linker with β-Ala linker dramatically reduced the renal uptake of all six 99mTc-peptides. 99mTc-4 exhibited the highest melanoma uptake (15.66 ± 6.19% ID/g) and the lowest kidney uptake (20.18 ± 3.86% ID/g) among these 99mTc-peptides at 2 h postinjection. The B16/F1 melanoma lesions could be clearly visualized by single photon emission computed tomography (SPECT)/CT using 99mTc-4 as an imaging probe. PMID:25290883

Substitution of the Lys linker with the β-Ala linker dramatically decreased the renal uptake of 99mTc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated α-melanocyte stimulating hormone peptides.

PubMed

Flook, Adam M; Yang, Jianquan; Miao, Yubin

2014-11-13

The purpose of this study was to examine whether the substitution of the Lys linker with the β-Ala could reduce the renal uptake of (99m)Tc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated α-melanocyte stimulating hormone (α-MSH) peptides. RSD-β-Ala-(Arg(11))CCMSH (1) {c[Arg-Ser-Asp-dTyr-Asp]-β-Ala-Cys-Cys-Glu-His-dPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2}, RTD-β-Ala-(Arg(11))CCMSH (2), RVD-β-Ala-(Arg(11))CCMSH (3), RAD-β-Ala-(Arg(11))CCMSH (4), NAD-β-Ala-(Arg(11))CCMSH (5), and EAD-β-Ala-(Arg(11))CCMSH (6) peptides were synthesized and evaluated for their melanocortin 1 (MC1) receptor binding affinities in B16/F1 melanoma cells. The biodistribution of their (99m)Tc-conjugates were determined in B16/F1 melanoma-bearing C57 mice. The substitution of the Lys linker with β-Ala linker dramatically reduced the renal uptake of all six (99m)Tc-peptides. (99m)Tc-4 exhibited the highest melanoma uptake (15.66 ± 6.19% ID/g) and the lowest kidney uptake (20.18 ± 3.86% ID/g) among these (99m)Tc-peptides at 2 h postinjection. The B16/F1 melanoma lesions could be clearly visualized by single photon emission computed tomography (SPECT)/CT using (99m)Tc-4 as an imaging probe.

Communicating with Facility Leadership; Metrics for Successful Antimicrobial Stewardship Programs (Asp) in Acute Care and Long-Term Care Facilities.

PubMed

Beganovic, Maya; LaPlante, Kerry L

2018-06-01

Up to 50% of hospital-administered and 70% of nursing home-administered antimicrobials are inappropriately prescribed. There is a great need to focus local, national and global efforts on appropriate antibiotic use. Formal programs dedicated to appropriate antibiotic use have been established in most US hospitals. These antimicrobial stewardship programs (ASP) exist to ensure that the correct drug, dose and duration of an antimicrobial is given, and only when there is a true bacterial infection (as opposed to bacterial colonization or a viral infection). These programs increase patient safety and reduce unintended consequences including Clostridium difficile infections, medication-related adverse effects, and antimicrobial resistance. Most of these programs are co-lead by an interdisciplinary team consisting of an infectious diseases (ID) pharmacist and an ID physician. However, consistent and meaningful metrics to study the impact of ASPs have not been elucidated. With the Joint Commission Standards for Acute Care facilities, and Centers for Medicare and Medicare (CMS) for long-term care facilities making antimicrobial stewardship (AMS) a condition of participation, both facilities will be scrambling to create appropriate quality care indicators to measure program success. One major theme across all healthcare settings is that ASPs must collaborate with facility leadership and key stakeholders at each institution in order to have an impactful benefit on patient quality of care, and safety. It is the purpose of this review to offer several economic, process, and patient-outcome measurements for ASP to optimally communicate with facility leadership. [Full article available at http://rimed.org/rimedicaljournal-2018-06.asp].

Attenuated enzootic (pestoides) isolates of Yersinia pestis express active aspartase.

PubMed

Bearden, Scott W; Sexton, Christopher; Pare, Joshua; Fowler, Janet M; Arvidson, Cindy G; Yerman, Lyudmyla; Viola, Ronald E; Brubaker, Robert R

2009-01-01

It is established that Yersinia pestis, the causative agent of bubonic plague, recently evolved from enteropathogenic Yersinia pseudotuberculosis by undergoing chromosomal degeneration while acquiring two unique plasmids that facilitate tissue invasion (pPCP) and dissemination by fleabite (pMT). Thereafter, plague bacilli spread from central Asia to sylvatic foci throughout the world. These epidemic isolates exhibit a broad host range including man as opposed to enzootic (pestoides) variants that remain in ancient reservoirs where infection is limited to muroid rodents. Cells of Y. pseudotuberculosis are known to express glucose-6-phosphate dehydrogenase (Zwf) and aspartase (AspA); these activities are not detectable in epidemic Y. pestis due to missense mutations (substitution of proline for serine at amino position 155 of Zwf and leucine for valine at position 363 of AspA). In this study, functional Zwf was found in pestoides strains E, F and G but not seven other enzootic isolates; enzymic activity was associated with retention of serine at amino acid position 155. Essentially, full AspA activity occurred in pestoides isolates where valine (pestoides A, B, C and D) or serine (pestoides E, F, G and I) occupied position 363. Reduced activity occurred in strains Angola and A16, which contained phenylalanine at this position. The kcat but not Km of purified AspA from strain Angola was significantly reduced. In this context, aspA of the recently described attenuated enzootic microtus biovar encodes active valine at position 363, further indicating that functional AspA is a biomarker for avirulence of Y. pestis in man.

Large angle magnetic suspension test fixture

NASA Technical Reports Server (NTRS)

Britcher, Colin P.

1994-01-01

Over the past few decades, research has proven the feasibility of the concept of noncontacting magnetic bearing systems which operate with no wear or vibration. As a result, magnetic bearing systems are beginning to emerge as integral parts of modern industrial and aerospace systems. Further applications research is still required. NASA has loaned an existing magnetic bearing device, the Annular Suspension and Pointing System (ASPS), to ODU to permit student design teams the opportunity to pursue some of these studies. The ASPS is a protoype for a high-accuracy space payload pointing and vibration isolation system. The project objectives are to carry out modifications and improvements to the ASPS hardware to permit recommissioning in a 1-g (ground-based) environment. Following recommissioning, new applications will be studied and demonstrated, including a rotary joint for solar panels. The first teams designed and manufactured pole shims to reduce the air-gaps and raise the vertical force capability as well as on control system studies. The most recent team concentrated on the operation of a single bearing station, which was successfully accomplished with a PC-based digital controller. The paper will review the history and technical background of the ASPS hardware, followed by presentation of the progress made and the current status of the project.

Brief Report: Abnormal Association between the Thalamus and Brain Size in Asperger's Disorder

ERIC Educational Resources Information Center

Hardan, Antonio Y.; Girgis, Ragy R.; Adams, Jason; Gilbert, Andrew R.; Melhem, Nadine M.; Keshavan, Matcheri S.; Minshew, Nancy J.

2008-01-01

The objective of this study was to examine the relationship between thalamic volume and brain size in individuals with Asperger's disorder (ASP). Volumetric measurements of the thalamus were performed on MRI scans obtained from 12 individuals with ASP (age range: 10-35 years) and 12 healthy controls (age range: 9-33 years). A positive correlation…

A Comparison of Repetitive Behaviors in Aspergers Disorder and High Functioning Autism

ERIC Educational Resources Information Center

Cuccaro, Michael L.; Nations, Laura; Brinkley, Jason; Abramson, Ruth K.; Wright, Harry H.; Hall, Alicia; Gilbert, John; Pericak-Vance, Margaret A.

2007-01-01

In this study we compared 33 IQ and age matched pairs of individuals with Aspergers Disorder (ASP) and high functioning autism (HFA) on measures of repetitive behavior. On the Repetitive Behavior Scale-Revised (RBS-R), the ASP and HFA groups showed no differences in RBS-R Intensity score (severity) score or Frequency score (number of problems…

Implementing Accelerated Schools in New Orleans: The Satellite Center Project as an Agent of Change.

ERIC Educational Resources Information Center

Miron, Louis F.; And Others

An overview is provided of the Accelerated Schools Project (ASP) as implemented in one urban elementary school in New Orleans, emphasizing the role of the University of New Orleans Satellite Center. The present student population of the school studied is 405 students in grades pre-kindergarten through six. The ASP is a non-traditional strategy for…

Promoting Physical Activity within Under-Resourced Afterschool Programs: A Qualitative Investigation of Staff Experiences and Motivational Strategies for Engaging Youth

ERIC Educational Resources Information Center

Zarrett, Nicole; Abraczinskas, Michelle; Skiles Cook, Brittany; Wilson, Dawn K.; Ragaban, Faten

2018-01-01

Afterschool programs (ASPs) have become increasingly recognized as a key context to support youth daily physical activity (PA) accrual. Using Self-Determination Theory (SDT) as a framework, this study examined staff perspectives on the strengths and barriers within under-resourced ASPs for establishing a social-motivational climate for encouraging…

Probing electrostatic interactions and ligand binding in aspartyl-tRNA synthetase through site-directed mutagenesis and computer simulations.

PubMed

Thompson, Damien; Lazennec, Christine; Plateau, Pierre; Simonson, Thomas

2008-05-15

Faithful genetic code translation requires that each aminoacyl-tRNA synthetase recognise its cognate amino acid ligand specifically. Aspartyl-tRNA synthetase (AspRS) distinguishes between its negatively-charged Asp substrate and two competitors, neutral Asn and di-negative succinate, using a complex network of electrostatic interactions. Here, we used molecular dynamics simulations and site-directed mutagenesis experiments to probe these interactions further. We attempt to decrease the Asp/Asn binding free energy difference via single, double and triple mutations that reduce the net positive charge in the active site of Escherichia coli AspRS. Earlier, Glutamine 199 was changed to a negatively-charged glutamate, giving a computed reduction in Asp affinity in good agreement with experiment. Here, Lysine 198 was changed to a neutral leucine; then, Lys198 and Gln199 were mutated simultaneously. Both mutants are predicted to have reduced Asp binding and improved Asn binding, but the changes are insufficient to overcome the initial, high specificity of the native enzyme, which retains a preference for Asp. Probing the aminoacyl-adenylation reaction through pyrophosphate exchange experiments, we found no detectable activity for the mutant enzymes, indicating weaker Asp binding and/or poorer transition state stabilization. The simulations show that the mutations' effect is partly offset by proton uptake by a nearby histidine. Therefore, we performed additional simulations where the nearby Histidines 448 and 449 were mutated to neutral or negative residues: (Lys198Leu, His448Gln, His449Gln), and (Lys198Leu, His448Glu, His449Gln). This led to unexpected conformational changes and loss of active site preorganization, suggesting that the AspRS active site has a limited structural tolerance for electrostatic modifications. The data give insights into the complex electrostatic network in the AspRS active site and illustrate the difficulty in engineering charged-to-neutral changes of the preferred ligand. 2007 Wiley-Liss, Inc.

Aspergillus fumigatus proteases, Asp f 5 and Asp f 13, are essential for airway inflammation and remodelling in a murine inhalation model.

PubMed

Namvar, S; Warn, P; Farnell, E; Bromley, M; Fraczek, M; Bowyer, P; Herrick, S

2015-05-01

In susceptible individuals, exposure to Aspergillus fumigatus can lead to the development of atopic lung diseases such as allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS). Protease allergens including Asp f 5 and Asp f 13 from Aspergillus fumigatus are thought to be important for initiation and progression of allergic asthma. To assess the importance of secreted protease allergens Asp f 5 (matrix metalloprotease) and Asp f 13 (serine protease) in Aspergillus fumigatus-induced inflammation, airway hyperactivity, atopy and airway wall remodelling in a murine model following chronic exposure to secreted allergens. BALB/c mice were repeatedly intranasally dosed over the course of 5 weeks with culture filtrate from wild-type (WT), Asp f 5 null (∆5) or Asp f 13 null (∆13) strains of Aspergillus fumigatus. Airway hyper-reactivity was measured by non-invasive whole-body plethysmography, Th2 response and airway inflammation by ELISA and cell counts, whilst airway remodelling was assessed by histological analysis. Parent WT and ∆5 culture filtrates showed high protease activity, whilst protease activity in ∆13 culture filtrate was low. Chronic intranasal exposure to the three different filtrates led to comparable airway hyper-reactivity and Th2 response. However, protease allergen deleted strains, in particular ∆13 culture filtrate, induced significantly less airway inflammation and remodelling compared to WT culture filtrate. Aspergillus fumigatus-secreted allergen proteases, Asp f 5 and Asp f 13, are important for recruitment of inflammatory cells and remodelling of the airways in this murine model. However, deletion of a single allergen protease fails to alleviate airway hyper-reactivity and allergic immune response. Targeting protease activity of Aspergillus fumigatus in conditions such as SAFS or ABPA may have beneficial effects in preventing key aspects of airway pathology. © 2014 John Wiley & Sons Ltd.

[Carcinogenesis and its mechanism of mutant-type[12Asp]K-ras4B gene].

PubMed

Gui, Li-ming; Wei, Li-hui; Zhang, Ying-mei; Wang, Jian-liu; Wang, Ying; Chen, Ying; Ma, Da-long

2002-01-01

Ras gene plays an important role in the extra- and intra-cellular signal transduction pathway. It mediates series cascade reactions, and eventually actives transcriptional factors in nucleus. It is unknown on the mechanism of carcinogenesis of Ras gene in endometrial carcinoma, though K-ras mutant is very common in endometrial atypical hyperplasia and carcinoma. On basis of discovering the mutation in 12th codon of K-ras in endometrial carcinoma cell line, HEC-1A, we explored the carcinogenesis and molecular mechanism of mutant-type [12Asp] K-ras4B gene. (1) Full-length [12Asp]K-ras4B cDNA was amplified with RT-PCR, then inserted into pcDI eukaryotic expressive vector. (2) Morphological change, growth kinetics in vitro and tumorigencity in nude mice in vivo after-before transfection were observed. (3) To test the cell growth kinetics by methyl thiazolium tetrazolium (MTT) and [3H]thymidine incorporation method. (1) The authors have successfully constructed eukaryotic expression plasmid pcDI-[12Asp] K-ras4B; (2) To confirm that [12Asp] K-ras4B mutant can trigger the neoplastic transformation of NIH3T3 cells by test in vitro and in vivo. (3) After pMCV-RasN17 plasmid, a Ras mutant were transfected into pcDI-[12Asp] K-ras4B cells, the growth of this cell were restrained significantly in comparison with control group. (4) These findings indicate the expression of RafS621A resulted in remarkable inhibition in proliferation of pcDI-[12Asp]K-ras4B cell (P < 0.05). However, RafCAAX mutant can enhance pcDI-[12Asp]K-ras4B cell growth (P < 0.05). (1) [12Asp]K-ras4B gene alone is able to cause neoplastic transformation in NIH3T3 cells in vitro and in vivo. (2) [12Asp]K-ras4B-induced NIH3T3 cells neoplastic transformation required Raf signaling pathway.

Identification of angiotensin I in several vertebrate species: its structural and functional evolution.

PubMed

Takei, Yoshio; Joss, Jean M P; Kloas, Werner; Rankin, J Cliff

2004-02-01

In order to delineate further the molecular evolution of the renin-angiotensin system in vertebrates, angiotensin I (ANG I) has been isolated after incubation of plasma and kidney extracts of emu (Dromiceus novaehollandiae), axolotl (Ambystoma mexicanum), and sea lamprey (Petromyzon marinus). The identified sequences were [Asp1, Val5, Asn9] ANG I in emu, [Asp1, Val5, His9] ANG I in axolotl, and [Asn1, Val5, Thr9] ANG I in sea lamprey. These results confirmed the previous findings that tetrapods have Asp and fishes including cyclostomes have Asn at the N-terminus, and that the amino acid residue at position 9 of ANG I was highly variable but, those at other positions were well conserved among different species. Since Asp and Asn are convertible during incubation, angiotensinogen sequences were searched in the genome and/or EST database to determine the N-terminal amino acid residue from the gene. The screening detected 12 tetrapod (10 mammalian, one avian, and one amphibian) and seven teleostean angiotensinogen sequences. Among them, all tetrapods have [Asp1] ANG except for Xenopus, and all teleosts have [Asn1] ANG, thereby confirming the above rule. Comparison of the vasopressor activity in the eel revealed that [Asn1] ANG I and II were more potent than [Asp1] peptides, which was opposite to the previous results in mammals and birds, in which [Asp1] ANG I and II were more potent. Collectively, the present results support the general rule that tetrapods have [Asp1] ANG and fishes including cyclostomes have [Asn1] ANG. However, an aquatic anuran (Xenopus) has [Asn1] ANG in its gene despite another aquatic urodele (axolotl) has [Asp1] ANG. From the functional viewpoint, homologous [Asn1] ANG was more potent in fish as is homologous [Asp1] ANG in tetrapods, suggesting that ANG II molecule has undergone co-evolution with its receptor during vertebrate phylogeny.

A ripple-spreading genetic algorithm for the aircraft sequencing problem.

PubMed

Hu, Xiao-Bing; Di Paolo, Ezequiel A

2011-01-01

When genetic algorithms (GAs) are applied to combinatorial problems, permutation representations are usually adopted. As a result, such GAs are often confronted with feasibility and memory-efficiency problems. With the aircraft sequencing problem (ASP) as a study case, this paper reports on a novel binary-representation-based GA scheme for combinatorial problems. Unlike existing GAs for the ASP, which typically use permutation representations based on aircraft landing order, the new GA introduces a novel ripple-spreading model which transforms the original landing-order-based ASP solutions into value-based ones. In the new scheme, arriving aircraft are projected as points into an artificial space. A deterministic method inspired by the natural phenomenon of ripple-spreading on liquid surfaces is developed, which uses a few parameters as input to connect points on this space to form a landing sequence. A traditional GA, free of feasibility and memory-efficiency problems, can then be used to evolve the ripple-spreading related parameters in order to find an optimal sequence. Since the ripple-spreading model is the centerpiece of the new algorithm, it is called the ripple-spreading GA (RSGA). The advantages of the proposed RSGA are illustrated by extensive comparative studies for the case of the ASP.

Elucidating the role of many-body forces in liquid water. I. Simulations of water clusters on the VRT(ASP-W) potential surfaces.

PubMed

Goldman, Nir; Saykally, R J

2004-03-08

We test two new potentials for water, fit to vibration-rotation tunneling (VRT) data by employing diffusion quantum Monte Carlo simulations to calculate the vibrational ground-state properties of water clusters. These potentials, VRT(ASP-W)II and VRT(ASP-W)III, are fits of the highly detailed ASP-W (anisotropic site potential with Woermer dispersion) ab initio potential to (D(2)O)(2) microwave and far-infrared data, and along with the SAPT5s (five-site symmetry adapted perturbation theory) potentials, are the most accurate water dimer potential surfaces in the literature. The results from VRT(ASP-W)II and III are compared to those from the original ASP-W potential, the SAPT5s family of potentials, and several bulk water potentials. Only VRT(ASP-W)III and the spectroscopically "tuned" SAPT5st (with N-body induction included) accurately reproduce the vibrational ground-state structures of water clusters up to the hexamer. Finally, the importance of many-body induction and three-body dispersion are examined, and it is shown that the latter can have significant effects on water cluster properties despite its small magnitude.

Elucidating the role of many-body forces in liquid water. I. Simulations of water clusters on the VRT(ASP-W) potential surfaces

NASA Astrophysics Data System (ADS)

Goldman, Nir; Saykally, R. J.

2004-03-01

We test two new potentials for water, fit to vibration-rotation tunneling (VRT) data by employing diffusion quantum Monte Carlo simulations to calculate the vibrational ground-state properties of water clusters. These potentials, VRT(ASP-W)II and VRT(ASP-W)III, are fits of the highly detailed ASP-W (anisotropic site potential with Woermer dispersion) ab initio potential to (D2O)2 microwave and far-infrared data, and along with the SAPT5s (five-site symmetry adapted perturbation theory) potentials, are the most accurate water dimer potential surfaces in the literature. The results from VRT(ASP-W)II and III are compared to those from the original ASP-W potential, the SAPT5s family of potentials, and several bulk water potentials. Only VRT(ASP-W)III and the spectroscopically "tuned" SAPT5st (with N-body induction included) accurately reproduce the vibrational ground-state structures of water clusters up to the hexamer. Finally, the importance of many-body induction and three-body dispersion are examined, and it is shown that the latter can have significant effects on water cluster properties despite its small magnitude.

Purification and characterisation of a novel antistaphylococcal peptide (ASP-1) from Bacillus sp. URID 12.1.

PubMed

Chalasani, Ajay Ghosh; Roy, Utpal; Nema, Sushma

2018-01-01

A strong antistaphylococcal peptide (ASP-1) from Bacillus subtilis URID 12.1 strain that is active against cefoxitin- and methicillin-resistant Staphylococcus aureus clinical isolates was purified to homogeneity by solvent extraction, silica gel-based adsorption chromatography and reversed-phase high-performance liquid chromatography. The peptide sequence of ASP-1 as determined by MALDI-TOF/MS and ESI-FTICR-MS was acetylated Phe-Thr-Ala-Val-Dhb-Phe-Ile/Leu. The peptide was further analysed by alkaline hydrolysis, ESI-Q-TOF-MS and an ion mobility assay, which detected the presence of a lactone ring in the intact peptide and a cyclic nature, subsequently revealing the linearised peptide sequence as acPhe-Leu-Phe-Thr-Val-Ala-Dhb. Based on the molecular mass (804.5 Da), peptide sequence and amino acid composition, ASP-1 was identified as a lactone ring-containing peptide similar to TL-119, a poorly studied cyclic depsipeptide. Circular dichroism spectroscopy revealed its predominantly random structure in aqueous solution and its β-sheet conformation in methanol. Minimum inhibitory concentrations (MICs) of the purified peptide against S. aureus and methicillin-resistant S. aureus (MRSA) ranged from 2 µg/mL to 64 µg/mL. At sub-MICs and 1× MIC, ASP-1 showed a strong antibiofilm characteristic. ASP-1 at a concentration of 128 µg/mL did not show haemolytic activity, and no cytotoxicity was observed against hepatic carcinoma and breast carcinoma cell lines at the same concentration. Peptide ASP-1 with anti-MRSA and antibiofilm abilities and non-haemolytic and non-cytotoxic properties has not been reported previously. These findings suggest that it may serve as a lead molecule for developing alternative topical antibacterial agents. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Characterization of a Novel BCHE “Silent” Allele: Point Mutation (p.Val204Asp) Causes Loss of Activity and Prolonged Apnea with Suxamethonium

PubMed Central

Delacour, Herve; Lushchekina, Sofya; Mabboux, Isabelle; Bousquet, Aurore; Ceppa, Franck; Schopfer, Lawrence M.; Lockridge, Oksana; Masson, Patrick

2014-01-01

Butyrylcholinesterase deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium) in patients who have mutations in the BCHE gene. Here, we report a case of prolonged neuromuscular block after administration of suxamethonium leading to the discovery of a novel BCHE variant (c.695T>A, p.Val204Asp). Inhibition studies, kinetic analysis and molecular dynamics were undertaken to understand how this mutation disrupts the catalytic triad and determines a “silent” phenotype. Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine (BTC) and benzoylcholine, and values of dibucaine and fluoride numbers fit with heterozygous atypical silent genotype. Electrophoretic analysis of plasma BChE of the proband and his mother showed that patient has a reduced amount of tetrameric enzyme in plasma and that minor fast-moving BChE components: monomer, dimer, and monomer-albumin conjugate are missing. Kinetic analysis showed that the p.Val204Asp/p.Asp70Gly-p.Ala539Thr BChE displays a pure Michaelian behavior with BTC as the substrate. Both catalytic parameters Km = 265 µM for BTC, two times higher than that of the atypical enzyme, and a low Vmax are consistent with the absence of activity against suxamethonium. Molecular dynamic (MD) simulations showed that the overall effect of the mutation p.Val204Asp is disruption of hydrogen bonding between Gln223 and Glu441, leading Ser198 and His438 to move away from each other with subsequent disruption of the catalytic triad functionality regardless of the type of substrate. MD also showed that the enzyme volume is increased, suggesting a pre-denaturation state. This fits with the reduced concentration of p.Ala204Asp/p.Asp70Gly-p.Ala539Thr tetrameric enzyme in the plasma and non-detectable fast moving-bands on electrophoresis gels. PMID:25054547

Ground state destabilization from a positioned general base in the ketosteroid isomerase active site.

PubMed

Ruben, Eliza A; Schwans, Jason P; Sonnett, Matthew; Natarajan, Aditya; Gonzalez, Ana; Tsai, Yingssu; Herschlag, Daniel

2013-02-12

We compared the binding affinities of ground state analogues for bacterial ketosteroid isomerase (KSI) with a wild-type anionic Asp general base and with uncharged Asn and Ala in the general base position to provide a measure of potential ground state destabilization that could arise from the close juxtaposition of the anionic Asp and hydrophobic steroid in the reaction's Michaelis complex. The analogue binding affinity increased ~1 order of magnitude for the Asp38Asn mutation and ~2 orders of magnitude for the Asp38Ala mutation, relative to the affinity with Asp38, for KSI from two sources. The increased level of binding suggests that the abutment of a charged general base and a hydrophobic steroid is modestly destabilizing, relative to a standard state in water, and that this destabilization is relieved in the transition state and intermediate in which the charge on the general base has been neutralized because of proton abstraction. Stronger binding also arose from mutation of Pro39, the residue adjacent to the Asp general base, consistent with an ability of the Asp general base to now reorient to avoid the destabilizing interaction. Consistent with this model, the Pro mutants reduced or eliminated the increased level of binding upon replacement of Asp38 with Asn or Ala. These results, supported by additional structural observations, suggest that ground state destabilization from the negatively charged Asp38 general base provides a modest contribution to KSI catalysis. They also provide a clear illustration of the well-recognized concept that enzymes evolve for catalytic function and not, in general, to maximize ground state binding. This ground state destabilization mechanism may be common to the many enzymes with anionic side chains that deprotonate carbon acids.

Structure-guided modification of Rhizomucor miehei lipase for production of structured lipids.

PubMed

Zhang, Jun-Hui; Jiang, Yu-Yan; Lin, Ying; Sun, Yu-Fei; Zheng, Sui-Ping; Han, Shuang-Yan

2013-01-01

To improve the performance of yeast surface-displayed Rhizomucor miehei lipase (RML) in the production of human milk fat substitute (HMFS), we mutated amino acids in the lipase substrate-binding pocket based on protein hydrophobicity, to improve esterification activity. Five mutants: Asn87Ile, Asn87Ile/Asp91Val, His108Leu/Lys109Ile, Asp256Ile/His257Leu, and His108Leu/Lys109Ile/Asp256Ile/His257Leu were obtained and their hydrolytic and esterification activities were assayed. Using Discovery Studio 3.1 to build models and calculate the binding energy between lipase and substrates, compared to wild-type, the mutant Asp256Ile/His257Leu was found to have significantly lower energy when oleic acid (3.97 KJ/mol decrease) and tripalmitin (7.55 KJ/mol decrease) were substrates. This result was in accordance with the esterification activity of Asp256Ile/His257Leu (2.37-fold of wild-type). The four mutants were also evaluated for the production of HMFS in organic solvent and in a solvent-free system. Asp256Ile/His257Leu had an oleic acid incorporation of 28.27% for catalyzing tripalmitin and oleic acid, and 53.18% for the reaction of palm oil with oleic acid. The efficiency of Asp256Ile/His257Leu was 1.82-fold and 1.65-fold that of the wild-type enzyme for the two reactions. The oleic acid incorporation of Asp256Ile/His257Leu was similar to commercial Lipozyme RM IM for palm oil acidolysis with oleic acid. Yeast surface-displayed RML mutant Asp256Ile/His257Leu is a potential, economically feasible catalyst for the production of structured lipids.

Probing the Catalytic Mechanism of Vibrio harveyi GH20 β-N-Acetylglucosaminidase by Chemical Rescue

PubMed Central

Meekrathok, Piyanat; Suginta, Wipa

2016-01-01

Background Vibrio harveyi GH20 β-N-acetylglucosaminidase (VhGlcNAcase) is a chitinolytic enzyme responsible for the successive degradation of chitin fragments to GlcNAc monomers, activating the onset of the chitin catabolic cascade in marine Vibrios. Methods Two invariant acidic pairs (Asp303-Asp304 and Asp437-Glu438) of VhGlcNAcase were mutated using a site-directed mutagenesis strategy. The effects of these mutations were examined and the catalytic roles of these active-site residues were elucidated using a chemical rescue approach. Enhancement of the enzymic activity of the VhGlcNAcase mutants was evaluated by a colorimetric assay using pNP-GlcNAc as substrate. Results Substitution of Asp303, Asp304, Asp437 or Glu438 with Ala/Asn/Gln produced a dramatic loss of the GlcNAcase activity. However, the activity of the inactive D437A mutant was recovered in the presence of sodium formate. Our kinetic data suggest that formate ion plays a nucleophilic role by mimicking the β-COO-side chain of Asp437, thereby stabilizing the reaction intermediate during both the glycosylation and the deglycosylation steps. Conclusions Chemical rescue of the inactive D437A mutant of VhGlcNAcase by an added nucleophile helped to identify Asp437 as the catalytic nucleophile/base, and hence its acidic partner Glu438 as the catalytic proton donor/acceptor. General Significance Identification of the catalytic nucleophile of VhGlcNAcases supports the proposal of a substrate-assisted mechanism of GH20 GlcNAcases, requiring the catalytic pair Asp437-Glu438 for catalysis. The results suggest the mechanistic basis of the participation of β-N-acetylglucosaminidase in the chitin catabolic pathway of marine Vibrios. PMID:26870945

Exploiting excess sharing: a more powerful test of linkage for affected sib pairs than the transmission/disequilibrium test.

PubMed Central

Wicks, J

2000-01-01

The transmission/disequilibrium test (TDT) is a popular, simple, and powerful test of linkage, which can be used to analyze data consisting of transmissions to the affected members of families with any kind pedigree structure, including affected sib pairs (ASPs). Although it is based on the preferential transmission of a particular marker allele across families, it is not a valid test of association for ASPs. Martin et al. devised a similar statistic for ASPs, Tsp, which is also based on preferential transmission of a marker allele but which is a valid test of both linkage and association for ASPs. It is, however, less powerful than the TDT as a test of linkage for ASPs. What I show is that the differences between the TDT and Tsp are due to the fact that, although both statistics are based on preferential transmission of a marker allele, the TDT also exploits excess sharing in identity-by-descent transmissions to ASPs. Furthermore, I show that both of these statistics are members of a family of "TDT-like" statistics for ASPs. The statistics in this family are based on preferential transmission but also, to varying extents, exploit excess sharing. From this family of statistics, we see that, although the TDT exploits excess sharing to some extent, it is possible to do so to a greater extent-and thus produce a more powerful test of linkage, for ASPs, than is provided by the TDT. Power simulations conducted under a number of disease models are used to verify that the most powerful member of this family of TDT-like statistics is more powerful than the TDT for ASPs. PMID:10788332

Exploiting excess sharing: a more powerful test of linkage for affected sib pairs than the transmission/disequilibrium test.

PubMed

Wicks, J

2000-06-01

The transmission/disequilibrium test (TDT) is a popular, simple, and powerful test of linkage, which can be used to analyze data consisting of transmissions to the affected members of families with any kind pedigree structure, including affected sib pairs (ASPs). Although it is based on the preferential transmission of a particular marker allele across families, it is not a valid test of association for ASPs. Martin et al. devised a similar statistic for ASPs, Tsp, which is also based on preferential transmission of a marker allele but which is a valid test of both linkage and association for ASPs. It is, however, less powerful than the TDT as a test of linkage for ASPs. What I show is that the differences between the TDT and Tsp are due to the fact that, although both statistics are based on preferential transmission of a marker allele, the TDT also exploits excess sharing in identity-by-descent transmissions to ASPs. Furthermore, I show that both of these statistics are members of a family of "TDT-like" statistics for ASPs. The statistics in this family are based on preferential transmission but also, to varying extents, exploit excess sharing. From this family of statistics, we see that, although the TDT exploits excess sharing to some extent, it is possible to do so to a greater extent-and thus produce a more powerful test of linkage, for ASPs, than is provided by the TDT. Power simulations conducted under a number of disease models are used to verify that the most powerful member of this family of TDT-like statistics is more powerful than the TDT for ASPs.

NOS3 Glu298Asp genotype and blood pressure response to endurance training: the HERITAGE family study.

PubMed

Rankinen, T; Rice, T; Pérusse, L; Chagnon, Y C; Gagnon, J; Leon, A S; Skinner, J S; Wilmore, J H; Rao, D C; Bouchard, C

2000-11-01

Endothelium-dependent vasodilation is a mechanism that may affect blood pressure response to endurance training. Because NO plays a central role in this process, the endothelial NO synthase gene is a good candidate for the regulation of exercise blood pressure. We investigated the associations between an endothelial NO synthase gene polymorphism (Glu298Asp) and endurance training-induced changes in resting and submaximal exercise blood pressure in 471 white subjects of the HERITAGE Family Study. Two submaximal exercise tests at 50 W were conducted both before and after a 20-week endurance training program. Steady-state exercise blood pressure was measured twice in each test with an automated unit. The Glu298Asp polymorphism was typed with a PCR-based method and digestion with BAN:II. Both systolic and diastolic blood pressure at 50 W decreased in response to the training program, whereas resting blood pressure remained unchanged. The decrease in diastolic blood pressure at 50 W was greater (P=0.0005, adjusted for age, gender, baseline body mass index, and baseline diastolic blood pressure at 50 W) in the Glu/Glu homozygotes (4.4 [SEM 0.4] mm Hg, n=187) than in the heterozygotes (3.1 [0.4] mm Hg, n=213) and the Asp/Asp homozygotes (1.3 [0.7] mm Hg, n=71). The genotype accounted for 2.3% of the variance in diastolic blood pressure at 50 W training response. Both the Glu298 homozygotes and the heterozygotes had a greater (P=0.013) training-induced reduction in rate-pressure product at 50 W than the Asp298 homozygotes. These data suggest that DNA sequence variation in the endothelial NO synthase gene locus is associated with the endurance training-induced decreases in submaximal exercise diastolic blood pressure and rate-pressure product in sedentary normotensive white subjects.

Multivariate time series modeling of short-term system scale irrigation demand

NASA Astrophysics Data System (ADS)

Perera, Kushan C.; Western, Andrew W.; George, Biju; Nawarathna, Bandara

2015-12-01

Travel time limits the ability of irrigation system operators to react to short-term irrigation demand fluctuations that result from variations in weather, including very hot periods and rainfall events, as well as the various other pressures and opportunities that farmers face. Short-term system-wide irrigation demand forecasts can assist in system operation. Here we developed a multivariate time series (ARMAX) model to forecast irrigation demands with respect to aggregated service points flows (IDCGi, ASP) and off take regulator flows (IDCGi, OTR) based across 5 command areas, which included area covered under four irrigation channels and the study area. These command area specific ARMAX models forecast 1-5 days ahead daily IDCGi, ASP and IDCGi, OTR using the real time flow data recorded at the service points and the uppermost regulators and observed meteorological data collected from automatic weather stations. The model efficiency and the predictive performance were quantified using the root mean squared error (RMSE), Nash-Sutcliffe model efficiency coefficient (NSE), anomaly correlation coefficient (ACC) and mean square skill score (MSSS). During the evaluation period, NSE for IDCGi, ASP and IDCGi, OTR across 5 command areas were ranged 0.98-0.78. These models were capable of generating skillful forecasts (MSSS ⩾ 0.5 and ACC ⩾ 0.6) of IDCGi, ASP and IDCGi, OTR for all 5 lead days and IDCGi, ASP and IDCGi, OTR forecasts were better than using the long term monthly mean irrigation demand. Overall these predictive performance from the ARMAX time series models were higher than almost all the previous studies we are aware. Further, IDCGi, ASP and IDCGi, OTR forecasts have improved the operators' ability to react for near future irrigation demand fluctuations as the developed ARMAX time series models were self-adaptive to reflect the short-term changes in the irrigation demand with respect to various pressures and opportunities that farmers' face, such as changing water policy, continued development of water markets, drought and changing technology.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shanmugam, Ganesh; Polavarapu, Prasad L.; Hallgas, Balazs

The effects of D-amino acids at Asp{sup 23} and Ser{sup 26} residues on the conformational preference of {beta}-amyloid (A{beta}) peptide fragment (A{beta}{sub 20-29}) have been studied using different spectroscopic techniques, namely vibrational circular dichroism (VCD), vibrational absorption, and electronic circular dichroism. To study the structure of the A{beta}{sub 20-29}, [D-Asp{sup 23}]A{beta}{sub 20-29}, and [D-Ser{sup 26}]A{beta}{sub 20-29} peptides under different conditions, the spectra were measured in 10 mM acetate buffer (pH 3) and in 2,2,2-trifluoroethanol (TFE). The spectroscopic results indicated that at pH 3, A{beta}{sub 20-29} peptide takes random coil with {beta}-turn structure, while [D-Ser{sup 26}]A{beta}{sub 20-29} peptide adopts significant amountmore » of polyproline II (PPII) type structure along with {beta}-turn contribution and D-Asp-substituted peptide ([D-Asp{sup 23}]A{beta}{sub 20-29}) adopts predominantly PPII type structure. The increased propensity for PPII conformation upon D-amino acid substitution, in acidic medium, has important biological implications. In TFE, A{beta}{sub 20-29}, [D-Asp{sup 23}]A{beta}{sub 20-29}, and [D-Ser{sup 26}]A{beta}{sub 20-29} peptides adopt 3{sub 10}-helix, {alpha}-helix, and random coil with some {beta}-turn structures, respectively. The VCD data obtained for the A{beta} peptide films suggested that the secondary structures for the peptide films are not the same as those for corresponding solution and are also different among the A{beta} peptides studied here. This observation suggests that dehydration can have a significant influence on the structural preferences of these peptides.« less

Plasma fatty acid ethanolamides are associated with postprandial triglycerides, ApoCIII and ApoE in humans consuming high fructose corn syrup-sweetened beverage.

PubMed

Allister Price, Candice; Argueta, Donovan A; Medici, Valentina; Bremer, Andrew A; Lee, Vivien; Nunez, Marinelle V; Chen, Guoxia X; Keim, Nancy L; Havel, Peter J; Stanhope, Kimber L; DiPatrizio, Nicholas V

2018-04-10

Epidemiological and clinical research studies have provided ample evidence demonstrating that consumption of sugar-sweetened beverages (SSB) increases risk factors involved in the development of obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD). Our previous study demonstrated that when compared to aspartame (Asp), two weeks of high-fructose corn syrup (HFCS)-sweetened beverages provided at 25% of daily energy requirement (Ereq) was associated with increased body weight, postprandial (pp) triglycerides (TG), and fasting and pp CVD risk factors in young adults. The fatty acid ethanolamide, anandamide (AEA), and the monoacylglycerol, 2-arachidonoyl-sn-glycerol (2-AG), are two primary endocannabinoids (ECs) that play a role in regulating food intake, increasing adipose storage, and regulating lipid metabolism. Therefore, we measured plasma concentrations of ECs and their analogs, oleoylethanolamide (OEA), docosahexaenoyl ethanolamide (DHEA), and docosahexaenoyl glycerol (DHG), in participants from our previous study who consumed HFCS- or Asp-sweetened beverages to determine associations with weight gain and CVD risk factors. Two-week exposure to either HFCS- or Asp-sweetened beverages resulted in significant differences in the changes in fasting levels of OEA and DHEA between groups after the testing period. Subjects who consumed Asp, but not HFCS, displayed a reduction in AEA, OEA and DHEA after the testing period. In contrast, there were significant positive relationships between AEA, OEA, and DHEA versus ppTG, ppApoCIII and ppApoE in those consuming HFCS, but not in those consuming Asp. Our findings reveal previously unknown associations between circulating ECs and EC-related molecules with markers of lipid metabolism and CVD risk after HFCS-consumption.

The ASP at 125: Advancing Science Literacy in an Age of Acceleration

NASA Astrophysics Data System (ADS)

Manning, Jim

2014-01-01

On February 7, 2014, the Astronomical Society of the Pacific will celebrate its 125th birthday and a century and a quarter of advancing astronomy and astronomy/science education during a period of revolutionary change in our understanding of the universe. In keeping with both the retrospective and forward-looking nature of such milestones, the presenter will: 1) share highlights of the Society’s work in supporting the communication of astronomy research through its professional publications, and creating innovative astronomy education and public outreach projects and networks to advance student, teacher and public understanding of astronomy and science; 2) report on current NASA- and NSF-funded efforts and on plans going forward; 3) and solicit input from the assembled community on how the ASP can best serve its various constituencies and the cause of science education, communication and literacy at a time when both the universe and life on Earth are accelerating at unprecedented rates. Birthdays are for celebrating; come celebrate with us as we rededicate ourselves to a mission of advancing science literacy through astronomy.

Distribution to the Astronomy Community of the Compressed Digitized Sky Survey

NASA Astrophysics Data System (ADS)

Postman, Marc

1996-03-01

The Space Telescope Science Institute has compressed an all-sky collection of ground-based images and has printed the data on a two volume, 102 CD-ROM disc set. The first part of the survey (containing images of the southern sky) was published in May 1994. The second volume (containing images of the northern sky) was published in January 1995. Software which manages the image retrieval is included with each volume. The Astronomical Society of the Pacific (ASP) is handling the distribution of the lOx compressed data and has sold 310 sets as of October 1996. ASP is also handling the distribution of the recently published 100x version of the northern sky survey which is publicly available at a low cost. The target markets for the 100x compressed data set are the amateur astronomy community, educational institutions, and the general public. During the next year, we plan to publish the first version of a photometric calibration database which will allow users of the compressed sky survey to determine the brightness of stars in the images.

Distribution to the Astronomy Community of the Compressed Digitized Sky Survey

NASA Technical Reports Server (NTRS)

Postman, Marc

1996-01-01

The Space Telescope Science Institute has compressed an all-sky collection of ground-based images and has printed the data on a two volume, 102 CD-ROM disc set. The first part of the survey (containing images of the southern sky) was published in May 1994. The second volume (containing images of the northern sky) was published in January 1995. Software which manages the image retrieval is included with each volume. The Astronomical Society of the Pacific (ASP) is handling the distribution of the lOx compressed data and has sold 310 sets as of October 1996. ASP is also handling the distribution of the recently published 100x version of the northern sky survey which is publicly available at a low cost. The target markets for the 100x compressed data set are the amateur astronomy community, educational institutions, and the general public. During the next year, we plan to publish the first version of a photometric calibration database which will allow users of the compressed sky survey to determine the brightness of stars in the images.

Multinational Consensus: Insulin Initiation with Insulin Degludec/Aspart (IDegAsp).

PubMed

Kalra, Sanjay; Atkin, Stephen; Cervera, Antonio; Das, Ashok Kumar; Demir, Ozgur; Demir, Tevfik; Fariduddin, Md; Vo, Khoa Tuan; Ku, Bon Jeong; Kumar, Ajay; Latif, Zafar A; Malek, Rachid; Matawaran, Bien J; Mehta, Roopa; Tran, Nam Quang; Panelo, Araceli; Ruder, Sundeep; Saldana, Joel Rodriquez; Shaikh, Khalid A; Shakya, Amit; Shrestha, Dina; Unnikrishnan, A G

2018-05-23

Insulin degludec/aspart (IDegAsp) is the first soluble insulin co-formulation, combining a long-acting insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp). In type 2 diabetes patients with oral antidiabetes agent (OAD) inadequacy, insulin initiation with IDegAsp once daily provides superior long-term glycemic control compared to insulin glargine, with similar fasting plasma glucose (FPG) and insulin doses, and numerically lower rates of overall and nocturnal hypoglycemia. Furthermore, in patients with uncontrolled type 2 diabetes previously treated with insulins, IDegAsp twice daily effectively improves glycated hemoglobin and FPG, with fewer hypoglycemic episodes versus premix insulins and basal bolus therapy. In patients with type 1 diabetes mellitus, IDegAsp once daily with two doses of IAsp is a convenient, yet effective, regimen as compared to the conventional 4-5 injection-based basal bolus therapy. IDegAsp is an appropriate and reasonable option for initiation of insulin therapy in both type 1 and type 2 diabetes.

The volitional inhibition of anticipatory ocular pursuit using a stop signal.

PubMed

Jarrett, Christian Beresford; Barnes, Graham R

2003-10-01

Unlike limb movements, smooth pursuit eye movements cannot normally be performed in the absence of a target. However, when subjects have a high expectancy of an imminent target appearance, the situation changes, and anticipatory smooth pursuit (ASP) tends to precede target onset by several hundred milliseconds. The velocity of this ASP is scaled predictively according to expected target velocity. And when an upcoming target is unexpectedly altered, or fails to appear, ASP continues regardless for approximately 150-200 ms before modification by visual feedback begins [J. Neurophysiol., 84 (2000) 2340]. These and other observations led to the earlier suggestion that ASP might be ballistic, being pre-programmed from start to finish. Two experiments with different timing parameters were therefore performed to test this hypothesis using a version of Logan's [Psychol. Rev., 91 (1984) 295] stop signal task. The aim was to test whether ASP could be stopped at will, and if so, whether the time taken to stop varied as a function of the time since ASP onset. Results showed that in response to a stop signal, ASP can be inhibited at any point in its trajectory, and for the majority of subjects in experiment 1, and all the subjects in experiment 2, with a latency that does not change significantly with target speed or time since ASP onset. These results provide the first demonstration that anticipatory movements can be stopped volitionally in response to a stop signal. Possible cognitive and neurophysiological mechanisms underlying this process are discussed.

ACE-like hydrolysis of gastrin analogs and CCK-8 by fundic mucosal cells of different species with release of the amidated C-terminal dipeptide.

PubMed

Dubreuil, P; Fulcrand, P; Rodriguez, M; Laur, J; Bali, J P; Martinez, J

1990-06-19

Various gastrin analogues and CCK-8 (Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2) are hydrolyzed in vitro by angiotensin-converting enzyme (ACE), the main and initial cleavage occurring at the Met-Asp (or Leu-Asp) bond, releasing the C-terminal dipeptide amide Asp-Phe-NH2. Tetragastrin analogues (e.g., Boc-Trp-Leu-Asp-Phe-NH2) are degraded by a vesicular membrane fraction from rat gastric mucosa, yielding the C-terminal dipeptide Asp-Phe-NH2. We report here on the degradation of gastrin analogues and CCK-8 by a gastric mucosal cell preparation containing specific gastrin receptors. We have shown that gastrin analogues were specifically degraded by gastric mucosal cells from different species (e.g., rabbit and dog) at 37 degrees C (pH 7.4), releasing the C-terminal dipeptide Asp-Phe-NH2, similarly to ACE. This cleavage was found to be temperature and pH sensitive, and was inhibited by metalloproteinase inhibitors and by captopril, strongly suggesting that this enzymatic system closely resembles ACE. We have also demonstrated that a close correlation seems to exist between the apparent affinity of the gastrin analogues for gastrin receptors on gastric mucosal cells, and their ability of being hydrolyzed by this cell preparation. Moreover, all gastrin analogues which have been demonstrated to act as gastrin antagonists remained unaffected in the incubation conditions.

Embedding Positive Behavior Intervention and Supports in Afterschool Programs

ERIC Educational Resources Information Center

Farrell, Anne F.; Collier-Meek, Melissa A.; Pons, Shelby R.

2013-01-01

There is growing recognition that after-school programs (ASPs) provide opportunities for positive youth development. Many ASPs focus on behavior and socio-emotional challenges, provide evidence-based interventions to improve homework completion and academic skills, and offer physical activities and nutritious foods. Generally speaking, ASPs offer…

Improved ASP I/O performance. [For 370/195

DOE Office of Scientific and Technical Information (OSTI.GOV)

Engert, D.E.

1975-11-01

An improvement to the I/0 routines of ASP is described, which can save 25% of the EXCPs issued by ASP. Unused buffers in the buffer pool are used to retain parts of the single track table, and only two modules are changed. 4 figures (auth)

Implementation of an antimicrobial stewardship program targeting residents with urinary tract infections in three community long-term care facilities: a quasi-experimental study using time-series analysis.

PubMed

Doernberg, Sarah B; Dudas, Victoria; Trivedi, Kavita K

2015-01-01

Asymptomatic bacteriuria in the elderly commonly results in antibiotic administration and, in turn, contributes to antimicrobial resistance, adverse drug events, and increased costs. This is a major problem in the long-term care facility (LTCF) setting, where residents frequently transition to and from the acute-care setting, often transporting drug-resistant organisms across the continuum of care. The goal of this study was to assess the feasibility and efficacy of antimicrobial stewardship programs (ASPs) targeting urinary tract infections (UTIs) at community LTCFs. This was a quasi-experimental study targeting antibiotic prescriptions for UTI using time-series analysis with 6-month retrospective pre-intervention and 6-month intervention period at three community LTCFs. The ASP team (infectious diseases (ID) pharmacist and ID physician) performed weekly prospective audit and feedback of consecutive prescriptions for UTI. Loeb clinical consensus criteria were used to assess appropriateness of antibiotics; recommendations were communicated to the primary treating provider by the ID pharmacist. Resident outcomes were recorded at subsequent visits. Generalized estimating equations using segmented regression were used to evaluate the impact of the ASP intervention on rates of antibiotic prescribing and antibiotic resistance. One-hundred and four antibiotic prescriptions for UTI were evaluated during the intervention, and recommendations were made for change in therapy in 40 (38 %), out of which 10 (25 %) were implemented. Only eight (8 %) residents started on antibiotics for UTI met clinical criteria for antibiotic initiation. An immediate 26 % decrease in antibiotic prescriptions for UTI during the ASP was identified with a 6 % reduction continuing through the intervention period (95 % Confidence Interval ([CI)] for the difference: -8 to -3 %). Similarly, a 25 % immediate decrease in all antibiotic prescriptions was noted after introduction of the ASP with a 5 % reduction continuing throughout the intervention period (95 % CI: -8 to -2 %). No significant effect was noted on resistant organisms or Clostridium difficile. Weekly prospective audit and feedback ASP in three community LTCFs over 6 months resulted in antibiotic utilization decreases but many lost opportunities for intervention.

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

PubMed

Sarwar, Nadeem; Butterworth, Adam S; Freitag, Daniel F; Gregson, John; Willeit, Peter; Gorman, Donal N; Gao, Pei; Saleheen, Danish; Rendon, Augusto; Nelson, Christopher P; Braund, Peter S; Hall, Alistair S; Chasman, Daniel I; Tybjærg-Hansen, Anne; Chambers, John C; Benjamin, Emelia J; Franks, Paul W; Clarke, Robert; Wilde, Arthur A M; Trip, Mieke D; Steri, Maristella; Witteman, Jacqueline C M; Qi, Lu; van der Schoot, C Ellen; de Faire, Ulf; Erdmann, Jeanette; Stringham, Heather M; Koenig, Wolfgang; Rader, Daniel J; Melzer, David; Reich, David; Psaty, Bruce M; Kleber, Marcus E; Panagiotakos, Demosthenes B; Willeit, Johann; Wennberg, Patrik; Woodward, Mark; Adamovic, Svetlana; Rimm, Eric B; Meade, Tom W; Gillum, Richard F; Shaffer, Jonathan A; Hofman, Albert; Onat, Altan; Sundström, Johan; Wassertheil-Smoller, Sylvia; Mellström, Dan; Gallacher, John; Cushman, Mary; Tracy, Russell P; Kauhanen, Jussi; Karlsson, Magnus; Salonen, Jukka T; Wilhelmsen, Lars; Amouyel, Philippe; Cantin, Bernard; Best, Lyle G; Ben-Shlomo, Yoav; Manson, JoAnn E; Davey-Smith, George; de Bakker, Paul I W; O'Donnell, Christopher J; Wilson, James F; Wilson, Anthony G; Assimes, Themistocles L; Jansson, John-Olov; Ohlsson, Claes; Tivesten, Åsa; Ljunggren, Östen; Reilly, Muredach P; Hamsten, Anders; Ingelsson, Erik; Cambien, Francois; Hung, Joseph; Thomas, G Neil; Boehnke, Michael; Schunkert, Heribert; Asselbergs, Folkert W; Kastelein, John J P; Gudnason, Vilmundur; Salomaa, Veikko; Harris, Tamara B; Kooner, Jaspal S; Allin, Kristine H; Nordestgaard, Børge G; Hopewell, Jemma C; Goodall, Alison H; Ridker, Paul M; Hólm, Hilma; Watkins, Hugh; Ouwehand, Willem H; Samani, Nilesh J; Kaptoge, Stephen; Di Angelantonio, Emanuele; Harari, Olivier; Danesh, John

2012-03-31

Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Phosphorylation of cMyBP-C Affects Contractile Mechanisms in a Site-specific Manner

PubMed Central

Wang, Li; Ji, Xiang; Barefield, David; Sadayappan, Sakthivel; Kawai, Masakata

2014-01-01

Cardiac myosin binding protein-C (cMyBP-C) is a cardiac-specific, thick-filament regulatory protein that is differentially phosphorylated at Ser273, Ser282, and Ser302 by various kinases and modulates contraction. In this study, phosphorylation-site-specific effects of cMyBP-C on myocardial contractility and cross-bridge kinetics were studied by sinusoidal analysis in papillary and trabecular muscle fibers isolated from t/t (cMyBP-C-null) mice and in their counterparts in which cMyBP-C contains the ADA (Ala273-Asp282-Ala302), DAD (Asp273-Ala282-Asp302), and SAS (Ser273-Ala282-Ser302) mutations; the results were compared to those from mice expressing the wild-type (WT) transgene on the t/t background. Under standard activating conditions, DAD fibers showed significant decreases in tension (∼50%), stiffness, the fast apparent rate constant 2πc, and its magnitude C, as well as its magnitude H, but an increase in the medium rate constant 2πb, with respect to WT. The t/t fibers showed a smaller drop in stiffness and a significant decrease in 2πc that can be explained by isoform shift of myosin heavy chain. In the pCa-tension study using the 8 mM phosphate (Pi) solution, there was hardly any difference in Ca2+ sensitivity (pCa50) and cooperativity (nH) between the mutant and WT samples. However, in the solutions without Pi, DAD showed increased nH and slightly decreased pCa50. We infer from these observations that the nonphosphorylatable residue 282 combined with phosphomimetic residues Asp273 and/or Asp302 (in DAD) is detrimental to cardiomyocytes by lowering isometric tension and altering cross-bridge kinetics with decreased 2πc and increased 2πb. In contrast, a single change of residue 282 to nonphosphorylatable Ala (SAS), or to phosphomimetic Asps together with the changes of residues 273 and 302 to nonphosphorylatable Ala (ADA) causes minute changes in fiber mechanics. PMID:24606935

Answer Set Programming and Other Computing Paradigms

ERIC Educational Resources Information Center

Meng, Yunsong

2013-01-01

Answer Set Programming (ASP) is one of the most prominent and successful knowledge representation paradigms. The success of ASP is due to its expressive non-monotonic modeling language and its efficient computational methods originating from building propositional satisfiability solvers. The wide adoption of ASP has motivated several extensions to…

Canadian Ranger Rifle: Human Factors Requirements Validation

DTIC Science & Technology

2010-08-01

index-eng.asp retrieved 9 February 2010 2 http://www.armee.forces.gc.ca/land-terre/cr-rc/history- histoire -eng.asp retrieved 9 February 2010 3 http... histoire -eng.asp Department of National Defence. (2010). Canadian Ranger Patrol (CRPG). Retrieved June 3, 2010, from http://www.army.forces.gc.ca

Selectivity Mechanism of the Voltage-gated Proton Channel, HV1

NASA Astrophysics Data System (ADS)

Dudev, Todor; Musset, Boris; Morgan, Deri; Cherny, Vladimir V.; Smith, Susan M. E.; Mazmanian, Karine; Decoursey, Thomas E.; Lim, Carmay

2015-05-01

Voltage-gated proton channels, HV1, trigger bioluminescence in dinoflagellates, enable calcification in coccolithophores, and play multifarious roles in human health. Because the proton concentration is minuscule, exquisite selectivity for protons over other ions is critical to HV1 function. The selectivity of the open HV1 channel requires an aspartate near an arginine in the selectivity filter (SF), a narrow region that dictates proton selectivity, but the mechanism of proton selectivity is unknown. Here we use a reduced quantum model to elucidate how the Asp-Arg SF selects protons but excludes other ions. Attached to a ring scaffold, the Asp and Arg side chains formed bidentate hydrogen bonds that occlude the pore. Introducing H3O+ protonated the SF, breaking the Asp-Arg linkage and opening the conduction pathway, whereas Na+ or Cl- was trapped by the SF residue of opposite charge, leaving the linkage intact, thus preventing permeation. An Asp-Lys SF behaved like the Asp-Arg one and was experimentally verified to be proton-selective, as predicted. Hence, interacting acidic and basic residues form favorable AspH0-H2O0-Arg+ interactions with hydronium but unfavorable Asp--X-/X+-Arg+ interactions with anions/cations. This proposed mechanism may apply to other proton-selective molecules engaged in bioenergetics, homeostasis, and signaling.

Genetic immunization based on the ubiquitin-fusion degradation pathway against Trypanosoma cruzi

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chou, Bin; Department of Parasitology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582; Hiromatsu, Kenji, E-mail: khiromatsu@fukuoka-u.ac.jp

2010-02-12

Cytotoxic CD8{sup +} T cells are particularly important to the development of protective immunity against the intracellular protozoan parasite, Trypanosoma cruzi, the etiological agent of Chagas disease. We have developed a new effective strategy of genetic immunization by activating CD8{sup +} T cells through the ubiquitin-fusion degradation (UFD) pathway. We constructed expression plasmids encoding the amastigote surface protein-2 (ASP-2) of T. cruzi. To induce the UFD pathway, a chimeric gene encoding ubiquitin fused to ASP-2 (pUB-ASP-2) was constructed. Mice immunized with pUB-ASP-2 presented lower parasitemia and longer survival period, compared with mice immunized with pASP-2 alone. Depletion of CD8{sup +}more » T cells abolished protection against T. cruzi in mice immunized with pUB-ASP-2 while depletion of CD4{sup +} T cells did not influence the effective immunity. Mice deficient in LMP2 or LMP7, subunits of immunoproteasomes, were not able to develop protective immunity induced. These results suggest that ubiquitin-fused antigens expressed in antigen-presenting cells were effectively degraded via the UFD pathway, and subsequently activated CD8{sup +} T cells. Consequently, immunization with pUB-ASP-2 was able to induce potent protective immunity against infection of T. cruzi.« less

Proteolytic cleavage of polymeric tau protein by caspase-3: implications for Alzheimer disease.

PubMed

Jarero-Basulto, Jose J; Luna-Muñoz, Jose; Mena, Raul; Kristofikova, Zdena; Ripova, Daniela; Perry, George; Binder, Lester I; Garcia-Sierra, Francisco

2013-12-01

Truncated tau protein at Asp(421) is associated with neurofibrillary pathology in Alzheimer disease (AD); however, little is known about its presence in the form of nonfibrillary aggregates. Here, we report immunohistochemical staining of the Tau-C3 antibody, which recognizes Asp(421)-truncated tau, in a group of AD cases with different extents of cognitive impairment. In the hippocampus, we found distinct nonfibrillary aggregates of Asp(421)-truncated tau. Unlike Asp(421)-composed neurofibrillary tangles, however, these nonfibrillary pathologies did not increase significantly with respect to the Braak staging and, therefore, make no significant contribution to cognitive impairment. On the other hand, despite in vitro evidence that caspase-3 cleaves monomeric tau at Asp(421), to date, this truncation has not been demonstrated to be executed by this protease in polymeric tau entities. We determined that Asp(421) truncation can be produced by caspase-3 in oligomeric and multimeric complexes of recombinant full-length tau in isolated native tau filaments in vitro and in situ in neurofibrillary tangles analyzed in fresh brain slices from AD cases. Our data suggest that generation of this pathologic Asp(421) truncation of tau in long-lasting fibrillary structures may produce further permanent toxicity for neurons in the brains of patients with AD.

Incorporating pharmacy student activities into an antimicrobial stewardship program in a long-term acute care hospital.

PubMed

Benson, John M

2014-02-01

The impact on antimicrobial costs of an antimicrobial stewardship program (ASP) that integrated pharmacy students as integral members was evaluated. Demographic and discharge disposition data and antimicrobial acquisition cost data were retrospectively collected for all patients admitted to Promise Hospital of Salt Lake between June 1, 2009, and May 31, 2012. During this study, the primary role of pharmacy students in the ASP was to monitor all infection-related patient problems in the facility and meet daily with the infectious diseases pharmacist and clinical pharmacist to develop recommendations for optimizing antimicrobial use. The primary outcome measure was the mean antimicrobial acquisition cost per patient per day, calculated before ASP implementation (baseline period) and two years after ASP implementation (intervention period). The acquisition costs of antimicrobial agents per patient day were compared before and two years after implementation of the ASP involving pharmacy students. Statistical significance was determined using Student's t test for continuous data and the chi-square test for nominal data. The rate of patient discharge to skilled nursing facilities was significantly higher during the intervention period versus the baseline period (p = 0.016); no other significant comparisons were found. The mean ± S.D. antimicrobial costs per patient day were $75.37 ± $11.85 in the baseline period and $64.13 ± $13.78 in the intervention period (p = 0.022). This difference represents a cost savings of $261,630 during the two-year intervention period. Decreased antimicrobial costs were observed over a two-year period after implementation of an ASP that incorporated pharmacy students as integral members of the program.

Extensive deamidation of RNase A inhibits its oligomerization through 3D domain swapping.

PubMed

Fagagnini, Andrea; Montioli, Riccardo; Caloiu, Andra; Ribó, Marc; Laurents, Douglas V; Gotte, Giovanni

2017-01-01

Bovine pancreatic ribonuclease A (RNase A) is the monomeric prototype of the so-called secretory 'pancreatic-type' RNase super-family. Like the naturally domain-swapped dimeric bovine seminal variant, BS-RNase, and its glycosylated RNase B isoform, RNase A forms N- and C-terminal 3D domain-swapped oligomers after lyophilization from acid solutions, or if subjected to thermal denaturation at high protein concentration. All mentioned RNases can undergo deamidation at Asn67, forming Asp or isoAsp derivatives that modify the protein net charge and consequently its enzymatic activity. In addition, deamidation slightly affects RNase B self-association through the 3D domain swapping (3D-DS) mechanism. We report here the influence of extensive deamidation on RNase A tendency to oligomerize through 3D-DS. In particular, deamidation of Asn67 alone slightly decreases the propensity of the protein to oligomerize, with the Asp derivative being less affected than the isoAsp one. Contrarily, the additional Asp and/or isoAsp conversion of residues other than N67 almost nullifies RNase A oligomerization capability. In addition, Gln deamidation, although less kinetically favorable, may affect RNase A self-association. Using 2D and 3D NMR we identified the Asn/Gln residues most prone to undergo deamidation. Together with CD spectroscopy, NMR also indicates that poly-deamidated RNase A generally maintains its native tertiary structure. Again, we investigated in silico the effect of the residues undergoing deamidation on RNase A dimers structures. Finally, the effect of deamidation on RNase A oligomerization is discussed in comparison with studies on deamidation-prone proteins involved in amyloid formation. Copyright © 2016. Published by Elsevier B.V.

Modulation of calcium oxalate dihydrate growth by selective crystal-face binding of phosphorylated osteopontin and polyaspartate peptide showing occlusion by sectoral (compositional) zoning.

PubMed

Chien, Yung-Ching; Masica, David L; Gray, Jeffrey J; Nguyen, Sarah; Vali, Hojatollah; McKee, Marc D

2009-08-28

Calcium oxalate dihydrate (COD) mineral and the urinary protein osteopontin/uropontin (OPN) are commonly found in kidney stones. To investigate the effects of OPN on COD growth, COD crystals were grown with phosphorylated OPN or a polyaspartic acid-rich peptide of OPN (DDLDDDDD, poly-Asp(86-93)). Crystals grown with OPN showed increased dimensions of the {110} prismatic faces attributable to selective inhibition at this crystallographic face. At high concentrations of OPN, elongated crystals with dominant {110} faces were produced, often with intergrown, interpenetrating twin crystals. Poly-Asp(86-93) dose-dependently elongated crystal morphology along the {110} faces in a manner similar to OPN. In crystal growth studies using fluorescently tagged poly-Asp(86-93) followed by imaging of crystal interiors using confocal microscopy, sectoral (compositional) zoning in COD was observed resulting from selective binding and incorporation (occlusion) of peptide exclusively into {110} crystal sectors. Computational modeling of poly-Asp(86-93) adsorption to COD {110} and {101} surfaces also suggests increased stabilization of the COD {110} surface and negligible change to the natively stable {101} surface. Ultrastructural, colloidal-gold immunolocalization of OPN by transmission electron microscopy in human stones confirmed an intracrystalline distribution of OPN. In summary, OPN and its poly-Asp(86-93) sequence similarly affect COD mineral growth; the {110} crystallographic faces become enhanced and dominant attributable to {110} face inhibition by the protein/peptide, and peptides can incorporate into the mineral phase. We, thus, conclude that the poly-Asp(86-93) domain is central to the OPN ability to interact with the {110} faces of COD, where it binds to inhibit crystal growth with subsequent intracrystalline incorporation (occlusion).

Effect of collagen turnover on the accumulation of advanced glycation end products.

PubMed

Verzijl, N; DeGroot, J; Thorpe, S R; Bank, R A; Shaw, J N; Lyons, T J; Bijlsma, J W; Lafeber, F P; Baynes, J W; TeKoppele, J M

2000-12-15

Collagen molecules in articular cartilage have an exceptionally long lifetime, which makes them susceptible to the accumulation of advanced glycation end products (AGEs). In fact, in comparison to other collagen-rich tissues, articular cartilage contains relatively high amounts of the AGE pentosidine. To test the hypothesis that this higher AGE accumulation is primarily the result of the slow turnover of cartilage collagen, AGE levels in cartilage and skin collagen were compared with the degree of racemization of aspartic acid (% d-Asp, a measure of the residence time of a protein). AGE (N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, and pentosidine) and % d-Asp concentrations increased linearly with age in both cartilage and skin collagen (p < 0.0001). The rate of increase in AGEs was greater in cartilage collagen than in skin collagen (p < 0.0001). % d-Asp was also higher in cartilage collagen than in skin collagen (p < 0.0001), indicating that cartilage collagen has a longer residence time in the tissue, and thus a slower turnover, than skin collagen. In both types of collagen, AGE concentrations increased linearly with % d-Asp (p < 0.0005). Interestingly, the slopes of the curves of AGEs versus % d-Asp, i.e. the rates of accumulation of AGEs corrected for turnover, were identical for cartilage and skin collagen. The present study thus provides the first experimental evidence that protein turnover is a major determinant in AGE accumulation in different collagen types. From the age-related increases in % d-Asp the half-life of cartilage collagen was calculated to be 117 years and that of skin collagen 15 years, thereby providing the first reasonable estimates of the half-lives of these collagens.

Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gudmundsson, Sanna; Wilbe, Maria; Ekvall, Sara

Revertant mosaicism (RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c.148G >more » A, p.Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultra-deep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p.Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p.Asp50Asn mutation. Finally to our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.« less

Alpha B- and βA3-crystallins containing d-aspartic acids exist in a monomeric state.

PubMed

Sakaue, Hiroaki; Takata, Takumi; Fujii, Norihiko; Sasaki, Hiroshi; Fujii, Noriko

2015-01-01

Crystallin stability and subunit-subunit interaction are essential for eye lens transparency. There are three types of crystallins in lens, designated as α-, β-, and γ-crystallins. Alpha-crystallin is a hetero-polymer of about 800kDa, consisting of 35-40 subunits of two different αA- and αB-subunits, each of 20kDa. The β/γ-crystallin superfamily comprises oligomeric β-crystallin (2-6 subunits) and monomeric γ-crystallin. Since lens proteins have very long half-lives, they undergo numerous post-translational modifications including racemization, isomerization, deamidation, oxidation, glycation, and truncation, which may decrease crystallin solubility and ultimately cause cataract formation. Racemization and isomerization of aspartyl (Asp) residues have been detected only in polymeric α- and oligomeric β-crystallin, while the situation in monomeric γ-crystallin has not been studied. Here, we investigated the racemization and isomerization of Asp in the γ-crystallin fraction of elderly donors. The results show that Asp residues of γS-, γD- and γC-crystallins were not racemized and isomerized. However, strikingly, we found that a portion of αB-crystallin and βA3-crystallin moved to the lower molecular weight fraction which is the same size of γ-crystallin. In those fractions, Asp-96 of αB-crystallin and Asp-37 of βA3-crystallin were highly inverted, which do not occur in the native lens higher molecular weight fraction. Our results indicate the possibility that the inversion of Asp residues may induce dissociation of αB- and βA3-crystallins from the polymeric and oligomeric states. This is the first report that stereoinversion of amino acids disturbs lens protein assembly in aged human lens. Copyright © 2014 Elsevier B.V. All rights reserved.

Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26

DOE PAGES

Gudmundsson, Sanna; Wilbe, Maria; Ekvall, Sara; ...

2017-02-01

Revertant mosaicism (RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c.148G >more » A, p.Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultra-deep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p.Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p.Asp50Asn mutation. Finally to our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.« less

Making healthy eating policy practice: A group randomized controlled trial on changes in snack quality, costs, and consumption in after school programs

PubMed Central

Beets, Michael W.; Weaver, R. Glenn; Turner-McGrievy, Gabrielle; Huberty, Jennifer; Ward, Dianne S.; Freedman, Darcy; Hutto, Brent; Moore, Justin B.; Beighle, Aaron

2017-01-01

Purpose The aim of this study was to evaluate an intervention designed to assist after school programs (ASPs) in meeting snack nutrition policies that specify that a fruit or vegetable (FV) be served daily, and sugar-sweetened beverages/foods and artificially flavored foods eliminated. Design One-year group randomized controlled trial Setting Afterschool programs operating in South Carolina, US. Subjects Twenty ASPs serving over 1,700 children were recruited, match-paired post-baseline on enrollment size and days FV were served/week (days/wk), and randomized to either an intervention (n=10) or control (n=10) groups. Intervention Strategies To Enhance Practice for Healthy Eating (STEPs-HE), a multi-step adaptive intervention framework, which assists ASP leaders and staff to serve snacks that meet nutrition policies while maintaining cost. Measures Direct observation of snacks served and consumed, and monthly snack expenditures via receipts. Analysis Nonparametric and mixed-model repeated-measures Results By post-assessment, intervention ASPs increased serving FV to 3.9±2.1 vs. 0.7±1.7days/wk and decreased serving sugar-sweetened beverages to 0.1±0.7 vs. 1.8±2.4days/wk and foods to 0.3±1.1 vs. 2.7±2.5days/wk compared to controls, respectively. Cost of snacks increased by $0.02/snack in the intervention ASPs ($0.36 to $0.38) compared to a $0.01/snack decrease in the control ($0.39 to $0.38). Across both assessments and groups 80–100% of children consumed FV. Conclusions The STEPs-HE intervention can assist ASPs in meeting nationally endorsed nutrition policies with marginal increases in cost. PMID:26158679

Immunocytochemical localization of glutamic acid decarboxylase (GAD) and substance P in neural areas mediating motion-induced emesis: Effects of vagal stimulation on GAD immunoreactivity

NASA Technical Reports Server (NTRS)

Damelio, F.; Gibbs, M. A.; Mehler, W. R.; Daunton, Nancy G.; Fox, Robert A.

1991-01-01

Immunocytochemical methods were employed to localize the neurotransmitter amino acid gamma-aminobutyric acid (GABA) by means of its biosynthetic enzyme glutamic acid decarboxylase (GAD) and the neuropeptide substance P in the area postrema (AP), area subpostrema (ASP), nucleus of the tractus solitarius (NTS), and gelatinous nucleus (GEL). In addition, electrical stimulation was applied to the night vagus nerve at the cervical level to assess the effects on GAD-immunoreactivity (GAR-IR). GAD-IR terminals and fibers were observed in the AP, ASP, NTS, and GEL. They showed pronounced density at the level of the ASP and gradual decrease towards the solitary complex. Nerve cells were not labelled in our preparations. Ultrastructural studies showed symmetric or asymmetric synaptic contracts between labelled terminals and non-immunoreactive dendrites, axons, or neurons. Some of the labelled terminals contained both clear- and dense-core vesicles. Our preliminary findings, after electrical stimulation of the vagus nerve, revealed a bilateral decrease of GAD-IR that was particularly evident at the level of the ASP. SP-immunoreactive (SP-IR) terminals and fibers showed varying densities in the AP, ASP, NTS, and GEL. In our preparations, the lateral sub-division of the NTS showed the greatest accumulation. The ASP showed medium density of immunoreactive varicosities and terminals and the AP and GEL displayed scattered varicose axon terminals. The electron microscopy revealed that all immunoreactive terminals contained clear-core vesicles which make symmetric or asymmetric synaptic contact with unlabelled dendrites. It is suggested that the GABAergic terminals might correspond to vagal afferent projections and that GAD/GABA and substance P might be co-localized in the same terminal allowing the possibility of a regulated release of the transmitters in relation to demands.

Chemical stability of insulin. 1. Hydrolytic degradation during storage of pharmaceutical preparations.

PubMed

Brange, J; Langkjaer, L; Havelund, S; Vølund, A

1992-06-01

Hydrolysis of insulin has been studied during storage of various preparations at different temperatures. Insulin deteriorates rapidly in acid solutions due to extensive deamidation at residue AsnA21. In neutral formulations deamidation takes place at residue AsnB3 at a substantially reduced rate under formation of a mixture of isoAsp and Asp derivatives. The rate of hydrolysis at B3 is independent of the strength of the preparation, and in most cases the species of insulin, but varies with storage temperature and formulation. Total transformation at B3 is considerably reduced when insulin is in the crystalline as compared to the amorphous or soluble state, indicating that formation of the rate-limiting cyclic imide decreases when the flexibility of the tertiary structure is reduced. Neutral solutions containing phenol showed reduced deamidation probably because of a stabilizing effect of phenol on the tertiary structure (alpha-helix formation) around the deamidating residue, resulting in a reduced probability for formation of the intermediate imide. The ratio of isoAsp/Asp derivative was independent of time and temperature, suggesting a pathway involving only intermediate imide formation, without any direct side-chain hydrolysis. However, increasing formation of Asp relative to isoAsp derivative was observed with decreasing flexibility of the insulin three-dimensional structure in the formulation. In certain crystalline suspensions a cleavage of the peptide bond A8-A9 was observed. Formation of this split product is species dependent: bovine greater than porcine greater than human insulin. The hydrolytic cleavage of the peptide backbone takes place only in preparations containing rhombohedral crystals in addition to free zinc ions.

An automated, open-source pipeline for mass production of digital elevation models (DEMs) from very-high-resolution commercial stereo satellite imagery

NASA Astrophysics Data System (ADS)

Shean, David E.; Alexandrov, Oleg; Moratto, Zachary M.; Smith, Benjamin E.; Joughin, Ian R.; Porter, Claire; Morin, Paul

2016-06-01

We adapted the automated, open source NASA Ames Stereo Pipeline (ASP) to generate digital elevation models (DEMs) and orthoimages from very-high-resolution (VHR) commercial imagery of the Earth. These modifications include support for rigorous and rational polynomial coefficient (RPC) sensor models, sensor geometry correction, bundle adjustment, point cloud co-registration, and significant improvements to the ASP code base. We outline a processing workflow for ˜0.5 m ground sample distance (GSD) DigitalGlobe WorldView-1 and WorldView-2 along-track stereo image data, with an overview of ASP capabilities, an evaluation of ASP correlator options, benchmark test results, and two case studies of DEM accuracy. Output DEM products are posted at ˜2 m with direct geolocation accuracy of <5.0 m CE90/LE90. An automated iterative closest-point (ICP) co-registration tool reduces absolute vertical and horizontal error to <0.5 m where appropriate ground-control data are available, with observed standard deviation of ˜0.1-0.5 m for overlapping, co-registered DEMs (n = 14, 17). While ASP can be used to process individual stereo pairs on a local workstation, the methods presented here were developed for large-scale batch processing in a high-performance computing environment. We are leveraging these resources to produce dense time series and regional mosaics for the Earth's polar regions.

Vibrational Spectroscopy of Cation and Anion Channelrhodopsins

NASA Astrophysics Data System (ADS)

Yi, Adrian S.

Optogenetics is a technique to control and monitor cell activity with light by expression of specific microbial rhodopsins. Cation channelrhodopsins (CCRs) and anion channelrhodopsins (ACRs) have been demonstrated to activate and silence cell activity, respectively. In this dissertation, the molecular mechanisms of two channelrhodopsins are studied: a CCR from Chlamydomonas augustae (CaChR1) and an ACR from Guillardia theta (GtACR1). The recently discovered GtACR1is especially interesting, as it achieves neural silencing with 1/1000th of the light intensity compared to previous microbial rhodopsin silencing ion pumps. Static and time-resolved resonance Raman, FTIR difference, and UV-visible spectroscopies were utilized in addition to various biochemical and genetic techniques to explore the molecular mechanisms of these channelrhodopsins. In CaChR1, Glu169 and Asp299 residues are located nearby the Schiff base (SB) similar to the homologous residues Asp85 and Asp212, which exist in an ionized state in unphotolyzed bacteriorhodopsin (BR) and play a key role in proton pumping. We observe significant changes in the protonation states of the SB, Glu169, and Asp299 of CaChR1 leading up to the open-channel P2 state, where all three groups exist in a charge neutral state. This unusual charge neutrality along with the position of these groups in the CaChR1 ion channel suggests that charge neutrality plays an important role in cation gating and selectivity in these low efficiency CCRs. Significant differences exist in the photocycle and protonation/hydrogen bonding states of key residues inGtACR1compared to BR and CaChR1. Resonance Raman studies reveal that in the unphotolyzed state of GtACR1, residues Glu68, Ser97 (BR Asp85 homolog), and Asp234 (BR Asp212 homolog) located near the SB exist in charge neutral states. Furthermore, upon K formation, these residues do not change their protonation states. At room temperature, a slow decay of the red-shifted K intermediate is observed, which exists in equilibrium with the L intermediate. At 80 K, a lower thermal barrier for K → L transition is observed compared to BR and CaChR1. This effect may be due to substitution of a Met residue at position 105 for the highly conserved Leu or Ile residue.

Mutagenesis of the C2 domain of protein kinase C-alpha. Differential roles of Ca2+ ligands and membrane binding residues.

PubMed

Medkova, M; Cho, W

1998-07-10

The C2 domains of conventional protein kinase C (PKC) have been implicated in their Ca2+-dependent membrane binding. The C2 domain of PKC-alpha contains several Ca2+ ligands that bind multiple Ca2+ ions and other putative membrane binding residues. To understand the roles of individual Ca2+ ligands and protein-bound Ca2+ ions in the membrane binding and activation of PKC-alpha, we mutated five putative Ca2+ ligands (D187N, D193N, D246N, D248N, and D254N) and measured the effects of mutations on vesicle binding, enzyme activity, and monolayer penetration of PKC-alpha. Altered properties of these mutants indicate that individual Ca2+ ions and their ligands have different roles in the membrane binding and activation of PKC-alpha. The binding of Ca2+ to Asp187, Asp193, and Asp246 of PKC-alpha is important for the initial binding of protein to membrane surfaces. On the other hand, the binding of another Ca2+ to Asp187, Asp246, Asp248, and Asp254 induces the conformational change of PKC-alpha, which in turn triggers its membrane penetration and activation. Among these Ca2+ ligands, Asp246 was shown to be most essential for both membrane binding and activation of PKC-alpha, presumably due to its coordination to multiple Ca2+ ions. Furthermore, to identify the residues in the C2 domain that are involved in membrane binding of PKC-alpha, we mutated four putative membrane binding residues (Trp245, Trp247, Arg249, and Arg252). Membrane binding and enzymatic properties of two double-site mutants (W245A/W247A and R249A/R252A) indicate that Arg249 and Arg252 are involved in electrostatic interactions of PKC-alpha with anionic membranes, whereas Trp245 and Trp247 participate in its penetration into membranes and resulting hydrophobic interactions. Taken together, these studies provide the first experimental evidence for the role of C2 domain of conventional PKC as a membrane docking unit as well as a module that triggers conformational changes to activate the protein.

Pinpoint chemical modification of Asp160 in the 49 kDa subunit of bovine mitochondrial complex I via a combination of ligand-directed tosyl chemistry and click chemistry.

PubMed

Masuya, Takahiro; Murai, Masatoshi; Morisaka, Hironobu; Miyoshi, Hideto

2014-12-16

Through a ligand-directed tosyl (LDT) chemistry strategy using the synthetic acetogenin ligand AL1, we succeeded in the pinpoint alkynylation (-C≡CH) of Asp160 in the 49 kDa subunit of bovine complex I, which may be located in the inner part of the putative quinone binding cavity of the enzyme [Masuya, T., et al. (2014) Biochemistry, 53, 2307-2317]. This study provided a promising technique for diverse chemical modifications of complex I. To further improve this technique for its adaptation to intact complex I, we here synthesized the new acetogenin ligand AL2, possessing an azido (-N₃) group in place of the terminal alkyne in AL1, and attempted the pinpoint azidation of complex I in bovine heart submitochondrial particles. Careful proteomic analyses revealed that, just as in the case of AL1, azidation occurred at 49 kDa Asp160 with a reaction yield of ∼50%, verifying the high site specificity of our LDT chemistry using acetogenin ligands. This finding prompted us to speculate that a reactivity of the azido group incorporated into Asp160 (Asp160-N₃) against externally added chemicals can be employed to characterize the structural features of the quinone/inhibitor binding cavity. Consequently, we used a ring-strained cycloalkyne possessing a rhodamine fluorophore (TAMRA-DIBO), which can covalently attach to an azido group via so-called click chemistry without Cu¹⁺ catalysis, as the reaction partner of Asp160-N₃. We found that bulky TAMRA-DIBO is capable of reacting directly with Asp160-N₃ in intact complex I. Unexpectedly, the presence of an excess amount of short-chain ubiquinones as well as some strong inhibitors (e.g., quinazoline and fenpyroximate) did not interfere with the reaction between TAMRA-DIBO and Asp160-N₃; nevertheless, bullatacin, a member of the natural acetogenins, markedly interfered with this reaction. Taking the marked bulkiness of TAMRA-DIBO into consideration, it appears to be difficult to reconcile these results with the proposal that only a narrow entry point accessing to the quinone/inhibitor binding cavity exists in complex I [Baradaran, R., et al. (2013) Nature, 494, 443-448]; rather, they suggest that there may be another access path for TAMRA-DIBO to the cavity.

A Cyclic Nucleotide-Gated Channel Mutation Associated with Canine Daylight Blindness Provides Insight into a Role for the S2 Segment Tri-Asp motif in Channel Biogenesis

PubMed Central

Tanaka, Naoto; Delemotte, Lucie; Klein, Michael L.; Komáromy, András M.; Tanaka, Jacqueline C.

2014-01-01

Cone cyclic nucleotide-gated channels are tetramers formed by CNGA3 and CNGB3 subunits; CNGA3 subunits function as homotetrameric channels but CNGB3 exhibits channel function only when co-expressed with CNGA3. An aspartatic acid (Asp) to asparagine (Asn) missense mutation at position 262 in the canine CNGB3 (D262N) subunit results in loss of cone function (daylight blindness), suggesting an important role for this aspartic acid residue in channel biogenesis and/or function. Asp 262 is located in a conserved region of the second transmembrane segment containing three Asp residues designated the Tri-Asp motif. This motif is conserved in all CNG channels. Here we examine mutations in canine CNGA3 homomeric channels using a combination of experimental and computational approaches. Mutations of these conserved Asp residues result in the absence of nucleotide-activated currents in heterologous expression. A fluorescent tag on CNGA3 shows mislocalization of mutant channels. Co-expressing CNGB3 Tri-Asp mutants with wild type CNGA3 results in some functional channels, however, their electrophysiological characterization matches the properties of homomeric CNGA3 channels. This failure to record heteromeric currents suggests that Asp/Asn mutations affect heteromeric subunit assembly. A homology model of S1–S6 of the CNGA3 channel was generated and relaxed in a membrane using molecular dynamics simulations. The model predicts that the Tri-Asp motif is involved in non-specific salt bridge pairings with positive residues of S3/S4. We propose that the D262N mutation in dogs with CNGB3-day blindness results in the loss of these inter-helical interactions altering the electrostatic equilibrium within in the S1–S4 bundle. Because residues analogous to Tri-Asp in the voltage-gated Shaker potassium channel family were implicated in monomer folding, we hypothesize that destabilizing these electrostatic interactions impairs the monomer folding state in D262N mutant CNG channels during biogenesis. PMID:24586388

Metabolism of aspartame by human and pig intestinal microvillar peptidases.

PubMed Central

Hooper, N M; Hesp, R J; Tieku, S

1994-01-01

The artificial sweetener aspartame (N-L-alpha-aspartyl-L-phenyl-alanine-1-methyl ester; Nutrasweet), its decomposition product alpha Asp-Phe and the related peptide alpha Asp-PheNH2 were rapidly hydrolysed by microvillar membranes prepared from human duodenum, jejunum and ileum, and from pig duodenum and kidney. The metabolism of aspartame by the human and pig intestinal microvillar membrane preparations was inhibited significantly (> 78%) by amastatin or 1,10-phenanthroline, and partially (> 38%) by actinonin or bestatin, and was activated 2.9-4.5-fold by CaCl2. The inhibition by amastatin and 1,10-phenanthroline, and the activation by CaCl2 are characteristic of the cell-surface ectoenzyme aminopeptidase A (EC 3.4.11.7) and a purified preparation of this enzyme hydrolysed aspartame with a Km of 0.25 mM and a Vmax of 126 mumol/min per mg. A purified preparation of aminopeptidase W (EC 3.4.11.16) also hydrolysed aspartame but with a Km of 4.96 mM and a Vmax of 110 mumol/min per mg. However, rentiapril, an inhibitor of aminopeptidase W, caused only slight inhibition (maximally 19%) of the hydrolysis of aspartame by the microvillar membrane preparations. Similar patterns of inhibition and kinetic parameters were observed for alpha Asp-Phe and alpha Asp-PheNH2. Two other decomposition products of aspartame, beta Asp-PheMe and cyclo-Asp-Phe, were essentially resistant to hydrolysis by both the human and pig intestinal microvillar membrane preparations and the purified preparations of aminopeptidases A and W. Although the relatively selective inhibitor of aminopeptidase N (EC 3.4.11.2), actinonin, partially inhibited the metabolism of aspartame, alpha Asp-Phe and alpha Asp-PheNH2 by the human and pig intestinal microvillar membrane preparations, these peptides were not hydrolysed by a purified preparation of aminopeptidase N. Membrane dipeptidase (EC 3.4.13.19) only hydrolysed the unblocked dipeptide, alpha Asp-Phe, but the selective inhibitor of this enzyme, cilastatin, did not block the metabolism of alpha Asp-Phe by the microvillar membrane preparations. PMID:8141778

Effect of early pregnancy diagnosis by per rectum amniotic sac palpation on pregnancy loss, calving rates, and abnormalities in newborn dairy calves.

PubMed

Romano, Juan E; Bryan, Kelsey; Ramos, Roney S; Velez, Juan; Pinedo, Pablo

2016-02-01

The objectives of the present study were to evaluate the effect of per rectal amniotic sac palpation (ASP) for pregnancy diagnosis during the late embryonic period on pregnancy loss, calving rates, and abnormalities in newborn calves. A controlled, randomized, blocked, blind experiment containing 680 lactating pregnant dairy cows with a viable embryo diagnosed by transrectal ultrasonography was performed. Two dairy operation sites (farm A and farm B) were selected. At each farm, the cows were randomly divided into control (CON) and ASP groups. The CON group was not subjected to pregnancy diagnosis via per rectum palpation. The ASP examinations were performed by one experienced veterinarian between Days 34 and 45 after breeding. All cows were reevaluated by transrectal ultrasonography only between 2 and 4 weeks later. Two calving rates were calculated: calving rate 1 (cows that calved from the initial number of pregnant cows) and calving rate 2 (cows that calved from cows pregnant at reexamination). In farm A, the percentages of early pregnancy loss were 11.5% (19 of 165) and 13.2% (24 of 182) for the CON and the ASP groups, respectively (P = 0.64). In farm B, the percentage of early pregnancy loss was 11.2% (19 of 170) for the CON group and 8.8% (14 of 159; P = 0.48) for the ASP group. In farm A, the percentage of late pregnancy loss was 7.6% (11 of 145) for the CON group and 5.5% (8 of 155; P = 0.39) for the ASP group. In farm B, the percentage of late pregnancy loss was 3.7% (5 of 137) for the CON group and 6.3% (8 of 127; P = 0.32) for the ASP group. In farm A, early pregnancy loss was higher than late pregnancy loss (12.4% vs. 6.3%; P = 0.01), and in farm B, the same tendency was detected (10.0% vs. 4.9%, for early and late pregnancy loss, respectively; P = 0.02). In farm A, calving rate 1 was 81.2% (134 of 165) for the CON group and 80.8% (147 of 182; P = 0.92) for the ASP group. Calving rate 2 for the same groups was 92.4% (134 of 145) and 94.8% (147 of 155), respectively (P = 0.68). In farm B, calving rate 1 was 77.7% (132 of 170) for the CON group and 74.8% (119 of 159; P = 0.55) for the ASP group. Calving rates 2 for the same groups were 87.4% (132 of 151) and 82.1% (119 of 145), respectively (P = 0.20). Two female calves with atresia coli were diagnosed only in the CON group. It was concluded that ASP during the late embryonic period for pregnancy diagnosis did not increase the pregnancy loss, affect calving rates, or produce abnormalities in calves. Copyright © 2016 Elsevier Inc. All rights reserved.

Role of C-Terminal Cysteine Residues of Aspergillus fumigatus Allergen Asp f 4 in Immunoglobulin E Binding

PubMed Central

Ramachandran, Harikrishnan; Banerjee, Banani; Greenberger, Paul A.; Kelly, Kevin J.; Fink, Jordan N.; Kurup, Viswanath P.

2004-01-01

Among the several allergens cloned and expressed from Aspergillus fumigatus, Asp f 4 is a major one associated with allergic bronchopulmonary aspergillosis (ABPA). The structure-function relationship of allergens is important in understanding the immunopathogenesis, diagnosis, and treatment of allergic diseases. These include the epitopes, conformational or linear, deletion of the N or C terminus or both N and C termini, and glycosylation or nonglycosylation, all of which affect immune responses. Similarly, the role of cysteine residues present in allergens may yield useful information regarding the conformational structure of allergens and the immunoglobulin E (IgE) epitope interaction. Such information may help in developing new strategies towards immunotherapy. In order to define the role of cysteine in the interaction of the antibody with Asp f 4, we have constructed mutants by selectively deleting cysteine residues from the C-terminal region of the Asp f 4. Immunological evaluation of these engineered recombinant constructs was conducted by using sera from patients with ABPA, Aspergillus skin test-positive asthmatics, and healthy controls. The results demonstrate strong IgE binding with Asp f 4 and two truncated mutants, Asp f 41-234 (amino acids [aa] 1 to 234) and Asp f 41-241 (aa 1 to 241), while another mutant, Asp f 41-196 (aa 1 to 196), showed reactivity with fewer patients. The result suggests that deletion of cysteines and the alteration of IgE epitopes at the C-terminal end resulted in conformational changes, which may have a potential role in the immunomodulation of the disease. PMID:15013973

Implementation of an ASP model offsite backup archive for clinical images utilizing Internet 2

NASA Astrophysics Data System (ADS)

Liu, Brent J.; Chao, Sander S.; Documet, Jorge; Lee, Jasper; Lee, Michael; Topic, Ian; Williams, Lanita

2005-04-01

With the development of PACS technology and an increasing demand by medical facilities to become filmless, there is a need for a fast and efficient method of providing data backup for disaster recovery and downtime scenarios. At the Image Processing Informatics Lab (IPI), an ASP Backup Archive was developed using a fault-tolerant server with a T1 connection to serve the PACS at the St. John's Health Center (SJHC) Santa Monica, California. The ASP archive server has been in clinical operation for more than 18 months, and its performance was presented at this SPIE Conference last year. This paper extends the ASP Backup Archive to serve the PACS at the USC Healthcare Consultation Center II (HCC2) utilizing an Internet2 connection. HCC2 is a new outpatient facility that recently opened in April 2004. The Internet2 connectivity between USC's HCC2 and IPI has been established for over one year. There are two novelties of the current ASP model: 1) Use of Internet2 for daily clinical operation, and 2) Modifying the existing backup archive to handle two sites in the ASP model. This paper presents the evaluation of the ASP Backup Archive based on the following two criteria: 1) Reliability and performance of the Internet2 connection between HCC2 and IPI using DICOM image transfer in a clinical environment, and 2) Ability of the ASP Fault-Tolerant backup archive to support two separate clinical PACS sites simultaneously. The performances of using T1 and Internet2 at the two different sites are also compared.

Social media as a tool for antimicrobial stewardship.

PubMed

Pisano, Jennifer; Pettit, Natasha; Bartlett, Allison; Bhagat, Palak; Han, Zhe; Liao, Chuanhong; Landon, Emily

2016-11-01

To increase the reach of our antimicrobial stewardship program (ASP), social media platforms, Facebook and Twitter, were used to increase internal medicine residents' (IMRs') antibiotic (Abx) knowledge and awareness of ASP resources. Fifty-five of 110 (50%) IMRs consented to participate; 39 (71%) completed both pre- and postintervention surveys and followed our ASP on social media. Along with 20 basic Abx and infectious diseases (IDs) questions, this survey assessed IMR awareness of ASP initiatives, social media usage, and attitudes and beliefs surrounding Abx resistance. Over 6 months, IMRs received posts and Tweets of basic Abx/IDs trivia while promoting use of educational tools and clinical pathways on our ASP Web site. To compare pre- and postsurvey responses, McNemar test or Stuart-Maxwell test was used for categorical variables, and paired t test or Wilcoxon signed-rank test was used for continuous variables, as appropriate. Of the IMRs, 98% and 58% use Facebook and Twitter, respectively. To compare pre- and postintervention, median scores for Abx knowledge increased from 12 (interquartile range, 8-13) to 13 (interquartile range, 11-15; P = .048); IMRs knowing how to access the ASP Web site increased from 70% to 94%. More IMRs indicated that they used the clinical pathways "sometimes, frequently, or always" after the intervention (33% vs 61%, P = .004). Social media is a valuable tool to reinforce ASP initiatives while encouraging the use of ASP resources to promote antimicrobial mindfulness. Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

Brain stimulation over Broca’s area differentially modulates naming skills in neurotypical adults and individuals with Asperger’s syndrome

PubMed Central

Fecteau, Shirley; Agosta, Sara; Oberman, Lindsay; Pascual-Leone, Alvaro

2012-01-01

In the present study we tested the hypothesis that, in subjects with Asperger’s syndrome (ASP), the dynamics of language-related regions might be abnormal, so that repetitive transcranial magnetic stimulation (rTMS) over Broca’s area leads to differential behavioral effects as seen in neurotypical controls. We conducted a five-stimulation-site, double-blind, multiple crossover, pseudo-randomized, sham-controlled study in 10 individuals with ASP and 10 age- and gender-matched healthy subjects. Object naming was assessed before and after low-frequency rTMS of the left pars opercularis, left pars triangularis, right pars opercularis and right pars triangularis, and sham stimulation, as guided stereotaxically by each individual’s brain magnetic resonance imaging. In ASP participants, naming improved after rTMS of the left pars triangularis as compared with sham stimulation, whereas rTMS of the adjacent left opercularis lengthened naming latency. In healthy subjects, stimulation of parts of Broca’s area did not lead to significant changes in naming skills, consistent with published data. Overall, these findings support our hypothesis of abnormal language neural network dynamics in individuals with ASP. From a methodological point of view, this work illustrates the use of rTMS to study the dynamics of brain–behavior relations by revealing the differential behavioral impact of non-invasive brain stimulation in a neuropsychiatric disorder. PMID:21676037

26 CFR 51.4T - Information provided by the agencies (temporary).

Code of Federal Regulations, 2013 CFR

2013-04-01

... sales price (ASP) for each Healthcare Common Procedure Coding System (HCPCS) code for the sales year...IdentifiableDataFiles/03_PartBNationalSummaryDataFile.asp to obtain the number of allowed billing units per... respective NDCs) manufactured by a single entity, CMS will multiply the annual weighted ASP by the total...

26 CFR 51.4T - Information provided by the agencies (temporary).

Code of Federal Regulations, 2014 CFR

2014-04-01

... sales price (ASP) for each Healthcare Common Procedure Coding System (HCPCS) code for the sales year...IdentifiableDataFiles/03_PartBNationalSummaryDataFile.asp to obtain the number of allowed billing units per... respective NDCs) manufactured by a single entity, CMS will multiply the annual weighted ASP by the total...

26 CFR 51.4T - Information provided by the agencies (temporary).

Code of Federal Regulations, 2012 CFR

2012-04-01

... sales price (ASP) for each Healthcare Common Procedure Coding System (HCPCS) code for the sales year...IdentifiableDataFiles/03_PartBNationalSummaryDataFile.asp to obtain the number of allowed billing units per... respective NDCs) manufactured by a single entity, CMS will multiply the annual weighted ASP by the total...

Defining Standards and Policies for Promoting Physical Activity in Afterschool Programs

ERIC Educational Resources Information Center

Beets, Michael W.; Wallner, Megan; Beighle, Aaron

2010-01-01

Background: National guidelines exist that define "quality" afterschool programs (3-6 pm, ASP). No widely adopted national standards/policies exist, however, for ASP providers for the promotion of physical activity (PA). To address this gap, state-level ASP organizations have developed or adopted standards/policies related to PA. The extent to…

75 FR 57271 - Creating an Offshore Wind Industry in the United States: A National Vision

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-20

... Webinar is available at: http://www.windpoweringamerica.gov/filter_detail.asp?itemid=2817 . Information on the September 21 seminar is available at: http://www.windpoweringamerica.gov/filter_detail.asp?itemid.../filter_detail.asp?itemid=2820 . Disclaimer DOE will not reimburse costs associated with participation in...

Impact of magnetic isolation on pointing system performance in the presence of structural flexibility

NASA Technical Reports Server (NTRS)

Seller, J.

1985-01-01

The inertial pointing stability of a gimbal pointing system (AGS) was compared with a magnetic pointing/gimbal followup system (ASPS), under certain conditions of system structural flexibility and disturbance inputs from the gimbal support structure. Separate 3 degree-of-freedom (3DOF) linear models based on NASTRAN modal flexibility data for the gimbal and support structures were generated for the ASPS configurations. Using the models inertial pointing control loops providing 6dB of gain margin and 45 deg of phase margin were defined for each configuration. The pointing loop bandwidth obtained for the ASPS is more than twice the level achieved for the AGS configuration. The AGS limit is attributed to the gimbal and support structure flexibility. As a result of the higher ASPS pointing loop bandwidth and the disturbance rejection provided by the magnetic isolation ASPS pointing performane is significantly better than that of the AGS system. The low frequency peak of the ASPS transfer function from base disturbance to payload angular motion is almost 60dB lower than AGS low frequency peak.

Molecular Mechanisms Elicited by d-Aspartate in Leydig Cells and Spermatogonia

PubMed Central

Di Fiore, Maria Maddalena; Santillo, Alessandra; Falvo, Sara; Longobardi, Salvatore; Chieffi Baccari, Gabriella

2016-01-01

A bulk of evidence suggests that d-aspartate (d-Asp) regulates steroidogenesis and spermatogenesis in vertebrate testes. This review article focuses on intracellular signaling mechanisms elicited by d-Asp possibly via binding to the N-methyl-d-aspartate receptor (NMDAR) in both Leydig cells, and spermatogonia. In Leydig cells, the amino acid upregulates androgen production by eliciting the adenylate cyclase-cAMP and/or mitogen-activated protein kinase (MAPK) pathways. d-Asp treatment enhances gene and protein expression of enzymes involved in the steroidogenic cascade. d-Asp also directly affects spermatogonial mitotic activity. In spermatogonial GC-1 cells, d-Asp induces phosphorylation of MAPK and AKT serine-threonine kinase proteins, and stimulates expression of proliferating cell nuclear antigen (PCNA) and aurora kinase B (AURKB). Further stimulation of spermatogonial GC-1 cell proliferation might come from estradiol/estrogen receptor β (ESR2) interaction. d-Asp modulates androgen and estrogen levels as well as the expression of their receptors in the rat epididymis by acting on mRNA levels of Srd5a1 and Cyp19a1 enzymes, hence suggesting involvement in spermatozoa maturation. PMID:27428949

Changes in D-aspartic acid and D-glutamic acid levels in the tissues and physiological fluids of mice with various D-aspartate oxidase activities.

PubMed

Han, Hai; Miyoshi, Yurika; Koga, Reiko; Mita, Masashi; Konno, Ryuichi; Hamase, Kenji

2015-12-10

D-Aspartic acid (D-Asp) and D-glutamic acid (D-Glu) are currently paid attention as modulators of neuronal transmission and hormonal secretion. These two D-amino acids are metabolized only by D-aspartate oxidase (DDO) in mammals. Therefore, in order to design and develop new drugs controlling the D-Asp and D-Glu amounts via regulation of the DDO activities, changes in these acidic D-amino acid amounts in various tissues are expected to be clarified in model animals having various DDO activities. In the present study, the amounts of Asp and Glu enantiomers in 6 brain tissues, 11 peripheral tissues and 2 physiological fluids of DDO(+/+), DDO(+/-) and DDO(-/-) mice were determined using a sensitive and selective two-dimensional HPLC system. As a result, the amounts of D-Asp were drastically increased with the decrease in the DDO activity in all the tested tissues and physiological fluids. On the other hand, the amounts of D-Glu were almost the same among the 3 strains of mice. The present results are useful for designing new drug candidates, such as DDO inhibitors, and further studies are expected. Copyright © 2015 Elsevier B.V. All rights reserved.

Flexible Xxx–Asp/Asn and Gly–Xxx Residues of Equine Cytochrome c in Matrix-Assisted Laser Desorption/Ionization In-Source Decay Mass Spectrometry

PubMed Central

Takayama, Mitsuo

2012-01-01

The backbone flexibility of a protein has been studied from the standpoint of the susceptibility of amino acid residues to in-source decay (ISD) in matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS). Residues more susceptible to MALDI-ISD, namely Xxx–Asp/Asn and Gly–Xxx, were identified from the discontinuous intense peak of c′-ions originating from specific cleavage at N–Cα bonds of the backbone of equine cytochrome c. The identity of the residues susceptible to ISD was consistent with the known flexible backbone amides as estimated by hydrogen/deuterium exchange (HDX) experiments. The identity of these flexible amino acid residues (Asp, Asn, and Gly) is consistent with the fact that these residues are preferred in flexible secondary structure free from intramolecular hydrogen-bonded structures such as α-helix and β-sheet. The MALDI-ISD spectrum of equine cytochrome c gave not only intense N-terminal side c′-ions originating from N–Cα bond cleavage at Xxx–Asp/Asn and Gly–Xxx residues, but also C-terminal side complement z′-ions originating from the same cleavage sites. The present study implies that MALDI-ISD can give information about backbone flexibility of proteins, comparable with the protection factors estimated by HDX. PMID:24349908

Flexible xxx-asp/asn and gly-xxx residues of equine cytochrome C in matrix-assisted laser desorption/ionization in-source decay mass spectrometry.

PubMed

Takayama, Mitsuo

2012-01-01

The backbone flexibility of a protein has been studied from the standpoint of the susceptibility of amino acid residues to in-source decay (ISD) in matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS). Residues more susceptible to MALDI-ISD, namely Xxx-Asp/Asn and Gly-Xxx, were identified from the discontinuous intense peak of c'-ions originating from specific cleavage at N-Cα bonds of the backbone of equine cytochrome c. The identity of the residues susceptible to ISD was consistent with the known flexible backbone amides as estimated by hydrogen/deuterium exchange (HDX) experiments. The identity of these flexible amino acid residues (Asp, Asn, and Gly) is consistent with the fact that these residues are preferred in flexible secondary structure free from intramolecular hydrogen-bonded structures such as α-helix and β-sheet. The MALDI-ISD spectrum of equine cytochrome c gave not only intense N-terminal side c'-ions originating from N-Cα bond cleavage at Xxx-Asp/Asn and Gly-Xxx residues, but also C-terminal side complement z'-ions originating from the same cleavage sites. The present study implies that MALDI-ISD can give information about backbone flexibility of proteins, comparable with the protection factors estimated by HDX.

The glutaminase activity of l-asparaginase is not required for anticancer activity against ASNS-negative cells

PubMed Central

Chan, Wai Kin; Lorenzi, Philip L.; Anishkin, Andriy; Purwaha, Preeti; Rogers, David M.; Sukharev, Sergei; Rempe, Susan B.; Weinstein, John N.

2014-01-01

l-Asparaginase (l-ASP) is a key component of therapy for acute lymphoblastic leukemia. Its mechanism of action, however, is still poorly understood, in part because of its dual asparaginase and glutaminase activities. Here, we show that l-ASP’s glutaminase activity is not always required for the enzyme’s anticancer effect. We first used molecular dynamics simulations of the clinically standard Escherichia coli l-ASP to predict what mutated forms could be engineered to retain activity against asparagine but not glutamine. Dynamic mapping of enzyme substrate contacts identified Q59 as a promising mutagenesis target for that purpose. Saturation mutagenesis followed by enzymatic screening identified Q59L as a variant that retains asparaginase activity but shows undetectable glutaminase activity. Unlike wild-type l-ASP, Q59L is inactive against cancer cells that express measurable asparagine synthetase (ASNS). Q59L is potently active, however, against ASNS-negative cells. Those observations indicate that the glutaminase activity of l-ASP is necessary for anticancer activity against ASNS-positive cell types but not ASNS-negative cell types. Because the clinical toxicity of l-ASP is thought to stem from its glutaminase activity, these findings suggest the hypothesis that glutaminase-negative variants of l-ASP would provide larger therapeutic indices than wild-type l-ASP for ASNS-negative cancers. PMID:24659632

Antimicrobial Stewardship Programs: Appropriate Measures and Metrics to Study their Impact.

PubMed

Morris, Andrew M

Antimicrobial stewardship is a new field that struggles to find the right balance between meaningful and useful metrics to study the impact of antimicrobial stewardship programs (ASPs). ASP metrics primarily measure antimicrobial use, although microbiological resistance and clinical outcomes are also important measures of the impact an ASP has on a hospital and its patient population. Antimicrobial measures looking at consumption are the most commonly used measures, and are focused on defined daily doses, days of therapy, and costs, usually standardized per 1,000 patient-days. Each measure provides slightly different information, with their own upsides and downfalls. Point prevalence measurement of antimicrobial use is an increasingly used approach to understanding consumption that does not entirely rely on sophisticated electronic information systems, and is also replicable. Appropriateness measures hold appeal and promise, but have not been developed to the degree that makes them useful and widely applicable. The primary reason why antimicrobial stewardship is necessary is the growth of antimicrobial resistance. Accordingly, antimicrobial resistance is an important metric of the impact of an ASP. The most common approach to measuring resistance for ASP purposes is to report rates of common or important community- or nosocomial-acquired antimicrobial-resistant organisms, such as methicillin-resistant Staphylococcus aureus and Clostridium difficile. Such an approach is dependent on detection methods, community rates of resistance, and co-interventions, and therefore may not be the most accurate or reflective measure of antimicrobial stewardship interventions. Development of an index to reflect the net burden of resistance holds theoretical promise, but has yet to be realized. Finally, programs must consider patient outcome measures. Mortality is the most objective and reliable method, but has several drawbacks. Disease- or organism-specific mortality, or cure, are increasingly used metrics.

Physical and Social-Motivational Contextual Correlates of Youth Physical Activity in Underresourced Afterschool Programs.

PubMed

Zarrett, Nicole; Sorensen, Carl; Cook, Brittany Skiles

2015-08-01

Afterschool programs (ASPs) have become increasingly recognized as a key context to support youth daily physical activity (PA) accrual. The purpose of the present study was to assess the physical and social-motivational climate characteristics of ASPs associated with youth PA, and variations in contextual correlates of PA by youth sex. Systematic observations of 7 ASPs serving underserved youth (minority, low income) was conducted using the System for Observing Play and Leisure Activity in Youth and a social-motivational climate observation tool founded on self-determination theory. For five program days at each site, teams of two coders conducted continuous observations of youth PA (sedentary, moderate, vigorous), five physical features (e.g., equipment availability), eight staff interactions (e.g., encourage PA), and seven motivational climate components (e.g., inclusive). Aligned with previous research, regressions controlling for variations by site indicated that organized PA, provision of portable equipment, and staff PA participation and supervision are key correlates of youth PA. Moreover, as the first study to systematically observe motivational-context characteristics of ASPs, we identified several key modifiable motivational features that are necessary to address in order to increase youth engagement in PA during the out-of-school hours. Among motivational features assessed, "relatedness" components (positive peer relations, inclusive/cooperative activities) were primary correlates of girls' PA. In contrast, all three motivational features specified by self-determination theory (support for autonomy, mastery/competence, and inclusion/relatedness) were correlated with boys' PA. Findings are discussed in terms of policy and practice for understanding strengths and needs of ASPs to effectively engage youth in PA. © 2015 Society for Public Health Education.

The selective conversion of glutamic acid in amino acid mixtures using glutamate decarboxylase--a means of separating amino acids for synthesizing biobased chemicals.

PubMed

Teng, Yinglai; Scott, Elinor L; Sanders, Johan P M

2014-01-01

Amino acids (AAs) derived from hydrolysis of protein rest streams are interesting feedstocks for the chemical industry due to their functionality. However, separation of AAs is required before they can be used for further applications. Electrodialysis may be applied to separate AAs, but its efficiency is limited when separating AAs with similar isoelectric points. To aid the separation, specific conversion of an AA to a useful product with different charge behavior to the remaining compounds is desired. Here the separation of L-aspartic acid (Asp) and L-glutamic acid (Glu) was studied. L-Glutamate α-decarboxylase (GAD, Type I, EC 4.1.1.15) was applied to specifically convert Glu into γ-aminobutyric acid (GABA). GABA has a different charge behavior from Asp therefore allowing a potential separation by electrodialysis. Competitive inhibition and reduced operational stability caused by Asp could be eliminated by maintaining a sufficiently high concentration of Glu. Immobilization of GAD does not reduce the enzyme's initial activity. However, the operational stability was slightly reduced. An initial study on the reaction operating in a continuous mode was performed using a column reactor packed with immobilized GAD. As the reaction mixture was only passed once through the reactor, the conversion of Glu was lower than expected. To complete the conversion of Glu, the stream containing Asp and unreacted Glu might be recirculated back to the reactor after GABA has been removed. Overall, the reaction by GAD is specific to Glu and can be applied to aid the electrodialysis separation of Asp and Glu. © 2014 American Institute of Chemical Engineers.

Point-of-care Beta-lactam Allergy Skin Testing by Antimicrobial Stewardship Programs: A Pragmatic Multicenter Prospective Evaluation.

PubMed

Leis, Jerome A; Palmay, Lesley; Ho, Grace; Raybardhan, Sumit; Gill, Suzanne; Kan, Tiffany; Campbell, Jackie; Kiss, Alex; McCready, Janine B; Das, Pavani; Minnema, Brian; Powis, Jeff E; Walker, Sandra A N; Ferguson, Heather; Wong, Benny; Weber, Elizabeth

2017-06-01

Beta-lactam allergy skin testing (BLAST) is recommended by antimicrobial stewardship program (ASP) guidelines, yet few studies have systematically evaluated its impact when delivered at point-of-care. We conducted a pragmatic multicenter prospective evaluation of the use of point-of-care BLAST by ASPs. In staggered 3-month intervals, ASP teams at three hospitals received training by allergists to offer BLAST for eligible patients with infectious diseases receiving non-preferred beta-lactam therapy due to severity of their allergy. The primary outcome was the proportion of patients receiving the preferred beta-lactam therapy. Of 827 patients with reported beta-lactam allergy over 15-months, beta-lactam therapy was preferred among 632(76%). During baseline periods, 50% (124/246) received preferred beta-lactam therapy based on history, compared with 60% (232/386) during the intervention periods (p=0.02), which improved further to 81% (313/386) upon provision of BLAST (p<0.001) without any increase in incidence of adverse drug reactions (4% vs. 3%; p=0.4). After adjusting for patient variables and the correlation between hospitals, the intervention period was associated with a 4.5-fold greater odds of receiving preferred beta-lactam therapy (95% CI, 2.4-8.2; p<0.0001). The use of BLAST at the point-of-care across three hospital ASPs resulted in greater use of preferred beta-lactam therapy without increasing the risk of adverse drug reactions. Longer term studies are needed to better assess the safety and clinical impact of this ASP intervention. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Amyloid-β peptide structure in aqueous solution varies with fragment size

NASA Astrophysics Data System (ADS)

Wise-Scira, Olivia; Xu, Liang; Kitahara, Taizo; Perry, George; Coskuner, Orkid

2011-11-01

Various fragment sizes of the amyloid-β (Aβ) peptide have been utilized to mimic the properties of the full-length Aβ peptide in solution. Among these smaller fragments, Aβ16 and Aβ28 have been investigated extensively. In this work, we report the structural and thermodynamic properties of the Aβ16, Aβ28, and Aβ42 peptides in an aqueous solution environment. We performed replica exchange molecular dynamics simulations along with thermodynamic calculations for investigating the conformational free energies, secondary and tertiary structures of the Aβ16, Aβ28, and Aβ42 peptides. The results show that the thermodynamic properties vary from each other for these peptides. Furthermore, the secondary structures in the Asp1-Lys16 and Asp1-Lys28 regions of Aβ42 cannot be completely captured by the Aβ16 and Aβ28 fragments. For example, the β-sheet structures in the N-terminal region of Aβ16 and Aβ28 are either not present or the abundance is significantly decreased in Aβ42. The α-helix and β-sheet abundances in Aβ28 and Aβ42 show trends - to some extent - with the potential of mean forces but no such trend could be obtained for Aβ16. Interestingly, Arg5 forms salt bridges with large abundances in all three peptides. The formation of a salt bridge between Asp23-Lys28 is more preferred over the Glu22-Lys28 salt bridge in Aβ28 but this trend is vice versa for Aβ42. This study shows that the Asp1-Lys16 and Asp1-Lys28 regions of the full length Aβ42 peptide cannot be completely mimicked by studying the Aβ16 and Aβ28 peptides.

"We Only Speak English Here": English Dominance in Language Diverse, Immigrant After-School Programs

ERIC Educational Resources Information Center

Gast, Melanie Jones; Okamoto, Dina G.; Feldman, Valerie

2017-01-01

Past research suggests that community after-school programs (ASPs) are crucial sites for culturally relevant programming for minority and immigrant youth; yet, we know little about how ASPs address language in their programming. Using an ethnographic fieldwork approach, we examine the goals and practices of ASP workers serving immigrant youth with…

77 FR 16113 - ASP Ventures Corp., Order of Suspension of Trading

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-19

... SECURITIES AND EXCHANGE COMMISSION [File No. 500-1] ASP Ventures Corp., Order of Suspension of Trading March 15, 2012. It appears to the Securities and Exchange Commission that there is a lack of current and accurate information concerning the securities of ASP Ventures Corp. because it has not filed any periodic reports since the period ended...

Salty or Sweet? Nutritional Quality, Consumption, and Cost of Snacks Served in Afterschool Programs

ERIC Educational Resources Information Center

Beets, Michael W.; Weaver, Robert G.; Tilley, Falon; Turner-McGrievy, Gabrielle; Huberty, Jennifer; Ward, Dianne S.; Freedman, Darcy A.

2015-01-01

Background: Snacks served in afterschool programs (ASPs, 3-6?pm) represent an important opportunity to promote healthy eating. ASP policies suggest a fruit/vegetable is served daily, while sugar-sweetened foods/beverages and artificially flavored snacks are eliminated. Limited information exists on the types of snacks served in ASPs, if snacks…

Identifying Strategies Programs Adopt to Meet Healthy Eating and Physical Activity Standards in Afterschool Programs

ERIC Educational Resources Information Center

Weaver, Robert G.; Moore, Justin B.; Turner-McGrievy, Brie; Saunders, Ruth; Beighle, Aaron; Khan, M. Mahmud; Chandler, Jessica; Brazendale, Keith; Randell, Allison; Webster, Collin; Beets, Michael W.

2017-01-01

Background: The YMCA of USA has adopted Healthy Eating and Physical Activity (HEPA) Standards for its afterschool programs (ASPs). Little is known about strategies YMCA ASPs are implementing to achieve Standards and these strategies' effectiveness. Aims: (1) Identify strategies implemented in YMCA ASPs and (2) evaluate the relationship between…

Fault-tolerant back-up archive using an ASP model for disaster recovery

NASA Astrophysics Data System (ADS)

Liu, Brent J.; Huang, H. K.; Cao, Fei; Documet, Luis; Sarti, Dennis A.

2002-05-01

A single point of failure in PACS during a disaster scenario is the main archive storage and server. When a major disaster occurs, it is possible to lose an entire hospital's PACS data. Few current PACS archives feature disaster recovery, but the design is limited at best. These drawbacks include the frequency with which the back-up is physically removed to an offsite facility, the operational costs associated to maintain the back-up, the ease-of-use to perform the backup consistently and efficiently, and the ease-of-use to perform the PACS image data recovery. This paper describes a novel approach towards a fault-tolerant solution for disaster recovery of short-term PACS image data using an Application Service Provider model for service. The ASP back-up archive provides instantaneous, automatic backup of acquired PACS image data and instantaneous recovery of stored PACS image data all at a low operational cost. A back-up archive server and RAID storage device is implemented offsite from the main PACS archive location. In the example of this particular hospital, it was determined that at least 2 months worth of PACS image exams were needed for back-up. Clinical data from a hospital PACS is sent to this ASP storage server in parallel to the exams being archived in the main server. A disaster scenario was simulated and the PACS exams were sent from the offsite ASP storage server back to the hospital PACS. Initially, connectivity between the main archive and the ASP storage server is established via a T-1 connection. In the future, other more cost-effective means of connectivity will be researched such as the Internet 2. A disaster scenario was initiated and the disaster recovery process using the ASP back-up archive server was success in repopulating the clinical PACS within a short period of time. The ASP back-up archive was able to recover two months of PACS image data for comparison studies with no complex operational procedures. Furthermore, no image data loss was encountered during the recovery.

Long QT syndrome type 5-Lite: Defining the clinical phenotype associated with the potentially proarrhythmic p.Asp85Asn-KCNE1 common genetic variant.

PubMed

Lane, Conor; Giudicessi, John R; Ye, Dan; Tester, David J; Rohatgi, Ram K; Bos, J Martijn; Ackerman, Michael J

2018-04-03

Long QT syndrome (LQTS) genetic test reports commonly exclude potentially proarrhythmic common variants such as p.Asp85Asn-KCNE1. The purpose of this study was to determine whether a discernible phenotype is associated with p.Asp85Asn-KCNE1 and whether relatively common KCNE1 variants underlie transient QT prolongation pedigrees with negative commercial LQTS genetic tests. Retrospective review was used to compare demographics, symptomatology, and QT parameters of individuals with p.Asp85Asn-KCNE1 in the absence of other rare/ultra-rare variants in LQTS-susceptibility genes and those who underwent comprehensive LQTS genetic testing. Compared to the Genome Aggregation Database, p.Asp85Asn-KCNE1 was more prevalent in individuals undergoing LQTS genetic testing (33/1248 [2.6%] vs 1552/126,652 [1.2%]; P = .0001). In 19 of 33 patients (58%), only p.Asp85Asn-KCNE1 was observed. These patients were predominantly female (90% vs 62%; P = .02) and were less likely to experience syncope (0% vs 34%; P = .0007), receive β-blockers (53% vs 85%; P = .001), or require an implantable cardioverter-defibrillator (5.3% vs 33%; P = .01). However, they exhibited a similar degree of QT prolongation (QTc 460 ms vs 467 ms; P = NS). Whole exome sequencing of 2 commercially genotype-negative pedigrees revealed that p.Asp85Asn-KCNE1 and p.Arg36His-KCNE1 traced with a transient QT prolongation phenotype. Functional characterization of p.Arg36His-KCNE1 demonstrated loss of function, with a 47% reduction in peak I Ks current density in the heterozygous state. We provide further evidence that relatively common variants in KCNE1 may result in a mild QT phenotype designated as "LQT5-Lite" to distinguish such potentially proarrhythmic common variants (ie, functional risk alleles) from rare pathogenic variants that truly confer monogenic disease susceptibility, albeit with incomplete penetrance. Copyright © 2018. Published by Elsevier Inc.

Making healthy eating and physical activity policy practice: the design and overview of a group randomized controlled trial in afterschool programs.

PubMed

Beets, Michael W; Glenn Weaver, R; Turner-McGrievy, Gabrielle; Huberty, Jennifer; Ward, Dianne S; Freedman, Darcy A; Saunders, Ruth; Pate, Russell R; Beighle, Aaron; Hutto, Brent; Moore, Justin B

2014-07-01

National and state organizations have developed policies calling upon afterschool programs (ASPs, 3-6 pm) to serve a fruit or vegetable (FV) each day for snack, while eliminating foods and beverages high in added-sugars, and to ensure children accumulate a minimum of 30 min/d of moderate-to-vigorous physical activity (MVPA). Few efficacious and cost-effective strategies exist to assist ASP providers in achieving these important public health goals. This paper reports on the design and conceptual framework of Making Healthy Eating and Physical Activity (HEPA) Policy Practice in ASPs, a 3-year group randomized controlled trial testing the effectiveness of strategies designed to improve snacks served and increase MVPA in children attending community-based ASPs. Twenty ASPs, serving over 1800 children (6-12 years) will be enrolled and match-paired based on enrollment size, average daily min/d MVPA, and days/week FV served, with ASPs randomized after baseline data collection to immediate intervention or a 1-year delayed group. The framework employed, STEPs (Strategies To Enhance Practice), focuses on intentional programming of HEPA in each ASPs' daily schedule, and includes a grocery store partnership to reduce price barriers to purchasing FV, professional development training to promote physical activity to develop core physical activity competencies, as well as ongoing technical support/assistance. Primary outcome measures include children's accelerometry-derived MVPA and time spend sedentary while attending an ASP, direct observation of staff HEPA promoting and inhibiting behaviors, types of snacks served, and child consumption of snacks, as well as, cost of snacks via receipts and detailed accounting of intervention delivery costs to estimate cost-effectiveness. Copyright © 2014 Elsevier Inc. All rights reserved.

Pharmacist-driven antimicrobial stewardship program in an institution without infectious diseases physician support.

PubMed

Waters, C Dustin

2015-03-15

Improved drug-utilization and cost outcomes achieved by a pharmacist-led antimicrobial stewardship program (ASP) are described. Pharmacists may be tasked to lead ASP development and implementation with little or no support from an infectious diseases (ID) physician and other hospital personnel whose involvement on ASP teams is recommended (e.g., clinical microbiologists, infection control specialists, hospital epidemiologists). Several years ago, Intermountain Healthcare's 325-bed McKay-Dee Hospital in Utah implemented an ASP led by an antimicrobial stewardship pharmacist. In addition to reviewing patient profiles and meeting with physicians to discuss cases daily (Monday-Friday), the pharmacist was available to provide afterhours phone consultations; support was provided by an infection prevention nurse, two physician ASP champions, the pharmacy leadership, pharmacy informatics and hospital laboratory personnel, and the chief medical officer. In the program's first 33 months, the pharmacist made a total of 2,457 interventions or recommendations, with an acceptance rate of 91.8%. Comparison of selected outcomes during one-year periods before and after ASP implementation indicated substantial decreases in the utilization of four commonly used antimicrobial agents and classes (carbapenems, daptomycin, echinocandins, and levofloxacin) in the postimplementation period, with a significant decline in the average length of stay for community-acquired pneumonia (mean ± S.D., 2.69 ± 0.10 days versus 3.40 ± 0.23 days; p = 0.03). Two years after ASP implementation, annual cost savings attributed to the program were estimated at $355,000. In the absence of ID physician support and oversight, the pharmacist-led ASP achieved substantial reductions in antimicrobial utilization and associated expenditures. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

The Bacillus subtilis and Bacillus halodurans Aspartyl-tRNA Synthetases Retain Recognition of tRNA(Asn).

PubMed

Nair, Nilendra; Raff, Hannah; Islam, Mohammed Tarek; Feen, Melanie; Garofalo, Denise M; Sheppard, Kelly

2016-02-13

Synthesis of asparaginyl-tRNA (Asn-tRNA(Asn)) in bacteria can be formed either by directly ligating Asn to tRNA(Asn) using an asparaginyl-tRNA synthetase (AsnRS) or by synthesizing Asn on the tRNA. In the latter two-step indirect pathway, a non-discriminating aspartyl-tRNA synthetase (ND-AspRS) attaches Asp to tRNA(Asn) and the amidotransferase GatCAB transamidates the Asp to Asn on the tRNA. GatCAB can be similarly used for Gln-tRNA(Gln) formation. Most bacteria are predicted to use only one route for Asn-tRNA(Asn) formation. Given that Bacillus halodurans and Bacillus subtilis encode AsnRS for Asn-tRNA(Asn) formation and Asn synthetases to synthesize Asn and GatCAB for Gln-tRNA(Gln) synthesis, their AspRS enzymes were thought to be specific for tRNA(Asp). However, we demonstrate that the AspRSs are non-discriminating and can be used with GatCAB to synthesize Asn. The results explain why B. subtilis with its Asn synthetase genes knocked out is still an Asn prototroph. Our phylogenetic analysis suggests that this may be common among Firmicutes and 30% of all bacteria. In addition, the phylogeny revealed that discrimination toward tRNA(Asp) by AspRS has evolved independently multiple times. The retention of the indirect pathway in B. subtilis and B. halodurans likely reflects the ancient link between Asn biosynthesis and its use in translation that enabled Asn to be added to the genetic code. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Modeling the Complex Photochemistry of Biomass Burning Plumes in Plume-Scale, Regional, and Global Air Quality Models

NASA Astrophysics Data System (ADS)

Alvarado, M. J.; Lonsdale, C. R.; Yokelson, R. J.; Travis, K.; Fischer, E. V.; Lin, J. C.

2014-12-01

Forecasting the impacts of biomass burning (BB) plumes on air quality is difficult due to the complex photochemistry that takes place in the concentrated young BB plumes. The spatial grid of global and regional scale Eulerian models is generally too large to resolve BB photochemistry, which can lead to errors in predicting the formation of secondary organic aerosol (SOA) and O3, as well as the partitioning of NOyspecies. AER's Aerosol Simulation Program (ASP v2.1) can be used within plume-scale Lagrangian models to simulate this complex photochemistry. We will present results of validation studies of the ASP model against aircraft observations of young BB smoke plumes. We will also present initial results from the coupling of ASP v2.1 into the Lagrangian particle dispersion model STILT-Chem in order to better examine the interactions between BB plume chemistry and dispersion. In addition, we have used ASP to develop a sub-grid scale parameterization of the near-source chemistry of BB plumes for use in regional and global air quality models. The parameterization takes inputs from the host model, such as solar zenith angle, temperature, and fire fuel type, and calculates enhancement ratios of O3, NOx, PAN, aerosol nitrate, and other NOy species, as well as organic aerosol (OA). We will present results from the ASP-based BB parameterization as well as its implementation into the global atmospheric composition model GEOS-Chem for the SEAC4RS campaign.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Chunya; Skelton, Adam A.; Chen, Mingjun

Here the binding of a negatively charged residue, aspartic acid (Asp) in tripeptide arginine-glycine-aspartic acid, onto a negatively charged hydroxylated rutile (110) surface in aqueous solution, containing divalent (Mg 2+, Ca 2+, or Sr 2+) or monovalent (Na +, K +, or Rb +) cations, was studied by molecular dynamics (MD) simulations. The results indicate that ionic radii and charges will significantly affect the hydration, adsorption geometry, and distance of cations from the rutile surface, thereby regulating the Asp/rutile binding mode. The adsorption strength of monovalent cations on the rutile surface in the order Na + > K + >more » Rb + shows a “reverse” lyotropic trend, while the divalent cations on the same surface exhibit a “regular” lyotropic behavior with decreasing crystallographic radii (the adsorption strength of divalent cations: Sr 2+ > Ca 2+ > Mg 2+). The Asp side chain in NaCl, KCl, and RbCl solutions remains stably H-bonded to the surface hydroxyls and the inner-sphere adsorbed compensating monovalent cations act as a bridge between the COO – group and the rutile, helping to “trap” the negatively charged Asp side chain on the negatively charged surface. In contrast, the mediating divalent cations actively participate in linking the COO– group to the rutile surface; thus the Asp side chain can remain stably on the rutile (110) surface, even if it is not involved in any hydrogen bonds with the surface hydroxyls. Inner- and outer-sphere geometries are all possible mediation modes for divalent cations in bridging the peptide to the rutile surface.« less

Ca-asp bound X-ray structure and inhibition of Bacillus anthracis dihydroorotase (DHOase).

PubMed

Rice, Amy J; Lei, Hao; Santarsiero, Bernard D; Lee, Hyun; Johnson, Michael E

2016-10-01

Dihydroorotase (DHOase) is the third enzyme in the de novo pyrimidine synthesis pathway and is responsible for the reversible cyclization of carbamyl-aspartate (Ca-asp) to dihydroorotate (DHO). DHOase is further divided into two classes based on several structural characteristics, one of which is the length of the flexible catalytic loop that interacts with the substrate, Ca-asp, regulating the enzyme activity. Here, we present the crystal structure of Class I Bacillus anthracis DHOase with Ca-asp in the active site, which shows the peptide backbone of glycine in the shorter loop forming the necessary hydrogen bonds with the substrate, in place of the two threonines found in Class II DHOases. Despite the differences in the catalytic loop, the structure confirms that the key interactions between the substrate and active site residues are similar between Class I and Class II DHOase enzymes, which we further validated by mutagenesis studies. B. anthracis DHOase is also a potential antibacterial drug target. In order to identify prospective inhibitors, we performed high-throughput screening against several libraries using a colorimetric enzymatic assay and an orthogonal fluorescence thermal binding assay. Surface plasmon resonance was used for determining binding affinity (KD) and competition analysis with Ca-asp. Our results highlight that the primary difference between Class I and Class II DHOase is the catalytic loop. We also identify several compounds that can potentially be further optimized as potential B. anthracis inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.

The aspartyl protease TgASP5 mediates the export of the Toxoplasma GRA16 and GRA24 effectors into host cells.

PubMed

Curt-Varesano, Aurélie; Braun, Laurence; Ranquet, Caroline; Hakimi, Mohamed-Ali; Bougdour, Alexandre

2016-02-01

Toxoplasma gondii and Plasmodium species are obligatory intracellular parasites that export proteins into the infected cells in order to interfere with host-signalling pathways, acquire nutrients or evade host defense mechanisms. With regard to export mechanism, a wealth of information in Plasmodium spp. is available, while the mechanisms operating in T. gondii remain uncertain. The recent discovery of exported proteins in T. gondii, mainly represented by dense granule resident proteins, might explain this discrepancy and offers a unique opportunity to study the export mechanism in T. gondii. Here, we report that GRA16 export is mediated by two protein elements present in its N-terminal region. Because the first element contains a putative Plasmodium export element linear motif (RRLAE), we hypothesized that GRA16 export depended on a maturation process involving protein cleavage. Using both N- and C-terminal epitope tags, we provide evidence for protein proteolysis occurring in the N-terminus of GRA16. We show that TgASP5, the T. gondii homolog of Plasmodium plasmepsin V, is essential for GRA16 export and is directly responsible for its maturation in a Plasmodium export element-dependent manner. Interestingly, TgASP5 is also involved in GRA24 export, although the GRA24 maturation mechanism is TgASP5-independent. Our data reveal different modus operandi for protein export, in which TgASP5 should play multiple functions. © 2015 John Wiley & Sons Ltd.

Application of L-Aspartic Acid-Capped ZnS:Mn Colloidal Nanocrystals as a Photosensor for the Detection of Copper (II) Ions in Aqueous Solution

PubMed Central

Heo, Jungho; Hwang, Cheong-Soo

2016-01-01

Water-dispersible ZnS:Mn nanocrystals (NCs) were synthesized by capping the surface with polar L-aspartic acid (Asp) molecules. The obtained ZnS:Mn-Asp NC product was optically and physically characterized using the corresponding spectroscopic methods. The ultra violet-visible (UV-VIS) absorption spectrum and photoluminescence (PL) emission spectrum of the NCs showed broad peaks at 320 and 590 nm, respectively. The average particle size measured from the obtained high resolution-transmission electron microscopy (HR-TEM) image was 5.25 nm, which was also in accordance with the Debye-Scherrer calculations using the X-ray diffraction (XRD) data. Moreover, the surface charge and degree of aggregation of the ZnS:Mn-Asp NCs were determined by electrophoretic and hydrodynamic light scattering methods, respectively. These results indicated the formation of agglomerates in water with an average size of 19.8 nm, and a negative surface charge (−4.58 mV) in water at ambient temperature. The negatively-charged NCs were applied as a photosensor for the detection of specific cations in aqueous solution. Accordingly, the ZnS:Mn-Asp NCs showed an exclusive luminescence quenching upon addition of copper (II) cations. The kinetic mechanism study on the luminescence quenching of the NCs by the addition of the Cu2+ ions proposed an energy transfer through the ionic binding between the two oppositely-charged ZnS:Mn-Asp NCs and Cu2+ ions. PMID:28335210

Development of allele-specific primer PCR for a swine TLR2 SNP and comparison of the frequency among several pig breeds of Japan and the Czech Republic.

PubMed

Muneta, Yoshihiro; Minagawa, Yu; Kusumoto, Masahiro; Shinkai, Hiroki; Uenishi, Hirohide; Splichal, Igor

2012-05-01

In the present study, we have developed an allele-specific primer-polymerase chain reaction (ASP-PCR) for genotyping a single nucleotide polymorphism (SNP) of swine Toll-like receptor 2 (TLR2) (C406G), which is related to the prevalence of pneumonia caused by Mycoplasma hyopneumoniae. We also compared the allele frequency among several pig breeds of Japan and the Czech Republic. Allele-specific primers were constructed by introducing 1-base mismatch sequence before the SNP site. The swine TLR2 C406G mutation was successfully determined by the ASP-PCR using genomic DNA samples in Japan as previously genotyped by a sequencing method. Using the PCR condition determined, genomic DNA samples from pig blood obtained from 110 pigs from 7 different breeds in the Czech Republic were genotyped by the ASP-PCR. The genotyping results from the ASP-PCR were completely matched with the results from the sequencing method. The allele frequency of the swine TLR2 C406G mutation was 27.5% in the Czech Republic and 3.6% in Japan. The C406G mutation was only found in the Landrace breed in Japan, and was almost exclusively found in the Landrace breed in the Czech Republic as well. These results indicated the usefulness of ASP-PCR for detecting a specific SNP for swine TLR2.

The study on the relationship between IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymorphisms and type 2 diabetes in the Kurdish ethnic group in West Iran.

PubMed

Haghani, Karimeh; Bakhtiyari, Salar

2012-11-01

An association between the IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymorphisms and type 2 diabetes mellitus (T2DM) in different ethnic groups is controversial. We aimed to identify the association of these polymorphisms with T2DM in the Kurdish ethnic group of Iran. Study groups included 336 T2DM and 341 normoglycemic subjects. Genotyping was determined by polymerase chain reaction-restriction fragment length polymorphism. Genotypic and allelic frequencies were then evaluated. GR and RR genotypes of IRS-1 Gly972Arg variant gave a higher risk for T2DM (odds ratios [OR]=1.76 and OR=3.86, respectively). IRS-1 Gly972Arg polymorphism was found to be significantly associated with T2DM (OR=1.63) for the dominant model (GG vs. GR+RR). GD genotypes of the IRS-2 Gly1057Asp variant gave a higher risk for T2DM (OR=1.63). The dominant model analysis of the IRS-2 Gly1057Asp genotypes (GG vs. GD+DD) also showed an enhanced association with T2DM (OR=1.69). Among several combinations, GR/GD gave the highest risk for T2DM (OR=3.1). Other combinations were also significantly associated with T2DM, including, GR/GG (OR=1.86), RR/GG (OR=1.76), GG/GD (OR=1.83), and GG/DD (OR=2.35). HbA1c, serum triglyceride, and systolic blood pressure were higher in the control subjects with GR+RR genotypes compared with the GG genotype. Among the T2DM subjects, fasting plasma glucose was significantly lower in subjects with the GG genotype in relation to those with the GR+RR genotypes. Normoglycemic subjects carrying GD+DD genotypes of IRS-2 Gly1057Asp variation had a significantly higher fasting plasma glucose and total cholesterol, as compared with those with the GG genotype. Our findings revealed that IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymorphisms are associated with T2DM in the Kurdish ethnic group.

Appropriateness of Antibiotic Prescribing in U. S. Children’s Hospitals: A National Point Prevalence Survey

PubMed Central

Tribble, Alison; Lee, Brian; Handy, Lori; Gerber, Jeffrey S; Hersh, Adam L; Kronman, Matthew; Terrill, Cindy; Newland, Jason

2017-01-01

Abstract Background Multiple studies estimate that inappropriate antibiotic prescribing ranges from 30–50% in hospitalized patients, but few have included pediatric patients. Pediatric studies characterizing inappropriate prescribing are needed to target and improve antimicrobial stewardship program (ASP) efforts. Methods Cross-sectional analysis of antimicrobial prescribing at 30 U.S. children’s hospitals. Participating hospitals were academic, tertiary care hospitals in the Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS) collaborative. Subjects were children 0–17 years with an active antibiotic order at 0800 on a single day during three consecutive calendar quarters (Q3 2016 – Q1 2017). Each hospital’s ASP used a standardized survey to collect data on antibiotic orders and evaluate appropriateness. Data were pooled from the three surveys. The primary outcome was the pooled estimate for the percentage of prescriptions classified as inappropriate. Secondary outcomes were pooled estimates for indication, reason for inappropriate use, and ASP review status for each antibiotic. Results Of 19,598 children hospitalized on survey days, 6,922 (35%) had ≥1 active antibiotic order. Median age of children receiving antibiotics was 3.7 years (0.5, 10.9). Figures 1 and 2 show the most common antibiotics and indications. Of all antibiotic orders, 1,514 (15%) were classified as inappropriate, and 19% of patients with antibiotic orders had at least one inappropriate order. The most common reasons for inappropriate use were bug-drug mismatch (26%), surgical prophylaxis > 24 hours (18%) and unnecessary duplicate therapy (12%). ASPs would not have routinely reviewed 50% of all inappropriate orders. An additional 22% of inappropriate orders were for antibiotics typically reviewed by ASPs, but were yet to be reviewed at the time of the survey. Conclusion Across 30 children’s hospitals, approximately 1 in 3 hospitalized children is receiving an antibiotic at any given time. Almost 20% of these children are receiving inappropriate therapy, and a substantial portion of inappropriate use is not captured by current ASP practices. Figures 1 and 2: Disclosures C. Terrill, Merck: Grant Investigator, Research grant; Allergan: Grant Investigator, Research grant; J. Newland, Merck: Grant Investigator, Research grant; Allergan: Grant Investigator, Research grant.

Patients with Advanced, Rare Sarcoma Respond to Cediranib | Center for Cancer Research

Cancer.gov

Alveolar soft part sarcomas (ASPS) are highly vascular tumors that usually affect adolescents and young adults. Comprising less than one percent of soft tissue sarcomas, ASPS can be cured with surgery. However, its tendency to metastasize and its lack of response to standard soft tissue sarcoma chemotherapy regimens makes ASPS a particularly lethal cancer with a five-year

78 FR 60271 - Hollow Dam Power Company; Ampersand Hollow Dam Hydro, LLC; Notice of Application for Transfer of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-01

...Library link of Commission's Web site at http://www.ferc.gov/docs-filing/elibrary.asp . Enter the docket...) and the instructions on the Commission's Web site under http://www.ferc.gov/docs-filing/efiling.asp... system at http://www.ferc.gov/docs-filing/ecomment.asp . You must include your name and contact...

An Arabidopsis ATP-dependent, DEAD-box RNA helicase loses activity upon iosAsp formation but is restored by Protein Isoaspartyl Methltransferase

USDA-ARS?s Scientific Manuscript database

Arabidopsis thaliana PLANT RNA HELICASE75 (AtPRH75) demonstrated an ATP-dependent, RNA duplex unwinding capacity and an ATP-independent, RNA duplex reforming ability. It is known to accumulate isoAsp, but the consequences of isoAsp formation in AtPRH75 are unknown. Duplex unwinding was abolished by ...

Site-directed mutagenesis of the conserved Asp-443 and Asp-498 carboxy-terminal residues of HIV-1 reverse transcriptase.

PubMed Central

Mizrahi, V; Usdin, M T; Harington, A; Dudding, L R

1990-01-01

Substitution of the conserved Asp-443 residue of HIV-1 reverse transcriptase by asparagine specifically suppressed the ribonuclease H activity of the enzyme without affecting the reverse transcriptase activity, suggesting involvement of this ionizable residue at the ribonuclease H active site. An analogous asparagine substitution of the Asp-498 residue yielded an unstable enzyme that was difficult to enzymatically characterize. However, the instability caused by the Asn-498 mutation was relieved by the introduction of a second distal Asn-443 substitution, yielding an enzyme with wild type reverse transcriptase activity, but lacking ribonuclease H activity. Images PMID:1699202

Design of the annular suspension and pointing system /ASPS/ through decoupling and pole placement. [for Space Shuttle

NASA Technical Reports Server (NTRS)

Kuo, B. C.; Lin, W. C. W.

1980-01-01

A decoupling and pole-placement technique has been developed for the Annular Suspension and Pointing System (ASPS) of the Space Shuttle which uses bandwidths as performance criteria. The dynamics of the continuous-data ASPS allows the three degrees of freedom to be totally decoupled by state feedback through constant gains, so that the bandwidth of each degree of freedom can be independently specified without interaction. Although it is found that the digital ASPS cannot be completely decoupled, the bandwidth requirements are satisfied by pole placement and a trial-and-error method based on approximate decoupling.

Effects of peptides Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly on hormonal activity and structure of the thyroid gland in hypophysectomized young chickens and old hens.

PubMed

Kuznik, B I; Pateyuk, A V; Rusaeva, N S; Baranchugova, L M; Obydenko, V I

2011-02-01

Hypophysectomy in 5-days chickens and old hens was followed by hormonal disturbances and structural changes in the thyroid gland. Administration of peptides Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly synthesized on the basis the amino acid composition of extracts from the anterior and posterior lobes of the pituitary gland, respectively, to hypophysectomized birds for 40 days significantly reduced the degree of these changes. The normalizing effect of synthetic peptides on the concentration of thyrotrophic hormone and thyroid hormones in old hens was less pronounced than in chickens.

Structural specificity of Rn nuclease I as probed on yeast tRNA(Phe) and tRNA(Asp).

PubMed Central

Przykorska, A; el Adlouni, C; Keith, G; Szarkowski, J W; Dirheimer, G

1992-01-01

A single-strand-specific nuclease from rye germ (Rn nuclease I) was characterized as a tool for secondary and tertiary structure investigation of RNAs. To test the procedure, yeast tRNA(Phe) and tRNA(Asp) for which the tertiary structures are known, as well as the 3'-half of tRNA(Asp) were used as substrates. In tRNA(Phe) the nuclease introduced main primary cuts at positions U33 and A35 of the anticodon loop and G18 and G19 of the D loop. No primary cuts were observed within the double stranded stems. In tRNA(Asp) the main cuts occurred at positions U33, G34, U35, C36 of the anticodon loop and G18 and C20:1 positions in the D loop. No cuts were observed in the T loop in intact tRNA(Asp) but strong primary cleavages occurred at positions psi 55, C56, A57 within that loop in the absence of the tertiary interactions between T and D loops (use of 3'-half tRNA(Asp)). These results show that Rn nuclease I is specific for exposed single-stranded regions. Images PMID:1542562

Lock-and-key dimerization in dense Brownian systems of hard annular sector particles

NASA Astrophysics Data System (ADS)

Hodson, Wade D.; Mason, Thomas G.

2016-08-01

We develop a translational-rotational cage model that describes the behavior of dense two-dimensional (2D) Brownian systems of hard annular sector particles (ASPs), resembling C shapes. At high particle densities, pairs of ASPs can form mutually interdigitating lock-and-key dimers. This cage model considers either one or two mobile central ASPs which can translate and rotate within a static cage of surrounding ASPs that mimics the system's average local structure and density. By comparing with recent measurements made on dispersions of microscale lithographic ASPs [P. Y. Wang and T. G. Mason, J. Am. Chem. Soc. 137, 15308 (2015), 10.1021/jacs.5b10549], we show that mobile two-particle predictions of the probability of dimerization Pdimer, equilibrium constant K , and 2D osmotic pressure Π2 D as a function of the particle area fraction ϕA correspond closely to these experiments. By contrast, predictions based on only a single mobile particle do not agree well with either the two-particle predictions or the experimental data. Thus, we show that collective entropy can play an essential role in the behavior of dense Brownian systems composed of nontrivial hard shapes, such as ASPs.

ASP Strategies and Appropriate Antibiotic Use

PubMed Central

Lee, Brian R; Tribble, Alison; Handy, Lori; Gerber, Jeffrey S; Hersh, Adam L; Kronman, Matthew; Terrill, Cindy; Newland, Jason

2017-01-01

Abstract Background The Infectious Diseases Society of America (IDSA) recommends hospitals implement antimicrobial stewardship programs (ASP) in order to decrease inappropriate antibiotic use due to the rise in antibiotic-resistant infections. Data are limited on the extent to which different ASP strategies influence appropriate antibiotic use. Methods We conducted an online survey in 2016 of U.S. Children’s Hospitals to collect hospital-level information on dedicated ASP effort, ASP monitoring activities, use of audit-feedback, formulary restrictions, rapid diagnostics, etc. During the same period the ASP teams at these hospitals completed 3 point prevalence surveys that documented details on all admitted patients 0–17 years receiving any antibiotics, determined what ASP modifications could be made, and if the antibiotic was appropriate. We employed hierarchical, multivariable logit models to examine which ASP-related, hospital-level strategies were associated with appropriate antibiotic use. Results Thirty hospitals participated. A total of 6,921 patients were included, representing 10,068 total antibiotics. Of these orders, 8,554 (85.0%) were categorized as appropriate, though this varied across sites (range: 68-92%). Additionally, 78.2% of antibiotics did not have recommended modifications. Appropriate antibiotic use was significantly higher for hospitals that relied on rapid diagnostics (aOR: 1.6; P < 0.001) or monitored their days of therapy (DOT) rate (aOR: 1.4; P < 0.001), whereas the presence of either audit-feedback (aOR: 1.04; P = 0.75) or formulary restrictions (aOR: 0.83; P = 0.059) were not associated. Having annual education for all prescribers had increased likelihood of antibiotics having no modification recommendations (aOR: 1.45; P = 0.037). Total ASP FTE was not correlated with hospital-level percent appropriate use (corr: −0.05; P = 0.79) or antibiotic modification recommendations (corr: −0.08; P = 0.67). Conclusion Routine monitoring of DOT rates and utilization of rapid diagnostics were associated with appropriate antibiotic use. Additional analysis is needed to understand additional factors that can aid hospitals in developing and maintaining ASPs to reduce inappropriate antibiotic use. Disclosures B. R. Lee, Merck: Grant Investigator, Grant recipient. PCORI: Grant Investigator, Grant recipient. C. Terrill, Merck: Grant Investigator, Research grant Allergan: Grant Investigator, Research grant. J. Newland, Merck: Grant Investigator, Research grant. Allergan: Grant Investigator, Research grant

[Theory of mind in Asperger syndrome].

PubMed

Duverger, H; Da Fonseca, D; Bailly, D; Deruelle, C

2007-09-01

Theory of mind deficit can be used to explain social and communication impairments that define the autism spectrum disorder. Theory of mind is the ability to attribute mental states to self and others in order to understand and predict behavior. It involves the distinction between the real world and mental representations of the world. Several studies established that high functioning autistic individuals and individuals with Asperger syndrome (ASP) tend to be as proficient as controls in understanding first order false belief tasks. In contrast, they still lag behind their typical peers in understanding second order false belief tasks or more advanced tasks of theory of mind (e.g., Baron-Cohen, 1993). Most of these studies focus on the adult population and it seems particularly interesting to investigate whether children with ASP would present the same pattern of strengths and deficits as adults. In our research, children with ASP were tested in an advanced task of theory of mind based on a visual presentation of comic strips and in a more traditional assessment of false belief understanding: the Smarties test. Two experimental groups participated in this study: a group of 16 high functioning children and adolescents with autism or with Asperger syndrome (ASP) and a group of 16 typically developing children matched on gender and age (CONT). The task was designed to assess the ability of children with ASP to infer the mental state of others. Stimuli were 26 different comic strips depicting a short story. Each comic strip was composed of three pictures and was shown on the upper half of the screen. Then three pictures numbered 1 to 3 showing possible outcomes of the scenario were superimposed on the bottom half of the screen. Only one of these three pictures represented a plausible conclusion to the scenario. This experiment contained two conditions: A Character intention (CI) condition and a Physical causality (PC) condition. The comic strips in the CI condition involved one character whose intentions had to be inferred by the subject in order to choose the correct picture. Comic strips in PC condition only required to understand physical causalities. Subjects were asked to watch the comic strip attentively and then they were required to make a choice between the three story endings by pressing the corresponding keyboard button. Both answers and response times were recorded. Additionally, all participants were enrolled in the classical false belief (Smarties) task. Comic strips: An ANOVA [2 groups (CONT/ASP) x 2 conditions (CI/PC)] was performed on the number of correct responses. Neither the Group nor the Condition factor was significant (p>0.05). In contrast, the interaction Group x Condition reached significance level [F(1-30)=4.3, p<0.05)]. Further analysis revealed that performance of the ASP group was significantly higher in the CP (M=10.8, SD=2.5) than in the CI (M=9.8, SD=2) condition [t (1-14)=2.9, p<0.001)], whereas there was no condition difference in the control group (p>0.05). False belief: all ASP participants succeeded in the task. Our data clearly demonstrated that children and adolescents with Asperger syndrome or high functioning autism exhibited an impairment in understanding the intention of others. In the comic strip task, children with ASP have more difficulties in the character's intention condition than in the physical causality condition. This impairment is not imputable to a deficit in taking into account the context (Weack Central Coherence theory) since they performed as well as controls in the physical causality condition which also required the processing of the whole scene. In contrast, all children with ASP succeeded at the false belief task. These contradictory findings suggest that, although testing theory of mind, the two tasks do not tap similar mechanisms. It is possible that the use of verbal material in the false belief task improved performance of the ASP children who are known to present particular strengths in this domain. Another possible explanation that needs further testing would be that the level of complexity differs between the two tasks.

XPD Asp312Asn and Lys751Gln polymorphisms and breast cancer susceptibility: a meta-analysis.

PubMed

Yan, Yulan; Liang, Hongjie; Light, Morning; Li, Taijie; Deng, Yan; Li, Meng; Li, Shan; Qin, Xue

2014-03-01

The association between xeroderma pigmentosum complementation group D (XPD) Asp312Asn and Lys751Gln gene polymorphisms and breast cancer risk has been widely reported, but the results were inconsistent. In order to derive a more precise estimation of the relationship, a meta-analysis was performed. A comprehensive search strategy was conducted towards the electronic databases including Medline, PubMed, Web of Science, Embase, and Chinese Biomedical Literature Database (Chinese). The association between the XPD polymorphism and breast cancer risk was conducted by odds ratios (ORs) and 95% confidence intervals (95% CIs). A total of 22 studies with 18,136 cases and 18,351 controls were included in our meta-analysis. Among these, 12 studies with 7,667 cases and 7,480 controls for Asp312Asn polymorphism and 20 studies with 10,469 cases and 10,871 controls for Lys751Gln polymorphism. With regard to Asp312Asn polymorphism, no significantly associated was found with breast cancer risk. However, significant association was found between Lys751Gln polymorphism and breast cancer risk under all genetic models in overall populations (C vs. A-OR = 1.10, 95% CI = 1.04-1.17, P = 0.002; CC vs. AA-OR = 1.17, 95% CI = 1.06-1.30, P = 0.003; AC vs. AA-OR = 1.06, 95% CI = 1.01-1.12, P = 0.032; CC vs. AC/AA-OR = 1.17, 95% CI = 1.04-1.32, P = 0.009; CC/AC vs. AA-OR = 1.07, 95% CI = 1.02-1.12, P = 0.005). In subgroup analysis base on ethnicity, significance was found in Caucasians and mix. The results suggest that XPD Asp312Asn polymorphism was not associated with breast cancer. The XPD Lys751Gln polymorphism significantly increased breast cancer risk, especially for Caucasian and mix.

The Maturation of Oocyte Follicular Epithelium of Podarcis s. sicula Is Promoted by d-Aspartic Acid

PubMed Central

Raucci, Franca; Di Fiore, Maria Maddalena

2010-01-01

We investigated whether the maturation of oocyte follicular epithelium of lizard is affected by d-aspartic acid (d-Asp). Our results demonstrated that d-Asp is endogenously present in the oocytes, and its distribution varies during the reproductive cycle and following intraperitoneal administration. At previtellogenesis, it is observed in the cytoplasm and nucleus of pyriform cells, in intermediate cells, in some small cells of the granulosa, in the ooplasm, and in some thecal elements. At vitellogenesis, d-Asp is localized in the proximity of the zona pellucida, in the theca, and in the ooplasm. Injected d-Asp is mainly captured by pyriform cells and ooplasm of previtellogenic oocytes, but a moderate accumulation is evident in the cytoplasm of some small granulosa cells and in the theca. d-Asp also increases the ovarian and plasmatic levels of 17β-estradiol and decreases those of testosterone. As a direct and/or indirect consequence of d-Asp, previtellogenic oocytes grow up and mature, resulting in a higher accumulation of carbohydrates in the granulosa, zona pellucida, and ooplasm, but also a reduction in the thickness of the granulosa layer and an increase of the theca stratum. Taken together, our results show that d-Asp may be related to the synchrony of reproduction, either enhancing the growth and maturation of follicular epithelium or influencing its endocrine functions. (J Histochem Cytochem 58:157–171, 2010) PMID:19826072

Identification and expression of an allergen Asp f 13 from Aspergillus fumigatus and epitope mapping using human IgE antibodies and rabbit polyclonal antibodies.

PubMed Central

Chow, L P; Liu, S L; Yu, C J; Liao, H K; Tsai, J J; Tang, T K

2000-01-01

The Aspergillus genus of fungi is known to be one of the most prevalent aeroallergens. On two-dimensional immunoblotting using patients' sera containing IgE specific for Asp f 13, an allergen with a molecular mass of 33 kDa and a pI of 6.2 was identified. This allergen was also present in A. fumigatus culture filtrates. Furthermore, the sequence of the Asp f 13 cDNA was identical to that for alkaline protease isolated from A. fumigatus and showed 42-49% identity of amino acids with two proteases from P. cyclopium and T. album and with the Pen c 1 allergen from P. citrinum. Asp f 13 coding sequences were expressed in Escherichia coli as a [His](6)-tagged fusion protein which was purified by Ni(2+)-chelate affinity chromatography. Recombinant Asp f 13 was recognized by rabbit polyclonal antibodies against Asp f 13 and by IgE antibodies from subject allergic to A. fumigatus. To identify and characterize the linear epitopes of this allergen, a combination of chemical and enzymatic cleavage and immunoblotting techniques, with subsequent N-terminal sequencing and mass spectrometry, were performed. At least 13 different linear epitopes reacting with the rabbit anti-Asp f 13 antiserum were identified, located throughout the entire molecule. In contrast, IgE from A. fumigatus-sensitive patients bound to three immunodominant epitopes at the C-terminal of the protein. PMID:10677362

Comparability of activity monitors used in Asian and Western-country studies for assessing free-living sedentary behaviour.

PubMed

Kurita, Satoshi; Yano, Shohei; Ishii, Kaori; Shibata, Ai; Sasai, Hiroyuki; Nakata, Yoshio; Fukushima, Noritoshi; Inoue, Shigeru; Tanaka, Shigeho; Sugiyama, Takemi; Owen, Neville; Oka, Koichiro

2017-01-01

This study aims to compare the outputs of the waist-worn Active style Pro HJA-350IT (ASP; used in studies with Asian populations), the waist-worn ActiGragh™GT3X+ using the normal filter (GT3X+) and the thigh-worn activPAL3 (AP) in assessing adults' sedentary behaviour (total sedentary time, number of breaks) under free-living conditions. Fifty healthy workers wore the three monitors simultaneously during their waking hours on two days, including a work day and a non-work day. Valid data were at least 10 hours of wearing time, and the differences between monitors on the sedentary outputs using the AP as criterion measurement were analyzed by ANOVA. The number of participants who had complete valid data for work day and non-work day was 47 and 44, respectively. Total sedentary time and breaks estimated by the AP were respectively 466.5 ± 146.8 min and 64.3 ± 24.9 times on the work day and 497.7 ± 138.3 min and 44.6 ± 15.4 times on the non-work day. In total sedentary time, the ASP estimated 29.7 min (95%CI = 7.9 to 51.5) significantly shorter than the AP on the work day but showed no significant difference against the AP on the non-work day. The GT3X+ estimated 80.1 min (54.6 to 105.6) and 52.3 (26.4 to 78.2) significantly longer than the AP on the work day and the non-work day, respectively. For the number of breaks from sedentary time, on both days, the ASP and the GT3X+ estimated significantly more than the AP: 14.1 to 15.8 times (6.3 to 22.5) for the ASP and 27.7 to 28.8 times (21.8 to 34.8) for the GT3X+. Compared to the AP as the criterion, the ASP can underestimate total sedentary time and the GT3X+ can overestimate it, and more so at the lower levels of sedentary time. For breaks from sedentary time, compared to the AP, both the GT3X+ the ASP can overestimate.

Caprine PrP variants harboring Asp-146, His-154 and Gln-211 alleles display reduced convertibility upon interaction with pathogenic murine prion protein in scrapie infected cells.

PubMed

Kanata, Eirini; Arsenakis, Minas; Sklaviadis, Theodoros

2016-09-02

Scrapie, the prion disease of sheep and goats, is a devastating malady of small ruminants. Due to its infectious nature, epidemic outbreaks may occur in flocks/herds consisting of highly susceptible animals. Field studies identified scrapie-protective caprine PrP variants, harboring specific single amino acid changes (Met-142, Arg-143, Asp-146, Ser-146, His-154, Gln-211 and Lys-222). Their effects are under further evaluation, and aim to determine the most protective allele. We assessed some of these variants (Asp-146, His-154, Gln-211 and Lys-222), after their exogenous expression as murine-caprine chimeras in a scrapie- infected murine cell line. We report that exogenously expressed PrPs undergo conformational conversion upon interaction with the endogenous pathological murine prion protein (PrP SC ), which results in the detection of goat-specific and partially PK-resistant moieties. These moieties display a PK-resistance pattern distinct from the one detected in natural goat scrapie cases. Within this cellular model, distinct conformational conversion potentials were assigned to the tested variants. Molecules carrying the Asp-146, His-154 and Gln-211 alleles showed significantly lower conversion levels compared to wild type, confirming their protective effects against scrapie. Although we utilized a heterologous conversion system, this is to our knowledge, the first study of caprine PrP variants in a cellular context of scrapie, that confirms the protective effects of some of the studied alleles.

Development of PEGylated carboxylic acid-modified polyamidoamine dendrimers as bone-targeting carriers for the treatment of bone diseases.

PubMed

Yamashita, Shugo; Katsumi, Hidemasa; Hibino, Nozomi; Isobe, Yugo; Yagi, Yumiko; Kusamori, Kosuke; Sakane, Toshiyasu; Yamamoto, Akira

2017-09-28

In this study, we aimed to develop a polyethylene glycol (PEG)-conjugated third generation polyamidoamine (PAMAM) dendrimer with multiple carboxylic acids as a bone-targeting carrier for the treatment of bone diseases. We conjugated PAMAM backbones to various carboxylic acids [aspartic acid (Asp), glutamic acid (Glu), succinic acid (Suc), or aconitic acid (Aco)] to obtain four different types of carboxylic acid-modified PAMAMs. PEG was covalently bound to carboxylic acid-modified PAMAMs to obtain PEGylated carboxylic acid-modified PAMAMs. In a tissue distribution study, the amount of 111 In-labeled unmodified PAMAM taken up by the bone after intravenous injection in mice was 11.3%. In contrast, the dose of 111 In-labeled PEG(5)-Asp-PAMAM, PEG(5)-Glu-PAMAM, PEG(5)-Suc-PAMAM, or PEG(5)-Aco-PAMAM that accumulated in the bone after injection was approximately 46.0, 15.6, 22.6, and 24.5%, respectively. The bone clearance rates of 111 In-labeled PEGylated carboxylic acid-modified PAMAMs were proportional to their affinities to hydroxyapatite and Ca 2+ . An intra-bone distribution study showed that fluorescein isothiocyanate-labeled PEG(5)-Asp-PAMAM predominantly accumulated on eroded and quiescent surfaces, a pattern associated with the pathogenesis of bone diseases, such as rheumatoid arthritis and osteoporosis. Our findings indicate that PEG(5)-Asp-PAMAM is a promising drug carrier for efficient drug targeting to the bones. Copyright © 2017 Elsevier B.V. All rights reserved.

Water-Solubilized, Cap-Stabilized, Helical Polyalanines: Calibration Standards for NMR and CD Analyses

PubMed Central

Heitmann, Björn; Job, Gabriel E.; Kennedy, Robert J.; Walker, Sharon M.; Kemp, Daniel S.

2006-01-01

NMR and CD studies are reported for two length series of solubilized, spaced, highly helical polyalanines that are N-capped by the optimal helix stabilizer βAsp-Hel and C-capped by β-aminoalanine beta and that are studied in water at 2 °C, pH 1–8. NMR analysis yields a structural characterization of the peptide AcβAspHelAla8betaNH2 and selected members of one βAspHelAlanbeta series. At pH > 4.5 the βAspHel cap provides a preorganized triad of carboxylate anion and two amide residues that is complementary to the helical polyalanine N-terminus. The C-terminal β-aminoalanine assumes a helix-stabilizing conformation consistent with literature precedents. H(N)CO NMR experiments applied to capped, uniformly 13C- and 15N-labeled Ala8 and Ala12 peptides define Alan hydrogen bonding signatures as α-helical without detectable 310 character. Relative NH→ND exchange rates yield site protection factors PFi that define uniquely high fractional helicities FH for the peptide Alan regions. These Alan calibration series, studied in water and lacking helix-stabilizing tertiary structure, yield the first 13C NMR chemical shifts, 3JHNHα coupling constants, and CD ellipticities [θMolar]λ,n characteristic of a fully helical alanine within an Alan context. CD data are used to assign parameters X and [θ]λ,∞, required for rigorous calculation of FH values from CD ellipticities. PMID:15701003

Estimation of the Binding Free Energy of AC1NX476 to HIV-1 Protease Wild Type and Mutations Using Free Energy Perturbation Method.

PubMed

Ngo, Son Tung; Mai, Binh Khanh; Hiep, Dinh Minh; Li, Mai Suan

2015-10-01

The binding mechanism of AC1NX476 to HIV-1 protease wild type and mutations was studied by the docking and molecular dynamics simulations. The binding free energy was calculated using the double-annihilation binding free energy method. It is shown that the binding affinity of AC1NX476 to wild type is higher than not only ritonavir but also darunavir, making AC1NX476 become attractive candidate for HIV treatment. Our theoretical results are in excellent agreement with the experimental data as the correlation coefficient between calculated and experimentally measured binding free energies R = 0.993. Residues Asp25-A, Asp29-A, Asp30-A, Ile47-A, Gly48-A, and Val50-A from chain A, and Asp25-B from chain B play a crucial role in the ligand binding. The mutations were found to reduce the receptor-ligand interaction by widening the binding cavity, and the binding propensity is mainly driven by the van der Waals interaction. Our finding may be useful for designing potential drugs to combat with HIV. © 2015 John Wiley & Sons A/S.

Characterization and Evolutionary Implications of the Triad Asp-Xxx-Glu in Group II Phosphopantetheinyl Transferases

PubMed Central

Wang, Yue-Yue; Li, Yu-Dong; Liu, Jian-Bo; Ran, Xin-Xin; Guo, Yuan-Yang; Ren, Ni-Ni; Chen, Xin; Jiang, Hui; Li, Yong-Quan

2014-01-01

Phosphopantetheinyl transferases (PPTases), which play an essential role in both primary and secondary metabolism, are magnesium binding enzymes. In this study, we characterized the magnesium binding residues of all known group II PPTases by biochemical and evolutionary analysis. Our results suggested that group II PPTases could be classified into two subgroups, two-magnesium-binding-residue-PPTases containing the triad Asp-Xxx-Glu and three-magnesium-binding-residue-PPTases containing the triad Asp-Glu-Glu. Mutations of two three-magnesium-binding-residue-PPTases and one two-magnesium-binding-residue-PPTase indicate that the first and the third residues in the triads are essential to activities; the second residues in the triads are non-essential. Although variations of the second residues in the triad Asp-Xxx-Glu exist throughout the whole phylogenetic tree, the second residues are conserved in animals, plants, algae, and most prokaryotes, respectively. Evolutionary analysis suggests that: the animal group II PPTases may originate from one common ancestor; the plant two-magnesium-binding-residue-PPTases may originate from one common ancestor; the plant three-magnesium-binding-residue-PPTases may derive from horizontal gene transfer from prokaryotes. PMID:25036863

Characterization and evolutionary implications of the triad Asp-Xxx-Glu in group II phosphopantetheinyl transferases.

PubMed

Wang, Yue-Yue; Li, Yu-Dong; Liu, Jian-Bo; Ran, Xin-Xin; Guo, Yuan-Yang; Ren, Ni-Ni; Chen, Xin; Jiang, Hui; Li, Yong-Quan

2014-01-01

Phosphopantetheinyl transferases (PPTases), which play an essential role in both primary and secondary metabolism, are magnesium binding enzymes. In this study, we characterized the magnesium binding residues of all known group II PPTases by biochemical and evolutionary analysis. Our results suggested that group II PPTases could be classified into two subgroups, two-magnesium-binding-residue-PPTases containing the triad Asp-Xxx-Glu and three-magnesium-binding-residue-PPTases containing the triad Asp-Glu-Glu. Mutations of two three-magnesium-binding-residue-PPTases and one two-magnesium-binding-residue-PPTase indicate that the first and the third residues in the triads are essential to activities; the second residues in the triads are non-essential. Although variations of the second residues in the triad Asp-Xxx-Glu exist throughout the whole phylogenetic tree, the second residues are conserved in animals, plants, algae, and most prokaryotes, respectively. Evolutionary analysis suggests that: the animal group II PPTases may originate from one common ancestor; the plant two-magnesium-binding-residue-PPTases may originate from one common ancestor; the plant three-magnesium-binding-residue-PPTases may derive from horizontal gene transfer from prokaryotes.

Toll like receptor-4 gene polymorphisms in patients with solitary cysticercus granuloma.

PubMed

Singh, Akhilesh; Garg, Ravindra Kumar; Jain, Amita; Malhotra, Hardeep Singh; Prakash, Shantanu; Verma, Rajesh; Sharma, Praveen Kumar

2015-08-15

Solitary cysticercus granuloma (SCG) of the brain is the most common type of neurocysticercosis in India. In this study, we evaluated TLR4 polymorphisms in patients with SCG. One-hundred-forty-three patients with SCG and 134 controls were enrolled. Assessment for TLR4 Asp299Gly and Thr399Ile polymorphism was done. TLR4 genotype was determined by PCR-sequencing chain termination method. The patients were followed for 6 months. Asp/Gly (P=0.024) and Thr/Ile (P=0.004) genotypes were significantly associated with the SCG. The Gly (Asp/Gly plus Gly/Gly) genotype (P=0.025) and Ile (Thr/Ile plus Ile/Ile) genotype (P=0.008) were significantly associated with the SCG. Gly/Gly and Ile/Ile genotypes were not significantly associated with SCG (P=0.767 for Gly/Gly, P=0.936 for Ile/Ile). At 6 months, TLR4 299Asp/Gly (P=0.02) and 399Ile/Thr (P=0.023) polymorphisms were significantly associated with the calcification or persistence of SCG. TLR4 polymorphisms are associated with the susceptibility to infection with SCG. Copyright © 2015 Elsevier B.V. All rights reserved.

Characteristics of Pediatric Antimicrobial Stewardship Programs: Current Status of the Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS) Collaborative

PubMed Central

McPherson, Christopher; Lee, Brian R.; Terrill, Cindy; Hersh, Adam L.; Gerber, Jeffrey S.; Kronman, Matthew P.; Newland, Jason G.

2018-01-01

In response to the growing epidemic of antibiotic-resistant bacterial infections, antimicrobial stewardship programs (ASP) have been rapidly implemented in the United States (US). This study examines the prevalence of the Centers for Disease Control and Prevention’s (CDC) seven core elements of a successful ASP within a large subset of US Children’s Hospitals. In 2016, a survey was conducted of 52 pediatric hospitals assessing the presence of the seven core elements: leadership commitment, accountability, drug expertise, action, tracking, reporting, and education. Forty-nine hospitals (94%) had established ASPs and 41 hospitals (79%) included all seven core elements. Physician accountability (87%) and a dedicated ASP pharmacist or drug expert (88%) were present in the vast majority of hospitals. However, substantial variability existed in the financial support allotted to these positions. This variability did not predict program actions, tracking, reporting, and education. When compared with previous surveys, these results document a dramatic increase in the prevalence and resources of pediatric stewardship programs, although continued expansion is warranted. Further research is required to understand the feasibility of various core stewardship activities and the impact on patient outcomes in the setting of finite resources. PMID:29370071

Characteristics of Pediatric Antimicrobial Stewardship Programs: Current Status of the Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS) Collaborative.

PubMed

McPherson, Christopher; Lee, Brian R; Terrill, Cindy; Hersh, Adam L; Gerber, Jeffrey S; Kronman, Matthew P; Newland, Jason G

2018-01-25

In response to the growing epidemic of antibiotic-resistant bacterial infections, antimicrobial stewardship programs (ASP) have been rapidly implemented in the United States (US). This study examines the prevalence of the Centers for Disease Control and Prevention's (CDC) seven core elements of a successful ASP within a large subset of US Children's Hospitals. In 2016, a survey was conducted of 52 pediatric hospitals assessing the presence of the seven core elements: leadership commitment, accountability, drug expertise, action, tracking, reporting, and education. Forty-nine hospitals (94%) had established ASPs and 41 hospitals (79%) included all seven core elements. Physician accountability (87%) and a dedicated ASP pharmacist or drug expert (88%) were present in the vast majority of hospitals. However, substantial variability existed in the financial support allotted to these positions. This variability did not predict program actions, tracking, reporting, and education. When compared with previous surveys, these results document a dramatic increase in the prevalence and resources of pediatric stewardship programs, although continued expansion is warranted. Further research is required to understand the feasibility of various core stewardship activities and the impact on patient outcomes in the setting of finite resources.

A comparative study of the use and understanding of self-presentational display rules in children with high functioning autism and Asperger's disorder.

PubMed

Barbaro, Josephine; Dissanayake, Cheryl

2007-08-01

The use and understanding of self-presentational display rules (SPDRs) was investigated in 21 children with high-functioning autism (HFA), 18 children with Asperger's disorder (AspD) and 20 typically developing (TD) children (all male, aged 4- to 11-years, matched on mental age). Their behaviour was coded during a deception scenario to assess use of SPDRs; understanding of SPDRs was assessed via three real/apparent emotion-understanding vignettes. The children with HFA and AspD used less effective SPDRs than the TD children, but there were no group differences in understanding SPDRs. The children with HFA and AspD did not differ on their use or understanding of SPDRs, and the results are discussed in relation to the similarities and differences between these diagnostic conditions.

Antecedents to the adoption of ASPS in healthcare.

PubMed

Randeree, Ebrahim; Judd, Susan P; Kishore, Rajiv; Rao, H Raghav

2003-01-01

The objective of this exploratory study was to identify drivers of adoption for a new form of information technology outsourcing--the ASP model--in the healthcare industry. Primary data were collected in January 2002 from a nationwide survey of senior-level healthcare information technology executives. Cost management (supplier presence, asset specificity, production costs, transaction costs, resource availability) and relative advantage (reliability, customizability, strategic alignment, and magnitude of potential loss) were found to have the largest influences on adoption behavior.

Pseudoautosomal region in schizophrenia: linkage analysis of seven loci by sib-pair and lod-score methods.

PubMed

d'Amato, T; Waksman, G; Martinez, M; Laurent, C; Gorwood, P; Campion, D; Jay, M; Petit, C; Savoye, C; Bastard, C

1994-05-01

In a previous study, we reported a nonrandom segregation between schizophrenia and the pseudoautosomal locus DXYS14 in a sample of 33 sibships. That study has been extended by the addition of 16 new sibships from 16 different families. Data from six other loci of the pseudoautosomal region and of the immediately adjacent part of the X specific region have also been analyzed. Two methods of linkage analysis were used: the affected sibling pair (ASP) method and the lod-score method. Lod-score analyses were performed on the basis of three different models--A, B, and C--all shown to be consistent with the epidemiological data on schizophrenia. No clear evidence for linkage was obtained with any of these models. However, whatever the genetic model and the disease classification, maximum lod scores were positive with most of the markers, with the highest scores generally being obtained for the DXYS14 locus. When the ASP method was used, the earlier finding of nonrandom segregation between schizophrenia and the DXYS14 locus was still supported in this larger data set, at an increased level of statistical significance. Findings of ASP analyses were not significant for the other loci. Thus, findings obtained from analyses using the ASP method, but not the lod-score method, were consistent with the pseudoautosomal hypothesis for schizophrenia.

Polyaspartic Acid Concentration Controls the Rate of Calcium Phosphate Nanorod Formation in High Concentration Systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krogstad, Daniel V.; Wang, Dongbo; Lin-Gibson, Sheng

Polyelectrolytes are known to greatly affect calcium phosphate (CaP) mineralization. The reaction kinetics as well as the CaP phase, morphology and aggregation state depend on the relative concentrations of the polyelectrolyte and the inorganic ions in a complex, nonlinear manner. This study examines the structural evolution and kinetics of polyaspartic acid (pAsp) directed CaP mineralization at high concentrations of polyelectrolytes, calcium, and total phosphate (19–30 mg/mL pAsp, 50–100 mM Ca2+, Ca/P = 2). Using a novel combination of characterization techniques including cryogenic transmission electron microscopy (cryo-TEM), spectrophotometry, X-ray total scattering pair distribution function analysis, and attenuated total reflectance Fourier transformmore » infrared spectroscopy (ATR-FTIR), it was determined that the CaP mineralization occurred over four transition steps. The steps include the formation of aggregates of pAsp stabilized CaP spherical nanoparticles (sNP), crystallization of sNP, oriented attachment of the sNP into nanorods, and further crystallization of the nanorods. The intermediate aggregate sizes and the reaction kinetics were found to be highly polymer concentration dependent while the sizes of the particles were not concentration dependent. This study demonstrates the complex role of pAsp in controlling the mechanism as well as the kinetics of CaP mineralization.« less

Community partnership to address snack quality and cost in after-school programs.

PubMed

Beets, Michael W; Tilley, Falon; Turner-McGrievy, Gabrielle; Weaver, Robert G; Jones, Sonya

2014-08-01

Policies call on after-school programs (ASPs) to serve more nutritious snacks. A major barrier for improving snack quality is cost. This study describes the impact on snack quality and expenditures from a community partnership between ASPs and local grocery stores. Four large-scale ASPs (serving ˜500 children, aged 6-12 years, each day) and a single local grocery store chain participated in this study. The nutritional quality of snacks served was recorded preintervention (18 weeks spring/fall 2011) and postintervention (7 weeks spring 2012) via direct observation, along with cost/child/snack/day. Preintervention snacks were low-nutrient-density salty snacks (eg, chips, 3.0 servings/week), sugar-sweetened beverages (eg, powdered-lemonade, 1.9 servings/week), and desserts (eg, cookies, 2.1 servings/week), with only 0.4 servings/week of fruits and no vegetables. By postintervention, fruits (3.5 servings/week) and vegetables (1.2 servings/week) were increased, whereas sugar-sweetened beverages and desserts were eliminated. Snack expenditures were $0.26 versus $0.24 from preintervention to postintervention. Partnership savings versus purchasing snacks at full retail cost was 24.5% or $0.25/serving versus $0.34/serving. This innovative partnership can serve as a model in communities where ASPs seek to identify low-cost alternatives to providing nutritious snacks. © 2014, American School Health Association.

Community Partnership to Address Snack Quality and Cost in Afterschool Programs

PubMed Central

Tilley, Falon; Turner-McGrievy, Gabrielle; Weaver, Robert Glenn; Jones, Sonya

2014-01-01

Background Policies call on afterschool programs (ASPs) to serve more nutritious snacks. A major barrier for improving snack quality is cost. This study describes the impact on snack quality and expenditures from a community-partnership between ASPs and local grocery stores. Methods Four large-scale ASPs (serving ∼500 children aged 6-12 years each day) and a single local grocery store chain participated in the study. The nutritional quality of snacks served was recorded pre-intervention (18 weeks spring/fall 2011) and post-intervention (7 weeks spring 2012) via direct observation, along with cost/child/snack/day. Results Pre-intervention snacks were low-nutrient-density salty snacks (eg, chips, 3.0 servings/week), sugar-sweetened beverages (eg, powdered-lemonade, 1.9 servings/week), and desserts (eg, cookies, 2.1servings/week), with only 0.4 servings/week of fruits and no vegetables. By post-intervention, fruits (3.5 servings/week) and vegetables (1.2 servings/week) increased, while sugar-sweetened beverages and desserts were eliminated. Snack expenditures were $0.26 versus $0.24 from pre-intervention to post-intervention. Partnership savings versus purchasing snacks at full retail cost was 24.5% or $0.25/serving versus $0.34/serving. Conclusions This innovative partnership can serve as a model in communities where ASPs seek to identify low-cost alternatives to providing nutritious snacks. PMID:25040123

Multi-Stage ADRs for Current and Future Astronomy Missions: Performance and Requirements for Cryogen-Free Operation

NASA Technical Reports Server (NTRS)

Shirron, Peter; Kimball, Mark; Vlahacos, Kosta

2010-01-01

The cooling requirements for current (e.g. Astro-H) and future (e.g. IXO and ASP) astronomy missions pose significant challenges for the sub-Kelvin Cooler. In particular, the use of large detector arrays increases the cooling power needed, and the variety of cryocoolers that can be used for pre-cooling greatly expands the range of temperatures at which the sub-Kelvin cooler can be designed to reject heat. In most cases, there is also a need for a stable higher temperature stage for cooling amplifiers or telescope components. NASA/GSFC is currently building a 3-stage ADR for the Astro-H mission, and is developing a 5-stage ADR suitable for IXO and ASP, as well as many other missions in the early planning stages. The architecture of these ADRs allows them to be adapted rather easily for different cooling requirements and to accommodate different cryocooler capabilities (operating temperature and cooling power). This paper will discuss the performance of these ADRs, which operate in both continuous, and single-shot cooling modes, and the minimum cryocooler capabilities needed to meet the requirements of future missions.

Ionization potential depression in an atomic-solid-plasma picture

NASA Astrophysics Data System (ADS)

Rosmej, F. B.

2018-05-01

Exotic solid density matter such as heated hollow crystals allow extended material studies while their physical properties and models such as the famous ionization potential depression are presently under renewed controversial discussion. Here we develop an atomic-solid-plasma (ASP) model that permits ionization potential depression studies also for single and multiple core hole states. Numerical calculations show very good agreement with recently available data not only in absolute values but also for Z-scaled properties while currently employed methods fail. For much above solid density compression, the ASP model predicts increased K-edge energies that are related to a Fermi surface rising. This is in good agreement with recent quantum molecular dynamics simulations. For hot dense matter a quantum number dependent optical electron finite temperature ion sphere model is developed that fits well with line shift and line disappearance data from dense laser produced plasma experiments. Finally, the physical transparency of the ASP picture allows a critical discussion of current methods.

Lower rates of hypoglycemia during maintenance treatment with insulin degludec/insulin aspart versus biphasic insulin aspart 30: a combined analysis of two Phase 3a studies in type 2 diabetes.

PubMed

Christiansen, Jens Sandahl; Niskanen, Leo; Rasmussen, Søren; Johansen, Thue; Fulcher, Greg

2016-09-01

Insulin degludec/insulin aspart (IDegAsp) is a soluble coformulation of the basal analog insulin degludec and the rapid-acting prandial insulin aspart in a single injection. The present combined analysis of two Phase 3a trials compared the incidence of hypoglycemia in participants treated twice daily with IDegAsp or biphasic insulin aspart 30 (BIAsp 30). Hypoglycemia data were analyzed from two similarly designed randomized controlled open-label treat-to-target Phase 3a clinical trials of adults with type 2 diabetes (T2D). Participants were treated twice daily with IDegAsp or BIAsp 30, with breakfast and their main evening meal. Over 26 weeks, the rates of overall confirmed, nocturnal confirmed and severe hypoglycemic events were 19%, 57%, and 39% lower, respectively, with IDegAsp (n = 504) than BIAsp 30 (n = 364); estimated rate ratios were 0.81 (95% confidence interval [CI] 0.67, 0.98; P = 0.0341), 0.43 (95% CI 0.31, 0.59; P = 0.0001), and 0.61 (95% CI 0.26, 1.45; P = NS). The between-treatment differences were more pronounced during the maintenance period (≥16 weeks); compared with BIAsp 30, rates of overall confirmed, nocturnal confirmed and severe hypoglycemic events with IDegAsp were 0.69 (95% CI 0.55, 0.87; -31%; P = 0.0015); 0.38 (95% CI 0.25, 0.58; -62%; P < 0.0001), and 0.16 (95% CI 0.04, 0.59; -84%; P = 0.0061), respectively. Compared with BIAsp 30 twice daily, IDegAsp twice daily provided similar improvements in glycemic control with a lower risk of hypoglycemia, particularly nocturnal hypoglycemia, in subjects with T2D previously treated with insulin. © 2016 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.

Alveolar Soft Part Sarcoma of the Female Genital Tract: A Morphologic, Immunohistochemical, and Molecular Cytogenetic Study of 10 Cases With Emphasis on its Distinction From Morphologic Mimics.

PubMed

Schoolmeester, J Kenneth; Carlson, Joseph; Keeney, Gary L; Fritchie, Karen J; Oliva, Esther; Young, Robert H; Nucci, Marisa R

2017-05-01

Alveolar soft part sarcoma (ASPS) is a morphologically distinctive neoplasm of unknown differentiation that bears a characteristic gene fusion involving ASPSCR1 and TFE3. ASPS can occur in the female genital tract, but is rare. Eleven cases with an initial diagnosis of ASPS at female genital tract sites were evaluated for their morphologic features and immunoprofile using a panel of antibodies (TFE3, HMB45, melan-A, smooth muscle actin, desmin, and h-Caldesmon). In addition, the presence of TFE3 rearrangement and subsequent ASPSCR1-TFE3 fusion were determined by fluorescence in situ hybridization. Ten tumors retained their classification as ASPS based on their morphologic appearance, immunohistochemical profile, and demonstration of ASPSCR1-TFE3 fusion. The remaining case was reclassified as conventional-type PEComa due to its pattern of HMB45, melan-A, and desmin positivity as well as absence of TFE3 rearrangement. Sites of the 10 ASPS were uterine corpus (3), cervix (2), uterus not further specified (2), vagina (2), and vulva (1). The age of the patients ranged from 15 to 68 years (mean 34 y, median 32 y). The tumors demonstrated a spectrum of morphologic features, but all had a consistent immunophenotype of strong TFE3 nuclear expression and lack of muscle (smooth muscle actin, desmin, h-Caldesmon) and melanocytic (melan-A, HMB45) markers, except focal positivity for HMB45 in 1. Follow-up was available for 4 patients ranging from 1 to 35 months (mean 15 mo, median 25 mo) and they were alive and had no evidence of recurrence or metastasis at last follow-up. Distinguishing ASPS from its morphologic mimics, particularly PEComa, is important due to increasingly efficacious targeted agents such as MET-selective and VEGF signaling inhibitors in the former and mTOR inhibition therapy in the latter.

Bioproduction of L-Aspartic Acid and Cinnamic Acid by L-Aspartate Ammonia Lyase from Pseudomonas aeruginosa PAO1.

PubMed

Patel, Arti T; Akhani, Rekha C; Patel, Manisha J; Dedania, Samir R; Patel, Darshan H

2017-06-01

Aspartase (L-aspartate ammonia lyase, EC 4.3.1.1) catalyses the reversible amination and deamination of L-aspartic acid to fumaric acid which can be used to produce important biochemical. In this study, we have explored the characteristics of aspartase from Pseudomonas aeruginosa PAO1 (PA-AspA). To overproduce PA-AspA, the 1425-bp gene was introduced in Escherichia coli BL21 and purified. A 51.0-kDa protein was observed as a homogenous purified protein on SDS-PAGE. The enzyme was optimally active at pH 8.0 and 35 °C. PA-AspA has retained 56% activity after 7 days of incubation at 35 °C, which displays the hyperthermostablility characteristics of the enzyme. PA-AspA is activated in the presence of metal ions and Mg2+ is found to be most effective. Among the substrates tested for specificity of PA-AspA, L-phenylalanine (38.35 ± 2.68) showed the highest specific activity followed by L-aspartic acid (31.21 ± 3.31) and fumarate (5.42 ± 2.94). K m values for L-phenylalanine, L-aspartic acid and fumarate were 1.71 mM, 0.346 μM and 2 M, respectively. The catalytic efficiency (k cat /K m ) for L-aspartic acid (14.18 s -1  mM -1 ) was higher than that for L-phenylalanine (4.65 s -1  mM -1 ). For bioconversion, from an initial concentration of 1000 mM of fumarate and 30 mM of L-phenylalanine, PA-AspA was found to convert 395.31 μM L-aspartic acid and 3.47 mM cinnamic acid, respectively.

Role of loop L5-6 connecting transmembrane segments M5 and M6 in biogenesis and functioning of yeast Pma1 H+-ATPase.

PubMed

Petrov, V V

2015-01-01

The L5-6 loop is a short extracytoplasmic stretch (714-DNSLDID) connecting transmembrane segments M5 and M6 and forming along with segments M4 and M8 the core through which cations are transported by H+-, Ca2+-, K+,Na+-, H+,K+-, and other P2-ATPases. To study structure-function relationships within this loop of the yeast plasma membrane Pma1 H+-ATPase, alanine- and cysteine-scanning mutagenesis has been employed. Ala and Cys substitutions for the most conserved residue (Leu717) led to complete block in biogenesis preventing the enzyme from reaching secretory vesicles. The Ala replacement at Asp714 led to five-fold decrease in the mutant expression and loss of its activity, while the Cys substitution blocked biogenesis completely. Replacements of other residues did not lead to loss of enzymatic activity. Additional replacements were made for Asp714 and Asp720 (Asp®Asn/Glu). Of the substitutions made at Asp714, only D714N partially restored the mutant enzyme biogenesis and functioning. However, all mutant enzymes with substituted Asp720 were active. The expressed mutants (34-95% of the wild-type level) showed activity high enough (35-108%) to be analyzed in detail. One of the mutants (I719A) had three-fold reduced coupling ratio between ATP hydrolysis and H+ transport; however, the I719C mutation was rather indistinguishable from the wild-type enzyme. Thus, substitutions at two of the seven positions seriously affected biogenesis and/or functioning of the enzyme. Taken together, these results suggest that the M5-M6 loop residues play an important role in protein stability and function, and they are probably responsible for proper arrangement of transmembrane segments M5 and M6 and other domains of the enzyme. This might also be important for the regulation of the enzyme.

Analysis of the surface expression of c-kit and occurrence of the c-kit Asp816Val activating mutation in T cells, B cells, and myelomonocytic cells in patients with mastocytosis.

PubMed

Akin, C; Kirshenbaum, A S; Semere, T; Worobec, A S; Scott, L M; Metcalfe, D D

2000-02-01

The Asp816Val c-kit activating mutation is detectable in the peripheral blood cells of some patients with mastocytosis and in lesional skin biopsies obtained from adult patients with urticaria pigmentosa. These observations led to the conclusion that this mutation is present in mast cells and mast cell precursors that express c-kit. However, the distribution of the Asp816Val mutation among hematopoietic lineages is unknown. To determine the distribution of the Asp816Val mutation among hematopoietic lineages and to explore its relationship to clinical disease, we examined cells bearing differentiation markers for myelomonocytic cells as well as T and B lymphocytes, in both peripheral blood and bone marrow obtained from patients with mastocytosis. The presence of Asp816Val c-kit mutation in cells magnetically sorted from peripheral blood or bone marrow according to surface differentiation markers was studied by reverse transcriptase polymerase chain reaction (RT-PCR) restriction fragment length polymorphism (RFLP) analysis. The surface expression of c-kit was determined by flow cytometry. The mutation was detectable by RT-PCR in at least one cell lineage in the bone marrow in 7 of 7 patients examined and in the peripheral blood of 11 of 11 adult patients with urticaria pigmentosa and indolent disease. The mutation was identified most frequently in B cells and myeloid cells. Flow cytometric analysis demonstrated that the differentiated cells expressing mutated c-kit were negative for surface KIT. These results are consistent with the conclusion that the c-kit Asp816Val mutation occurs in an early progenitor cell and is carried by myelomonocytic cells, T cells, and B cells in addition to mast cells. However, unlike mast cells, these myelomonocytic cells, T cells, and B cells do not concomitantly express surface c-kit and thus may be less susceptible to the effects of this mutation.

[Effects of hypophyseal Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly synthetic peptides on immunity, hemostasis, morphology and functions of the thyroid gland in neonatally hypophysectomized chicken and one-year-old birds].

PubMed

Kuznik, B I; Pateiuk, A V; Rusaeva, N S; Baranchugova, L M; Obydenko, V I

2010-01-01

Neonatal hypophysectomy in chicken produces enlarged follicles of the thyroid gland, accumulation of colloids, impressed follicular epithelium, increased nucleus-cytoplasm ratio in thyrocytes, atrophied inter-follicular epithelium, depressed immunity, development of hypercoagulation and depressed fibrinolysis. When hypophysectomy is performed in one-year-old birds the impairments developing in thyroid morphology, immunity and hemostasis are less pronounced. Peptides of the anterior (Lys-Glu-Asp-Gly) and posterior (Ala-Glu-Asp-Gly) thyroid lobes injected to hypophysectomized birds prevent atrophic changes of the thyroid gland, normalize immune and hemostatic parameters.

High-stability Shuttle pointing system

NASA Technical Reports Server (NTRS)

Van Riper, R.

1981-01-01

It was recognized that precision pointing provided by the Orbiter's attitude control system would not be good enough for Shuttle payload scientific experiments or certain Defense department payloads. The Annular Suspension Pointing System (ASPS) is being developed to satisfy these more exacting pointing requirements. The ASPS is a modular pointing system which consists of two principal parts, including an ASPS Gimbal System (AGS) which provides three conventional ball-bearing gimbals and an ASPS Vernier System (AVS) which magnetically isolates the payload. AGS performance requirements are discussed and an AGS system description is given. The overall AGS system consists of the mechanical hardware, sensors, electronics, and software. Attention is also given to system simulation and performance prediction, and support facilities.

Serum protein adsorption and platelet adhesion on aspartic-acid-immobilized polysulfone membranes.

PubMed

Higuchi, Akon; Hashiba, Hirokazu; Hayashi, Rika; Yoon, Boo Ok; Sakurai, Masaru; Hara, Mariko

2004-01-01

Polysulfone (PSf) membranes that covalently conjugated with aspartic acid (ASP-PSf) were prepared and analyzed for hemocompatability. Compared to PSf or other types of surface-modified PSf membranes, the ASP-PSf membranes had a reduced ability to adsorb protein from either a plasma solution or a mixed solution of albumin, globulin and fibrinogen. This appears to be due to the creation of a hydrophilic surface by the aspartic acid zwitterion immobilized on the ASP-PSf membranes. Furthermore, the analyses of membrane protein adsorption showed that a mixed protein solution recapitulates the cooperative adsorption of proteins that occurs in plasma. We also found that the number of adhering platelets was the lowest on the ASP-PSf membranes and, in general, that platelet adhesion decreased in parallel with fibrinogen adsorption. In summary, aspartic acid immobilized on the ASP-PSf membranes, which have zwitterions with a net zero charge, effectively contributes to the hydrophilic and hemocompatible sites on the surface of the hydrophobic PSf membranes.

Update on the Use of l-Asparaginase in Infants and Adolescent Patients with Acute Lymphoblastic Leukemia

PubMed Central

Andrade, Augusto F; Borges, Kleiton S; Silveira, Vanessa S

2014-01-01

Great improvements have been made in acute lymphoblastic leukemia (ALL) treatment in the past decades, especially due to the use of l-asparaginase (l-ASP). Despite the significant success rate, several side effects mainly caused by toxicity, asparaginase silent inactivation, and cellular resistance, encourage an open debate regarding the optimal dosage and formulation of l-ASP. Alternative sources of asparaginases have been constantly investigated in order to overcome hypersensitivity clinical toxicity. Additionally, genomic modulation as gene expression profiling, genetic polymorphisms, and epigenetic changes is also being investigated concerning their role in cellular resistance to l-ASP. Understanding the mechanisms that mediate the resistance to l-ASP treatment may bring new insights into ALL pathobiology and contribute to the development of more effective treatment strategies. In summary, this review presents an overview on l-ASP data and focuses on cellular mechanisms underlying resistance and alternative therapies for the use of asparaginase in childhood ALL treatment. PMID:25210485

Products of cholecystokinin (CCK)-octapeptide proteolysis interact with central CCK receptors.

PubMed

Steardo, L; Knight, M; Tamminga, C A; Chase, T N

1985-03-15

Peptidases present in central nervous system (CNS) synaptic membranes, hydrolyze the neuroactive peptide cholecystokinin-octapeptide (CCK-8; Asp-Tyr-SO3H-Met-Gly-Trp-Met-Asp-Phe-NH2). In order to determine the pathway of degradation, synthetic CCK-8 was incubated at 37 degrees C with purified synaptic membranes; at various intervals reaction samples were removed from the reaction mixture and analysed by high-performance liquid chromatography to identify and quantify the peptide fragments. The results indicate an initial endopeptidase cleavage at the Met-Gly bond producing CCK-5 (Gly-Trp-Met-Asp-Phe-NH2). The carboxyl-terminal pentapeptide is further proteolysed to CCK-4 (Trp-Met-Asp-Phe-NH2) by a puromycin-sensitive aminopeptidase and to CCK-3 (Met-Asp-Phe-NH2) and Gly-Trp by an endopeptidase action. CCK-3 and CCK-2 appear to be relatively stable end-products. Moreover, these proteolytic fragments are shown to bind to the CCK receptor in brain with varying potencies.

Immunohistochemical localization of D-aspartate oxidase in porcine peripheral tissues.

PubMed

Yamamoto, Atsushi; Tanaka, Hiroyuki; Ishida, Tetsuo; Horiike, Kihachiro

2011-07-01

D-Aspartate (D-Asp) is an endogenous substance in mammals. Degradation of D-Asp is carried out only by D-aspartate oxidase (DDO). We measured DDO activity in porcine tissues, and produced an anti-porcine DDO antibody to examine the cellular localization of DDO. All the tissues examined showed DDO activities, whereas the substrate D-Asp was not detected in kidney cortex, liver, heart, and gastric mucosa. In the kidney, intensive immunohistochemical staining for DDO was found in the epithelial cells of the proximal tubules. In the liver, the epithelial cells of interlobular bile ducts, liver sinusoid-lining cells with cytoplasmic processes, and the smooth muscle cells of arterioles were strongly stained for DDO. In the heart, cardiomyocytes and the smooth muscle cells of arterioles showed DDO-immunoreactivity. In the gastric mucosa, only the chief cells were DDO-positive. These newly identified DDO-positive cells seem to actively degrade D-Asp to prevent an excess of D-Asp from exerting harmful effects on the respective functions of porcine tissues.

The effect of airsacculitis on bird weights, uniformity, fecal contamination, processing errors, and populations of Campylobacter spp. and Escherichia coli.

PubMed

Russell, S M

2003-08-01

A study was conducted to determine if the presence of airsacculitis in broiler chickens contributes to loss of saleable yield, lack of uniformity, fecal contamination, processing errors, and increases in populations of pathogenic and indicator bacteria. In a commercial processing facility, groups of carcasses from airsacculitis (AS)-positive (ASP) and airsacculitis-negative (ASN) flocks were selected from the line and weighed, evaluated for cut or torn areas on the digestive tracts, and assessed for Campylobacter and Escherichia coli counts. Additionally, fecal contamination was monitored and recorded. The presence of AS reduced (P < or = 0.05) carcass weight averages in two of five repetitions. Although not significantly different in repetitions 1, 4, and 5, the means were higher for ASN flocks. The net loss averaged over five repetitions was 84 g/carcass, equating to a loss of 14,686.9 k (32,379 lb) of chicken meat for one growout house per year as the result of AS infection. ASP carcasses had higher (P < or = 0.05) fecal contamination in four of five repetitions. The number of total digestive tract cuts or tears were much higher on ASP carcasses at 42, 49, 37, 60, and 59% as compared to 14, 12, 17, 24, and 16% for ASN carcasses in repetitions 1 to 5, respectively. In three of the five replications, the presence of AS in the flocks increased (P < or = 0.05) the number of Campylobacter recovered from broiler carcasses. Hence, there appears to be a relationship between the presence of AS and Campylobacter-positive carcasses. Escherichia coli counts for ASP flocks were significantly higher than ASN flocks in repetitions 1 and 3. In repetition 5, E. coli numbers were significantly lower for the AS flock. These data differ from previous unpublished data from two separate pilot studies that demonstrated that E. coli counts for ASP flocks are significantly higher than ASN flocks. This difference may be attributed to the fact that in the pilot studies visibly infected carcasses were sampled, and in this study healthy birds that had passed inspection were sampled within an ASP flock. Because flocks of chickens showing signs of AS have lower weights, more fecal contamination, more processing errors, and higher levels of Campylobacter spp., broiler companies should emphasize control of AS in the flocks as a means of preventing subsequent food-borne bacterial infection.

Efficient peptide ligation between allyl-protected Asp and Cys followed by palladium-mediated deprotection.

PubMed

Kamo, Naoki; Hayashi, Gosuke; Okamoto, Akimitsu

2018-04-24

An efficient method for peptide ligation between C-terminal Asp(OAllyl) and N-terminal Cys has been developed. Peptide ligation and removal of the allyl group at the Asp carboxylate side chain proceeded in one pot by adding a small amount of Pd/TPPTS complex. Based on this efficient synthetic method, PEP-19 (61 amino acids), which is highly expressed in Purkinje cells, was synthesized.

Crystallization and preliminary X-ray diffraction analysis of the periplasmic domain of the Escherichia coli aspartate receptor Tar and its complex with aspartate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mise, Takeshi; Matsunami, Hideyuki; Samatey, Fadel A.

The periplasmic domain of the E. coli aspartate receptor Tar was cloned, expressed, purified and crystallized with and without bound ligand. The crystals obtained diffracted to resolutions of 1.58 and 1.95 Å, respectively. The cell-surface receptor Tar mediates bacterial chemotaxis toward an attractant, aspartate (Asp), and away from a repellent, Ni{sup 2+}. To understand the molecular mechanisms underlying the induction of Tar activity by its ligands, the Escherichia coli Tar periplasmic domain with and without bound aspartate (Asp-Tar and apo-Tar, respectively) were each crystallized in two different forms. Using ammonium sulfate as a precipitant, crystals of apo-Tar1 and Asp-Tar1 weremore » grown and diffracted to resolutions of 2.10 and 2.40 Å, respectively. Alternatively, using sodium chloride as a precipitant, crystals of apo-Tar2 and Asp-Tar2 were grown and diffracted to resolutions of 1.95 and 1.58 Å, respectively. Crystals of apo-Tar1 and Asp-Tar1 adopted space group P4{sub 1}2{sub 1}2, while those of apo-Tar2 and Asp-Tar2 adopted space groups P2{sub 1}2{sub 1}2{sub 1} and C2, respectively.« less

Use of computer decision support in an antimicrobial stewardship program (ASP).

PubMed

Evans, R S; Olson, J A; Stenehjem, E; Buckel, W R; Thorell, E A; Howe, S; Wu, X; Jones, P S; Lloyd, J F

2015-01-01

Document information needs, gaps within the current electronic applications and reports, and workflow interruptions requiring manual information searches that decreased the ability of our antimicrobial stewardship program (ASP) at Intermountain Healthcare (IH) to prospectively audit and provide feedback to clinicians to improve antimicrobial use. A framework was used to provide access to patient information contained in the electronic medical record, the enterprise-wide data warehouse, the data-driven alert file and the enterprise-wide encounter file to generate alerts and reports via pagers, emails and through the Centers for Diseases and Control's National Healthcare Surveillance Network. Four new applications were developed and used by ASPs at Intermountain Medical Center (IMC) and Primary Children's Hospital (PCH) based on the design and input from the pharmacists and infectious diseases physicians and the new Center for Diseases Control and Prevention/National Healthcare Safety Network (NHSN) antibiotic utilization specifications. Data from IMC and PCH now show a general decrease in the use of drugs initially targeted by the ASP at both facilities. To be effective, ASPs need an enormous amount of "timely" information. Members of the ASP at IH report these new applications help them improve antibiotic use by allowing efficient, timely review and effective prioritization of patients receiving antimicrobials in order to optimize patient care.

Modification of Pectin and Hemicellulose Polysaccharides in Relation to Aril Breakdown of Harvested Longan Fruit

PubMed Central

Wang, Duoduo; Zhang, Haiyan; Wu, Fuwang; Li, Taotao; Liang, Yuxiang; Duan, Xuewu

2013-01-01

To investigate the modification of cell wall polysaccharides in relation to aril breakdown in harvested longan fruit, three pectin fractions (WSP, water soluble pectin; CSP, CDTA-soluble pectin; ASP, alkali soluble pectin) and one hemicellulose fraction (4 M KOH-SHC, 4 M KOH-soluble hemicellulose) were extracted, and their contents, monosaccharide compositions and molecular weights were evaluated. As aril breakdown intensified, CSP content increased while ASP and 4 M KOH-SHC contents decreased, suggesting the solubilization and conversion of cell wall components. Furthermore, the molar percentage of arabinose (Ara), as the main component of the side-chains, decreased largely in CSP and ASP while that of rhamnose (Rha), as branch point for the attachment of neutral sugar side chains, increased during aril breakdown. Analysis of (Ara + Gal)/Rha ratio showed that the depolymerization of CSP and ASP happened predominantly in side-chains formed of Ara residues. For 4 M KOH-SHC, more backbones were depolymerized during aril breakdown. Moreover, it was found that the molecular weights of CSP, ASP and 4 M KOH-SHC polysaccharides tended to decrease as aril breakdown intensified. These results suggest that both enhanced depolymerization and structural modifications of polysaccharides in the CSP, ASP and 4 M KOH-SHC fractions might be responsible for aril breakdown of harvested longan fruit. PMID:24287911

Helical peptides with three pairs of Asp-Arg and Glu-Arg residues in different orientations and spacings.

PubMed Central

Huyghues-Despointes, B. M.; Scholtz, J. M.; Baldwin, R. L.

1993-01-01

The helix-stabilizing effects of repeating pairs of Asp-Arg and Glu-Arg residues have been characterized using a peptide system of the same design used earlier to study Glu-Lys (Marqusee, S. & Baldwin, R.L., 1987, Proc. Natl. Acad. Sci. USA 84, 8898-8902) and Asp-Lys ion pairs (Marqusee, S. & Baldwin, R.L., 1990, In Protein Folding [Gierasch, L.M. & King, J., Eds.], pp. 85-94, AAAS, Washington, D.C.). The consequences of breaking ion pair and charge-helix dipole interactions by titration to pH 2 have been compared with the results of screening these interactions with NaCl at pH 7.0 and pH 2.5. The four peptides in each set contain three pairs of acidic (A) and basic (B) residues spaced either i, i + 4 or i, i + 3 apart. In one peptide of each kind the pairwise order of residues is AB, with the charges oriented favorably to the helix macrodipole, and in the other peptide the order is BA. The results are as follows: (1) Remarkably, both Asp-Arg and Glu-Arg peptides show the same pattern of helix stabilization at pH 7.0 found earlier for Glu-Lys and Asp-Lys peptides: i + 4 AB > i + 4 BA approximately i + 3 AB > i + 3 BA. (2) The ion pairs and charge-helix dipole interactions cannot be cleanly separated, but the results suggest that both interactions make important contributions to helix stability.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8443591

Conserved Asp-137 imparts flexibility to tropomyosin and affects function.

PubMed

Sumida, John P; Wu, Eleanor; Lehrer, Sherwin S

2008-03-14

Tropomyosin (Tm) is an alpha-helical coiled-coil that controls muscle contraction by sterically regulating the myosin-actin interaction. Tm moves between three states on F-actin as either a uniform or a non-uniform semi-flexible rod. Tm is stabilized by hydrophobic residues in the "a" and "d" positions of the heptad repeat. The highly conserved Asp-137 is unusual in that it introduces a negative charge on each chain in a position typically occupied by hydrophobic residues. The occurrence of two charged residues in the hydrophobic region is expected to destabilize the region and impart flexibility. To determine whether this region is unstable, we have substituted hydrophobic Leu for Asp-137 and studied changes in Tm susceptibility to limited proteolysis by trypsin and changes in regulation. We found that native and Tm controls that contain Asp-137 were readily cleaved at Arg-133 with t 1/2 of 5 min. In contrast, the Leu-137 mutant was not cleaved under the same conditions. Actin stabilized Tm, causing a 10-fold reduction in the rate of cleavage at Arg-133. The actin-myosin subfragment S1 ATPase activity was greater for the Leu mutant compared with controls in the absence of troponin and in the presence of troponin and Ca2+. We conclude that the highly conserved Asp-137 destabilizes the middle of Tm, resulting in a more flexible region that is important for the cooperative activation of the thin filament by myosin. We thus have shown a link between the dynamic properties of Tm and its function.

Impact of Implementing Antibiotic Stewardship Programs in 15 Small Hospitals: A Cluster-Randomized Intervention.

PubMed

Stenehjem, Edward; Hersh, Adam L; Buckel, Whitney R; Jones, Peter; Sheng, Xiaoming; Evans, R Scott; Burke, John P; Lopansri, Bert K; Srivastava, Rajendu; Greene, Tom; Pavia, Andrew T

2018-02-23

Studies on the implementation of antibiotic stewardship programs (ASPs) in small hospitals are limited. Accreditation organizations now require all hospitals to have ASPs. The objective of this cluster-randomized intervention was to assess the effectiveness of implementing ASPs in Intermountain Healthcare's 15 small hospitals. Each hospital was randomized to 1 of 3 ASPs of escalating intensity. Program 1 hospitals were provided basic antibiotic stewardship education and tools, access to an infectious disease hotline, and antibiotic utilization data. Program 2 hospitals received those interventions plus advanced education, audit and feedback for select antibiotics, and locally controlled antibiotic restrictions. Program 3 hospitals received program 2 interventions plus audit and feedback on the majority of antibiotics, and an infectious diseases-trained clinician approved restricted antibiotics and reviewed microbiology results. Changes in total and broad-spectrum antibiotic use within programs (intervention versus baseline) and the difference between programs in the magnitude of change in antibiotic use (eg, program 3 vs 1) were evaluated with mixed models. Program 3 hospitals showed reductions in total (rate ratio, 0.89; confidence interval, .80-.99) and broad-spectrum (0.76; .63-.91) antibiotic use when the intervention period was compared with the baseline period. Program 1 and 2 hospitals did not experience a reduction in antibiotic use. Comparison of the magnitude of effects between programs showed a similar trend favoring program 3, but this was not statistically significant. Only the most intensive ASP intervention was associated with reduction in total and broad-spectrum antibiotic use when compared with baseline. NCT03245879.

Clinical and economic impact of an antibiotics stewardship programme in a regional hospital in Hong Kong.

PubMed

Ng, C K; Wu, T C; Chan, W M J; Leung, Y S W; Li, C K P; Tsang, D N C; Leung, G M

2008-10-01

Inappropriate use of antibiotics is one of the important factors attributing to emergence of drug-resistant pathogens. Infection with multidrug-resistant pathogens adversely affects quality of medical care. Queen Elizabeth Hospital, an 1800-bed acute service hospital in Hong Kong. Antibiotics are commonly prescribed for treating acute infections. Reduce inappropriate prescription of broad-spectrum antibiotics and overall antibiotic prescription through implementation of a multidisciplinary antibiotics stewardship programme (ASP). A multidisciplinary programme involving policy and guideline formulation, education and feedback, monthly antibiotic consumption and cost monitoring, antimicrobial susceptibility pattern reporting and concurrent feedbacks for commonly prescribed broad-spectrum antibiotics was implemented in 2004. Predefined logistics to prescribe "restricted" antibiotics were formulated and implemented with collaborative efforts from clinical and non-clinical departments. The programme was supported by management at department and hospital levels. Broad-spectrum antibiotics were prescribed inappropriately in 28.9% (n = 192) clinical scenarios. The ASP reduced the restricted and total antibiotic consumption as well as the antibiotics-related costs. Predefined clinical outcomes were not adversely affected. Economic analysis suggested that the extra human cost in running ASP could be offset by savings from antibiotic expenditure. It is cost-effective to implement a multidisciplinary ASP in acute service hospitals as the programme reduces antibiotic consumption and results in overall cost savings. The quality of medical care is not jeopardized as the important clinical outcomes are not adversely affected. The generalisability and sustainability of ASPs in other clinical contexts warrant further studies to ensure the continuous success of this programme.

Engineering thermal stability of L-asparaginase by in vitro directed evolution.

PubMed

Kotzia, Georgia A; Labrou, Nikolaos E

2009-03-01

L-asparaginase (EC 3.5.1.1, L-ASNase) catalyses the hydrolysis of l-Asn, producing L-Asp and ammonia. This enzyme is an anti-neoplastic agent; it is used extensively in the chemotherapy of acute lymphoblastic leukaemia. In this study, we describe the use of in vitro directed evolution to create a new enzyme variant with improved thermal stability. A library of enzyme variants was created by a staggered extension process using the genes that code for the L-ASNases from Erwinia chrysanthemi and Erwinia carotovora. The amino acid sequences of the parental L-ASNases show 77% identity, but their half-inactivation temperature (T(m)) differs by 10 degrees C. A thermostable variant of the E. chrysamthemi enzyme was identified that contained a single point mutation (Asp133Val). The T(m) of this variant was 55.8 degrees C, whereas the wild-type enzyme has a T(m) of 46.4 degrees C. At 50 degrees C, the half-life values for the wild-type and mutant enzymes were 2.7 and 159.7 h, respectively. Analysis of the electrostatic potential of the wild-type enzyme showed that Asp133 is located at a neutral region on the enzyme surface and makes a significant and unfavourable electrostatic contribution to overall stability. Site-saturation mutagenesis at position 133 was used to further analyse the contribution of this position on thermostability. Screening of a library of random Asp133 mutants confirmed that this position is indeed involved in thermostability and showed that the Asp133Leu mutation confers optimal thermostability.

Effects of early pregnancy diagnosis by per rectal palpation of the amniotic sac on pregnancy loss in dairy cattle.

PubMed

Romano, Juan E; Fahning, Melvyn L

2013-11-15

To determine effects of per rectal amniotic sac palpation (ASP) for pregnancy diagnosis during early gestation on pregnancy loss in lactating cows. Controlled, randomized block design. 368 pregnant dairy cows. Pregnancy was detected via transrectal ultrasonography (TRUS) at day 29 (day of estrus = day 0), and cows were allocated into a control group (n = 167 cows) and ASP group (180). Control cows were not subjected to pregnancy diagnosis via palpation per rectum. Per rectal ASP was performed between days 34 and 43 by only 1 experienced veterinarian. All cows were reevaluated with TRUS on days 45, 60, and 90. 21 cows were removed because of illness. Pregnancy loss between days 29 and 90 occurred in 44 of 347 (12.7%) cows. Pregnancy loss for the control and ASP groups from days 29 to 90 occurred in 22 of 167 (13.2%) and 22 of 180 (12.2%) cows, respectively. Late embryonic pregnancy loss (days 29 to 45) for the control and ASP groups occurred in 18 (10.8%) and 15 (8.3%) cows, respectively. Early fetal pregnancy loss (days 46 to 60) for the control and ASP groups occurred in 2 of 149 (1.3%) and 6 of 165 (3.6%) cows, respectively, and late fetal pregnancy loss (days 61 to 90) for the same groups occurred in 2 of 147 (1.4%) and 1 of 159 (0.6%) cows, respectively. Pregnancy diagnosis via per rectal ASP during early gestation did not increase pregnancy loss in dairy cattle.

Epitope Capsid-Incorporation: New Effective Approach for Vaccine Development for Chagas Disease

PubMed Central

Matthews, Qiana L.; Farrow, Anitra L.; Rachakonda, Girish; Gu, Linlin; Nde, Pius; Krendelchtchikov, Alexandre; Pratap, Siddharth; Sakhare, Shruti S.; Sabbaj, Steffanie; Lima, Maria F.; Villalta, Fernando

2016-01-01

Background Previously we reported that a hexon-modified adenovirus (Ad) vector containing the invasive neutralizing epitope of Trypanosoma cruzi (T. cruzi) trypomastigote gp83 (Ad5-gp83) provided immunoprotection against T. cruzi infection. The purpose of this work was to design an improved vaccine for T. cruzi using a novel epitope capsid incorporation strategy. Thus, we evaluated the immunoprotection raised by co-immunization with Ad5-gp83 and an Ad vector containing an epitope (ASP-M) of the T. cruzi amastigote surface protein 2. Methods Protein IX (pIX)-modified Ad vector (Ad5-pIX-ASP-M) was generated, characterized, and validated. C3H/He mice were immunized with Ad5-pIX-ASP-M and Ad5-gp83 and the cell-mediated responses were evaluated by enzyme-linked immunospot (ELISPOT) assay and intracellular staining. Immunized mice were challenged with T. cruzi to evaluate the vaccine efficacy. Results Our findings indicate that Ad5-pIX-ASP-M was viable. Specific CD8+ T-cell mediated responses prior to the challenge show an increase in IFNγ and TNFα production. A single immunization with Ad5-pIX-ASP-M provided protection from T. cruzi infection, but co-immunizations with Ad5-pIX-ASP-M and Ad5-gp83 provided a higher immunoprotection and increased survival rate of mice. Conclusions Overall, these results suggest that the combination of gp83 and ASP-M specific epitopes onto the capsid-incorporated adenoviruses would provide superior protection against Chagas disease as compared with Ad5-gp83 alone. PMID:27709126

A tonoplast Glu/Asp/GABA exchanger that affects tomato fruit amino acid composition.

PubMed

Snowden, Christopher J; Thomas, Benjamin; Baxter, Charles J; Smith, J Andrew C; Sweetlove, Lee J

2015-03-01

Vacuolar accumulation of acidic metabolites is an important aspect of tomato fruit flavour and nutritional quality. The amino acids Asp and Glu accumulate to high concentrations during ripening, while γ-aminobutyrate (GABA) shows an approximately stoichiometric decline. Given that GABA can be catabolised to form Glu and subsequently Asp, and the requirement for the fruit to maintain osmotic homeostasis during ripening, we hypothesised the existence of a tonoplast transporter that exports GABA from the vacuole in exchange for import of either Asp or Glu. We show here that the tomato vacuolar membrane possesses such a transport property: transport of Glu across isolated tonoplast vesicle membranes was trans-stimulated in counterexchange mode by GABA, Glu and Asp. We identified SlCAT9 as a candidate protein for this exchanger using quantitative proteomics of a tonoplast-enriched membrane fraction. Transient expression of a SlCAT9-YFP fusion in tobacco confirmed a tonoplast localisation. The function of the protein was examined by overexpression of SlCAT9 in transgenic tomato plants. Tonoplast vesicles isolated from transgenic plants showed higher rates of Glu and GABA transport than wild-type (WT) only when assayed in counterexchange mode with Glu, Asp, or GABA. Moreover, there were substantial increases in the content of all three cognate amino acids in ripe fruit from the transgenic plants. We conclude that SlCAT9 is a tonoplast Glu/Asp/GABA exchanger that strongly influences the accumulation of these amino acids during fruit development. © 2015 The Authors The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.

Post-translational Transformation of Methionine to Aspartate Is Catalyzed by Heme Iron and Driven by Peroxide

PubMed Central

Strader, Michael Brad; Hicks, Wayne A.; Kassa, Tigist; Singleton, Eileen; Soman, Jayashree; Olson, John S.; Weiss, Mitchell J.; Mollan, Todd L.; Wilson, Michael T.; Alayash, Abdu I.

2014-01-01

A pathogenic V67M mutation occurs at the E11 helical position within the heme pockets of variant human fetal and adult hemoglobins (Hb). Subsequent post-translational modification of Met to Asp was reported in γ subunits of human fetal Hb Toms River (γ67(E11)Val → Met) and β subunits of adult Hb (HbA) Bristol-Alesha (β67(E11)Val → Met) that were associated with hemolytic anemia. Using kinetic, proteomic, and crystal structural analysis, we were able to show that the Met → Asp transformation involves heme cycling through its oxoferryl state in the recombinant versions of both proteins. The conversion to Met and Asp enhanced the spontaneous autoxidation of the mutants relative to wild-type HbA and human fetal Hb, and the levels of Asp were elevated with increasing levels of hydrogen peroxide (H2O2). Using H218O2, we verified incorporation of 18O into the Asp carboxyl side chain confirming the role of H2O2 in the oxidation of the Met side chain. Under similar experimental conditions, there was no conversion to Asp at the αMet(E11) position in the corresponding HbA Evans (α62(E11)Val → Met). The crystal structures of the three recombinant Met(E11) mutants revealed similar thioether side chain orientations. However, as in the solution experiments, autoxidation of the Hb mutant crystals leads to electron density maps indicative of Asp(E11) formation in β subunits but not in α subunits. This novel post-translational modification highlights the nonequivalence of human Hb α, β, and γ subunits with respect to redox reactivity and may have direct implications to α/β hemoglobinopathies and design of oxidatively stable Hb-based oxygen therapeutics. PMID:24939847

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richter, H.T.; Brown, L.S.; Lanyi, J.K.

Because asp-85 is the acceptor of the retinal Schiff base proton during light-driven proton transport by bacteriorhodopsin, modulation of its pK{sub a} in the photocycle is to be expected. The complex titration of asp-85 in the unphotolyzed protein was suggested to reflect the dependence of this residue on the protonation state of another, unidentified group. from the pH dependencies of the rate constant for the thermal equilibration of retinal isomeric states (dark adaptation) and the deprotonation kinetics of the Schiff base during the photocycle in the E204Q and E204D mutants, we identify the residue as glu-204. The nature of itsmore » interaction with our recent finding that glu-204 is the origin of the proton released to the extracellular surface upon protonation of asp-85 during that transport. We propose, therefore, that the following series of events occur in the photocycle. Protonation of asp-85 in the proton equilibrium with the Schiff base of the photoisomerized retinal results in the dissociation of glu-204 and proton release to the extracellular surface upon protonation of asp-85 during the transport. We propose, therefore, that the following series of events occur in the photocycle. Protonation of asp-85 in the proton equilibrium with the Schiff base shifts toward complete proton transfer. This constitutes the first phase of the reprotonation switch because it excludes asp-85 as a donor in the reprotonation of the Schiff base that follows. The sequential structural changes of the protein that ensue, detected earlier by diffraction, are suggested to facilitate the change of the access of the Schiff base toward the cytoplasmic side at the second phase of the switch, and the lowering the pK{sub a} of asp-96, so as to make it a proton donor, as the third phase. 77 refs., 6 figs.« less

Post-translational transformation of methionine to aspartate is catalyzed by heme iron and driven by peroxide: a novel subunit-specific mechanism in hemoglobin.

PubMed

Strader, Michael Brad; Hicks, Wayne A; Kassa, Tigist; Singleton, Eileen; Soman, Jayashree; Olson, John S; Weiss, Mitchell J; Mollan, Todd L; Wilson, Michael T; Alayash, Abdu I

2014-08-08

A pathogenic V67M mutation occurs at the E11 helical position within the heme pockets of variant human fetal and adult hemoglobins (Hb). Subsequent post-translational modification of Met to Asp was reported in γ subunits of human fetal Hb Toms River (γ67(E11)Val → Met) and β subunits of adult Hb (HbA) Bristol-Alesha (β67(E11)Val → Met) that were associated with hemolytic anemia. Using kinetic, proteomic, and crystal structural analysis, we were able to show that the Met → Asp transformation involves heme cycling through its oxoferryl state in the recombinant versions of both proteins. The conversion to Met and Asp enhanced the spontaneous autoxidation of the mutants relative to wild-type HbA and human fetal Hb, and the levels of Asp were elevated with increasing levels of hydrogen peroxide (H2O2). Using H2(18)O2, we verified incorporation of (18)O into the Asp carboxyl side chain confirming the role of H2O2 in the oxidation of the Met side chain. Under similar experimental conditions, there was no conversion to Asp at the αMet(E11) position in the corresponding HbA Evans (α62(E11)Val → Met). The crystal structures of the three recombinant Met(E11) mutants revealed similar thioether side chain orientations. However, as in the solution experiments, autoxidation of the Hb mutant crystals leads to electron density maps indicative of Asp(E11) formation in β subunits but not in α subunits. This novel post-translational modification highlights the nonequivalence of human Hb α, β, and γ subunits with respect to redox reactivity and may have direct implications to α/β hemoglobinopathies and design of oxidatively stable Hb-based oxygen therapeutics. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Why PACS is no longer a four-letter word.

PubMed

Chopra, R M

2000-01-01

The real value of PACS is not realized until widespread adoption exists among physicians other than interpreting radiologists. Referring physicians at the office level, in the operating room and in other departments must be willing to embrace the reading of images on monitors. That takes time. The payoff for a PACS system is therefore not realized until sometime in the future. Given the huge up-front capital expenditure required of PACS solutions, it is no wonder that the decision has historically been a difficult one to make. Enter the application service provider (ASP). The marriage of the ASP model to PACS seems to be one of the true "killer apps" currently available in the healthcare technology space. An ASP can host and maintain the software inherent in PACS solutions. Images are centrally archived over the short-, medium-, and long-term timeframe, utilizing state-of-art data management facilities. Some ASPs also provide the necessary bandwidth to office sites and the small amount of hardware that is required onsite, such as viewing stations or monitors. Costs for Internet-based image management under the ASP model rely on a pay-as-you-go formula, which may include all software, support, required hardware and bandwidth as part of the service. There may be a minor up-front fee for installation. The ASP pricing model eliminates the huge gamble an organization takes on "big iron" PACS purchases. Those benefits rely on the first rule of finance: a dollar today is worth more than a dollar tomorrow. PACS and ASPs were made for one another. Because the financial benefits of PACS are realized over time, the timing of cash flows is extremely important. Other benefits inherent in the ASP model such as scalability, diminished need for IT personnel, software version integrity and better pricing because of economies of scale are attractive also.

Structure of a two-CAP-domain protein from the human hookworm parasite Necator americanus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asojo, Oluwatoyin A., E-mail: oasojo@unmc.edu

2011-05-01

The first structure of a two-CAP-domain protein, Na-ASP-1, from the major human hookworm parasite N. americanus refined to a resolution limit of 2.2 Å is presented. Major proteins secreted by the infective larval stage hookworms upon host entry include Ancylostoma secreted proteins (ASPs), which are characterized by one or two CAP (cysteine-rich secretory protein/antigen 5/pathogenesis related-1) domains. The CAP domain has been reported in diverse phylogenetically unrelated proteins, but has no confirmed function. The first structure of a two-CAP-domain protein, Na-ASP-1, from the major human hookworm parasite Necator americanus was refined to a resolution limit of 2.2 Å. The structuremore » was solved by molecular replacement (MR) using Na-ASP-2, a one-CAP-domain ASP, as the search model. The correct MR solution could only be obtained by truncating the polyalanine model of Na-ASP-2 and removing several loops. The structure reveals two CAP domains linked by an extended loop. Overall, the carboxyl-terminal CAP domain is more similar to Na-ASP-2 than to the amino-terminal CAP domain. A large central cavity extends from the amino-terminal CAP domain to the carboxyl-terminal CAP domain, encompassing the putative CAP-binding cavity. The putative CAP-binding cavity is a characteristic cavity in the carboxyl-terminal CAP domain that contains a His and Glu pair. These residues are conserved in all single-CAP-domain proteins, but are absent in the amino-terminal CAP domain. The conserved His residues are oriented such that they appear to be capable of directly coordinating a zinc ion as observed for CAP proteins from reptile venoms. This first structure of a two-CAP-domain ASP can serve as a template for homology modeling of other two-CAP-domain proteins.« less

Layer by layer: complex analysis with OCT technology

NASA Astrophysics Data System (ADS)

Florin, Christian

2017-03-01

Standard visualisation systems capture two- dimensional images and need more or less fast image processing systems. Now, the ASP Array (Actives sensor pixel array) opens a new world in imaging. On the ASP array, each pixel is provided with its own lens and with its own signal pre-processing. The OCT technology works in "real time" with highest accuracy. In the ASP array systems functionalities of the data acquisition and signal processing are even integrated onto the "pixel level". For the extraction of interferometric features, the time-of-flight principle (TOF) is used. The ASP architecture offers the demodulation of the optical signal within a pixel with up to 100 kHz and the reconstruction of the amplitude and its phase. The dynamics of image capture with the ASP array is higher by two orders of magnitude in comparison with conventional image sensors!!! The OCT- Technology allows a topographic imaging in real time with an extremely high geometric spatial resolution. The optical path length is generated by an axial movement of the reference mirror. The amplitude-modulated optical signal and the carrier frequency are proportional to the scan rate and contains the depth information. Each maximum of the signal envelope corresponds to a reflection (or scattering) within a sample. The ASP array produces at same time 300 * 300 axial Interferorgrams which touch each other on all sides. The signal demodulation for detecting the envelope is not limited by the frame rate of the ASP array in comparison to standard OCT systems. If an optical signal arrives to a pixel of the ASP Array an electrical signal is generated. The background is faded to saturation of pixels by high light intensity to avoid. The sampled signal is integrated continuously multiplied by a signal of the same frequency and two paths whose phase is shifted by 90 degrees from each other are averaged. The outputs of the two paths are routed to the PC, where the envelope amplitude and the phase calculate a three-dimensional tomographic image. For 3D measuring technique specially designed ASP- arrays with a very high image rate are available. If ASP- Arrays are coupled with the OCT method, layer thicknesses can be determined without contact, sealing seams can be inspected or geometrical shapes can be measured. From a stack of hundreds of single OCT images, interesting images can be selected and fed to the computer to analyse them.

[Regulation of [12Asp]K-ras4B on transcriptional activity of estrogen receptor in endometrial carcinoma HEC-1A cell lines].

PubMed

Gui, Li-ming; Wei, Li-hui; Xu, Ming-xu; Wang, Jian-liu; Zhong, Ying-cheng; Li, Xiao-ping; Tu, Zheng; Sun, Peng-ming; Ma, Da-long

2004-01-01

To investigate the effect of mutant-type [(12)Asp]K-ras4B gene on the expression of estrogen receptor (ER) alpha and beta and their transcriptional activity as a transcription factor in endometrial carcinoma HEC-1A cell line. (1) Effect of [(12)Asp]K-ras4B on the expression of ER alpha and beta were determined using Western blot assay. (2) Eukaryotic expression plasmid pGL3-luciferase-ERE containing luciferase report gene and estrogen receptor element (ERE) was constructed, and co-transfected into NIH3T3 and HEC-1A cell lines with pEGFP-N1 to examine the effect of [(12)Asp]K-ras4B on ER transcription that is regulated by estradiol. In addition, they were transfected into pSV5-HER0 (containing full length wide type ERalpha cDNA) and pCMV-rafS621A (inhibiting raf kinase) plasmids to test the effect of [(12)Asp]K-ras4B/raf signal pathway on transcriptional activity of ER proteins. (1) Protein level of ERs expressed in pcDI transfected control cells was low while it was increased for 3.6-fold (97 +/- 25, 349 +/- 67, P < 0.01) and 1.9-fold (128 +/- 37, 349 +/- 30, P < 0.05) in ERalpha and ERbeta, respectively, in pcDI-[(12)Asp]K-ras4B NIH3T3 cells after transfection. (2) In pcDI-[(12)Asp]K-ras4B NIH3T3 cells, the ratios for ERalpha and and ERbeta levels before transfection of rafS621A plasmids to that after the transfection, were 2.4:1 (724 +/- 45, 310 +/- 46, P < 0.05) and 1.8:1 (493 +/- 20, 284 +/- 20, P < 0.01), respectively; In HEC-1A cells, these ratios were 2.1:1 (566 +/- 22, 279 +/- 30, P < 0.01) and 2.4:1 (405 +/- 33, 165 +/- 15, P < 0.01), respectively. (3) In low serum (2%) culture condition, estradiol (E(2)) stimulated luciferase activity with an increase of 13-fold (130 +/- 42, 1681 +/- 242, P < 0.01) in pcDI-[(12)Asp] K-ras4B NIH3T3 cells, 19-fold (141 +/- 39, 2644 +/- 331, P < 0.001) in HEC-1A cells, respectively, when compared with those in the absence of E(2). (4) In pSV5-HER0 transfected pcDI-[(12)Asp] K-ras4B NIH3T3 cells and HEC-1A cells, compared to the untransfected cells, the ER transcriptional activity in the transfected cells increased markedly. The luciferase activity was increased for 8-fold (1048 +/- 91, 8099 +/- 452, P < 0.01) and 6-fold (2148 +/- 259, 12,705 +/- 2670, P < 0.001), respectively. rafS621A mutant had suppressive effects on luciferase activities in HEC-1A cells and pcDI-[(12)Asp]K-ras4B NIH3T3 cells. The ratio of luciferase activities in pcDI-[(12)Asp]K-ras4B NIH3T3 and HEC-1A cells, before and after transfection was 7.8:1 (1184 +/- 168, 152 +/- 27, P < 0.05) and 6.4:1 (1949 +/- 212, 304 +/- 60, P < 0.01), respectively. (1) [(12)Asp]K-ras4B can enhance the expression of ERalpha and beta proteins. This may be correlated with [(12)Asp]K-ras4B/raf signaling pathway. (2) The effect of mutant-type [(12)Asp]K-ras4B gene on ERs transcriptional activity in HEC-1A cells appears to need E(2).

Autism and Classical Eyeblink Conditioning: Performance Changes of the Conditioned Response Related to Autism Spectrum Disorder Diagnosis

PubMed Central

Welsh, John P.; Oristaglio, Jeffrey T.

2016-01-01

Changes in the timing performance of conditioned responses (CRs) acquired during trace and delay eyeblink conditioning (EBC) are presented for diagnostic subgroups of children having autism spectrum disorder (ASD) aged 6–15 years. Children diagnosed with autistic disorder (AD) were analyzed separately from children diagnosed with either Asperger’s syndrome or Pervasive developmental disorder (Asp/PDD) not otherwise specified and compared to an age- and IQ-matched group of children who were typically developing (TD). Within-subject and between-groups contrasts in CR performance on sequential exposure to trace and delay EBC were analyzed to determine whether any differences would expose underlying functional heterogeneities of the cerebral and cerebellar systems, in ASD subgroups. The EBC parameters measured were percentage CRs, CR onset latency, and CR peak latency. Neither AD nor Asp/PDD groups were impaired in CR acquisition during trace or delay EBC. Both AD and Asp/PDD altered CR timing, but not always in the same way. Although the AD group showed normal CR timing during trace EBC, the Asp/PDD group showed a significant 27 and 28 ms increase in CR onset and peak latency, respectively, during trace EBC. In contrast, the direction of the timing change was opposite during delay EBC, during which the Asp/PDD group showed a significant 29 ms decrease in CR onset latency and the AD group showed a larger 77 ms decrease in CR onset latency. Only the AD group showed a decrease in CR peak latency during delay EBC, demonstrating another difference between AD and Asp/PDD. The difference in CR onset latency during delay EBC for both AD and Asp/PDD was due to an abnormal prevalence of early onset CRs that were intermixed with CRs having normal timing, as observed both in CR onset histograms and mean CR waveforms. In conclusion, significant heterogeneity in EBC performance was apparent between diagnostic groups, and this may indicate that EBC performance can report the heterogeneity in the neurobiological predispositions for ASD. The findings will inform further explorations with larger cohorts, different sensory modalities, and different EBC paradigms and provide a reference set for future EBC studies of children having ASD and non-human models. PMID:27563293

Structure characterization of lipocyclopeptide antibiotics, aspartocins A, B & C, by ESI-MSMS and ESI-nozzle-skimmer-MSMS.

PubMed

Siegel, Marshall M; Kong, Fangming; Feng, Xidong; Carter, Guy T

2009-12-01

Three lipocyclopeptide antibiotics, aspartocins A (1), B (2), and C (3), were obtained from the aspartocin complex by HPLC separation methodology. Their structures were elucidated using previously published chemical degradation results coupled with spectroscopic studies including ESI-MS, ESI-Nozzle Skimmer-MSMS and NMR. All three aspartocin compounds share the same cyclic decapeptide core of cyclo [Dab2 (Asp1-FA)-Pip3-MeAsp4-Asp5-Gly6-Asp7-Gly8-Dab9-Val10-Pro11]. They differ only in the fatty acid side chain moiety (FA) corresponding to (Z)-13-methyltetradec-3-ene-carbonyl, (+,Z)-12-methyltetradec-3-ene-carbonyl and (Z)-12-methyltridec-3-ene-carbonyl for aspartocins A (1), B (2), and C (3), respectively. All of the sequence ions were observed by ESI-MSMS of the doubly charged parent ions. However, a number of the sequence ions observed were of low abundance. To fully sequence the lipocyclopeptide antibiotic structures, these low abundance sequence ions together with complementary sequence ions were confirmed by ESI-Nozzle-Skimmer-MSMS of the singly charged linear peptide parent fragment ions H-Asp5-Gly6-Asp7-Gly8-Dab9-Val10-Pro11-Dab2(1+)-Asp1-FA. Cyclization of the aspartocins was demonstrated to occur via the beta-amino group of Dab2 from ions of moderate intensity in the ESI-MSMS spectra. As the fatty acid moieties do not undergo internal fragmentations under the experimental ESI mass spectral conditions used, the 14 Da mass difference between the fatty acid moieties of aspartocins A (1) and B (2) versus aspartocin C (3) was used as an internal mass tag to differentiate fragment ions containing fatty acid moieties and those not containing the fatty acid moieties. The most numerous and abundant fragment ions observed in the tandem mass spectra are due to the cleavage of the tertiary nitrogen amide of the pipecolic acid residue-3 (16 fragment ions) and the proline residue-11 (7 fragment ions). In addition, the neutral loss of ethanimine from alpha,beta-diaminobutyric acid residue 9 was observed for the parent molecular ion and for 7 fragment ions. Copyright 2009 John Wiley & Sons, Ltd.

The role of a second-shell residue in modifying substrate and inhibitor interactions in the SHV beta-lactamase: a study of ambler position Asn276.

PubMed

Drawz, Sarah M; Bethel, Christopher R; Hujer, Kristine M; Hurless, Kelly N; Distler, Anne M; Caselli, Emilia; Prati, Fabio; Bonomo, Robert A

2009-06-02

Inhibitor-resistant class A beta-lactamases of the TEM and SHV families that arise by single amino acid substitutions are a significant threat to the efficacy of beta-lactam/beta-lactamase inhibitor combinations. To better understand the basis of the inhibitor-resistant phenotype in SHV, we performed mutagenesis to examine the role of a second-shell residue, Asn276. Of the 19 variants expressed in Escherichia coli, only the Asn276Asp enzyme demonstrated reduced susceptibility to ampicillin/clavulanate (MIC increased from 50/2 --> 50/8 microg/mL) while maintaining high-level resistance to ampicillin (MIC = 8192 microg/mL). Steady-state kinetic analyses of Asn276Asp revealed slightly diminished k(cat)/K(m) for all substrates tested. In contrast, we observed a 5-fold increase in K(i) for clavulanate (7.4 +/- 0.9 microM for Asn276Asp vs 1.4 +/- 0.2 microM for SHV-1) and a 40% reduction in k(inact)/K(I) (0.013 +/- 0.002 microM(-1 )s(-1) for Asn276Asp vs 0.021 +/- 0.004 microM(-1) s(-1) for SHV-1). Timed electrospray ionization mass spectrometry of clavulanate-inhibited SHV-1 and SHV Asn276Asp showed nearly identical mass adducts, arguing for a similar pathway of inactivation. Molecular modeling shows that novel electrostatic interactions are formed between Arg244Neta2 and both 276AspOdelta1 and Odelta2; these new forces restrict the spatial position of Arg244, a residue important in the recognition of the C(3)/C(4) carboxylate of beta-lactam substrates and inhibitors. Testing the functional consequences of this interaction, we noted considerable free energy costs (+DeltaDeltaG) for substrates and inhibitors. A rigid carbapenem (meropenem) was most affected by the Asn276Asp substitution (46-fold increase in K(i) vs SHV-1). We conclude that residue 276 is an important second-shell residue in class A beta-lactamase-mediated resistance to substrates and inhibitors, and only Asn is able to precisely modulate the conformational flexibility of Arg244 required for successful evolution in nature.

A broad survey of cathepsin K immunoreactivity in human neoplasms.

PubMed

Zheng, Gang; Martignoni, Guido; Antonescu, Cristina; Montgomery, Elizabeth; Eberhart, Charles; Netto, George; Taube, Janis; Westra, William; Epstein, Jonathan I; Lotan, Tamara; Maitra, Anirban; Gabrielson, Edward; Torbenson, Michael; Iacobuzio-Donahue, Christine; Demarzo, Angelo; Shih, Ie Ming; Illei, Peter; Wu, T C; Argani, Pedram

2013-02-01

Cathepsin K is consistently and diffusely expressed in alveolar soft part sarcoma (ASPS) and a subset of translocation renal cell carcinomas (RCCs). However, cathepsin K expression in human neoplasms has not been systematically analyzed. We constructed tissue microarrays (TMA) from a wide variety of human neoplasms, and performed cathepsin K immunohistochemistry (IHC). Only 2.7% of 1,140 carcinomas from various sites exhibited cathepsin K labeling, thus suggesting that among carcinomas, cathepsin K labeling is highly specific for translocation RCC. In contrast to carcinomas, cathepsin K labeling was relatively common (54.6%) in the 414 mesenchymal lesions studied, including granular cell tumor, melanoma, and histiocytic lesions, but not paraganglioma, all of which are in the morphologic differential diagnosis of ASPS. Cathepsin K IHC can be helpful in distinguishing ASPS and translocation RCC from some but not all of the lesions in their differential diagnosis.

Coercive and Prosocial Fathering, Antisocial Personality, and Growth in Children's Post-Divorce Noncompliance

PubMed Central

DeGarmo, David S.

2009-01-01

The study employed multiple methods including direct observation of fathering behaviors and child noncompliance to better address our understanding of the quantity and quality of divorced father contact. A weighted county sample of 230 divorced-father families with a focal child aged 4 to 11 years was employed to test whether fathers' antisocial personality (ASP) moderated effects of monthly contact with children in predicting children's observed noncompliance over 18 months. Latent growth models obtained significant individual differences in levels of noncompliance and growth rates. ASP significantly moderated the beneficial impact of fathers' monthly contact. Fathers' observed parenting practices significantly predicted levels but not growth rates. Parenting did not account for the effect of Contact × ASP suggesting both environmental and potentially genetic influences on child adjustment. Findings were robust across boys and girls and age levels. Implications for preventive intervention are discussed. PMID:20438456

The effect of the flexibility of hydrogen bonding network on low-frequency motions of amino acids. Evidence from Terahertz spectroscopy and DFT calculations

NASA Astrophysics Data System (ADS)

Li, Yin; Lukács, András; Bordács, Sándor; Móczár, János; Nyitrai, Miklós; Hebling, János

2018-02-01

Low-frequency modes of L-Asp and L-Asn were studied in the range from 0.1 to 3.0 THz using time-domain Terahertz spectroscopy and density functional theory calculation. The results show that PBE-D2 shows more success than BLYP-D2 in prediction of THz absorption spectra. To compare their low-frequency modes, we adopted ;vibrational character ID strips; proposed by Schmuttenmaer and coworkers [Journal of Physical Chemistry B, 117, 10444(2013)]. We found that the most intense THz absorption peaks of two compounds both involve severe distortion of their hydrogen bonding networks. Due to less rigid hydrogen bonding network in L-Asp, the side chain (carboxyl group) of L-Asp exhibits larger motions than that (carboxamide group) of L-Asn in low-frequency modes.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ayeb, M.E.; Bahraoui, E.M.; Granier, C.

Two antibody subpopulations directed against Anemonia sulcata toxin I or II have been purified by immunoaffinity chromatography. These antibodies are specific for a single antigenic region and were used in a structure-antigenicity relationship study using homologous toxins and chemically modified derivatives of A. sulcata toxin II. Asp-7 and/or Asp=9 and Gln-47 of toxin II were found to be implicated in the antigenic region recognized by the two antibody subpopulations. On the contrary, Arg-14, Lys-35, -36, and -46, and ..cap alpha..-NH/sub 2/ of the glycine residue of A. sulcata toxin II are not involved in the corresponding antigenic region. When assayedmore » for interaction with the sodium channel, the antigenic region of toxin II, including Asp-9 and Gln-47, appeared fully accessible to its specific antibodies, suggesting that it is not involved in the binding of the toxin to its receptor.« less

Structural studies of α-melanocyte-stimulating hormone and a novel β-melanocyte-stimulating hormone from the neurointermediate lobe of the pituitary of the dogfish Squalus acanthias

PubMed Central

Bennett, Hugh P. J.; Lowry, Philip J.; McMartin, Colin; Scott, Alexander P.

1974-01-01

A melanocyte-stimulating hormone (MSH) has been isolated from extracts of the neurointermediate lobe of the pituitary of the dogfish Squalus acanthias by gel-filtration and ion-exchange chromatography. It had approximately 1% of the potency of mammalian α-MSH on bioassays in vitro on frog skin and dogfish skin. Sequence analysis revealed it to be a hexadecapeptide with the following primary structure: Asp-Gly-Asp-Asp-Tyr-Lys-Phe-Gly-His-Phe-Arg-Trp-Ser-Val-Pro-Leu. It appears to be related to the β-MSH species of mammalian species but has only the sequence -His-Phe-Arg-Trp- in common with the heptapeptide core -Met-Glu-His-Phe-Arg-Trp-Gly- which is characteristic not only of the MSH peptides but also of the adrenocorticotrophins and lipotrophins studied so far. An α-MSH was also isolated, 50% of which was amidated at the C-terminus group. Sequence data from this study taken in conjunction with those from a previous study (Lowry & Chadwick, 1970b) revealed it to be a tridecapeptide which is identical with the N-terminal sequence of dogfish adrenocorticotrophin. PMID:4375978

Microzooplankton herbivory and community structure in the Amundsen Sea, Antarctica

NASA Astrophysics Data System (ADS)

Yang, Eun Jin; Jiang, Yong; Lee, SangHoon

2016-01-01

We examined microzooplankton abundance, community structure, and grazing impact on phytoplankton in the Amundsen Sea, Western Antarctica, during the early austral summer from December 2010 to January 2011. Our study area was divided into three regions based on topography, hydrographic properties, and trophic conditions: (1) the Oceanic Zone (OZ), with free sea ice and low phytoplankton biomass dominated by diatoms; (2) the Sea Ice Zone (SIZ), covered by heavy sea ice with colder water, lower salinity, and dominated by diatoms; and (3) the Amundsen Sea Polynya (ASP), with high phytoplankton biomass dominated by Phaeocystis antarctica. Microzooplankton biomass and communities associated with phytoplankton biomass and composition varied among regions. Heterotrophic dinoflagellates (HDF) were the most significant grazers in the ASP and OZ, whereas ciliates co-dominated with HDF in the SIZ. Microzooplankton grazing impact is significant in our study area, particularly in the ASP, and consumed 55.4-107.6% of phytoplankton production (average 77.3%), with grazing impact increasing with prey and grazer biomass. This result implies that a significant proportion of the phytoplankton production is not removed by sinking or other grazers but grazed by microzooplankton. Compared with diatom-based systems, Phaeocystis-based production would be largely remineralized and/or channeled through the microbial food web through microzooplankton grazing. In these waters the major herbivorous fate of phytoplankton is likely mediated by the microzooplankton population. Our study confirms the importance of herbivorous protists in the planktonic ecosystems of high latitudes. In conclusion, microzooplankton herbivory may be a driving force controlling phytoplankton growth in early summer in the Amundsen Sea, particularly in the ASP.

Proton Transfers in a Channelrhodopsin-1 Studied by Fourier Transform Infrared (FTIR) Difference Spectroscopy and Site-directed Mutagenesis*

PubMed Central

Ogren, John I.; Yi, Adrian; Mamaev, Sergey; Li, Hai; Spudich, John L.; Rothschild, Kenneth J.

2015-01-01

Channelrhodopsin-1 from the alga Chlamydomonas augustae (CaChR1) is a low-efficiency light-activated cation channel that exhibits properties useful for optogenetic applications such as a slow light inactivation and a red-shifted visible absorption maximum as compared with the more extensively studied channelrhodopsin-2 from Chlamydomonas reinhardtii (CrChR2). Previously, both resonance Raman and low-temperature FTIR difference spectroscopy revealed that unlike CrChR2, CaChR1 under our conditions exhibits an almost pure all-trans retinal composition in the unphotolyzed ground state and undergoes an all-trans to 13-cis isomerization during the primary phototransition typical of other microbial rhodopsins such as bacteriorhodopsin (BR). Here, we apply static and rapid-scan FTIR difference spectroscopy along with site-directed mutagenesis to characterize the proton transfer events occurring upon the formation of the long-lived conducting P2380 state of CaChR1. Assignment of carboxylic C=O stretch bands indicates that Asp-299 (homolog to Asp-212 in BR) becomes protonated and Asp-169 (homolog to Asp-85 in BR) undergoes a net change in hydrogen bonding relative to the unphotolyzed ground state of CaChR1. These data along with earlier FTIR measurements on the CaChR1 → P1 transition are consistent with a two-step proton relay mechanism that transfers a proton from Glu-169 to Asp-299 during the primary phototransition and from the Schiff base to Glu-169 during P2380 formation. The unusual charge neutrality of both Schiff base counterions in the P2380 conducting state suggests that these residues may function as part of a cation selective filter in the open channel state of CaChR1 as well as other low-efficiency ChRs. PMID:25802337

Structure-activity relationships of the unique and potent agouti-related protein (AGRP)-melanocortin chimeric Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH2 peptide template.

PubMed

Wilczynski, Andrzej; Wilson, Krista R; Scott, Joseph W; Edison, Arthur S; Haskell-Luevano, Carrie

2005-04-21

The melanocortin receptor system consists of endogenous agonists, antagonists, G-protein coupled receptors, and auxiliary proteins that are involved in the regulation of complex physiological functions such as energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. Herein, we report the structure-activity relationship (SAR) of a new chimeric hAGRP-melanocortin agonist peptide template Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) that was characterized using amino acids previously reported in other melanocortin agonist templates. Twenty peptides were examined in this study, and six peptides were selected for (1)H NMR and computer-assisted molecular modeling structural analysis. The most notable results include the identification that modification of the chimeric template at the His position with Pro and Phe resulted in ligands that were nM mouse melanocortin-3 receptor (mMC3R) antagonists and nM mouse melanocortin-4 receptor (mMC4R) agonists. The peptides Tyr-c[beta-Asp-His-DPhe-Ala-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) and Tyr-c[beta-Asp-His-DNal(1')-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) resulted in 730- and 560-fold, respectively, mMC4R versus mMC3R selective agonists that also possessed nM agonist potency at the mMC1R and mMC5R. Structural studies identified a reverse turn occurring in the His-DPhe-Arg-Trp domain, with subtle differences observed that may account for the differences in melanocortin receptor pharmacology. Specifically, a gamma-turn secondary structure involving the DPhe(4) in the central position of the Tyr-c[beta-Asp-Phe-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) peptide may differentiate the mixed mMC3R antagonist and mMC4R agonist pharmacology.

ASP8273 tolerability and antitumor activity in TKI-naive Japanese patients with EGFR mutation-positive non-small cell lung cancer.

PubMed

Azuma, Koichi; Nishio, Makoto; Hayashi, Hidetoshi; Kiura, Katsuyuki; Satouchi, Miyako; Sugawara, Shunichi; Hida, Toyoaki; Iwamoto, Yasuo; Inoue, Akira; Takeda, Koji; Ikeda, Satoshi; Nakagawa, Tomoki; Takeda, Kentaro; Asahina, Seitaro; Komatsu, Kanji; Morita, Satoshi; Fukuoka, Masahiro; Nakagawa, Kazuhiko

2018-05-28

Epidermal growth factor receptor (EGFR) activating mutations occur in approximately 50% of East Asian patients with non-small cell lung cancer (NSCLC) and confer sensitivity to tyrosine kinase inhibitors (TKI). ASP8273 is an orally administered, irreversible EGFR-TKI that inhibits EGFR activating mutations and has demonstrated clinical activity in patients with EGFR mutation-positive NSCLC. EGFR-TKI-naïve Japanese adult patients (≥20 years) with NSCLC harboring EGFR mutations were enrolled in this open-label, single-arm, Phase 2 study (NCT02500927). Patients received ASP8273 300mg once daily until discontinuation criteria were met. The primary endpoint was to determine the safety of ASP8273 300mg; secondary endpoint was antitumor activity defined by RECIST v1.1. Thirty-one patients (12M/19F; median age 64 years [range: 31-82]) with EGFR mutation-positive NSCLC were enrolled; as of 23 February 2016, 25 patients (81%) were still on study. Of the 31 patients, 27 (87%) had an ex19del (n=13, 42%) or a L858R (n=14, 45%) EGFR activating mutation; 2 (7%) had L861Q mutation and 5 (16%) had other EGFR activating mutations, two had an activating mutation and the T790M resistance mutation. The most commonly reported treatment-emergent adverse event was diarrhea [n=24, 77%]. All patients had at least 1 post-baseline scan; 1 patient (3%) achieved a confirmed complete response, 13 (42%) had a confirmed partial response, and 15 (48%) had confirmed stable disease (disease control rate: 94% [n=29/31]) per investigator assessment. Once-daily ASP8273 300 mg was generally well tolerated and demonstrated antitumor activity in TKI-naïve Japanese patients with EGFR mutation-positive NSCLC. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Proton transfers in a channelrhodopsin-1 studied by Fourier transform infrared (FTIR) difference spectroscopy and site-directed mutagenesis.

PubMed

Ogren, John I; Yi, Adrian; Mamaev, Sergey; Li, Hai; Spudich, John L; Rothschild, Kenneth J

2015-05-15

Channelrhodopsin-1 from the alga Chlamydomonas augustae (CaChR1) is a low-efficiency light-activated cation channel that exhibits properties useful for optogenetic applications such as a slow light inactivation and a red-shifted visible absorption maximum as compared with the more extensively studied channelrhodopsin-2 from Chlamydomonas reinhardtii (CrChR2). Previously, both resonance Raman and low-temperature FTIR difference spectroscopy revealed that unlike CrChR2, CaChR1 under our conditions exhibits an almost pure all-trans retinal composition in the unphotolyzed ground state and undergoes an all-trans to 13-cis isomerization during the primary phototransition typical of other microbial rhodopsins such as bacteriorhodopsin (BR). Here, we apply static and rapid-scan FTIR difference spectroscopy along with site-directed mutagenesis to characterize the proton transfer events occurring upon the formation of the long-lived conducting P2 (380) state of CaChR1. Assignment of carboxylic C=O stretch bands indicates that Asp-299 (homolog to Asp-212 in BR) becomes protonated and Asp-169 (homolog to Asp-85 in BR) undergoes a net change in hydrogen bonding relative to the unphotolyzed ground state of CaChR1. These data along with earlier FTIR measurements on the CaChR1 → P1 transition are consistent with a two-step proton relay mechanism that transfers a proton from Glu-169 to Asp-299 during the primary phototransition and from the Schiff base to Glu-169 during P2 (380) formation. The unusual charge neutrality of both Schiff base counterions in the P2 (380) conducting state suggests that these residues may function as part of a cation selective filter in the open channel state of CaChR1 as well as other low-efficiency ChRs. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

May TLR4 Asp299Gly and IL17 His161Arg polymorphism be associated with progression of primary measles infection to subacute sclerosing panencephalitis?

PubMed

Karakas-Celik, Sevim; Piskin, Ibrahim Etem; Keni, Mehmet Fatih; Calık, Mustafa; Iscan, Akın; Dursun, Ahmet

2014-09-01

SSPE is a progressive neurological disorder of children. Only some of the children who are infected with measles virus develop SSPE, which supports individual variation. TLR-2 and TLR-4 play an important role in innate immunity by recognizing envelope proteins of MV. Another important cytokine that plays an important role in orchestrating innate immune function is IL-17. The purpose of our study is to elucidate whether the TLR2, TLR4, IL17F and IL17A gene polymorphisms are susceptibility genes for the development of SSPE. Using the PCR-RFLP methods, the single nucleotide polymorphisms of TLR2 (Arg753Gln, Arg677Trp, -194 to -174 del), TLR4 (Asp299Gly and Thr399Ile) IL17F (His161Arg, Glu126Gly) and IL17A were studied in 54 patients with SSPE and 81 healthy controls. For Asp299Gly polymorphism of the TLR4 gene we found that there were no control individuals who were homozygous carriers of the Gly/Gly genotype, and the risk for SSPE increased at approximately 4.7 fold for the heterozygous carriers of the Asp/Gly genotype (OR 4.727, 95%-CI 1.192-18.742; P=0.01), when compared to healthy controls. Also our findings demonstrate that homozygosity for the Arg161 variant of the IL17F His161Arg polymorphism is inversely associated with development of SSPE (OR 0.114 95%-CI 0.026-0.494; P<0.001). In conclusion, it is suggested that variation in susceptibility to SSPE disease may be in part due to variations in TLR4 and IL17 function resulting from polymorphisms of TLR4 Asp299Gly and IL17F His161Arg. Copyright © 2014 Elsevier B.V. All rights reserved.

Evolution subverting essentiality: Dispensability of the cell attachment Arg-Gly-Asp motif in multiply passaged foot-and-mouth disease virus

PubMed Central

Martínez, Miguel A.; Verdaguer, Nuria; Mateu, Mauricio G.; Domingo, Esteban

1997-01-01

Aphthoviruses use a conserved Arg-Gly-Asp triplet for attachment to host cells and this motif is believed to be essential for virus viability. Here we report that this triplet—which is also a widespread motif involved in cell-to-cell adhesion—can become dispensable upon short-term evolution of the virus harboring it. Foot-and-mouth disease virus (FMDV), which was multiply passaged in cell culture, showed an altered repertoire of antigenic variants resistant to a neutralizing monoclonal antibody. The altered repertoire includes variants with substitutions at the Arg-Gly-Asp motif. Mutants lacking this sequence replicated normally in cell culture and were indistinguishable from the parental virus. Studies with individual FMDV clones indicate that amino acid replacements on the capsid surface located around the loop harboring the Arg-Gly-Asp triplet may mediate in the dispensability of this motif. The results show that FMDV quasispecies evolving in a constant biological environment have the capability of rendering totally dispensable a receptor recognition motif previously invariant, and to ensure an alternative pathway for normal viral replication. Thus, variability of highly conserved motifs, even those that viruses have adapted from functional cellular motifs, can contribute to phenotypic flexibility of RNA viruses in nature. PMID:9192645

Formation of crystalline nanoparticles by iron binding to pentapeptide (Asp-His-Thr-Lys-Glu) from egg white hydrolysates.

PubMed

Sun, Na; Cui, Pengbo; Li, Dongmei; Jin, Ziqi; Zhang, Shuyu; Lin, Songyi

2017-09-20

A novel peptide from egg white, Asp-His-Thr-Lys-Glu (DHTKE), contains specific amino acids associated with iron binding. The present study aims to better understand the molecular basis of interactions between the DHTKE peptide and iron ions. The ultraviolet-visible and fluorescence spectra indicate an interaction between the DHTKE peptide and iron ions, which leads to the formation of a DHTKE-iron complex. Notably, Asp, Glu, His, and Lys in the DHTKE peptide play crucial roles in the formation of the DHTKE-iron complex, and the iron-binding site of the DHTKE peptide corresponds primarily to the amide and carboxyl groups. The DHTKE peptide can bind iron ions in a 1 : 2 ratio with a binding constant of 1.312 × 10 5 M -1 . Moreover, the DHTKE-iron complex belongs to thermodynamically stable nanoparticles that are present in the crystalline structure, which might be attributed to peptide folding induced by iron binding. Meanwhile, the DHTKE-iron complex exhibits a relatively high iron-releasing percentage and exerts excellent solubility in the human gastrointestinal tract in vitro. This suggests a potential application of peptides containing Asp, Glu, His, or Lys residues as potential iron supplements.

Resistance mutations of Pro197, Asp376 and Trp574 in the acetohydroxyacid synthase (AHAS) affect pigments, growths, and competitiveness of Descurainia sophia L.

PubMed

Zhang, Yongzhi; Xu, Yufang; Wang, Shipeng; Li, Xuefeng; Zheng, Mingqi

2017-11-27

D. Sophia is one of the most problematic weed species infesting winter wheat in China, and has evolved high resistance to tribenuron-methyl. Amino acid substitutions at site of Pro197, Asp376 and Trp574 in acetohydroxyacid synthase (AHAS) were mainly responsible for D. sophia resistance to tribenuron-methyl. In this study, D. sophia plant individually homozygous for specific AHAS mutation (Pro197Leu, Pro197His, Pro197Ser, Pro197Thr, Asp376Glu and Trp574Leu) were generated. In addition, the effects of resistance mutations on pigments, growths and competitiveness of susceptible (S) and resistant (R) plants of D. sophia were investigated. The results indicated the R plants carrying Pro197Leu or Pro197His or Asp376Glu or Trp574Leu displayed stronger competitiveness than S plants. The adverse effects on R plants aggravated with the increase of R plants proportion, which made the R plants against domination the weed community in absent of herbicide selection. Therefore, these resistance mutation have no obvious adverse effects on the pigments (chlorophyll a, chlorophyll b and carotenoid), relative growth rates (RGR), leaf area ratio (LAR) and net assimilation rate (NAR) of R plants.

Early life-history predator-prey reversal in two cyprinid fishes.

PubMed

Šmejkal, Marek; Baran, Roman; Blabolil, Petr; Vejřík, Lukáš; Prchalová, Marie; Bartoň, Daniel; Mrkvička, Tomáš; Kubečka, Jan

2017-07-31

Predator-prey relationships are often perceived simply as a situation in which a predator enhances its own fitness while reducing the fitness of its prey. However, this relationship may become reversed when the prey feeds on the juvenile predator stages. We investigated this phenomenon in a model asp (Leuciscus aspius; predator)-bleak (Alburnus alburnus; prey) relationship. The adhesive asp eggs are available for bleak predation after a spawning event for only tens of seconds before they adhere to the stones, where bleak do not forage. Gut content analysis demonstrated that eggs were utilized in high quantities, especially in the spawning peak of the asp reproductive season. Furthermore, using underwater video, we recorded the bleak feeding efficiency on naturally drifting asp eggs as the percentage of eggs eaten. Within the 40 cm egg trajectory captured by our cameras, total egg mortality was 21.2 ± 2.2% on average. The highest survival chances occurred among eggs drifting in aggregations, since the short drifting distance together with their aggregated distribution satiated bleak and part of the egg aggregation could attach to the spawning ground. This study emphasizes the potential efficiency of predator egg utilization by prey, which may have further consequences in predator-prey dynamics.